15.26.3 Tumours of the pancreas 3227

15.26.3 Tumours of the pancreas 3227

15.26.3  Tumours of the pancreas 3227 plastic stents. Several studies have shown higher efficiency, prob- ably due to the larger diameter (equivalent to seven 10 Fr plastic stents). They are also associated with a reduced number of endo- scopic procedures and a lower incidence of stent obstructions, but large comparative prospective studies are needed to prove their safety, removability, and efficacy before they can be recommended as a first-​line treatment. Pseudocysts Indications for pseudocyst drainage are persistent symptoms and cyst-​related complications, including gastrointestinal or biliary obstruction, infection, rupturing, or bleeding from a pseudoaneurysm. The risk of developing these complications is low (<10%), but so is the chance of spontaneous cyst resolution. Available data suggest that for cysts smaller than 6 cm, a wait-​and-​ see policy is defendable. Rapid growth is still considered an indi- cation for drainage. Endoscopic drainage by placement of multiple side-​by-​side pig- tail stents, either transpapillary or transmurally, under EUS guid- ance is highly effective (>90–​95%), and should be the treatment of first choice (Fig. 15.26.2.5). In the case of a concurrent pancre- atic duct disruption or obstruction, treatment not only entails cyst drainage, but also addressing pancreatic ductal abnormalities to prevent recurrence once the cystogastrostomy stents are removed, 6 to 8 weeks after cyst resolution. Percutaneous drainage or surgery should be reserved for patients in whom endoscopic drainage is not possible or has failed. Future developments Many patients with chronic pancreatitis suffer from refractory pain and have a reduced quality of life. Physicians struggle to effectively manage this disease and patients with chronic pan- creatitis consume a disproportionate volume of healthcare re- sources. Evidence-​based treatment algorithms are urgently needed. Early interventions, endoscopic or surgical, may improve quality of life, preserve pancreatic function, and reduce associated healthcare costs. FURTHER READING Cahen DL, et al. (2007). Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med, 356, 676–​84. Conwell D, et al. (2014). American Pancreatic Association practice guidelines in chronic pancreatitis. Evidence-​based report on diag- nostic guidelines. Pancreas, 43, 1143–​62. Dite P, et al. (2003). A prospective, randomized trial comparing endo- scopic and surgical therapy for chronic pancreatitis. Endoscopy, 35, 553–​8. Dumonceau JM, et al. (2012). ESGE guideline for endoscopic treat- ment of chronic pancreatitis. Endoscopy, 44, 784–​96. Etemad B, Whitcomb DC (2001). Chronic pancreatitis:  diagnosis, classification, and new genetic developments. Gastroenterology, 120, 682–​707. Greer JB, Thrower E, Yadah D (2015). Epidemiologic and mechanistic associations between smoking and pancreatitis. Curr Treat Options Gastroenterol, 13, 332–​46. Kawakami H, Itoi T, Sakamoto N (2014). Endoscopic ultrasound-​ guided transluminal drainage for peripancreatic fluid collec- tions: where are we now? Gut Liver, 8, 341–​55. Maydeo A, et al. (2007). Endotherapy for chronic pancreatitis with intracanalar stones. Endoscopy, 39, 653–​8. Mounzer R, Whitcomb DC (2013). Genetics of acute and chronic pan- creatitis. Curr Opin Gastroenterol, 29, 544–​51. Rickels MR, et al. (2013). PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology, 13, 336–​42. Sankaran S, et al. (2015). Frequency of progression from acute to chronic pancreatitis and risk factors: a meta-​analysis. Gastroenterology, 149, 1490–​500. Schneider A, Löhr JM, Singer MV (2007). The M-​ANNHEIM classi- fication of chronic pancreatitis: introduction of a unifying classifi- cation system based on a review of previous classifications of the disease. J Gastroenterol, 42, 101–​19. Sikkens ECM, et al. (2010). Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol, 24, 337–​47. Yang CJ, et al. (2015). Surgery for chronic pancreatitis: the role of early surgery in pain management. Pancreas, 44, 819–​23. Ye X, et al. (2015). Impact of smoking on the risk of pancreatitis: a sys- tematic review and meta-​analysis. PLoS One, 10, e0124075. Zhou Y, et al. (2015). Frey procedure for chronic pancreatitis: evidence-​ based assessment of short-​ and long-​term results in comparison to pancreatoduodenectomy and Beger procedure: a meta-​analysis. Pancreatology, 15, 372–​9. 15.26.3  Tumours of the pancreas James R.A. Skipworth and Stephen P. Pereira ESSENTIALS Pancreatic cancer, most commonly in the form of a solid ductal adenocarcinoma, accounts for 3% of all cancers but ranks in the top five leading causes of cancer deaths in most developed countries, reflecting the fact that it has a very poor prognosis (median survival 6–​9 months). It is a disease of older age (85% of patients >65 years), and commoner in smokers. Most patients present with locally advanced or metastatic disease, often with obstructive jaundice. Pain is unusual in early disease, but when present is characteristically described as ‘gnawing’, ever pre- sent, and frequently radiating into the back. Weight loss is commonly due to anorexia as a result of jaundice or pain, but can occasionally be the only presenting symptom. Serum biochemistry will typically show elevated bilirubin and a cholestatic picture of liver enzymes, with particular elevation of al- kaline phosphatase and γ-​glutamyl transferase. Transabdominal ultrasonography is usually the primary investigation in a patient with jaundice and can detect pancreatic tumours greater than 2 cm in size or hepatic metastases with a diagnostic accuracy of 75%, but iden- tifies smaller tumours much less reliably. The essential investigations

section 15  Gastroenterological disorders 3228 for the diagnosis and staging of pancreatic cancer are contrast-​ phased CT scan and occasionally MRI. The only curative treatment for pancreatic cancer is surgical exci- sion. This is technically feasible in up to 20% patients at presentation, but even after careful selection almost 40% of these will have positive microscopic resection margins, and overall postoperative survival is only around 10% at 5 years, the remainder experiencing metastatic disease in the peritoneum, liver, or lungs. Adjuvant chemotherapy with gemcitabine can double the 5-​year survival rate. Palliative management may require biliary stenting for jaundice, duodenal stenting (or surgical bypass) for gastric outlet obstruction, pain control, and palliative chemotherapy. Introduction A plethora of tumours can develop within the pancreas, but pan- creatic ductal adenocarcinoma is by far the commonest, comprising 85 to 90% of pancreatic tumours. Other pancreatic tumours can be solid or cystic and are usually derived from the endocrine or exo- crine pancreas itself, although metastatic tumours derived from other primary sources can rarely be diagnosed. This chapter will focus principally on pancreatic ductal adenocarcinoma, although there is some discussion of other tumour types. Pancreatic ductal adenocarcinoma is the 10th most common cancer in the United Kingdom but the fourth commonest cause of cancer death, predominantly because over 80% of patients have lo- cally advanced or metastatic disease at presentation and are there- fore not able to undergo surgical resection, the only potentially curative treatment modality. Overall survival following a diagnosis of pancreatic ductal adenocarcinoma therefore remains extremely poor, with most patients able to be offered palliative management strategies only. Aetiology The underlying cause of pancreatic ductal adenocarcinoma re- mains largely unknown, with the vast majority of cases occurring sporadically, although certain risk factors have been identified (Table 15.26.3.1). Those with chronic pancreatitis from any aeti- ology have a 15 times increased risk of developing pancreatic ductal adenocarcinoma, and those with PRSS1 (cationic tryp- sinogen) gene mutations leading to hereditary pancreatitis carry a lifetime risk of up to 55%. However, overall, less than 10% of pancreatic ductal adenocarcinoma diagnoses have been shown to have a hereditary or genetic element, and although a specific gene defect cannot usually be identified, those with two or more first-​degree relatives carry an elevated risk, and in some families there may be an autosomal dominant transmission with impaired penetrance. There is also an elevated risk in certain specific fa- milial cancer syndromes, such as Li–​Fraumeni syndrome (TP53 mutation), Lynch syndrome (microsatellite instability), Peutz–​ Jeghers syndrome (microsatellite instability), familial atypical multiple mole melanoma, hereditary nonpolyposis colorectal car- cinoma, familial breast–​ovarian cancer (associated with BRCA1/​ BRCA2 mutations), and familial adenomatous polyposis (APC gene mutation). All such individuals are eligible for screen­ ing as part of the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer study (EUROPAC; http//​:www. europac-​org.eu). Other known risk factors for sporadic pancreatic ductal adeno- carcinoma include smoking, obesity, and a new diagnosis (within the last 2 years) of diabetes mellitus in those over the age of 50 years. Meta-​analyses demonstrate that type 2 diabetes increases an individual’s risk of pancreatic cancer by at least 40%, but it remains unclear whether diabetes is related to the cause of pancreatic ductal adenocarcinoma, or simply an early sign of its presence. Obesity has been linked to the development of many cancers and meta-​analyses demonstrate that as body mass index, waist circum- ference, or waist-​to-​hip ratio increases, the risk of pancreatic cancer increases. Tobacco smoking potentially accounts for 29% of pancreatic cancer diagnoses in the United Kingdom and the risk increases with the number of pack-​years smoked and the number of cigar- ettes smoked per day, with an associated odds ratio of 3.4 in those who smoke over 35 cigarettes per day and an odds ratio of 2.4 in those with 40 pack-​years. This risk decreases following smoking ces- sation, becoming equivalent to the rest of the population at approxi- mately 20 years after stopping. Similarly, the risk of pancreatic ductal adenocarcinoma increases with the number of alcoholic drinks con- sumed per day, being 60% higher in those consuming five or more alcoholic drinks per day. There are no confirmed protective factors against the devel- opment of pancreatic ductal adenocarcinoma, but both physical Table 15.26.3.1  Risk factors for pancreatic ductal adenocarcinoma Increased risk Possible increased risk Possible decreased risk Familial/​genetic Alcohol consumption Folate Chronic pancreatitis Occupational exposure to chemicals, e.g.: • Thorium-​232 and its decay products (contrast medium
in early X-​ray diagnostics) • Benzidine • β-​Naphthylamine Fruit Smoking X-​rays Physical activity Obesity Gamma radiation Aspirin Diabetes mellitus type 2 Red meat

15.26.3  Tumours of the pancreas 3229 activity and aspirin have been shown to reduce the risk of many cancers, probably including pancreatic ductal adenocarcinoma. Due to the overall low incidence of pancreatic ductal adenocar- cinoma and a lack of specific associated risk factors, development of an accurate screening tool has proved problematic and, at pre- sent, there are no general population screening programmes for pancreatic ductal adenocarcinoma. There may be some benefit in screening selected, high-​risk individuals (e.g. family history of pan- creatic ductal adenocarcinoma (two first-​degree relatives or three diagnoses within the immediate family), and hereditary pancreatitis predisposing genetic syndromes), but the most suitable screening modality remains unclear. Epidemiology The incidence of pancreatic ductal adenocarcinoma is higher in Western and industrialized nations, with rates in Europe and North America remaining among the highest in the world, possibly due to the prevalence of smoking, obesity, and diabetes. In the United Kingdom, approximately 8800 people were diagnosed with pancre- atic cancer in 2014, while approximately 8300 people died from the disease (Cancer Research UK figures). Pancreatic ductal adenocar- cinoma is slightly more common in men, and in North America the incidence is 1.5 times higher in African Americans than Caucasians, although the overall incidence in African nations remains low. In the United Kingdom, the number of diagnoses of pancreatic cancer has continued to rise over the last 30 to 40 years, although the age-​standardized mortality rates remain stable, potentially due to the increasing overall age of the population in Western coun- tries. The incidence of pancreatic ductal adenocarcinoma in the United Kingdom is approximately 12 per 100  000 and increases with age: only 25% of diagnoses are made in patients under 65 years (and it is extremely uncommon in those under 40 years), and ap- proximately 80% of all cases are diagnosed in those between 60 and 80 years of age (Cancer Research UK). Approximately half of all pa- tients present as medical/​surgical emergencies, usually with abdom- inal pain or obstructive jaundice, whereas those presenting from the community have seen their general practitioner an average of three times before a diagnosis is made. Pathogenesis/​pathology The pathogenesis of pancreatic ductal adenocarcinoma remains poorly understood despite major advances in molecular biology. Three histological precursors have now been identified: pancreatic intraepithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary neoplasm (see ‘Other pancreatic tumours’), and each are associated with specific molecular and genetic abnormalities. There are multiple combinations of both inherited and acquired al- terations in specific core-​signalling pathways and cancer-​associated genes leading to activation of oncogenes (e.g. KRAS), inactivation of tumour suppressor genes (e.g. TP53 and SMAD4), and inactiva- tion of genome maintenance and DNA repair genes (e.g. MSH2 and hMLH1). Recent comprehensive genome-​wide analysis has served to emphasize the high degree of complexity and heterogeneity in the genomics of pancreatic ductal adenocarcinoma. Such genetic and molecular complexity is rendered more difficult by an intrinsic chemotherapeutic resistance attributable to the presence of a dense stromal reaction that appears to significantly impair the local pan- creatic delivery of chemotherapy and other drugs. There are multiple pancreatic ductal adenocarcinoma mouse models, but—​although progress continues to be made—​findings from these models have thus far proved poorly applicable to clinical practice for either diag- nosis or risk stratification. Clinical features Patients with pancreatic ductal adenocarcinoma can present with a multitude of symptoms (Table 15.26.3.2), largely dependent upon the specific intrapancreatic location of the lesion and whether the tumour remains localized or has metastasized. The early diagnosis of pancreatic ductal adenocarcinoma is therefore reliant upon an understanding of such anatomically dependant symptoms. Approximately 50% of patients will develop a tumour in the head of the pancreas, most of whom will present with painless jaun- dice (classical presenting symptom of pancreatic ductal adenocar- cinoma) secondary to obstruction of the intrapancreatic common bile duct (although occasionally this can be due to the presence of liver metastases or nodal infiltration at the liver hilum), whereas others will present with, or go on to develop, pain in the epigastrium or back. Those with masses in the pancreatic body or tail away from the common bile duct will generally present with pain or pancrea- titis without jaundice, and because of this will often present with more advanced disease. Nonspecific early symptoms are common and include abdom- inal or back discomfort, and dyspepsia and reflux symptoms re- sistant to simple therapies (both often postprandial due to common bile duct obstruction), both of which may be misinterpreted by patients and general practitioners leading to diagnostic delay; and swift or unintentional weight loss, which is an independent pre- dictor of poor outcome. Further early symptoms include nausea and vomiting, change in bowel habit (often due to pancreatic hor- monal imbalance but can be due to extensive obstruction leading to exocrine dysfunction and malabsorption), weight loss and loss of appetite, and new-​onset diabetes not associated with the meta- bolic syndrome. Later symptoms include rapid and unintentional weight loss, and ascites. Table 15.26.3.2  Important clinical features of pancreatic cancer Early Late Nonspecific epigastric or back discomfort (70%) Obstructive jaundice (50%) Dyspepsia/​reflux resistant to simple therapies Epigastric or back pain Nausea and vomiting Unintentional, rapid weight loss Loss of appetite/​anorexia Change in bowel habit New diabetes without risk factors for metabolic condition

section 15  Gastroenterological disorders 3230 Clinical evaluation includes a full history, including the patient’s current performance status, nutritional status and significant comorbidities, and a thorough clinical examination assessing for the presence of jaundice, lymphadenopathy, and anaemia, as well as abdominal tenderness or masses. This then leads on to investiga- tion and tissue diagnosis (Fig. 15.26.3.1). Differential diagnosis The differential diagnosis of pancreatic ductal adenocarcinoma depends largely upon the mode of presentation but remains wide (Table 15.26.3.3). Diagnosis is usually reached following radio- logical assessment and confirmed with tissue biopsy. Following radiological confirmation of a pancreatic mass, usually with CT, the differential diagnoses are much narrower and include other pancreatic tumours or inflammatory masses/​pseudocysts associated with chronic pancreatitis or autoimmune (IgG4-​ related) pancreatitis. Investigation Blood tests Blood analysis is a routine part of assessment and should include the following: Full blood count: to assess for the presence of chol- angitis in those with biliary obstruction or anaemia as a result of chronic disease or gastrointestinal bleeding. Renal function: to as- sess for the presence of electrolyte imbalance and as a baseline as- sessment prior to treatment. Liver function: the presence of raised bilirubin, alkaline phosphatase and γ-​glutamyl transferase with normal or only slightly elevated transaminases may indicate bil- iary obstruction, but cannot distinguish between benign or malig- nant causes, or the site of obstruction (e.g. pancreas, liver hilum, Fig. 15.26.3.1  Investigation and tissue diagnosis for pancreatic ductal adenocarcinoma. Table 15.26.3.3  Differential diagnoses of pancreatic ductal adenocarcinoma Presenting complaint Differential diagnosis Obstructive jaundice Other pancreatic tumours; gallstone or gallbladder disease; periampullary tumours, e.g. ampullary cancer, cholangiocarcinoma, duodenal cancer; benign biliary strictures; acute, chronic or autoimmune pancreatitis with or without mass or pseudocyst; primary sclerosing cholangitis Epigastric or back discomfort, dyspepsia Other pancreatic tumours; acute, chronic, or autoimmune pancreatitis with or without mass or pseudocyst; gallstone or gallbladder disease; gastro-​oesophageal reflux disease; aortic aneurysm; mesenteric ischaemia; small-​bowel obstruction Change in bowel habit Colorectal carcinoma; inflammatory bowel disease; irritable bowel disease; gastroenteritis

15.26.3  Tumours of the pancreas 3231 or intrahepatic). Clotting studies: patients with jaundice and hep- atic impairment may have impaired coagulation. Further, most patients will require intervention in the form of endoscopy, per- cutaneous drainage, or surgery and a baseline assessment of co- agulation function is therefore required. A raised serum amylase suggests pancreatic inflammation: this may occur in the presence of a tumour but is more common in acute pancreatitis and less so in chronic pancreatitis. Carbohydrate antigen (CA)-​19-​9 may be elevated in pancreatic cancer but also in biliary tract cancers, such as cholangiocarcinoma, and is often raised in the presence of jaundice of any cause, both benign and malignant, and in some in- stances of pancreatitis or cirrhosis. However, it can also be normal in the presence of pancreatic cancer and has a sensitivity and speci- ficity of approximately 80%. Testing of hepatitis serology is appro- priate as part of the assessment of jaundice. Radiological assessment Radiological imaging remains the diagnostic method of choice for the diagnosis of pancreatic adenocarcinoma. Potential modalities include the following: Ultrasonography This can demonstrate the presence of dilated intra-​ and extrahepatic biliary ducts but is often unable to further delineate the cause (e.g. bile duct stones or a mass in the head of the pancreas). Its use can lead to delays in diagnosis if employed inappropriately in pa- tients where there is a high suspicion of malignancy. CT Multislice, high-​resolution, contrast-​enhanced CT of the chest, ab- domen, and pelvis provides detailed information on the presence and exact location of the primary tumour, as well as the presence of any locally advanced or distant disease. In particular, the precise relationship of the tumour with local vascular structures such as the superior mesenteric vein and artery, and portal vein is crucial in the assessment of resectability. Current CT scanners are capable of ac- curately predicting resectability in up to 90% of patients. MRI The superior soft tissue delineation of MRI can be helpful in the characterization of noncontour-​deforming pancreatic masses, as well as the presence of hepatic and peritoneal involvement, but CT remains the radiological modality of choice. Tissue diagnosis Prior to consideration of surgery or chemoradiotherapy, a tissue diagnosis is usually required, although this should not delay po- tentially curative resection. This can, on occasion, be crucial as a diagnosis of neuroendocrine tumour or lymphoma (for example) may radically alter treatment strategies. Inflammatory lesions due to acute or chronic pancreatitis can also mimic malignant lesions. Methods of achieving a tissue diagnosis include the following: Endoscopic ultrasonography-​guided fine needle aspiration Cytology from a pancreatic mass or aspiration of cyst material at the time of endoscopic ultrasonography (EUS) can help in the confirm- ation of diagnosis. Endoscopic retrograde cholangiopancreatography Biliary brushings at the time of stenting in those with obstruc­ tive jaundice can confirm the diagnosis of pancreatic ductal adenocarcinoma. Percutaneous biopsy This can be used if the other methods are inconclusive or par- ticularly if there is locally advanced or metastatic disease which is amenable to radiologically guided biopsy. Preoperative assessment Prior to surgery, further potential investigation modalities may include positron emission tomography (PET)-​CT. The United Kingdom PET PANC study, a multicentre, prospective diagnostic accuracy and clinical value study of PET-​CT in suspected pancre- atic malignancy, showed that PET-​CT improved diagnostic ac- curacy and reduced the rate of unnecessary resections. EUS can be used to assess for the presence of locally advanced disease and for tissue diagnosis. Staging laparoscopy is used to assess for the presence of hepatic, peritoneal, or distant disease and can be per- formed immediately before planned resection to avoid the neces- sity for two general anaesthetics. Staging Pancreatic ductal adenocarcinoma typically metastasizes to re- gional lymph nodes and then to hepatic, pulmonary, and peri- toneal sites. Bone metastases are less common but can also occur. Tumours may also extend locally to surrounding struc- tures such as the duodenum, stomach, and colon. The standard staging system for pancreatic ductal adenocarcinoma is via the American Joint Committee on Cancer TNM classification (Table 15.26.3.4). Table 15.26.3.4  American Joint Committee on Cancer TNM classification of pancreatic ductal adenocarcinoma Primary tumour (T) TX: primary tumour cannot be assessed T0: no evidence of primary tumour Tis: carcinoma in situ T1: tumour limited to the pancreas, <2 cm in greatest dimension T2: tumour limited to the pancreas, >2 cm in greatest dimension T3: tumour extends beyond the pancreas, but without involvement of the coeliac axis or superior mesenteric artery T4: tumour involves the coeliac axis or the superior mesenteric artery (unresectable primary tumour) Regional lymph nodes (N) NX: regional lymph nodes cannot be assessed N0: no regional lymph node metastasis N1: regional lymph node metastasis Distant metastases (M) M0: no distant metastases M1: distant metastases

section 15  Gastroenterological disorders 3232 Management General principles All patients should be managed at a regional tertiary centre and in a multidisciplinary setting, with input from surgeons, gastro- enterologists, radiologists, palliative care physicians, and allied health professionals (e.g. dieticians/​nutritionists and physiother- apists) and with close collaboration between hospital and primary care practitioners. Treatment strategies should be discussed in a multidisciplinary meeting and conclusions finalized regarding disease suitability for resection (curative intent, with or without neoadjuvant or adjuvant treatment), downstaging, or palliation (see Fig. 15.26.3.2). The general principles of management include optimization of pancreatic endocrine (management of diabetes or impaired glu- cose tolerance) and exocrine function (with pancreatic replacement therapy as necessary), together with enhancement of nutrition and caloric intake to counteract the effects of cachexia and optimize pa- tients for further treatment (surgery or chemoradiotherapy), and control of pain, nausea, or other symptoms. Healthy patients should be optimized for surgery as soon as possible, but those with lesions in the head of the pancreas will often require relief of malignant biliary obstruction via endoscopic stenting or external biliary drainage, as well as management of sepsis/​chol- angitis where appropriate. Severe, intractable epigastric or back pain requires progression along the World Health Organization analgesic ladder, with long-​acting opiates often necessary, assessment by pain and palliative care teams, and occasional input from radiological and endoscopic specialists for administration of percutaneous, CT-​guided or EUS-​guided coeliac plexus blocks for those with advanced disease. Depression is common and both patients and their families may re- quire psychological, psychiatric, or bereavement support services. Biliary drainage Wherever possible, patients should proceed directly to exped- ited surgery without biliary drainage, as several studies have dem- onstrated a significantly lower number of complications with this strategy (39% early surgery vs 74% biliary drainage followed by sur- gery in a Dutch study of 196 patients). Biliary drainage is therefore usually required only if the serum bilirubin is extremely high (>200 μmol/​litre), the patient has biliary sepsis, there is diagnostic uncer- tainty, or there is likely to be a delay until surgery. In patients with locally advanced or metastatic disease, endo- scopic biliary stenting may be required to relieve jaundice and pre- vent sepsis, and is associated with lower complication rates than percutaneous biliary drainage or surgical biliary bypass. Endoscopic stent insertion can be performed as soon as a treat- ment strategy is decided. Preoperatively (depending upon local availability and expertise), fully covered self-​expanding metal stents, rather than plastic stents, are preferred in patients who are deeply jaundiced or cholangitic, or in whom there is another reason for delaying surgery more than 1 to 2 weeks. Uncovered self-​expanding metal stents are generally reserved for patients with cytologically/​ histologically confirmed unresectable disease. Endoscopic stents carry a risk of endoscopic retrograde cholangiopancreatography-​ induced acute pancreatitis, stent migration, or later stent occlusion, but overall are associated with a low complication profile. If patients are found to have unresectable disease at operation, a surgical biliary bypass is often the management method of choice and can be combined with gastrojejunostomy for those patients in whom gastric outlet obstruction is suspected or imminent. Gastric outlet ob- struction occurs in 10 to 20% of patients with locally advanced disease and those with successful endoscopic or percutaneous biliary drainage can be managed either by surgical bypass (open or laparoscopic) in pa- tients with good performance status or via endoscopic stent insertion. Fig. 15.26.3.2  Treatment algorithm for patients with pancreatic ductal adenocarcinoma.

15.26.3  Tumours of the pancreas 3233 Surgical resection Most patients with pancreatic ductal adenocarcinoma present with distant metastases or locally advanced disease (involvement of nearby structures that would prevent a clear resection margin), hence only 10–​15% of patients are able to undergo surgical resection. Specific operative strategies depend upon the site and extent of disease: tu- mours in the head of the pancreas require pancreaticoduodenectomy, either via a classical Whipple’s procedure or via pylorus-​preserving pancreaticoduodenectomy (usually open but occasionally laparo- scopic), whereas tumours in the body or tail can be resected via distal pancreatectomy with or without concurrent splenectomy (laparo- scopic where possible; involvement of the spleen or splenic vessels is not a contraindication to surgery). All pancreatic surgery carries a potential risk of significant com- plications and patient selection is therefore crucial. Since the intro- duction of the National Cancer Plan in 2001 in the United Kingdom, all such resectional pancreatic surgery is now undertaken in re- gional specialized centres as there is good evidence that central- ization of such services results in improved rates of morbidity and mortality (now 1–​2% in high-​volume centres), as well as oncological outcomes. There has been much recent discussion regarding the defin- itions of operable and locally advanced disease (inoperable but no progression to distant metastases), and the concept of borderline operable disease has recently been introduced (Table 15.26.3.5). The ESPAC-​5 trial (European Study group for Pancreatic Cancer—​ Trial 5F), a multicentre, prospective, randomized, feasibility phase II trial comparing neoadjuvant therapy to immediate surgical ex- ploration in patients with borderline resectable pancreatic cancer, is currently recruiting. Chemotherapy Advanced disease In patients with advanced disease, chemotherapy improves both survival and quality of life as compared to best supportive care alone. Overall, gemcitabine (a nucleoside analogue) is the most commonly used chemotherapeutic agent. The phase III, multicentre GemCap study randomized patients to receive gemcitabine alone or in com- bination with capecitabine (an oral prodrug enzymatically degraded to 5-​fluorouracil, a pyrimidine analogue) in 533 patients with ad- vanced pancreatic ductal adenocarcinoma to demonstrate a trend to- wards improved survival in patients receiving combination therapy (7.1 vs 6.2 months overall survival; 1-​year survival 24.3% vs 22%; p = 0.077). The phase III randomized MPACT study demonstrated a significantly improved overall survival in patients administered weekly nab-​paclitaxel (a mitotic inhibitor) with gemcitabine, as compared to gemcitabine alone (8.5 vs 6.7  months; p  =  0.0001). Gemcitabine-​based therapy is therefore a common combination regimen and has been shown to significantly improve progression-​ free and overall survival, as well as overall objective response rates, although this can be offset by the greater toxicity profile associated with combination therapy. Trials of biological agents have largely yielded disappointing re- sults, although a Canadian phase III trial did demonstrate a small improvement in overall survival with the addition of erlotinib (an epidermal growth factor receptor inhibitor) to gemcitabine, as com- pared to gemcitabine alone (6.2 vs 5.9 months; p = 0.038). Other agents are under investigation. In a French multicentre study of FOLFIRINOX (oxaliplatin (platinum-​based chemotherapeutic agent), irinotecan (topoisomerase I  inhibitor), fluorouracil, and leucovorin (folic acid derivative)) or gemcitabine, there was im- proved survival in the FOLFIRINOX group (11.1 vs 6.8 months; p <0.001). Similarly, a recent meta-​analysis demonstrated that cetuximab-​based therapy (monoclonal antibody) led to improve- ments in progression-​free survival, overall survival, and overall re- sponse rate as compared to noncetuximab therapy. Neoadjuvant therapy Neoadjuvant therapy can be utilized in attempts to downstage the primary pancreatic tumour and enhance the probability of a disease-​ free margin at subsequent surgical resection (e.g. ESPAC-​5 trial), or in efforts to select patients with stable or treatment-​responsive disease prior to surgery. A meta-analysis of 38 studies incorporating 3484 pa- tients, 49.9% of which underwent neoadjuvant treatment, suggests a significant increase in overall survival with the use of neoadjuvant treatment on an intention to treat basis alone, but particularly in those patients that actually underwent resection (26.1 months neoadjuvant and surgery vs. 15.0 months surgery alone). More recent data suggest even more promising results with the use of FOLFIRINOX rather than standard gemcitabine-based regimens. However, the efficacy of neoadjuvant treatment remains uncertain and further trial data are required. All pa­tients require restaging following neoadjuvant treat- ment and be­fore ultimate decisions regarding surgery. Adjuvant therapy The use of adjuvant chemotherapy improves survival in patients with resectable pancreatic cancer that have adequately recovered from surgery. Younger patients with good life expectancy and per- formance status should be considered for adjuvant therapies (4–​8 weeks following resection) such as systemic gemcitabine regimens Table 15.26.3.5  Definitions of operable, borderline operable, and locally advanced disease in the presence of no distant metastases Operable Borderline operable Locally advanced

1. Tumour confined to pancreas with no evidence of involvement of venous or arterial structures, or other organs, e.g. abutment, distortion, encasement, or tumour thrombus On radiological assessment, clear fat planes should be visible between the tumour and all nearby structures,
   e.g. superior mesenteric vein (SMV), portal vein (PV), inferior vena cava (IVC), superior mesenteric artery (SMA), common hepatic artery (CHA), coeliac axis, aorta
2. Involvement of loco-​regional venous structures (SMV or PV),
   e.g. abutment, impingement, or distortion
3. Short segment (<2 cm) encasement of, or tumour thrombus within, SMV or PV but with suitable vessel proximally and distally to allow resection and reconstruction
4. Gastroduodenal artery (GDA) involvement (e.g. abutment, impingement, or encasement) up to the level of the common hepatic artery
5. Abutment of SMA or CHA of <180° of the circumference of the
   vessel wall
6. Long segment (>2 cm) venous encasement of SMV or PV

7. 180° abutment of SMA or CHA National Comprehensive Cancer Network. NCCN Guidelines Version 2.2015. Pancreatic Adenocarcinoma. (http://​www.nccn.org).

section 15  Gastroenterological disorders 3234 in combination with capecitabine or oxaliplatin, which have been associated with improved overall survival and response rates, as compared to gemcitabine monotherapy. Chemoradiotherapy regi- mens may also benefit those patients with positive resection margins (R1 or R2), but further clinical trial data are needed. Ablative therapies Relatively few patients present at a stage suitable for surgical resec- tion and most have only a limited response to surgery, hence the development of novel therapeutic strategies are necessary for both those with inoperable disease and those with resectable disease that are unfit to proceed with surgery. Recent technological improve- ments in the delivery of ablative therapies, which have become standard in other solid tumour types, have reduced complications and renewed interest in their potential applications. Radiofrequency ablation Radiofrequency ablation can be applied endoscopically and some trials have demonstrated an improvement in tumour-​related symp- toms, particularly reductions in back pain and analgesic require- ments, as well as reductions in CA19-​9 levels following ablation, with one single-​centre study of 25 patients reporting increased survival as compared to those receiving standard therapy (33 vs 13 months; p = 0.0048). However, studies have generally involved small cohorts with limited follow-​up. Current guidance from the National Institute for Health and Care Excellence recommends that radiofrequency ablation should only be utilized in the context of clinical trials. Experience with microwave ablation, which can be applied per- cutaneously or intraoperatively, is even more limited. Cryoablation can be used to freeze pancreatic lesions either percutaneously or at the same time as palliative bypass surgery or endoscopic biliary/​ duodenal stenting, and can be used in association with other mo- dality therapies. The largest experience of cryoablation derives from centres in Asia, which have reported improvements in pain control, CA19-​9 levels, performance status, and survival after treatment. Photodynamic therapy Photodynamic therapy can be delivered under endoscopic guidance and has been used in small numbers of patients, and preliminary experience of high-​intensity focused ultrasonography has also been reported. NanoKnife or irreversible electroporation is a nonthermal ablative therapy that involves the use of electrodes placed within the tumour to deliver currents of up to 3 kV, thus irreversibly damaging the cell membrane and resulting in apoptosis. Unlike thermal tech- niques, it can be utilized in tumours close to important vessels and structures without significant risk of damage. Studies remain limited, but its performance under general anaesthetic has thus far been promising in a few patients. Other applications and considerations Ablative techniques can also be utilized to treat malignant biliary strictures including tumour ingrowth into uncovered self-​expanding metal stents, although studies again remain limited. Further poten- tial applications include use in patients with premalignant condi- tions such as mucinous cystic neoplasms of the pancreas, but further evidence is required. Overall, long-​term data remains lacking and large, prospective randomized studies will be required before con- sidering their use as part of standard care algorithms. Prognosis Overall, the prognosis following a diagnosis of pancreatic ductal adenocarcinoma remains poor and has not improved significantly over the last 20 years despite improvements in imaging techniques, operative strategies, and chemotherapy. The annual mortality rate from pancreatic cancer is approximately 11 per 100 000 popula- tion, and currently both 1-​ and 5-​year survival rates for pancreatic cancer are lower in the United Kingdom than most other parts of Europe. The 1-​year survival rates remain at 10 to 20% and patients presenting with locally advanced or metastatic disease have a me- dian survival of only 6 to 10 months or 3 to 6 months, respectively. The few patients suitable for surgical resection have an improved median survival of 10 to 20 months, yet only 5 to 20% survive 5 years. Other pancreatic tumours Ductal adenocarcinomas comprise 95% of pancreatic cancers but a number of benign and malignant, solid and cystic tumours can be diagnosed within the pancreas, most of which are managed by sur- gical resection with overall good outcomes. All patients with pan- creatic tumours should be assessed in the aforementioned way and managed in a tertiary, multidisciplinary setting. Neoplasms of the exocrine pancreas Acinar cell carcinomas The second commonest type of pancreatic malignancy, comprising approximately 5% of all exocrine pancreatic tumours. It generally has a similar presentation and demographic profile to pancreatic ductal adenocarcinoma, but up to 20% can produce functional di- gestive enzymes, resulting in classical symptoms of subcutaneous fat necrosis (presenting as skin rashes and nodules), polyarthritis, and eosinophilia (Schmid’s triad). They are often associated with a raised serum lipase and can grow to a considerable size. Histologically, tu- mour cells resemble pancreatic acinar cells but have a characteristic cytoplasmic appearance, which contains granules enclosing enzyme precursors. When localized, acinar cell carcinomas should be surgi- cally excised. Adenosquamous carcinoma There is limited information on the rare adenosquamous carcinoma, which is also known as adenoacanthoma, mixed carcinoma, and mucoepidermoid carcinoma. Histologically, it contains at least 30% malignant squamous cell carcinoma, although both glandular and squamous differentiation must be present. Presentation, assessment, and treatment are similar to pancreatic ductal adenocarcinoma, al- though tumours are more likely to be large and located within the tail of the pancreas. Following resection, which is a positive pre- dictor of survival, histology often demonstrates poor differenti- ation with lymph node and vascular invasion. Overall prognosis is particularly poor.

15.26.3  Tumours of the pancreas 3235 Colloid (mucinous, noncystic) carcinomas These are rare and often mistakenly categorized as pancreatic ductal adenocarcinoma or mucinous cystadenocarcinoma. Histologically, nodular extracellular mucin lakes can be found with scanty ma- lignant epithelial cells floating within them in various patterns of distribution, which often represents the invasive component of intraductal papillary neoplasm or mucinous cystic neoplasm. Patients tend to present with larger but lower grade tumours than patients with pancreatic ductal adenocarcinoma and hence there is a comparatively better prognosis. Intraductal papillary neoplasms A premalignant, precursor condition to pancreatic ductal adeno- carcinoma that can arise within the main pancreatic duct or side branches of the duct (or both, known as mixed type). Comparatively slow growth often enables early diagnosis and potentially curative surgical resection. They produce mucin, are usually unifocal (but can be multifocal), and microscopically have differentiated papil- lary features. Intraductal papillary neoplasms above a certain size may be assessed via EUS-​fine needle aspiration of cyst contents for assessment of viscosity and amylase, and carcinoembryonic antigen levels. Immunohistochemical staining with mucin antibodies al- lows differentiation into gastric, intestinal, pancreaticobiliary and oncocytic subtypes, all of which carry a slightly different prog- nosis. Intraductal papillary neoplasms affecting the main duct have higher malignant potential and should always be excised, whereas current guidelines recommend that side-​branch intraductal papil- lary neoplasms should be resected if over 3 cm in size and/​or rap- idly enlarging, with ongoing surveillance by noninvasive imaging for smaller lesions. Secondary tumours Metastatic pancreatic tumours are rare and may be derived from a breast, renal, or sarcomatous primary tumour. These can be excised for both diagnosis and treatment. Mucinous cystic neoplasms These are rare cystic neoplasms that contain thick mucin and are often located in the tail and body of the pancreas. Mucinous cystic neoplasms are usually diagnosed in females between the fourth and sixth decades of life and can be differentiated from intraductal pap- illary neoplasms by a lack of connection to the pancreatic ductal system and an ovarian-​type stromal component. Mucinous cystic neoplasms should be excised to prevent malignant transformation. Pancreatic intraepithelial neoplasia A precursor lesion of pancreatic ductal adenocarcinoma, which is usually too small to be detected with current imaging techniques and which tends to involve ducts of less than 5  mm in diam- eter. The presence of noninvasive pancreatic intraepithelial neo- plasia describes a microscopic proliferative epithelial lesion of the pancreas and affected ducts are found to be lined by columnar to cuboidal mucinous cells, although mucin may be depleted in high-​ grade lesions. It can be divided into three grades (1–​3) according to cytological and architectural atypia, and higher-​grade pancreatic intraepithelial neoplasia lesions have been demonstrated to be asso- ciated with higher frequencies of genetic alterations, which become more similar to pancreatic ductal adenocarcinoma as the pancreatic intraepithelial neoplasia grade increases to grade 3. Pancreatoblastomas Rare malignant tumours that occur mainly in boys in their fourth or fifth year of age. They are the commonest pancreatic neoplasm in children and are often associated with a raised α-​fetoprotein. Radiologically they appear as solid tumours, which can be large, and microscopically as flat nests of cells that can exhibit acinar, squa- mous, or endocrine differentiation. Presentation is often with ab- dominal pain, jaundice, and vomiting in the presence of advanced or metastatic disease. Lesions should be resected where possible, with subsequent adjuvant chemotherapy even in low-​grade disease. Patients presenting with advanced disease should undergo chemo- therapy as a first-​line treatment. Serous cyst neoplasms Previously referred to as serous cystadenomas, these are the com- monest cystic pancreatic tumours and are benign and usually asymptomatic. They characteristically have a honeycomb structure with a microcystic (or more rarely macrocystic) internal arrange- ment. They only very rarely undergo malignant transformation, but they can grow to a significant size, requiring excision for the treat- ment of local symptoms or progressive/​rapid growth. Solid pseudopapillary neoplasms Solid pseudopapillary neoplasms are usually diagnosed in younger women and are benign in over 90% of cases. Rarely, they can undergo transformation to low-​grade malignant tumours (which rarely me- tastasize) containing a mixture of solid and papillary elements, which often have a necrotic core. Radiologically they can be diffi- cult to distinguish from pancreatic ductal adenocarcinoma, hence surgical resection is generally recommended. Prognosis is excellent, with 95% 5-​year survival. Neuroendocrine tumours Tumours arising from the endocrine pancreas are significantly less common than exocrine tumours, accounting for up to 5% of all pan- creatic tumours. Clinically, they can be associated with various fa- milial syndromes, particularly multiple endocrine neoplasia type 1, but are more often sporadically diagnosed. Macroscopically they are often small, yellow, or tan masses, which can be firm due to an accompanying desmoplastic reaction. Microscopically, they tend to have minimal pleomorphism with bland cytopathology and cyto- plasm containing secretory granules. They can be benign or malig- nant and although approximately 60% are nonsecretory, and most are morphologically small, some can produce high levels of func- tioning peptides and hormones, producing a spectrum of symp- toms depending upon the hormone produced. Similarly, some neuroendocrine tumours will possess specific receptors capable of hormonal uptake, which can be exploited via targeting for both radiological diagnosis and treatment. CT remains the diagnostic method of choice where possible, but smaller functional tumours can be difficult to demonstrate with conventional imaging techniques. These can be localized fol- lowing intravenous administration of somatostatin analogues such as octreotide (a synthetic analogue of somatostatin with a longer

section 15  Gastroenterological disorders 3236 half-​life), which can be combined with PET to offer whole-​body tumour localization. Treatments can be aimed at disease cure or symptom alleviation, depending upon tumour site and disease extent. Low-​grade or benign neuroendocrine tumours can be often be watched and followed with sequential imaging, whereas small and localized tumours can be re- sected to prevent spread or hormone-​related symptoms. Metastatic tumours can be surgically debulked for palliation and symptom control, improved quality of life, and occasionally prolonged length of life. Systemic somatostatin analogues (e.g. lanreotide) adminis- tered subcutaneously or intramuscularly can block hormonal re- lease and help in the control of symptoms, as well as occasionally reducing tumour size. Further systemic chemotherapeutic agents include everolimus (inhibitor of mammalian target of rapamycin) and sunitinib (receptor tyrosine kinase inhibitor), which can be used independently or combined with 5-​fluorouracil, doxorubicin (anthracycline, antitumour antibiotic), or cisplatin (platinum based) in combination regimens. Locally directed treatment can be given in the form of peptide receptor radionuclide therapy, which can be tar- geted to the tumour via previously established hormone receptors. Hepatic metastases can often be the source of significant symptoms in patients with functional tumours. Treatments include transarterial chemoembolization, where spheres lined with chemotherapy agents are directly embolized into tumour vessels, thus obstructing tumour blood flow and directly delivering chemotherapy. This can lead to a significant (up to 80%) reduction in tumour size. Selective internal ra- diation therapy (yttrium-​labelled radioactive microspheres delivered directly to the tumour) can also be used in some cases. Functional tumours are routinely classified according to the hor- mone that is most strongly secreted, as follows: Insulinomas These result in hypoglycaemic episodes that can be sudden, severe, and extremely troublesome, and can be diagnosed in those with a biochemical profile of low serum glucose associated with elevated insulin, proinsulin, and C-​peptide levels. Insulinomas can be local- ized by conventional radiology modalities supplemented by angiog- raphy and should be treated via surgical resection wherever possible. Glucagonomas Patients exhibit increased serum glucagon levels, activating gluconeogenesis and lipolysis, and resulting in hyperglucagonaemia, decreased amino acid levels, anaemia, diarrhoea, and weight loss. Necrolytic migratory erythema is the presenting problem in up to three-​quarters of patients and is characterized by the presence of erythematous blisters and swelling in the lower abdomen, groins, axillae, and buttocks. Diabetes is often present. An elevated blood serum glucagon (in the absence of liver disease) is usually diagnostic but can be supplemented by assessment of blood amino acids and skin biopsies to confirm necrolytic migratory erythema. Tumours should be localized via radiological imaging and resected. Vasoactive intestinal peptide-​omas These are rare neuroendocrine tumours originating from non-​β-​ islet cells of the pancreas and which may be associated with mul- tiple endocrine neoplasia type 1 syndrome. Excess production of vasoactive intestinal peptide leads to the development of profuse watery diarrhoea, hypokalaemia, achlorhydria, hypercalcaemia, and hyperglycaemia, as well as flushing and hypotension due to excess vasodilation. Treatment is via surgical resection, which is possible in a third of patients, with the rest requiring somatostatin analogue radionuclide therapy. Somatostatinomas These are tumours of pancreatic delta cells that produce somato- statin, clinically manifesting as diabetes (inhibition of insulin), steatorrhoea (inhibition of pancreatic exocrine hormones), gall- stones (inhibition of cholecystokinin), and achlorhydria (inhibition of gastrin), as well as a reduction in rates of gastric emptying and in- testinal peristalsis, and are also associated with psammoma bodies, microscopic collections of calcium. Treatment is via surgical resec- tion supplemented with chemotherapy as necessary. FURTHER READING Aune D, et al. (2012). Body mass index, abdominal fatness and pancre- atic cancer risk: a systematic review and non-​linear dose-​response meta-​analysis of prospective studies. Ann Oncol, 23, 843–​52. Bosetti C, et al. (2012). Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-​Control Consortium (Panc4). Ann Oncol, 23, 1880–​8. Callery MP, et al. (2009). Pretreatment assessment of resectable and borderline resectable pancreatic cancer:  expert consensus state- ment. Ann Surg Oncol, 16, 1727–​33. Canto MI, et al. (2013). International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut, 62, 339–​47. Conroy T, et al. (2011). FOLFIRINOX versus gemcitabine for meta- static pancreatic cancer. N Engl J Med, 364, 1817–​25. Cunningham D, et al. (2009). Phase III randomised comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol, 27, 5513–​18. Ducreux M, et al. (2015). Cancer of the pancreas: ESMO clinical prac- tice guidelines for diagnosis, treatment and follow-​up. Ann Oncol, 26 Suppl 5, v56–​v68. Duell EJ, et al. (2012). Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer Case-​Control Consortium (PanC4). Ann Oncol, 23, 2964–​70. Elena JW, et al. (2013). Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control, 24, 13–​25. Hu J, et al. (2011). A meta-​analysis of gemcitabine containing chemo- therapy for locally advanced and metastatic pancreatic adenocar- cinoma. J Hematol Oncol, 4, 11. Jacobs EJ, et al. (2010). Family history of cancer and risk of pancre- atic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer, 127, 1421–​8. Klein AP (2013). Identifying people at a high risk of developing pan- creatic cancer. Nat Rev Cancer, 13, 66–​74. Kirkegård J, Mortensen FV, Cronin-Fenton D (2017). Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Am J Gastroenterol, 112, 1366–72. Liu L, et al. (2010). Cetuximab-​based therapy versus non-​cetuximab therapy for advanced cancer: a meta-​analysis of 17 randomized con- trolled trials. Cancer Chemother Pharmacol, 65, 849–​61. Lucenteforte E, et  al. (2012). Alcohol consumption and pancreatic cancer:  a pooled analysis in the International Pancreatic Cancer Case-​Control Consortium (PanC4). Ann Oncol, 23, 374–​82.

15.26.3  Tumours of the pancreas 3237 Moore MJ, et al. (2007). Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 25, 1960–​6. National Comprehensive Cancer Network (NCCN) (2017). NCCN Clinical practice guidelines in oncology. Pancreatic adenocarcinoma. V.2.2017. NCCN, Fort Washington, PA. National Institute for Health and Care Excellence (NICE) (2013). Using radiofrequency energy to treat malignant bile or pancreatic duct obstructions caused by cholangiocarcinoma or pancreatic adenocarci- noma. NICE, London. Parkin DM, Boyd L, Walker LC (2011). The fraction of cancer attrib- utable to lifestyle and environmental factors in the UK in 2010.
Br J Cancer, 105 Suppl 2, S77–​81. Sant M, et al. (2009). EUROCARE-​4. Survival of cancer patients diag- nosed in 1995–​1999. Results and commentary. Eur J Cancer, 45, 931–​91. Tanaka M, et al. (2012). International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology, 12, 183–​97. Tempero MA, et  al. (2017). Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 15, 1028–​61. van der Gaag NA, et al. (2010). Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med, 362, 129–​37. Versteijne E, et al. (2018). Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg, 105(8), 946–58. Vincent A, et al. (2011). Pancreatic cancer. Lancet, 378, 607–​20. VonHoff DD, et al. (2013). Increased survival in pancreatic cancer with nab-​paclitaxel plus gemcitabine. N Engl J Med, 369, 1691–​703. Website Cancer Research UK (CRUK): http://​www.cancerresearchuk.org

   VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 Index Tables, figures, and boxes are indicated by t, f, and b following the page number Note: For the benefit of digital users, indexed terms that span two pages (e.g., 52–​53) may, on occasion, appear on only one of those pages. AA amyloidosis  2217, 2219, 4262, 6161 associated conditions  2219, 2220b clinical features  2220 management  2232 systemic  4259 AAI pacemakers  3359–​60 A band  6305f, 6305 abatacept (CTLA4-​Ig)  101t, 104–​5 diabetes mellitus type 1  2500 rheumatoid arthritis management  4437t systemic lupus erythematosus management  4511 Abbreviated Mental Test score (AMT-​4)  542, 6451b, 6451 confusion  6455, 6456 ABCA1 deficiency see Tangier disease (ABCA1 deficiency) ABCD2 score, transient ischaemic attacks  6014 ABCDE approach  3845 acute respiratory failure  3869 airway and breathing  3845 cardiac arrest  3845 circulation  3845 coronary reperfusion  3845 post-​intensive care syndrome  3927 ABCDEFG approach  3832t abciximab  3635 ABC mnemonic, irritable bowel syndrome  2951, 2952f ABC (airway, breathing, and circulation) traumatic brain injury  6044 abdominal actinomycoses  1173 abdominal aortic aneurysm  3685 cardiovascular syphilis  3540 definition  3685 detection pre-​rupture  3686f, 3686 endovascular aneurysm repair  3687 epidemiology  3682t, 3685 medical management  3687 ruptured aneurysm  3686 adult screening  142f, 149t, 150 surgery  3687 abdominal bruit  3758–​59 abdominal muscles  4113 abdominal pain  2730 acute abdomen  2730 acute porphyria  2039, 2050 acute rheumatic fever  3514f, 3514 arterial occlusion in acute kidney disease  4825 chronic pain  2728t, 2730, 2731f chronic upper urinary tract obstruction  5129 constipation/​faecal incontinence  598 Crohn’s disease  2927 familial chylomicronaemia  2076 hepatocellular carcinoma  3180 hereditary fructose intolerance (fructosaemia)  1997 mesenteric ischaemia  3685 recurrent pain  2728t, 2730, 2731f retroperitoneal fibrosis  5132 temporal lobe seizures  5863–​64 ulcerative colitis  2940 abdominal wall anterior defects  2968 abetalipoproteinaemia  2071 differential diagnosis  2168t, 2169t Abiotrophia infections  973 abiraterone  5145 ABO system  5566, 5566t compatibility in transplantation  404t incompatibility, haemolytic disease of the newborn  5486 matching in lung transplantation  4295 absence seizures  5864, 5865f absent pulmonary valve syndrome  3587 absorbents  5152 ABSORB III trial  3659 absorption enhancers, dermatological vehicles  5762 lipids  2064, 2065f pharmacokinetic drug interactions  93, 94t pharmacokinetics  78f, 78 older patient  572 prevention, drug overdose management  6639t rate see pharmacokinetics absorptive function tests  2878 abuse, ageing  543, 545t Academy of Medical Royal Colleges (AoMRC)  6541 acamprosate  3145, 6490 Acanthamoeba infection granulomatous amoebic encephalitis  1393 keratitis  1393, 6408t, 6427–​28, 6428f acanthocytosis  5463 acanthosis nigricans diabetes mellitus  5747f, 5747 insulin resistance  2474 acarbose  2497 Acari (ticks)  1813 ACCENT 1 study  2933 acclimatization see high terrestrial altitudes ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial blood pressure control in diabetic nephropathy  4982 glycaemic control in diabetic nephropathy  4980 hypertension diagnostic thresholds  3762–​63 ACE (angiotensin-​converting enzyme) adult values  6582t assay  5785 sarcoidosis  5744 vasoconstrictors  3246f, 3249 ACE inhibitors acute kidney injury prevention  4811 acute rheumatic fever management  3516 adverse reactions  3414 ascites  3067 atherosclerotic renovascular disease  5045 autonomic nervous system disorders  6161 CKD  4836 distal renal tubular acidosis with hyperkalaemia (previous type IV)  5109 hyperkalaemia  4760 pityriasis rosea  5628 renal disease  4778 urticaria/​angioedema  5673 aortic regurgitation management  3454 blood pressure control in CKD  4842 cardiogenic anasarca management  3405 cardiorenal syndrome  3424–​25 chronic heart failure management  3414f, 3414 CKD in pregnancy  2594t congenitally corrected transposition of the great arteries  3583 contraindications, pregnancy, and breastfeeding  3414 dilated cardiomyopathy management  3481 drug interactions, lithium  6468 Duchenne’s muscular dystrophy management  6317–​18 focal segmental glomerulosclerosis management  4926, 4927 frailty and sarcopenia management  530 HIV-​related dilated cardiomyopathy  3535–​36 hypertension in diabetes  2524 hypertension management  3766t, 3768 contraindications  3767t hypertension with acute stroke  3809 left ventricular dysfunction management  3649 malignant hypertension management  3805, 3806t mechanism of action  3414 membranoproliferative glomerulonephritis  4941 minimal-​change nephrotic syndrome management  4921 mitral regurgitation management  3446 nonalcoholic fatty liver disease  3152 poisoning by  1734 post-​renal transplant hypertension  4899–​900 pregnancy  2707 primary aldosteronism screening  2354 renal disease, effects of  5155–​56 scleroderma renal crisis management  5008 stable angina prevention  3623 STEMI management  3651 acemetacin  4449 aceruloplasminaemia (ACP)  2099t, 6252t, 6253 with iron deposition (haemosiderosis) in basal ganglia  2113

2 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 acetaminophen see paracetamol (acetaminophen) acetazolamide epilepsy management  5875 familial hypokalaemic periodic paralysis management  4756 idiopathic intracranial hypertension management  6058 acetone poisoning  1762 N-​acetylaspartic aciduria (Canavan’s disease)  1968, 1969f acetylcholine (ACh)  6304–​5 nicotinic acetylcholine receptor binding  248 nitric oxide synthesis  3247 receptor deficiency  6301 acetylcholinesterase inhibitors  5851 acetyl CoA  1842 N-​acetylcysteine  1744 alcoholic liver disease management  3144 drug-​induced liver injury  3157 liver failure management  3099 meconium ileus  2972 α-​N-​acetylgalactosaminidase (NAGA)  6231 N-​acetylglutamate synthetase deficiency  1949t, 1953 acetylsalicylic acid (ASA)  4594 achalasia  2728 Achilles tendinopathy  4412t achlorhydria  2867 achondroplasia  4656 achondroplasia-​like dwarfism  4656 Achromobacter infection  4157 aciclovir adverse reactions  702t encephalopathy adverse reactions  4819 herpes simplex virus infection  2807 pregnancy  2681 resistance  740 herpes zoster infection  2808 renal disease, effects of  5163t skin disease management  5770 viral encephalitis management  6094 viral meningitis management  6094 acid–​base disorders  2182, 2182t anion gap acidosis see anion gap acidosis compensation for  2183b diagnosis  2183b, 2183 serum anion gap  2184 type characterization  2183 epithelial cell transport and  2185 extracellular fluid chemistry  2184, 2185f gastrointestinal tract  2192 colon  2194f, 2194 small intestine  2192, 2193f stomach  2192 intake associated  2197 kidney and  2186 collecting duct  2189f, 2189 distal tubule  2188f, 2188 proximal tubule  2186f, 2186 thick ascending limb of Henlé’s loop  2187, 2188f management  2198 mesenteric venous thrombosis  3002 neurological disorders  6373 skin  2194 sweat gland ducts  2194f, 2194 symptoms  2198 see also hyperchloraemic acidosis; hyperchloraemic alkalosis; metabolic acidosis; metabolic alkalosis acid–​base homeostasis arterial blood gas testing  3964, 3964t, 3965f bowel resection  2913 CKD pathophysiology  4836 collecting duct  5105 COPD  4118 proximal tubule  5105f, 5105 acid maltase deficiency (glycogenosis type II)  6337 acidosis CKD  4844 diabetic ketoacidosis  2506, 2509 hyperkalaemia causes  4761 metabolic see metabolic acidosis severe malaria infections  1405 acidotic breathing see Kussmaul respiration (acidotic breathing) acid poisoning  1762 acid suppression acute upper gastrointestinal bleeding management  2776 gastro-​oesophageal reflux disease management  2832 acinar cells  3210 carcinoma  3234 ACLF see acute-​on-​chronic liver failure (ACLF) acne  5703 aetiology  5703 clinical features  5704f, 5704 clinical investigations  5704 comorbidities  5708 complication  5708 cyanotic heart disease  3564 differential diagnosis  5704, 5705t epidemiology  5703 management  5704, 5705t pathogenesis  5704f, 5704 pregnancy  2649 prognosis  5707 psychosocial effects  5708 variants  5707 acne conglobata  5707 acne excoria  5707 acne fulminans  5707 aconite (Aconitum)  204, 1829 acoustic neuroma  464 acquired angio-​oedema  4045 acquired aplastic anaemia  5338 aetiology  5338, 5339t clinical features  5339t, 5341 clinical investigations  5341 abdominal ultrasound  5342 anti-​DNA antibodies  5341 antinuclear antibodies  5341 bone marrow aspirate  5341, 5342f bone marrow cytogenetics  5342 chest radiographs  5342 folate  5341 full blood count  5341 inherited disease screens  5342 liver function tests  5341 molecular genetics  5342 PNH screen  5341 trephine biopsy  5341 virology  5341 vitamin B12  5341 incidence  5338 management  5343f, 5343 haematopoietic stem cell transplantation  5344 immunosuppressive management  5345 infections  5343 psychological support  5343 transfusions  5343 paroxysmal nocturnal haemoglobinuria vs.  5351f, 5351 pathogenesis  5340 prognosis  5343 acquired chorea see chorea acquired coagulation disorders  5546, 5548t acquired von Willebrand’s syndrome  5555 desmopressin  5549 factor V inhibitors  5554 factor VII inhibitors  5555 factor IX inhibitors  5555 factor X inhibitors  5554 factor XI inhibitors  5555 factor XIII inhibitors  5554 general clinical approach  5546 heparin  5555 heparin-​like anticoagulants  5555 hyperfibrinolysis  5555 cardiopulmonary bypass surgery  5555 malignancies  5555 thrombotic management  5555 hypoprothrombinaemia  5554 immunoglobulin-​mediated factor deficiency  5553 acquired factor VIII inhibitor  5550t, 5554 macrovascular thrombosis  5557 adenocarcinoma-​associated disseminated intravascular coagulation  5559f, 5559 antiphospholipid antibody syndrome (lupus anticoagulant)  5559 heparin-​induced thrombocytopenia (HIT)  5557 protamine-​induced thrombocytopenia  5559 management  5547 microvascular thrombosis  5560 coumarin-​induced limb gangrene  5560 coumarin-​induced skin necrosis  5560f, 5560, 5560t purpura fulminans  5560 septicaemia  5561 symmetrical peripheral gangrene  5560, 5561f systemic inflammatory response syndromes  5561 thrombotic microangiopathy  5561 pharmacological therapies  5549 plasma cell dyscrasia  5555 prohaemorrhagic coagulation disorders  5546, 5549 acute haemolysis  5553 acute ischaemic hepatitis (shock liver)  5552 direct oral anticoagulant overanticoagulation (DOACs)  5551 disseminated intravascular coagulation see disseminated intravascular coagulation (DIC) haemodilution in transfusion  5552 immunological disorders  5553 infections  5553 liver disease see liver disease obstetric complications  5553 trauma  5552 vascular anomalies  5553 vitamin K deficiency  5549 vitamin K-​dependent coagulation factors  5549 prothrombotic coagulation disorders  5547, 5557 screening tests  5548t, 5550t secondary to plasma cell dyscrasia  5551b, 5555 specific factor conjugates  5549 thrombin inhibitors  5554 venom induced  5556 snake bites  5556, 5560t acquired haemolytic anaemia  5479 immune haemolytic anaemias  5480 alloimmune haemolytic anaemias see alloimmune haemolytic anaemias autoimmune haemolytic anaemias see autoimmune haemolytic anaemias nonimmune acquired haemolytic anaemias  5486b, 5486 chemicals  5486, 5487t infection  5486 mechanical causes  5487 thermal haemolysis  5487 acquired haemophagocytic lymphohistiocytosis  5261f, 5261 acquired hepatocerebral degeneration  6370 acquired hypoparathyroidism  2321b, 2328 acquired idiopathic sideroblastic anaemia (refractory anaemia with ring sideroblasts)  5452b, 5453 aetiology  5454 clinical features  5454 laboratory features  5454 management  5454 pathogenesis  5453f, 5454 prognosis  5454, 5454t acquired lymphangiectases (acquired lymphangioma)  5722

  Index 3 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 acquired melanocytic naevi (moles)  5733, 5734f acquired methaemoglobulinaemia 
5449 acquired nephrogenic diabetes insipidus  4770 acquired neuromyotonia  6341 acquired neutropenia, hypersplenism see hypersplenism acquired nonimmune haemolytic anaemias  5479 acquired non-​QT syndrome  3384 acquired pernicious anaemia  5408, 5413 aetiology  5413 clinical features  5414 cardiovascular disease  5416f, 5416 malignancy  5416 mental deterioration  5416 neural tube defects  5415 definition  5413 pathology  5414 acquired thrombotic thrombocytopenic purpura  5527 ACR see American College of Rheumatology (ACR) acral lentiginous melanoma  5738, 5739f acrocyanosis/​perniosis (cold injury)  5713 acrodermatitis chronica atrophicans, Lyme borreliosis  1184 acrodermatitis enteropathica  1878f, 1878 acromegaly  2266 cardiac disease  3497 clinical features  2266b, 2266 diagnosis  2267 insulin tolerance test  2263 management  2267 mortality  2267 myopathies  6339 neuropathies  6187 pregnancy  2641 acrylamide neuropathies  6188 ACS see acute coronary syndrome (ACS) ACTH see adrenocorticotrophic hormone (ACTH) ACTH-​dependent Cushing’s syndrome see Cushing’s syndrome ACTH-​independent Cushing’s syndrome see Cushing’s syndrome actin  269–​70 filaments  214–​15 actinic prurigo (AP)  5690, 5691f Actinomyces bovis infection  3174 Actinomyces israelii infection  3174, 6430 actinomycoses  1170 aetiology  1170, 1171t clinical manifestations  1173 abdominal actinomycoses  1173 bone disease  1174 cervicofacial actinomycoses  1173 CNS infections  1174 cutaneous actinomycoses  1174 endocarditis  1174 thoracic actinomycoses  1173, 1173t diagnosis  1174 bacteriology  1172f, 1174 clinical chemistry  1174 haematology  1174 radiography  1174 serology  1175 epidemiology  1171 management  1175 pathogenesis/​pathology  1171 histopathology  1172f, 1172 synergistic polymicrobial disease  1171, 1172t prognosis  1175 Action on Smoking for Health (ASH)  4104 action potentials  247 demyelination  6028 activated partial thromboplastin time (APTT)  3730 acquired coagulation disorders  5548t bleeding tendencies  5513 activation-​induced cell death (AICD)  277–​78 active tubular secretion, drug excretion  81–​82 activin  262 hormone signalling  2252, 2255f iron overload  5400 activities of daily living (ADLs)  565 ACUITY trial  3638 acupressure  109b acupuncture  109b, 203 Chinese vs. Western  203 osteoarthritis management  4479t tension-​type headaches  5995 acute abdomen  2730, 2765 aetiology  2765, 2766t clinical features  2765 examination  2766 history  2765 investigation  2766 imaging  2767f, 2767, 2768f laboratory tests  2767 management  2768 surgery  2769t medical causes  2769 acute porphyria  2770 acute urinary retention  2770 Addisonian crisis  2770 cocaine abuse  2770 constipation  2770 diabetic ketoacidosis  2769 gastroenteritis  2770 herpes zoster  2770 pneumonia  2770 rectus sheath haematoma  2770 spontaneous splenic rupture  2770 medical wards  2768 cardiac disease  2769 colonic pseudo-​obstruction (Ogilvie’s syndrome)  2768 elderly  2769 iatrogenic problems  2769 immunosuppression  2768 inflammatory bowel disease  2769 liver disease  2769 presentation  6612 acute aortic syndrome  3674 aetiology  3675f, 3676f, 3676, 3677b risk factors  3676 classification  3676f, 3676 clinical features  3674b, 3677 follow-​up  3680 investigations  3677 blood tests  3678 chest radiography  3677f, 3677 ECG  3678 imaging studies  3678f, 3678, 3678t, 3679f management  3679 emergency management  3679 surgery  3679 pathogenesis  3675f, 3675, 3676f prognosis  3680 acute asthma see asthma acute calcific periarthritis  4493f, 4493 acute calcium pyrophosphate crystal deposition  4490, 4493 acute care for elders (ACE)  553 acute cellular rejection heart transplantation  3429 liver transplantation  3103, 3105 renal transplant  4886, 4886t acute chest syndrome, sickle cell disorders  5443, 5446 acute confusional state cognitive impairment  6451 presentation  6621 acute coronary syndrome (ACS)  3626 aetiology  3627, 3628f atherosclerosis see atherosclerosis chest pain  3278 clinical definition  3627 clinical presentation  3628 definition  3628 ECG  3278, 3304, 3305t probability  3305 prognosis  3304 triage  3305 management without ST-​ elevation  3628, 3633 anticoagulant management  3636, 3638 anti-​ischaemic management  3633, 3634b antiplatelet management  3634, 3638, 3642f, 3642 coronary artery bypass surgery  3641 emergency departments  3640b, 3640 glycoprotein IIb/​IIIb inhibitors  3635, 3636b high-​risk status  3640 integrated management  3639 low molecular weight management  3642 low-​risk status  3636t, 3640 P2Y12 receptor inhibitors  3635, 3636t potassium channel activators  3634b revascularization  3638 risk stratification  3630t, 3639 secondary prevention  3642, 3643t outcomes  3629, 3630t biochemical markers  3630, 3631f, 3631t clinical syndrome  3629 ECG  3628t, 3630 imaging  3632 large-​scale observational registry studies  3629 trial data  3629 prognosis  3628t risk characterization  3632, 3633b, 3633t secondary prevention  3642, 3643t secondary prevention measures (STEMI or non-​STEMI)  3651 cardiovascular risk reduction  3651, 3651t, 3652t nonpharmacological interventions  3651 pharmacological interventions  3651 STEMI see ST-​segment elevation myocardial infarction (STEMI) see also non-​ST elevation myocardial infarction (NSTEMI); ST-​segment elevation myocardial infarction (STEMI); unstable angina (UA) acute cutaneous lupus erythematosus (ACLE)  5652b, 5653f, 5653 Acute Dialysis Quality Initiative  3422, 3422t acute disseminated encephalomyelitis (ADEM)  6038 diagnosis  6132 epidemiology  6084 acute eosinophilic pneumonia (Löffler’s syndrome, simple pulmonary eosinophilia)  4239,
4278–​79, 4600f, 4600 acute exacerbation of chronic obstructive pulmonary disorder (AECOPD) see chronic obstructive pulmonary disorder (COPD) acute fatty liver of pregnancy (AFLP)  2592, 2621, 2704 acute generalized exanthematous pustulosis (AGEP)  5754t, 5759 acute hospitals  548, 549b components  551, 552b, 561b, 561 dignity  614b, 614 acute infantile spinal muscular atrophy type I (Werdnig–​ Hoffman disease)  6173 acute inflammatory demyelinating polyradiculoneuropathy (AIDP)  6177 acute interstitial nephritis (AIN)  4951 acute kidney injury  4826 aetiology  4951, 4952b drugs  4951

4 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 immune disease  4952 infections  4952 clinical features  4954, 4954t drug-​induced  4954 clinical investigations  4955 differential diagnosis  4954 epidemiology  4954 future developments  4955 historical perspective  4951 management  4955 pathogenesis  4953 pathology  4953f, 4953 prognosis  4955 acute interstitial pneumonia (Hamman–​Rich syndrome)  4170 acute ischaemic hepatitis (shock liver)  5552 acute kidney injury (AKI)  4769, 4807 acute interstitial nephritis diagnosis  4955 age distribution  4809f causes  4808, 4809b, 4809, 4810t, 4819 acute interstitial nephritis  4826 glomerulonephritis  4823b, 4826 haematological causes  4827 hepatorenal syndrome  4827 nephrotoxins  4822b, 4822 vascular causes  4824 see also prerenal failure clinical approach  4807, 4810 clinical features  4814 biochemical changes  4815 complications  4815 hyperkalaemia  4815, 4816t pulmonary oedema  4816 definition  4808 diagnosis  4810, 4813 accuracy  4813 CT  4814 fluid input/​output  4810 inflammatory cause  4814f, 4814 physical signs  4810 serum creatinine  4810 ultrasound  4814f, 4815 urinary obstruction  4813 weight measurement  4810 epidemiology  4808 immunoglobulin A nephropathy  4912 malarial renal disease  5053 management  4807, 4818 critical care in pregnancy  2702 drugs  4819 fluid replacement  4817 haemorrhage management  4819b, 4819 immunoglobulin A nephropathy and  4915 nutrition  4818 peritoneal dialysis  4875 potassium requirements  4817 renal biopsy  4818 renal replacement therapy  4817 sepsis  4819 sodium requirements  4817 pregnancy in  2589 aetiology  2589, 2590t, 2591 clinical approach  2589, 2591t diagnosis  2589 epidemiology  2589 presentation  6613 prevention  4811f, 4811 care bundles  4811, 4812t, 4813f glycaemic control  4811 risk factors  4811, 4812t snake bites  1799 stages of  4808t systemic cancer effects  5042f tropical renal disease  5051f, 5051 urinary tract obstruction  4769 urine biomarkers  4787 volume depletion  4817 acute leg ischaemia see leg ischaemia acute leukaemias oral manifestations  2824f, 2824 primary myelofibrosis  5252 renal disease in  5025 acute liver failure (ALF)  3090t, 3094 classification  3094 clinical features  3094 cognitive changes  6369–​70 neurological disease  6369 definition  3089–​90 hepatic encephalopathy management see hepatic encephalopathy type A liver transplantation indications  3101 pathophysiology  3094b, 3095 drug-​induced  3094 prognosis  3095f, 3095 acute lower gastrointestinal bleeding  2778, 6609 aetiology  2778, 2778t angiodysplasia  2778, 2779f benign anorectal disease  2778 colonic tumours  2778 diverticular disease  2778 iatrogenic haemorrhage  2779 inflammatory bowel disease  2778 clinical features  2779 history  2779 epidemiology  2778 examination  2779 management  2779, 2780f bleeding localization  2779 capsule endoscopy  2781 obscure bleeding  2781 resuscitation  2779 surgery  2781 acute lymphatic filariasis see lymphatic filariasis acute lymphoblastic leukaemia (ALL)  5269 clinical features  5272b, 5272 clinical investigations  5272, 5273b, 5274f complications/​long-​term follow-​up  5279 long-​term toxic effects  5279 short-​term toxic effects  5279b, 5279 current multidrug chemotherapy  5273 consolidation phase  5273 induction phase  5273 intensification phase  5273 differential diagnosis  5272 epidemiology  443, 5270 future developments  5279 genetics  5270, 5271t chromosomal abnormalities  5272f immunophenotyping  5271t management  5269–​70, 5273 allogeneic haematopoietic stem cell transplantation  5275 BCR-​ABL-​like ALL  5275 BCR-​ABL-​positive ALL  5275 chimeric antigen receptor T cells  478 CNS-​directed prophylaxis  5275 elderly people  5275 initial management  5273 relapsed/​refractory ALL  5275 pathogenesis  5270 prognosis  5271t, 5272f, 5276f, 5276, 5277f, 5278f children  5278f, 5279 relapses  5271–​72 remissions  5271–​72 acute mesenteric ischaemia  2999 blood tests  3000 gangrene  3000–​01, 3001f intestinal tissue damage  3000 investigations  3000f, 3000 leucocytosis  3000 acute myeloid leukaemia (AML)  5205 causation  5205 diagnosis  5206 epidemiology  443, 5205, 5206f future developments  5205 incidence  413 management  5206 bone marrow transplantation  5209 chemotherapeutic regimens  5207 chemotherapy consolidation  5208 DNA methylation  5209 general considerations  5206, 5207f maintenance chemotherapy  5209 older patients  5208 outcomes  5208 relapsed disease  5208 remission definition  5207 targeted management  5209 prognostic factors  5206b, 5206f, 5206 supportive care  5210 blood product support  5210 during chemotherapy  5210 hyperleucocytosis  5210 infections  5211 management initiation  5210 metabolic complications  5210 prior to cytotoxic management  5210 tumour lysis syndrome  5210 acute myocardial infarction (AMI)  3307 atrial infarction  3307 cardiogenic shock  3887 coronary artery spasm  3308 C-​reactive protein  2203 definition  3629b, 3629 mitral regurgitation  3442 PCI outcomes  3662 posterior infarction  3308 right ventricular infarction  3307f, 3307 septal ischaemia  3308 acute necrotizing myelitis (Foix–​Alajouanine syndrome)  6039, 6133, 6134 acute-​on-​chronic liver failure (ACLF)  3090f,
3090, 3090t definition  3089–​90 diagnosis  3090, 3091f, 3091t pathophysiology  3092 inflammatory response  3092 organ dysfunction  3093 precipitating factors  3092, 3092t predisposing factors  3092 prognosis  3091 acute-​on-​chronic respiratory failure  6605 acute pancreatitis  3209 aetiology  3211b, 3211, 3212 alcohol  3211 autoimmune pancreatitis  3212 benign pancreatic duct stricture  3212 drugs  3211 gallstones  3211 genetics  3212 hyperlipidaemia  3212 hyperparathyroidism  3212 hypothermia  3212 iatrogenic stories  3212 parasitic infections  3213 periampullary/​obstructive pancreatic tumours  3212 sphincter of Oddi dyskinesia  3213 trauma  3212 viral infections  3211 clinical features  3210 complications  3218 acute pancreatic pseudocyst  3218 haemorrhage  3217f, 3218 pancreatic ascites  3218 portal vein thrombosis  3217f, 3218 splenic vein thrombosis  3217f, 3218 visceral fistulation  3217f, 3218 C-​reactive protein  2203 diagnosis  3210b, 3210f, 3210 biochemical abnormalities  3210 differential diagnosis  3210b, 3210 epidemiology  3209 hypertriglyceridaemia  2096 laboratory data sets  3833t management  3213 antibiotics  3214 ERCP  3214 nutrition support  3214 postacute pancreatic fluid/​ necrotic collection see postacute pancreatic fluid/​ necrotic collection surgery  2769t pathology  3210 severity grading  3210, 3213, 3213t, 3214t

  Index 5 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 acute phase response  2199 C-​reactive protein  2200 familial Mediterranean fever  2212 rheumatological diseases  4401f, 4401 see also C-​reactive protein (CRP) acute physiological conservative therapy (APCM)  6139, 6140 outcome/​prognosis  6140, 6141t acute porphyrias  6620 acute abdomen  2770 acute intermittent porphyria  2042f, 2042 5-​aminolevulinate dehydrogenase deficiency (Doss’ porphyria)  2043 attack management  2050 carbohydrate loading  2051 haem management  2051 immediate  2050 attack prevention  2052 gene management  2052 hormonal interventions  2052 liver transplantation  2052 clinical features  2039, 2040b complications  2041 acute encephalopathy  2041 CKD  2041 hepatic carcinoma  2042 neurological complications  2041 complications management  2051 hypertension  2051 hyponatraemic seizures  2051 definition  2035 diagnosis  2041 epidemiology  2035 genetic variants  2044 coproporphyrinogen oxidase  2044 ferrochelatase  2044 porphobilinogen deaminase (hydroxymethylbilane synthase)  2044 protoporphyrinogen oxidase  2044 hereditary coproporphyria  2043 pathogenesis  2038, 2039b, 2040b alcohol tolerance  2039 smoking  2039 prognosis  2041 variegate porphyria  2043 acute presentation of diseases  6591 endocrine disease  6614 gallstones  3199 gastrointestinal disease  6608 heart and circulation  6591 infectious diseases  6629 liver disease  6608 metabolic disease  6614 neurological disease  6621 psychiatric disease  6637 renal disease  6613 respiratory system  6605 acute promyelocytic leukaemia (APS)  5211 management  5211 arsenic trioxide  112 complications  5212 residual disease measurement  5212 supportive care  5212 acute pulmonary embolism  3716, 6601 clinical features  3717 accuracy  3719, 3719t signs  3718, 3719t symptoms  3717 diagnosis  3719t, 3724 differential diagnosis  3719 incidence  3716 investigations  3720 arterial blood gases  3724 biomarkers  3724 blood tests  3724 chest radiography  3723, 3724t contrast-​enhanced spiral CT  3721, 3722f, 3723t D-​dimer  3720, 3725 echocardiography  3724 electrocardiography  3723, 3723t MRI  3722 pulmonary angiography  3721, 3722f serial noninvasive leg tests  3726 SPECT ventilation–​perfusion lung scan imaging  3721 thrombus detection  3720 ventilation–​perfusion lung scans  3715t, 3720f, 3720 management  3717t, 3726 anticoagulants  3726f, 3726 antithrombotic management  3723t, 3726 catheter intervention  3728 inferior vena cava filters  3717t, 3727 pulmonary embolectomy  3728 resuscitation  3726 thrombolytic management  3726 predisposing factors  3716, 3718t recommendations  3725 elderly  3725 impaired renal function  3725 iodinated contrast material allergies  3725 male reproduction  3725 patients in extremis  3726 pregnancy  3725 women of reproductive age  3725 acute respiratory distress syndrome (ARDS)  3873 aetiology  3874f, 3874 clinical features  3875 clinical investigations  3875f, 3875 definition  3873, 3874b, 3874f differential diagnosis  3875, 3875t epidemiology  3874 general supportive measures  3879 pathogenesis  3875 pathology  3875 pharmacotherapy  3878 prognosis/​outcome  3879 ventilatory management  3875 indications/​ contraindications  3878b acute respiratory failure (ARF)  3868 clinical approach  3869 examination  3869, 3869t history  3869 clinical investigations  3869 arterial gas analysis  3869b, 3869, 3870t chest radiographs  3870 computed tomography  3870 echocardiography  3870 electrocardiography  3870 fibreoptic bronchoscopy  3870 infection screening  3870 ultrasound  3870 definition  3868 epidemiology  3868, 3868t management  3871 airway management  3871 mechanical ventilation  3872, 3872t oxygen management  3871, 3871t pregnancy  2617 respiratory monitoring  3870 arterial oxygen saturation  3870 capnography  3871 indwelling arterial catheter  3870 lung function estimation  3870 pulse oximetry  3870 acute rheumatic fever  3509 associated poststreptococcal syndromes  3514 clinical features  3512, 3512t arthritis  3512 carditis  3512 elevated acute-​phase reactants  3514 erythema marginatum  3513 fever  3513 subcutaneous nodules  3513 Sydenham’s chorea  3512 diagnosis  3514, 3515t differential diagnosis  3515t epidemiology  3510 follow-​up  3517 recurrence  3517 management  3516 bed rest  3516 cardiac failure management  3516 chorea management  3517 corticosteroids  3516 penicillin  3516 salicylates  3516 pathogenesis  3510, 3511f host factors  3510 immune response  3511 infection site  3511 infective organism  3510 prevention  3517 primary prevention  3517 secondary prevention  3517 prognosis  3517 acute sarcoid arthritis (Löfgren’s syndrome)  4600f, 4600 acute schistosomiasis (Katayama fever)  1544, 1545f acute toxic injury to respiratory tract  4267, 4268t assessment and management  4269 supportive care  4269 clinical features  4268 acute airway effects  4268 acute pneumonitis/​pulmonary oedema  4268f, 4268 asphyxiants  4269 burns  4268 fume events  4269 nonpulmonary effects  4269 soluble irritant gases  4268 sulphur mustard  4268 acute unilateral vestibulopathy (vestibular neuritis)  5930b acute upper gastrointestinal bleeding  2771 aetiology/​pathogenesis  2771, 2771t erosive disease  2772 Mallory–​Weiss tears  2772 peptic ulcer disease  2771 varices  2771 causative lesion management  2777 nonvariceal upper gastrointestinal bleeding  2777 variceal upper gastrointestinal bleeding  2777f, 2777 clinical features  2772 examination  2772 history  2772b, 2772 diagnosis and haemostasis  2775 drug management  2776 endoscopy  2774b, 2775f, 2775 radiological studies  2775 surgery  2776 differential diagnosis  2772 epidemiology  2772 investigations  2772 coagulopathy  2772 endoscopy  2772 full blood count  2772 management  2772b, 2773f, 2773 monitoring  2774 resuscitation  2773b, 2773 risk assessment  2773, 2774t, 2775t prevention  2772 prognosis  2774t, 2775t, 2778 recurrence prevention  2778 acylcarnitine  1946 acyl-​coenzyme A (CoA) oxidase deficiency  2158 AD see Alzheimer’s disease (AD) ADAGIO study  5953 adalimumab  101t drug-​induced lupus  4609–​10 psoriasis management  5627 rheumatoid arthritis management  4437t rheumatoid arthritis management in pregnancy  2662 sarcoidosis management  4216t ulcerative colitis management  2945 ADAM33  4061 ADAMTS13 deficiency  5541 adapalene  5767 adaptive immunity  325, 472 antigen specificity  326 Behçet’s syndrome  4580 dendritic cells  472 diagnosis in  334f, 335 diversity generation  329 downregulation of  334 failure of  335 pathogen response  335 drug-​induced liver injury  3158, 3159f

6 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 future developments  336f, 336 gastrointestinal tract immune system  2785 innate immune system vs.  326 management in  336 memory  330 generation  333 maintenance of  333 naive state  330, 331f priming of  331 prophylaxis in  335 psoriasis  5624 rheumatoid arthritis  4424 T cells  473 transplantation see transplantation immunology Addenbrooke’s Cognitive Assessment III (ACE-​III)  6455 Addenbrooke’s Cognitive Examination (ACE-​R)  5920–​21 Addison’s disease  2347 aetiology  2347t dementia  5857 myopathies  6340 onset of  2158 pernicious anaemia see acquired pernicious anaemia pregnancy  2640 prevalence  2347 Addisonian crisis acute abdomen  2770 acute presentation  6618 secondary hypoadrenalism (ACTH deficiency)  2350 α-​adducin  3743 adefovir  3116t adenine phosphoribosyltransferase deficiency  2027 adeno-​associated viral vectors inborn errors of metabolism management  1937 lysosomal disease gene management  2138 adenocarcinoma associated disseminated intravascular coagulation  5559f, 5559 lung cancer  4340–​41 management  4352 nasal cancer  430 oesophageal neoplasms see oesophageal cancer renal cancer  439 small-​bowel imaging  2753f,
2753 stomach cancer  2984 adenosine antiarrhythmia management  3365t stress MPS  3328 tachycardia management  3364 adenosine deaminase (ADA) deficiency  2028 severe combined immunodeficiency  352 erythrocyte enzymopathies  5470 fructose phosphatase deficiency  2001 pleural effusions  4310, 4311 adenosquamous carcinoma, pancreatic tumours  3234 S-​adenosylhomocysteine hydrolase  1949t, 1983 adenovirus infection  725t, 728 aetiology  725t bronchiectasis  4145 clinical features  728 epidemiology  728 gastrointestinal system  3010t, 3011 management and prevention  729 meningitis  6083 pneumonia  4010t subacute (Quervain’s) thyroiditis  2300–​1 transmission  3014t virus-​positive myocarditis management  3464–​65 adenylate cyclase deficiency  5469 adenylosuccinase deficiency  2027 adhesins  5077–​78 adhesive capsulitis  4412t Adie’s tonic pupil  6122 adipose tissue energy transport from  1845 hormone synthesis  2245 see also obesity adjustment disorders  6506 aetiology  6506 assessment  6507 clinical features  6507 differential diagnosis  6507 low mood  6463 epidemiology  6506 outcome  6508 Adjuvant on Line  506 ADLs see activities of daily living (ADLs) adolescents cystic fibrosis  4164 growth  2419 idiopathic scoliosis  4329 self-​harm  6459 adrenal gland(s)  2246 autopsy methods  6559 corticosteroid synthesis  2332f, 2332 function monitoring, neuropsychiatric adult peroxisomal disorders  2163 adrenal gland disorders  2331 acute failure  4085, 4086 atrophy, ACTH deficiency  2272 cardiac disease  3497 congenital hyperplasia see congenital adrenal hyperplasia (CAH) cortex disorders  2331, 2333f adrenal incidentalomas see adrenal gland incidentalomas adrenocortical carcinoma  2359 Cushing’s syndrome see Cushing’s syndrome drug-​induced secretion  2550 glucocorticoid deficiency  2347 glucocorticoid excess see Cushing’s syndrome mineralocorticoid excess see mineralocorticoid excess Cushing’s syndrome see Cushing’s syndrome lesion biopsies, adrenal incidentalomas  2359 multiple endocrine neoplasia type 1  2459 necrosis, Addison’s disease  2348 neurological disorders  6370 pregnancy  2640 adrenal gland incidentalomas  2358 imaging  2358 CT  2344f, 2358 FDG-​PET/​CT  2359 MRI  2358f, 2358 investigations  2358 adrenal lesion biopsy  2359 endocrinological tests  2358 adrenal gland insufficiency acute distributive shock  3888 secondary hypoadrenalism management  2351 acute-​on-​chronic liver failure  3094 cancer  492 drug-​induced  2550 iatrogenic Cushing’s syndrome and  2334 malabsorption  2876t mineralocorticoid deficiency  2357 neurological disorders  6371 adrenal gland tumours adenomas Cushing’s syndrome  2335, 2343 management  2343 carcinomas androgen-​secreting, hirsutism in women  2385 Cushing’s syndrome  2335 pregnancy  2640 prognosis  2343 see also adrenal gland incidentalomas lung cancer metastases  4346, 4347f adrenal hormones biosynthesis pathways  2362f diseases of  2333t measurement, drug-​induced changes  2550 replacement management in chronic acute insufficiency  2352 adrenaline (epinephrine) acute upper gastrointestinal bleeding management  2775 anaphylaxis management  3855 asthma management  4086 autoinjection, anaphylaxis  3857 circulatory support  3889 gastrointestinal bleeding  2743 hypoglycaemia  2510 macronutrient metabolism  1851t normal blood values  6583t phaeochromocytomas  3792 α-​adrenergic blocking drugs falls in elderly  583t hypertension management  3768 malignant hypertension management  3806t phaeochromocytoma management  3794 renal disease, effects of  5155 urinary incontinence  594 adrenergic receptors  3889 β2-​adrenoceptor agonists  4128 adrenocortical carcinoma  2359, 2538 Cushing’s syndrome  2339 management, metyrapone  2345–​46 adrenocorticotrophic hormone (ACTH)  2271 basal pituitary function tests  2262 circadian rhythms  86 critical care response  3909, 3911 deficiency, hyperkalaemic, hyperchloraemic alkalosis  2191 excess, myopathies  6339 glucagon stimulation test  2263 membranous nephropathy management  4932 normal blood values  6583t opsoclonus–​myoclonus  6388–​89 pancreatic neuroendocrine tumours  2455 placental production  2566 secondary hypoadrenalism  2342f, 2343f, 2350 secretion disorders  2271 Cushing’s disease  2272 deficiency  2271 Nelson’s syndrome  2272 short Synacthen test  2263 structure  2271 tuberous sclerosis complex management  6204 adrenoleucodystrophy  6040, 6210 aetiology  2157–​58 diagnosis  6133 heterozygotes  2158 historical perspective  2157 adrenomyeloneuropathy (AMN)  6210, 6211 juvenile form  2158 adult basic life support algorithm  6591f adult-​onset hereditary dystonia see hereditary dystonia adult-​onset Still’s disease (AOST)  4598 diagnosis  4598, 4599f, 4599t differential diagnosis  4598 laboratory tests  4598 management  4599 prevalence  4598 Adult Psychiatric Morbidity Survey (APMS)  6487 adult T-​cell leukaemia/​lymphoma (ATL)  443, 5301 cutaneous lymphoma  5740 HTLV-​1 infection  942 advance care plans  627 advance decisions to refuse therapy (ADRT)  618 advanced glycation end products (AGE)  2514 advance directives end-​of-​life care  618 incompetent patients  23 advanced life support (ALS)  3840 algorithm  6592f cardiac arrest  3840 nonshockable rhythms  3839, 3841, 3842, 3844b

  Index 7 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 airway and ventilation  3842 percutaneous coronary intervention  3842 reversible causes  3843 shockable rhythm management  3839, 3841, 3844b defibrillation  3841, 3844b advanced sleep phase syndrome  5894 Advanced Trauma Life Support (ATLS)  543 traumatic brain injury  6044 ADVANCE study  4981 adventitia  3242, 3252, 5494 adverse drug reactions  71, 87 classification  88 delayed effects  90 dose-​related  88 long-​term effects  90 non-​dose-​related  88 detection  92 incidence  88 older patient  574, 574t, 575 pharmacodynamics  88 pharmacokinetics  88 pharmacology in older people  574t prevention  93 skin  5593 therapeutic benefits vs.  72 type A (predicted)  72 type B  72 advocacy groups  17 adynamic bone  4847 AECOPD see chronic obstructive pulmonary disorder (COPD) AEIOU TIPS  3834b Aeromonas hydrophila
infection  1040 afamelanotide  2050 afatinib  4355 AFFIRM trial  3369–​70 affluent society disease  1891, 1892t afibrinogenaemia  5542–​43 aflatoxin  423 Africa breast cancer epidemiology  435–​36 Central Africa, drug falsification  125 cervical cancer epidemiology  436 colonic diverticular disease  2960 disease incidence/​prevalence  169 drug quality  125 fibre and cancer aetiology  423 histoplasmosis  1351f, 1351 iodine deficiency disorders  1874 large bowel cancer  429 liver cancer epidemiology  429 lyssaviruses  818 oesophageal cancer  427 rhabdovirus reservoir species  808 smoking  4339–​40 stomach cancer  428 testicular cancer epidemiology  438–​39 tick bite fever  1238 see also North Africa; sub-​Saharan Africa African-​Caribbean people hypertrophic cardiomyopathy  3471 malignant hypertension  3803 African trypanosomiasis  1451 aetiology  1452 antigenic variation  1454 clinical features  1452t, 1453f, 1454f, 1454 travellers  1455f, 1455 Trypanosoma brucei gambiense  1454f, 1454 Trypanosoma brucei rhodensiae  1455 clinical investigations  1455 laboratory findings  1456 MRI  1456 control  1453b diagnosis  1455 differential diagnosis  1455 elimination efforts  1459 epidemiology  1452f eye diseases/​disorders  6433 historical perspective  1452 individual protection  1459 management  1456 new drug candidates  1459 stage I drugs  1456, 1456t, 1457t stage II drugs  1457t, 1458 prevention  1459 transmission  1453f, 1453 afterload mitral regurgitation  3443 outflow resistance, nitric oxide  3270 agalsidase alfa (Replagal)  2139, 2146 agalsidase beta (Fabrazyme)  2139, 2146 age acute lymphoblastic leukaemia prognosis  5276 cancer aetiology  415 chronic heart failure  3409 coronary heart disease adjusted risk  1894t cryptosporidiosis  1427 drug metabolism  80–​81 fascioscapulohumeral muscular dystrophy  6319 hypertension epidemiology  3738–​39 limb-​girdle muscular dystrophies  6325f, 6325 lung transplantation donors  4295 myocarditis  3459–​60 Neisseria meningitidis infection  1013 obstructive sleep apnoea  4052 pneumonia  4013 pregnancy outcome  2576 small intestine bacterial overgrowth  2881 travel and expedition medicine  719 tuberculosis  1129 venous thromboembolism in pregnancy  2612 ageing acute abdomen  2769 acute pulmonary embolism  3725 anaemia of inflammation  5407 ANCA-​associated vasculitis  4559 aortic stiffening  3746, 3749 assessment  564 cognitive impairment  564 exercise ECG testing  3313 functional status  565 geriatric syndromes  564 multimorbidities  564 bladder and bowels  589 see also urinary incontinence (UI) cancer  492 acute lymphoblastic leukaemia management  5275 acute myeloid leukaemia management  5208 Hodgkin’s lymphoma management  5286 cognitive disorder management  568 communications/​shared decision-​making  567 comorbidities  513f constipation see constipation/​ faecal incontinence deconditioning  560 delirium see delirium dementia see dementia dignity  612 acute hospital care  614b, 614 autonomy  612 doctor conduct  613b, 613f, 613 end-​of-​life care  616 see also end-​of-​life care philosophy  612b, 612 role  612 transgressions  613b views about  613b, 613 disasters  192 disease complications  549 elder abuse  614 clinical assessment  615b, 615, 616b cultural differences  615 identification of  615 outcome  616 prevalence  614–​15, 615t prevention  616 responses to  616b, 616 risk factors  615b evolutionary implications  40 faecal incontinence see constipation/​faecal incontinence fragility fractures  586 hip fractures  587 models of care  586 vitamin D  583, 587 see also falls, ageing healthcare models  552b hierarchical model  513f HIV/​AIDS and  927 hospitalization  548 acute determination  557 discrete wards  553, 554f initial assessment  550 multidisciplinary teams  554 non-​addressed needs  550 physical deconditioning  560, 561f specialist vs. generalist care  553, 554f standardized valid assessment and  553, 555f see also acute hospitals hypertension management  3776 immobility  560 impaired functional recovery  568 intercellular communication  516 circadian rhythms  518f, 518 hypothalamic–​pituitary–​adrenal axis  518 immunosenescence  516 inflammation  516, 517f microbiome  517 macromolecular changes  511 epigenetics  513 genomic instability  513 protein structure modification  514f, 514 macular degeneration  6406f, 6407, 6408t, 6412f malignant hypertension  3803 management plans  549 medical certificate of death  6543 metabolism  515 futile cycles  515 models  519 neurodegenerative disorders  601, 601f cell death  601 disease model  602f pathology  601 see also Parkinson’s disease (PD) nonpharmacological managements  575 nutrition  515, 560 caloric restriction  515f, 515, 516f well-​being optimization  534 oncology services  563, 564 optimal management  567 orthogeriatrics  568 osteoarthritis  4473, 4474f palliative care  555 Parkinson’s disease vs.  603, 610t population figures  512f protein intake importance  1900 rheumatoid arthritis  4419, 4420t, 4421f, 4427t rich country healthcare economics  161–​62 risk prediction tools  565 risk profile modification  566 cognitive function  567 functional status  567 geriatric syndrome  566 hospital-​acquired deconditioning  567 organ-​specific pathology  566 physiological reserve  566 self-​harm  6459 skin  5594 stem cell senescence  516f, 516 parabiosis  516 stress  519 surgery  563, 564 emergency surgery  568 novel approaches  569 optimal management  567 postoperative complications  563–​64, 568 timing effects  569 urgent/​critical care  539 epidemiology  539 well-​being optimization  532

8 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 chronic disease management  536 complex multicomponent interventions  535b, 535 focused interventions  535 mental health  534 nutrition  534 physical activity  533, 534b preventative care  536 primary promotion  533 secondary promotion  535 young people vs.  549, 550f AGEP see acute generalized exanthematous pustulosis (AGEP) aggrecan  4377 Aggregatibacter actinomycetemcomitans 
2801 agraphia  5826 Aicardi–​Goutières syndrome  221t, 6246–​47, 6363 AIDA trials  3659 AIDS see HIV/​AIDS AIM-​HIGH study  60, 2093–​94 AIN see acute interstitial nephritis (AIN) air embolism  4872 airflow dynamic tests  3943 limitation, asthma diagnosis  4076 limitation in chronic respiratory failure  4285, 4286f obstruction, COPD  4110, 4111f air (atmospheric) pollution  1677 air quality guidelines and standards  1684, 1685t air quality index  1686t, 1687 ambient (outdoor) air pollution  1679 carbon monoxide (CO)  1681 nitrogen oxides  1680 ozone  1681 particulate matter  1680 polycyclic aromatic hydrocarbons (PAHs)  1681 sulphur dioxide (SO2)  1680 cancer aetiology  421 coronary heart disease risk factors  3612 health effect measurement  1679 indoor air pollution  1681, 1682 biological pollutants  1683 cooking emissions  1682 low-​ and middle-​income countries  1683 radon  1683 sick building syndrome  1683 tobacco smoke  1682 lung cancer  432, 4340 sources and types  1678, 1678t air quality index  1686t, 1687 air travel see aviation medicine airways anatomy  3938f, 3938 alveoli  3937 clearance, cystic fibrosis  4159 clinical significance  3944 collapse, emphysema  4000 dead space  3941 disease, breathlessness (dyspnoea)  3281, 3283 dynamic airway compression  3942 gas transport  3944 hyperreactivity measures, asthma diagnosis  4077 hyperresponsiveness, COPD  4102 inflammation acute exacerbations of COPD  4138 asthma diagnosis  4077 malignancy, upper airway obstruction  4042 management ABCDE approach  3845 acute respiratory failure management  3871 advanced life support  3842 hepatic encephalopathy type A management  3086 practical procedures  6650 mucociliary function  3942 obstruction, lung cancer management  4356 particle deposition  3941 patency, anaphylaxis management  3856 practical procedures see practical procedures protection larynx  3935 variceal bleeding  3072 resistance lung volume vs.  3958 respiratory function  3957 responsiveness, asthma  4070–​71 smooth muscle  3943 sport and exercise medicine  6568 surface tension  3944 surfactant  3945 akathisia  6515 AKI see acute kidney injury (AKI) akinetopsia  5920 Alagille’s syndrome neonatal cholestasis  3192, 3192t Notch mutations  264 AL amyloidosis  2221, 3495, 6161 associated conditions  2221 clinical features  2221 definition  5017 diagnosis  5017, 5018f, 5018t management  2232, 5018 renal disease in  5017 clinical presentation  5017 alanine aminotransferase (ALT) acute hepatitis  3111 alcohol abuse  6526 alcoholic liver disease  3144–​45 autoimmune hepatitis  3122 drug-​induced liver disease  3155, 3161 inflammatory myopathies  4542 jaundice  3054 liver disease in pregnancy  2620 metabolism of  1850 nitrogen disposal  1848 prehepatic jaundice  3051 alanine-​glyoxylate aminotransferase (AGT) primary hyperoxaluria  2175 structure  2176–​77, 2177f alanine transaminase  2566t albendazole ascariasis management  1509 lymphatic filariasis management  1493 Strongyloides stercoralis infection management  1502 albinism  6437 Albright’s hereditary osteodystrophy  1910t G-​protein coupled receptors  258–​59 albumin adult values  6581t CSF  5783–​84 drug binding  79 drug-​induced liver disease  3155 normal blood values  6586t transfusions  5566 urinary concentration  4785 urinary/​faecal reference intervals  6587t albumin:creatinine ratio (ACR) diabetic nephropathy diagnosis  4980t, 4984 hypertension diagnosis  3760 proteinuria  4766 urine  4785 albuminuria  5034 Alcaligenes infection  4157 AL cardiac amyloidosis  3495 alcohol/​alcohol abuse  6486, 6524 abstinence chronic pancreatitis management  3223 liver disease management  3145 acute pancreatitis  3211 acute porphyrias  2039 aetiology  6486 genetic factors  6486 psychological factors  6487 social factors  6487 assessment  6487b autonomic nervous system disorders  6161 binge drinking  2195, 6525 cancer aetiology  418, 1896, 6488 hepatocellular carcinoma  3180 liver cancer  429 mortality  425t cerebellar degeneration  6374 chronic alcoholism ataxia  5981 small intestine bacterial overgrowth  2882 chronic heart failure management  3412 clinical abuse  6489 CNS developmental abnormalities  6363 coronary heart disease risk factors  3612 defective peripheral lipolysis  2077 defective red cell maturation  5455 definition  6524 dementia  6374, 6488 diabetes management  2489 differential diagnosis bipolar disorder  6499 low mood  6463 schizophrenia  6515 drowning  1692 drug-​induced Cushing’s syndrome  2550 epidemiology  6487 epilepsy  5866 erectile dysfunction  2409t essential hypertension pathogenesis  3744 falls in elderly  582 folate deficiency  5419 harmful drinking  6487, 6525 identification  6526 hazardous drinking  6525 identification  6526 hereditary haemochromatosis  2109 hypertension  1895, 3763t, 3764 hypoglycaemia  2536 diabetes mellitus  2533 hypogonadism/​infertility  2550–​51 interventions  6526 dependence  6528 extended brief interventions  6528 simple brief advice  6526 jaundice  3053 ketoacidosis  2195 laryngeal cancer epidemiology  430–​31 legal limit  6581t male reproductive disorders  2393t management  6489 critical care  3904 hospital admission  6525 opportunities for  6525f, 6525 pharmacological management  6489 psychological management  6489, 6489t medical consequences  6487 cardiovascular system  6487 endocrinology  6488 gastrointestinal system  6487 injuries  6488 musculoskeletal system  6487 neurological system  6488 see also neurological disorders pregnancy  6488 pulmonary system  6488 metabolism of  3143, 3144f myopathies  6340, 6375 neuropathy  6189 occasional heavy (binge) drinking  6525 oesophageal disease  2841t Parkinson’s disease  603 peptic ulcer disease  2851 peripheral neuropathy  6374 porphyria cutanea tarda  2047 pregnancy  2580 preventative medicine  133t pregnancy  134t prognosis  6528 pseudo-​Cushing’s syndrome  2336 public health risk  6524 saturnine gout  2021 self-​harm  6459 steatohepatitis  3043, 3044f, 3044, 3045f tobacco and  428 violent trauma assessment  6546

  Index 9 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 withdrawal  3145, 6489b, 6489, 6489t acute presentation  6637 delirium tremens  87 management  6489b, 6489, 6489t see also delirium tremens; Wernicke’s encephalopathy alcoholic liver disease (ALD)  3142, 6487 acute-​on-​chronic liver failure prognosis  3092 clinical features  3144 alcoholic hepatitis  3145 cirrhosis  3145 diagnosis  3144 differential diagnosis hepatic encephalopathy  3084 hepatitis  3112 disease recurrence post-​liver transplantation  3106, 3106t epidemiology  3142 risk factors  3143b, 3143 hepatitis  3145 investigations  3144 jaundice  3054 management  3145 abstinence  3145 acute disease  3145 cirrhosis  3146 liver transplantation  3146 nutrition  3145 steroids  3145 pathology/​pathophysiology  3143f, 3143 alcohol metabolism  3143 patient selection in liver transplantation  3102b, 3102 prognostic scores  3146t variceal upper gastrointestinal bleeding  2777 VLDL overproduction in liver  2074 Alcoholics Anonymous (AA)  6489 alcohol use disorders identification test (AUDIT)  6526, 6527f aldolase  1996, 4542 deficiency  5469 see also hereditary fructose intolerance
(fructosaemia) aldosterone actions  2332 antagonists  5154 ascites pathogenesis  3059–​60 biosynthesis defects, mineralocorticoid deficiency  2357 distal convoluted tubule  4727f, 4727 ectopic secretion  2547 hypertension  3745 normal blood values  6583t primary aldosteronism  3783 producing adenomas (APA) (Conn’s adenomas)  2353 production  2352 renin ratio  3783 aldosteronism, primary see primary aldosteronism alemtuzumab (CAMPATH-​1)  101t, 105, 297 adverse reactions  404t, 4891 multiple sclerosis management  6037 renal transplant immunosuppression  4888 transplantation  406 transplant immunosuppression  404 alert bracelets anaphylaxis prevention  3857 chronic acute insufficiency management  2352 Alexander’s disease  6214, 6215f juvenile-​onset  6214 alexia  5921 without agraphia  5826 ALFSG (US Acute Liver Failure Study Group)  3100 alglucerase (Ceredase)  2136 Gaucher’s disease type 1 management  2143 Algrove’s syndrome  2349 alkaline phosphatase (ALP) adult values  6582t autoimmune hepatitis  3122 bone mineralization  4624 drug-​induced liver disease  3155 malabsorption  2877 plasma bone turnover measure  4626 skeletal disorders  4628 prehepatic jaundice  3051 primary biliary cholangitis  3128 PSC  3138 secondary liver tumours  3190 alkaptonuria  1975, 4608, 4616, 4652f, 4652 biochemical investigations  4629t management  1936 signs and symptoms  4629t Alkhurma virus infection  844, 954 alkylating agents cancer chemotherapy  500f, 500 essential thrombocythaemia management  5245 ALL see acute lymphoblastic leukaemia (ALL) allergens avoidance allergic rhinitis management  4064 allergy management  371, 376 anaphylaxis prevention  3858 asthma management  4082 atopic dermatitis/​eczema  5635 drug allergies  377 latex allergy  376 inhalation tests in asthma  4071 severe/​difficult-​to-​treat asthma  4092 specific IgE detection  4063 allergic (IgE-​mediated) angio-​oedema  372 allergic bronchopulmonary aspergillosis (ABPA) asthma  4078 bronchiectasis  4143 cryptogenic organizing pneumonia vs.  4189 cystic fibrosis  4159 allergic bronchopulmonary mycosis  4240f, 4240 allergic contact dermatitis  5631 causality confirmation  5633 chemical sensitization power  5632 clinical features  5632f, 5632 experimental evidence  5632 individual sensitivity  5632 management  5633 prevalence  5632 scalp  5728 allergic rhinitis  4059 aetiology  4060 environmental allergies  4060 genetic influences  4060 clinical diagnosis  4062f, 4062 examination  4063 history  4062b, 4062 clinical features  371 epidemiology  4061 history  4059 investigations  4063 allergen-​specific IgE detection  4063 skin prick tests  4063, 4064b management  4064b, 4064f, 4064 allergen avoidance  4064 immunotherapy  4062f, 4065 pharmacotherapy  4065 saline irrigation  4064 surgery  4066 occupational rhinitis  4060 pathogenesis  4061 animal models  4061, 4062f perennial allergic rhinitis  4060 seasonal allergic rhinitis  4060f, 4060 Allergic Rhinitis and its Impact on Asthma (ARIA)  4059 allergies  368 aetiology  369, 370 allergic bronchopulmonary aspergillosis (ABPA) see allergic bronchopulmonary aspergillosis (ABPA) anaphylaxis  373 blood transfusion complications  5572 clinical allergy  370f, 370 clinical features  371 angio-​oedema  372 asthma  371, 4071 atopy  369 conjunctivitis  371, 6408t eczema  372 eosinophilia  5254, 5255, 5256t hypersensitivity type I  369f, 369 non-​IgE-​mediated reactions  369 oedema  4045 urticaria  372 clinical investigations  376 challenge tests  376 intradermal tests  376 serum-​specific IgE assays  376 skin-​prick tests  376 tryptase  376 contact dermatitis see allergic contact dermatitis diagnostic criteria  376 differential diagnosis  376 drug reactions  88 anaphylactoid reactions  89 insulin  2492 oral hypoglycaemic agents  2495 pseudoallergic reactions  89 type I  89 type II  89 type III  89 type IV  89 evolutionary aetiology  40–​41 future work  378 historical perspective  369 hymenoptera venom allergy  374 management  376 allergen avoidance  371, 376 anti-​IgE  377 health economics  377 immunotherapy  377 pharmacotherapy  377 nonvenomous arthropods  1579 nuts  328–​29, 374 pathogenesis  369 steps in  369f, 369 prevalence  369 prevention  371 rhinitis see allergic rhinitis sensitization as predictor  370 uncertainty areas  377 alloantibodies  5567 allogeneic haematopoietic stem cell transplantation acute lymphoblastic leukaemia management  5275 donors  5579, 5582 myelodysplastic syndromes management  5204 plasma cell myeloma management  5317 allografts acute rejection  392, 393f definition  393t rejection, C-​reactive protein  2204 alloimmune haemolytic anaemias  5484 acute haemolytic transfusion reactions  5484 delayed haemolytic transfusion reactions  5485 haemolytic disease of the newborn  5485 passenger lymphocyte haemolysis  5485 alloimmune thrombocytopenia see platelet destruction disorders allopurinol adverse reactions  2022 hypersensitivity  4610 gout management  2022, 4489 gout post-​renal transplant  4902 hereditary renal hypouricaemia and uric acid stones management  2024 hypoxanthine-​guanine transferase deficiency management  2026 uric acid urolithiasis management  2023–​24 aloe vera drug interactions  205t skin disease management  5766 alopecia areata  5729f, 5729

10 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 Alpers–​Huttenlocher syndrome  6263, 6345t, 6346 Alpers’ syndrome  6245 α1-​adrenergic blockers chronic prostatitis management  5086 CKD in pregnancy  2594t primary aldosteronism screening  2354 α-​dystrinopathies, congenital muscular dystrophies (CMDs)  6293 α-​fetoprotein (AFP) ataxia-​oculomotor apraxia type 2  6263 ataxia telangiectasia  6209 hepatocellular carcinoma  3180 hepatocellular carcinoma biopsy  3181–​82 neural tube defects prenatal diagnosis  6352, 6354 normal blood values  6585t precocious puberty  2432 screening test  140f, 140 testicular cancer assessment  5145 alphavirus infections  821, 822t arthritis  4462 arthritis-​ and rash-​associated  823 Barmah Forest virus  824 Chikungunya virus  823 Mayaro virus  824, 825f O’nyong-​nyong virus  824 Ross River virus  824 Sindbis virus  824 laboratory diagnosis  823 neuroinvasive diseases  825 Eastern equine encephalitis virus  825 Venezuelan equine encephalitis antigenic complex  825 Western equine encephalitis virus  826 Alport’s syndrome thin membrane nephropathy vs.  4919 X-​linked  5069, 5069t ALS see advanced life support (ALS) alteplase acute pulmonary embolism management  3727 STEMI management  3648 alternative complement pathway see complement Alu elements  224 aluminium associated bone disorders  4667 normal blood values  6586t phosphide poisoning  1757 pneumoconioses  4233 poisoning  1751 alveoli  3942f anatomy  3938f, 3938 blood–​gas barrier  3938 capillary leakage, drug-​induced alveolar disease  4276 drug-​induced disease see drug-​ induced alveolar disease gas exchange  3944 hyperventilation, polycythaemias  5230 hypoventilation  4287 hypercapnia  4284f, 4284 hypoxaemia  4284 interconnected structure  3944 macrophages inhaled particles clearance  4220 sarcoidosis  4210 small  3944 ventilation, chronic respiratory failure management  4289 wall inflammation in COPD  4107 Alzheimer’s disease (AD)  603, 5835, 6234, 6478 amyloid beta (Aβ)  2222, 2226, 6234–​35 apoptosis  279 APP duplication  6235 cerebral amyloid  2222 clinical features  604t, 5839, 6478 amnesia  5839 aphasia  5825 atypical disease  5841 episodic (autobiographical) memory  5827 copy number variants  226t diagnosis  6133 histology  5835–​36 epidemiology  5836 familial disease  5836 sporadic disease  5836 histopathology  6235 historical perspective  5835 investigations  5841f, 5841 imaging  5815–​16 management  5842 drug management  6480 nonpharmacological management  5842 pharmacological management  5842 medical ethics  21 pathology  5836, 5839f, 6234–​35 pathophysiology  5836, 5840f, 5841f prognosis  5842 psychoses  6482 risk factors  5836 Amanita phalloides (death cap)  5062 amatoxin poisoning  1821, 1823f amaurosis fugax  6413 amblyopia (lazy eye)  6407 ambulatory blood pressure monitoring (ABPM)  3756b, 3756 blood pressure measurement  3755 hypertension diagnosis  3740, 3741f amenorrhoea causes  2378, 2378t CKD  4839 definition  2378 gonadotrophin deficiency  2268 hypothalamic/​pituitary disorders  2380, 2381f oligomenorrhoea vs.  2378 American Academy of Allergy, Asthma and Immunology (AAAAI)  3850, 3858 American Association for the Study of Liver Diseases (AASLD)  3080, 3123 American College of Cardiology (ACC) acute coronary syndrome  3304 endocarditis prevention  3529 lipidaemia management guidelines  2085t myocardial infarction definition  3629 stroke risk assessment  3370 American College of Chest Physicians (ACCP)  3371, 4322–​23 American College of Critical Care Medicine  3904 American College of Rheumatology (ACR)  5640 acute gouty arthritis  2019–​20, 2020b ANCA-​associated vasculitis  4557, 4565 eosinophilic granulomatosis with polyangiitis  4201–​2 giant cell arteritis  4549–​50, 4549t osteoarthritis  4470–​71, 4471t rheumatoid arthritis classification criteria  4431 rheumatoid arthritis remission criteria  4433, 4433t small-​vessel vasculitis  4573–​74 systemic lupus erythematosus classification  4500, 4500t systemic sclerosis  4519 Takayasu arteritis  4552 American College of Surgeons National Surgical Quality Improvement Program  570 American Diabetes Association (ADA)  2468–​69, 2496, 4984 American-​European Consensus Conference (AECC)  3873–​74 American Geriatrics Society  570 American Heart Association (AHA) acute rheumatic fever  3514 endocarditis prophylaxis  3530–​32 lipidaemia management guidelines  2085t myocardial infarction definition  3629 stroke risk assessment  3370 sugar consumption recommendations  1995 American mucosal leishmaniasis (espundia)  1470, 1471f American Society of Anesthesiologists (ASA)  565–​66, 3862 American Thoracic Society breathlessness  3947 COPD  4099 idiopathic interstitial pneumonia  4168, 4168t idiopathic pulmonary fibrosis  4177 occupational asthma  4073 American trypanosomiasis see Chagas’ disease (American trypanosomiasis) amikacin adverse reactions, acute kidney injury  4822 normal blood values  6588t renal disease, effects of  5163t tuberculosis management  4030 amiloride adverse reactions, hypokalaemia  4751 ascites management  3063 Gitelman’s syndrome management  5117–​19 hypertension management  3767 primary aldosteronism management  2355–​56, 3785 2-​amino/​2-​oxoadipic aciduria  1949t, 1962 amino acids aminoaciduria  5112, 5120, 5120t cystinuria  5120t, 5121 definition  5120 Hartnup’s disease  5120t, 5121 lysinuric protein intolerance (LPI)  5120t, 5121 renal lead toxicity  4969 analysis  1946b, 1946 disorders amino acidaemias  6220 eye diseases/​disorders  6437 metabolism  1846, 1847f, 1853t derivation of  1847 energy production  1848f, 1848 intertissue flux  1849, 1850f liver  3040 nutritional support  1917 proximal tubule function  4792 aminoglutethimide adverse reactions  2393t, 2545–​46 Cushing’s syndrome management  2347 aminoglycosides adverse reactions  702t, 2187, 3067, 4822 management monitoring, pharmacokinetics  99 peritonitis in peritoneal dialysis  4877 aminosalicylates Crohn’s disease management  2932 drug-​induced chronic tubulointerstitial nephritis  4957t, 4958f, 4962, 4963f inflammatory bowel disease in pregnancy  2625t renal disease, effects of  5153 ulcerative colitis management  2945, 2947 amiodarone adverse reactions  90 drug-​induced hyperthyroidism  2550 eye diseases/​disorders  6439 neuropathies  6189 thyroid disease  2550 thyroid hormone  2301 thyrotoxicosis  2301 antiarrhythmia management  3365t arrhythmias in hypertrophic cardiomyopathy management  3476 arrhythmogenic right ventricular cardiomyopathy management  3487

  Index 11 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 cardiac arrest  3844 chronic heart failure management  3416 drug-​induced interstitial pneumonitis and fibrosis  4277f, 4277, 4278f renal disease, effects of  5155t sarcoidosis management  3496 ventricular tachycardia management  3382 amitriptyline diabetic neuropathy management  2522 headache prevention  6001 migraine prevention  5993t motor neuron disease management  6166–​67 normal blood values  6588t pain management  631 tension-​type headaches  5995 AML see acute myeloid leukaemia (AML) amlodipine hypertension management  3766t, 3768 pre-​eclampsia management  2587 renal disease, effects of  5156 ammonia adult values  6581t formation of  1848–​49 hepatic encephalopathy type A  3081 hepatic encephalopathy type C pathogenesis  3082 liver metabolism  3040 poisoning  1768 amnesia Alzheimer’s disease  5839 episodic (autobiographical) memory loss  5827, 5828f, 5828t traumatic brain injury  6045 amodiaquine  1410t amoebiasis  1384 African trypanosomiasis see Chagas’ disease (American trypanosomiasis) appendicitis  1387 Chagas’ disease see Chagas’ disease (American trypanosomiasis) colitis with dysentery  1386 free-​living amoebae  1392 Acanthamoeba infection see Acanthamoeba infection Balamuthia infection  1392f, 1393, 1394f Naegleria fowleri infection
see Naegleria fowleri infection Sappinia infection  1393 parasitic gut amoebae  1391 see also Entamoeba histolytica infection amoxicillin adverse drug reactions  89 HACK endocarditis management  3529 Helicobacter pylori infection management  2857, 2858 renal disease, effects of  5163t small intestine bacterial overgrowth management  2883 amphetamines adverse reactions, erectile dysfunction  2409t drug-​induced pulmonary vasculature  4279 amphibians, animal poisons  1800f, 1800 amphotericin B adverse reactions  702t Candida albicans infection management  5091–​92 coccidioidomycosis management  1364 Cryptococcus neoformans in HIV/​ AIDS  6105 haemodialysis/​peritoneal dialysis  5151 ampulla of Vater  3033f anatomy  2723f, 3196–​97 amrinone  3890 Amsler charts  6399 amyloid beta (Aβ) Alzheimer’s disease  6234–​35 amyloid fibrils  2226 amyloid fibrils  2225 proteins/​precursors  2225 amyloid A (AA)  2226 amyloid beta (Aβ)  2226 amyloid P component  2228 apolipoprotein A-​I/​A-​II  2227 β2-​microglobulin  2228 cystatin C  2227 gelosin  2227 glycosaminoglycans  2228 immunoglobulin light chain  2225 islet amyloid polypeptide (IAPP)  2228 lysozyme  2227 transthyretin  2226 amyloidosis  2218, 4600 β-​2M  4600 AA amyloidosis see AA amyloidosis acquired syndrome  2219t AL amyloidosis see AL amyloidosis amyloid light chain  4600 amyloid protein  2218 cerebral amyloid  2222b, 2222 cerebral amyloid angiopathy  2223 hereditary cerebral amyloid angiopathy  2223 hereditary cerebral haemorrhage with amyloidosis  2223 prion disease associated  2223 sporadic cerebral Aβ amyloidosis  2223 see also Alzheimer’s disease (AD) chronic heart failure  3410t clinical types  2219 clinicopathological correlation  2219, 2219t, 2220t diagnosis  2229 biochemical tests  2230 biopsies  2229 genetic tests  2230 histochemistry  2229 scintigraphy  2230 serum amyloid P  2230, 2231f structural imaging  2230 endocrine amyloid  2225 haemodialysis-​associated  2224 heart muscle disease  3494 hereditary systemic amyloidosis  2223 familial amyloid cardiomyopathy  2220t, 2224 familial amyloid polyneuropathy (hereditary transthyretin amyloidosis)  2223 familial amyloid polyneuropathy with predominant cranial neuropathy  2224 familial Mediterranean fever  2224 non-​neuropathic systemic amyloidosis  2224 immunocyte dyscrasia associated see AL amyloidosis leprosy  5057 leucocyte chemotactic factor 2 amyloidosis  2224 malabsorption  2876t management  2232 future work  2233 general measures  2233 monoclonal immunoglobulin light-​chain associated see AL amyloidosis neuropathies  6193 pulmonary see pulmonary amyloidosis rare localized amyloidosis syndromes  2225 reactive systemic see AA amyloidosis renal disease  5039 secondary  4600 renal disease and  5008 senile amyloidosis  2221 senile focal amyloidosis  2222 wild-​type transthyretin (cardiac) amyloidosis  2221 senile focal  2222 spill-​over proteinuria  4786 systemic  4777 see also amyloid fibrils amyotrophic lateral sclerosis (ALS)  6167t, 6168, 6270 clinical features  6170f, 6170 clinical variants  6171 definition  6166 diagnostic concerns  6171 differential diagnosis  6171 epidemiology  6270–​71 family history  6168–​69 genetics  6168–​69, 6168t, 6271–​72, 6271t, 6272t chromosome 9 open reading frame 72  6273 fused in sarcoma (FUS)  6274 superoxide dismutase 1  6273 transactive response DNA-​ binding protein 43  6273 management  6171 disease-​modifying management  6171 paraneoplastic neurological syndromes  6390 pathology  6169f, 6169, 6270–​71 prognosis  6171 anaemia  5359 acquired aplastic anaemia see acquired aplastic anaemia adaptations to  5359, 5360, 5360t cardiovascular changes  5361f, 5362 erythropoietin  5361 intrinsic red cell adaptation  5360, 5361b, 5361f pulmonary function  5362 tissue perfusion local changes  5361 cardiogenic anasarca  3403 causes  5359, 5362 blood loss  5363 defective red cell maturation  5363b, 5363 haemolytic anaemia  5364b, 5364 red cell precursor defective proliferation  5362, 5363b chronic heart failure and  3412t, 3419 CKD  4852 clinical significance  4853 epidemiology  4853 management, 4853, 4854t pathogenesis  4852, 4853f classification  5359, 5362b, 5362 clinical approach  5359, 5364 clinical assessment  5364 haematological investigation  5365b, 5365 clinical manifestations  5359, 5362 consequences  5370 Crohn’s disease  2928 defective red cell maturation  5450, 5451b alcohol  5455 arsenic  5455 congenital dyserythropoietic anaemias  5455 drugs  5455 lead  5455 zinc  5455 see also sideroblastic anaemias definition  5360, 5366, 5366t erythropoietic protoporphyria  2049 eye diseases/​disorders  6417 folate deficiency see folate deficiency haematological system  4430t haemolytic see haemolytic anaemia heart failure  3395 low-​ and middle-​income countries  5367f, 5367 folate deficiency  5368 infection  5368 inherited anaemias  5369, 5369t iron deficiency  5368 malabsorption  5369 vitamin B12 deficiency  5368 management  5365 niacin deficiency  5425 nicotinic acid deficiency  5425 pantothenic acid deficiency  5425

12 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 plasma cell myeloma management  5319 post-​renal transplant  4902 pregnancy  2572, 2687 folate deficiency  2688 physiology  2687 vitamin B12 deficiency  2688 prevalence  5360, 5366, 5367t prevention  5370 primary myelofibrosis  5251 protein deficiency  5425 riboflavin deficiency  5425 scleroderma renal crisis  5008 sport and exercise medicine  6571, 6571t stomach cancer  2984 thiamine deficiency  5425 ulcerative colitis  2942 vitamin B6 deficiency  5425 vitamin B12 deficiency see vitamin B12 (cobalamin) deficiency vitamin C deficiency  5424 biochemistry  5424 nutritional aspects  5424 vitamin E deficiency  5425 world health challenge  5366 anaemia of inflammation  5402 aetiology  5402b, 5402 clinical features  5404 clinical investigation  5405b, 5405 bone marrow aspiration  5406 clinical chemistry  5405 haematology  5405 laboratory investigations  5405 controversies  5407 differential diagnosis  5404b, 5404 bone marrow failure  5405 drugs  5405 iron deficiency anaemia  5404 microangiopathic anaemia  5405 renal failure  5404 elderly  5407 epidemiology  5403 future development  5407 management  5406 blood transfusion  5406 erythropoietin-​stimulating agents  5406 iron management  5406 outcome  5407 pathogenesis  5403f, 5403 pathology  5403 prognosis  5407 anaerobic bacteria  1055 anaerobic bacteraemia  1057 antibiotic prophylaxis  1060 clinical spectrum  1057 anaerobic bacteraemia  1057 bone and joint infections  1058 central nervous system infections  1057 gastrointestinal infections  1058 genitourinary infections  1058 head and neck infections  1057 intra-​abdominal infections  1058 pleuropulmonary infections  1058 skin and soft tissue infections  1058 definition  1055 diagnosis  1059 anaerobic blood culture  1059 clinical clues  1059 specimen collection  1059 epidemiology  1055 history  1055 human commensal flora  1055 gastrointestinal tract  1056 genitourinary tract  1056, 1057f oral cavity  1056 skin  1056 upper respiratory tract  1056 management  1059 antibiotic susceptibility and resistance  1059 surgery  1060 pathogenesis  1056 small intestine bacterial overgrowth  2880 taxonomy  1055, 1056t anaerobic blood culture, anaerobic bacteria diagnosis  1059 anaesthesia anaphylaxis  375 chloride channel effects  84 leprosy  1157 renal impairment  5161 risks in, Duchenne’s muscular dystrophy  6319 topical rapid (premature) ejaculation management  2410 skin disease management  5766 see also sedation/​sedatives anakinra  101t, 104 cryopyrin-​associated periodic syndromes management  2214 gout management  4489 analgesia autosomal dominant polycystic kidney disease management  5067 chronic pancreatitis management  3223 critical limb ischaemia  3683 diabetic neuropathy management  2522 Fabry’s disease management  6227 herpes simplex virus 1 infection  2807 migraine management  5992 nonopioid  631 critical care in  3901 migraine management in pregnancy  2643 Paget’s disease management  4642 renal disease, effects of  5159, 5159t sickle cell disorder management  5446 STEMI  3646 urinary stones management  5128 see also pain therapy analgesic nephropathy  4957 clinical features  4958 diagnosis  4958, 4959f differential diagnosis  4957t epidemiology  4957 management  4958 pathogenesis  4956, 4957 pathology  4957 Anapen®  3857 anaphylaxis acute presentation  6604 anaphylaxis  373, 3849 aetiology  3851 cofactor ’summation anaphylaxis’  3852, 3852t drug-​induced  3851 exercise-​induced  3852 food-​induced  3851 idiopathic  3852 insect-​sting  3851 latex-​induced  3852 perioperative  3852 radiocontrast media  3852 allergic drug reactions  89 anaesthesia  375 clinical features  373b, 3853, 3853t cardiovascular system  3852t, 3854 cutaneous reactions  3852t, 3854f gastrointestinal system  3852t, 3854 general reactions  3853, 3854f neurological system  3852t, 3854 respiratory manifestations  3850f, 3852t, 3853 clinical investigations  3854 definition  3850b, 3850 severity grading  3850, 3851t diagnosis  3837t differential diagnosis  3854 discharge checklist  3857t drug-​induced asthma  4274 drug reactions  89 epidemiology  328–​29, 329f, 3853 future development  3858 immediate management  3855b, 3855 immunology referral  3857 observation  3856 ongoing management  3857 pathophysiology  3852 inflammatory mediators  3852 prevention  3857 second-​line management  3856 systemic  1807, 1808 Anaphylaxis Campaign  3858 anaplasmosis see human ehrlichioses and anaplasmosis anaplastic astrocytoma  6051–​52, 6052f anatomic abnormalities, oesophagus see oesophageal disease ANCA see anti-​neutrophil cytoplasmic antibodies (ANCA) Ancylostoma caninum infection  1505 Ancylostoma duodenale infection gastrointestinal system  3010t transmission  3015t Anderson–​Fabry disease (angiokeratoma corporis diffusum universale), cardiac disease  3499 Anderson–​Hynes pyeloplasty  5130 Anderson’s syndrome  252 androgen insensitivity syndromes (AIS) cryptorchidism  2402 disorders of sex development  2443–​44 androgen receptors (ARs)  2381f, 2391 blockers acne management  5706 cancer chemotherapy  501 sexual differentiation  2436–​37 testosterone metabolism  2391 androgens action defects  46, 2443 adverse reactions, liver tumours  3164 biosynthesis defects  46, 2438f replacement therapy, male hypogonadism  2399 Andrographis paniculata  203 Angelman’s syndrome  227, 5685 angina chronic heart failure and  3418 diabetic complications  2525 see also stable angina; unstable angina (UA) angina pectoris  3277, 3278f angiodysplasia acute lower gastrointestinal bleeding  2778, 2779f CT  2754 gastrointestinal vascular disorders  3004, 3005f imaging, capsule endoscopy  2754 management colonoscopy  2735, 2737f endoscopy  2743 angio-​oedema anaphylaxis  3854 skin drug reactions  5754t, 5756b, 5756 angiofollicular lymph node hyperplasia see Castleman’s disease (angiofollicular lymph node hyperplasia) angiogenesis  5709 blood vessels  3251 cancer  447 endothelium  3251f, 3251–​52 inhibitors, cancer chemotherapy  502, 503t psoriasis  5625 angiography brainstem death diagnosis  5909 cardiac surgery assessment  3667 colonic diverticular disease haemorrhage  2965 coronary artery disease in HIV/​ AIDS  3537 hepatocellular carcinoma  3181 Kawasaki’s disease  4593 myocarditis  3462–​63 quantitative  3343 renal imaging  4801f, 4801 angioimmunoblastic T-​cell lymphoma  5300 angiokeratoma  1616f, 1616 angiokeratoma corporis diffusum see Fabry’s disease (angiokeratoma corporis diffusum) angioma  1616 angiomyolipoma benign liver tumours  3189 renal tumours  5071–​72, 5072f

  Index 13 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 angio-​oedema allergy  372 upper airway obstruction  4045 angioplasty Budd–​Chiari syndrome management  3167 leg ischaemia management  3684–​85 Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study  5047 disease outcomes  5047–​48 angiosarcoma (lymphangiosarcoma)  3186, 5719 angiostrongyliasis  1516 Angiostrongylus cantonensis infection  1517 aetiology  1517 clinical features  1517, 1518f diagnosis  1518 epidemiology  1517 management, prognosis, and control  1518 pathology  1517 Angiostrongylus costaricensis infection  1518 aetiology  1518 diagnosis and management  1519 epidemiology  1518 pathology and clinical features  1518 angiotensin-​converting enzyme see ACE (angiotensin-​ converting enzyme) angiotensin-​converting enzyme inhibitors see ACE inhibitors angiotensin II circulatory support  3890 hypertension  3744–​45, 3747f, 3747 pre-​eclampsia  2584–​85 angiotensinogen  2352, 3743 angiotensin receptor blockers (ARBs) acute kidney injury prevention  4811 adverse reactions atherosclerotic renovascular disease  5045 distal renal tubular acidosis with hyperkalaemia (previous type IV)  5109 hyperkalaemia  4760 renal disease  4778 chronic heart failure management  3414f, 3415 CKD in pregnancy  2594t dilated cardiomyopathy management  3481 drug interactions, lithium  6468 focal segmental glomerulosclerosis management  4926, 4927 hypertension management  3766t, 3768 acute stroke  3809 CKD  4842 contraindications  3767t diabetes  2525 left ventricular dysfunction management  3649 membranoproliferative glomerulonephritis  4941 minimal-​change nephrotic syndrome management  4921 nonalcoholic fatty liver disease  3152 post-​renal transplant hypertension  4899–​900 primary aldosteronism screening  2354 renal disease, effects of  5155–​56 STEMI management  3651 systemic sclerosis management  4524t angiotensin receptor–​neprilysin inhibitor (ARNI)  3414f, 3415 animal poisons/​toxins  1778, 1781 amphibians  1800f, 1800 aquatic animal ingestion  1802 carp gallbladder ingestion  1803 Ciguatera fish poisoning  1803 diagnosis  1804 histamine-​like syndrome (scombrotoxic poisoning)  1803 management  1804 paralytic shellfish poisoning  1803 prevention  1804 tetrodotoxin poisoning  1803 arthropods see venomous arthropods birds  1801f, 1801 fish  1801f, 1801, 1802f clinical features  1802 epidemiology  1801f, 1801, 1802f incidence  1801 management  1802 prevention  1802 venom composition  1802 leeches (Hirudinea)  1814 aquatic leeches  1814 land leeches  1814 lizards  1800f, 1800 mammals  1781 snakes see snake bites tropical renal disease  5060, 5061 venomous marine invertebrates see venomous marine invertebrates animals bites, acute presentation  6634 disease models allergic rhinitis  4061, 4062f antiglomerular basement membrane disease  4944 antiglomerular basement membrane disease pathogenesis  4943 cystic fibrosis  4164 gene editing  288 hypersensitivity pneumonitis  4250 inborn errors of metabolism  1939 myocarditis  3461 osteoarthritis pathology  4377 prerenal failure/​acute tubular necrosis  4820 leptospirosis  1199 mechanical injuries  1779 clinical features  1780 epidemiology  1779 management  1780 prevention  1780 rabies see rabies stings, acute presentation  6634 anion gap acidosis  2183b, 2194, 2195f acid–​base disorders diagnosis  2184 ethylene glycol  2196, 2196t metabolic acidosis  2184b, 2184 methanol  2197 5-​oxoprolinuria  2189f, 2197 salicylate intoxication  2197 see also diabetic ketoacidosis; lactic acidosis aniridia  6401t, 6437 anisakidosis  1509f, 1509 gastrointestinal system  3010t transmission  3015t ankylosing spondylitis  4446 clinical features  4446f, 4446 diagnosis  4447, 4447t epidemiology  4446 heart muscle disease  3493 immunopathology  4446 interstitial lung disease  4197 laboratory tests  4447 management  4448 medication in pregnancy  2709 neurological disorders  6378 pathogenesis  4446 physical examination extra-​articular organs  4447 spine/​thoracic cage  4447 prognosis  4449 pulmonary disease  4197 radiology  4447 sacroiliac CT  4448 sacroiliac MRI  4448 sacroiliac radiology  4447, 4448f spinal MRI  4448 spinal radiology  4448f, 4448, 4449f spinal disorders  4332 ulcerative colitis  2944 Ann Arbor staging Hodgkin’s lymphoma  5282, 5283t non-​Hodgkin’s lymphoma  5291, 5292t annular erythemas  5671 erythema annulare centrifugum  5671, 5672f erythema gyratum repens  5672 erythema migrans  5672f, 5672 lesion shape/​grouping  5598 anogenital lumps/​bumps  1613 clinical approach  1613, 1614f deep palpable lesions  1619 cystic/​nodular lesions  1619 oedema/​swellings  1620 superficial lesions  1613 crusty lesions  1618 flesh-​coloured lesions  1613 pigmented lesions  1617 plaque/​flat lesions  1618 pustular lesions  1618 red lesions  1616 anogenital warts  878, 1615f, 1615 clinical features  879, 880f, 881f diagnosis  879 epidemiology  879 management  879 anorexia nervosa acute abdomen  2766 aetiology  6510b cancer  488 classification/​diagnosis  6509b clinical features  6510 detection and diagnosis  6511 dyslipidaemia  2084 epidemiology  6510f, 6510 hypothalamopituitary function  2548 management, medical complication management  6511, 6512b outcome  6513 secondary hypoadrenalism (ACTH deficiency)  2350 ulcerative colitis  2940 anovulation  2378 bone health in athletes  6567 polycystic ovary syndrome  2382–​83 ANS see autonomic nervous system (ANS) Antabuse (disulfiram) see disulfiram (Antabuse) antenatal screening  141t, 143 anterior ischaemic optic neuropathy (AION)  5916, 6414–​16 anterior lobe (adenohypophysis), pituitary gland see pituitary gland anterior pituitary gland assessment  2262 function testing  2262 imaging  2263 neuro-​ophthalmological evaluation  2264 craniopharyngiomas see craniopharyngiomas disorders  2258 hormones  2264 adrenocorticotrophic hormone (ACTH) see adrenocorticotrophic hormone (ACTH) follicle-​stimulating hormone (FSH) see follicle-​ stimulating hormone (FSH) growth hormone (GH) see growth hormone (GH) luteinizing hormone (LH) see luteinizing hormone (LH) prolactin (PRL) see prolactin (PRL) thyroid-​stimulating hormone (TSH) see thyroid-​ stimulating hormone (TSH) hypophysitis  2276 hypopituitarism  2273b, 2273 pituitary adenomas  2273 pituitary apoplexy  2274 pituitary carcinomas  2274 radiotherapy  2264 Rathke’s cleft cysts  2276 surgery  2264

14 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 tumours, multiple endocrine neoplasia type 1 (MEN1)  2323 anterior uveitis  6420, 6421f, 6422f anthracyclines  500 anthrax  1094 aetiology  1095, 1096f clinical features  1098 cutaneous anthrax  1098, 1099f gastrointestinal anthrax  1099f, 1099 inhalational anthrax  1099, 1100f injection anthrax  1100 meningeal anthrax  1100 clinical investigations  1100 diagnosis  1098 differential diagnosis  1100 ecology  1096 epidemiology  1096 burden of disease  1097 deliberate release  1097 distribution of disease  1097f, 1097 forms of disease  1096, 1096t outbreak examples  1097 future developments  1102 historical importance  1095 management  1100 pathogenesis  1098 organ-​specific  1098 prevention  1101 prognosis  1101 special circumstances  1101 anti-​androgens adverse reactions, erectile dysfunction  2409t hidradenitis suppurativa management  5700 metastatic prostate cancer management  5145 skin disease management  5770 anti-​anxiety drugs  6465t, 6470 withdrawal of  6466 see also benzodiazepines anti-​arrhythmic drugs cardiorenal syndrome  3426 chronic heart failure management  3416 falls in elderly  583t pain management  632t pulmonary arterial hypertension  3704 renal disease, effects of  5155, 5155t STEMI/​non-​STEMI ACS  3652 tachycardia management  3364, 3364t, 3365t antibacterial agents  686t adverse reactions  702t mode of action  687, 687t nucleic acid inhibitors  687 protein synthesis inhibitors  687 poisoning by  1734 antibiotics acne management  5705, 5705t acute diverticulitis management  2963 acute pancreatitis management  3214 acute rhinitis management  4007 acute sinusitis management  4007 adverse reactions allergies  375 diarrhoea  672 induced-​anaphylaxis  4274 anaerobic bacteria management  1059 atopic dermatitis/​eczema management  5635 Bartonella infection  1270 broad-​spectrum  690, 2883 chronic osteomyelitis management  4694 colonoscopy  2736 Crohn’s disease management  2932 cystic fibrosis management  4158 endocarditis management  3529 enteric fever management  1048, 1048t gastrointestinal immune system  2783–​85 gastrointestinal infections  3023 gastrointestinal system immunology  2725–​26 Haemophilus influenzae type b management  1070 leg ulcers  5715 leptospirosis prevention  1204 liver failure management  3098 Neisseria meningitidis infection management  1021, 1022, 1022t Neisseria meningitidis infection prevention  1025 nosocomial infections  670 over-​prescription of  15 pelvic inflammatory disease management  1624, 1624t pharyngitis/​tonsillitis  4005 pharyngitis/​tonsillitis management  4005f, 4005 PSC management  3139, 3140 reactive arthritis management  4468 relapsing fever management  1196 renal disease, effects of  5162, 5163t resistance  692 Chlamydia trachomatis infection  1287 enzymatic inactivation  693 Haemophilus influenzae infection  1069 impermeability resistance  693 metabolic bypass resistance  694 Neisseria gonorrhoeae infection see Neisseria gonorrhoeae infection pneumococcal infections see pneumococcal infections prevalence  698t staphylococci infections  992 surveillance of  694 target site alterations  693 testing, Helicobacter pylori infection  2857, 2858 sepsis management  659 septic arthritis management  4460, 4461t small intestine bacterial overgrowth management  2883b, 2883 syphilis management  1220, 1220t systemic sclerosis management  4524t topical, acne management  5705 uncomplicated acute pyelonephritis management  5083 uncomplicated cystitis management  5079t, 5083f, 5083, 5084t variceal bleeding  3072 see also antimicrobial therapy antibody deficiency  357 associated with thymoma  359 autosomal recessive antibody deficiencies with B lymphopenia  358 common variable immunodeficiency see common variable immunodeficiency (CVID) IgA deficiency  359 IgG subclass deficiency  360 immunoglobulin replacement management  360 adverse reactions  360 dosages  358b, 360 physiological antibody deficiencies  359 prognosis  361 selective antibody deficiency with normal immunoglobulins  359 supplementary management  361 transient hypogammaglobulinaemia of infancy  359 X-​linked agammaglobulinaemia 
358 antibody fragments  107 antibody-​mediated rejection (ABMR) late (chronic) renal transplant rejection  4888 transplantation  400 transplant rejection  400 anti-​C1q antibodies assays of  323, 323t lupus nephritis  5002 anti-​CD20 antibody see rituximab anticholinergic drugs contraindications, Parkinson’s disease  5953 COPD management  4126, 4128f, 4128, 4128t death rattle  637 detrusor sphincter dyssynergia  6143 falls in elderly  583t Parkinson’s disease management  604 urinary incontinence  594 anticoagulants  3729 ACS management  3636, 3638 acute cerebral infarction management  6018 acute pulmonary embolism management  3726f, 3726 acute upper gastrointestinal bleeding management  2777 arrhythmias in hypertrophic cardiomyopathy management  3476 arterial occlusion in acute kidney disease  4825 atrial fibrillation  3733 cerebral infarction management  6018 cholesterol embolism  3688 chronic heart failure management  3416 CKD in pregnancy  2594t dilated cardiomyopathy management  3482 Ebstein anomaly management  3569 endothelial cells  5492, 5492t falls in elderly  587 fibrinolysis  3733 haemodialysis  4869b, 4869 heart valve surgery see heart valve surgery hypertension with myocardial infarction/​unstable angina  3808 INR control  3372, 3372t, 3373f ischaemic stroke prevention  6019 lumbar puncture contraindications  5782 mechanical heart valves  3733 oral fragility fractures  587 renal disease, effects of  5157 stroke prevention  3370, 3372t thromboembolism prevention  3370 use of  3372 oral direct inhibitors  3731, 3732f factor Xa inhibitors  3732 thrombin (IIa) inhibitors  3732 perioperative management  3734, 3734t poisoning by  1734 pregnancy in  3733 primary intracerebral haemorrhage management  6023 pulmonary arterial hypertension management  3704 renal disease, effects of  5157 restrictive cardiomyopathy management  3484 schedules  6603t STEMI/​non-​STEMI ACS  3651 vascular dementia management  5854 venous thromboembolism  3729 anticonvulsant drugs adverse reactions hypogonadism/​ infertility  2550–​51 liver enzyme induction  5876 male reproductive disorders  2393t osteomalacia/​rickets  4638 vitamin D metabolism  5876–​77 diabetic neuropathy management  2522 drug interactions, sodium valproate  6468 epilepsy management  5870f, 5870, 5873t adherence problems  5871 breastfeeding  5877 combinations  5871

  Index 15 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 dosage  5871 driving  5878 drug monitoring  5877 drug withdrawal  5877 enzyme induction  5876 first drug failure  5871 generic prescribing  5871 pregnancy  5877 rarely used medications  5876 second-​line agents  5875 third-​line agents  5875 focal epilepsy  5870–​71 folate deficiency  5419 HIV-​associated neuropathy  6108 mechanism of action  5871, 5872f migraine prevention  5993t pain management  631, 632t poisoning by  1735 antidepressant drugs  6465t, 6466, 6497t adverse reactions  6466, 6466t bulimia nervosa management  6512 depressive disorder management  6496, 6497t haemodialysis/​peritoneal dialysis  5151 low mood management  6464 mechanism of action  6466 newer types  6467 pain management  632t poisoning by  1735 somatic symptom disorder management  6462, 6519 withdrawal of  6466 see also selective serotonin reuptake inhibitors (SSRIs); tricyclic antidepressants (TCAs) antidiabetic agents, poisoning by  1736 antidiarrhoeal drugs  3020 antidiuretic hormone (ADH) ascites pathogenesis  3059 hyponatraemia  4732, 4733f pregnancy in  2564–​65 prerenal failure/​acute tubular necrosis diagnosis  4821 water excretion  4730–​31 water metabolism disorders  4730 see also vasopressin antidromic tachycardia  3378f, 3379f, 3380 antidrug antibodies (ADAs)  106 anti-​epileptic drugs N-​acetylaspartic aciduria (Canavan’s disease) management  1969 adverse reactions, eye diseases/​ disorders  6437 autoimmune encephalopathy with NMDAR antibodies  6395 autoimmune limbic encephalitis with VGKC-​ complex antibodies management  6394 drug interactions, antipsychotic drugs  6469–​70 pregnancy  2643 renal disease, effects of  5159 vertigo management  5927t antifibrotic drugs  3048, 3048t idiopathic pulmonary fibrosis management  4183 renal disease, effects of  5157 antifungal agents  686t adverse reactions  702t allergic bronchopulmonary mycosis  4240 mode of action  689 postoperative renal transplantation management  5162t skin disease management  5765, 5769 antigen-​presenting cells (APCs) B cells as  333 rheumatoid arthritis aetiology  4416 transplant rejection  399 antigens avoidance, hypersensitivity pneumonitis management  4253 hypersensitivity pneumonitis  4248 presentation B cells/​T cells  327f lysosomes  2124 receptors, lymphocytes  5264, 5265f recognition B cells  328f, 328 CD4+ T cells  328f T-​cell receptor  327 T cells, T cell subset bridging  328 specificity  326 tests bacterial meningitis  5785 pneumococcal infection  983 tuberculosis diagnosis  1141 variation in African trypanosomiasis  1454 biology of pathogenic organisms  654 antiglomerular basement membrane antibodies, ANCA-​ associated vasculitis (AAV) and  4992 antiglomerular basement membrane disease  4577, 4943 acute kidney injury causes  4826 ANCA-​associated vasculitis  4559–​60 clinical investigations  4947 diagnosis  4947, 4947t differential diagnosis  4947, 4947t epidemiology  4945 historical aspects  4943 management  4947 pathogenesis  4943 animal models  4944 autoantibody specificity  4943, 4944f disease mediators  4943 genetic susceptibility  4944 pathological findings  4945 prognosis  4948t, 4949 serological findings  4944 symptoms and signs  4945 pulmonary system  4946f, 4946 renal system  4946 variants and overlap syndromes  4946 ANCA positivity and vasculitis overlap  4946 isolated lung haemorrhage  4946 membranous nephropathy  4946 post-​transplant disease in Alport’s syndrome  4947 see also Goodpasture’s syndrome antihistamines allergic rhinitis management  4064, 4065 allergy management  371, 377 anaphylaxis management  3856 poisoning by  1737 renal disease, effects of  5158 skin disease management  5766 tongue swelling management  377 antihypertensive drugs acute kidney injury prevention  4811 advanced renal impairment management  5161t adverse reactions, erectile dysfunction  2409t blood pressure control in CKD  4842 blood pressure control in diabetic nephropathy  4981 CKD in pregnancy  2594t CKD management  4842, 4843f falls in elderly  583t ischaemic stroke prevention  6019 pharmacodynamics in older people  573 postoperative renal transplantation management  5162t pre-​eclampsia management  2587 rebound phenomena  90 renal disease, effects of  5155 anti-​inflammatory agents AA amyloidosis management  2232 acute pancreatitis management  3214 acute respiratory distress syndrome management  3879 ankylosing spondylitis management  4448 autoimmune disease management  391 bronchiectasis management  4148 bullous pemphigoid management  5614 cystic fibrosis  4160 delirium management  6477 linear IgA disease management  5616 monogenic inflammatory bowel disease  2975–​76 mucous membrane pemphigoid  5615–​16 septic shock without meningitis  1020 anti-​integrin therapy Crohn’s disease management  2933 ulcerative colitis management  2946 antimalarial drugs poisoning by  1737 rheumatoid arthritis management  4435 skin disease management  5769 antimicrobial therapy  684, 686t adverse reactions  701f, 701, 702f, 702t eye diseases/​disorders  6439 asthma management  4089 autosomal dominant polycystic kidney disease management  5067 bronchiectasis management  4148, 4149f bronchiolitis obliterans  4187 Chlamydia trachomatis infection management  1288, 1288t cystic fibrosis  4158 formularies  703, 704t future of  703 gastrointestinal infection management  3020 leptospirosis management  1202, 1203b Lyme borreliosis management  1185t pharmacokinetics  694 bioavailability  694, 696f distribution  694 excretion  696 metabolism  695 pharmacodynamics  696, 696t, 697f, 697t, 698t pharmacology  687 mode of action  687 pneumonia management  4018, 4018t, 4019t practice guidelines  703 principles of use  697, 698t, 699t bactericidal vs. bacteriostatic agents  700 dose selection  700 management duration  700 prophylactic use  698 prophylactic  698 HIV/​AIDS, pulmonary complications  4032 traumatic haemothorax  4319 Pseudomonas aeruginosa infection  1043 raised intracranial pressure  3896 skin disease management  5769 spectrum of activity  690 broad spectrum  690 combined drug management  690, 692b, 692f narrow-​spectrum  690 susceptibility testing  690, 691f urinary incontinence  594 see also antibiotics anti-​mitochondrial antibody (AMA) jaundice  3055 primary biliary cholangitis  3128 antimotility agents gastrointestinal infections management  3020 renal disease, effects of  5153 antiMüllerian hormone (AMH)  2379 sexual differentiation  2436 antimuscarinic bronchodilators acute asthma management  4095 renal disease, effects of  5158 anti-​muscle-​specific tyrosine kinase (MUSK) antibodies, myasthenia gravis  6296f, 6296–​97, 6299

16 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 anti-​neutrophil cytoplasmic antibodies (ANCA)  5640 antiglomerular basement membrane disease pathogenesis  4944–​45 cerebral vasculitis  6379 immune-​mediated alveolar haemorrhage  4236 pulmonary arterial hypertension  3700 rheumatological diseases  4403 systemic vasculitis pathogenesis  4989 vasculitis see anti-​neutrophil cytoplasmic antibodies (ANCA)-​associated vasculitis (AAV) anti-​neutrophil cytoplasmic antibodies (ANCA)-​associated vasculitis (AAV)  4405, 4496, 4556, 4557f, 5644b, 5644 aetiology  4559 secondary causes  4559, 4559t anti-​glomerular basement membrane antibodies and  4992 cholesterol embolism vs.  3689 clinical features  4561, 4561t, 4991b, 4992 cardiac system  4564 eye  4564 gastrointestinal system  4564 nervous system  4564 prodromal phase  4561 renal system  4562, 4563f respiratory system  4562f, 4562 skin  4564 systemic features  4562 diagnosis  4565 epidemiology  4496t, 4558 age  4559 ethnicity  4558 gender  4559 geography  4558 incidence  4558, 4558t prevalence  4558, 4558t eye diseases/​disorders  6424 future directions  4568 heart muscle disease  3494 history  4557, 4558t imaging  4564 infective endocarditis  5036f, 5036 laboratory features  4564 management  4565, 4565t, 4566t induction management  4565, 4567 refractory disease  4567 relapses  4567 remission maintenance management  4567, 4567t outcomes  4567, 4568f pathology  4560f, 4560 polymyalgia rheumatica vs.  4586 vasculitis overlap  4946 see also eosinophilic granulomatosis with polyangiitis (EGPA/​ Churg–​Strauss syndrome); granulomatosis with polyangiitis (GPA/​ Wegener’s granulomatosis); microscopic polyangiitis (MPA) anti-​NMDA-​receptor antibodies  5959 autoimmune encephalitis  6483 anti-​nuclear antibodies (ANA)  4497, 4497t acquired aplastic anaemia  5341 idiopathic photodermatoses  5689 pulmonary arterial hypertension  3700 rheumatological disease tests  4403, 4404b scleroderma renal crisis  5008 systemic lupus erythematosus  4508 anti-​onconeural antibodies  6385, 6385t, 6386f anti-​oxidants acute respiratory distress syndrome management  3878 cancer aetiology  1896–​97 chronic pancreatitis management  3224 dermatological vehicles  5762 drug-​induced liver injury  3158 malnutrition  1886 neuropsychiatric adult peroxisomal disorders  2163 selenium  1877 vitamin E  1861 anti-​phospholipid antibodies  4502, 5006, 5559 antiphospholipid syndrome (APL)  4502 classification criteria  2658t heart muscle disease  3492 immunological tests  4404 liver disease and  3177 pregnancy  2655, 2658 avoidance of  2667 indications  2659 management  2659, 2661t post-​partum issues  2660, 2661t pre-​eclampsia development  2659 systemic lupus erythematosus development  2659 antiplatelet drugs ACS management  3634, 3638, 3642f, 3642 acute upper gastrointestinal bleeding management  2777 bleeding tendencies  5518 cardiac surgery assessment  3667b, 3667 cerebral infarction management  6018 chronic heart failure management  3416 CKD in pregnancy  2594t clinical trials  59t, 60 ischaemic stroke prevention  6019 peptic ulcer disease  2851 peptic ulcer disease recurrence prevention  2858t, 2859 renal disease, effects of  5157 vascular dementia management  5854 antiproliferative agents immunosuppression in transplantation  402 postoperative renal transplantation management  5162t transplant immunosuppression  402 antiprotozoal agents  686t adverse reactions  702t antipsychotic drugs  6465t, 6468 adverse reactions  6469, 6515 dementia  5835 eye diseases/​disorders  6437 male reproductive disorders  2393t bipolar disorder management  6500 delirium management  558, 6477 drug interactions  6469 falls in elderly  583t indications  6469 main types  6469 poisoning by  1738 renal disease, effects of  5158 schizophrenia management  6515, 6515t, 6516 see also clozapine; olanzapine; quetiapine; risperidone antiretroviral therapy drug-​induced alveolar disease  4278 HIV/​AIDS see HIV/​AIDS antirheumatic drugs adverse reactions, renal disease  5001, 5010 pregnancy  2664t, 2666 anti-​RNA polymerase III antibodies scleroderma management in pregnancy  2666 systemic sclerosis  4522 anti-​Ro antibodies neonatal lupus syndrome  2658 systemic lupus erythematosus  4508–​9 systemic lupus erythematosus in pregnancy  4511 antisense oligonucleotides (ASOs)  232 Becker’s muscular dystrophy management  6281 Duchenne’s muscular dystrophy management  6281 familial hypercholesterolaemia management  2079 spinal muscular atrophy  6269 antispasmodic drugs colonoscopy  2736 irritable bowel syndrome management  2957, 2957t renal disease, effects of  5152 uncomplicated diverticular disease  2962–​63 antithrombin coagulation inhibitors  5505 deficiency  2240–​41 antithrombotic therapy acute pulmonary embolism management  3723t, 3726 bleeding risk  3371, 3371t, 3372t, 3373f postoperative renal transplantation management  5162t antithymocyte/​antilymphocyte globulin (ATG/​ALG) acute cellular renal transplant rejection  4886–​87 adverse reactions  404t post-​lung transplantation  4299 transplant immunosuppression  404 anti-​thyroglobulin antibodies primary thyroid epithelial tumours investigations and diagnosis  2305 thyroid status determination  2289 antithyroid drugs adverse reactions  2298b, 2298 Graves’ disease management  2298 induced hypothyroidism  2298 α1-​antitrypsin bronchiectasis  4147t COPD investigations  4118 COPD management  4132 cystic fibrosis management  4160–​61 normal blood values  6586t α1-​antitrypsin deficiency  2235, 5670, 5671f bronchiectasis  4144 clinical features  2239 emphysema  2239 liver disease  2239 clinical investigation  2240 COPD  4110 epidemiology  2239 genetic basis  221t genetics  2235, 2236t lung and liver disease  3171 management  2240 future work  2241 molecular basis  2238 liver disease  2236t, 2238f, 2238 lung disease  2239 neonatal cholestasis  3191 prognosis  2240 structure  2235 antituberculous drugs  1142, 1142t, 1143t anti-​tumour necrosis-​α (TNFα) drugs Crohn’s disease management  2933, 2934 inflammatory bowel disease in pregnancy  2625t psoriatic arthritis management  4452 rheumatoid arthritis management in pregnancy  2662, 2663t ulcerative colitis management  2945, 2946 antivenom therapy see snake bites antiviral agents  686t acute hepatitis B  3112 adverse reactions  702t Bell’s (idiopathic facial) palsy management  6124 chronic hepatitis B management  3116, 3116t human cytomegalovirus infection  749 immune complex-​mediated membranoproliferative glomerulonephritis management  4942 influenza virus infection management  732

  Index 17 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 liver failure management  3099 mode of action  688, 688t pregnancy  2617 skin disease management  5770 Antley–​Bixler syndrome  2371 anuria  4770 anxiety/​anxiety disorders  6501 aetiology  6502 constipation/​faecal incontinence  595 medical conditions  6503t assessment  6448, 6449b, 6503 detection  6502t, 6503 diagnosis  6504 clinical features  6502, 6502t differential diagnosis  6503, 6503t, 6504t epidemiology  6502 management  6504 pharmacotherapy  6504, 6505t psychological managements  6505 selective serotonin-​ noradrenaline reuptake inhibitors  6470 specialized management referral  6505, 6505t medically unexplained symptoms vs.  6461 Parkinson’s disease  610 self-​harm  6457 signs  6449 specific disorders  6502 see also generalized anxiety disorder (GAD); obsessive–​ compulsive disorder (OCD); panic disorder; phobia; social anxiety disorder (social phobia) symptoms  6448 urinary incontinence  593t aortic aneurysms cardiovascular syphilis  3540 diagnosis  4407 preventative medicine  133t aortic dissection acute  3675f, 3675 blood pressure management  3809 chest pain  3279b, 3279 diagnosis  3837t differential diagnosis, STEMI  3646 aortic regurgitation  3451 acute aortic syndrome  3677 aortic sclerosis vs.  3450 cardiovascular syphilis  3539, 3540f, 3540 causes  3451, 3451t clinical presentation  3452 physical examination  3452 symptoms  3452 differential diagnosis  3454 investigations  3452 cardiac catheterization  3454 chest radiography  3452, 3453f ECG  3452 echocardiography  3453f, 3453 management  3454 medical management  3454 surgery  3454 pathophysiology and complications  3451 pregnancy  2603 transthoracic echocardiography  3316f, 3317 aortic stenosis  3447 acute rheumatic fever  3512 causes  3447 chronic heart failure risk factor  3412t clinical presentation  3448 physical examination  3448 symptoms  3448 differential diagnosis  3450 investigations  3448 cardiac catheterization  3450 chest radiography  3448 ECG  3448 echocardiography  3448, 3449f management  3450 medical management  3450 PCI  3663 surgery  3450 pathophysiology and complications  3447 coronary circulation  3448 left ventricular response  3447 PCI  3664f pregnancy  2602 transthoracic echocardiography  3316, 3317f aortic valve disease  3447 aortic regurgitation see aortic regurgitation aortic stenosis see aortic stenosis endocarditis  3520–​21 investigations of valve stenosis  3455 mitral regurgitation vs.  3445 mixed aortic disease  3455 pathophysiology and complications  3455 right ventricular response  3455 repair/​replacement  3451 acute aortic syndrome  3675f aortic stenosis  3451 medication in pregnancy  2710 right heart valve disease  3455 AOST see adult-​onset Still’s disease (AOST) APCs see antigen-​presenting cells (APCs) aphasia  5824 anomia (naming)  5824 comprehension  5824 fluency  5824 frontotemporal dementia  5845 paraphasic errors  5824 repetition  5824 semantic  5825 syndromes  5824 Broca’s aphasia  5824 conduction aphasia  5825 degenerative dementias  5825 global aphasia  5825 Wernicke’s aphasia  5824, 5825 apixaban  3732 ACS management  3638 acute pulmonary embolism management  3727 peptic ulcer disease recurrence problem  2859 aplastic anaemia  5336, 5337 acquired see acquired aplastic anaemia definition  5337, 5338t, 5339t hereditary spherocytosis  5459 inherited  5346 pregnancy  2691 apocrine gland disorders see sweat gland disorders apolipoprotein(s)  2063, 2063t apolipoprotein A-​I/​A-​II, amyloid fibrils  2227 apolipoprotein B (apoB)  2064, 3597 apomorphine, Parkinson’s disease management  5953 apoptosis  266, 267f activation of  270 death-​signalling receptors  270, 271b, 271f mitochondrial signals  271, 272f, 273f autoimmunity  381 cell recognition  276f, 276 cell stress  273 DNA damage response  273b, 274 heat-​shock response  274 metabolic response  274 stress-​activated kinase receptor  274 unfolded protein response  274 definition  266 disease and  277 cardiovascular disease  278 CNS degeneration  279 immune disorders  277 infections  278 tumour biology  279 inflammation inhibition  267 radiotherapy  499 structural changes  266, 268f systemic lupus erythematosus pathology  4502 see also caspases apparent mineralocorticoid excess (AME)  3797f, 3798 hypokalaemia causes  4754 appendicitis  1898 acute  2769t acute ileitis vs.  2928 pregnancy  2625 APP gene Alzheimer’s disease  5836–​38, 6235 Dutch mutation  6235 familial Alzheimer’s
disease  5836 apraxia  5827 buccofacial apraxia  5829 conceptual  5828 conceptual apraxia  5829 ideomotor (conceptual) apraxia  5828 ideomotor (production) apraxia  5828 limb–​kinetic apraxia  5828 production  5828 screening for  5828–​29 apremilast  4452, 4583 APS see acute promyelocytic leukaemia (APS) aquatic animal ingestion, animal poisons see animal poisons/​ toxins aquatic leeches, animal poisons  1814 Araneae see venomous arthropods Archaebacteria  209 ARC syndrome  3192t, 5122t ARDS see acute respiratory distress syndrome (ARDS) arenaviruses  862 aetiology  863 Argentine haemorrhagic fever see South American haemorrhagic fevers clinical features  865 diagnosis  868 laboratory diagnosis  868, 869t differential diagnosis  868 epidemiology  863 future developments  870 genetics  863 management  864, 865b, 869 pathogenesis  863 pathology  863 prevention  864 ribavirin postexposure prophylaxis  864 rodent control  864 vaccines  865 Whitewater Arroyo-​like virus  868 see also Lassa fever; lymphocytic choriomeningitis virus infections ARF see acute respiratory failure (ARF) arginine stimulation tests  2427, 6587t arginine vasopressin (AVP) critical care response  3909 pancreatic neuroendocrine tumours  2455 syndrome of inappropriate antidiuresis  2544 Argyll–​Robertson pupil  6122, 6429 Aristichythys nobies  5061 Aristolachia  204 aristolochic acid drug-​induced chronic tubulointerstitial nephritis  4959 see also Balkan endemic nephropathy (BEN); Chinese herbal nephropathy poisonous plants  1832 Armillifer infections  1583f, 1583, 1584f Arnold–​Chiari malformation  5998 aromatase inhibitors adverse reactions, drug-​induced tendinopathies  4609 cancer chemotherapy  501 metastatic breast cancer  507 aromatherapy  202t arrested puberty  2434 arrhythmogenic right ventricular cardiomyopathy  3388, 3484, 3569, 3569t causes  3484 clinical features  3484 definition  3484

18 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 dilated cardiomyopathy overlap  3484 investigation  3484, 3485t cardiac MRI  3486, 3487f ECG  3486f, 3486 echocardiography  3486 endomyocardial biopsy  3487 exercise testing  3486 management  3487 pathology and pathophysiology  3484 arsenic cancer aetiology  421t, 422t defective red cell maturation  5455 neuropathies  6188 normal blood values  6586t poisoning  1752 squamous cell carcinoma  435 arsenic trioxide  112, 113f acute promyelocytic leukaemia management  112 commercial development  114 mechanism of action  112 arsine, poisoning  1763 artemisin  110, 1410t discovery of  110 history of  110, 111f arterial blood gases  3955, 3962 acid–​base balance  3964, 3964t, 3965f acute pulmonary embolism  3724 acute respiratory failure  3869b, 3869, 3870t anatomical shunt estimation  3964 COPD  4117 COPD investigations  4118 haemoglobin–​oxygen dissociation curves  3963f, 3963 metabolic acidosis  3964t, 3965, 3965t metabolic alkalosis  3964t, 3965, 3965t Pneumocystis jiroveci pneumonia investigation  1372 practical procedures  6649, 6649t respiratory acidosis  3964, 3964t, 3965t respiratory alkalosis  3964, 3964t, 3965t respiratory failure  3964 scoliosis  4331 severe asthma attacks  4094 strong ion approach  3966 ventilation–​perfusion mismatching  3963, 3963t arterial cannulation, procedure  6644, 6646 arterial occlusive disease  6012 acute kidney injury cause  4825 arterial oxygen saturation (SaO2), acute respiratory failure  3870 arterial partial pressure of carbon dioxide (PaCO2)  3962 normal blood values  6583t pregnancy  2613 arterial partial pressure of oxygen (PaO2)  3962 diffuse parenchymal lung diseases  4173 normal blood values  6583t pregnancy  2613 Arterial Revascularization Trial (ART)  3667 arteriovenous fistulae  5714 haemodialysis vascular access  4866 arteriovenous malformations (AVMs)  6362 pregnancy  2646 arteritis giant cell arteritis  4548 retina  6401t arthralgia cryoglobulinaemic vasculitis  4576 immune complexes in endocarditis  3522 rubella in pregnancy  2679 systemic lupus erythematosus  4505 arthritis acute rheumatic fever  3512 adult haemochromatosis  2107f, 2107 bacterial infections see septic arthritis Behçet’s syndrome  4581 Chlamydia pneumoniae infection  1293 Chlamydia trachomatis infection  1285 coeliac disease  4454 C-​reactive protein  2202–​3 immune complexes, Neisseria meningitidis infection  1021 inflammatory bowel disease and  4452 Mycoplasma infections  1303 Neisseria meningitidis infection  1021 psoriatic see psoriatic arthritis reactive see reactive arthritis rheumatoid see rheumatoid arthritis (RA) rubella in pregnancy  2679 septic see septic arthritis synovial membrane  4384f urinary incontinence  593t viral infections  4461 aetiology  4461, 4461t clinical features  4461 investigations  4462 management  4463 pathogenesis  4461, 4461t arthropathies collagenous colitis and  4454 crystal-​related see crystal-​related arthropathies hereditary haemochromatosis  2111 intestinal bypass surgery and  4454 psoriatic arthritis  4451 ulcerative colitis  2944 artificial nutrition support  1914, 1915f complications  1918, 1919t cost-​effectiveness  1924 ethics of  1922 future development  1924 hospital support team  1924 indications for  1916, 1916t burns  1923 critical illness  1923 gastrointestinal disease  1924 liver disease  1923 renal disease  1923 intestinal transplantation  1922f, 1922 long-​term artificial nutrition support  1922 palliative care  1924 perioperative nutrition  1924 requirement estimation  1917 carbohydrates  1918 electrolytes  1917, 1917t energy  1917 fluid  1917 lipids  1918 minerals and trace elements  1918 protein  1917, 1918f vitamins  1918 screening/​assessment  1914 body mass index  1916 examination  1916 history  1915 sepsis  1923 trauma  1923 see also enteral nutrition; parenteral feeding ASA see American Society of Anesthesiologists (ASA) asbestos amosite (brown asbestos)  4225 cancer aetiology  422t crocidolite (blue asbestos)  4225 fibre structure  4224f, 4224 lung cancer aetiology  432 macroscopic appearance  4225f, 4225 mesothelioma (of pleura/​ peritoneum) epidemiology  433 microscopic  4225f, 4225 pleural mesothelioma  4362 tobacco and  424 asbestosis  4224 aetiology and pathology  4225 clinical features  4222f, 4226, 4227f differential diagnosis  4226 investigations  4227 prevention and management  4227 prognosis  4227 asbestos-​related pleural disease, benign  4319 clinical features  4320 diffuse pleural thickening  4320 pleural effusion  4320 pleural plaques  4320f, 4320 rounded atelectasis  4321f, 4321 pathogenesis  4319, 4320f ascariasis (Ascaris lumbricoides infection)  1507 acute eosinophilic pneumonia (Löffler’s syndrome, simple pulmonary eosinophilia)  4239 acute pancreatitis  3213 clinical features  1508f, 1508 diagnosis  1508f, 1508 epidemiology  1507 gastrointestinal system  3010t life cycle  1507f, 1507, 1508f management  1508 transmission  3015t ascites  3058 aetiology  3058, 3061t amylase  3061 clinical features  3060f, 3060 complications  3065 hepatorenal syndrome  3067 hypercatabolic state  3067 paraumbilical hernia  3067 pleural effusion  3067 respiratory disease  3067 see also spontaneous bacterial peritonitis (SBP) drug prescribing  3067 fertility issues  3067 future work  3067 historical aspects  3058 investigations  3056t jaundice  3053–​54, 3055, 3056t laboratory diagnosis  3060 cell count  3061 cytology  3061 fluid culture  3061 fluid investigations  3061, 3061t paracentesis  3061 volume measures  3061 management  3062b, 3062 bed rest  3062 colloid replacement  3063 dietary salt restriction  3062 diuretics  3062 intravenous albumin infusion  3064 therapeutic paracentesis  3063 water restriction  3062 pathogenesis  3059f, 3059, 3060f renal dysfunction  3059 portal hypertension  3069 prognosis  3064 protein concentration  3061, 3061t refractory ascites management  3064 shunts  3064 ascorbic acid see vitamin C (ascorbic acid) Ashkenazi Jews Canavan’s disease  6218 cystic fibrosis epidemiology  4154 familial Mediterranean fever  2211 Gaucher’s disease type I  6227 glycogen storage disease type IV (adult polyglucosan body storage disease)  6221 GM2 gangliosidosis  6225 lysosomal storage disorders  6222–​24 Riley–​Day syndrome (familial dysautonomia)  6160–​61 Tay-​Sachs disease  2133 Asia breast cancer epidemiology  435–​36 colonic diverticular disease  2960 diffuse panbronchiolitis  4190 fibre and cancer aetiology  423 iodine deficiency disorders  1874 large bowel cancer  429 oesophageal cancer  427 oral cancer  426 prostate cancer epidemiology  438 rhabdovirus reservoir species  808 smoking  4339–​40 ASOs see antisense oligonucleotides (ASOs)

  Index 19 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 aspartate transferase (AST) acute hepatitis  3111 alcohol abuse  6526 alcoholic liver disease  3144–​45 autoimmune hepatitis  3122 inflammatory myopathies  4542 liver disease in pregnancy  2620 nitrogen disposal  1848 prehepatic jaundice  3051 aspartylglucosaminuria  6205t, 6231 aspergillosis  1354, 1534b cystic fibrosis respiratory management  4159 HIV/​AIDS  4036 liver disease  3175 post-​lung transplantation  4297, 4298f renal transplant immunosuppression  4894 severe/​difficult-​to-​treat asthma  4092 skin testing, bronchiectasis  4147t Aspergillus infections aflatoxin poisoning  1820 allergic bronchopulmonary mycosis  4240 cystic fibrosis  4157, 4159 HIV/​AIDS  3535 keratitis  6423 liver cancer  419 aspiration pneumonia  4021 polymyositis/​ dermatomyositis  4193 pregnancy  2616 aspirin ACS management  3634 acute cerebral infarction management  6018 acute myocardial infarction management, clinical trials see International Study of Infant Survival 2 (ISIS-​2) acute rheumatic fever management  3516 adverse reactions asthma  4072, 4073, 4074t, 4275 antiphospholipid syndrome management in pregnancy  2659 chronic heart failure management  3417 CKD in pregnancy  2594t diabetic nephropathy management  4984 essential thrombocythaemia management  5244 giant cell arteritis management  4550 hypertension risk management  3775 ischaemic stroke prevention  6019 leg ischaemia management  3684 metabolism  1745f migraine management  5994 peptic ulcer disease  2851 pharyngitis/​tonsillitis management  4006 polycythaemia vera management  5237–​38 pre-​eclampsia management  2586 preventative medicine  133t renal disease, effects of  5159t stable angina prevention  3623 STEMI management  3647 systemic lupus erythematosus management  4510 ASPRE study  2586 ASSERT trial  3371 Assessment of SpondyloArthritis Society (ASAS)  4464–​65 Association of British Neurologists  6036 Association of the British Pharmaceutical Industry  165 astemizole acquired long-​QT syndrome  251 allergic rhinitis management  4065 asthenozoospermia  2401 asthma  4067, 4069f acute attacks  4093 management  4094b, 4094 moderate  4093 severe  4093, 4094b acute presentation  6606 acute respiratory failure  3869 airway obstruction mechanisms  3943 allergy  371 breathlessness  3948 bronchoscopy  4000f, 4001 carbon monoxide diffusing capacity  3963t clinical features  4075 signs  4076 symptoms  4075 COPD  4102 cough  3949 diagnosis  3837t, 4076 airflow limitation  4076 airway hyperreactivity measures  4077 airway inflammation  4077 imaging  4078 reversibility and variability  4076, 4077f differential diagnosis  4080 COPD  4122, 4122t exercise-​induced breathlessness  4080 generalized airways obstruction  4080 hyperventilation  4080 localized airways obstruction  4080 vocal cord dysfunction  4080 drug-​induced  89, 90, 4273, 4274t anaphylaxis  4274 aspirin  4275 β-​adrenergic antagonists  4274 cholinergic drugs  4274 drug formulations  4275 drug masking  4275 nonsteroidal anti-​inflammatory drugs  4275 drug management  4083 anti-​IgE management  4089 antileukotrienes  4088 antimicrobial therapy  4089 β2-​adrenoceptor agonists  4083, 4084t, 4086 bronchial thermoplasty  4089 corticosteroids  4084 future therapies  4089 immunosuppressive management  4089 long-​acting muscarinic antagonists  4087 methylxanthines  4087, 4088t stepped approach  4083, 4084t epidemiology  4068 childhood microbial exposure  4069 geographical variations  4069 prevalence  4069 HIV/​AIDS  4038 inducers/​provokers  4070, 4071t, 4072f atopy and allergy  4071 drugs  4073 obesity  4073 occupation  4073 see also occupational asthma pollution  4072 psychological factors  4073 respiratory virus infections  4071 smoking  4072 management  4081, 4082f, 4082 allergen avoidance  4082 immunotherapy  4083 management selection  4081 patient education  4082b, 4082 pathophysiology  4070 biomarkers  4070 phenotype  4070 pregnancy  2616 prognosis  4075 children  4075 wheezing  4075 severe/​difficult-​to-​treat  4091 assessment  4091b Asthma Control questionnaire  4091 Asthma Control Test  4092 features  4091b management  4092 symptoms, breathlessness (dyspnoea)  3281 Asthma Control questionnaire, severe/​difficult-​to-​treat asthma  4091 Asthma Control Test, severe/​difficult-​ to-​treat asthma  4092 ASTRAL trials  3788 astrocytoma  440 astrovirus infection  801f, 801 gastroenteritis  803 gastrointestinal system  3010t, 3012 transmission  3014t asymmetric dimethylarginine (ADMA)  3270 Asymptomatic Carotid Surgery Trial (ACST-​1)  56, 57f atacicept  101t ataxia  5976 autosomal dominant cerebellar ataxias  5983t, 5984, 5985f autosomal recessive disease  5983 defective DNA repair  5982t, 5984 Friedreich’s ataxia  5982t, 5983 oculomotor apraxia and  5982t, 5984 cerebellar disease  5977 eye movements  5979 gait  5977 limb ataxia  5978 muscle tone  5978 posture  5977 speech  5978 tremor  5978 cerebellum disorders  5979 acute/​subacute onset  5979 chronic progressive course  5981 developmental disorders  5979, 5980t episodic course  5980, 5983t vascular disorders  5980 coeliac disease  2887 differential diagnosis  5978t hemiparesis  6017–​18 idiopathic degenerative late-​onset ataxia (ILOCA)  5985 investigations  5979 anatomy quantification  5979 genetics  5979, 5982t, 5983t imaging  5979 lysosomal disease  2131 management  6387t multiple sclerosis  6032 myoclonus with see myoclonus progressive metabolic ataxias  5982 degenerative disorders  5982, 5982t, 5983t endocrine disorders  5982 metabolic disorders  5982 spinal cord disorders  6130 symptoms  5977, 5978t dysarthria  5977 gait disturbances  5977 limb coordination  5977 ocular motor symptoms  5977 tremor  5977 visual symptoms  5977 vitamin E deficiency (AVED)  1861, 6263 Whipple’s disease  2910 ataxia neuropathy spectrum (ANS)  6263, 6345t ataxia-​oculomotor apraxias  6262, 6263 ataxia telangiectasia (AT)  221t, 458t, 466, 5717, 5984, 6209 ATM gene mutations  466 cancer  420 cancer susceptibility  415 clinical features  6209 gastrointestinal manifestations  2788t immunodeficiencies  356 investigations  6209 management  6209 atenolol hypertension management  3766t malignant hypertension management  3805 renal disease, effects of  5155 atezolizumab  508 ATG see antithymocyte/​ antilymphocyte globulin (ATG/​ALG) atherectomy see percutaneous coronary intervention (PCI) atheroma diabetes  2523

20 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 essential hypertension pathophysiology  3749 metabolic syndrome (syndrome X)  2475 see also atherosclerosis atherosclerosis  3596 accelerated renal transplant complications  4900, 4900t rheumatoid arthritis complications  4439 acute coronary syndromes  3600 plaque rupture/​erosion  3600 vulnerable plaques  3601 atherosclerotic plaques  3599 arterial wall remodelling  3600 cell death  3599 disease progression  3600 neovascularization  3600 plaque calcification  3600 cardiovascular disease assessment for  2089 cholesterol and  2056 epidemiology  2056, 2057f familial hypercholesterolaemia 
2079 hypertriglyceridaemia  2094 LDL-​cholesterol  2089–​90 Chlamydia pneumoniae infection  1293 extracellular matrix  3599 hypertension and  3749 initiation  3597 leucocyte recruitment  3597, 3598f management  5712 progression  3598 regression  3601, 3602f clinical studies  3601 smooth muscle cells  3599 systemic lupus erythematosus in pregnancy  2656 atherosclerotic renovascular disease (ARVD)  5044 cardiorenal syndrome  3423 clinical features  5045, 5046f clinical investigations  5045 epidemiology  5045 future development  5048 management  5045 prognosis  5048 atherothrombosis  6012–​13 Athlete Biological Passport  6572 athletes see sport and exercise medicine ATLAS 2 study  3638 atmospheric ozone, aviation medicine  1658 atmospheric pollution see air (atmospheric) pollution atopic dermatitis  5633 allergen avoidance  5635 allergy and  5634 clinical features  5631f, 5633 definitions  5633 distribution on body  5599f incidence  5633 management  5635b, 5635 allergen avoidance  5635 infections  5635 itch  5635 skin inflammation  5635b, 5635 microbes  5635 natural history  5633 pathogenesis  5633 prevalence  5633 sites  5597, 5598f see also eczema atopic eruption of pregnancy  2651f, 2651, 2651t, 2652t ATP energy production in muscle  6307 mitochondria  211 synthesis  1839 ATP7B gene Menkes’ disease  2120 Wilson’s disease  2115, 2118, 3195, 5963, 6248 ATP-​binding cassette (ABC) transporters drug-​induced liver injury  3157 drug tissue distribution  80 ATP-​sensitive K+ (KATP) channel insulin secretory disease  254 neonatal diabetes  255 Atractaspidinae (family Lamiprophilidae)  1782f, 1782, 1788 atrial arrangement, congenital heart disease  3561, 3563t atrial fibrillation  3367 aetiology  3368b, 3368 cardiac surgery complications  3672 chronic heart failure and  3418 chronic heart failure risk factor  3412t classification  3368b, 3368 diagnosis  3368f, 3368 dilated cardiomyopathy  3479 emergency presentation  3369b, 3369 malignant hypertension  3804 management  3368 anticoagulants  3733 digoxin  77–​78 mechanisms  3367 mitral stenosis complications  3438, 3441 palpitation  3292 paroxysmal atrial fibrillation  3370f permanent atrial fibrillation  3370 persistent atrial fibrillation  3369 pre-​excited atrial fibrillation  3380f, 3380 presentation  3368 stroke prevention  3371t, 3373f, 3374, 3375t, 3376f thromboembolism prevention  3370 oral anticoagulants  3370 transthoracic echocardiography  3320f, 3320 atrial flutter cardiac arrhythmias  3368b, 3375, 3377f complete transposition of the great arteries  3582 atrial hypertrophy, ECG  3301 atrial infarction  3307 atrial natriuretic peptide (ANP)  3270 AKI in pregnancy  2589 hypertension  3748 atrial septal defects (ASDs)  3570 clinical signs  3571 heart disease interactions  3571 pulmonary vascular disease  3565t, 3571 investigations  3572 management  3572 types  3570f, 3570 coronary sinus defect  3572 ostium primum atrial septal defect  3572 ostium secundum  3571 patent foramen ovale  3570 sinus venosus atrial septal defect  3572 atrial septostomy  3706 atrioventricular block  3308 aetiology  3355, 3356b myocardial infarction  3355, 3356f first-​degree  3355, 3356f second-​degree  3355–​56, 3356f third-​degree  3355, 3356f, 3357f atrioventricular (AV) node  3264, 3265f conduction disorders, bradycardias  3354 congenital heart disease  3562f, 3562 metabolism  3268 myocytes  3257–​59 re-​entry tachycardia  3377, 3378f, 3379f atrioventricular septal defects (AVSD)  3574, 3575f clinical presentation  3575 complete  3575 investigation  3575 partial  3575 atrophic vaginitis  1605 management, UTI prevention  5085 atropine anaphylaxis management  3856 bradycardia management  3353–​54 ATTITUDE trial  3768 atypical haemolytic uraemic syndrome (aHUS)  321 diagnosis  5031 genetics  5029, 5030t management  5031 noninherited type  5030 pathogenesis  4991b, 4992f, 4995b, 5028 renal transplantation  5032 atypical mycobacterial infection diagnosis  4029 management  4030, 4030t atypical neuroaxonal dystrophy (atypical NAD)  6253 auditory system  5931, 5932f higher brain function  5823 rehabilitation  5935 see also hearing disorders auscultation aortic regurgitation  3452 aortic stenosis  3448 respiratory disease see respiratory disease, clinical examination Australia multiple sclerosis  6030 stomach cancer  428 tobacco as cancer cause  417t Australia and New Zealand Dialysis and Transplant Registry  4834 Australian bat lyssavirus  819f, 819 autism macrocephaly  6356 measles persistent infection  781 autoantibodies  380 ANCA-​associated vasculitis  4557f antiglomerular basement membrane disease  4943, 4944f autoimmune diseases  389t autoimmune encephalitis  6483, 6483t autoimmune hepatitis  3122–​23, 3124f, 3124t autoimmune rheumatic disorders  4497 blood transfusions  5568 bronchiectasis  4147t congenital noninflammatory diarrhoea  2974 dermatomyositis  5661 diffuse parenchymal lung diseases  4173 inflammatory myopathies  4542, 4543t rheumatoid arthritis  4424–​25, 4432 rheumatological diseases  4403 systemic lupus erythematosus  4501t, 4508 systemic lupus erythematosus pathology  4501, 4501t, 4502 autoimmune acquired hypoparathyroidism 
2315t, 2316f, 2329 autoimmune bullous disease  5612 differential diagnosis  5614t intraepidermal diseases  5613t, 5617f, 5617 paraneoplastic pemphigus  5613t, 5619 pemphigus foliaceus  5613t, 5619 pemphigus vulgaris  5613t, 5617, 5618f pregnancy  2654 subepidermal diseases  5612, 5613t, 5614f bullous pemphigoid  5612, 5613t, 5615f dermatitis herpetiformis  5613t, 5616f, 5616 epidermolysis bullosa acquisita  5613t, 5616 linear IgA disease  5613t, 5615f, 5616 mucous membrane pemphigoid  5613t, 5614, 5615f autoimmune diseases/​disorders  379 aetiology  380 environmental factors  382 genetics  380 B-​lymphocyte stimulator  104 chorea  5959 clinical features  388, 389t, 390t coeliac disease and  2891

  Index 21 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 complement impaired activation  319 diabetes mellitus type 1 as  2477 distal renal tubular acidosis type 1  2191 encephalopathy with NMDAR antibodies  6395 epidemiology  380 Epstein–​Barr virus infection  763 evolutionary aetiology  40–​41 gastrointestinal dysmotility  2794 gastrointestinal tract see gastrointestinal tract heart muscle disease  3490 hepatitis see autoimmune hepatitis hypocalciuric hypercalcaemia (AHH)  2325 insulin syndrome (IAS: Hirata’s disease)  2539 management  390 lost function replacement  391 pathway control  391 organic psychoses  6483, 6483t pathogenesis  382 amplification principles  388 autoantigens  388 central tolerance  382 disease-​specific autoantigens  388 effector mechanisms  387 mechanisms  383 peripheral tolerance  382 pericarditis  3502 premature ovarian insufficiency  2379 prognosis  390 retroperitoneal fibrosis  5131–​32 rheumatoid arthritis complications  4439 systemic gastrointestinal tract  2795, 2795t immune complex-​mediated membranoproliferative glomerulonephritis  4937–​38 autoimmune encephalitis  6483 autoantibodies  6483, 6483t disease associations  6483, 6483t autoimmune haemolytic anaemias  389t, 5480, 5481t cold autoimmune haemolytic anaemia  5482f, 5482 drug-​induced  5483 management  4510 mixed-​type autoimmune haemolytic
anaemia  5483 paroxysmal cold haemoglobinuria  5481 ulcerative colitis  2945 warm autoimmune haemolytic anaemia  5481f, 5481 autoimmune hepatitis  389t, 3119, 3173, 3176 aetiology and pathogenesis  3120 environmental factors  3120 genetics  3120 immunology  3120 childhood liver disease  3194f, 3194 clinical features  3121, 3122t cross-​over syndromes  3126 diagnosis  3123t differential diagnosis  3122, 3122t, 3123b epidemiology  3120 hepatitis vs.  3111 inactive disease  3126 inflammatory bowel disease  3172 investigations  3122, 3124f, 3124t jaundice  3054 liver transplantation  3105 recurrence after  3106t malabsorption  2877 management  3123 liver transplantation  3123 pharmacology  3123, 3125f older children  3194 pathology  3121f, 3121 physical examination  3122 pregnancy  3126 prognosis  3126 liver transplantation  3126 type 1  3121, 3121t type 2  3121, 3121t autoimmune hypothyroidism  2292 clinical features  2292 disease associations  2293 autoimmune limbic encephalitis with VGKC-​complex antibodies  6393 clinical features  6393 differential diagnosis  6394, 6395t epidemiology  6393 investigations  6393, 6394f management  6394 pathogenesis  6394 autoimmune lymphoproliferative syndrome (ALPS)  361 autoimmune neutropenia hypersplenism  5193 pregnancy  2694 autoimmune pancreatitis  2794 acute pancreatitis  3212 chronic pancreatitis vs.  3221 autoimmune polyendocrine syndrome type I  381 eye diseases/​disorders  6434 autoimmune polyendocrinopathy–​ candidiasis–​ ectodermal dystrophy (APECED)  2329, 2477 autoimmune polyglandular syndrome type 2  2293 autoimmune pulmonary alveolar proteinosis  4259 autoimmune retinopathy (AIO)  6425 autoimmune rheumatic disorders  4387t, 4390f, 4390t, 4391, 4391t, 4495 clinical features  4498 clinical spectrum  4496, 4497t definition  4495, 4496t epidemiology  4495, 4496t heart muscle disease  3491, 3491t immunopathogenesis  4497 lung involvement  4191 ankylosing spondylitis  4197 lymphoid follicles  4191–​92, 4192f mixed connective tissue disease  4197 pleural thickening  4191–​92, 4192f polymyositis/​ dermatomyositis  4193 relapsing polychondritis  4196 rheumatoid arthritis  4194 Sjögren’s syndrome  4195 systemic lupus erythematosus  4196 systemic sclerosis  4192 undifferentiated connective tissue disease  4197 autoimmune sclerosing cholangitis  3126 autoimmune thyroid disease, coeliac disease  2887, 2888 autoinduction  87 autoinflammation and PLCγ2-​ associated antibody deficiency and immune dysregulation (APLAID)  2208t, 2215 autologous haematopoietic stem cell transplantation  5579, 5587 MALT lymphoma management  2901 metachromatic leucodystrophy management  6213 multiple sclerosis management  6037 plasma cell myeloma management  5313f, 5316 renal disease in myeloma  5020 Autologous Stem Cell Transplantation International Scleroderma (ASTIS) study  4519 autonomic nervous system (ANS) insulin secretion effects  2470 pulmonary vasomotor tone regulation  3693–​94 terminals at target organs  6151, 6152f autonomic nervous system disorders  6150, 6151f classification  6151, 6153b clinical features  6151, 6154b, 6155f, 6156t investigations  6154f, 6154, 6156b management  6154b, 6157b, 6157, 6158t multiple sclerosis  6031 primary autonomic failure  6158 acute/​subacute dysautonomias  6160 chronic autonomic failure  6158, 6160f principles  6150 secondary disorders  6160 amyloid neuropathy  6161 autonomic (neurally) mediated syncope  6161, 6163f, 6164f diabetes mellitus  6151, 6161 dopamine β-​hydroxylase deficiency  6152f, 6161 drugs  6153b, 6161 initial orthostatic hypotension  6155f, 6165 intermittent autonomic dysfunction  6153b, 6161 postural tachycardia syndrome  6164f, 6164 primary (essential) hyperhidrosis  6165 Riley–​Day syndrome (familial dysautonomia)  6160 spinal cord injury  6161, 6162f autonomic neuropathy  6371 diabetic neuropathy  2519 autophagic pathway caspases  267–​68 lysosomal hydrolases  213–​14 lysosomes  2122 autopsy see post-​mortem examination autosomal Alport’s syndrome  5069 autosomal dominant cerebellar ataxias  5983t, 5984, 5985f autosomal dominant Charcot–​ Marie–​Tooth disease see Charcot–​Marie–​Tooth (CMT) disease autosomal dominant hypercholesterolaemia 
2080 autosomal dominant hyper IgE syndrome  357 autosomal dominant hypocalcaemia  2315t, 2316f, 2327 autosomal dominant hypophosphataemic rickets (ADHR)  5114, 5115t autosomal dominant ichthyosis  5606 autosomal dominant isolated renal hypomagnesaemia  5118t, 5119 autosomal dominant limb-​ girdle muscular dystrophies  6321b, 6322 autosomal dominant nocturnal frontal lobe epilepsy  6242 autosomal dominant partial epilepsy with auditory features (ADPEAF)  6242 autosomal dominant polycystic kidney disease (ADPKD)  5065 diagnosis  5065 at-​risk subjects  5065 exclusion diagnosis  5066 family history absence  5066f, 5066, 5066t ultrasound  5066f, 5066 genetic counselling  5068 management  5067, 5068 pathogenesis  5067 pregnancy  2595 symptoms  5066 external manifestations  5067 renal manifestations  5066 UTI  5087 autosomal dominant renal hypomagnesaemia  5118t, 5119 autosomal dominant tubulointerstitial kidney disease (ADTKD)  2021 autosomal recessive ataxia (ARSACS)  5984, 5985f autosomal recessive hypercholesterolaemia (ARH)  2063f, 2080 autosomal recessive hypophosphataemic rickets (ARHR)  5114, 5115t

22 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 autosomal recessive inheritance, Mendelian inheritance  220 autosomal recessive polycystic kidney disease  5068 autosomal recessive spastic ataxia of Charlevoix-​Saguenay (ARSACS)  6262 aviation medicine  1656 clinical aspects  1662 fitness to fly  1663 infectious disease spread  1663 jet lag  1662 newly emerging infectious diseases  1664 traveller’s thrombosis  1663 cyanotic heart disease  3565 flight physiology  1658 altitude-​induced decompression illness  1662 hypoxia  1658, 1659f, 1660f oxygen equipment  1660 pressure cabins  1660, 1661f pressure change mechanical effects  1661f, 1661 oxygen equipment  1660 oxygen management in COPD management  4135 physics of the flight environment  1657f, 1657 atmospheric ozone  1658 atmospheric pressure  1657, 1658f atmospheric temperature  1658 cosmic radiation  1658 pneumothorax  4325 pressure cabins  1660, 1661f pressure change mechanical effects  1661f travel and expedition medicine  714 AVMs see arteriovenous malformations (AVMs) axillary nerve (C5, C6), neuropathies  6182 axis, 12-​lead ECG reading  3298f, 3298, 3299f axitinib  485 primary thyroid epithelial tumour management  2308 axonal polyneuropathy chronic idiopathic  6195 nerve conduction studies  5799f, 5799, 5800f Ayurvedic medicine  108, 109b azathioprine acute pancreatitis  3211 adverse reactions  404t, 4890, 4891t cancer aetiology  421t drug-​induced liver injury  3156 nodular regenerative hyperplasia  3164 antiphospholipid syndrome management in pregnancy  2660 arthritis and inflammatory bowel disease  4453 autoimmune hepatitis management  3123 Behçet’s syndrome management  4583 CKD in pregnancy  2594t Crohn’s disease management  2932, 2933 cryptogenic organizing pneumonia management  4189 dermatomyositis management  5661–​62 drug-​induced alveolar disease  4278 immunoglobulin A nephropathy management  4915–​16 interstitial nephritis with granuloma in sarcoidosis  5015 Lambert–​Eaton myasthenic syndrome management  6301 liver transplantation  3103–​4 mucous membrane pemphigoid management  2819 multiple sclerosis management, pregnancy in  2645t myasthenia gravis in pregnancy  6300 non proliferative lupus nephritis class V management  5004 ocular symptoms in myasthenia gravis management  6299 oral lichen planus management  2818 pemphigus vulgaris management  5618 polyarteritis nodosa management  4573 polymyalgia rheumatica management  4588 post-​lung transplantation  4299 primary biliary cholangitis management  3134t recurrent aphthous stomatitis management  2816 renal disease, effects of  5153 rheumatoid arthritis management in pregnancy  2664t SAPHO syndrome  4454 sarcoidosis management  4216, 4216t, 4217, 5745, 6382 skin disease management  5768 systemic lupus erythematosus management  4511 systemic vasculitis maintenance management  4996 transplant immunosuppression  402 azithromycin bronchiectasis management  4148–​49 bronchiolitis obliterans syndrome management  4301–​2 chlamydia in pregnancy  2683 COPD management  4130–​31 renal disease, effects of  5163t scrub typhus management  1255 urethritis  1608 azoospermia  2401 cystic fibrosis  4156, 4163 B cell(s) activation, transplantation  397f, 397 antigen presentation  327f, 333 antigen receptors  5264 antigen recognition  328f, 328 clonal proliferation  333f, 333 development  331 diversity generation  329f, 329, 330t functions of  333 memory  334 priming  333f, 333 progenitors  5265–​66 stimulator protein  241 stimulators  104 tolerance mechanisms  334, 383 transplantation  397f, 400 B-​cell diseases/​disorders ANCA-​associated vasculitis  4560 atherosclerosis  3599 inflammatory disease-​like immunopathology  2788t inflammatory myopathies  4538–​39 lymphopenia  358 rheumatoid arthritis  4424 synovial membrane  4385 systemic lupus erythematosus pathology  4501 ulcerative colitis  2939 B-​cell malignancies Gaucher’s disease type 1  2142 lymphoma cutaneous lymphoma  5740 renal disease in  5025 non-​Hodgkin’s lymphoma  4428–​30 B cell receptor (BCR)  328 B7.1 (CD80)  474 B7.2 (CD86)  474 Babesia divergens infection  1415, 1416f Babesia microti infection  1415 babesiosis  1414 clinical features  1415 Babesia divergens infection  1415, 1416f Babesia microti infection  1415 diagnosis  1415 epidemiology  1414 management  1415 pathogenesis  1415 prevention  1415 Bacillus anthracis infection see anthrax bacillus Calmette–​Guérin (BCG) vaccine non muscle-​invasive bladder cancer management  5139 tuberculosis prevention  1149 tuberculous meningitis prognosis  6081 Bacillus cereus infection  1040 gastrointestinal system  3009t, 3011 toxin production  3017 transmission  3014t background activity, EEG  5787f, 5787 back pain  4406 acute abdomen  2765–​66 diffuse musculoskeletal
pain  4411 regional pain disorders  4411, 4412t warning signs  4386t see also low back pain; neck pain baclofen glutaric aciduria type I management  1963 multiple sclerosis management  6035 spasticity in spinal cord injury  6144 trigeminal neuralgia management  6123 bacteraemia Bartonella infection  1268 coagulase-​negative staphylococci see coagulase-​negative staphylococci endocarditis  3521 haemodialysis access  4871 Haemophilus influenzae type b  1069 Pseudomonas aeruginosa infection  1041, 1042f Staphylococcus aureus infection  1002f, 1002, 1003t bacterial infections acute prostatitis  5085 ANCA-​associated vasculitis  4559 angiomatosis Bartonella infection  1267, 1271 HIV/​AIDS  918 asymptomatic bacteriuria  5075–​76 pregnancy  2577, 2596 screening, preventative medicine in pregnancy  134t UTI  5078 cancer aetiology  419 causative organisms  1307 CNS see bacterial meningitis cranium, imaging  5814 C-​reactive protein  2202 destructive thyroiditis  2300 endocarditis, congenital heart disease  3593t, 3594 eye diseases/​disorders  6429 gastrointestinal infections  3009t, 3011, 3014t glomerulonephritis see glomerulonephritis (GN) interstitial nephritis  5037 liver disease  3174 liver transplantation complications  3104 osteomyelitis  4692 overgrowth Crohn’s disease  2935 diarrhoea  2759t small intestine bacterial overgrowth management  2883 peliosis, Bartonella infection  1268, 1271 pericarditis  3502 pneumonia, HIV/​AIDS  911 pneumonitis, HIV/​AIDS  4032 pregnancy  2682 renal transplant immunosuppression 
4892t, 4894 respiratory tract in cystic fibrosis  4153–​54 septic arthritis  4457, 4458 skin see skin infections tropical malabsorption  2922f, 2923

  Index 23 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 tropical sprue  2918 vaginosis  1603, 1604 Mycoplasma infections  1304 pelvic inflammatory disease  1622 pregnancy  2682 bacterial meningitis  6060 aetiology  6061 bacterial species  6062t antimicrobial therapy  6070, 6072t, 6073t shunt-​associated  6072 clinical features  6066 community-​acquired  6066, 6067f CSF shunts  6068 clinical investigations  6068 CSF examination  6068 lumbar puncture  6068 pre-​lumbar puncture CT  6068, 6069b, 6069f differential diagnosis  6068 epidemiology  6064 future developments  6081 genetic factors  6081 immunization  6081 new adjunctive therapies  6081 randomized clinical trials  6081 genetics  6062 management  6070 antimicrobial therapy see antimicrobial therapy complications  6075 dexamethasone management  6073 management algorithm  6069b, 6070, 6071f pathogenesis  6062, 6064f pathology  6063 post-​traumatic stress see post-​ traumatic meningitis prevention  6065 chemoprophylaxis  6066, 6073t immunization  6065 prognosis  6075 recurrent  6069 aetiology  6061 tuberculous see tuberculous meningitis (TBM) BAL see bronchoalveolar lavage (BAL) Balamuthia infection  1392f, 1393, 1394f balantidiasis  1447 aetiology  1447f, 1447, 1448f clinical features  1448 epidemiology  1448 gastrointestinal system  3010t laboratory diagnosis  1449 management  1445, 1449 pathogenesis  1448 pathology  1448 prevention  1449 transmission  3015t Bálint’s syndrome  5826, 5921 Balkan endemic nephropathy (BEN)  4959, 4961, 5052–​53 clinical features  4962 tubular proteinuria  4787 diagnosis  4962 differential diagnosis  4957t epidemiology  4961f, 4961 management  4962 pathogenesis  4961 environmental factors  4961 genetics  4961 pathology  4962 Balo’s concentric sclerosis  6039 Baltic myoclonus see Unverricht–​ Lundberg disease (Baltic myoclonus) Bangladesh health financing and MDG  174, 175f Millennium Development Goals  172 Bannayan–​Riley–​Ruvalcaba syndrome (BRRS)  6208 Barakat’s syndrome  2329 barbiturates folate deficiency  5419 mechanism of action  5871 Bardet–​Biedl syndrome  1910t, 5072t, 6358–​59 delayed puberty  2433 eye diseases/​disorders  6436 male reproductive disorders  2393t bare metal stents  3657, 3658f bariatric surgery  2096 gastrointestinal tract hormones  2869, 2869t obstructive sleep apnoea management  4056 weight control in diabetes management  2490 baricitinib  244 rheumatoid arthritis management  4437 baritosis  4233–​34 barium studies Crohn’s disease  2753 enema  2748 colon imaging  2755 small bowel imaging  2750 small intestine malrotation with/​ without volvulus  2970, 2971f swallow  2748f, 2748 bronchiectasis  4147t extrinsic oesophageal compression  2846 gastro-​oesophageal reflux disease  2830 ulcerative colitis  2942f, 2942 Barker hypothesis of the Developmental Origins of Disease  519 Barmah Forest virus  824 barogenic oesophageal rupture (Boerhaave’s syndrome)  2846 baroreceptors, systemic arterial blood pressure regulation  3269 baroreflex stimulation, hypertension management  3775 barotrauma of ascent, diving medicine  1668 barotrauma of descent, diving medicine  1667 Barrett’s oesophagus see oesophageal columnar metaplasia (Barrett’s oesophagus) barrier contraception  1627, 1632f, 2604, 2715 barrier removal, drug compliance improvement  76 Barthel Index  550, 552f, 565 Bartholin cysts  1620f, 1620 bartholinitis, Chlamydia trachomatis infection  1284 Barth’s syndrome  1958 Bartonella infection  1262 aetiology and genetics  1263, 1264f, 1265f clinical features and pathology  1264 bacillary angiomatosis  1267, 1271 bacillary peliosis  1268, 1271 bacteraemia  1268 cat-​scratch disease (CSD)  1267f, 1267, 1271 endocarditis  1268, 1271 prolonged fever  1268 trench fever  1266, 1271 diagnosis  1268, 1268t, 1269f culture  1269f, 1269 immunodetection  1269f, 1269 molecular biology  1270 serology  1270f, 1270 specimen collection  1268 endocarditis  3525t epidemiology  1265t, 1267f management  1270 antibiotic susceptibility  1270 prevention  1271 Bartonella bacilliformis infection  1272 aetiology  1272, 1273f clinical features  1275, 1276f, 1277f diagnosis  1273f, 1277 epidemiology  1273, 1274f, 1275f laboratory features  1277 management  1278 pathogenesis  1274, 1275f, 1276f prevention  1278 prognosis  1277 Bartonella henselae infection inflammatory eye disease  6430 Parinaud oculoglandular syndrome  6407–​10 Bartter’s syndrome  2188, 3799, 4754f, 4755 aetiology  2188 clinical features, calcium urinary stones  5098t Gitelman’s syndrome vs.  5117 hypo-​/​hypermagnesaemia  5118t loop of Henle  4721f, 4726 potassium disturbances  4793–​94 type I  4755 type II  4755 type III  4755 type IV  4755 type V  4755 basal cell carcinoma (BCC)  435, 5735f, 5735 incidence, change over time  414 post-​renal transplant  4899 renal transplants  5748 basal cell naevus syndrome (Gorlin’s syndrome)  458t, 465 Hedgehog (Hh) pathways  260 PTCH gene  465 basal cell papilloma/​seborrhoeic warts (seborrhoeic keratosis)  5732, 5733f basal ganglia  5940 adult-​onset disease  2113 attention  5823 cognitive domain  5823 functional anatomy  5941 function/​dysfunction  5943 gross anatomy  5940f, 5940 hyperdirect pathway  5943 lesions, paroxysmal dyskinesia  5973 oscillations  5943 pathways  5941f, 5941, 5942f propionic aciduria  1959–​60 rate model of function  5942f, 5942 thalamus  5940f basal pontine syndrome (locked-​in syndrome)  6008 baseline electrocardiogram, exercise ECG testing  3313 Basidiobolus mucormycosis  1348 basilar artery  6006, 6012f, 6013f basiliximab  405, 4888 basophils  309–​10, 5190f, 5196 allergic rhinitis  4061 Bassen–​Kornzweig syndrome  6250 Batten’s disease see ceroid lipofuscinosis (Batten’s disease); neuronal ceroid lipofuscinoses (NCLs) batteries, poisoning  1772 BBB see bundle branch block (BBB) BCAR (benign drug-​induced skin disease) see skin drug reactions BCC see basal cell carcinoma (BCC) BCG see bacillus Calmette–​Guérin (BCG) vaccine BCL-​2 family proteins  271–​72, 273f, 275 BCNU see carmustine (BCNU) BCR-​ABL inhibitors, skin drug reactions  5759 BCR-​ABL-​like acute lymphoblastic leukaemia, acute lymphoblastic leukaemia management  5275 BCR-​ABL oncoprotein, chronic myeloid leukaemia  5217f, 5217 BCR-​ABL-​positive acute lymphoblastic leukaemia, acute lymphoblastic leukaemia management  5275 BDP see beclomethasone propionate (BDP) BEACOPP chemotherapy, Hodgkin’s lymphoma management  5284t, 5285 Beau’s lines, nail disorders  5726 Becker’s muscular dystrophy (BMD)  3478, 3497, 3557t, 6279, 6342 cardiovascular abnormalities  3491t carrier manifestation  6315 clinical symptoms  6280 diagnosis  6313–​15, 6316f management  6319

24 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 antisense oligonucleotides  6281 cell management  6281 gene management  6281 novel pharmacological approaches  6281 stop-​codon read-​through  6281 utrophin modulation  6281 presentation  6315 prognosis  6316b, 6316–​17 beclomethasone propionate (BDP)  4085, 4088, 4128 bedbugs  1570, 1571f bedsores  5714 bee stings  5061 see also venomous arthropods beetles (Coleoptera)  1808f, 1808 behaviour activation  6472 Alzheimer’s disease  5841 central auditory function tests  5934 confusion assessment  6455 dementia management  6481, 6481t frontotemporal dementia  6236 health inequalities  158 hypoxanthine-​guanine transferase deficiency  2026 neurological disorders  5829 obesity management  1910 preventative care risk modification  131 risk factors, preventative medicine  128, 129t variant Creutzfeldt–​Jakob disease  6115–​16 weight management programmes  6531, 6532f behavioural variant frontotemporal dementia (bvFTD)  5844, 5845, 6482 Behçet’s disease/​syndrome  4579, 5750, 6381 aetiology  4580 classification criteria  4582b, 4582 clinical findings  4580, 4580t cardiac system  4582 dementia  5858 eye  4581, 6421f, 6422, 6426f gastrointestinal system  2795t, 3003t, 4582 heart muscle disease  3494 hepatic artery aneurysm  3168–​69 lung involvement  4205 mucocutaneous system  4580, 4581f musculoskeletal system  4581 neurological system  4581 vascular system  4581, 4582f clinical investigations  4582 diagnosis  6133 differential diagnosis  4582 multiple sclerosis  6035 epidemiology  4580 genetics  4580 management  4583t, 4584, 6381 pathogenesis  4580 pregnancy  2665 prognosis  4584 belatacept (LEA29Y)  405, 4889–​90 belching  2729 belimumab  101t, 104, 4511, 5006 Bell’s palsy facial nerve (cranial nerve VII)  6123 herpes simplex virus infection  2807 pregnancy  2647t bendroflumethiazide  2524–​25, 3766t, 5154 Benecol  2093 Bengal famine (1943)  189, 190, 190t benign drug-​induced skin disease (BCAR) see skin drug reactions benign epilepsy with centrotemporal spikes  6241 benign familial haematuria  5070 benign familial infantile seizures  6238, 6241t benign familial neonatal infantile seizures (BFNIS)  5865–​66, 6238, 6239t benign hereditary chorea  5959 benign intracranial hypertension see idiopathic intracranial hypertension (IIH) benign melanocytic lesions (melanocytic naevi/​moles/​ freckles)  1618 benign myoclonic epilepsy of infancy  6240 benign oesophageal strictures, upper gastrointestinal tract endoscopy  2743 benign pancreatic duct stricture, acute pancreatitis  3212 benign small bowel tumours, imaging  2753 benign tumours, dementia  5857 benzathine benzylpenicillin  3516, 3517–​18, 3542 benzbromarone  2023, 4489 benzene  422t, 1763 benzimidazole  1446, 1532 benzodiazepines  6470 abuse of  6491 anxiety disorders management  6504, 6505, 6505t breathlessness  636 chorea in acute rheumatic fever management  3517 colonoscopy sedation  2735–​36 critical care  3904 delirium  558 falls in elderly  583t glutaric aciduria type I management  1963 mechanism of action  5871 multiple sclerosis management  6035 pharmacodynamics in older people  573 poisoning by  1738 renal disease, effects of  5158 seizure management in acute porphyria  2051–​52 tension-​type headaches  5995 withdrawal  6492 see also lorazepam benzofurans  1748 benzoic acid  5763 benzoyl peroxide (BPO)  5705, 5765 benzyl alcohol poisoning  1763 benzylpenicillin  2684, 5163t beriberi acute pernicious  1863 Berlin patient, HIV/​AIDS  931f, 931 Bertiella infections  1525 berylliosis  4232, 4233f beryllium  422t, 4209–​10 β-​3 agonists, urinary incontinence  594 β2-​agonists acute respiratory distress syndrome management  3879 acute severe asthma management  4095 asthma management  4083, 4084t, 4086 COPD management  4126, 4127 long-​acting  4084, 4086 moderate asthma attacks  4093 poisoning by  1739 regular use vs. as-​needed  4086 safety of  4086 β-​antagonists (beta blockers) ACS management  3634 adverse reactions asthma induction  4073, 4274 erectile dysfunction  2409t poisoning  1738 aortic regurgitation management  3454 arrhythmias in hypertrophic cardiomyopathy management  3476 arrhythmogenic right ventricular cardiomyopathy management  3487 atrial fibrillation management  3418 blood pressure in aortic dissection management  3809 cardiogenic anasarca management  3405 chest pain in hypertrophic cardiomyopathy management  3476 chronic heart failure management  3414f, 3415 CKD in pregnancy  2594t dilated cardiomyopathy management  3482 Duchenne’s muscular dystrophy management  6317–​18 dyspnoea in hypertrophic cardiomyopathy management  3476 exercise ECG testing  3313 hypertension management  3766t, 3767 acute porphyria  2051 contraindications  3767t diabetes  2525 malignant hypertension  3805, 3806t hypertrophic cardiomyopathy management  3474–​75 Marfan’s syndrome management 
3556, 4650, 4681 migraine prevention  5993t multiple sclerosis management  6035 phaeochromocytoma management  3794–​95 pharmacodynamics in older people  573 postural tachycardia syndrome management  6165 pseudoxanthoma elasticum management  4685 renal disease, effects of  5155 stable angina management  3623 tachycardia management  3364 thyrotoxic periodic paralysis management  4756 ventricular tachycardia management  3382 vertigo management  5927t withdrawal syndromes  87 β-​cell failure, diabetes mellitus type 2  2479f, 2483 betaine  1982 β-​lactam antibiotics  1059, 4954, 5079t β2-​microglobulin amyloid fibrils  2228 haemodialysis-​associated amyloidosis  2224 normal blood values  6586t renal tubular proteinuria  4786 urinary/​faecal reference intervals  6587t β-​oxidation defects, primary metabolic myopathies  6338 Bethlem myopathy  6293, 6322 bevacizumab  484–​85, 502, 2455, 6207 bezafibrate  2072t BH3-​only proapoptotic proteins, apoptosis activation  272f, 272–​73 Bhanja virus  861 Bhopal disaster  4269–​70 Bhutan health financing and MDG  174 Millennium Development Goals  172 bicalutamide  501, 2393t bicarbonate (HCO3-​) adult values  6581t normal blood values  6583t reabsorption, early (S1) proximal convoluted tubule  4723 reabsorption in proximal tubule  5105 bicipital tendonitis  4412t biclonal gammopathies, monoclonal gammopathy of undetermined significance  5313 bicuspid aortic valve  3570 pregnancy  2602, 2603f bicycle ergometry  3311, 3311t, 3968 Biermer’s anaemia see acquired pernicious anaemia bilateral adrenalectomy  2343–​44, 2546 bilateral sequential single lung transplantation  4295, 4296f bilateral tonic–​clonic seizures, epilepsy  5864 bile composition-​affecting drugs  5153

  Index 25 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 formation, liver  3038f, 3038 manufacture of  3197b, 3197 physiological functions  3038t bile acids excretion and reabsorption  2061 malabsorption diarrhoea  2759t irritable bowel syndrome  2955 primary biliary cholangitis  3130f, 3130 synthesis, cholesterol  2061f, 2061 bile acid sequestrants (resins)  2074t, 2092, 5153 bile duct congenital disorders  3207 choledochal cysts  3207f, 3207, 3208f, 3208t stones, jaundice  3055 bile salt export pump (BSEP)  3192f, 3192, 3192t bile salts diarrhoea, cholecystectomy  3204 malabsorption  2878 metabolism, liver  3039 bilharzia see schistosomiasis biliary canaculi  3036, 3037t, 3196–​97 biliary colic  2769t, 3199 biliary tract anatomy  3033f, 3034 common bile duct  3033f anatomy  2723f, 3197f stones, management  3202 drainage, pancreatic ductal adenocarcinoma management  3232 imaging, jaundice  3056 self-​expandable stents  2746f, 2746 biliary tract disorders  3196 atresia, neonatal cholestasis  3191f, 3191 biliary strictures  3206 ERCP see endoscopic retrograde cholangiopancreatography (ERCP) IgG4-​related sclerosing cholangitis  3206 primary sclerosing cholangitis  3206 secondary sclerosing cholangitis  3207 clinical features  3197, 3197t cystadenoma, benign liver tumours  3190 cystic fibrosis  4153 dyspepsia, gallstones  3200 indeterminate biliary structures  3205f, 3205, 3205t obstructive jaundice  3197t, 3205 investigations  3197 imaging  3198 laboratory investigations  3197 tumour markers  3198 leaks, endoscopic retrograde cholangiography  2745 liver transplantation  3104 obstruction chronic pancreatitis  3221 chronic pancreatitis management  3226 biliary tree anatomy  3196–​97 endoscopy see endoscopy physiology  3196 bilirubin acute hepatitis  3111 adult values  6581t circulating pool  3050 congestive hepatopathy  3168 CSF pressure  5783 drug-​induced liver disease  3155 evolutionary aspects  41 metabolism, liver  3039f, 3039 physiology of  3049, 3050f primary biliary cholangitis  3135 subarachnoid haemorrhage  6024–​25 binge eating disorder classification/​diagnosis  6509b clinical features  6511 cognitive behavioural management  6532 epidemiology  6510f management  6512, 6513b biochemical analysis  6577 amyloidosis diagnosis  2230 blood gases  6583t carcinoid syndrome  2872 chylothorax  4317 complication diagnosis  6577 congenital adrenal hyperplasia management  2364 development of  6577 diagnosis  6577 diagnostic enzymes  6582t disease monitoring  6577 faecal reference intervals  6587t hormones  6583t human prion diseases  6117 immunoproteins  6586t lysosomal disease diagnosis  2135 management response  6577 metals  6586t nonalcoholic fatty liver disease  3151 organ system profiles  6582t Paget’s disease  4640 post-​test odds  6580 pre-​test odds  6580 prognosis  6577 protein-​dependent inborn errors of metabolism emergency management  1948 proteins  6586t receiver–​operator characteristic curve see receiver–​operator characteristic (ROC) curve reference intervals  6578 respiratory chain disorders  6347 routine tests  6581t screening  6578 skeletal disorders  4628 spinal cord disorders  6131–​32 tests  6578 accuracy  6578 precision  6578 sensitivity  6578 specificity  6578 therapeutic drugs  6587t trace elements  6586t tumour markers  6585t urinary reference intervals  6587t vitamins  6585t Wilson’s disease  2117 biocompatible dialysis membranes, haemodialysis  4864b, 4864 bioimpedance scanning (BIA)  523, 1916 bioinformatics  67, 70t analytical tools  68, 69t common semantic turns  68, 68t data storage  68 digital imaging  69 infectious diseases  69 oncology research  68 pharmacogenomics  69 biological disease-​modifying anti-​ rheumatic drugs  4437, 4437t biological membranes, dynamic cells  215, 216f biological pollutants, indoor air pollution  1683 biological therapies  100, 101t biosimilars  106 B-​lymphocyte stimulators  104 classification  102, 103t cytokine management  241–​42 drug-​induced interstitial pneumonitis and fibrosis  4278 future developments  106 antibody fragments  107 stratified medicine  106 immune-​mediated inflammatory disease  101t, 102, 103f cytokine targets  102 growth factor targets  102 immunogenicity  106 immunosuppressants, adverse reactions  4890 intercellular interactions  104 adhesion molecule blockers  105 costimulation blockade  104, 105f pancreatic ductal adenocarcinoma management  3233 pathogenic cell depletion  105 pregnancy  2666 psoriasis management  5626 rheumatoid arthritis management in pregnancy  2662 skin disease management  5768, 5770 systemic lupus erythematosus management  4511 therapeutic antibodies  100, 102f see also therapeutic antibodies biological valves, heart valve surgery  3670 biological weapons see bioterrorism biomarkers ACS outcomes  3630, 3631f, 3631t acute pulmonary embolism  3724 asthma pathophysiology  4070 cardiac arrest prognosis  3846 cardiogenic pulmonary oedema  3400–​1 cardiovascular biomarkers, pneumonia  4018 coronary heart disease  3613 critical care surgery  3863 interstitial lung disease in rheumatological disease  4198 left ventricular wall stress  3632 myocardial damage  3630 nosocomial pneumonia diagnosis  4025 osteoarthritis pathogenesis  4478 osteoporosis  4699 pleural mesothelioma  4363 pneumonia management  4018 stable angina  3622 biopsies adenocarcinoma/​gastro-​ oesophageal junction tumours  2843 amyloidosis diagnosis  2229 brain see brain bronchial see bronchi cancer investigations  489 cutaneous lymphoma  5740 endomyocardium see endomyocardial biopsies hereditary fructose intolerance (fructosaemia)  1999 kidney see renal biopsies lymphoproliferative disorders  5267 McLeod’s syndrome  6251 oral cancer  2806 percutaneous  4002 pancreatic ductal adenocarcinoma  3231 percutaneous lung biopsy  4002 pleural biopsy  4002 polyarteritis nodosa  4570 pyoderma gangrenosum  4603 silicosis  4229–​30 skin see skin biopsies vascular peripheral neuropathy  6192 see also endobronchial ultrasound-​ guided fine needle aspiration biopsies (EUS-​FNA); endoscopic biopsies; fine needle aspiration biopsies; percutaneous needle biopsies; transbronchial lung biopsies (TBLB) biopterin metabolism defects  1971, 1973f clinical presentation  1973 diagnosis  1973 management  1973 outcome  1973 bioresorbable stents  3659 biosimilars  106 insulins  2493 psoriasis management  5627 bioterrorism  1718 areas of uncertainty/​ controversy  1723 biological weapons, 1719 infectious and contagious diseases  1719 infectious not contagious diseases  1720 toxins  1720 clinical features  1721 decontamination  1723 differential diagnosis  1721 dissemination of  1720 early detection  1721 epidemiology  1720f, 1720 investigations  1722

26 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 ethical aspects  1723 future developments  1723 historical perspective  1719 isolation  1722 legal aspects  1723 postexposure prophylaxis  1722 prevention  1720 public education  1722 quarantine  1722 risk communication  1722 surveillance  1721 biotin (vitamin H)  1856t, 1868 biotinidase deficiency management  1965–​66 deficiency  1868 functions  1868 holocarboxylase synthetase deficiency management  1966–​67 nutritional support  1918 requirements  1868 structure  1868f biotinidase deficiency  1955f, 1965, 1966f BiPAP  3834, 6292 biphasic anaphylaxis  3856 bipolar disorder  6498 aetiology  6498 clinical features  6498, 6499f depression  6499 hypomania  6498b, 6499 mania  6498b, 6499 differential diagnosis  6499 medical comorbidities  6500 psychiatric comorbidities  6499 schizophrenia  6515 epidemiology  6498 maintenance management  6500 drug management  6500 psychological management  6498b, 6500, 6501b management  6500, 6500t acute depression  6500 acute mania  6500 antipsychotic drugs  6469 sodium valproate  6468 mania  6448 outcome  6501 pregnancy  6501 bird fancier’s lung  4247 bird poisons  1801f, 1801 Birmingham Atrial Fibrillation in the Aged (BAFTA) study  3372 Birmingham Vasculitis Activity Score (BVAS)  4554, 4554t, 4566, 4997 birth (delivery) brachial plexus traction lesions  6180–​81 cardiac disease and  2600 decisions, critical care in pregnancy  2702, 2702t HIV/​AIDS in pregnancy  2679 inflammatory bowel disease  2625 malnutrition  1883 pregnancy in diabetes mellitus  2636 premature see premature birth preventative programme effectiveness  135 timing of, pre-​eclampsia management  2586 venous thromboembolism  2612 management  2610 see also labour birth asphyxia, cerebral palsies  6365 Birt–​Hogg–​Dubé syndrome  466, 5071t chromophobe renal cell carcinoma  5140 FOLLICULIN gene  465, 466 genetics  5071 predisposition genes  461t bismuth chelate (tripotassium dicitratobismuthate), poisoning by  1739 bisoprolol  3365t, 3415–​16 bisphosphonates adverse reactions eye diseases/​disorders  6437 osteonecrosis of the jaw  4704 bone metastases management  4357, 4712 Duchenne’s muscular dystrophy management  6318 osteoporosis management  4700 CKD  4848 Paget’s disease management  4642 septic arthritis management  4460 bites  6552, 6553f nonvenomous arthropods see nonvenomous arthropods bivalirudin  3638, 5157 BK virus infection interstitial nephritis  5037 renal transplant immunosuppression  4893 UTI post-​renal transplantation  5088 black cohosh (Actaea racemosa)  203 drug interactions  205t safety  204 black piedra  1344 black urine  4783 bladder catheterization cardiogenic shock  3406 urinary incontinence  594 diary, urinary incontinence  591 bladder cancer  5136 aetiology  5136 assessment  5137 asymptomatic nonvisible haematuria  4767 clinical features  5136 epidemiology  440, 5136 artificial sweeteners  440 medicines  440 occupation  440 parasitic infections  440 tobacco  440 incidence  413t management  5139 localized muscle-​invasive disease  5138f, 5139 metastatic muscle-​invasive disease  5140, 5140t non muscle-​invasive disease  5139, 5139t programmed death-​1 blocking  483 pathogenesis  5136 prognosis  5137 staging  5137 bladder disorders abnormal emptying, UTI  5076, 5077b, 5086 multiple sclerosis  6031, 6035 spinal cord injury  6143 Blalock–​Taussig shunt, tetralogy of Fallot  3585f, 3585, 3585t Blastocystis infection  1449 aetiology  1450 biology  1450f, 1450 clinical features  1451 diagnosis  1450 epidemiology  1450 management  1451 pathogenicity evidence  1451 blastomycosis  1352 liver disease  3175 Blau’s syndrome  2208t, 2214, 2215f bleaches  1772, 5679 bleeding see haemorrhage bleeding tendencies  5509 anaemia causes  5363 clinical assessment  5510 clinical examination  5511 general aspects  5512 mucosa  5512 musculoskeletal system  5512 skin  5511 splenomegaly  5512 haemolysis  5385 history taking  5510 bleeding patterns  5510 dental extraction  5511 drug history  5511 epistaxis  5511 family history  5511 gingival bleeding  5511 haemostatic capacity assessment  5510 menorrhagia  5511 purpura  5510 severity  5510 surgery  5511 unusual sites  5511 investigations  5512, 5517 acquired haemophilia  5519 acquired von Willebrand’s syndrome  5519 activated partial thromboplastin time  5513 anatomical imaging  5518 antiplatelet drugs  5518 bleeding time  5517 blood count  5513 blood film  5513 critically ill patients  5518 dilutional coagulopathy  5518 direct oral anticoagulants  5518 disseminated intravascular coagulation  5518 drug-​induced bleeding  5518 factor assays  5516f, 5516, 5517t fibrinogen level  5516 haemostasis assessment  5513, 5514t haemostasis global tests  5517 hyperfibrinolysis  5520 laboratory tests  5512 liver disease  5519 mixing studies  5516 neonatal bleeding  5520 platelet function analysis  5516 prothrombin time  5513 renal disease  5519 surgical bleeding  5518 thrombin time  5516 thrombocytopenia  5519 vitamin K antagonists  5518 von Willebrand protein levels  5519 iron deficiency
investigation  5388 management  5520 acute bleeding  5520 nonacute bleeding  5520 see also coagulation disorders bleeding time acquired coagulation disorders  5548t bleeding tendencies  5517 bleomycin adverse reactions, nodular regenerative hyperplasia  3164 drug-​induced alveolar disease  4278 drug-​induced pulmonary vasculature  4280 skin disease management  5768 bleomycin/​etoposide/​cisplatin (BEP)  5147 blepharitis  6408t, 6411, 6413f, 6414f blinatumomab  479 blindness causes  6400 age-​specific macular degeneration  6406f, 6407, 6408t, 6412f cataract  6400, 6401t diabetic retinopathy  6404, 6408t, 6411f glaucoma  6404, 6406f uncorrected refractive error  6407 epidemiology  6400, 6406f falls in elderly  581 giant cell arteritis  6381 gradual vision loss  6400t mitochondrial DNA point mutations  6346 paraneoplastic neurological syndromes  6390 subacute vision loss  6400t vitamin A deficiency  1856, 1888 see also vision disorders Blomstrand’s disease, hypoparathyroidism  2329 blood cellular components  5173t CSF  5783 development  5170 high terrestrial altitude acclimatization  1703 HIV/​AIDS in LMICs  935 blood-​borne infections, travel and expedition medicine  716 blood–​brain barrier  6063, 6070 blood count bleeding tendencies  5513 haematological malignancies  5182 systemic lupus erythematosus  4509

  Index 27 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 blood cultures acute osteomyelitis  4693 autosomal dominant polycystic kidney disease  5087–​88 endocarditis  3524, 3525t pneumonia management response  4020 blood diseases/​disorders  5169 folate deficiency  5419 blood disorders malignancies, oral manifestations  2824 blood films bleeding tendencies  5513 haematological malignancies  5182 lysosomal disease diagnosis  2135 blood gases biochemical analysis  6583t normal values  6583t blood gas tension  4283 gas transport in the tissues  4285, 4285t hypercapnia  4284 alveolar hypoventilation  4284f, 4284 combined effects  4284 ventilation/​perfusion abnormality  4284 hypoxaemia  4283, 4283t alveolar hypoventilation  4284 anatomical shunting  4284 diffusion limitation  4284 ventilation/​perfusion mismatch  4283f, 4283 pulmonary gas exchange  4283 special circumstances  4284 blood glucose concentration/​ measurement diabetes mellitus  2467, 2501 sports medicine  6569–​70 diabetes mellitus type 2  2484 gender assessment in DSD  2446–​47 hypoglycaemia in diabetes mellitus  2532 phaeochromocytomas  3793 status epilepticus  5878 viral infections of CNS  6091–​92 blood group systems  5566, 5567t, 5568f ABO system see ABO system compatibility in liver transplantation  3102 Rh system  5566 blood natriuretic peptide (BNP)  3282, 3283f, 3283t blood oxygen level-​dependent magnetic resonance imaging (BOLD-​MRI)  4801, 5048 blood pressure measurement monitors  3756 blood pressure (BP) acute aortic syndrome  3677 ageing  543 cardiorenal syndrome  3423 chronic heart failure  3420 chronic tubulointerstitial nephritis agricultural communities  4964 coronary heart disease risk factors  3607f, 3607, 3608f diabetic nephropathy  4976, 4983, 4984 drop, spinal cord injury  6140–​41 epidemiology trials  64f, 64, 65f hypertension  3740, 3741f, 3755b, 3755, 3756t management CKD management  4840, 4843f diabetic nephropathy prevention  4981 liver disease in pregnancy  2620–​21 melatonin  2558 measurement scleroderma management in pregnancy  2666 pregnancy  2563, 2578, 2597–​98 salt in diet  1895 stroke and  1895 urinary stones  5095f, 5095 vasopressin release  2279 blood products acute myeloid leukaemia  5210 HIV/​AIDS transmission  930 LMICs  935 blood substitutes, blood transfusion  5577 blood-​sucking flies (Diptera)  1569, 1569t, 1570f, 1571f blood tests acute aortic syndrome  3678 acute mesenteric ischaemia  3000 acute pulmonary embolism  3724 autoimmune encephalopathy with NMDAR antibodies  6395 autoimmune limbic encephalitis with VGKC-​complex antibodies  6393 bronchiolitis obliterans  4187 chronic heart failure  3420 cryptogenic organizing pneumonia  4189 dementia  6479 diabetic ketoacidosis  2506–​7 diffuse parenchymal lung disease diagnosis  4173 dyslipidaemia diagnosis  2088 hepatic encephalopathy  3085 idiopathic pulmonary fibrosis  4181 iron status evaluation  5374 liver failure investigations  3095, 3096t low back pain diagnosis  4409 malabsorption  2877 muscle disorders  6308 osteoarthritis  4478 pancreatic ductal adenocarcinoma investigations  3230 pelvic inflammatory disease management  1624 primary intracerebral haemorrhage  6023 primary thyroid epithelial tumours  2305 PSC  3138 pulmonary arterial hypertension investigations  3700 rheumatological diseases see rheumatological diseases septic arthritis  4458 Sjögren’s syndrome  4534 spinal cord disorders  6131–​32 syncope  5900 systemic lupus erythematosus  4509 blood transfusions  5563 acquired aplastic anaemia management  5343 acute respiratory distress syndrome  3879 anaemia of inflammation management  5406 antibodies  5567 alloantibodies  5567 autoantibodies  5568 compatibility testing  5568 autologous  5577 collection of  5564 complications  5564, 5571, 5571t, 5572t acute intravascular haemolytic reaction  5571 acute lung injury  5573 acute pain transfusion reaction  5574 allergic reactions  5572 associated circulatory overload  5573 associated dyspnoea  5573 delayed extravascular haemolytic reactions  5571 febrile non haemolytic reactions  5572 hypotension transfusion reaction  5574 post-​transfusion purpura  5574 septic reactions  5572 transfusion-​associated circulatory overload  5573 transfusion-​associated dyspnoea  5573 transfusion-​associated graft-​ versus-​host disease  5573 transfusion malaria  1407 transfusion-​related acute lung injury  5573 transmitted hepatitis  3111 component alternatives  5577 autologous transfusion  5577 blood substitutes  5577 growth factors  5577 component use  5563, 5566t, 5568 cryoprecipitate  5570 granulocytes  5571 plasma  5570 plasma derivatives  5570 platelets  5565f, 5569 red blood cells  5569 disease transmission  5574, 5574t gastrointestinal infections transmission  3016 haematopoietic stem cell transplantation management  5586 iron overload  5392 molecular testing  5577 Neisseria meningitidis infection management  1023 peptic ulcer bleeding management  2857 pretransfusion testing  5565f, 5565 processing  5564, 5565f special blood products  5575 cytomegalovirus-​safe products  5576 frozen products  5576 irradiation  5575 leucoreduction  5575 pathogen reduction  5576 volume reduction  5576 washed blood products  5576 variceal bleeding  3072 blood vessels adventitia  3242, 3252 angiogenesis  3251 cell growth  3251 cellular adhesion  3250 cellular constituents  3242 chest radiography  3980 disorders of cyanotic heart disease  3564 Fabry’s disease  2144 skin see skin diseases/​disorders endothelium  3242, 3243f anatomy  3243f, 3243 angiogenesis  3251f, 3251–​52 development  3242–​43 metabolism  3252 microvesicles  3252 platelet inhibition  3250 signal detection  3243 transport  3252 vascular damage and repair  3243, 3244f intima  3242 media  3242 pericytes  3244f, 3244 perivascular adipose tissue  3252 proinflammatory cytokines  3251 vascular smooth muscle cells  3245 vasoconstriction see vasoconstrictor drugs blood vessel walls  5491f, 5491 adventitia  5494 endothelial cells  5492 anticoagulant properties  5492, 5492t procoagulant properties  5492t, 5493f, 5493 receptors  5493, 5493t vascular tone  5492, 5492t extracellular matrix  5493, 5494t smooth muscle cells  5494 blood volume anaemia in pregnancy  2687 medication in pregnancy  2707 systemic arterial blood pressure regulation  3269f, 3269 bloody diarrhoea (dysentery) acute  3018 Bloom’s syndrome  458t, 467, 5689t BLM gene  467 cancer susceptibility  415 blue rubber bleb naevus syndrome  3006t, 5718 blue urine  4783 BMI see body mass index (BMI) BMPs see bone morphogenetic proteins (BMPs) BNP see brain natriuretic peptide (BNP) BOADICEA model  467 bocavirus infection  725t, 733, 953 Bochdalek posterior diaphragmatic hernia  4374

28 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 BODE index, COPD  4121, 4121t body lice  1575 body mass index (BMI) acute fatty liver of pregnancy  2622 artificial nutrition assessment  1916 COPD  4116 hypertension  3744 malabsorption  2877 obesity definition  6529f, 6531 obesity diagnosis  1903, 1908 osteoporosis clinical risk factors  4699 pregnancy  2568 pregnancy outcomes  2576 primary spontaneous pneumothorax  4322 renal transplant recipients  4882 body plethysmography  3957–​58, 4117 body temperature, C-​reactive protein  2205 Bolivian haemorrhagic fever see arenaviruses bolus consistency, dysphagia management  2842 bombesin  2866 bone biochemical measures of turnover  4626, 4626t biopsies osteomalacia/​rickets  4635 skeletal disorders  4631 calcium balance  4624f, 4624 cells  4618, 4639f collagen  4622 formation  4620 healing, spinal cord injury  6137 mass of  4621 change  4697f, 4697 see also osteoporosis mineralization  4624 noncollagen proteins  4622 pain CKD in vs., 4830 osteomalacia/​rickets  4634 skeletal disorders  4627 phosphorus balance  4624f, 4624 physiology  4616 remodelling  4698 remodelling cycle  4618–​19 resorption  4618, 4620, 4699 shape/​alignment in osteoarthritis  4474 sport and exercise medicine  6567 structure  4618 system profiles  6582t bone age  2425, 2432 bone cancer  4709 chondrosarcoma  4710, 4711f classification  4709t epidemiology  433, 434f Ewing sarcoma  4710, 4712f extrapulmonary tuberculosis  4028 investigation  4709 metastases  4712f, 4712 carcinoid syndrome management  2874 local disease vs.  4710 osteosarcoma see osteosarcoma presentation  4709 staging of  4710 warning signs  4393t bone disease  4393, 4393t actinomycoses  1174 anaerobic bacterial infections  1058 bone cancer see bone cancer cancer see bone cancer cystic fibrosis  4163 fractures, 4627 osteochondritis dissecans see osteochondritis dissecans osteochondrosis see osteochondrosis osteomyelitis see osteomyelitis osteonecrosis see osteonecrosis osteoporosis see osteoporosis Pseudomonas aeruginosa infection  1043 tuberculosis  1137 bone marrow aspirate  5341, 5342f, 5406 B cell development  331 cytogenetics, acquired aplastic anaemia  5342 decreased platelet production disorders  5530 examination, haematological malignancies  5183 haematopoiesis in adults  5174 haematopoietic stem cell transplantation  5582 megaloblastic anaemia  5420f, 5420 myelodysplastic syndromes  5202 transplantation  5172 acute myeloid leukaemia management  5209 Gaucher’s disease type 1 management  2143 haemorrhagic cystitis, human polyomaviruses  884 human cytomegalovirus infection  747 metachromatic leucodystrophy management  6212 mitochondrial myopathies  6349 mucopolysaccharidoses management  2148 paroxysmal nocturnal haemoglobinuria management  5349f, 5352 purine nucleoside phosphorylase deficiency  2029 bone marrow failure (BMF) disorders  5325, 5336, 5337f anaemia of inflammation vs.  5405 erythroid cell lineage effects  5346 see also pure red-​cell aplasia future development  5348 inherited syndromes  5325, 5325b, 5326t congenital dyserythropoietic anaemia see congenital dyserythropoietic anaemia congenital thrombocytopenias see congenital thrombocytopenias Diamond–​Blackfan anaemia see Diamond–​Blackfan anaemia dyskeratosis congenita see dyskeratosis congenita Fanconi’s anaemia see Fanconi’s anaemia severe congenital neutropenia (SCN) see severe congenital neutropenia (SCN) Shwachman–​Diamond syndrome see Shwachman–​ Diamond syndrome management, eculizumab  5353 paroxysmal nocturnal haemoglobinuria see paroxysmal nocturnal haemoglobinuria (PNH) see also aplastic anaemia; pure red cell aplasia bone mineral density (BMD)  586, 4698 bone morphogenetic proteins (BMPs)  243, 262, 3697, 4616–​18 borderline lepromatous leprosy (BL)  1158, 1159f borderline leprosy (BB)  1158, 1159f borderline tuberculoid leprosy (BT)  1158f, 1158, 1159f Bordetella infection  1073 aetiology  1073 clinical features  1074 clinical investigations  1075 diagnosis  1075 differential diagnosis  1074 epidemiology  1073 morbidity  1073 mortality  1073 prevention  1074 management  1075, 1075t pathogenesis/​pathology  1074 prognosis  1076 Bornholm disease (epidemic pleurodynia)  791, 3950 Borrelia burgdorferi infection see Lyme borreliosis Borrelia recurrens infection see relapsing fevers bortezomib  502–​3 adverse reactions, neuropathies  6188 AL amyloidosis management  2232 monoclonal Ig-​dependent diseases management  5021 renal disease in myeloma  5020 bosentan  2713, 3706, 5155 Bosniak classification, renal cancer  5141, 5141t botulinum antitoxin  3021 botulinum toxin glutaric aciduria type I management  1963 headache prevention  6001 hemifacial spasm management  6124 hyperhidrosis management  5703 idiopathic achalasia management  2839 migraine prevention  5993t neuronal ceroid fucinoses management  2152 Parkinson’s disease  607–​8 tension-​type headaches  5995 botulism  1121 diagnosis  1122 history  1121 infant botulism  1123 management  1122 occurrence  1121 pathogenesis  1121 physical examination  1122 toxin  1121 wound botulism  1123 Bourbon virus  956 Bourneville’s disease see tuberous sclerosis complex (Bourneville’s disease) bovine spongiform encephalopathy (BSE)  6110, 6115 Bowditch effect  3272, 3274 bowel resection  2911 acute phase management  2913 anatomy  2913 nutritional support  2913, 2913t sepsis  2913 surgery  2913 aetiology  2912 chronic phase management  2914 feeding and adaptation  2914f, 2914, 2914t long-​term plans  2914f, 2914, 2915t socialization  2914 long-​term complications  2915, 2915t management  2913 pathophysiology  2912 electrolyte depletion  2912f, 2912 gut motility  2912 hormones  2912 micronutrients  2913 secretion  2912 vitamins  2913 water depletion  2912f, 2912 surgery  2915 intestinal function optimization  2915 transplantation  2915 Bowenoid papulosis  1618 Bowen’s disease  5734 BPO see benzoyl peroxide (BPO) brachytherapy  499t, 503, 3661 bradycardias  3353 acute presentation  6598 aetiology  3353 cardiac syncope  3289t causes  3354 asystole  3356 atrioventricular conduction disorders  3354 see also atrioventricular block neurocardiogenic syncope  3354 sinoatrial disease  3354f, 3354, 3355f complete transposition of the great arteries  3582 management  3353 acute management  3353, 3354t pacemaker management  3356 pacemaker management see pacemakers raised intracranial pressure  3895 symptoms  3352 syncope  3289 vasovagal syncope  5897 bradykinesia, Parkinson’s disease  602, 5949

  Index 29 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 BRAF gene malignant melanoma  453–​54, 5738 non-​small cell lung cancer  4342 papillary thyroid carcinoma  2302–​3 brain abscesses, traumatic brain injury  6046 activity monitoring critical care  3904 sedatives  3904 acute-​on-​chronic liver failure  3094 anoxic damage  6369 atrophy, cerebrotendinous xanthomatosis  6221–​22 autopsy methods  6559 biopsies human prion diseases  6118 toxoplasmosis in HIV/​ AIDS  6103 cancer  414 optic chiasm disorders  5919 death  5908 brainstem-​auditory evoked potentials  5790 definition  3915t frailty in ageing  527 higher functions see higher brain function hypertension pathophysiology  3750 imaging cardiac arrest  3845 Wilson’s disease  2118 lung cancer metastases  4346f, 4346 neurological disease see paraneoplastic neurological syndromes (PNS) oxygen deprivation  6369 postmortem examinations  6559 reductive adaptation  1885 statin adverse reactions  2074t, 2092 support, liver failure management  3098 traumatic injury see traumatic brain injury weight in Alzheimer’s
disease  5836 see also central nervous system (CNS) brain natriuretic peptide (BNP)  2221, 3748, 3863, 6583t brainstem auditory evoked potentials evoked potentials  5790 hearing disorders  5934f, 5934 neuropsychiatric adult peroxisomal disorders  2162 autonomic nervous system  6150–​51 circulation  6006 coma  5903f, 5904 encephalitis  6390 glioma imaging  5813 multiple sclerosis  6031 reflexes  3846, 6542 coma  5907 reticular activating complex  5945 reticular formation nuclei  5823 syndromes see neurological disorders brainstem death  5908 actions following  5909 ancillary tests  5909, 5910f children  5909 conduct of tests  5909b, 5909 diagnostic criteria  5908 prerequisites  5908 branched-​chain amino acid metabolism disorders  1949t, 1954 3-​hydroxyisobutyryl-​CoA hydrolase deficiency  1949t, 1961 isovaleric aciduria (isovaleryl-​CoA deficiency)  1945b, 1949t, 1955f, 1956 malonic aciduria  1962 maple syrup urine disease see maple syrup urine disease 2-​methyl-​3-​hydroxybutyryl-​ CoA dehydrogenase deficiency  1949t, 1959 3-​methylcrotonylglycinuria  1949t, 1955f, 1957 3-​methylglutaconic acidosis  1957 methylmalonic aciduria  1949t, 1955f, 1960 primary 3-​methylglutaconic acidosis  1957 3-​methylglutaconic aciduria type  1957 propionic aciduria  1949t, 1955f, 1959, 1960f secondary 3-​methylglutaconic acidosis  1958 DNAJC19 defect (dilated cardiomyopathy with ataxia (DCMA) syndrome/​3-​ methylglutaconic aciduria type V)  1949t, 1958 3-​methylglutaconic aciduria type III  1958 3-​methylglutaconic aciduria type IV  1949t, 1958 OAP3 defect (Costeff’s syndrome/​3-​ methylglutaconic aciduria type III)  1949t TAZ defect (Barth’s syndrome/​
3-​methylglutaconic aciduria type II)  1949t, 1958 short-​chain enoyl-​CoA hydratase deficiency  1961 branched-​chain amino acids (BCAAs)  1849–​50, 3087 branch retinal artery occlusion  6413, 6414f, 6415f Braunwald classification, ACS  3628t, 3629–​30 Brazil  430–​31, 4228 BRCA1 gene breast cancer predisposition  133t, 462 colorectal cancer  2988–​89 DNA sequencing  450 ovarian cancer predisposition  463 BRCA2 gene breast cancer predisposition  133t, 462 coding of  447 DNA sequencing  450 Fanconi’s anaemia  467 melanoma predisposition  463 ovarian cancer predisposition  463 prostate cancer  5143 breakthrough pain  632 breast cancer adult screening  149t aetiology  424 age-​related incidence  415 carcinogenesis  459 cutaneous metastases  5741 diagnosis  505 epidemiology  435, 436f genetics  462 BRCA1 gene  462 BRCA2 gene  462 CDIII gene  462 genome-​wide association studies  224t predisposition  461t TP53 gene  462 incidence  413t migrant groups  414t management see breast cancer management paraneoplastic cerebellar degeneration  6388 paraneoplastic neurological syndromes  6386 pregnancy  2699 preventative medicine  133t prognosis  505–​6 screening  505 Breast Cancer Linkage Consortium  460–​62 breast cancer management  505 adjuvant management  506 chemotherapy  506 endocrine management  506 HER2-​positive breast cancer  505–​6 radiotherapy  506 metastatic disease  507 chemotherapy  507 endocrine management  507 neoadjuvant systemic management  507 personalized management  453t surgery  506 breast disease, benign  2406 breast inflammation  2407 breast pain (mastalgia)  2407 congenital abnormalities  2406 development abnormalities  2406 benign cystic change  2406 fibroadenomas  2406f, 2406 macrocysts  2407 diabetic mastopathy (lymphocytic lobulitis)  2407 fat necrosis  2407 fibromatosis  2407 hamartoma  2407 male breast  2408 nipple areolar complex  2407 nipple discharge  2407f, 2407 phyllodes tumour  2407 breast disorders benign disease see breast disease, benign cancer see breast cancer inflammation  2407 pain (mastalgia)  2407 breastfeeding ACE inhibitors contraindications  3414 adverse drug reactions  91, 92t anticonvulsants  5877 critical care in pregnancy  2702 diabetes mellitus and  2636 epilepsy management in  2643 hypoglycaemia in diabetes mellitus  2533 medications in  2709 promotion of  134t see also lactation breathing mechanics, respiratory function tests  3957 pattern in respiratory disease  3951 sleep, during  4049f, 4049 heart failure  4050 regulation  4050, 4051f REM sleep  4050 respiratory muscles  4050, 4051f breathlessness (dyspnoea)  3280f, 3280 causes  3281, 3281t, 3948 acute pulmonary embolism  3718–​19, 3724 airways disease  3281, 3283 asthma  3948 carcinoid syndrome  2871 chronic thromboembolic pulmonary hypertension  3708 COPD  4113 Eisenmenger’s syndrome  3565 hepatopulmonary syndrome  3070 Langerhans cell histiocytosis  4256 left ventricular failure  3277t, 3281 lung cancer  4344 metastatic pleural malignancy  4366 preserved ventricular function with  3283 pulmonary arterial hypertension  3696t, 3699 pulmonary embolism  3281, 3283 respiratory disease  3947, 3948t scoliosis  4331 classification  3281t management hypertrophic cardiomyopathy  3476 palliative care  634t, 635 normal pregnancy  2578 pregnancy  2615 time course  3281 breath sounds, respiratory disease  3954 breath tests malabsorption  2878 small intestine bacterial overgrowth  2882, 2882t brief counselling  6472

30 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 Bristol Stool Chart  598b, 598f, 598, 2759–​61, 2762f British and American Thyroid Association  2306, 2307t British Heart Foundation  58–​59, 178–​79 British Hypertension Society (BHS)  3755b, 3755, 3772, 3773f, 4984 British Medical Association (BMA)  156, 156t British Medical Council (BMC)  185, 6071f, 6081 British National Formulary (BNF)  73, 92 British Society for Allergy and Clinical Immunology  3858 British Society for Rheumatology  4587 British Society of Antimicrobial Chemotherapy  3530 British Society of Gastroenterology  2741, 3123 British Society of Rehabilitation Medicine  6043 British Thoracic Society (BTS) acute exacerbations of COPD  4138–​39 asthma management  4081, 4082f, 4083 COPD  4103 diffuse parenchymal lung diseases  4167 pneumothorax management  4322–​23 tuberculous meningitis management  6079 British United Provident Association (BUPA)  3862, 3862t Brittle Cornea Syndrome see Ehlers–​ Danlos syndrome (EDS) brittle diabetes  2485t, 2499 brivaracetam  5873t, 5875 broadband UVB  5625, 5767 broad-​complex tachycardias  3361, 3362f broad-​spectrum antibiotics  690, 2883 Broca’s aphasia  5824 brodalumab  104, 4090 bromhidrosis  5700 bromocriptine  2498 aromatic L-​amino acid decarboxylase deficiency management  1977 drug-​induced pleural disease  4280 idiopathic oedema of women management  3824–​25 Parkinson’s disease management  5953 peripartum myocarditis  3463 prolactinoma management  2270–​71 bronchi  3939, 3940, 3941f adenomas  4358 biopsies bronchoscopy  3995 chronic bronchitis  4105–​6, 4106t carcinoids  4358 carcinoma  431 cartilage rings  3943 chest radiography  3980 iron loss  5384 mainstem branching angles  3940 stent placement  3973, 3974f bronchial arteriography, thoracic imaging  3978, 3980f bronchial brushings, bronchoscopy  3995 bronchial hyper-​responsiveness HIV/​AIDS  4038 sport and exercise medicine  6568 bronchiectasis  4142 aetiology  4143, 4143t associated conditions  4145 cystic fibrosis  4147 HIV/​AIDS  4038 rheumatoid arthritis  4194 ulcerative colitis  4145 clinical features  4145 cough  3949 examination  4146 history  4145 complications  4150 definition  4142 differential diagnosis, COPD  4122t epidemiology  4142 future work  4150 idiopathic  4142 investigations and diagnosis  4146, 4147t cause determination  4147, 4147t chest radiography  3990, 3991f disease state determination  4146, 4146t imaging  4146f, 4146 management  4147b, 4147 anti-​inflammatory management  4148 antimicrobial therapy  4148, 4149f bronchodilators  4148 inhaled antibiotics  4148 lung transplants  4150 macrolides  4148 monitoring  4149 sputum clearance  4147, 4148t surgery  4149 pathogenesis  4143, 4144f developmental defects  4143 excessive immune response  4144f, 4144 immune deficiency  4144 infections  4143, 4145 mechanical obstruction  4145f, 4145 mucociliary clearance deficiency  4143, 4144 toxic insult  4145 pathology  4143 microscopic features  4143 prognosis  4150 bronchioles  3940, 3941f, 4185 terminal see terminal bronchioles bronchiolitis obliterans  4186 causes  4186t clinical features  4186, 4186t differential diagnosis  4187 histopathology  4186, 4187f investigations  4186, 4187f management  4187 rheumatoid arthritis  4194 see also cryptogenic organizing pneumonia; follicular bronchiolitis bronchiolitis obliterans syndrome (BOS)  4300–​1, 4301t bronchiolitis, severe constrictive  4270f, 4270 bronchiolitis/​small airways disease, COPD pathology  4107, 4108f bronchitis, chronic  4080, 4105, 4106f, 4106t bronchoalveolar lavage (BAL) bronchoscopy  3997, 3997t diffuse alveolar haemorrhage  4235 diffuse parenchymal lung disease diagnosis  4174 hypersensitivity pneumonitis  4250, 4252 idiopathic pulmonary fibrosis  4181 interstitial lung disease in rheumatological disease  4198 neutrophils, interstitial lung disease in rheumatological disease  4198 nosocomial pneumonia diagnosis  4025 pulmonary alveolar proteinosis  4260 sarcoidosis  4209, 4210, 4214, 4218 bronchodilators acute asthma management  4094 acute exacerbations of COPD  4139 bronchiectasis management  4148 COPD management  4126, 4127f, 4127 cystic fibrosis  4160 renal disease, effects of  5158 bronchogenic cysts  4373f, 4373 bronchoscopic lung volume reduction  4133 bronchoscopy  3993 contraindications  3993 diagnostic role  3998 diffuse lung disease  3997t, 3998 lung cancer  3998, 4351 mediastinal tumours and cysts  4370 respiratory infection  3999 equipment  3993 disinfection  3994 fibreoptic, 3870, 3875, 4203 indications  3993, 3994t patient preparation  3994, 3995b Pneumocystis jiroveci pneumonia  1373 procedure  3995, 3996f techniques  3995 bronchial biopsies  3995 bronchial brushings  3995 bronchial washing  3995 bronchoalveolar lavage  3997, 3997t endobronchial ultrasound-​ guided transbronchial needle aspiration  3998f, 3998 fluorescence bronchoscopy  3997 magnetic navigation  3998 narrow band imaging  3997 radial ultrasound  3998 transbronchial fine needle aspiration  3996 transbronchial lung biopsy  3997 therapeutic role  4000 adenocarcinoma/​gastro-​ oesophageal junction tumours  2843 ANCA-​associated vasculitis  4562 asthma  4000f, 4001 bronchiectasis  4147t diffuse alveolar haemorrhage  4235 emphysema  4000f, 4000 lung cancer  4000 nosocomial pneumonia  4025 post-​lung transplantation management  4300 pulmonary Kaposi’s sarcoma  4037f, 4037 broom (Cytisus scoparius)  204, 205t brown urine  4783 brucellosis  1102 clinical features  1103, 1104f, 1104t, 1105t cardiac involvement  1105, 1107f genitourinary tract  1105 neurologic complications  1105 osteoarticular complications  1104 sacroiliitis  1105 vertebral osteomyelitis  1104–​5, 1106f diagnosis  1107 endocarditis  3525t epidemiology  1103 inflammatory eye disease  6430 liver disease  3174, 3175t management  1107 pathogenesis  1103 prevention  1108 Bruce protocol, exercise ECG testing  3310 Brugada’s syndrome  3387f, 3387, 3387t, 5900 Brugia malayi infection chyluria  5056 filarial nephropathy  5056 geographical distribution  1489, 1490 tropical eosinophilia  4239 vectors  1489 see also lymphatic filariasis Brugia timori infection  1490 see also lymphatic filariasis B-​type natriuretic peptide (BNP)  3270, 3614 buccal drug formulations  74 Budd–​Chiari syndrome  3166 acute  3166 causes  3166t chronic  3166–​67 clinical features  3166

  Index 31 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 diagnosis  3167f, 3167, 3168f management  3167 prognosis  3167 subacute  3166–​67 budesonide  3123, 3134t, 4084–​85 Buerger’s disease see thromboangiitis obliterans (Buerger’s disease) bufavirus  953 bulimia nervosa classification/​diagnosis  6509b clinical features  6510 detection and diagnosis  6511 epidemiology  6510f, 6510 multiple sclerosis  6032 outcome  6513 bullous ichthyosiform erythroderma (epidermolytic hyperkeratosis)  5606 bullous pemphigoid  5612, 5613t, 5615f bumetanide  3414, 5154, 5161 bundle branch block (BBB)  3302, 3355 bundle of His  3264–​65, 3302 Bunyamwera virus  855 Bunyaviridae  852 Hantavirus see Hantavirus Nairovirus  857 Crimean–​Congo haemorrhagic fever virus  857, 859f novel human viruses  955 orthobunyavirus  854 Bunyamwera virus  855 California encephalitis virus  855 Inkoo virus  855 Jamestown Canyon virus  855 oropouche virus  856 snowshoe hare virus  855 Tahyna virus  855 phlebovirus  859 Rift Valley fever virus see Rift Valley fever virus sandfly fever Naples virus  859 sandfly fever Sicilian virus  859 severe fever with thrombocytopenia syndrome virus  860 heartland virus  861 taxonomy  852, 853t trivial infections  854t unassigned viruses  861 Bhanja virus  861 Bwamba virus  861 Nyando virus  861 Tataguine virus  861 Wanowrie virus  861 vectors  852 viral structure  854f bupropion  1911, 4125, 6535 Burden of Lung Disease study, COPD  4101, 4102f Burkholderia cepacia infection, cystic fibrosis  4157, 4158 Burkholderia mallei infection (glanders)  1080 Burkholderia pseudomallei infection see melioidosis Burkitt’s lymphoma  442, 5299 aetiology  2893 clinical presentation  2894 endemic (African)  759 epidemiology  2892 Epstein–​Barr virus infection  759, 760 histomorphological features  2895t, 2897, 2898f HIV/​AIDS  760 immunohistochemistry  2898f, 2898, 2901t incidence  413 management  2901 pathogenesis  2894 prognosis  2901 burns acute toxic injury to respiratory tract  4268 artificial nutrition support  1923 electrical injuries  1699 lightning  1698 skin  5593 Buruli ulcers  1167, 5697 aetiology  1167 clinical features  1168 disseminated disease  1169 localized disease  1168f, 1168 differential diagnosis  1169 epidemiology  1168 laboratory diagnosis  1169 management  1169 pathogenesis  1168 pathology  1169 prevention  1169 socioeconomic impact  1169 transmission  1168 busulfan  421t, 3164, 4278 butterflies (Lepidoptera)  1808f, 1808 butterfly rash, systemic lupus erythematosus  4506f, 4506 N-​butyldeoxynojirimycin (miglustat/​ Zavesca)  2140, 2150 butyrophenones  2409t, 6515t BVAS see Birmingham Vasculitis Activity Score (BVAS) Bwamba virus  861 C1 inhibitor assays of  323t normal blood values  6586t primary immunodeficiencies  339t C1 inhibitor deficiency  319, 372, 2240–​41 aetiology  319 antibodies to  319 clinical features  321 diagnosis  321 management  321 pathogenesis  319 see also hereditary angio-​oedema (HAE) C1q  316, 317f, 320t, 4503 C1r  317f, 320t C1s  317f, 320t C2  317f, 318, 320t, 339t C3  318–​19, 320t, 323t, 6586t C3a  316f, 317f, 398 C3b  277, 316f, 317, 318f, 398 C3 convertase  316f C3 deposition, mesangial proliferative glomerulonephritis  4934 C3 glomerulonephritis (C3GN)  321, 4939–​40, 5024 C3 nephritic factor, assays of  323, 323t C4 classical complement pathway  317f deficiency  320t lectin complement pathway  317f level measures  323t normal blood values  6586t primary immunodeficiencies  339t C4b2a  317f, 398 C5a  316f, 318, 398 C5b  316f, 318f C5 convertase  316f C6  318f, 318, 320t C7  318f, 318, 320t C8  318f, 318, 320t C9  318f, 318, 320t CA 19-​9 biliary disease  3198 cancer diagnosis  489 cholangiocarcinoma  3184 normal blood values  6585t pancreatic ductal adenocarcinoma  3230–​31 CA 125  489, 6585t cabergoline acromegaly management  2267–​68 Cushing’s syndrome management  2346 drug-​induced pleural disease  4280 ectopic ACTH production  2347 Parkinson’s disease management  5953 prolactinoma management  2270–​71 cachexia  637, 3412t cadaveric islet cell transplantation  289 cadmium associated bone disorders  4667 cancer aetiology  422t chronic tubulointerstitial nephritis  4970 normal blood values  6586t poisoning  1752 caeruloplasmin  1872, 3195, 6586t Caesarean section  2612, 2662, 2698 caffeine consumption  2581, 3765 CAGE questionnaire  6450b, 6450 calamine  5763 calcific arteriography, renal disease  5748 calcineurin inhibitors adverse reactions  4890, 4890t hyperkalaemia  4761 renal disease  5010–​11 CKD in pregnancy  2594t cutaneous lupus erythematosus management  5657 focal segmental glomerulosclerosis management  4926–​27 frequently-​relapsing minimal-​change nephrotic syndrome management  4922 immunosuppression in transplantation  402 membranous nephropathy management  4932 minimal-​change nephrotic syndrome management  4922 non proliferative lupus nephritis class I/​II management  5004 post-​lung transplantation  4299 postoperative renal transplantation management  5162t psoriasis management  5625 skin disease management  5764 transplant immunosuppression  404 calciotropic hormones, ectopic secretion  2543 calciphylaxis (calcific uraemic arteriolopathy/​small vessel calcification)  4849, 5712f, 5712 calcipotriol  5625, 5764 calcitonin bone resorption  4620–​21 calcium/​phosphate balance  4625 ectopic secretion  2547 medullary thyroid carcinoma  2461–​62 normal blood values  6585t Paget’s disease management  4642 pancreatic neuroendocrine tumours  2455 renal calcium handling  5094 calcitonin gene-​related peptide (CGRP)  2867 antagonists, migraine  5992, 5993t calcitriol (1,25-​dihydroxy-​vitamin D)  2322, 2327, 5094, 5625 calcium adult values  6581t balance in bone  4624f, 4624 bone mineralization  4624 cardiac myocyte contraction  3256f, 3263 deficiency, lactose intolerance  2905 ectopic secretion  2549 homeostasis  2314f, 2315t, 2316f malignant hyperthermia  6342 regulation in extracellular fluid  2314f, 2314 intracellular protein binding  211 metabolism  5013b, 5013, 5014t, 5497 pregnancy  2573 primary hyperparathyroidism 
2321–​22 pulmonary alveolar microlithiasis  4266–​67 sarcoidosis  4214 secondary hyperparathyroidism in CKD-​mineral bone disorder, 4850 small intestine absorption  2725t supplements chronic hypocalcaemia management  2327 CKD-​mineral bone disorder management  4845 osteoporosis management  4701 supplements, PSC management  3139 urinary/​faecal reference intervals  6587t

32 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 calcium acetate, Canavan’s disease management  6218, 6219f calcium antagonists chest pain in hypertrophic cardiomyopathy management  3476 exercise ECG testing  3313 hypertension management, contraindications  3767t hypertrophic cardiomyopathy management  3474–​75 malignant hypertension management  3805 primary aldosteronism management  2355–​56 stable angina  3623 calcium channel blockers (CCBs) anxiety disorders management  6505t aortic regurgitation management  3454 blood pressure control in diabetes nephropathy  4984 CKD in pregnancy  2594t hyperhidrosis management  5703 hypertension in diabetes  2525 hypertension management  3766t, 3767 ion movement inhibition  84 limb lymphoedema  3816 malignant hypertension management  3806t oedema management  3821 photoallergy  5692 poisoning by  1739 primary aldosteronism  3785 primary aldosteronism screening  2354 pulmonary arterial hypertension management  3705 renal disease, effects of  5156 STEMI/​non-​STEMI ACS  3652 systemic sclerosis management  4524t uncomplicated diverticular disease  2962 calcium entry blockers, ACS management  3634 calcium gluconate  2326–​27, 2587 calcium oxalate  2174 calcium pyrophosphate crystal deposition  4488t, 4490, 4491f associated diseases/​ disorders  4490 joint insult  4491 metabolic disease  4491, 4491t osteoarthritis  4491 classification  4490 familial predisposition  4490 clinical features  4490 acute type  4490 incidental findings  4490 osteoarthritis and  4490 uncommon presentation  4490 diagnosis  4492 differential diagnosis  4492 investigations  4492f, 4492 management  4493 acute attacks  4493 osteoarthritis and  4493 calcium stones  5098 calcium oxalate stones  2177, 5093, 5094t, 5096f, 5098, 5100f primary hyperoxaluria  2178 calcium phosphate stones  5093, 5094t, 5098–​99, 5100f, 5101 environment  5098, 5099t genetics  5098, 5098t hyperoxaluria  5099 dietary hyperoxaluria  5099 enteric hyperoxaluria  5100 primary hyperoxaluria  5098t, 5100 hyperuricosuria  5101 hypocitraturia  5099t, 5101 idiopathic hypercalciuria  5099, 5099t management  5098 pathogenesis  5098 pathology  5098, 5100f prevention, trials in  5099t primary hyperparathyroidism  5099 see also nephrocalcinosis California encephalitis virus  855, 6084 Callilepis laureola (impila) poisoning, renal disease  5061 caloric restriction  515f, 515, 516f, 2384 calpainopathies  6323t, 6325, 6326b, 6326 CAMPATH-​1 see alemtuzumab (CAMPATH-​1) Campbell de Morgan spots (cherry angiomas)  5710, 5716 camphor  5763 Campylobacter infection  1039 clinical features  1039 acute bloody diarrhoea (dysentery)  3018 gastrointestinal system  3009t, 3011 reactive arthritis  3021 epidemiology  1039 laboratory diagnosis  1039 management  1039 pathogenesis  1039 transmission  3014t, 3015, 3016f Campylobacter jejuni infection  2920, 6190 CAMT, congenital thrombocytopenias  5335 Camurati–​Engelmann disease (progressive diaphyseal dysplasia)  4657f, 4657 transforming growth factor beta superfamily  262–​63 canakinumab  101t, 104 atherosclerosis regression  3601 cryopyrin-​associated periodic syndromes management  2214 gout management  4489 nomenclature  103t canakinumab pegol  101t Canavan’s disease  1968, 1969f, 6210, 6218 treatment  6219f cancer  1896 apoptosis  279 breast see breast cancer causes see cancer aetiology cerebral metastases  491 childhood, later life, effects in  2697 diabetes insipidus  2280–​81 diagnosis  487 circulating DNA  299, 300f, 301 early diagnosis  488 epidemiology  411 epilepsy  5866 genetics see cancer genetics hallmarks of  446f, 446 blood supply  447 cell cycle regulation  446 cell death  447 cellular energetics dysregulation  447 metastases  447 HIV/​AIDS  3535 incidence community differences  412, 413t migrant groups  413, 414t pregnancy  2696 information and support  493 diagnosis  493 further stages  493, 494f investigations  489 biopsy  489 colonoscopy  2738f, 2738 imaging  489 molecular characterization  490 serum tumour markers  489 liver see liver cancer localized symptoms  488 management  490 chemotherapy see cancer chemotherapy genetic counselling  467 immunotherapy see cancer immunotherapy late sequelae  495t, 496 management aims  490 management modalities  491 multidisciplinary teams  490 pain  631t renal disease, effects of  5160 surgery  491 mass reduction, carcinoid syndrome management  2873 mortality  412f, 412 prevalence  487 oncological emergencies  492 patient groups  492 frail/​elderly  492 inherited cancer  493 pregnancy  492 pregnancy see pregnancy presentation of  487 preventability  412 products, malignancy-​associated renal disease  5042 protective factors  1896 regression, apoptosis  279 rickets  4638 screening  19, 142–​43, 148 cost-​effectiveness  489 small bowel imaging  2752, 2753f, 2754f staging  490 surviving  495 systemic features  488 acquired pernicious anaemia  5416 associated renal disease see malignancy-​associated renal disease cerebral vasculitis  6380 C-​reactive protein  2204 diarrhoea  2759t effusions  491 haemoptysis  3948t hyperfibrinolysis  5555 hyperthyroidism  2318b, 2324 inflammatory myopathies  4541 liver disease  3177 neutropenic sepsis  492 pain  630 palmoplantar keratosis  5610 pleural effusions  4311 PSC in  3140 systemic sclerosis  4516 upper airway obstruction  4045, 4046f vasculitis  5650 Wiskott–​Aldrich syndrome  354 urinary tract obstruction  5125 vaccines  474, 475f cell-​based vaccines  476 dendritic-​cell-​based vaccines  474 peptide-​based vaccines  475 viral vector-​based vaccines  476 cancer aetiology  415 agent interaction  424, 425t alcohol  418, 6488 mortality  425t avoidable causes  416 biological causes  415 age  415 genetics  415 sex  415 causal factors  1896, 1897t diet  423 carcinogens  423 fibre  423 meat and fat  423 mortality  425t overnutrition  423 retinoids and carotenoids  423 diphtheria  961f, 961, 962f folate deficiency  5414t, 5419 gastrointestinal tract immune deficiencies  2790 human polyomaviruses  885 immunosuppression  414 infections  419 bacterial infection  419 mortality  425t parasitic infections  420 viral infection see viral infections inherited see cancer genetics ionizing radiation  418 mortality  425t medical drugs  420, 421t mortality  425t multistep pathway  459 mutations see DNA mutations obesity  6530 occupation  420, 422t mortality  425t physical inactivity  424

  Index 33 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 pollution  420 mortality  425t post-​lung transplantation  4302 reproductive factors  424 tobacco  416 geography  417t mortality  425t ultraviolet radiation  419 mortality  425t see also carcinogenesis cancer-​associated retinopathy (CAR)  6425 cancer chemotherapy  498 acute myeloid leukaemia management  5208 adverse reactions eye diseases/​disorders  6439 gonadal failure association  2548 oesophageal disease  2846 steatohepatitis  3164 AL amyloidosis management  2232, 5019 alkylating agents  500f, 500 antimetabolites  500, 501f breast cancer adjuvant management  506 breast cancer metastatic disease  507 cancer aetiology  420 cancer in pregnancy  2696–​97 carcinoid syndrome management  2873 cell-​cycle phase specificity  498, 498t classification  498 cytokines  473 cytotoxic antibiotics  500, 501t Entamoeba histolytica infection management  1390 Ewing sarcoma management  4711 hair, effects on  5730 hormone therapies  500 androgen receptor antagonists  501 aromatase inhibitors  501 exogenous hormones  502 gonadotrophin production inhibitors  502 oestrogen receptor modulation  501 intracranial tumours management  6053 late effects  504 leprosy management  1164f, 1164, 1164t leukaemia epidemiology  444 localized muscle-​invasive
bladder cancer management  5139 lymphatic filariasis  1494 mechanism of action  498 metastatic breast cancer  507 metastatic muscle-​invasive bladder cancer management  5140, 5140t mitotic spindle agents  500 monoclonal Ig-​dependent diseases management  5021 nausea and vomiting  635 neutropenic enterocolitis  2791–​92 non-​small cell carcinoma management  4354 pancreatic ductal adenocarcinoma management  3233 platinum compounds  500 pleural mesothelioma management  4365 primary myelofibrosis management  5252 radiation pneumonitis  4271 renal disease in myeloma  5020 small-​cell lung cancer management  4355 stomach cancer  2984 targeted therapies  502, 502t angiogenesis inhibitors  502, 503t immunomodulatory agents  503 nomenclature  502t proteasome inhibitors  502 signal transduction inhibitors  502 topoisomerase inhibitors  500 cancer chemotherapy acute myeloid leukaemia management  5207 cancer genetics  456, 493 cancer types  462 chromosome fragility syndromes  466 dominant inheritance  457 gene identification  459 associated risks  460, 461t association studies  460 cytogenetics  459 direct sequencing  460 linkage analysis  460 phenotypic features  460 whole genome sequencing  460 historical perspective  457, 458t, 459f identification  467 at-​risk family identification  468 genetic testing  469 risk assessment  467 screening  468 management  467 lifestyle changes  468 management options  469 prevention strategies  468 mechanism of action  459 predisposition  462 predisposition mechanisms  457 rare syndromes  458t, 463 hereditary retinoblastoma  463b, 463 X-​linked inheritance  457–​59 Cancer Genome Anatomy Project  453–​54 Cancer Genome Atlas (TCGA)  68–​ 69, 449–​50 cancer immunotherapy chimeric antigen receptor T cells  477, 479f clinical considerations  478 generation of  477–​78 mechanism of action  477 combination therapies  484 checkpoint blockade and VEGF-​ targeted agents  484 CTLA4 and PD-​1 blockade  485 cytotoxic T lymphocyte antigen-​4 blocking  479 adverse reactions  481 clinical considerations  480 mechanism of action  479 toxicity  481 future work  485 immune agonists  484 programmed death-​1 blocking  481 adverse reactions  483 clinical considerations  482 development of  481 mechanism of action  481 toxicity  483 T-​cell redirecting engineered antibodies  478 clinical considerations  478 mechanism of action  478 cancer-​induced bone pain (CIBP)  629, 630 cancrum oris  2813 candesartan  3766t, 5993t, 6001 candidaemia  1345f, 1353b, 1353 Candida infections see candidiasis candida intertrigo  1343 candidiasis diabetes complications  2504 cutaneous infections  5747 endocarditis  3528 infective oesophagitis  2836t keratitis  6423 liver disease  3175 oral candidiasis (thrush)  1343 renal transplant immunosuppression  4894 potentially malignant oral lesions  2805 pregnancy  2685t severe/​difficult-​to-​treat asthma  4092 skin disorders, pregnancy  2650 superficial see superficial candidiasis systemic  1353 aetiology  1353b, 1353 candidaemia  1345f, 1353b, 1353 clinical features  1353 deep focal candidiasis  1354 disseminated candidiasis  1353, 1354 endocarditis  1354 epidemiology  1353 laboratory diagnosis  1344f, 1353 management  1354 urinary tract infection  1354 UTI  5091 CANDLE  2208t cannabis adverse reactions, male reproductive disorders  2393t poisoning  1748 spasticity in spinal cord injury  6144 substance misuse  6491 canthariasis, nonvenomous arthropod infestations  1579f, 1579 capacity  3161, 6457 functional capacity  3861 critical care surgery  3862 see also competence capecitabine  2981, 2994, 3233 capillariasis  1509, 2920t Capital in the Twenty-​first Century (Piketty)  163 Caplan’s syndrome, coal workers pneumoconiosis  4223f, 4223 capnography, acute respiratory failure  3871 capsaicin  4479t, 5159t capsule colonoscopy  2737 capsule endoscopy  2749 acute lower gastrointestinal bleeding management  2781 angiodysplasia  2754 small intestinal lymphangiectasia  2974 captopril  2354, 3766t, 3805, 3824–​25 CARASIL  6204f, 6246 carbamate insecticide poisoning  1758 carbamazepine adverse reactions syndrome of inappropriate antidiuresis  2551 alcohol withdrawal management  6489 bipolar disorder management  6500 chorea in acute rheumatic fever management  3517 diabetic neuropathy management  2522 epilepsy management  5872, 5873t monitoring  5876–​77 hormonal contraceptive interactions  2716 mechanism of action  5871 multiple sclerosis management  6035 neuroacanthosis management  6251–​52 normal blood values  6588t poisoning by  1735 renal disease, effects of  5159 seizure management in acute porphyria  2051–​52 trigeminal neuralgia management  6123 carbamoyl-​phosphate synthase deficiency, urea cycle defects  1949t, 1953 carbamylation, glomerular filtration rate measurement  4790 carbidopa  604, 1977, 3824–​25, 5953 carbimazole  2298, 2638, 2710 carbohydrate(s) acute porphyria management  2050–​51 artificial nutrition requirements  1918 dietary change  1899 diet, diabetes management  2489 digestion  2902 luminal phase  2902, 2903f mucosal phase  2902 eye diseases/​disorders  6437 malabsorption in diarrhoea  2759t metabolism  1841 diabetes mellitus type 1  2472f, 2480

34 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 glucose metabolism see glucose metabolism insulin  2472f, 2472 lactate and ethanol metabolism  1842f, 1842 lipid metabolism interactions  1846 liver  3039, 3040f pregnancy  2567, 2572 stores of  1839, 1840t metabolism disorders  1985 galactose see galactose metabolism disorders glycogen storage diseases see glycogen storage diseases (GSDs) restriction, hypoglycaemia  2538 carbohydrate intolerance  2903, 2903t lactose see lactose intolerance management  2906 dietary exclusion  2904b, 2906 disaccharide replacement  2907 intestinal biome manipulation  2907 carbon dioxide airway smooth muscle  3943 poisoning  1764 respiratory acidosis/​alkalosis  2185 carbon disulphide  1764, 6188 carbonic anhydrase 2 deficiency  4659 carbonic anhydrase deficiency  1954, 4616 carbon monoxide (CO) ambient (outdoor) air pollution  1681 intoxication, polycythaemias  5231 poisoning  1764 uptake, respiratory function tests  3961, 3961t, 3962t carbon skeleton metabolism, protein metabolism  1848f, 1849 carboplatin  500, 5148t carboxyhaemoglobulinaemia  5450 carboxylase deficiencies  1949t, 1964, 1965f biotinidase deficiency  1949t, 1955f, 1965, 1966f holocarboxylase synthetase deficiency  1949t, 1966 carbuncles, Staphylococcus aureus infection  996, 997f, 998t carcinoembryonic antigen (CEA)  489, 6585t carcinogenesis adverse drug reactions  90 apoptosis  279f, 279 see also cancer aetiology carcinoid crisis  2871, 2873 carcinoid syndrome  2870 biochemistry  2871f, 2871 clinical features  2870 breathlessness  2871 carcinoid crisis  2871 chronic heart failure  3410t diarrhoea  2871 flushing  2870 heart disease  2871 pellagra  2871 complication management/​ avoidance  2874 bony metastases  2874 heart disease  2874 vitamin supplements  2874 investigations  2872 biochemical tests  2872 cardiac disease screening  2873 histopathology  2872 radionuclide imaging  2872f, 2872 structural imaging  2872f, 2872 malabsorption  2876t management  2873 carcinoid crisis  2873 chemotherapy  2873 interferon-​α  2873 peptide receptor radionuclide management  2873 somatostatin analogues (SSTA)  2873 symptomatic management  2873 tumour mass reduction  2873 prognosis  2874 carcinoma erysipeloides (carcinoma telangiectasia)  5721f, 5721 cardiac action potential  3259, 3259t, 3260f, 3261t membrane potential  3259 ion channels  3259 origins of  3259, 3259t phase 0  3259, 3259t, 3260f phase 1  3260f, 3260 phase 2  3260f, 3260 phase 3  3260f, 3260, 3261t phase 4  3260f, 3262 regional variations  3261t, 3262f, 3262 cardiac arrest  3839 acute presentation  6591 advanced life support  3840 see also advanced life support (ALS) audit  3848 cardiopulmonary resuscitation  3840 see also cardiopulmonary resuscitation (CPR) Chain of Survival  3839f, 3839 critical care in pregnancy  2704, 2704t epidemiology  3839 future work  3848 historical perspective  3839 long-​term management  3847 electrophysiological assessment  3847 rehabilitation  3847 organ donation  3847 post-​resuscitation care  3845 ABCDE approach  3845 see also ABCDE approach brain imaging  3845 cerebral perfusion  3845 glucose control  3845 sedation  3845 seizure control  3845 temperature control  3845 prevention  3840 prognosis  3846, 3847f outcome prediction  3846 survival  3846 cardiac arrhythmias  3350 accelerated idioventricular rhythm  3385 acute porphyrias  2039 atrial arrhythmias  3367 see also atrial fibrillation atrial flutter  3368b, 3375, 3377f causes  3366 extrasystoles  3366 chest pain at rest  3277 CKD  3423f, 3425t, 3426 definitions  3352 diagnosis  3837t dilated cardiomyopathy  3479 Ebstein anomaly  3568 essential hypertension pathophysiology  3750 exercise ECG testing  3313 Fabry’s disease  2144 genetic syndromes  3385 genetic testing  3388 heart muscle disease  3388 see also arrhythmogenic right ventricular cardiomyopathy; dilated cardiomyopathy (DCM); hypertrophic cardiomyopathy (HCM) ion channel disease  3385 see also Brugada’s syndrome; catecholaminergic polymorphic ventricular tachycardia (CPVT);
short-​QT syndrome HIV/​AIDS  3537 investigations  3352 cardiac electrophysiology 
3353f, 3353 ECG  3352, 3352t long-​QT syndrome  3384 management dilated cardiomyopathy management  3482 hypertrophic cardiomyopathy  3476 pre-​excitation syndrome (Wolff–​Parkinson–​White syndrome)  3379f, 3379, 3380f symptoms  3352 torsades de pointes  3384 ventricular fibrillation  3385f, 3385 ventricular pre-​excitation, management  3380f, 3380, 3381 see also bradycardias; tachycardias cardiac catheterization/​ angiography  3339 aortic regurgitation  3454 aortic stenosis  3450 atrial septal defects  3572 atrioventricular septal defects  3575 cardiac flow and output  3342f, 3342 cardiovascular changes pregnancy  2598 complications  3348, 3349t constrictive pericarditis  3506 coronary arterial anatomy and function  3346 coronary arteriography/​ angiography  3346f, 3347f, 3347 coronary physiological measurements  3347 dilated cardiomyopathy  3481 Eisenmenger’s syndrome  3566 history of  3339 hypertrophic cardiomyopathy  3474 indications  3339 congenital disease  3340 congestive heart failure  3340 coronary artery disease  3339 pericardial disease  3340f, 3340 pulmonary vascular disease  3340 valvular disease  3339 intracardiac pressures  3341 methodology  3341 normal pressure  3341, 3341t waveform  3340f, 3342 intracardiac shunts  3343, 3344f intravascular ultrasound  3347, 3348f left heart catheterization  3341 left ventricular function  3345 contractility  3346 diastolic function  3346 global function  3345f, 3345 mitral regurgitation  3445 mitral stenosis  3440 patient preparation  3340 quantitative angiography  3343 right heart catheterization  3341 tetralogy of Fallot  3585 valvular regurgitation  3345 vascular access  3340 vascular resistance  3343, 3344f, 3344t vascular stenosis  3344, 3345f, 3345t cardiac computed tomography  3335 clinical uses  3336 coronary angiography  3336f, 3337f, 3337 coronary calcium scoring  3336 limitations  3336b see also computed tomographic coronary angiography (CTCA) cardiac cycle  3264, 3265f bundle of His  3264–​65 cardiac disease acute abdomen  2769 acute-​on-​chronic liver failure  3094 AL amyloidosis  2221 ANCA-​associated vasculitis  4564 Becker’s muscular dystrophy  6280 brucellosis  1105, 1107f carcinoid syndrome  2871 carcinoid syndrome management  2874 clinical presentation  3276 breathlessness (dyspnoea) see breathlessness (dyspnoea) chest pain see chest pain diagnosis, history  3276–​77 differential diagnosis vs.  3276 endocrine disorders  3496 epidemiology trials  64f, 64, 65f hypereosinophilic syndrome  5257 hypertension pathophysiology 
3749, 3750f

  Index 35 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 infections see also acute rheumatic fever; cardiovascular syphilis; endocarditis inherited metabolic disorders  3497 investigations  3277 iron overload management  5398 liver disease and  3170 malformations in antenatal screening  144t neuromuscular disorders  3497, 3498t polyarteritis nodosa  4571 pregnancy see pregnancy sarcoidosis  4210t, 4213 screening, carcinoid syndrome  2873 Sjögren’s syndrome  4533 tumours see cardiac tumours cardiac failure see heart failure cardiac genetic disease  3551 connective tissue disorders  3554 Ehlers–​Danlos syndrome see Ehlers–​Danlos syndrome (EDS) Loeys–​Dietz syndrome  3556f, 3556 Marfan’s syndrome see Marfan’s syndrome syndromic congenital heart disease  3552 aneuploidy disorders  3552 heart–​hand syndromes  3554 Mendelian syndromes  3552 cardiac glycosides  84, 1830f, 1830, 5153, 6439 cardiac hypertrophy  2144, 2148 cardiac magnetic resonance imaging (CMR)  3331 applications  3332 anatomy  3332 arrhythmogenic right ventricular cardiomyopathy  3486, 3487f blood flow  3332 cardiac myxoma  3546, 3547f chronic heart failure  3409 coarctation of the aorta  3576, 3577f, 3577 congenital heart disease  3332 coronary arteries  3334 dilated cardiomyopathy  3481 hypertrophic cardiomyopathy  3474 iron overload  3334 myocardial function and mass  3332f, 3332 myocardial oedema  3334 myocardial perfusion  3334f, 3334 myocardial viability  3333f, 3333 myocarditis  3462–​63 nonischaemic cardiomyopathies  3333f, 3333 disease prognosis  3335 mechanism of action  3331 nuclear imaging vs.  3331 perfusion imaging, stable angina  3620 phase contrast mapping  3332 safety  3331 steady state free precession images  3331 T1 and T2 parametric mapping  3334, 3335f cardiac myocytes  3255 connections between  3257, 3258f contractile apparatus structure  3255f, 3256 costameres  3256 intermediate filaments  3256 plasma membrane skeleton  3256 sarcomeres  3255–​56 thick filaments (myosin)  3256f, 3256 thin filaments (actin)  3256f, 3256 contraction  3262 control by Ca2+  3256f, 3263 excitation–​contraction coupling  3257f, 3260f, 3262 myofibrillar contraction mechanisms  3256f, 3263f, 3263, 3264f termination  3264 contraction termination Na+/​Ca2+ exchanger  3260f, 3261t, 3264 Na+/​K+ -​ATPase  3264 sarcoplasmic/​endoplasmic reticulum ATPase type 2  3257f, 3264 morphology  3255 plasma membrane currents  3261t plasma membrane–​sarcoplasmic reticulum coupling  3257f, 3257 subtypes  3257 cardiac myxoma  3544 clinical features  3545 differential diagnosis  3545 epidemiology  3544 investigations  3545 echocardiography  3545, 3546f management  3546 pathology  3544 physical signs  3545 prognosis  3546 cardiac output (CO) cardiac catheterization and angiography  3342f, 3342 cardiorenal syndrome  3423, 3424f circulatory support  3885 dye dilution  3343f, 3343 hypertension  3742 oximetry  3342, 3343f Paget’s disease  4640 pregnancy  2564f, 2564, 2597–​98 pregnancy in  2563 stroke volume  3274 thermodilution  3343 cardiac pacing procedures  6646, 6647t external (transcutaneous) pacing  6646 percussion pacing  6646 transcutaneous pacing  6647 transvenous pacing  6647, 6648f, 6648t cardiac physiology  3253 action potential see cardiac action potential cardiac myocytes see cardiac myocytes coronary blood flow  3272 function regulation  3268 heart rate  3272 outflow resistance to afterload  3269f, 3269 see also systemic arterial blood pressure regulation venous return, preload and Frank–​Starling relationship  3268f, 3268 nervous system and  3273 autonomic efferent activity  3273 cardiac reserve  3257f, 3274 sympathetic nervous system  3273 whole organ physiology  3264 cardiac cycle  3264, 3265f mechanical events  3265f, 3265, 3266f myocardial mechanics  3267f, 3267, 3267t myocardial metabolism  3268 normal volumes/​pressures/​ flows  3266, 3267t cardiac reserve  3257f, 3274 provocative test of  3410 training effects  3274 cardiac resynchronization therapy (CRT)  3359 chronic heart failure management  3414f, 3417 cardiac sarcoidosis  3466 cardiac sarcoma  3548, 3549f cardiac surgery acute renal failure  3668f, 3668 assessment  3667 operative risks  3667 complications  3672 atrial fibrillation  3672 conduction defects  3672 mortality  3672 neurological injury  3672 paravalvular leak  3673 pericardial effects  3672 pleural effusion  3672 prosthetic valve endocarditis  3673 prosthetic valve thrombosis  3673 sternal wound complications  3672 structural valve deterioration  3672 thromboembolism  3672 historical aspects  3667 pregnancy in  2599 see also coronary artery bypass grafting (CABG); heart valve surgery cardiac syncope  3285b, 3285, 3286f, 3289, 5898 epilepsy vs.  5867 cardiac tamponade acute presentation  6604 diagnosis  3837t obstructive shock  3888 cardiac transplantation  3428 complications  3430 cardiac allograft vasculopathy  3430f, 3430, 3431b hyperlipidaemia  3430 renal dysfunction  3430 dilated cardiomyopathy management  3482 liver transplantation and  3103 lung transplantation and  4295 pulmonary arterial hypertension management  3706 post-​transplantation  3429 immunosuppression  3429b, 3429 recipient selection  3428, 3431b donor–​recipient matching  3429 cardiac tumours  3544 benign tumours  3548 cardiac myxoma see cardiac myxoma involvement from other tumours  3549 liver disease  3170 cardiogenic anasarca  3403 clinical presentation  3403 differential diagnosis  3403, 3403t, 3404t investigations  3403 management  3404 pathophysiology  3403 cardiogenic pulmonary oedema  3399 clinical presentation  3399, 3401t investigations  3400, 3401f, 3402f management  3401 mechanical support  3402 medical management  3401 ventilatory support  3401 pathophysiology  3399f, 3399 pregnancy  2616 prognosis  3402 cardiogenic shock  3406, 3887 cardiomyopathy dilated see dilated cardiomyopathy (DCM) hypertrophic see hypertrophic cardiomyopathy (HCM) Noonan’s syndrome  3553 peripartum see peripartum cardiomyopathy pregnancy in  2600 restrictive see restrictive cardiomyopathy sarcoidosis  4213 cardiopulmonary exercise testing (CPET)  3862–​63, 3967f, 3968, 3969, 3969t Ebstein anomaly  3569 Eisenmenger’s syndrome  3566 cardiopulmonary resuscitation (CPR)  3840, 3841b drugs  3844 extracorporeal CPR  3844 mechanism of action  3840, 3842f related decisions  3848 renal disease, effects of  5157 rescuer, risks to  3840 cardiorenal syndrome  3421 adverse reactions  3424, 3425t definition  3422, 3422t

36 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 epidemiology  3422, 3422t haemodynamic effects  3423, 3424f management  3427, 3427t nephrotoxicity  3424, 3425t cardiotoxic plants see poisonous plants cardiovascular disease (CVD) acquired pernicious anaemia  5416f, 5416 acute coronary syndrome see acute coronary syndrome (ACS) apoptosis  278 arterial disease  3674 see also acute aortic syndrome; cholesterol embolism; peripheral arterial disease assessment, hypertension investigations  3760 autosomal dominant polycystic kidney disease  5067 biomarkers in pneumonia  4018 COPD  4136 C-​reactive protein  2206 diagnosis  3837t diphtheria  962, 963f haemoptysis  3948t HIV/​AIDS antiretroviral management  924 hypertension  3735 see also essential hypertension investigations CT see cardiac computed tomography echocardiography see echocardiography electrocardiography see electrocardiography (ECG) MRI see magnetic resonance imaging (MRI) nuclear imaging see nuclear imaging liver disease  3170 management herbal formulas  114, 115f renal disease, effects of  5153 Marfan’s syndrome  4681 neurological disorders  6369 obesity  1908 obstructive sleep apnoea  4054 oral hypoglycaemic agent adverse reactions  2495 osteoarthritis  4476 polycystic ovary syndrome  2383 polycythaemias  5230 post-​liver transplantation  3105 pulmonary circulation see pulmonary circulation smoking  6534 spinal cord injury  6138, 6142 vascular Parkinsonism  603–​4 venous thromboembolism  3711 prognosis  3712 see also acute pulmonary embolism; deep vein thrombosis (DVT) Cardiovascular Health Study (USA), heart failure  3393–​94 Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study  5047–​48 cardiovascular syphilis  3539 clinical presentation  1217, 3539 aortic regurgitation  3540f, 3540 coronary ostial stenosis  3540 syphilitic aneurysm  3540 diagnosis  1220, 3540, 3541f differential diagnosis  1218 HIV/​AIDS  3541 investigations  3540 medical management  3542 pathogenesis  3539 pathology  3539 surgery  3542f, 3542 cardiovascular system ACS management  3651, 3651t, 3652t alcohol abuse  6487 anaemia  5361f, 5362 anaphylaxis  3852t, 3854 cardiac physiology see cardiac physiology chronic renal failure complications  4855–​56t classic myotonic dystrophy type 1  6332 confusion assessment  6456 diagnosis of death  6542 drowning  1694 electrical injuries  1699 examination, falls in elderly  583 exercise testing  3966 hypertension management  3775 Kawasaki’s disease  4593 lightning  1698 malnutrition emergency management  1881t management, nonalcoholic fatty liver disease in  3152 occupational disease  1647 Parkinson’s disease  608 polycystic ovary syndrome  2383 pregnancy see pregnancy pseudoxanthoma elasticum  4682 rabies  812, 814f reductive adaptation  1885 respiratory disease  3954, 3954t rheumatoid arthritis  4426, 4427t sport and exercise medicine  6568, 6569t structure and function  3241 systemic lupus erythematosus  4507 systemic sclerosis management  4528 cardioversion, tachycardia management  3364 cardiovirus  954 carditis  1183, 3512 care after death  645, 646b care bundle approach, acute exacerbations of COPD  4139f, 4139–​40 carfilzomib  5318 carmustine (BCNU) adverse reactions eye diseases/​disorders  6439 nodular regenerative hyperplasia  3164 cancer aetiology  421t drug-​induced alveolar disease  4278 drug-​induced pulmonary vasculature  4280 intracranial tumours  6053 Carney’s complex (CNC)  2335f, 2335, 2462, 3544 carnitine deficiency  6309f, 6338 glutaric aciduria type I management  1963 isovaleric aciduria (isovaleryl-​CoA deficiency)  1956 protein-​dependent inborn errors of metabolism emergency management  1947 protein-​dependent inborn errors of metabolism management  1946–​47 carnitine palmitoyltransferase deficiency  6338 β-​carotene  423–​24, 2050 carotenoids  423 carotid artery disease  3668, 6559 carotid body ablation, hypertension management  3775 carotid bulb expansion, hypertension management  3775 carotid endarterectomy, ischaemic stroke  6019 carotid sinus hypersensitivity  6161–​ 62, 6164f syncope vs.  3285 carotid sinus syncope, epilepsy vs.  5867 carotid sinus syndrome (CSS)  584 carp gallbladder ingestion  1803 renal disease  5061 carpal tunnel syndrome  6182, 6193 diabetic neuropathy  6371 nerve conduction studies  5798–​99 normal pregnancy  2579 pregnancy  2647t thenar wasting  6182–​83, 6183f cartilage  4379 biology  4381 collagen  4381f, 4381 development  4380 extracellular matrix  4377, 4380f glycosaminoglycans  4381 metabolism  4381 proteoglycans  4381 structure  4380f carvedilol  3076, 3415–​16, 3446 CASPAR (Classification criteria for psoriatic arthritis)  4451 caspases  267–​68, 269f, 269t cell-​cycle proteins  270 cell death  277 cryopyrin-​associated periodic syndromes  2213–​14 cytoskeletal proteins  269 DNA damage and repair  270 inhibitor activation  275 mechanism of  268 nonapoptotic roles  269t, 270 proteases and  268 protein kinases  269 see also apoptosis Castleman’s disease (angiofollicular lymph node hyperplasia)  5301 HIV/​AIDS  918 human herpesvirus 8 infection  752 catamenial pneumothorax  4325 cataplexy differential diagnosis epilepsy  5868 syncope  5900 narcolepsy and see narcolepsy cataracts  6400, 6401t Cushing’s syndrome  2337 diabetic eye disease  2518 elderly  581 galactokinase deficiency  2004 myotonic dystrophy type 1  6332 catecholaminergic polymorphic ventricular tachycardia (CPVT)  3388 catecholamines analysis, phaeochromocytomas 
3792 diabetes mellitus type 1  2480 heart failure  3271 hypoglycaemia in diabetes mellitus  2534 phaeochromocytomas  3789, 3790f, 3792 secretory pathways  2247 catechol-​O-​methyltransferase (COMT)  3790f, 3792 cathinones, poisoning  1748 cat-​scratch disease (CSD)  1267f, 1267, 1271 causalgia, skin manifestations  5713 caustic ingestion, oesophageal disease  2846 cavernous malformations, primary intracerebral haemorrhage  6023 cavitation dental caries  2798–​99 Mycobacterium tuberculosis infection diagnosis  4028f, 4028–​29 pneumonia  4020 pulmonary lesions, chest radiography  3988, 3989f CC chemokines  313 C chemokines  313 CCK see cholecystokinin (CCK) CD4+ T cells (helper T cells)  326, 473 antigen presentation to  327f, 327 MHC class II  327 antigen recognition  328f atopic dermatitis/​eczema  5634 coeliac disease  2886 Crohn’s disease aetiology  2925, 2926 function  332 hepatitis B  3043–​44 hepatitis C  3044 hypersensitivity pneumonitis  4252 inflammatory myopathies  4538–​39 MHC recognition  474 reactive arthritis  4465–​66 rheumatoid arthritis  4424 rheumatoid arthritis pathogenesis  4424 transplantation  396, 397f, 397–​98, 399 CD8+ T cells (cytotoxic T cells)  326, 473 antigen presentation  326, 327f MHC class I binding  326

  Index 37 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 peptide transport  326 proteasome  326 antigen recognition  328f apoptosis and immunity  278 cancer immunity  473 diabetes mellitus type 1  2477 function  332 hepatitis B  3043–​44 hepatitis C  3044 hypersensitivity pneumonitis  4252 MHC recognition  474 primary biliary cholangitis  3129–​30 reactive arthritis  4465–​66 skin  5593 skin hyperpigmentation  5680 systemic vasculitis  4990–​91 transplantation  396, 399 CD28  277–​78, 396 CD34  3186, 5176–​77 CD40 deficiency  355, 396 CD40L deficiency, hyper IgM syndromes  355 CD56  310 CD154 (CD40L), transplant rejection  396 Cedar Sinai Hospital, MPS study  3329f, 3329 cediranib  503t ceftriaxone  1608, 2683, 2684 cell(s)  209 cytoplasm  210 cytoskeleton  211f, 214 actin filaments  214–​15 intermediate filaments  214 microtubules  214 death atherosclerotic plaques  3599 cancer  447 caspases  277 neurodegenerative disorders  601 division DNA mutations in cancer  447 multiple endocrine neoplasia type 1  2460 selenium  1877 dynamic cells  215 alternative splicing  216 biological membranes  215, 216f differential gene expression  215 post-​transcriptional gene silencing  217 post-​translational modifications  216 endocytosis see endocytosis endosomes  214 recycling endosomes  214 future developments  217 integral membrane proteins  210 lipid bilayers  210 macromolecular crowding  210 next-​generation sequencing  67 organelles  210, 211f endoplasmic reticulum  211f, 211 Golgi apparatus  212 lysosomes  212, 213f mitochondria  210, 211 nucleus  210 peroxisomes  211 plasma membranes  209f, 209 prokaryotes vs. eukaryotes  209 transcription  210 translation  210 cell-​based therapies Becker’s muscular dystrophy management  6281 cancer vaccines  476 Duchenne’s muscular dystrophy management  6281 inborn errors of metabolism management  1936 iron overload  5400 cell cycle inhibitors, post-​lung transplantation  4299 cell-​cycle phase specificity, cancer chemotherapy  498, 498t cell-​free DNA  454f, 454 cell membranes crystal-​related inflammation  4484 glycoproteins  210 ion channels  247 potential difference, ion channels  247 proteins  210 raft domains  215 cellular immune response abnormalities, PSC  3136 autoimmune rheumatic disorders  4497–​98 deficiencies in  340t reactive arthritis  4465–​66 cellulitis (erysipelas)  3817 bacterial infections  5696 dental caries  2799–​800, 2800f gout  4485 Haemophilus influenzae type b  1069 secondary lymphoedema  3816 skin diseases/​disorders  5720 Staphylococcus aureus infection  996, 997t Streptococcus pyogenes infection  969f, 969 centipedes and millipedes (Myriapoda)  1813f, 1813 central diabetes insipidus  4743, 4746 central nervous system (CNS) ANCA-​associated vasculitis  4564 brain see brain cancer see central nervous system cancer classic myotonic dystrophy type 1  6332 cystic fibrosis  4163 degeneration, apoptosis  279 developmental abnormalities see central nervous system developmental abnormalities directed prophylaxis, acute lymphoblastic leukaemia management  5275 electrophysiology  5786 see also electroencephalography (EEG) hypernatraemia  4742 infections actinomycoses  1174 anaerobic bacterial infections  1057 bacterial infection see bacterial meningitis coccidioidomycosis  1364 extrapulmonary tuberculosis  4028 herpes simplex virus management  740 lumbar puncture  5781 tuberculoma  1137 normal development  6351, 6352f superficial siderosis  6375 central nervous system cancer CSF  5784t epidemiology  440, 441f lymphomas chemotherapy  6053 intracranial tumours  6050f, 6050–​51 central nervous system developmental abnormalities  6350 associated clinical problems  6362 external factors  6363 see also cerebral palsies fetal cerebral ventriculomegaly  6362 hydrocephalus  6362f, 6362 complex malformations  6360 corpus callosum agenesis  6360 hydranencephaly  6361 porencephaly  6361f, 6361 schizencephaly  6361f, 6361 septo-​optic dysplasia  6362 cortical development disorders  6355, 6356f cortical microdysgenesis (dysplasia)  6358f, 6358 cortical organization disorders  6358 migration disorders  6356f, 6356 see also lissencephaly proliferation disorders  6355 see also macrocephaly; microcephaly diagnosis  6365 genetic counselling  6365, 6367 neural tube formation see neural tube defects (NTDs) posterior fossa structure malformation  6358 cerebellar aplasia  6359f, 6359 cerebellar hypoplasia  6359f, 6359 Chiari malformation  6359 vermis abnormalities  6359 see also Dandy–​Walker malformations; Dandy–​ Walker variant; Joubert syndrome prenatal diagnosis  6367 regionalization disorders  6354 holoprosencephaly (prosencephaly)  6355f, 6355 risk assessment  6367 spinal cord developmental abnormalities  6354 sacral agenesis  6354 syringomyelia  6353f, 6354 vascular development anomalies  6362 central neurofibromatosis type 2 (NF-​2)  5918 central pontine myelinolysis  6039 neurological disorders  6372 central precocious puberty (CPP)  2431 central retinal artery occlusion  6413, 6414f, 6415f central retinal vein occlusion (CRVO)  6408t, 6414–​16 central sleep apnoea  4050, 4056 central vein cannulation, procedure  6644 centriacinar (centrilobular) emphysema, COPD  4106–​7 centromeres  219, 229 CEP see congenital erythropoietic porphyria (CEP: Günther’s disease) cephalic tetanus  1111–​12, 1112f cephalosporins acute osteomyelitis management  4693 gonorrhoea resistance  1591–​92 HACK endocarditis management  3529 indications  1006t peritonitis in peritoneal dialysis  4877 toxicity  1006t cercariae, schistosomiasis  1541f, 1541 cercarial dermatitis (swimmer’s itch)  1544 cercopithecine herpesvirus 1 (herpes B virus) infection  752 aetiology  752 clinical features  752 epidemiology  752 laboratory diagnosis  753 management  753 prevention and control  753 cerebellum  5938 disorders abscesses  6099 aplasia  6359f, 6359 ataxia see ataxia ataxia in pyruvate dehydrogenase deficiency  2010 degeneration in alcohol abuse  6488 dysarthria  5940 hypoplasia  6359f, 6359 functional anatomy  5938 pontocerebellum  5939f, 5939 spinocerebellum  5938, 5939 vestibulocerebellum  5938, 5939 function/​dysfunction  5939 gross anatomy  5938 cytoarchitecture  5938f, 5938 cerebral abscesses  3562, 5814 cerebral amyloid  2223, 5855 see also amyloidosis cerebral aneurysms, pregnancy  2646 cerebral angiography imaging  5805 cerebral arteriovenous malformations  6022 cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)  5854–​55, 6034–​35, 6246, 6247f

38 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 cerebral cavernomas  6362 cerebral circulation  6012f, 6012 diagnosis of death  6542 cerebral degeneration  6488 cerebral demyelination complication, hyponatraemia management  4737 cerebral infarction classification  6016 diagnosis  6015 differential diagnosis  6015, 6016f essential hypertension pathophysiology  3750 management  6018 anticoagulants  6018 antiplatelet agents  6018 neuroprotective agents  6018 stroke units  6018 surgery  6017t, 6019 thrombectomy  6018 thrombolysis  6018 syndromes  6017 see also stroke cerebral ischaemia, investigations 
6014, 6015b cerebral malaria  1404, 1406f cerebral oedema diabetic ketoacidosis management  2508 hepatic encephalopathy type A  3086t hepatic encephalopathy type A management  3086 hyponatraemia  4732 management, liver failure  3098 cerebral palsies  6364 aetiology  6364 birth asphyxia  6365 genetics  6364 risk factors  6365 classification  6364 epidemiology  6364 imaging  6361f, 6365 cerebral perfusion pressure (CPP)  543, 3894 cerebral small vessel disease  5854, 5855f cerebral toxoplasmosis, HIV/​ AIDS  913f, 913 cerebral vasculitis  6378 clinical features  6379 diagnosis  6379 differential diagnosis  6379t management  6379, 6380 nonvasculitis systemic complications  6380 drug-​induced vasculitis  6380 infections  6380 lymphomatoid granulomatosis  6380 malignancy  6380 malignant angioendothelioma  6380 systemic vasculitis complications  6379 vascular cognitive impairment  5855 cerebral venous sinus thrombosis  5808 cerebral venous thrombosis  2646f, 2646 cerebral X-​linked adrenoleucodystrophy (CALD)  6210 cerebrospinal fluid (CSF)  5782, 5783t Alzheimer’s disease diagnosis  5842 angiotensin-​converting enzyme assay  5785 bacterial meningitis  6068 blood and pigments  5783 cell counts  5783 cytology  5783 examination Cryptococcus neoformans in HIV/​AIDS  6105 HIV dementia  6107 spinal cord disorders  6132 tuberculous meningitis  6078 glucose  5784 hypocretin levels, narcolepsy  5884 idiopathic intracranial hypertension  6055 immunoglobulins  5784 lactate  5785 longitudinally extensive transverse myelitis  6039 microbiology  5785 multiple sclerosis  6034 narcolepsy  5890 neurological conditions  5784t neurosyphilis diagnosis  6102 opening pressure  5783 bacterial meningitis  5783 PCR  5785 peripheral nerve disease diagnosis  6179 pressure, idiopathic intracranial hypertension  6057 primary thunderclap headache  5999 protein  5783 chronic inflammatory demyelinating polyradiculoneuropathy 
6191 diphtheritic polyneuropathy  6192 pyruvate dehydrogenase deficiency diagnosis  2011 serology  5785 shunting of  4732–​33 bacterial meningitis  6068 subarachnoid haemorrhage diagnosis  6024–​25 traumatic brain injury  6046 Venereal Diseases Research Laboratory (VDRL) test, neurosyphilis  6101 viral infections of CNS  6091 cerebrotendinous xanthomatosis (CTX)  6221, 6263 differential diagnosis  2168t psychoses  6485 cerebrovascular disease epilepsy  5866 Fabry’s disease  6227 herpes zoster infection  6096 imaging  5805 investigations, magnetic brain stimulation  5819 obstructive sleep apnoea  4054 cerebrovascular syncope  3289t, 3290 ceroid lipofuscinosis (Batten’s disease)  2151, 2169t, 5131 certolizumab  102, 2662, 2933 ceruloplasmin  2117 cervical cancer adult screening  148, 149t age-​related incidence  415 dietary protective factors  1897 epidemiology  436, 437f human papillomavirus and see human papillomavirus (HPV) infection incidence  413t migrant groups  414t pregnancy  2698 preventative medicine  133t cervical dystonia  5961 cervical intraepithelial neoplasia (CIN)  437, 2698 cervicitis  1284f, 1284 cervicofacial actinomycoses  1173 cervicogenic headache  6003 cestodes (tapeworms)  1520, 1522t cyclophyllidean tapeworms  1521f, 1521 gut infections  1521, 1522t cysticercosis see cysticercosis cystic hydatid disease see cystic hydatid disease (Echinococcus granulosa) Hymenolepsis nana infection  1524 pseudophyllidean tapeworms  1527 diphyllobothriasis  1527f, 1527 sparganosis  1527, 1528f Taenia  1522, 3010t Taenia asiatica infection  1522t, 1523 Taenia saginata infection see Taenia saginata infection Taenia solium infection  1522t, 1524 transmission  3015t tissue cyclophyllidean tapeworms  1525 Echinococcus multilocularis infection  1525, 1526f Multiceps infection  1526 Taenia crassiceps cysticercosis  1526 uncommon gut cestodes  1525 see also Taenia saginata infection CETP deficiency  2067f, 2083 cetrimide, skin disease management  5765 cetuximab  502, 5759 CFTR gene chronic pancreatitis  3220 cystic fibrosis  4152 meconium ileus  2972 mutations  4152f, 4152 CGA see comprehensive geriatric assessment (CGA) Chagas’ disease (American trypanosomiasis)  1459, 3466 aetiology  1460, 1461f apoptosis and infection  278 clinical features  1462f, 1463f, 1463, 1464f epidemiology  1461, 1461t eye diseases/​disorders  6433 laboratory diagnosis  1461f, 1464 management  1465 oesophageal disease  2838 pathogenesis and pathology  1462f, 1462, 1463f prevention and control  1465 unanswered questions and future research  1466f, 1466 vector  1460f, 1460 Chain of Survival, cardiac arrest  3839f, 3839 chancroid  1072, 1611 Changuinola virus  821 channelopathies, headache disorders  6247 Chapel Hill Consensus (CHC)  4391, 4392t, 4557f, 4557, 5640 hypocomplementaemic urticarial vasculitis  4577 polyarteritis nodosa management  4569 small-​vessel vasculitis  4573 Charcot joint  4605f, 4605, 4605t Charcot–​Marie–​Tooth (CMT) disease  6194 ataxia with chronic progressive course  5981 autosomal dominant  6277 type 1A  6277 type 1B  6277 type 2A  6278 type 4C  6278 type 4D  6278 type X1  6278 classification  6274, 6274t, 6275t clinical features  6194f, 6194 diagnosis  6274–​77 dominant intermediate  6278 genetics  6194 hereditary motor neuropathy (HMN)  6274 hereditary sensory and autonomic neuropathy (HSAN)  6274 hereditary sensory neuropathy (HSN)  6274 nerve conduction studies  5799–​800 type 1  6194 type 2  6194 Charcot’s arthropathy  2529 charities  17 Charlson Comorbidity Index  3862 Chédiak–​Higashi syndrome  2153 neutrophil function disorders  5195 skin hypopigmentation  5686 chelating agents  85, 202t, 5152 chemical nephrotoxins, tropical renal disease  5062 chemokines  313 autoimmune diseases  387 CD8+ T cells  332 innate immune system  472 transplant rejection  394 chemoprevention, inherited cancer prevention  468 chemoprophylaxis bacterial meningitis prevention  6066, 6073t malaria prevention  1412, 1412t chemo-​radiotherapy  504t oesophageal cancer management  2980 oesophageal squamous cell carcinoma  2845