SECTION 15 Gastroenterological disorders

15.1 Structure and function of the gastrointestina

15.1 Structure and function of the gastrointestinal tract 2721

15.1 Structure and function of
the gastrointestinal tract Michael E.B. FitzPatrick and Satish Keshav† ESSENTIALS The gastrointestinal tract is a hollow tube stretching from the oral cavity through the oesophagus, stomach, small intestine, colon, and rectum to the anal sphincter. Its function is the transport, digestion, and elimination of ingested material to supply nutrients, vitamins, minerals, and electrolytes that are essential for life, together with the protection of the rest of the body from injurious or allergenic material. The stomach acts as a storage, sterilizing, and digestive tank; the small intestine is the major site of digestion and absorp- tion; the colon’s function is to salvage water and electrolytes from the small intestinal effluent; and the rectum provides a storage func- tion, enabling the elimination of colonic residue (defecation) to be restricted to times of personal convenience. Introduction This chapter provides an overview of the anatomy and physiology of the gastrointestinal tract, excluding detail on the liver and pancreas, which are covered elsewhere, and focusing on aspects most relevant to understanding gastrointestinal symptoms and pathophysiology of disease. The prime function of the gastrointestinal tract is to absorb nutrients and water, and omnivorous humans must digest a wide variety of foods, defend against potentially pathogenic microorganisms, and cope with many potentially toxic xenobiotics. Furthermore, the gastrointestinal tract is entirely integrated with other endocrine and neurological sys- tems that are critical for regulating nutrition and metabolism. Anatomical overview The gut is a hollow tube-​like viscus extending from mouth to anus, derived from the embryonic endoderm. The pancreas and liver de- velop as evaginations of the central tube, and remain connected via the pancreaticobiliary duct system. Schematically, the hollow intestinal tract (Fig. 15.1.1) is ar- ranged as an inner layer of absorptive epithelium, underlying lamina propria, smooth muscle muscularis mucosae, loose con- nective tissue submucosa containing secretory glands, blood ves- sels, submucosal nerve plexus, and immune cells. Externally is the muscularis externa, generally comprising two layers of smooth muscle—​circular fibres innermost and longitudinal fibres outside. Between the muscle layers is the myenteric nerve plexus, and exter- nally the serosa is covered by a mesothelial epithelial layer. The macroscopic anatomy of the organs comprising the gastro- intestinal tract is shown in Fig. 15.1.2. Key features are discussed in the following subsections. Oesophagus The oesophagus propels a masticated food bolus from mouth and pharynx to the stomach and prevents reflux of stomach content. It is typically 25 cm long, and lies within the posterior mediastinum. It arises at the level of the cricoid cartilage opposite the sixth cer- vical vertebra and ends at the cardiac orifice of the stomach. It lies posterior to the trachea and thyroid gland in the neck, anterior to the vertebral bodies, with the common carotid arteries and re- current laryngeal nerves to either side. It passes posterior to the trachea and the left main bronchus at about 28 cm from the inci- sors, and the left atrium. It passes anterior to the thoracic verte- brae, the thoracic duct, and the azygos vein. The arterial supply is from the inferior thyroid artery, branches of the descending aorta, and the left gastric artery. The venous drainage is via the inferior thyroid veins, the azygos vein, and the left gastric veins. The left gastric and azygos veins form a portosystemic anastomosis at the lower oesophagus, which is where varices typically form in portal hypertension. The oesophagus lacks a serosal layer, lying in a sheath of con- nective tissue surrounding two muscular layers, an outer layer of longitudinal muscular fibres and an inner layer of circular muscular fibres. These are striated muscle in the superior two-​thirds of the oesophagus and involuntary smooth muscle in the inferior third. The oesophagus is lined by a stratified squamous epithelium up to the junction with the gastric cardia, at the so-​called z-​line. The †  It is with great regret that we report that Satish Keshav died on 23 January, 2019.

SECTION 15   Gastroenterologica l disorder 2722 oesophagus contains two functional sphincters, the upper oesopha- geal sphincter just distal to the pharynx and the lower oesophageal sphincter at of the junction with the stomach. Stomach The stomach can act as a reservoir, accommodating a typical meal, which it homogenizes into liquid chyme adding acid and pepsin to initiate digestion. It is J-​shaped (Fig. 15.1.3) and lies below the left dome of the diaphragm, posterior to the left lobe of the liver, anterior to pancreas and kidney, and anteromedial to the spleen. The entire stomach is covered by visceral peritoneum, and it forms the anterior wall of the lesser omental sac, with the greater omentum attached along its lateral, greater curve. The pyloric sphincter opens intermittently to propel chyme into the duodenum. The left gastric artery from the coeliac trunk and the right gas- tric artery from the hepatic artery supply the lesser curve, while the right gastroepiploic artery from the hepatic artery and the left gastroepiploic artery from the splenic artery supply the greater curve. The vagus nerve supplies efferent and afferent fibres with secretomotor and sensory functions. The gastric muscularis externa is thickened, with a third, inner layer of oblique muscle fibres in addition to longitudinal and cir- cular layers, which contract in a complex, coordinated manner, at a frequency of three times a minute, liquidizing, homogenizing and propelling food. Small intestine The small bowel is the major site of digestion and absorption. It varies in length between 3 and 10 m and is functionally divided into the duodenum, jejunum, and ileum. The duodenum forms a 25-​cm C shape around the head of the pan- creas, and is mainly retroperitoneal. The first part distal to the pylorus lies posterior to the liver and anterior to the portal vein and common bile duct. The second part (D2) lies anterior to the right kidney and lat- eral to the head of the pancreas. The main pancreatic duct enters D2 at the duodenal papilla, surrounded by the muscular sphincter of Oddi, while the accessory pancreatic duct (of Santorini) enters proximally (Fig. 15.1.3). The third part of the duodenum crosses right to left an- terior to the aorta and inferior vena cava and posterior to the superior mesenteric vessels, joining the jejunum at the ligament of Treitz. The jejunum runs into the ileum, and both are highly mobile on a long mesentery attached to the posterior abdominal wall. The whole small bowel distal to D2, as well as the caecum, as- cending colon, and transverse colon, is formed from the embry- onic midgut and derives its arterial supply from branches of the superior mesenteric artery which are arranged in arcades with considerable collateral circulation. The venous drainage is via the superior mesenteric vein into the hepatic portal vein. The mucosa of the small intestine is distinctive, with multiple adaptations that increase the surface area available for absorption of nutrients: macroscopically, circular folds (plicae circulares) are easily seen. The mucosa itself is arranged in finger-​like villi projecting into the lumen, and crypts that penetrate into the lamina propria (Fig. 15.1.1). The villi are lined with a layer of absorptive epithelial cells that themselves are covered on the apical surface by micro- villi. Stem cells from which the epithelial cells are constantly and rapidly replenished are situated near the base of the crypts. Other important specialized cells in the epithelium include Paneth cells, which have a role in antimicrobial host defence, goblet cells that secrete mucus, and neuroendocrine cells that produce a variety of enteric (gut) hormones. Epithelium Mucosa Muscularis mucosae Subserosa Circular muscle Mucosa-associated lymphoid tissue Myenteric plexus Mucosal gland Longitudinal muscle Serosa Enteroendocrine cell Enterocytes (absorptive cell) Goblet cells Progenitor cells Paneth cells Stem cells Intestinal crypt (of Lieberkühn) Villus Fig. 15.1.1  General arrangement of the layers of the gastrointestinal tract. The high-​magnification area shows the villi and crypts of the small intestine.

15.1  Structure and function of the gastrointestinal tract 2723 Colon The colon absorbs water and electrolytes from the small-​bowel ef- fluent to form solid stool for elimination. It is approximately 150 cm in length from the caecum, to which the ileum is attached via the ileocaecal valve, to the rectum, which opens into the anal canal. The appendix vermiformis is attached to the caecal pole. The longitu- dinal muscle layer is organized into three bands, the taeniae coli, stretching from the appendix to the rectum. The ascending and descending colon are partly retroperitoneal, resting against the posterior abdominal wall, while the transverse and sigmoid colon are peritoneal attached via a mesocolon. The arterial supply to the proximal colon is from the superior mesenteric artery, while the descending colon, sigmoid colon, and rectum, formed from em- bryonic hindgut, are supplied by the inferior mesenteric artery. The main venous drainage is via the inferior mesenteric vein into the portal circulation. Rectum and anus The rectum lies in the pelvis anterior to the sacrum and posterior to the vagina or prostate gland and seminal vesicles. It joins the anal canal, lined with a stratified squamous epithelium in its lower half. Defecation is controlled by the two anal sphincters—​the internal anal sphincter formed of involuntary smooth muscle and the ex- ternal anal sphincter formed of striated muscle under voluntary control. The anus receives a dual blood supply from vessels from the inferior mesenteric artery and from the inferior rectal vessels from the internal iliac arteries. The dual venous drainage communicates to form a portosystemic anastomosis. Physiology Oesophagus The swallowing reflux propels food from the oropharynx into the oesophagus while protecting the airway. This can be initiated vol- untarily or by touch receptors in the pharynx. First, the tongue pushes a bolus up and back in the pharynx while the soft palate is pulled upward, preventing the reflux of food into the naso- pharynx; then the larynx is elevated against the epiglottis and the vocal cords are pulled together to protect the airway. As the food bolus passes the upper oesophageal sphincter, the sphincter contracts reflexively. This initiates a coordin- ated, propulsive primary peristaltic wave, controlled by intrinsic neural pathways and the vagus nerve, propagating at 3 to 5 cm/​s. Oesophageal distention triggers waves of secondary peristalsis. The lower oesophageal sphincter relaxes at the time of pharyngeal stimulation and remains relaxed until the bolus enters the stomach (Fig. 15.1.4). Stomach A large number of secretory cells are located in gastric glands. In the fundus and body of the stomach, parietal cells secrete hydro- chloric acid and intrinsic factor, a glycoprotein required for ab- sorption of vitamin B12. Chief cells within the gastric body secrete pepsinogen, which is cleaved to the active protease pepsin by hydrochloric acid. Cells in the neck of gastric glands secrete an al- kaline mucous that protects the gastric mucosa. Endocrine cells in Liver Oesophagus Pancreas Colon Small intestine Caecum Rectum Appendix vermiformis Stomach Gallbladder Fig. 15.1.2  Schematic diagram of the organs of the gastrointestinal tract. Greater curve Lesser curve Pancreas Pylorus Pyloric sphincter Common bile duct Accessory duct of Santorini Duodenum Ampulla of vater Sphincter of Oddi Incisura angularis Antrum Fundus Cardia Fig. 15.1.3  Structure of the stomach showing cardia, fundus, body, lesser/​greater curves, incisura, antrum, and pylorus.

SECTION 15   Gastroenterologica l disorder 2724 the base of the gastric glands secrete somatostatin and gastrin (see ‘Hormonal control of gastrointestinal function’). The distensible fundus and body of the stomach create a reser- voir and the muscular distal antrum mechanically disrupts food and mixes it with gastric secretion. Small intestine Chyme entering the small intestine is mixed with pancreatic and biliary digestive secretions, in a process regulated by hormonal and neural mechanisms, responding to intestinal distension, intraluminal nutrients, osmolarity, and pH. Pancreatic secretions in- clude protease precursors, amylase, lipases, and nucleases that hydro- lyse macronutrients to monomers and oligomers that can be absorbed through the brush border of enterocytes via specific transporter pro- teins, generally cotransported with sodium or hydrogen ions. The small intestine has a prodigious capacity to absorb water (Table 15.1.1) driven by active and passive sodium and chloride absorption. The motor patterns of the small intestine are coordinated in both the fasting and fed state (Fig. 15.1.5). After a meal, contractions slowly propel contents along the small bowel allowing time for nu- trient absorption (Table 15.1.2). In the fasted state, coordinated intense contractions ensure that the small intestine is cleared of un- digested residue, preventing microbial overgrowth. Colon The colon absorbs most of the remaining electrolytes and water from the 1 to 2 litres of small intestinal effluent that enters it, leaving approximately 200 ml of faeces to be eliminated daily. The colon also salvages unabsorbed nutrients from the lumen, particularly carbohydrates, which are fermented by the anaerobic bacteria of the colonic microbiota to form short-​chain fatty acids, which are then absorbed. Rectum The rectum acts as a reservoir for faeces, allowing periodic defeca- tion. Coordination of the involuntary internal anal sphincter and the voluntary external anal sphincter, as well as the puborectalis Table 15.1.1  Fluid secretion and absorption along the length of the gastrointestinal tract (per day) Location Secretion Absorption Notes Mouth/​salivary glands 1500 ml − In addition to approximately 2000 ml fluid ingested/​day Stomach 2500 ml − Including hydrochloric acid, pepsinogen, and intrinsic factor Liver/​bile 500 ml − Pancreas 1500 ml − Bicarbonate-​rich secretions Small bowel − 6000 ml Colon − 1500–​2000 ml 200 ml eliminated in stool Pressure topography 0 5 10 Transition Zone Segment 1 UOS S 2 S 3 LOS 15 20 25 30 35 0 5 10 15 20 0 30 60 90 120 150 Pressure (mm Hg) Time (s) Length along oesophagus (cm) Pharynx Upper oesophageal sphincter Upper oesophagus Mid oesophagus Lower oesophagus Lower oesophageal sphincter Fig. 15.1.4  A diagram (left) and high resolution manometry reading (right) of the pressure changes in the pharynx, upper oesophageal sphincter (UOS), oesophagus, lower oesophageal sphincter (LOS), and proximal stomach following a swallow. This shows the primary peristaltic wave (Segment 1) and further segmental pressure events (S2, S3) in the oesophagus, and the sequence of sphincter relaxation. Reproduced from Mainie, I., High resolution manometry and multichannel intraluminal impedance oesophageal manometry in clinical practice, Frontline Gastroenterology, Vol 1 No 2, (2010) with permission from BMJ Publishing Group.

15.1  Structure and function of the gastrointestinal tract 2725 muscle, is required for defecation, passage of flatus, and mainten- ance of continence. Intestinal fluid balance Table 15.1.1 shows the varying pattern of fluid secretion and absorp- tion along the gastrointestinal tract. Vitamins and minerals are absorbed by various controlled pro- cesses in the small bowel. Some, such as vitamin B12, are absorbed in specific locations, with clinical relevance in cases of localized lu- minal disease or small-​bowel resection (see Table 15.1.2). Bile acids exhibit an enterohepatic circulation, first secreted in the bile before being absorbed in the terminal ileum. Regulatory mechanisms The gastrointestinal tract goes through periods of intense activity during meals and relative quiescence afterwards. A variety of neural and hormonal regulatory mechanisms coordinate this. Neural control of gastrointestinal function The gastrointestinal tract has an intrinsic, enteric nervous system con- trolling several reflexes. There are inputs from the brainstem via the vagus nerve that control the coordinated release of chyme from the stomach and the secretion of bile and pancreatic secretions to opti- mize digestion. Further reflexes via the prevertebral ganglia integrate contractile patterns and control contractile force in the bowel. Two key reflexes of the gastrointestinal tract coordinated by the enteral nervous system are peristalsis and the migrating motor complex. The peristaltic reflex ensures unidirectional propulsion of luminal contents from mouth to anus. Local luminal distension by a food bolus triggers ascending motor excitation leading to contractions on the oral side of the food bolus while also triggering muscle relax- ation distally, generating propulsion. The migrating motor complex is a coordinated contraction of the small bowel during fasting. A period of relative quiescence (phase I) is followed by a period of small, disorganized contractions (phase II). Then larger-​amplitude, coordinated contractions propagate down the small intestine. During this phase, the stomach contracts and the pylorus opens fully, allowing residual gastric and small-​ bowel contents to be flushed into the colon. This cycle repeats every 90 minutes unless a meal is consumed (Fig. 15.1.5). There are further neural interactions between the central and enteric nervous systems which are poorly understood. This brain–​ gut axis is thought to play a key role in a range of functional bowel disorders, such as irritable bowel syndrome and visceral hyper- sensitivity, and may well explain some of the gastrointestinal manifestations of psychological conditions, such as anxiety and depression. Hormonal control of gastrointestinal function Several hormones regulate gastrointestinal tract function, and the most important are shown in Table 15.1.3. These are released from enteroendocrine cells in the gastric mucosa, which sense changes in luminal contents and exert local paracrine, as well as more distant hormonal, effects. Immunological function of the gastrointestinal tract The gastrointestinal tract is a major site of contact with the external environment and the range of potentially pathogenic viruses, bac- teria, protozoa, fungi, and helminths that could be ingested with food. The gut’s physical barriers include a thick mucus layer, the mechanical effect of secretion and peristalsis, and tight junctions between epithelial cells, while gastric acid, alkaline intestinal secre- tions, bile acids, and high concentrations of digestive enzymes create a chemically hostile environment for microorganisms. In addition, intestinal epithelial cells, including highly specialized cells such as Table 15.1.2  Absorption of key vitamins and minerals within the gastrointestinal tract Vitamin/​mineral Site of absorption Relevant information Iron Duodenum Absorbed via divalent metal transporter protein, DMT1, transported basally via ferroportin Vitamin B12 Terminal ileum Absorbed bound to intrinsic factor secreted in the stomach Folate Jejunum Vitamins A, D, E, K Duodenum,
jejunum, ileum Fat-​soluble vitamins Calcium Jejunum Calcium lost in bile reabsorbed by small intestine. Calcium bound to phytates cannot be absorbed D1 D2 J1 J2 J3 30 min. Fig. 15.1.5  Peristalsis and the migrating motor complex (MMC): the MMC demonstrated in manometry readings from the duodenum
(D1/​2) and jejunum (J1–​3) showing two phase III contractions propagating down the gastrointestinal tract (marked with dotted lines). The quiescent phase I and small-​amplitude contractions of phase II can be seen between them. Reprinted by permission from Springer Nature: Soffer EE, Thongsawat S,
Ellerbroek S (1998) Prolonged ambulatory duodeno-​jejunal manometry
in humans: normal values and gender effect. Am J Gastro, 93, 1318–​23,
copyright © 1998.

SECTION 15   Gastroenterologica l disorder 2726 Paneth cells and goblet cells, secrete antimicrobial peptides and en- zymes such as defensins and lysozyme (Fig. 15.1.6). The intestinal wall also contains many immune cells, arranged within gut-​associated lymphoid tissues (GALTs), and distributed in the lamina propria and the epithelial layer. GALT includes lymphoid follicles and Peyer’s patches that lie just below the epithelial layer, which contains specialized M-​cells that allow transepithelial transport of luminal antigens. Plasma cells within the lamina propria secrete dimeric immunoglobulin A, which is transported into the lumen of the intestine by active secretion by epithelial cells, and has a role in regulating the composition of the intestinal microbiota. Although various mechanisms limit the survival of microorgan- isms, many do survive, and the intestinal lumen, particularly in the colon, contains a large population of commensal bacteria, including enterococci, clostridial species, Proteobacteria, and bifidobacteria. The role of this resident microbiota in health and disease is increas- ingly recognized, with complex interactions between specific bac- teria and the innate and adaptive immune system. In, for instance, inflammatory bowel disease, certain strains are more frequently found in the diseased intestine, and the overall diversity of bacterial species appears to be reduced. In a number of experimental models, transplantation of the microbiota has been shown to transfer com- plex traits, such as obesity and immune activity. This has led, in some cases, to attempts to treat disease through modification of the microbiome by prebiotics, probiotics, and faecal microbial trans- plantation. This suggests that when we consider the structure and function of the intestine, the microbial content, which includes ap- proximately 1013 bacterial cells, could be considered an intrinsic component of this organ system. FURTHER READING Ellis H, Mahadevan V (2013). Clinical anatomy:  applied anatomy for students and junior doctors, 13th edition. Wiley Blackwell, Chichester. Hollister EB, Chunxu G, Versalovic J (2014). Compositional and func- tional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology, 146, 1449–​58. Honda K, Littman DR (2016). The microbiota in adaptive immune homeostasis and disease. Nature, 535, 75–​84. Koeppen B, Stanton B (eds) (2017). Berne & Levy physiology, 7th edition. Elsevier, Philadelphia, PA. Standring S (ed) (2016). Gray’s anatomy: the anatomical basis of clinical practice, 41st edition. Churchill Livingstone, Edinburgh. Table 15.1.3  Gastrointestinal hormones and their functions Hormone Source Stimulus for release Targets Effect Gastrin G cells (gastric antrum) Oligopeptides in gastric lumen Gastrin-​releasing peptide from enteric neurons Parietal cells of stomach (directly and via histamine release from enterochromaffin-​like (ECL) cells Stimulates acid secretion from
parietal cells Cholecystokinin (CCK) I cells (duodenum) Fatty acids, protein Vagal afferent terminals Pancreatic acinar cells Inhibits gastric emptying and acid secretion Stimulates pancreatic enzyme secretion and gallbladder contraction Secretin S cells (duodenum) Low (acidic) luminal pH Pancreatic duct cells Stimulates pancreatic duct secretion Peptide YY L cells (terminal ileum and colon) Fatty acids, protein Enteral nervous system neurons in the stomach and small bowel Inhibits gastric emptying and reduces intestinal motility Somatostatin Delta cells (gastric antrum) Low (acidic) luminal pH G cells of stomach Reduces gastrin secretion leading to reduced parietal cell acid secretion Glucagon-​like peptide-​1 (GLP-​1) L cells (small intestine) Fatty acids, glucose Neurons, epithelial cells Glucose homeostasis Enteroendocrine cell Enterocytes (absorptive cell) Goblet cells Progenitor cells Paneth cells Stem cells Intestinal crypt (of Lieberkühn) Villus Fig. 15.1.6  The intestinal crypt and its cell types: Paneth cells and stem cells are located at the base of the intestinal crypts (of Lieberkühn). Absorptive enterocytes line the top of the crypts and form the majority of the cells of the villous mucosa interspersed with goblet cells and enteroendocrine cells, with progenitor cells in the middle of the crypts in between.

15.10 Malabsorption 2875

15.10 Malabsorption 2875

15.10.1 Differential diagnosis and investigation o

15.10.1 Differential diagnosis and investigation of malabsorption 2875

15.10 Malabsorption CONTENTS 15.10.1 Differential diagnosis and investigation of malabsorption  2875 Alastair Forbes and Victoria Mulcahy 15.10.2 Bacterial overgrowth of the small intestine  2879 Stephen J. Middleton and Raymond J. Playford 15.10.3 Coeliac disease  2884 Peter D. Mooney and David S. Sanders 15.10.4 Gastrointestinal lymphomas  2892 Kikkeri N. Naresh 15.10.5 Disaccharidase deficiency  2902 Timothy M. Cox 15.10.6 Whipple’s disease  2909 Florence Fenollar and Didier Raoult 15.10.7 Effects of massive bowel resection  2911 Stephen J. Middleton, Simon M. Gabe, and Raymond J. Playford 15.10.8 Malabsorption syndromes in the tropics  2916 Vineet Ahuja and Govind K. Makharia 15.10.1  Differential diagnosis and investigation of malabsorption Alastair Forbes and Victoria Mulcahy ESSENTIALS Malabsorption is defined as defective mucosal absorption in the intestine, with clinical presentation ranging from diarrhoea or steatorrhoea with massive weight loss, through to abdominal bloating, fatigue, changes in bowel habit, or anaemia. There are many causes, but the commonest in adult life are coeliac disease, Crohn’s disease, and bile salt malabsorption. Simple blood tests may prompt suspicion of malabsorption, will sometimes go a long way to providing a diagnosis, and will guide fur- ther investigation with specific tests, for example, serum antibody to tissue transglutaminase (coeliac disease), endoscopic examinations, imaging studies, breath tests, and tests of bile salt absorption. Treatment for malabsorption is directed (where possible) to the underlying cause as specific agents to address the malabsorption it- self are lacking. General nutritional support and replacement of indi- vidual deficiencies are crucial. Introduction Malabsorption leads to a wide spectrum of clinical presentations, ranging from dramatic diarrhoea or steatorrhoea with massive weight loss, through to more subtle features such as abdominal bloating, fatigue, changes in bowel habit, or anaemia. Malabsorption is defined as defective mucosal absorption and should be distin­ guished from maldigestion—​the defective hydrolysis of nutrients—​ with which it commonly coexists. The emphasis in this chapter will be on intestinal malabsorption: pancreatic insufficiency is addressed in Chapter 15.26.2. Normal absorption The processes of absorption are complex and involve several stages, commencing with the cerebral phase of digestion triggered by the sight, smell, and thought of food, which trigger the digestive pro­ cess, with salivary and gastric secretion mediated by the autonomic nervous system. The presence of nutrients in the mouth and upper gastrointestinal tract adds to these secretions via humoral and local neural mechanisms, but most of the digestive process is ini­ tiated in the duodenum. The delivery of chyme from the stomach is adjusted to allow efficient mixing with the pancreaticobiliary se­ cretions; this combination with bile salts and bicarbonate (as well as the pancreatic enzymes) provides optimal conditions for nu­ trient digestion. Digestion and fluid secretion dominate in the duodenum and proximal jejunum, while the bulk of nutrient absorption takes place in the distal jejunum and ileum. Enzymatic digestion occurs not only in the lumen but also in the intestinal brush border, absorption of small oligopeptides generally being superior to that of monomeric amino acids. The terminal ileum has special and almost unique cap­ acity for absorption of vitamin B12 and bile salts. In health, by the time the intestinal chyme leaves the ileum and enters the colon, most

section 15  Gastroenterological disorders 2876 nutrients have been digested and absorbed, the colon serving mainly to dehydrate the luminal contents through absorption of salt and water and temporarily to store the residuum. Absorption occurs through several pathways. Transcellular ab­ sorption occurs via entry to the cell at the brush border membrane, with passage through the cytoplasm, and exit from the cell at the basolateral membrane. This depends on passive and active trans­ port, and also on endocytosis. Passive transport by diffusion oc­ curs mainly when the molecules are small and can simply diffuse through the membrane via a paracellular route, and the term has come to include facilitated diffusion where transportation is aug­ mented by a transport protein and a concentration gradient. This allows small molecules to be transported across electrical and chemical gradients. Active transport generally uses a transport pro­ tein, but also requires energy to move nutrients against a concentra­ tion gradient. Endocytosis may occur when molecules are too big otherwise to cross the cell membrane, but in most cases digestion renders nutrients sufficiently small that absorption can proceed without this. In endocytosis, a portion of the cell membrane sur­ rounds and engulfs the target molecule(s). The membrane is then disassembled and the contents are released, a process sometimes accomplished by exocytosis. Causes of malabsorption There are many causes of malabsorption, including frank mucosal damage, congenital or acquired reduction in absorptive surface, defects in intracellular hydrolysis, and defects of ion transport, as well as malabsorption linked with maldigestion as in the case of pancreatic insufficiency, cholestasis, or impaired enterohepatic circulation. A list of potential causes can appear encyclopaedic (Table 15.10.1.1) and is yet not exhaustive, but most of these are either rare, or conditions (as in the case of diabetes) where the malabsorption contributes only a small part of the overall morbidity. The commonest causes of de novo presentation with malabsorp­ tion in adult life are coeliac disease, Crohn’s disease, and bile salt malabsorption. The patient’s age and medical background will guide the creation of an appropriate differential diagnosis. In many Table 15.10.1.1  Some causes of malabsorption and distinguishing associated features; all can be responsible for diarrhoea and weight loss, all may result in anaemia, and most will at times cause some abdominal discomfort Condition Associated features Adrenal insufficiency Hyponatraemia, hyperkalaemia Amyloidosis Nephrotic syndrome, cardiomyopathy, macroglossia Bacterial overgrowth Previous abdominal surgery, motility disorders, small-​bowel diverticula, strictures Bile salt malabsorption Often mild nonspecific symptoms Carcinoid syndrome Flushing, hypokalaemia, right heart failure symptoms Cholestatic liver disease Jaundice, features of chronic liver disease Coeliac disease Growth retardation, delayed menarche Crohn’s disease Abdominal pain, aphthous ulcers, extraintestinal features (arthritis, uveitis, erythema nodosum, pyoderma gangrenosum) Cystic fibrosis Respiratory features, growth retardation, history of meconium ileus/​distal intestinal obstruction syndrome, steatorrhoea Cystinuria Renal stones Chronic infections Tropical sprue, giardiasis, tuberculosis, HIV/​AIDS Diabetes mellitus Long-​term poor control and complications, gastroparesis Disaccharide deficiency Dietary links to symptoms Drugs Often unpredictable, but also orlistat, laxatives Diverticula (jejunal) Often mild nonspecific symptoms Eosinophilic enteritis Dysphagia Gastrectomy Vitamin B12 deficiency Hypogammaglobulinaemia Recurrent infections Intestinal ischaemia Ischaemia in other organs systems Intestinal lymphangiectasia Protein-​losing enteropathy Lymphoma Lymphadenopathy (clinical or on imaging) Pancreatic insufficiency Abdominal pain, steatorrhoea Radiation enteropathy History of radiotherapy Scleroderma Raynaud’s syndrome, dysphagia, skin changes, calcinosis Short bowel syndrome Major intestinal resection for any cause Specific transporter defects Usually childhood presentation Whipple’s disease Lymphadenopathy, fever, arthritis, endocarditis

15.10.1  Differential diagnosis and investigation of malabsorption 2877 cases, associated features will helpfully steer the clinician towards the correct explanation. Clinical features History: suspicion of malabsorption Malabsorption will be readily suspected in the patient with diar­ rhoea and weight loss in whom gastrointestinal pathology is already known, especially if there are few other symptoms. The primary diagnosis of malabsorption is, however, often delayed or overlooked entirely, as in its milder forms it may be difficult to recognize and assess. A suspicion of its presence will come from key factors in the patient’s history such as a family history of coeliac disease or previ­ ously unexplained anaemia. Questioning the patient should cover areas such as change in bowel habit, change in stool consistency or colour, bloating, and weight loss, but also symptoms referable to other systems such as (for example) musculoskeletal pain from malabsorption-​related vitamin D deficiency. Enquiry should include a detailed past medical history encompassing surgical history, previous medical treatments such as radiotherapy, and documentation of pancreatic disease or its risk factors, as well as family history. Attention to associated symptoms can also be productive (Table 15.10.1.1). Examination Examination of the patient with isolated malabsorption is of limited value, as apart from evidence of weight loss or growth re­ tardation there may be no signs. Nonetheless, conventional nu­ tritional screening including documentation of weight loss and current body mass index will often be informative. A more detailed assessment may include anthropometric measurements such as skin-​fold thickness and analysis of the body composition, but the diagnostic process will be most helped by the discovery of signs of anaemia (pallor, glossitis, cheilosis, stomatitis, koilonychia), of vitamin deficiencies (bruising, tetany, oedema, hyperpigmented dermatitis), or features of underlying conditions or past surgery (Table 15.10.1.1). Investigations General laboratory investigations Simple blood tests may prompt suspicion of malabsorption, will guide further investigation, and will sometimes go a long way to providing a diagnosis. Even in the absence of anaemia the mean cor­ puscular volume can indicate evidence of iron, vitamin B12, or folate deficiency. The dimorphic picture from combined iron and folate deficiency, with a consequently raised red cell distribution width, may be the first pointer to a diagnosis of coeliac disease. The lipid profile may also be suggestive, with triglycerides de­ creased in severe fat malabsorption, and cholesterol low in bile salt or fat malabsorption. A low albumin is more often a nonspecific marker of illness and inflammation, but may be dramatically low in lymphangiectasia and protein-​losing enteropathy. Alkaline phosphatase is increased in calcium and vitamin D malabsorption, and decreased with zinc malabsorption. Low levels of calcium, phosphorus, iron, ferritin, magnesium, and zinc may all point to malabsorption, as may a low folate or vitamin B12 when these have been measured to elucidate a finding of anaemia or ab­ normal mean corpuscular volume. Paradoxically, raised folate levels may be seen in malabsorption associated with small-​bowel bacteria overgrowth. Coagulation screening may lead to the discovery of vitamin K malabsorption. Specific laboratory investigations Exclusion of coeliac disease The most important serological testing in respect of malabsorption is that for coeliac disease, given the high prevalence of the condi­ tion and the remarkable (>95%) accuracy of serological prediction. Historic reliance on tests for antibodies to gluten and endomysium has been succeeded by use of the more sensitive antibody to tissue transglutaminase. Screening for antibodies to deamidated gliadin peptide is also valuable. Concurrent IgA deficiency accounts for most of the few false-​negative results, hence it is important to measure the immunoglobulins for this reason, as well as to detect other considerably rarer immunodeficiency states associated with malabsorption. Coeliac disease can also be excluded immunologically, since it does not develop unless the individual has alleles encoding HLA DQ2 or DQ8. This observation can be important in helping to confirm a diagnosis of noncoeliac gluten sensitivity in patients with dietary intolerance of wheat, but in whom other tests are normal. Other investigations Vitamin B12 deficiency may be associated with chronic disease or prior resection of the distal ileum, but also in pernicious an­ aemia where the defect is an autoimmune loss of the intrinsic factor which is required for its absorption. Antibodies to the gas­ tric parietal cells and/​or to intrinsic factor itself provide a specific diagnosis. Comparable risk occurs after total or subtotal gastrec­ tomy, and vitamin B12 deficiency may be seen in the context of severe chronic gastritis. The Schilling test, which depends on the intestine’s handling of radioisotopic vitamin B12, is now largely defunct. Biochemical assessment of pancreatic disease has a long and largely unhappy history, but the detection of a low faecal elastase can lend support to a diagnosis of exocrine pancreatic insufficiency. When standard liver biochemistry is abnormal it will be appro­ priate to seek serological evidence of autoimmune liver disease (especially primary biliary cholangitis) and to exclude metabolic causes which may occasionally be associated with malabsorption. Measurement of the gut hormones, such as gastrin, pep­ tide YY, vasoactive intestinal peptide, chromogranin A, and 5-​ hydroxyindoleacetic acid, will form part of the diagnostic pathway in patients with prominent diarrhoea in whom a neuroendocrine tumour is suspected. Measurement of faecal bile acids is not generally performed outside a research context. Raised faecal calprotectin is not a consequence of malabsorption, but may be found in those with Crohn’s disease-​related inflammation who also have an element of malabsorption. Stool and urine tests can be used to rule out laxative misuse if this is suspected.

section 15  Gastroenterological disorders 2878 Endoscopic tests The usual role of endoscopic assessment in patients suspected of having malabsorption is to provide duodenal histology to support or refute a diagnosis of coeliac disease. This will also permit diag­ nosis of chronic infection with giardia and of Whipple’s disease. Endoscopic appearances may be suggestive: mosaic-​like scalloping of the duodenal folds is suggestive of villous atrophy in coeliac dis­ ease; aphthous ulcers are typical of Crohn’s disease; and white punc­ tate lesions can be seen in primary or secondary lymphangiectasia. Ileocolonoscopy with terminal ileal views can show inflamma­ tion or ulceration indicative of Crohn’s disease, and colonic biop­ sies may yield a diagnosis of microscopic colitis which, by virtue of chronic diarrhoea, may generate a suspicion of malabsorption given its association with coeliac disease. Further small-​bowel views can be obtained with push enteroscopy, double-​balloon enteroscopy, or wireless capsule endoscopy, but the last cannot provide ma­ terial for the histological assessment which may be diagnostic­ ally critical in patients with small intestinal lymphoma, intestinal lymphangiectasia, or eosinophilic enteritis. Only very rarely is lapar­ otomy or laparoscopy required for full-​thickness biopsies from the jejunum or ileum. There are several congenital defects that can lead to malabsorption, including specific amino acid transport defects and monosaccharide transport defects. Paediatric centres are alert to these, but they are rarely encountered in adult practice. Metabolic assessment of small intestinal biopsies will be required in many cases. Autoimmune polyglandular syndrome type 1—​from a recessive defect in the auto­ immune regulator gene AIRE—​generally presents with low-​grade chronic or recurrent infection (typically candidal) and a set of endo­ crine deficiencies. There is usually an element of malabsorption and intestinal histology demonstrates mucosal atrophy. Imaging studies A simple abdominal X-​ray can detect pancreatic calcification in chronic pancreatitis. Small-​bowel barium enteroclysis or MRI may indicate a small-​bowel origin for disease via focal or diffuse abnor­ malities such as stagnant loops of bowel, diverticula, hypomobility, dilatation, or small-​bowel tumours. Signs of Crohn’s disease include ulceration, distorted, thickened folds, and fistulae. Postsurgical anatomy may usefully be ascertained and the length of remaining intestine in short-​bowel syndrome can be identified. CT imaging with contrast can also be used to assess inflammatory bowel disease, intestinal lymphoma, and pancreatic disease, with additional CT angiography if the clinical context suggests mesenteric ischaemia. Magnetic resonance cholangiopancreatography (and rarely, endo­ scopic retrograde cholangiopancreatography) can provide diag­ nostically discriminant information about the pancreas and biliary tree, particularly with respect to primary sclerosing cholangitis or chronic pancreatitis and tumours at these sites, each of which rarely presents with malabsorption. Specific radiology for neuroendocrine tumours can include octreotide scintigraphic scans or positron emission tomography imaging. Other diagnostic investigations Breath tests Hydrogen breath testing depends on the inability of human metabolism to produce hydrogen from carbohydrates and the efficient exhalation of any absorbed hydrogen produced by gut bacteria; it can therefore be used to identify small-​bowel bacterial overgrowth. Breath testing is also a more direct test of maldigestion/​ malabsorption in the case of lactose intolerance. Lactose is nor­ mally hydrolysed to glucose and galactose in the proximal small intestine, where these are then fully absorbed. In lactase deficiency, intact disaccharide reaches the colon and provides a substrate for colonic bacteria and the potential for hydrogen generation. Intestinal biopsy and assay of brush border enzymes is thus rarely required. Comparable breath tests in which the substrate is a lipid can be used to estimate maldigestion from pancreatic insufficiency. Tests of bile salt absorption Bile salt malabsorption in ileal disease or primary bile acid diar­ rhoea can be investigated with a synthetic bile salt retention scan. The patient swallows a capsule containing 75SeHCAT and is scanned at 1 to 3 h and then again at 7 days. The percentage retention is meas­ ured, and when less than 15% of the initial value indicates bile salt malabsorption from loss of its normal enterohepatic circulation. This may be found in any patient in whom there has been distal ileal resection, as well as in those with a primary defect. Radiolabelled bile salt breath tests are no longer performed. Tests of intestinal permeability and absorptive function The xylose absorption test relies on active uptake of this non­ metabolized pentose after oral administration and its subsequent detection in blood or urine, the notion being that this process de­ pends only on an intact mucosa and conditions that affect the mucosa would reduce absorption. Unfortunately the test is not robust—​neither its sensitivity nor specificity is sufficient to earn it clinical value—​and it has become obsolete. The permeability of the intestine is often disturbed in malabsorptive states, but the relationship is a complex one, also encompassing the effects of inflammation. Tests of permeability have accordingly not found a place in clinical practice, although in the research context assessment may utilize radiolabelled Cr-​EDTA, a sugar mixture such as rhamnose with lactulose, or a macromolecule such as poly­ ethylene glycol. Intestinal absorptive function thus remains poorly quantified, and there is no method that provides a numerical equivalent to (for example) the serum creatinine as a marker of renal impair­ ment. The most promising parameter in this respect is the plasma citrulline. This is a nonprotein amino acid which is almost exclu­ sively produced—​from glutamine—​in the small intestine. The levels are predictably low in patients with extreme short-​bowel syndrome and have prognostic significance. Modestly disturbed levels are more difficult to interpret in the individual patient, and at present assays are performed routinely only in patients with small-​bowel transplants in whom falling levels correlate well with insipient organ rejection. Management The treatment of malabsorption is always directed at its underlying cause, and the success or otherwise of this approach is dependent

15.10.2 Bacterial overgrowth of the small intestin

15.10.2 Bacterial overgrowth of the small intestine 2879

15.10.2  Bacterial overgrowth of the small intestine 2879 on the diagnosis and its response to treatment. There has until re­ cently been no overarching treatment for intestinal malabsorption itself. The endogenous hormone glucagon-​like peptide 2 is one of the glucagon family and is secreted from the L-​cells of the intestine in response to luminal nutrients, whence it acts as a small-​bowel growth factor. Its exogenous administration in patients with short-​ bowel syndrome confirms that the effect can be utilized thera­ peutically, and longer-​acting analogues are becoming available for clinical use. FURTHER READING Barkun AN, et al. (2013). Bile acid malabsorption in chronic diarrhea: pathophysiology and treatment. Can J Gastroenterol, 27, 653–​9. Battat R, et al. (2014). Vitamin B12 deficiency in inflammatory bowel disease:  prevalence, risk factors, evaluation, and management. Inflamm Bowel Dis, 20, 1120–​8. Cynober L, Moinard C, De Bandt JP (2010). Citrulline: a new major signaling molecule or just another player in the pharmaconutrition game? Clin Nutr, 29, 545–​51. Fasano A, et al. (2015). Nonceliac gluten sensitivity. Gastroenterology, 148, 1195–​204. Forbes A (2014). Crohn’s disease: rehabilitation after resection. Dig Dis, 32, 395–​8. Jeppesen PB, et al. (2012). Teduglutide reduces need for parenteral nu­ trition among patients with short bowel syndrome with intestinal failure. Gastroenterology, 143, 1473–​81. Juckett G, Trivedi R (2011). Evaluation of chronic diarrhea. Am Fam Physician, 84, 1119–​26. Kelly CP, et al. (2015). Advances in diagnosis and management of ce­ liac disease. Gastroenterology, 148, 1175–​86. Mooney PD, Hadjivassiliou M, Sanders DS (2014). Coeliac disease. BMJ, 348, g1561. Nadhem ON, et al. (2015). Review and practice guidelines for celiac disease in 2014. Postgrad Med, 127, 259–​65. Papadia C, et al. (2014). Diagnosing small bowel malabsorption: a re­ view. Intern Emerg Med, 9, 3–​8. 15.10.2  Bacterial overgrowth of
the small intestine Stephen J. Middleton and Raymond J. Playford ESSENTIALS Small intestinal bacterial overgrowth can be defined as the presence of excessive bacteria in the small intestine which can interfere with digestion and absorption. Predisposing causes include sustained hypochlorhydria induced by proton pump inhibitors, small intes- tinal dysmotility and stasis due to anatomical or motor abnormal- ities, and reduced antibacterial activity as seen in immunological deficiency and chronic pancreatitis. Presentation is predominantly from consequences of malabsorp­ tion, including gastrointestinal symptoms (e.g. diarrhoea or steatorrhoea) and features of specific nutrient malabsorption
(e.g. osteoporosis, anaemia, neuropathy, and night blindness). Definitive diagnosis is difficult, requiring a properly collected and appropriately cultured aspirate from the proximal small intestine re- vealing a total concentration of a mixed growth of bacteria generally greater than 105 organisms/​ml. Alternative investigations frequently used include glucose/​lactulose breath tests or either the 13C-​ or 14C-​xylose breath test, with elevated levels of 13CO2 or 14CO2 found in the breath. There may be low levels of cobalamin (metabolized by Gram-​negative anaerobes), increased serum folate (synthesized by overgrowth flora), and increased urinary indicans (intraluminal product of bacterial tryptophan metabolism). Aside from treatment of any nutritional deficiencies, spe- cific treatment is with an antimicrobial that is effective against both aerobic and anaerobic enteric bacteria (e.g. doxycycline, amoxicillin–​clavulanic acid, rifaximin, or ciprofloxacin), which can be administered in rotation to reduce antibiotic resistance. Where possible and appropriate, correction of any underlying cause should also be performed. Introduction Small intestinal bacterial overgrowth (SIBO) can be defined as the presence of excessive bacteria in the small intestine. It causes a var­ iety of symptoms and clinical manifestations which depend upon the type, density, and metabolic characteristics of colonizing bac­ teria and the response of the host. SIBO can result in diarrhoea, malabsorption syndromes re­ sulting in weight loss, specific nutritional deficiencies, and more generalized complications such as osteoporosis. Bloating, flatu­ lence, and abdominal discomfort are common and can result in clinical features similar to those of irritable bowel syndrome (IBS). There is increasing recognition that SIBO is commoner than previ­ ously thought and occurs in patients with normal gastrointestinal anatomy. It has been found to be a frequent cause of diarrhoea and malabsorption in elderly patients who have developed age-​related small-​bowel dysmotility. Prevalence The incidence of SIBO is increased in some disease states, but is also present in a few apparently healthy control subjects (Table 15.10.2.1). Gastrointestinal surgery, in particular the formation of a ‘blind loop’ such as that found in a Roux-​en-​Y reconstruction, has been widely appreciated as a cause of SIBO for many years. However, it is now evident that many conditions, particularly those that result in dysmotility, are also associated with SIBO in the absence of surgery and with normal anatomy. Of particular interest is the recent obser­ vation that many patients with clinical features of IBS also have SIBO, but it remains unclear if these patients have SIBO alone or both conditions exist in association.

section 15  Gastroenterological disorders 2880 Pathology SIBO is characterized by an increase in the density of bacteria com­ monly found as normal gut commensals and it is generally con­ sidered to result from a deficiency of the normal process which maintains homeostasis of resident enteric bacteria. Researchers have identified disturbances in gut motility, immune function, anatomy, and mucosal function as likely causes of SIBO. SIBO can be defined as a bacterial count in the small bowel of greater than 105 colony forming units (CFUs)/​ml, as compared to 103 CFUs/​ml which is considered to be the upper limit of normal. This is often associated with inflammatory changes in the small-​ bowel mucosa, including blunting of the villi, atrophy of mucosa and crypts, and elevation of the intraepithelial lymphocytes. These changes resolve with antibiotic therapy. Under normal circumstances, most resident bacteria in the small intestine are Gram positive. However, in SIBO, Gram-​negative or­ ganisms, enterococci and anaerobes, which are more typical of co­ lonic flora, become predominant and the pathological effects on intestinal function are considered to arise from their metabolic and immunogenic properties as well as their numbers. Bacteria that deconjugate bile salts tend to cause fat malabsorption, whereas those that ferment carbohydrate produce flatulence and bloating. Certain bacteria, particularly the Gram-​negative popu­ lation such as klebsiella, produce substances toxic to the intestinal mucosa leading to diarrhoea and malabsorption. Aetiological factors Abnormal luminal environment Hypochlorhydria Reduced gastric acid production is often associated with conditions such as gastric atrophy, Helicobacter pylori infection, and following vagotomy. Studies have found SIBO to be present in about 50% of pa­ tients taking standard doses of proton pump inhibitors and around 15% of those on H2 antagonists. Pancreatic exocrine deficiency Chronic pancreatitis is associated with a 30% incidence of SIBO, probably due to pancreatic exocrine insufficiency which leads to re­ duced levels of antibacterial proteolytic enzymes and maldigestion of food and luminal substances, facilitating the overgrowth of bac­ teria. Furthermore, associated motility disturbances due to the use of powerful analgesics cause stasis and reduced bacterial clearance. This may in part explain the high incidence of SIBO in cystic fi­ brosis (approximately 50%) and pancreatic cancer. Gastrointestinal dysmotility Under normal circumstances, regular sweeping peristaltic con­ tractions generated by the intermittent aboral migratory motor complex limit the amount of food remaining in the small intes­ tine between meals. Disturbances of motility which reduce the ef­ fectiveness of this process may result in the presence of excessive quantities of food debris in the lumen, which can promote bac­ terial proliferation and overgrowth. Neuropathic and myopathic processes often underlie motility disturbances, although these are not commonly histologically characterized as this requires a full-​thickness intestinal biopsy. Systemic diseases such as diabetes, scleroderma (Fig. 15.10.2.1), and polymyositis may cause intes­ tinal muscle damage. Cirrhosis and renal failure have been associ­ ated with disorders of peristalsis leading to stasis and SIBO. Isolated gastroparesis may result in considerable gastric residue and bacterial overgrowth, which may then provide the small intestine with excessive quantities of bacteria. This is often associated with diabetes but can also be caused by viral infections and certain medications. Patients diagnosed with IBS have recently been reported to have evidence of SIBO in 30 to 80% of cases. As SIBO produces symptoms which are similar to those of IBS, many believe that these patients have SIBO rather than IBS; others feel that SIBO has arisen because of dysmotility caused by IBS. Structural abnormalities Surgical procedures that result in regions of relative stasis are com­ monly associated with SIBO, with the blind loop fashioned in the Billroth II and Roux-​en-​Y anastomoses following antral gastrec­ tomy being good examples. Nonsurgical anatomical disorders asso­ ciated with stasis include diverticula, which can be large and sparse or small and numerous (Fig. 15.10.2.2). Stasis also occurs proximal to strictures where the intestine may be dilated in conditions such as Crohn’s disease, scleroderma, and following radiotherapy. Table 15.10.2.1  Conditions predisposing to SIBO Healthy subjectsa Structural abnormalities Small intestinal diverticulosis Small intestinal strictures Blind loops (Roux loops) Resection of ileocaecal valve Gastrectomy Coloenteric fistulation Disorders of motility Intestinal myopathy Intestinal neuropathy Gastroparesis Pseudo-​obstruction Drug induced intestinal stasis Age related dysmotility Parkinson’s disease Muscular dystrophy Mucosal damage/​dysfunction Crohn’s disease Coeliac disease Immunodeficiency Organ dysfunction Cirrhosis Renal failure Hypochlorhydria Pancreatitis Metabolic Diabetes Drugs Acid suppression Intestinal stasis (i.e. opiates) a Incidence reported as 0 to 20% in studies, uncertain aetiology.

15.10.2  Bacterial overgrowth of the small intestine 2881 Mucosal-​associated immune dysfunction Bacterial populations in the intestine are also regulated by the mu­ cosal immune system and its dysfunction can result in SIBO. Studies have demonstrated SIBO in patients with isolated subgroup as well as more generalized immunoglobulin deficiency and T-​cell dysfunction. This is also seen in patients following intestinal trans­ plantation who receive powerful immunosuppression and also have a degree of dysmotility. A high incidence of SIBO has also been re­ corded in chronic lymphocytic leukaemia (approximately 50%) and lymphoma. Disorders of the intestinal mucosa Conditions that cause damage and dysfunction of the mucosa such as coeliac disease, radiation enteritis, and Crohn’s disease are associated with SIBO, a common cause of ongoing diarrhoea in coeliac patients after treatment with a gluten-​free diet (approxi­ mately 60%). It is likely that in addition to associated motility dis­ turbances a dysfunctional mucosa allows excessive proliferation of bacteria through impairment of innate and acquired immunity. Age-​associated SIBO Studies in elderly populations have demonstrated an incidence of SIBO of between 15 and 30%. Immobility and comorbidity tend to be the main risk factors, and although age-​related dysmotility has been widely suggested as the underlying cause, this remains controversial. Miscellaneous conditions Several studies have detected an association between non­ alcoholic steatohepatitis (NASH) and SIBO. A role for SIBO in the pathogenesis of NASH has been postulated, and slow intes­ tinal transit times have been found in some experimental models of NASH. Patients with chronic alcoholism in the absence of cirrhosis have elevated levels of intestinal bacteria, believed to be a result of mucosal damage, and patients with Parkinson’s disease are more likely to have SIBO, which may be due to a neurological mani­ festation of the disorder or a consequence of drug therapy for the condition. Fig. 15.10.2.1  Small bowel filled by reflux during a barium enema performed in a patient with recurrent bloating and air-​filled small bowel loops on abdominal radiographs. This spot image shows the hide-​bound appearance with flattened edges of crowded thin folds (arrow). On the opposite wall, wide-​mouthed sacculations are present, permitting the diagnosis of scleroderma. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. (a) (b) Fig. 15.10.2.2  Malabsorption from small-​bowel diverticulosis. CT scan (a) shows dilated loops of small bowel and dilution of enteric contrast material. With small-​bowel malabsorption, fluid-​filled large diverticula may have the same diameter as dilated loops and be completely obscured. It may be the tiny diverticula (arrows) that are most clearly seen. (b) A spot radiograph from a small-​bowel series confirms small-​bowel diverticulosis with many large diverticula (arrow). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2882 Clinical features Clinical manifestations vary according to the metabolic and im­ munogenic properties of the bacteria and the response of the host. Abdominal bloating, discomfort or pain, and flatulence, with or without diarrhoea, commonly occur and often closely overlap with the symptoms of IBS making differential diagnosis difficult. When significant malabsorption is present, weight loss and steatorrhoea may occur, and specific nutrient deficiencies can cause metabolic bone disease and hypocalcaemia (vitamin D), polyneur­ opathy and megaloblastic anaemia (vitamin B12), iron deficiency anaemia, and (occasionally) protein-​losing enteropathy. Night blindness from vitamin A  deficiency and vitamin E deficiency causing neuropathy and T-​cell abnormalities has been reported. The main nutritional consequences are summarized in Box 15.10.2.1. In some cases, bacterial fermentation of sugars and easily fer­ mentable polysaccharides produces d-​lactate, for which there is no human metabolic pathway. Elevated serum levels of lactic acid may result in clinically significant d-​lactic acidosis. Diagnosis Bacterial culture Direct estimation of the quantity and nature of bacteria within the lumen of the small intestine is generally considered to be the gold standard for diagnosis. However, the difficulties associated with collection and culture of bacteria have made this unpopular as a clinical tool. Molecular techniques to quantify intestinal bacteria have not yet been validated but offer a potential solution to the diffi­ culties of culturing fastidious organisms. Breath tests The less invasive indirect diagnostic techniques are most commonly used in clinical practice. The hydrogen breath test is the simplest example and is based on the premise that hydrogen is not produced by mammalian cells and therefore a significant rise in detectable hydrogen in the breath, following consumption of a fermentable substrate, can be assumed to be arising from bacterial fermentation of that substrate (Table 15.10.2.2). The substrates used in this test include glucose, lactulose, and xylose. Glucose is usually completely absorbed by the intestine and there­ fore will rarely give rise to hydrogen from fermentation by colonic bacteria. For this reason, it is often preferred to lactulose, which is poorly absorbed and produces a hydrogen peak from colonic bac­ teria that must be distinguished from an earlier peak if small-​bowel bacterial fermentation is present. This distinction can sometimes be difficult to determine, and may lead to less diagnostic accuracy, particularly if intestinal transit is rapid (such as in short-​bowel syn­ drome), resulting in lower sensitivity and specificity. However, the proximal absorption of glucose may result in failure to detect over­ growth of the distal small intestine. Xylose is less easily absorbed and more reaches the distal small intestine, giving the potential ad­ vantage of providing a better assessment of the entire small bowel. Unfortunately, incomplete absorption is more likely and the risk of confusion with colonic fermentation is increased. Breath methane is also an indicator of bacterial fermentation, and a combination of measurements of methane and hydrogen is becoming more commonly used. This allows detection of those bac­ teria which produce either only hydrogen (approximately 50%) or methane (approximately 10–​15%). There is lack of consensus about the breath hydrogen levels used to define bacterial overgrowth. A rise in hydrogen concentration of at least 20 parts per million (ppm) after a glucose challenge and at least 12 ppm after lactulose are usually taken to indicate bacterial overgrowth. Their diagnostic accuracy is reported to be approxi­ mately 70% and 50% respectively. A further method of breath sample analysis using radioisotope-​ labelled substrates has been developed but is generally considered to be no more accurate than hydrogen and methane analysis. This Box 15.10.2.1  Main nutritional consequences of SIBO • Weight loss • Fat malabsorption (steatorrhoea) • Vitamin and mineral deficiency: —​ Fat-​soluble vitamins (A, D, E, K) —​ Vitamin B12 —​ Iron —​ Magnesium —​ Calcium • Increased serum levels of: —​ Folate —​ d-​lactate • Hypoproteinaemia/​hypoalbuminaemia Table 15.10.2.2  Indirect tests for detecting bacterial overgrowth of the small intestine Test Measurement End point Comment Glucose 50 g oral Breath hydrogen/​methane Rise in [breath] of ≥20/​≥12 ppm respectively Measurement of both gases improves accuracy Lactulose 10 g oral 13C/​14C-​d-​xylose oral Breath 13CO2/​14CO2 Individual laboratory normal ranges Limited by expense and radioactivity 13C/​14C-​glycocholate oral Breath 13CO2/​14CO2 Individual laboratory normal ranges Sensitivity lower as only detects deconjugating bacteria Bacterial metabolites in urine Urine 4-​hydroxyphenylacetic acid Individual laboratory normal ranges Useful in paediatric practice Urinary indicans Individual laboratory normal ranges Sensitivity and specificity is lower than breath tests Therapeutic trial of antibiotics Clinical effect Improvement of symptoms May cause diagnostic confusion as other conditions can respond to antibiotics

15.10.2  Bacterial overgrowth of the small intestine 2883 employs 13C-​ and 14C-​labelled xylose or glycocholic acid, which when fermented produces isotope-​labelled CO2 that is excreted and measured in breath samples. The use of isotopes is expensive, and they cannot be used in children and pregnancy. The glycocholic breath test only detects bacteria which are able to deconjugate, and these may be absent in up to 30% of cases of SIBO. Management The aims of treatment can be divided into three areas: eradicating the overgrowth of bacteria, restoring any nutritional deficiencies, and resolving the underlying cause where possible (Box 15.10.2.2). In many cases, the consequences of SIBO are minor and the risks and inconvenience of treatments such as long-​term antibiotics or reconstructive surgery may be greater than the potential bene­ fit. Patients may prefer symptomatic control with antidiarrhoeal agents. Eradicating bacterial overgrowth Antibiotics A mixed population of bacteria is present in bacterial overgrowth, making selection of antibiotics difficult, a matter further com­ pounded by the inability to culture more than about 20% of species present in the resident intestinal flora. Attempts to identify bacteria have found a mixture of aerobes (such as streptococci, Escherichia coli, staphylococci, and klebsiella) and anaerobes (such as bacteroides, lactobacillus, and clostridium). Broad-​spectrum anti­ biotics have therefore been used, often in rotation, to reduce the risk of developing colonization with resistant organisms. Tetracycline has been extensively employed in the past, but newer regimens including ciprofloxacin, amoxicillin/​clavulanate, and doxycyc­ line have been reported to have superior efficacy (Box 15.10.2.3). Recent studies of the efficacy of metronidazole and rifaximin have reported encouraging results with examples of long-​term remis­ sion, although most advocate repeated courses of 7 to 10 days or inclusion in a cyclical regimen with other antibiotics. Long-​term studies suggest that, after a single course, there is a relapse rate of at least 50% at 9 months. Resistant cases may respond to the oral administration of anti­ biotics with poor oral bioavailability such as gentamicin, but only anecdotal evidence of efficacy is available. Probiotics There have been few randomized controlled trails of probiotics as treatment for SIBO. A trial in paediatric patients with proton pump inhibitor-​induced SIBO failed to reveal any benefit from the combination of Lactobacillus rhamnosus and L.  acidoph- ilus. However, a randomized double-​blind trial of L.  casei and L.  acidophillus significantly reduced diarrhoea, whereas another randomized study did not find any benefit from L.  fermentum. Overall, it appears that there is inadequate evidence to support the use of probiotics as treatment for SIBO at present. Nutritional support The primary aim should be to replace any nutritional deficiencies and encourage normalization of body weight. Particular atten­ tion should be given to replacement of likely deficiencies detailed in Box 15.10.2.1. Enhanced absorption of energy-​providing foods may be possible by dietary manipulation to encourage consumption of those foods which appear to be absorbed. Patients with marked steatorrhea may benefit from a diet richer in carbohydrates than fat, and the opposite should be considered where bloating and flatulence are the main symptoms. Treating the cause of bacterial overgrowth Structural abnormalities such as strictures and blind loops may be amenable to reconstructive surgery and large, single small-​bowel diverticulum can sometimes be resected. Disorders of motility are difficult to treat: most neuropathies and myopathies do not respond adequately to medical treatment. Gastroparesis occasionally re­ sponds to prokinetic agents, and when associated with diabetes may improve with optimization of blood glucose control. The response to gastric pacemakers has generally been disappointing. When the result of a metabolic abnormality such as hypothyroidism or an elec­ trolyte disturbance, pseudo-​obstruction can often be treated, but unfortunately in many cases a reversible cause cannot be found. A careful review of all medications is important. Opiates are of particular concern, but antidepressants with anticholinergic prop­ erties can also sometimes be implicated. Control of inflammatory conditions of the mucosa such as coeliac disease and Crohn’s dis­ ease should be confirmed and optimized, and in cases of immuno­ deficiency, therapy such as immunoglobulin replacement must be adequate. FURTHER READING Dukowicz AC, Lacy BE, Levine GM (2007). Small intestinal bacterial overgrowth: a comprehensive review. Gastroenterol Hepatol (N Y), 3, 112–​22. Grace E, et  al. (2013). Review article:  small intestinal bacterial overgrowth—​prevalence, clinical features, current and developing diagnostic tests, and treatment. Aliment Pharmacol Ther, 38, 674–​88. Sachdev AH, Pimentel M (2013). Gastrointestinal bacterial over­ growth:  pathogenesis and clinical significance. Ther Adv Chronic Dis, 4, 223–​31. Box 15.10.2.2  Targets for treatment of SIBO • Treat overgrowth of bacteria • Resolve nutritional deficiencies • Treat the underlying cause of SIBO Box 15.10.2.3  Antibiotics with supporting evidence of efficacy in SIBO • Rifaximin • Ciprofloxacin • Norfloxacin • Amoxicillin/​clavulanate • Metronidazole + trimethoprim/​sulfamethoxazole • Metronidazole + cephalexin

15.10.3 Coeliac disease 2884

15.10.3 Coeliac disease 2884

section 15  Gastroenterological disorders 2884 15.10.3  Coeliac disease Peter D. Mooney and David S. Sanders ESSENTIALS Coeliac disease is a common disorder of the small intestine in which storage proteins in dietary wheat, rye, and barley (gliadin, secalins, and hordeins, usually referred to as ‘gluten’) induce an autoimmune enteropathy characterized by villous atrophy in genetically suscep- tible individuals. The prevalence of coeliac disease is 0.2 to 2% in populations with high consumption of gluten-​containing foods. Females are more commonly affected than males (1.5–​2:1), with typical presentation now in the forties. ‘Classical’ coeliac disease presented in childhood with malabsorption, but this is now rare. ‘Nonclassical’ presentations are now the norm, and highly variable, ranging from nonspecific ab- dominal symptoms to the consequences of malabsorption (e.g. an- aemia, osteoporosis) to nongastrointestinal symptoms (e.g. ataxia, dermatitis herpetiformis), and many have no symptoms at all. Diagnosis is made by serological testing for (usually) antitissue transglutaminase antibodies, which have excellent sensitivity and specificity, with confirmation by duodenal biopsy. Treatment is with a gluten-​free diet, which constitutes a major chal- lenge for some people. Most patients (but not all) can eat pure oats. Complications include lymphoma, osteoporosis, and other auto- immune conditions. Patients have a normal life expectancy, although quality of life is adversely affected. Introduction Coeliac disease was first described in a mainly paediatric population with failure to thrive and symptoms of malabsorption. Several ap­ parently successful treatments such a ‘banana diet’ and the ‘Dutch mussel diet’ were described before its pathogenesis was elucidated. By the 1950s, it became clear that these treatments were effective because of the inadvertent exclusion of gluten from the diet. Willem Dicke, a Dutch paediatrician, identified that wheat and subsequently gluten was the trigger for coeliac disease. Subsequent work identi­ fied villous atrophy as the characteristic small-​bowel lesion and gliadin antibodies confirmed an autoimmune pathogenesis. Once considered a rare condition, it is now apparent that coeliac disease is one of the most common autoimmune conditions encountered by physicians. It is also now clear that the presentation of coeliac disease is diverse and can be easily overlooked; although the rates of diagnosis for coeliac disease have improved, up to 75% of patients remain undiagnosed. Aetiology Coeliac disease is now recognized as a common autoimmune con­ dition characterized by a heightened immunological response to ingested gluten in genetically susceptible individuals. Gluten is an umbrella term for the storage proteins found in wheat (gliadin), barley (hordein), and rye (secalin). There is a strong genetic component to coeliac disease, with first-​ degree relatives of an index case having a 5 to 11% chance of being affected. The pairwise concordance rate for monozygotic twins is 71.4 to 75%, compared to 9.1 to 11% in dizygotic twins. Second-​ degree relatives also appear to be at increased risk (approximately 2.5%), although there is uncertainty as to the exact prevalence in this population. The genetic heritage is further strengthened by the association with specific human leucocyte antigens (HLAs), with 90 to 95% of patients with coeliac disease carrying genes encoding HLA DQ2 (encoded by DQA105 and DQB102). The vast majority of the remainder carry the HLA DQ8 (encoded by DQA103 and DQB10302) haplotype. Other HLA associations have been re­ ported, such as the half DQ2 heterodimer usually in the form DR7 (DQB1*0201), but the true significance of these rarer HLA types is not clear. The appropriate HLA is required to develop coeliac disease. However, up to 35% of Western populations carry an HLA type compatible with coeliac disease, yet only 2 to 5% of these patient go on to develop the condition. Other genetic factors, mainly involved in T-​cell regulation and inflammation, encoded by single nucleotide polymorphisms have been identified, although the risk associated with these genetic variations is small. Other environmental factors such as gastrointestinal infection, the composition of an individual’s microbiome, or timing of gluten introduction in childhood have all been proposed, but the exact mechanism of the onset of coeliac dis­ ease is yet to be fully elucidated. Epidemiology Until the 1980s, coeliac disease was considered a rare condition, usually presenting in childhood with estimated prevalence rates of 1 in 4000 to 8000. However, data from large-​scale screening studies in both adult and paediatric populations suggests that the estimated prevalence of coeliac disease in the United States of America and European populations ranges between 0.2 and 1.2%. Furthermore, some studies—​particularly from Scandinavia—​suggest that the true incidence of coeliac disease, along with other autoimmune condi­ tions, may be increasing. In common with other autoimmune con­ ditions, females are more commonly affected than males (1.5–​2:1) Historically, coeliac disease was considered a disease of mainly Caucasian populations, but it is now apparent that coeliac disease is a global problem. Coeliac disease is more prevalent in areas where wheat is a staple crop, and areas such as Northern Africa and the Middle East have also demonstrated a prevalence similar to Western populations. However, clinicians from both the Indian subcontinent and China are now increasingly recognizing patients with coeliac disease. There are several hypotheses to explain this increasing prevalence, including improved detection and an increased con­ sumption of wheat in these ethnic groups as their diet becomes more westernized, or an increasing trend in all autoimmune diseases. A reduction in the burden of infective illness in these areas as they develop may also be having an impact. Some areas, however, do have a significantly lower prevalence of coeliac disease, for example, ethnic groups such as black Sahawari

15.10.3  Coeliac disease 2885 populations from sub-​Saharan Africa and populations from the Far East appear to be at reduced risk. This may be in part due to reliance on other staple carbohydrate crops such as maize and rice, but there also appears to be a reduced prevalence of the HLA types associated with coeliac disease in these areas. Historical meta-​analyses estimated that for every patient identi­ fied as having coeliac disease, seven to eight individuals remained undiagnosed. Diagnostic rates for coeliac disease are increasing, with a recent United Kingdom study estimating that the prevalence of diagnosed coeliac disease is now 0.24%, up from 0.14% a decade previously. Nonetheless, this would still suggest that 75% of patients with coeliac disease remain undiagnosed. Pathology Villous atrophy was identified as the characteristic lesion associated with coeliac disease in the 1950s. As understanding grew, it became apparent that, in the presence of a positive serological marker, vil­ lous atrophy was diagnostic of coeliac disease. Various histological staging systems have been proposed, but the most widely used is the Marsh classification. These criteria, first reported in 1992, placed par­ ticular emphasis on the importance of the presence of intraepithelial lymphocytes in diagnosis and identified ‘preinfiltrative’ lesions in the absence of villous atrophy. In these criteria, a Marsh 1 lesion is described as elevated intraepithelial lymphocytes in the absence of villous atrophy, and a Marsh 2 lesion demonstrates crypt hyperplasia and raised intraepithelial lymphocytes. Finally, the ‘destructive le­ sion’ (Marsh 3)  requires crypt hyperplasia, raised intraepithelial lymphocytes, and villous atrophy. These criteria have undergone further modification by Oberhuber to further subdivide the de­ structive lesion, grading the severity of the villous atrophy on the basis of the villous height-​to-​crypt depth ratio, into partial villous atrophy (3a), subtotal villous atrophy (3b), and total villous atrophy (3c) (Table 15.10.3.1). For a cast-​iron diagnosis of coeliac disease, the presence of a Marsh 3 lesion is required. Figure 15.10.3.1 shows normal villi and villous atrophy. Marsh 1 and 2 lesions can be associated with a diagnosis of coeliac disease. A recent study randomized patients with Marsh 1 changes and a positive endomysial antibody (EMA) to a gluten-​free or gluten-​ containing diet. Those who continued on a gluten-​containing diet demonstrated deterioration in villous architecture, with reduced villous height-​to-​crypt depth ratio and a persistence of symptoms. Patients in the gluten-​free arm noted a significant improvement in symptoms and no change in the villous height-​to-​crypt depth ratio. However, it is important to recognize that Marsh 1 and 2 changes are relatively nonspecific and are also associated with many other conditions including Helicobacter pylori infection, or as a result of nonsteroidal anti-​inflammatory use. Coeliac disease is only subse­ quently confirmed on repeat gastroscopy and biopsy in 16 to 43.3% of patients. A list of differential diagnoses for Marsh 1 and 2 lesions is shown in Box 15.10.3.1, as a result of which a diagnosis of coeliac disease cannot be made based on the presence of increased intraepithelial lymphocytes alone. In these patients, a repeat gastroscopy and duodenal biopsy is recommended following a 6-​week gluten chal­ lenge of 10 g of gluten (equivalent to four slices of bread) per day. HLA genotyping may also be useful in this situation as the absence of the HLA DQ2 and DQ8 haplotypes has a near 100% negative predictive value. Table 15.10.3.1  Marsh–​Oberhuber classification for duodenal histology in coeliac disease Marsh–​Oberhuber classification Description 0 Normal 1 Raised IELs (≥25 per 100 enterocytes)—​a nonspecific finding that can be seen in coeliac disease 2 Raised IELs with crypt hyperplasia—​a nonspecific finding that can be seen in coeliac disease 3a Raised IELs with crypt hyperplasia and partial villous atrophy 3b Raised IELs with crypt hyperplasia and subtotal villous atrophy 3c Raised IELs with crypt hyperplasia and total villous atrophy IELs, intraepithelial lymphocytes (a) (b) Fig. 15.10.3.1  Duodenal biopsy stained with haematoxylin and eosin showing (a) normal villous architecture and (b) total villous atrophy with elevated intraepithelial lymphocytes (March 3c).

section 15  Gastroenterological disorders 2886 Pathogenesis In genetically predisposed individuals, the immune reaction that leads to enterocyte damage is initiated by exposure to toxic peptides in gluten. These toxic peptides result from the partial proteolysis of ingested gluten by gastrointestinal enzymes. To date, at least 50 T-​cell stimulatory epitopes in gluten proteins have been identified, although a unique 33-​mer gliadin fragment is considered the most immunogenic peptide. Importantly, this 33-​mer peptide is particularly resistant to further enzymatic degradation by gastric, pancreatic, and brush border peptidases because of its high content of proline and glutamine. Exactly how these partially degraded gliadin peptides are transported through the small-​bowel epithelium remains controversial. Both a paracellular route through tight junctions and epithelial transcytosis have been de­ scribed. Nonetheless, toxic gluten fragments enter the lamina propria and are deamidated by the enzyme tissue transglutaminase 2 (tTG-​ 2). This process increases the affinity of gluten for HLA DQ2 or DQ8 molecules, some of which remains bound to tTG-​2, inducing a more rigorous gluten response when presented to CD4+ T helper-​1 cells by antigen presenting cells. These activated CD4+ cells initiate the release of proinflammatory cytokines interferon-​γ (IFN-​γ) and tumour ne­ crosis factor-​α (TNF-​α) as well as interleukin (IL)-​21, which stimulates proliferation of intraepithelial lymphocytes. Additionally, B cells are stimulated by type 2 T-​helper cytokines to produce the characteristic autoantibodies seen in coeliac disease. It had previously been thought that coeliac disease was a disease of the adaptive immune system, but it is now apparent that the in­ nate immune system also plays an important role in the initiation of coeliac disease. Gluten peptides can elicit an innate immune re­ sponse indirectly by stimulating secretion of IL-​15 or directly in macrophages and dendritic cells via receptors such as Toll-​like re­ ceptor 4. This drives maturation of these cells and secretion of IL-​1, IL-​8, TNF-​α, and monocyte chemoattractant protein-​1 that serve to potentiate the adaptive immune response to gluten. Subse­quently, under the influence of IFN-​γ, matrix metalloproteinases are secreted by myofibroblasts, resulting in mucosal remodelling and villous at­ rophy. This in turn leads to the clinical symptoms of coeliac disease. Clinical features ‘Classical’ and ‘nonclassical’ presentations Until relatively recently, most patients diagnosed with coeliac disease were children presenting with symptoms of malabsorption: weight loss, chronic diarrhoea, or failure to thrive. A  recent consensus document on nomenclature defines this presentation as ‘classical’ coeliac disease, and it remains relatively rare. With improved detection, it is now clear that coeliac disease is common, presenting most frequently in adulthood. Furthermore, a ‘nonclassical’ presentation is now more prevalent, and this pres­ entation is highly variable: patients may complain of nonspecific abdominal symptoms such as abdominal pain and bloating, al­ tered bowel habit, or they may have no gastrointestinal symp­ toms and present with consequences of malabsorption such as anaemia or osteoporosis. Furthermore, coeliac disease may be paucisymptomatic or present with symptoms not clearly associ­ ated with enteropathy such as ataxia or abnormal liver function tests. It is possible that undiagnosed coeliac individuals may ap­ parently be asymptomatic, although screening studies have shown subsequent improvements in quality of life, suggesting that those affected had accepted their premorbid state as normal for them. The commonly used term ‘coeliac iceberg’ is the best way to de­ scribe the manifestations of coeliac disease as they are understood today (Fig. 15.10.3.2). Case finding The protean manifestations of coeliac disease mean that a case-​ finding approach in at-​risk groups is recommended by current national and international guidelines as the best method of case de­ tection. The aim of case finding is to identify patients at an early stage in their disease in order to alleviate symptoms and reduce the potential risks of developing complications of coeliac disease such as lymphoma, osteoporosis, or anaemia. Testing for coeliac disease is recommended in patient groups with a prevalence of coeliac disease greater than twice that of the general population. This has been demonstrated in multiple prospective case-​finding studies for patients with classical symp­ toms or sequelae of malabsorption such as anaemia or osteopor­ osis. These same studies also demonstrate increased prevalence of coeliac disease in patients with more nonspecific symptoms, al­ though there is significant heterogeneity in the patient populations studied. Nonspecific abdominal symptoms The best evidence for testing for nonspecific abdominal symptoms is in patients fulfilling clinical diagnostic criteria for irritable bowel syndrome. Data from meta-​analyses have demonstrated that irrit­ able bowel syndrome-​type symptoms are common in patients with coeliac disease, affecting 38% of patients. Furthermore, the preva­ lence of undiagnosed coeliac disease is 4.1% in those presenting with irritable bowel syndrome. Evidence for testing in patients with other abdominal symptoms is less compelling. A  systematic review of diagnostic testing for coeliac disease demonstrated a wide range of coeliac disease preva­ lence in patients presenting with all abdominal symptoms from 2 to 13%. A meta-​analysis of patients fulfilling the criteria for func­ tional dyspepsia showed no significant increase in coeliac disease compared to controls. However, dyspeptic symptoms are common in patients with coeliac disease and a gluten-​free diet has been shown to improve dyspeptic symptoms in newly diagnosed coeliac patients. For this reason, case finding may be justified in patients with nonspecific dyspeptic symptoms, particularly for those with intractable symptoms where no other cause is apparent. Box 15.10.3.1  Causes of intraepithelial lymphocytosis
(Marsh 1 and 2) • Coeliac disease • Helicobacter pylori infection • Drugs (NSAIDs, aspirin) • Small bowel bacterial overgrowth • Giardia • Gastroenteritis • Threadworm • Crohn’s disease • Sarcoidosis • Idiopathic

15.10.3  Coeliac disease 2887 Extraintestinal presentations Identification of patients with extraintestinal manifestations of coeliac disease is important to avoid missed diagnoses. Case finding is justified in these groups as there may be an improvement in the extraintestinal manifestations on a gluten-​free diet as well as po­ tentially reducing the risk of other known coeliac complications. Examples of this already discussed include patients with anaemia or osteoporosis, who may have subclinical malabsorption. Hepatitis Cryptogenic hepatitis is the most common hepatic manifestation of coeliac disease and testing patients with abnormal liver function tests with no clear cause may be justified. A recent meta-​analysis of unex­ plained transaminitis demonstrated a pooled prevalence of coeliac disease 4% (1–​7%), with 27% (13–​44%) of newly diagnosed coeliac disease patients having abnormal liver function tests. Clinicians must, however, be wary of the association between coeliac disease and other autoimmune liver disorders such as primary biliary chol­ angitis, primary sclerosing cholangitis, and autoimmune hepatitis. These conditions should be excluded in patients with coeliac disease and abnormal liver function tests before a diagnosis of coeliac hepa­ titis can be made. Transaminitis resolves spontaneously on institu­ tion of an effective gluten-​free diet within a year in most patients. Ataxia Idiopathic sporadic ataxia is another condition where case finding is recommended in the absence of gastrointestinal symptoms. In recent years, there has been increasing awareness of gluten ataxia as a distinct clinical entity. Studies have shown gluten-​related anti­ bodies (including antigliadin antibodies) in 11.5 to 41% of patients with idiopathic sporadic ataxia. These patients may derive benefit from a gluten-​free diet even in the absence of enteropathy, although up to a third of patients with ataxia and gluten-​related antibodies have villous atrophy on duodenal biopsy. The reason for the associ­ ation between dietary gluten exposure and ataxia remain to be fully elucidated, but there is increasing interest in the role of tTG-​6 anti­ bodies which are expressed in the cerebellum. Fatigue Unexplained fatigue may also be an indication for case finding for coeliac disease. Fatigue is an extremely common symptom in coeliac disease affecting 7–​44% of patients with reduced fatigue in patients who report good adherence to a gluten-​free diet. Testing for coeliac disease in patients with unexplained fatigue has an estimated preva­ lence of 0.8 to 3.3%. Other reasons for increased risk As well as patients with symptoms or obvious sequelae of coeliac disease, case finding is recommended in several groups where there is an increased risk of coeliac diagnosis. This includes patients with a first-​degree relative who have an estimated 10% risk of developing coeliac disease. There is also significant cross-​over between other autoimmune conditions and coeliac disease, particularly type 1 dia­ betes mellitus and autoimmune thyroid disease. Diagnosed coeliac disease (25%) Classical symptoms (0.2%) Nonclassical symptoms (0.8%) The Coeliac Disease Iceberg HLA status DQ2:DQ8 positive patients (Up to 100% coeliac disease; Up to 35% general population) Villous atrophy equivocal normal mucosa Undiagnosed coeliac disease (75%) Untested or subclinical Potential coeliac disease Increased intraepithelial lymphocytes ± positive serology Healthy individuals HLA DQ2 or DQ8 positive of uncertain significance Fig. 15.10.3.2  The coeliac disease iceberg. Patients above the waterline have diagnosed coeliac disease. The majority of these patients now present with nonclassical symptoms. Patients under the waterline have either subclinical coeliac disease or have not yet been tested. Patients also under the waterline include those with potential coeliac disease (positive coeliac disease serology with normal or raised intraepithelial lymphocytes without villous atrophy) and those with HLA DQ2 or DQ8 who do not have any other markers of coeliac disease. Some of these patients may go on to develop coeliac disease although the trigger for coeliac disease is not yet fully elucidated.

section 15  Gastroenterological disorders 2888 Prevalence rates for coeliac disease in type 1 diabetes range from 2 to 10%. Screening for coeliac disease is currently recommended by Diabetes UK in children and adolescents with newly diagnosed type 1 diabetes, with repeat testing if symptoms develop. There is limited evidence that a gluten-​free diet in patients with diabetes and coeliac disease may improve glycaemic control and reduce the risk of microvascular complications of diabetes. Screening for coeliac disease in patients with autoimmune thyroid disease is less clear cut, but may be recommended, particularly if large doses of replacement thyroxine are required, which may in­ dicate malabsorption of thyroxine. Estimated prevalence of coeliac disease is up to 7% in selected populations with autoimmune thyroid disease. There is also a well-​documented link between coeliac disease and the congenital genetic defects of Turner’s syndrome and Down’s syndrome. The prevalence of coeliac disease in these pa­ tients ranges from 4.7 to 6.4% for Turner’s syndrome and 0.3 to 4.6% for Down’s syndrome. The reasons for these associations are not known, but clinicians should be aware of this potential association and have a low threshold for coeliac testing in these groups, particularly in children where coeliac disease as well as their genetic disorder may be contributing to growth retardation. Table 15.10.3.2 summarizes the patient groups where testing is currently recommended. Differential diagnosis The clinical presentation of coeliac disease is diverse and fre­ quently nonspecific, hence the potential differential diagnosis for coeliac disease is also broad. There are also differential diagnoses to consider for causes of villous atrophy, and these are particu­ larly important to consider in patients with villous atrophy in the absence of a positive serological test. In this cohort of patients, coeliac disease remains the most common cause, accounting for 28 to 44% of cases. A comprehensive list of the causes of small-​bowel villous atrophy is shown in Table 15.10.3.3. The use of HLA genotyping can be useful in cases of seronega­ tive villous atrophy if it proves negative, but a thorough approach to investigating these patients to consider alternative diagnoses is required in all cases. Corroborative evidence such as a family history, evidence of functional hyposplenism, and response to a gluten-​free diet should be considered. Adequate gluten intake at the time of duodenal biopsy also needs to be ensured as a reduced-​ gluten diet may be sufficient to normalize serology but insuffi­ cient to allow healing of the duodenal mucosa. In some cases, a gluten challenge may be appropriate. Historical evidence suggests that endomysial antibody may be negative in early disease or with lesser degrees of villous atrophy (Box 15.10.3.2). It must also be noted that wheat or gluten can induce symptoms in noncoeliac patients and self-​reported sensitivity is not necessarily a result of coeliac disease. Table 15.10.3.2  Patient groups for whom case finding is advocated Gastrointestinal symptoms Estimated prevalence of coeliac disease (%) Abdominal pain 1.6–​3.2 Diarrhoea 3.9–​5.4 Irritable bowel syndrome 4.1 Steatorrhoea 3.9–​5.4 Unexplained abdominal symptoms 2–​13 Potential malabsorption Anaemia 2.3–​15 Osteoporosis or osteopenia 0–​3 Vitamin D, ferritin, folate, vitamin
B12 deficiency (No prevalence data available) Weight loss 2.7–​3.9 Groups with an increased risk of coeliac disease First-​degree relative with coeliac disease 5–​11 Type 1 diabetes 0.3–​11.3 Autoimmune thyroid disease 2.9–​3.3 Down’s syndrome 0.3–​4.6 Turner’s syndrome 4.6–​6.4 Others Prolonged fatigue (tired all the time) 0.8–​3.3 Idiopathic sporadic ataxia 3.8–​13.7 Unexplained subfertility 2.7–​3.0 Elevated serum transaminases without other cause 4 Table 15.10.3.3  Causes of villous atrophy and negative coeliac serology Cause Condition Coeliac disease Infective Giardiasis Helicobacter pylori Helminth infestation HIV enteropathy Norovirus (chronic infection) Small intestinal bacterial overgrowth (SIBO) Tuberculosis Whipple’s disease Immunological Autoimmune enteropathy Common variable immunodeficiency (CVID) Eosinophilic enteritis Graft-​versus-​host disease Drugs Nonsteroidal anti-​inflammatory drug (NSAIDs) Olmesartan Miscellaneous Amyloidosis Collagenous sprue Crohn’s disease Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) Ischaemic enteritis Lymphoma Mastocytosis Peptic duodenitis Radiation enteritis Tropical sprue Zollinger–​Ellison syndrome

15.10.3  Coeliac disease 2889 Clinical investigation Serology Improved serological testing has been one of the main reasons for the increased awareness and diagnosis of coeliac disease, and ser­ ology should be the initial screening test of choice. Modern sero­ logical tests have excellent sensitivity and specificity in appropriate patient groups. Blood tests are much less invasive than a small-​bowel biopsy and hence have increased the uptake of testing for coeliac disease, greatly improving our selection of appropriate patients for duodenal biopsy. Gliadin antibodies were the first widely available serological test, but these lacked the required sensitivity and specificity: they may be present in up to 12% of the general population and absent in cases of coeliac disease. For many years, therefore, the suspicion of coeliac disease was largely clinical. In the 1980s, endomysial antibody (EMA) testing was first de­ scribed and soon became commercially available. EMA tests detect IgA antibodies to antigens by direct immunofluorescence in monkey oesophagus or human umbilical tissue. Their drawbacks include the requirement for the development of multiple plates, which is labour intensive; the substrates are limited and are expensive, and the results are subjective. Subsequently, the enzyme tissue transglutaminase (tTG) was identified within the small-​bowel endomysium as the key autoantigen in coeliac disease. Enzyme-​linked immunosorbent as­ says (ELISAs) were subsequently developed, initially with guinea pig and then human recombinant tTG antigen. tTG assays are gener­ ally cheaper than EMA and may be more reliable as they provide a quantitative result. In general, tTG assays are more sensitive but less specific than EMA, particularly at low titres, but it is a weakness that there are a large number of commercially available tests, with their accuracy variable between manufacturers. Although gliadin antibodies have been superseded by EMA and tTG, more recently antideamidated gliadin peptide (DGP) as­ says have become available. As previously discussed, deamidated gliadin fragments have a higher affinity for HLA DQ2/​DQ8 mol­ ecules and as a result DGP antibodies would be expected to have superior sensitivity and specificity compared to standard gliadin antibodies. Early studies of DGP antibodies showed high diag­ nostic performance, equivalent to conventional tests, with both IgA and IgG isotypes appearing highly sensitive and specific. However, meta-​analysis in 2010 showed that although the IgA-​based assay performed well, there was no diagnostic advantage conferred by the use of DGP. With the advent of accurate coeliac serology, the focus of case finding for coeliac disease has rightly focused on increased sero­ logical testing in at-​risk groups. However, it must be noted that the sensitivity of even the best assays of tTG, EMA, and DGP are not 100% and cases of seronegative coeliac disease do exist, particularly when a single serological test is used in the diagnostic algorithm. One common reason for seronegative coeliac disease may be IgA de­ ficiency. Selective IgA deficiency is present in 2% of coeliac patients (compared to around 0.2% of the general population) and may cause false-​negative serology as standard tests are usually based on the IgA subclass of antibody. Immunoglobulin levels should be checked alongside standard serology and duodenal biopsy is recommended in IgA-​deficient patients. It is important to recognize, however, that IgA deficiency is not the only cause of seronegative coeliac disease: the mean rate of tTG negative coeliac disease was 7% in 11 studies reported in a recent meta-​analysis of IgA-​tTG. For this reason a duodenal biopsy may still be warranted in patients with a high suspicion of coeliac disease but negative serology, particularly those with unexplained anaemia, diarrhoea, or weight loss. Furthermore, first-​degree relatives of an index case, patients on immunosuppression, and those with early disease or refractory disease at diagnosis may also be at risk of sero­ negative coeliac disease. Endoscopy and duodenal biopsy Most coeliac patients are currently diagnosed on the basis of posi­ tive coeliac serology and a duodenal biopsy to confirm villous at­ rophy. Figure 15.10.3.3 shows magnification endoscopy of normal Box 15.10.3.2  Causes of seronegative coeliac disease • IgA deficiency • Self-​imposed gluten-​free or reduced-​gluten diet • Steroid or immunosuppressant use • Lesser degrees of villous atrophy • Refractory coeliac disease • Early diagnosis • Family history with first-​ or second-​degree relative (a) (b) Fig. 15.10.3.3  Magnification endoscopy showing (a) normal villi and (b) total villous atrophy.

section 15  Gastroenterological disorders 2890 villi and total villous atrophy. However, the 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition guide­ lines suggest an algorithm for avoiding biopsy in a few paediatric patients with significant symptoms, very high antibody titres (tTG

10 × level of normal and positive EMA) and an appropriate genetic phenotype. Although this is understandable for a paediatric popula­ tion where endoscopic evaluation may require a general anaesthetic, duodenal biopsy to confirm diagnosis is still required in adult popu­ lations for several reasons. Firstly, although the performance of serology appears to be ex­ cellent, the studies into each test are invariably performed in high-​ prevalence populations. This ascertainment bias overestimates the performance of a diagnostic test. As we lower the threshold for serological testing, the disease prevalence within the tested popula­ tion will fall, and as a result the positive predictive value of the test will suffer; for example, in a recent cohort of 2000 patients with a prevalence of coeliac disease of 3.9%, the positive predictive value of tTG was only 28.6% despite sensitivity and specificity of greater than 90%. Secondly, a clinical response to a gluten-​free diet is not diag­ nostic of coeliac disease, particularly in patients with irritable bowel syndrome symptoms which may be gluten sensitive in the absence of coeliac disease and Crohn’s disease that can be pseudo-​ improved by a gluten-​free diet. The presence of villous atrophy on a duodenal biopsy gives concrete evidence of coeliac disease which is helpful for counselling patients, ensuring prescription of gluten-​ free foods, and assessing improvement on a gluten-​free diet. If patients do not respond to a gluten-​free diet as expected, any un­ certainty in the initial diagnosis can make subsequent evaluation problematic. Finally, the diagnosis of coeliac disease has implications for first-​ degree relatives of an index case who have a 10% chance of diag­ nosis. It is difficult to recommend screening of relatives based on serology alone. Historical teaching suggested avoiding the duodenal bulb for bi­ opsy over concerns about confounding factors such as peptic duo­ denitis, Brunner’s glands, and gastric heterotopia. Recent evidence, however, suggests that interpretation of duodenal bulb biopsies is feasible and that in up to 10% of patients with coeliac disease, vil­ lous atrophy may be confined to the duodenal bulb. Current inter­ national guidelines therefore recommend taking duodenal bulb biopsies as well as those from the distal duodenum in cases of sus­ pected coeliac disease. Management At present, the only proven treatment for coeliac disease is a gluten-​ free diet. This should result in the autoimmune cascade being turned off and restoration of normal villous architecture. However, the rate of healing of the small intestinal mucosa is highly variable with 35 to 66% of patients still having persistent villous at 2 years fol­ lowing diagnosis. Whether this is due to the natural rate of healing or persistent gluten exposure is not clear, but it is known that small amounts of gluten exposure can prevent mucosal healing and inten­ sive dietetic input may help mucosal recovery. The commonly used ways to assess adherence include patient-​ reported adherence, dietetic assessment, a validated adherence questionnaire, coeliac serology, or a repeat duodenal biopsy. None of these methods is without its drawbacks, but persistent villous atrophy on duodenal biopsy may have prognostic significance as it is associated with a higher incidence of non-​Hodgkin’s lymphoma and increased hip fracture risk. Patients should have access to a dietician to assess adherence in conjunction with repeat serology and gastroenterology input to assess for resolution of symptoms. Repeat duodenal biopsy should probably be reserved for patients with elevated serological markers, persistent symptoms, or nu­ trient deficiencies. Prognosis Older estimates of mortality in coeliac disease suggested a reduced life expectancy and increased risk of malignancy, but as the in­ creased prevalence of coeliac disease has become apparent, contem­ porary studies suggest that patients have a normal life expectancy and may be at reduced risk of cardiovascular disease. Quality of life may, however, be adversely affected by coeliac dis­ ease diagnosis. Studies looking at patients with coeliac disease on a gluten-​free diet have shown this group to have a lower quality of life in both the short and long term compared to the general popula­ tion and patients with other chronic gastrointestinal conditions such as ulcerative colitis. Appropriate investigation and management of symptoms as well as support with a gluten-​free diet may improve quality of life. Complications Lymphoma Historical estimates for lymphoma suggested a relative risk of 40 to 100 times that of the general population, but as detection of coeliac disease has improved, contemporary studies have shown only a modest risk for malignancy. A recent meta-​analysis demonstrated a fourfold increased risk of non-​Hodgkin lymphoma (including enteropathy-​associated T-​cell lymphoma) compared to the general population, with an estimated 1 in 2000 coeliac patients developing lymphoma per year. Evidence for the protective effect of a gluten-​free diet against the development of lymphoma is circumstantial. Enteropathy-​ associated T-​cell lymphoma is frequently diagnosed at the same time of or soon after the diagnosis of coeliac disease, before the patient can start an effective gluten-​free diet. A recent large population-​ based study showed that persistent villous atrophy, which is more common in patients with poor adherence to a gluten-​free diet, was associated with an increased risk of lymphoma with a hazard ratio of 2.26 compared to those who demonstrated mucosal healing on follow-​up biopsy. Osteoporosis Osteoporosis is highly prevalent among coeliac sufferers, with 32 to 80% having reduced bone mineral density, and a strict gluten-​free

15.10.3  Coeliac disease 2891 diet has been shown to improve bone mineral density. In a re­ cent study of 95 patients with newly diagnosed coeliac disease, there was a significant improvement in the mean bone mineral density independent of other risk factors and the effect of exercise. However, patients with silent or subclinical disease may not have metabolic bone disease to the same extent as those with classical coeliac disease. Current national guidelines recommend that patients are given lifestyle advice to ensure adequate calcium intake, avoid smoking and excess alcohol, and advice on adherence to a strict gluten-​free diet. Baseline bloods for calcium, vitamin D, and alkaline phos­ phatase should be requested. Baseline DXA (dual-​energy X-​ray ab­ sorptiometry) to assess bone mineral density at diagnosis should be reserved for those with abnormal bloods or those at high risk of osteoporosis, which include those over the age of 70, recent weight loss of greater than 10%, a body mass index of less than 20 kg/​m2, history of fragility fracture, and physical inactivity. A further DXA should be requested if there is a suspected fragility fracture or in cases of suspected poor adherence. Loss of bone density at a greater than expected rate should prompt measurement of vitamin D levels, a dietetic referral, consideration of repeat intestinal mucosal biopsy, and review of additional risk factors. Autoimmune disease Coexisting autoimmune conditions are common in coeliac dis­ ease. There is limited, conflicting evidence that a gluten-​free diet may be protective in preventing development of other auto­ immune conditions. Circumstantial evidence comes from epi­ demiological studies looking at the age of diagnosis with coeliac disease compared to the numbers of patients suffering with other autoimmune conditions. In one study, older patients with coeliac disease appeared to have a significantly increased incidence of coexisting autoimmune conditions at diagnosis compared to younger coeliac patients, but two further studies showed no dif­ ference between age of diagnosis and levels of autoimmunity, and one demonstrated that patients younger than 36 at diagnosis ap­ peared to be at increased risk of other autoimmune conditions, al­ though those who were deemed adherent to a gluten-​free diet had a significantly lower incidence of autoimmune conditions. The reasons for this paradox are unclear, but the authors concluded that patients diagnosed at an older age may have a less severe phenotype and may therefore be at reduced risk of developing other autoimmune conditions. Future developments At present, the only known treatment for coeliac disease is a gluten-​ free diet. Most patients with coeliac disease will have symptomatic improvement on gluten-​free diet, but up to 30% will have persistent symptoms and—​as previously discussed—​many will have persistent villous atrophy. There may, therefore, be a clinical need for novel treatments for coeliac disease. Several avenues are being explored, including oral enzymes to break down gluten into nontoxic frag­ ments, zonulin inhibitors to reduce paracellular uptake of gluten, and efforts to induce gluten tolerance through a therapeutic ‘vac­ cine’. A comprehensive list of potential therapeutic targets is shown in Table 15.10.3.4. FURTHER READING Aziz I, et  al. (2015). Predictors for celiac disease in adult cases of duodenal intraepithelial lymphocytosis. J Clin Gastroenterol, 49, 477–​82. DeGaetani M, et al. (2013). Villous atrophy and negative celiac ser­ ology: a diagnostic and therapeutic dilemma. Am J Gastroenterol, 108, 647–​53. Ludvigsson JF, et al. (2014). Diagnosis and management of adult coeliac disease:  guidelines from the British Society of Gastroenterology. Gut, 63, 1210–​28. Mooney PD, Hadjivassiliou M, Sanders DS (2014). Emerging drugs for coeliac disease. Expert Opin Emerg Drugs, 19, 533–​44. Rubio-​Tapia A, et al. (2013). ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol, 108, 656–​76. Schuppan D, Junker Y, Barisani D (2009). Celiac disease from patho­ genesis to novel therapies. Gastroenterology, 137, 1912–​33. Table 15.10.3.4  Potential therapeutic targets for coeliac disease Therapeutic target Mode of action Difficulties Gluten-​specific proteases Degrade gluten into nontoxic fragments prior to entry into the duodenum Many glutenases are degraded in a gastric environment Even gastric stable glutenases in a perfect environment are unable to ensure gluten fully degraded prior to entry into the small bowel Zonulin inhibitor Regulate tight junction opening to prevent uptake of gluten into the lamina propria Not all gluten is transported through tight junctions—​up to 90% of gluten may be transported through the epithelial cells via transcytosis Therapeutic ‘vaccine’ Promote T-​cell gluten tolerance with repeated injections of subcutaneous gluten fragments Single drug in development only contains three of the many toxic gluten epitopes and only designed for patients with HLA DQ2 Tissue transglutaminase inhibitor Prevent deamination of gluten Tissue transglutaminase is involved in tissue homeostasis in multiple organ systems IL-​15 inhibitor IL-​15 secretion may be directly induced by gluten to initiate inflammatory cascade. May be crucial in the development of refractory coeliac disease Immunosuppression Therapeutic hook worm infection Suppress inflammatory immune response Only a single trial undertaken so far and has shown no benefit

15.10.4 Gastrointestinal lymphomas 2892

15.10.4 Gastrointestinal lymphomas 2892

section 15  Gastroenterological disorders 2892 15.10.4  Gastrointestinal lymphomas Kikkeri N. Naresh ESSENTIALS Primary gastrointestinal lymphoma is the most common extranodal lymphoma and is almost exclusively of non-​Hodgkin type. It is de- fined as lymphoma that has presented with the main bulk of disease in the gastrointestinal tract, with or without involvement of con- tiguous lymph nodes. MALT lymphoma is an indolent B-​cell lymphoma whose hist- ology recapitulates the features of mucosa-​associated lymphoid tissue (MALT). It most commonly affects the stomach, presenting with nonspecific dyspepsia. Most cases appear to be driven by Helicobacter pylori, with 75% regressing following eradication of the organism with appropriate antibiotics. Deeply invasive lymphomas and those with adverse histological or cytogenetic features are unlikely to respond. Mantle cell lymphoma and duodenal-type follicular lymphoma are adult B-​cell lymphomas that can present as gastrointes- tinal lymphomas. Diffuse large B-​cell lymphoma is an aggressive lymphoma that is relatively frequently encountered in gastrointestinal locations. Burkitt lymphoma is also an aggressive B-​cell lymphoma, and is the most frequent childhood gastrointestinal lymphoma. Enteropathy-​associated T-​cell lymphoma is an intestinal lymphoma of intraepithelial T lymphocytes that occurs most com- monly in the jejunum or ileum and is associated with coeliac disease. It presents with abdominal pain, often due to intestinal perforation. The prognosis is usually poor, with death frequently resulting from abdominal complications in patients already weakened by uncon- trolled malabsorption. Monomorphic epitheliotropic intestinal T cell lymphoma (MIETL) has been recently identified as a distinct type of high-grade T cell lymphoma. Introduction The gastrointestinal (GI) tract is the most common extranodal location for lymphomas. Designation as ‘primary GI lymphoma’ requires disease to be limited to the GI tract and contiguous lymph nodes at presentation. Such lymphomas are almost en­ tirely non-​Hodgkin lymphomas (NHLs), and while there are many types of non-​Hodgkin lymphomas, a small subset of types account for most GI lymphomas, with most being B cell in origin. Diffuse large B-​cell lymphoma (DLBCL) and extranodal marginal zone lymphoma of mucosa-​associated lymphoid tissue (MALT lymphoma) are particularly more frequent. Many other types of lymphomas can present in the GI tract, but each of them accounts for few of all GI lymphomas and these will not be discussed in this chapter. Common primary GI lymphomas are listed in Table 15.10.4.1. Epidemiology Epidemiological aspects of some of the GI lymphomas are dis­ tinct. These include primary gastric MALT lymphoma, immuno­ proliferative small intestinal disease (IPSID), Burkitt lymphoma, and enteropathy-​associated T-​cell lymphoma (EATL). MALT lymphoma The stomach is the most common site for MALT lymphoma, and MALT lymphoma accounts for nearly 50% of primary gastric lymphomas. A relatively high incidence is recorded in some parts of the world, such as north-​east Italy. Gastric MALT lymphoma has a strong association with Helicobacter pylori infection. IPSID is a rare disease and type of MALT lymphoma. This is mostly seen in the Middle East and in the Cape region of South Africa, and is associ­ ated with Campylobacter jejuni infection. Burkitt lymphoma Burkitt lymphoma occurs in three forms: endemic, nonendemic (sporadic), and immunodeficiency associated. Endemic Burkitt lymphoma is endemic in the malarial belt of equatorial Africa and Papua, New Guinea. It is a childhood malignancy. Immunodeficiency-​associated Burkitt lymphoma is mostly seen in patients infected with HIV and is often the initial presentation of AIDS. Enteropathy-​associated T-​cell lymphoma A type of EATL is more common in areas of high prevalence of coeliac disease, such as Northern Europe. Aetiology There have been insights into the aetiology of some of the GI lym­ phomas such as MALT lymphoma, Burkitt lymphoma, and EATL (Table 15.10.4.2). The aetiology of other lymphomas is unclear. MALT lymphoma and infective agents H.  pylori is implicated in the pathogenesis of gastric MALT lymphoma. There is a significantly higher frequency of preceding H. pylori infection in patients with gastric lymphoma, and H. pylori Table 15.10.4.1  Common primary GI lymphomas B cell Extranodal marginal zone lymphoma of mucosa-​associated lymphoid tissue (MALT lymphoma) Mantle cell lymphoma (MCL) and lymphomatous polyposis Duodenal-type follicular lymphoma (FL) Diffuse large B-​cell lymphoma (DLBCL) Burkitt lymphoma T cell Enteropathy-​associated T-​cell lymphoma (EATL)

15.10.4  Gastrointestinal lymphomas 2893 is demonstrated in many gastric MALT lymphomas. It is fascinating that normal gastric mucosa is devoid of organized lymphoid tissue. H. pylori infection induces acquisition of lymphoid tissue, and H. pylori-​associated follicular gastritis is a precursor lesion to gastric MALT lymphoma. Further evidence of the aetiological as­ sociation comes from the fact that the cells of low-​grade gastric MALT lymphoma respond to H. pylori antigens via a T-​cell-​medi­ ated mechanism in an in vitro setting. This is further corroborated by regression of H. pylori-​associated MALT lymphoma following eradication of H.  pylori using appropriate antibiotics. Similar to H. pylori, C. jejuni is associated with IPSID, which is a form of MALT lymphoma involving proximal small intestine. Burkitt lymphoma, malaria, and Epstein–​Barr virus Nearly all cases of endemic Burkitt’s lymphoma show an association with Epstein–​Barr virus (EBV), with EBV being present within the neo­ plastic B cells. A lesser proportion (approximately 30%) of other forms of Burkitt’s lymphoma is also associated with EBV. The precise role played by EBV in lymphomagenesis is still a matter of debate. Infection of B cells by EBV results in activation and enhanced proliferation within the germinal centres. This enhanced proliferation increases the chances of errors in DNA replication and acquisition of chromosomal translocations. In addition, EBV products such as EBV nuclear antigen 1 and EBV-​encoded small RNAs suppress apoptosis and enhance tumourigenicity respectively, and contribute to lymphomagenesis. Endemic Burkitt’s lymphoma also occurs in the same regions that are endemic to Plasmodium falciparum malaria. P. falciparum is thought to reduce patient immunity and cause exhaustion of the EBV-​specific T-​cell response. P. falciparum is also thought to stimu­ late latently EBV-​infected memory B cells via the Toll-​like receptor 9. These processes lead to activation and expansion of EBV-​infected B cells, contributing to lymphomagenesis. Enteropathy-​associated T-​cell lymphoma There is a strong association between coeliac disease and a sub­ type of EATL. These patients also have other features associated with coeliac disease, such as expression of HLA DQ2 or HLA DQ8, hyposplenism, and dermatitis herpetiformis. Pathogenesis Many B-​cell GI lymphomas are associated with specific chromo­ somal translocations, and these play pathogenetic roles. Genes involved in the translocations include oncogenes and tumour sup­ pressor genes (Table 15.10.4.2). Many of the B-​cell lymphomas limited to the GI tract express αβ-​integrin, which is a homing re­ ceptor that binds to mucosal addressin cell adhesion molecule-​1 (MAdCAM-​1) that is expressed on endothelial cells of GI mucosa. Infections and associated immune mechanisms also play a role in lymphomagenesis. Well-​established precursor lesions also exist for some of these lymphomas. MALT lymphoma H. pylori is associated in up to 90% of gastric MALT lymphomas. As stated previously, normal gastric mucosa does not show any signifi­ cant lymphoid tissue, and acquisition of lymphoid tissue, which is triggered by H. pylori, precedes development of MALT lymphoma. Hence, H.  pylori-​associated gastritis is a precursor lesion for H. pylori-​associated gastric MALT lymphoma. Trisomy of chromosome 3, 18, or others is not an infrequent finding in GI MALT lymphomas. A  small subset of GI MALT lymphomas is associated with chromosomal translocations involving MALT1 or BCL10 genes. These translocations target and activate the nuclear factor kappa B (NF-​κB) pathway. Table 15.10.4.2  Frequently associated genetic abnormalities and infective agents in GI lymphomas, and well-​recognized precursor lesions Chromosomal abnormalities Genes involved Infective agent Precursor lesions MALT lymphoma t(11;18)(q21;q21) t(14;18)(q32;q21) t(1;14)(q22;q32) +3 +18 API2–​MALT1 MALT1 BCL10 H. pylori C. jejuni H. pylori gastritis MCL t(11;14)(q13;q32) CCND1–​IGH None In situ mantle cell neoplasia Duodenal-type FL t(14;18)(q32;q21) t(2;18)(p12;q21) t(18;22)(q32;q11) Others BCL2–​IGH IGK–​BCL2 BCL2–​IGL None In situ follicular neoplasia DLBCL t(14;18)(q32;q21) 3q27 abnormalities 8q24 translocations Others BCL2–​IGH BCL6 MYC Epstein–​Barr virus (infecting neoplastic cells) in a minority of cases None Burkitt lymphoma t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11) MYC–​IGH IGK–​MYC MYC–​IGL Epstein–​Barr virus (infecting neoplastic cells) None EATL +9q34 −9p/−9p21 −17p12-13.2 −16q12.1 –​ None Refractory coeliac disease MEITL +9q34.3 +8q24 MYC None

section 15  Gastroenterological disorders 2894 Mantle cell lymphoma Over 95% of these lymphomas are associated with a CCND1–​IGH translocation. Duodenal-type follicular lymphoma Most are associated with a BCL2 translocation resulting in in­ creased and inappropriate BCL2 protein expression. BCL2 is a key antiapoptotic protein. Burkitt lymphoma The key cytogenetic abnormality is translocation of the MYC gene. In an overwhelming majority of cases, IGH partners the MYC gene, and in a few cases the partnering gene is IGK or IGL. Most cases do not show additional cytogenetic abnormalities (simple MYC), but MYC mutations are frequent. Abnormalities involving TP53, p73, BAX, p130/​RB2, and p16 also occur. Enteropathy-​associated T-​cell lymphoma Most patients with adult-​onset EATL have a previous history of coeliac disease or are diagnosed as having coeliac disease in the same clinical episode in which the lymphoma is diagnosed. A few patients have a history of childhood-​onset coeliac disease. In some cases, there is a prodromal period of refractory coeliac disease that is sometimes accompanied by intestinal ulceration (ulcerative jejunitis). A clonal population of T cells evolves during the transition from coeliac ­disease to refractory coeliac disease, and further clonal expansion ­occurs during transition from refractory coeliac disease to EATL. EATL is associated with complex cytogenetic abnormalities that include segmental amplifications of 9q34 region or deletions of 16q12.1 regions in most cases. EATL is associated with gains of 1q and 5q. Clinical presentation The age at presentation, site of frequent occurrence, presenting symptoms, and endoscopic features of different GI lymphomas are variable (Table 15.10.4.3). MALT lymphoma Gastric MALT lymphoma typically occurs in patients over 40 years of age, but can occur at any age. The sex incidence is equal. The presenting symptoms are usually those of nonspecific dyspepsia and more suggestive of gastritis or peptic ulcer than a neoplastic lesion. Most MALT lymphomas of the stomach arise in the antrum, and macroscopically are characterized by an ill-​ defined thickened, inflamed, and ulcerated mucosa, rather than a tumour mass. Most GI MALT lymphoma patients present in stage IE or IIE disease. Multiple extranodal sites may be involved in one-​quarter of gastric MALT lymphomas and in about one-​half of other GI MALT lymphomas. About one-​third of patients have an IgM paraprotein. IPSID is a disease of young adults and patients usually present with severe malabsorption. Most patients with IPSID demonstrate an aberrant alpha heavy chain in peripheral blood. Mantle cell lymphoma Primary GI MCL characteristically presents as multiple polyp­ osis in the small and large intestine, although presentation as ul­ cers, mucosal thickening, and as tumour masses is not uncommon. Median age of presentation is about 60, with a male predominance. Duodenal-type follicular lymphoma Most cases of primary GI follicular lymphoma occur in the small intestine, with the duodenum being the most frequent site, espe­ cially its second part. Most patients are adults with a median age in the fifties. On endoscopy they are typically seen as small polyps. Unlike nodal follicular lymphoma, most patients with duodenal- type ­follicular lymphoma have localized disease presenting as stage IE or IIE disease. Burkitt lymphoma Presentation depends on the clinical type of Burkitt’s lymphoma. Endemic Burkitt’s lymphoma patients are typically children, who usually present with rapidly growing bulky disease with high tu­ mour burden. Symptoms are typically of only a few weeks duration. Table 15.10.4.3  Clinical presentation and endoscopic features of common GI lymphomas Median age Sex predilection Frequent site Common presentation Endoscopic appearance MALT lymphoma ~60 years Similar Stomach Nonspecific dyspepsia Gastritis Peptic ulcer Ill-​defined thickened, inflamed, and ulcerated mucosa MCL ~60 years Male Small and large intestine Multiple polyposis Ulcers Mucosal thickening Tumour masses Multiple polyps Ulcers Mucosal thickening Duodenal-type FL ~50 years Female Duodenum Small polyps Small polyps DLBCL ~60 years Male Ileocaecal Tumour mass –​ Burkitt lymphoma Dependent on type Male Ileocaecal Rapidly growing tumour mass EATL Jejunum Abdominal pain Intestinal perforation Long-​standing history of coeliac disease

15.10.4  Gastrointestinal lymphomas 2895 Most patients are typically in stages III or IV. Some patients can pre­ sent with leukaemic central nervous system involvement. Diffuse large B-​cell lymphoma Among primary GI DLBCLs, the stomach and ileocaecal regions are the most frequent presenting sites. Presentation is related to the rap­ idly enlarging tumour mass. Enteropathy-​associated T-​cell lymphoma Most patients present with abdominal pain, often associated with intestinal perforation. Many with EATL have a previous history of coeliac disease. Pathology: histomorphological features Morphological features of each of the types of GI lymphomas are fairly distinctive (Table 15.10.4.4), hence it is possible to suggest a likely diagnosis based purely on morphological features, although confirmation of diagnosis with immunohistochemistry and (in some cases) cytogenetic or molecular genetic studies is essential. MALT lymphoma The histological features closely simulate those of Peyer’s patches (Fig. 15.10.4.1a). Reactive nonneoplastic follicles are surrounded Table 15.10.4.4  Characteristic histomorphological features of common GI lymphomas Pattern Cytological features Other characteristic features MALT lymphoma Diffuse pattern Marginal zone pattern Follicular colonization Centrocyte-​like ± plasmacytic differentiation Scattered larger cells Lymphoepithelial lesions MCL Diffuse pattern Nodular pattern Mantle zone pattern Monomorphic centrocytes Duodenal-type FL Follicular pattern Follicle centre centrocytes and centroblasts DLBCL Diffuse pattern Centroblasts Immunoblasts Anaplastic cells Variable reactive component Burkitt lymphoma Diffuse pattern Monomorphic, cohesive medium-​sized lymphoid cells with deeply basophilic cytoplasm, round nuclei, and multiple paracentrally located nucleoli Prominent mitoses and apoptoses Starry-​sky pattern EATL Diffuse pattern Variable Relatively monomorphic medium-​sized to large cells Marked pleomorphism with multinucleated cells Inflammatory component within the tumour Varying degrees of enteropathy in adjacent mucosa MEITL Diffuse pattern Monomorphic small to medium-​sized round cells with darkly staining nuclei Florid infiltration of intestinal crypt epithelium (a) (b) (c) Fig. 15.10.4.1  (a) Peyer’s patch comprising a B-​cell follicle surrounded by a mantle zone external to which is the marginal zone. There are collections of small B lymphocytes within the dome epithelium. (b) Gastric MALT lymphoma. The tumour cells surround the reactive B-​cell follicle in the marginal zone and invade gastric glands to form lymphoepithelial lesions. The overall structure is similar to the Peyer’s patch. (c) Detail of the neoplastic infiltrate in a gastric MALT lymphoma showing ‘centrocyte-​like’ cells invading gastric glands to form lymphoepithelial lesions (bottom right) and eosinophilic change in gastric gland epithelium (centre).

section 15  Gastroenterological disorders 2896 by the neoplastic lymphoid infiltrate in the region corresponding to the marginal zone in Peyer’s patch. The infiltrate extends into sur­ rounding lamina propria and invades individual gastric glands to form characteristic lymphoepithelial lesions. The cytological ap­ pearances of the cells of MALT lymphomas are characteristically centrocyte like, with more cytoplasm than the neoplastic cells of MCL or those of normal mantle cells (Figs. 15.10.4.1b and 15.10.4.1c). Rarely, cells can be smaller. Scattered larger cells are usually present amid centrocyte-​like cells. Plasma-​cell differentiation is prominent in about a third of cases, and this is characteristically seen beneath the surface epithelium. The lymphoma cells may colonize, and as a result partially or completely replace, reactive follicle centres. In later stages of disease, lymphomatous infiltrate extends beyond the mucosa into submucosa and invades the muscularis propria and beyond. In about 20% of cases, perigastric lymph nodes are involved by lymphoma. Differential diagnosis between MALT lymphoma and florid H. pylori-​associated chronic gastritis (follicular gastritis) can be difficult in some cases, necessitating establishment of B-​cell monoclonality by molecular methods for a diagnosis of MALT lymphoma. In some cases, disease progression coincides with an increase in the proportion of larger nucleolated neoplastic lymphoid cells. Eventually this can result in sheets of large lymphoid cells, heralding transformation of MALT lymphoma to DLBCL (Fig. 15.10.4.2). The histology of IPSID is similar to MALT lymphoma, except that plasma-​cell differentiation is much more prominent both in the intestine and mesenteric lymph nodes. Fig. 15.10.4.2  MALT lymphoma showing transformation from low-​ grade (small cell) histology (upper half of figure) to high-​grade (large cell) lymphoma (bottom half of figure). (c) (d) (e) (a) (b) Fig. 15.10.4.3  Mantle cell lymphoma: (a) Polyploidal lymphoid lesion in duodenum involving the mucosa. (b) There is a diffuse monomorphic infiltrate of lymphoid cells with morphology of small cleaved cells or centrocytes. Lymphoid cells express CD20 (c); CD5 (d); and cyclin D1 (e).

15.10.4  Gastrointestinal lymphomas 2897 Mantle cell lymphoma Morphological features of GI MCL are similar to those when the condition occurs elsewhere. There is a monomorphic infiltrate of centrocytes with scanty cytoplasm, minimally indented nuclei, and coarse chromatin. The infiltrate has a diffuse or a nodular pattern, or a combination of both. Lymphoepithelial lesions are not seen (Figs. 15.10.4.3a and 15.10.4.3b). Duodenal-type follicular lymphoma Morphological features of duodenal-type follicular lymphoma is highlighted by presence of neoplastic follicles in mucosa and sub­ mucosa. Follicles are devoid of mantle zones, and composed of centrocytes and centroblasts lacking zonation. Centroblasts are scanty; morphological features are usually of grade 1, and rarely grade 2 (Figs. 15.10.4.4a and 15.10.4.4b). Burkitt lymphoma Morphological features of GI Burkitt’s lymphoma are similar to those when the condition occurs elsewhere. It characteristically shows monomorphic diffuse sheets of medium-​sized lymphoid cells, which are cohesive with deeply basophilic cytoplasm, round nuclei, and multiple paracentrally located nucleoli. Mitoses and apoptoses are prominent. Tumour cells are accompanied by phagocytic histiocytes imparting a ‘starry-​sky’ appearance (Figs. 15.10.4.5a and 15.10.4.5b). Diffuse large B-​cell lymphoma Morphological features of GI-​DLBCL are similar to those when the condition occurs elsewhere. The morphology is variable: tumour cells can have features of centroblasts, immmunoblasts, anaplastic large cells, or other forms of large cell morphology, and the infil­ trate can either be monomorphic or pleomorphic. The pattern of involvement is typically diffuse, with variable degree of background fibrosis. The reactive component is also variable and includes small lymphocytes, histiocytes, and, less frequently, other inflammatory cells (Figs. 15.10.4.6a and 15.10.4.6b). Enteropathy-​associated T-​cell lymphoma Lesions usually present as multiple ulcerating raised mucosal masses. They can also present as one or more ulcers or as a large exophytic mass. Cytological features are variable. In most cases, the tumour cells are relatively monomorphic medium-​sized to large cells with round or angulated vesicular nuclei, prominent nucleoli, and moderate to abundant, pale-​staining cytoplasm. In others, the tumour ex­ hibits marked pleomorphism with multinucleated cells. Most cases show infiltration by inflammatory cells, including large numbers of histiocytes and eosinophils, and in some cases the inflammatory component can obscure the tumour cells. Necrosis is a prominent feature (Fig. 15.10.4.7). Infiltration of the epithelium of individual crypts is present in many cases. Intestinal mucosa adjacent to the tu­ mours (particularly jejunum), usually shows varying degrees of en­ teropathy comprising villous atrophy, crypt hyperplasia, increased lamina propria lymphocytes and plasma cells, and intraepithelial lymphocytosis (Fig. 15.10.4.8). In some, this may consist only of an increase in intraepithelial lymphocytes. Monomorphic epitheliotropic intestinal T cell lymphoma (MIETL) In this condition the neoplastic cells are small to medium sized, round and monomorphic, with darkly staining nuclei and a narrow (a) (b) (c) (d) (f) (g) (e) Fig. 15.10.4.4  Duodenal-type follicular lymphoma: (a-c) Duodenal mucosa is replaced by a dense lymphoid infiltrate with a prominent follicular pattern. (d) lesional cells are mostly centrocytes; with only occasional centroblasts; they express CD10 (e); CD10 (f); and BCL2 (g).

section 15  Gastroenterological disorders 2898 rim of pale cytoplasm (Fig. 15.10.4.9). Characteristically, there is florid infiltration of intestinal crypt epithelium. The adjacent in­ testinal mucosa shows villous atrophy and crypt hyperplasia, with striking intraepithelial lymphocytosis involving both crypt and sur­ face epithelium. MEITL lacks the inflammatory component and ne­ crosis is relatively less significant. In most cases, small intestine remote from the site of the tu­ mour show changes identical with those of coeliac disease—​ villous atrophy with crypt hyperplasia, plasmacytosis of the lamina propria, and an increase in intraepithelial small lympho­ cytes. In MEITL, the degree of intraepithelial lymphocytosis may be extreme. Pathology: immunohistochemistry Documenting characteristic immunophenotypes of different types of GI lymphoma is absolutely essential for definitive diag­ nosis and optimal patient management. This is best achieved by immunohistochemistry on paraffin sections (Table 15.10.4.5). MALT lymphoma Lymphoma cells express pan-​B-​cell antigens CD19, CD20, CD79a, and PAX5. They also express surface and to a lesser extent cyto­ plasmic IgM. They are typically negative for IgD and other heavy chains, and they show light-​chain restriction. The cells express other mature B-​cell antigens such as CD21 and CD35, but are typically negative for CD5 and CD10, although rare cases may show aber­ rant expression of CD5. CD43 expression is more common. They are negative for other T-​cell antigens. They consistently express BCL2, but are negative for BCL6 and cyclin D1, and variably positive for MUM1. CD21 and CD23 identify reactive, remnant, or colonized follicles. Proliferation as measured by Ki67 expression is usually less than 40%. Mantle cell lymphoma Lymphoma cells express pan-​B-​cell antigens CD19, CD20, CD79a, and PAX5. They also express surface IgM and IgD, show light-​chain restriction, show aberrant expression of CD5 and CD43, and are negative for CD10 and CD23, mostly nega­ tive for BCL6 and MUM1, and negative for other T-​cell antigens. They consistently express BCL2. The overwhelming majority (>95%) of cases express cyclin D1, and most express SOX11. CD21 and CD23 identify a nodular pattern if present (Figs. 15.10.4.3c–​15.10.4.3e). Duodenal-type follicular lymphoma Lymphoma cells express pan-​B-​cell antigens CD19, CD20, CD79a, and PAX5. Most cases express IgA. They express follicle centre cell markers CD10, BCL6, and similar others. They characteris­ tically express BCL2, and most cases of grade 1–​2 FL do not ex­ press MUM1. They are negative for cyclin D1, CD5, and CD43, and most are negative for CD23. CD21 and CD23 identify fol­ licular dendritic cell (FDC) meshworks within neoplastic follicles (Figs. 15.10.4.4c–​15.10.4.4e). Burkitt lymphoma Lymphoma cells express pan-​B-​cell antigens CD19, CD20, CD79a, and PAX5. They also express IgM and often CD43, and express (a) (b) (c) Fig. 15.10.4.5  Burkitt lymphoma: (a) Mucosa of stomach shows a dense lymphoid infiltrate with a diffuse pattern. (b) Lymphoid cells are relatively monomorphic and medium sized. They have multiple paracentrally located nucleoli. (c) Almost all lymphoid cells express Ki-​67. Lymphoid cells harboured MYC-​IGH translocation (not shown).

15.10  Gastrointestinal lymphomas 2899 (a) (b) (c) (d) (e) Fig. 15.10.4.6  Diffuse large B cell lymphoma: (a) Mucosa of stomach shows a dense lymphoid infiltrate with a diffuse pattern. (b) Lymphoid cells are large and have multiple prominent nucleoli. Lymphoid cells express CD20 (c); MUM1 (d); and BCL2 (e). (a) (b) (c) Fig. 15.10.4.7  EATL. Three different cases showing the cytological variability. In (a) the tumour is composed of large polymorphic lymphocytes; in (b) the tumour shows striking pleomorphism; and in (c) tumour cells are overrun by inflammatory cells, principally eosinophils.

section 15  Gastroenterological disorders 2900 follicle centre cell markers CD10, BCL6, and CD38. They char­ acteristically express c-​MYC, but not BCL2. They are also nega­ tive for CD44, CD5, cyclin D1 and TdT, and most are negative for MUM1. A proportion of cases are EBV associated, which is demonstrated by in situ hybridization with an EBER1 probe. Ki67 expression is typically seen in greater than 95% of the neoplastic cells (Fig. 15.10.4.5c). Diffuse large B-​cell lymphoma Lymphoma cells express pan-​B-​cell antigens CD19, CD20, CD79a, and PAX5. DLBCL is a heterogeneous disease, and expression of various antigens/​proteins varies among the subtypes of DLBCL, which is beyond the scope of this chapter (Fig. 15.10.4.6c–​15.10.4.6e). Enteropathy-​associated T-​cell lymphoma In EATL, the tumour cells express CD3, CD7, CD103, and cytotoxic mol­ ecules, and are typically negative for CD5, CD4, and CD56. Most cases express TCRβ+, and a small minority (<20%) express CD8. In almost all cases, a varying proportion of the tumour cells express CD30. The CD3-​positive intraepithelial lymphocytes in the adjacent enteropathic mucosa may show an abnormal immunophenotype, lacking expression of CD5, CD4, and CD8 (Fig. 15.10.4.8c and 15.10.8d). Monomorphic epitheliotropic intestinal
T-cell lymphoma In MEITL, the tumour cells express CD3, CD7, CD8, TCRβ, CD56, CD103, and cytotoxic molecules, and are typically negative for CD5 and CD4. The intraepithelial lymphocytes in the adjacent mucosa have a similar immunophenotype. Fig. 15.10.4.8  MEITL. The lymphoma is composed of monomorphic small lymphocytes. (b) (a) (c) (d) Fig. 15.10.4.9  Uninvolved mucosa adjacent to EATL showing (a) increased intraepithelial lymphocytes that are (b) CD3 positive, (c) CD8 negative, and (d) CD56 negative.

15.10.4  Gastrointestinal lymphomas 2901 Management MALT lymphoma All patients with gastric MALT lymphoma who are H. pylori posi­ tive should be given eradication therapy, following which those with early-​stage disease can be managed by surveillance endoscopy with multiple biopsies. Those who have early-​stage H. pylori-​negative dis­ ease are typically treated with local radiotherapy. Immunotherapy (rituximab, an anti-​CD20 monoclonal antibody), with or without chemotherapy, is offered to patients whose disease fails to respond or recurs after radiotherapy, and those with advanced-​stage disease. Targeted treatments, for example, ibrutinib (a tyrosine kinase in­ hibitor), and autologous haemopoietic cell transplantation are used in some cases. Mantle cell lymphoma Most patients require treatment at the time of diagnosis. Options in­ clude conventional chemotherapy/​immunotherapy (e.g. bendamustine and rituximab) followed by maintenance rituximab, conventional chemotherapy/​immunotherapy followed by autologous haemopoi­ etic cell transplantation, conventional chemotherapy/​immunotherapy with radiotherapy, or intensive chemotherapy. Duodenal-type follicular lymphoma Most patients with disease limited to duodenum have an indolent disease course, and treatment may not be required (watch-and- wait). They would rarely require treatment. In patients with nodal involvement, possibly of conventional FL also involving the duo­ denum or the gastrointestinal tract needs to be considered. Burkitt lymphoma There is no wide consensus on the best treatment for adults with Burkitt’s lymphoma. Intensive combination chemotherapy is typic­ ally given, along with central nervous system prophylaxis. The high risk of tumour lysis syndrome can be mitigated by intravenous hy­ dration and rasburicase. Diffuse large B-​cell lymphoma Molecular analysis helps to direct therapy, which for patients without MYC and BCL2 gene rearrangements typically involves rituximab in combination with anthracycline-​based chemotherapy. Enteropathy-​associated T-​cell lymphoma Treatment is with combination chemotherapy, as used for other ag­ gressive lymphomas. Prognosis MALT lymphoma Most gastric MALT lymphomas are associated with H. pylori, and nearly 75% of these regress following eradication of H. pylori using appropriate antibiotics. Deeply invasive lymphomas, those in which there are foci of high-​grade transformation, and cases with t(11;18) usually do not respond to antibiotics and require conventional chemotherapy. Overall, MALT lymphomas respond favourably to therapy and there is an excellent overall survival, approximating 90% at 10 years. The survival for cases in which there is evidence of trans­ formation to DLBCL is significantly worse: only 45% at 10 years. Mantle cell lymphoma In general, patients with this condition have a median survival in the range of 3 to 5 years. Duodenal-type follicular lymphoma Survival is extremely good, even without treatment. Burkitt lymphoma This is a potentially curable disease. With intensive regimens, cure rates of up to 90% in limited stage disease and 60 to 80% in patients with advanced stage disease are achievable. Diffuse large B-​cell lymphoma Cure can be achieved in many patients with DLBCL with appro­ priate treatment. Identifying subsets of DLBCL with different biology using protein and gene expression and mutation analysis (by next-​generation sequencing) is an area of active research and beyond the scope of this chapter. Enteropathy-​associated T-​cell lymphoma The prognosis is usually poor, with death frequently resulting from abdominal complications in patients already weakened by uncon­ trolled malabsorption. Table 15.10.4.5  Characteristic immunophenotype of common GI lymphomas Antigens positive for Antigens negative for Other characteristic features MALT lymphoma CD19, CD20, CD79a, PAX5, BCL2, and IgM CD5, CD10, BCL6, and cyclin D1 CD43+/​− CD21/​CD23+ FDC meshworks MCL CD19, CD20, CD79a, PAX5, BCL2, IgM, IgD, CD5, CD43, cyclin D1, and SOX11 CD10 and CD23 CD21/​CD23 + FDC meshworks in nodular areas Duodenal-type FL CD19, CD20, CD79a, PAX5, CD10, BCL6, and BCL2 CD5 and cyclin D1 CD21/​CD23 + FDC meshworks DLBCL CD19, CD20, CD79a, and PAX5, Cyclin D1 Variable expression of other markers Burkitt lymphoma CD19, CD20, CD79a, PAX5, CD10, BCL6, and CD38 TdT, CD5, cyclin D1, CD44, and BCL2 CD43+/​−, Ki67>95%, EBER−/​+ EATL CD3, CD7, CD103, TCRβ+, and cytotoxic molecules CD5, CD4, and CD56 CD30+/​− CD8−/​+ MEITL CD3, CD7, CD8, TCRβ, CD56, CD103, and cytotoxic molecules CD5 and CD4 −

15.10.5 Disaccharidase deficiency 2902

15.10.5 Disaccharidase deficiency 2902

section 15  Gastroenterological disorders 2902 FURTHER READING Cellier C, et  al. (2000). Refractory sprue, coeliac disease, and enteropathy-​associated T-​cell lymphoma. Lancet, 356, 203–​8. De Leeuw RJ, et al. (2007). Whole genome analysis and HLA geno­ typing of enteropathy-​type intestinal T-​cell lymphoma reveals two distinct lymphoma subtypes. Gastroenterology, 132, 1902–​11. Isaacson PG, Du M-​Q (2004). Malt lymphoma: from morphology to molecules. Nat Rev Cancer, 4, 6644–​53. Isaacson PG, Du M-​Q (2005). Gastrointestinal lymphoma:  where morphology meets molecular biology. J Pathol, 205, 255–​74. Swerdlow SH, et al. (eds) (2017). WHO classification of tumours of hae- matopoietic and lymphoid tissues. IARC, Lyon. Wotherspoon AC, et al. (1991). Helicobacter pylori-​associated gastritis and primary B-​cell gastric lymphoma. Lancet, 338, 1175–​6. Wotherspoon AC, et al. (1993). Regression of primary low-​grade B-​cell gastric lymphoma of mucosa-​associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet, 342, 575–​7. 15.10.5  Disaccharidase deficiency Timothy M. Cox ESSENTIALS Disaccharidases are abundant enzymes expressed on the microvillous membrane of the small intestine: apart from free glucose and fruc- tose, disaccharidases are required for the complete assimilation of nearly all carbohydrate present in food and drinks. The enzymes cleave disaccharides such as sucrose, maltose, and lactose, as well as dextrins derived from starch, into their component monosacchar- ides. Their activity is reduced in hereditary conditions or in general- ized intestinal diseases. Disaccharidase deficiency causes dietary intolerance of carbo- hydrate induced by the fermentation of undigested sugars in the distal small intestine and colon. Abdominal symptoms (e.g. nausea, bloating, distension, colicky pain, watery diarrhoea) are usually noticed within an hour of the ingestion of foods containing the offending sugars. By far the most common symptomatic disaccharidase deficiency is lactose intolerance. Lactase activity is high in healthy infants when milk is the principal food, but in most humans the activity declines after weaning and remains low (lactase nonpersistence), which greatly reduces the capacity to break down lactose. In contrast, those inheriting a Mendelian dominant trait that leads to sustained high intestinal lactase expression throughout life (lactase persistence) digest and tolerate large quantities (loading doses >50 g). The dis- tribution of lactase activity in adult populations is subject to great variation:  nonpersistence of lactase expression predominates in nearly every population in East Asia, whereas in those of Northern and central European origin, and in Afro-​Arabian nomads who have developed or maintained pastoralist dairy cultures, intestinal lactase expression is sustained lifelong. Intestinal lactase phenotypes can be identified by assay of mu- cosal biopsy samples or appropriate sugar tolerance tests, as can other (much rarer) genetically determined disaccharidase variants. The most convenient diagnostic screen involves hydrogen breath testing after oral loading. Disaccharide intolerance is readily treated by institution of a strict exclusion diet; oral enzymatic supplementation may benefit patients with severe enzymatic deficiency. Innovative and early phase clinical trials suggest that modulation of the host intestinal microbiome with a pure short-​chain galacto-​oligosaccharide may be beneficial in symptom control and in favouring the outgrowth of lactose-​fermenting flora. Physiology of carbohydrate digestion Luminal phase See Fig. 15.10.5.1. Free disaccharides occur in the diet or ori­ ginate from luminal hydrolysis of starch and glycogen by salivary and pancreatic α-​amylase. Since amylase cannot hydrolyse the α-​ 1,6 branching linkages that contribute to the complex arborized structure of starch and glycogen, and has little action on the linear α-​1,4 bonds adjacent to these points, the initial products of starch digestion are branched oligosaccharides containing at least one α-​ 1,6 bond. Maltase–​glucoamylase is a mucosal α-​glucosidase that removes glucose moieties sequentially from the nonreducing ter­ minus of linear oligosaccharides to generate limit α-​dextrins within the lumen; these are branched, short-​chain carbohydrate molecules. Mucosal phase Isomaltase (α-​dextrinase) catalyses the last stages of starch diges­ tion at the intestinal brush border by cleaving the α-​1,6 glycosidic bonds of the limit dextrins released by amylase. Isomaltase is a com­ ponent of the bifunctional complex sucrase–​isomaltase, the sucrase moiety of which catalyses the hydrolysis of sucrose into fructose and glucose. As with the α-​dextrins derived from starch, disaccharides sucrose, lactose, and trehalose are poorly absorbed: to be assimilated, these are also cleaved into their component monosaccharides by the cog­ nate glycosidases, sucrase, lactase, and trehalase which are also lo­ cated on the brush border (microvillus) membrane. Mucosal disaccharidases are optimally active at pH 6.0 and are present principally in the duodenum and jejunum; some activity persists in the ileum but is absent in the colon. Lactase is the fa­ miliar name for lactase–​phlorizin hydrolase, a membrane-​bound microvillous enzyme with β-​galactosidase activity responsible for the cleavage of lactose into its component glucose and galactose moieties. Specific carriers in the microvilli for the transport of glucose and galactose, as well as fructose, mediate the uptake of monosac­ charides released by the mucosal disaccharidases—​and absorption occurs rapidly. Active transport by the sodium-​dependent glucose–​ galactose carrier is accompanied by the passive flux of water from the lumen. Unabsorbed disaccharides are fermented by bacteria in the colon to short-​chain organic acids, hydrogen, and methane. Maldigestion of osmotically active sugars thus leads to retention

15.10.5  Disaccharidase deficiency 2903 of fluid in the gut. When digestion of disaccharides is incomplete, ingestion of carbohydrate induces pain caused by distension of the bowel with fluid and gas, accompanied by watery diarrhoea. For most carbohydrates, hydrolysis in the lumen and at the mu­ cosal surface is sufficiently rapid for the transport of glucose and fruc­ tose to occur at maximum efficiency. For lactose, however, the rate of mucosal hydrolysis, rather than glucose and galactose uptake, is often limiting. The functional reserve of lactase in the human intestine is restricted and when there is inflammation or infection of the small intestinal mucosa, assimilation of lactose is often noticeably impaired. Complete turnover of the enzyme molecules occurs several times during the lifespan of the mature enterocyte. While the biosynthesis of disaccharidases and their incorporation into the brush border membrane continues throughout the life of the epithelium, the en­ zymes are only active in mature epithelial cells on the upper reaches of small intestinal villi. Brush border disaccharidases are complex glycoproteins that undergo proteolytic processing; extensive glycan modification in the Golgi apparatus occurs before insertion into the membrane. The mature enzymes are derived from large, single-​chain polypeptides. The genetically determined mechanism by which lac­ tase expression decreases after infancy is not fully understood but influences transcription of the lactase gene. Maldigestion: the syndrome of carbohydrate intolerance See Table 15.10.5.1. Abdominal symptoms are usually noticed within 30 to 60 min of ingesting foods containing the offending sugars. There is nausea, bloating, and distension of the abdomen accom­ panied by borborygmi and flatulence. Colicky pain precedes watery diarrhoea, usually associated with flatus, and it may be explosive; the anal region is often sore as a result of stool acidity. Diarrhoea due to the maldigestion of carbohydrate, particularly starch intolerance, can occur several hours after ingestion of the noxious food or drink. These symptoms may be induced by only a few grams of the offending sugar. Intestinal hurry aggravates fat malabsorption and may obscure the underlying cause of the diarrhoea. Deficiency of particular disaccharidases is responsible for the dietary intoler­ ance of specific foods and drinks: milk-​containing products in the case of lactase deficiency; table sugar and starch in asucrasia; and mushrooms (and probably shellfish) in the rare trehalase deficiency. Given the ubiquity of sucrose and lactose in commercial foods, iden­ tification of a cause-​and-​effect relationship between particular items and the intolerance syndrome may be challenging. Lactose intolerance The ability to digest lactose after weaning requires the persistence of lactase activity in the intestinal mucosa. Most patients suffering from intolerance of lactose in the diet suffer either from lactase deficiency acquired as a result of intestinal disease, especially postinfective gastroenteritis in children, or as a result of genetically determined restriction of lactase expression. Primary lactase deficiencies Congenital lactase deficiency A few infants have been reported in whom diarrhoea occurred after the first feed with breast milk and who responded completely to a lactose-​free formula feed. This disorder is distinct from congenital glucose–​galactose malabsorption, in which lactose exclusion alone is ineffective. Congenital lactose intolerance is associated with mu­ tations in the human lactase gene which lead to a severe deficiency of mucosal lactase activity and, unlike the intolerance of lactose as­ sociated with prematurity or secondary to diffuse intestinal disease, are present from birth, and remain lifelong. This syndrome leads to lactosuria due to the abnormal absorption of intact lactose, prin­ cipally in the stomach; renal tubular acidosis and aminoaciduria have been recorded in this autosomal recessive disease that leads to vomiting, dehydration, and failure to thrive. Lactase deficiency of prematurity Unlike the other mucosal glycosidases, which appear early during fetal development, intestinal lactase activity is not fully expressed until after the 28th week of gestation and transient intolerance of Fig. 15.10.5.1  Carbohydrate digestion and absorption. Table 15.10.5.1  Deficiency of disaccharidases and carbohydrate intolerance Lactose intolerance Congenital (inherited) lactase deficiency Lactase restriction (genetically determined) Lactase deficiency secondary to intestinal disease Sucrose intolerancea Congenital asucrasia (inherited) Sucrase deficiency secondary to intestinal disease Trehalose intolerance Congenital atrehalasia a Accompanied by reduced tolerance of starch.

section 15  Gastroenterological disorders 2904 milk feeds is common before this age. Abdominal distress due to gaseous distension and diarrhoea requires careful attention to the diet and fluid balance in premature infants. Population genetics of lactase expression A marked decrease in intestinal lactase activity occurs after infancy in about 70% of the global population, but mucosal expression of the enzyme and the capacity to tolerate lactose in the diet varies greatly among human ethnic groups. There is strong evidence that genetic selection for the ability to digest lactose has occurred in re­ sponse to nutritional exposure, and possibly other environmental factors such as the length and intensity of sunlight exposure related to the generation of active vitamin D. Where dairy-​based products predominate in the diet, for example, in white-​skinned people of North European origin, lactase deficiency occurs in about 2% of the population; but studies in the United States of America indicate that lactase deficiency occurs in up to 80% of Hispanic, black, and Ashkenazi Jewish people, and almost all American Indians have lactase deficiency. The age of onset and its prevalence differ among various populations. About one-​fifth of Hispanic, Asian, and black children have lactase deficiency and lactose malabsorption before the age of 5 years. Retention of the capacity to digest lactose in adulthood is deter­ mined by a Mendelian dominant trait. Persistence of high intes­ tinal lactase activity is unusual in adult mammals, and in humans is believed to have been maintained by selection in populations that adopted dairy culture about 10 000 years ago. Thus, tolerance of lactose in milk and dairy products (and many processed and ready-​to-​eat foods; see Box 15.10.5.1), is found mainly in peoples of northern and central European descent. Lactose tolerance is also prevalent in the nomadic Tuareg and Bedouin, as well as the Peuhl of Senegal and Nigerian Fulani peoples, all of whom retain strong dairy-​based pastoral traditions. In about 5% of northern European adults, compared with more than 90% of adults in most of Africa and Asia, a genetically determined decline in mucosal lactase ac­ tivity occurs after weaning. Decreased mucosal lactose activity is associated with reduced synthesis of the precursor protein in the epithelial cells with apparently normal processing to the mature en­ zyme. The physiological decline in activity occurs between 3 and 5 years of age. Low lactase activity, considered in the clinical context as lactase deficiency, is thus the predominant trait among healthy adults world­ wide. Extensive family studies demonstrate transmission as a simple Mendelian factor: healthy adults with low lactase activity are homo­ zygous for an autosomal recessive determinant of a physiological decline of lactase activity after weaning (lactase nonpersistence or restriction, also referred to as adult-​type hypolactasia). Individuals in whom high lactase activity persists in adult life are either hetero­ zygous or homozygous for a dominant allele, the persistence allele, which prevents ‘physiological’ decline of lactase activity. Lactase persistence is thus the minor, low-​frequency variant, and its high prevalence in specific populations was probably maintained by natural selection in groups that settled to invest in dairy culture from Neolithic times. Recent studies of DNA samples obtained from late Neolithic humans (c.5000 years before present) originating from the Basque region of South-​West Europe, show that the frequency of determinants for lactase persistence (27%) was much lower than in modern Basque people. This suggests that evolutionary selection occurred after domestication of cattle, with the adoption of pas­ toral culture, and that the high frequency of lactase persistence in Europeans is only a recent phenomenon. The development of cheese manufacture, as well as yogurt and other milk fermentation prod­ ucts such as kvass in which the sugar content is markedly reduced, would allow individuals with diminished capacity to digest lactose to thrive. The elements which determine lactase activity in adults acts in cis with the lactase locus LCT on human chromosome 2q21; how­ ever, the molecular mechanism which regulates transcriptional and developmental expression of the enzyme in the intestine has yet to be definitively unravelled. The prevailing view is that genetically de­ termined persistence of intestinal lactase activity is accounted for by at least five independent single nucleotide variants in a regulatory region (a transcriptional enhancer) upstream of LCT. One single nucleotide variant, −13910*T (rs4988235), appears to have reached stable fixation in Europe, while others occur at variable frequencies in the Middle East and Africa. The additional sequence variants in the vicinity of the locus at position −13910 are strongly associated with determinants that lead to persistence of lactase expression in populations of sub-​Saharan African and Afro-​Arabian origin. The discovery of an association between these variants and lactase persistence in close proximity (within 100 bp), located within a DNA sequence with demonstrable enhancer functions, indicates that they contribute functionally to the persistence of lactase expression:  that they occur on distinct haplotype backgrounds strongly suggests that several mutations led independently to the phenotype of lactase persistence, with strong selection in the different human populations. The high frequencies at which these alleles are found in modern populations have been attributed to positive selection for lactase persistence, allowing free consumption of animal milk by adult humans without intolerance. It is compatible with a selective advantage, namely the potential for lifelong enhanced availability of critical nutrients such as vitamin D from animal sources, but other explanations are possible, including the provision of macronutrients such as dietary protein and fat. The ability of Arabian nomads to digest lactose may have advantaged their migration to Africa. The distribution of the LCT alleles ap­ pears also to have been affected by expansion, migration, and other Box 15.10.5.1  Foods containing lactose • Fresh, dried, skimmed, non-​fat, and condensed milks • Cream • Yoghurt • Cheese • Processed meats and sausages • Sauces, stuffings, salad dressings • Custard powder • Canned and dried soups • Biscuits, cakes, cookies, pancakes, waffles, dried cereals • Confectionery • Frozen and canned fruits • Instant coffee • Lactose is also frequently used as a filler in powdered medicines and tablets

15.10.5  Disaccharidase deficiency 2905 processes in human populations which are related to human cultural preferences and practices. The −13910*T (rs4988235) variant lies approximately 14 kb up­ stream of the LCT gene and is tightly linked to the persistent lac­ tase phenotype in several populations widespread in Europe. It represents part of a haplotype extended over more than 500 kb of genomic DNA. Homozygosity for the C allele at this nucleotide position is associated with nonpersistence of lactase expression in adults. Conservation of the haplotype indicates a recent origin and its high frequency suggests that it has been subject to positive se­ lection through evolution. This polymorphic site might itself de­ termine lactase expression since it has been shown in transcription assays in vitro that the presence of the −13910 T allele enhances binding of the Oct1 transcription factor, which promotes lactase gene expression. Clinical effects of lactose intolerance Symptoms develop on exposure to excessive milk-​ and lactose-​ containing foods or medicines in late childhood or early adult life. The selective pressures that maintain this physiological reduction in mucosal lactase deficiency in childhood are unknown but the concept of ‘lactase deficiency’ in adults is difficult to justify, since lactase persistence is the least frequent state. Nonetheless, with the increasing migration of peoples and the widespread adoption of Western-​style diets, physiological loss of lactase activity is a prevalent cause of abdominal distress. A significant proportion of patients with spastic colon, irritable bowel disease, or other ‘func­ tional’ abdominal disturbances may prove to have lactase defi­ ciency. Preliminary evidence based on molecular characterization of polymorphic genetic variants on human chromosome 2 associ­ ated with lactase expression, together with hydrogen and methane breath gas analysis and symptoms, suggests that there may be a genuine association between sensitivity to lactose and inflamma­ tory bowel disease. However, these putative associations require confirmation. The speculative possibility arises that lactase-​deficient subjects are at risk from osteoporosis in countries at high latitudes because of a dietary deficiency of calcium or vitamin D. There is a higher frequency of lactase nonpersistence in osteoporotic women when compared with appropriate control subjects; this extends in some studies to reduced bone mineralization density with increased frac­ tures. It is presumed, but not proven, that reduced calcium intake is responsible. In contrast, in lactase-​persistent subjects, increased milk consumption may contribute to hyperlipidaemia and coronary heart disease. Moreover, by analogy with the role of galactitol in galactokinase deficiency, a disorder of galactose metabolism asso­ ciated with cataract (‘galactose diabetes’), sustained consumption of large amounts of milk and lactose-​containing foods has been im­ plicated in the development of premature cataract. There have been several European reports that adults with idiopathic and diabetic senile and presenile cataracts have a higher frequency of lactase per­ sistence than population controls without cataract and at least one other study has shown that high intake of milk correlated with cor­ tical cataracts. Similar surveys in populations with a higher general prevalence of lactose persistence showed no correlation; but a high risk of cataract formation has been reported in subjects with high lactose intake and low activities of galactokinase. Diagnosis of lactose malabsorption Intolerance of dietary carbohydrate caused by the maldigestion of lactose may be suspected from the dietary history of a patient typ­ ically complaining of abdominal pain, flatulence, and diarrhoea. Symptoms are often related to changes in social circumstances and are frequently reported by Asian and some African immigrants to Western countries; they may also become manifest when lactose-​ rich foods are administered inappropriately to children and adults by Western agencies in famine relief programmes. In this respect, the promotion by large multinational corporations of commercial infant feeds heavily based on milk products has attracted adverse international criticism. The relative lack of functional reserve of mu­ cosal lactase activity also explains the frequency with which lactose malabsorption becomes manifest after partial gastrectomy and re­ lated procedures that accelerate delivery of dietary carbohydrate to the jejunum. The stool has an acidic pH (<6) and the osmolality of stool water is generally greater than 350 mosmol/​kg because of the presence of lactate and other organic anions; in infants and children with complete lactase deficiency, reducing substances may be abundant in the stool water. Breath-​hydrogen analysis is a useful confirma­ tory test. Hydrogen excretion, determined by rebreathing 2 h after the ingestion of 50 g of lactose, identifies patients with lactase defi­ ciency diagnosed by enzymatic assay of jejunal mucosa obtained by biopsy. This latter procedure is difficult to standardize and is now rarely justified outside the research setting. A recent meta-​analysis comparing the diagnostic accuracy of lactose breath-​hydrogen or lactose tolerance tests for predicting the North European lactase −13910 C/​T polymorphism confirms a high diagnostic sensitivity and specificity of both tests individually in relation to expected lac­ tase genotypes in well-​defined populations. Other investigations, such as the lactose barium-​meal examination and determination of blood glucose profile after oral challenge with lactose, are cum­ bersome and, because they give false-​positive results, are now ob­ solete. Several initiatives are under way to promote the diagnosis of lactose persistence/​nonpersistence by molecular analysis of the lactase–​phlorizin hydrolase gene, with particular emphasis on the polymorphic variants at position −13910. However, without a com­ plete molecular understanding of the mechanisms by which lactase activity is controlled and the occurrence of different lactase haplo­ types in different populations, genetic diagnosis may not be infal­ lible in all ethnic groups and the hydrogen breath test offers more a facile and confident means of diagnosis. Secondary lactase deficiency Lactase activity may be depressed by mucosal disease of the small in­ testine and often occurs transiently after infective gastroenteritis. It is particularly frequent in infants suffering from gastroenteritis due to enterocytopathic viruses, and continuing symptoms provoked by milk feeds can persist for days or some weeks. Dehydration may de­ velop rapidly in infants and is accompanied by prominent bloating; disacchariduria is found and acid, sour-​smelling stools may be ob­ vious. Malabsorbed carbohydrate may be suspected in the field or outpatient clinic by screening for reducing sugars and estimating the acidity of the stool using pH indicator paper, since excess volatile fatty acids will be generated by colonic bacteria. However, since in­ fants normally consume larger amounts of lactose, which favours

section 15  Gastroenterological disorders 2906 growth of colonic lactobacilli, their stool is normally more acidic (pH 5.0–​5.5) compared with samples from older children and adolescents. The symptoms of carbohydrate intolerance due to secondary deficiency of lactase usually resolve rapidly when dairy products are excluded. Decreased lactase activity also accompanies exten­ sive and long-​standing mucosal disease so that a milk intolerance syndrome due to maldigestion may complicate coeliac disease, intestinal giardiasis, and Crohn’s disease. If secondary lactose in­ tolerance is suspected, then the cause should be sought, including examination of the stool particularly for parasites such as Giardia lamblia and Cryptosporidium spp., and, if possible, enteroviral in­ fections including rotavirus. Blood tests for coeliac disease (total IgA concentration and antitissue transglutaminase antibodies) or immunodeficiency (leucocyte counts, lymphocyte subsets, and im­ munoglobulin concentrations as well as serology for HIV) may re­ veal the underlying cause. Where the diarrhoeal illness is persistent, mucosal biopsy of the small intestine may be needed to identify the cause of acquired lactose intolerance and the presence of underlying mucosal disorders such as coeliac disease. Biopsy also offers greater confidence in the detection of microbial or parasitic invasion; in this context, electron microscopy may provide a definitive diagnosis, for example, rotavirus or enteric protozoal infections in patients with common variable immunodeficiency and other immunodeficiency syndromes. In secondary deficiencies of disaccharidases, because of the crit­ ical relationship between lactase activity and the rate at which this sugar is digested, intolerance of lactose predominates. However, the use of high-​calorie preparations containing large quan­ tities of disaccharide and short-​chain carbohydrates other than lactose (especially maltose, sucrose, and dextrins) to supplement the nutrition of patients with intestinal disease, may exacerbate their symptoms and induce a florid carbohydrate intolerance syndrome. Sucrase–​isomaltase (α-​dextrinase) deficiency This recessively inherited enzyme deficiency of the mucosal brush border appears to be rare in all populations except the Inuit of Greenland, in whom the frequency of homozygotes is up to 10%. Cetacean mammals also lack sucrase–​isomaltase. One recent small- scale study suggests that sucrase-isomaltase deficiency may not only masquerade as irritable bowel syndrome, but be a prevalent cause—the enzyme was considered to be deficient in 11 of 31 adult patients with bloating, abdominal pain and diarrhoea. Of note, pain was not a feature of this group of patients nonetheless considered to have irritable bowel syndrome. Several defects of the human gene on chromosome 3q appear to be responsible; in some, there is ab­ errant glycosylation and the enzyme is inefficiently transported to the brush border as a result of abnormal folding and other cellular polarization defects. Intolerance of sucrose is responsible for most of the symptoms, which develop as table sugar and sugar-​containing foods are intro­ duced during weaning. Intolerance of starch is less prominent be­ cause the osmotic contribution of the larger α-​dextrin molecules that remain unsplit in the gut lumen is less. However, ingestion of large, starchy meals may induce cramping discomfort, flatulence, and diarrhoea. While taking a normal diet, patients with deficiency of sucrase–​isomaltase have persistent diarrhoea with the passage of acid and frothy stools containing increased concentrations of lactate and other short-​chain acids. The diagnosis may be suspected on the basis of the history of diarrhoea at weaning and on the character of the stools. In several well-​documented cases, inherited deficiency of sucrase–​isomaltase presents after childhood, and may first come to light in later adult life. No convincing explanation for this phenomenon has been ad­ vanced. Differentiation from coeliac disease, cow’s milk allergy, infective or postinfective gastroenteritis, pancreatic failure, and other disaccharide intolerance syndromes (particularly lactose in­ tolerance, caused by inflammatory bowel disease) is important, and biopsy of the jejunal mucosa for enzymatic assay and histological examination should be considered. In inherited sucrase–​isomaltase deficiency, these activities are selectively reduced to less than 10% of control values in histologically normal mucosa. Hydrogen breath tests after ingestion of sucrose and isomaltose may prove to be useful in diagnosis; hydrogen excretion decreases when patients receiving sacrosidase (as opposed to placebo) during oral challenge with su­ crose, demonstrating the operational effectiveness of enzyme sup­ plementation for this disorder. Trehalase deficiency A few patients have been reported with mushroom intolerance due to the absence of mucosal trehalase. Trehalase is a brush border α-​ glycosidase that cleaves the unusual 1α–​1α bond of trehalase into its component glucose moieties. Trehalose is found in the haemolymph of arthropods and in fungi, so that intolerance of crustacean shell­ fish as well as mushrooms in the diet might be expected. Given that intolerance of edible fungi is not uncommon, trehalase deficiency may prove to be more frequent than previously supposed but a study of 400 patients in the United Kingdom by enzymatic assay of intes­ tinal mucosal biopsies indicated that the deficiency was very rare in this population. Trehalase deficiency has also been reported to occur in at least 8% of Greenland Inuit (and in cetacean mammals from the same environment) but the functional significance of this is unknown. Management Dietary exclusion Dietary exclusion of the offending sugar is the best method of preventing symptoms in individuals with primary or acquired dis­ accharidase deficiency. Symptoms recur as soon as excessive lactose or sucrose is reintroduced and advice from a professional dietitian may be needed to avoid indiscretions. This is especially important in the case of young infants and children with marked deficiency of particular disaccharidases, where special food supplements may be required (see ‘Disaccharidase replacement’). In hypolactasia, complete elimination is not usually required, as lactase deficiency is rarely absolute; nevertheless, if symptoms persist there are many potential sources of lactose that warrant careful exploration (see Box 15.10.5.1). Milk preparations that are substantially free of lac­ tose or lactose-​reduced milks (and lactose-​free whole milk for in­ fants) are widely available in many developed countries. Many individuals who are intolerant of milk can tolerate milk chocolate

15.10.5  Disaccharidase deficiency 2907 or plain yogurt, because the bacteria in the yogurt partially break down the lactose into glucose and galactose before consumption; moreover, the fat content present in a semisolid state delays gastric emptying and gastrointestinal transit, providing more time for en­ dogenous lactase activity to digest the ingested lactose load. Aged cheeses also have a lower content of lactose than other cheeses and are often better tolerated. In general, defining the individual’s prac­ tical tolerance limits for milk with a meal, and the use of reduced lactose-​content foods including hard cheeses, yogurt, and lactose-​ hydrolysed milk products is a recommended approach to dietary management. Disaccharidase replacement Lactase-​replacement, or milk or dairy products that have been pretreated with lactase, are available; these may allow a lactose-​ intolerant person to ingest milk products without inducing symp­ toms of intolerance. Long-​term avoidance of milk products to control intestinal symptoms may have consequences for optimal bone mineralization in children, since it has been shown that those who avoid milk ingest smaller amounts of calcium than are needed for normal bone mineralization. For this reason, and because the vitamin D content in milk substitutes may vary considerably, labels should be examined to check the content of particular brands and to ensure that sufficient vitamin D is being supplied, especially to young growing children. Appropriate vitamin supplements are clearly indicated according to daily recommended doses according to age and sex. Addition of β-​galactosidases obtained from yeast or other micro­ organisms added to dairy products before consumption may alter the taste and prove unacceptable, but in the United States of America, β-​galactosidase obtained from yeast (LactAid) has been shown to reduce symptoms as well as breath-​hydrogen excretion in subjects with maldigestion of lactose. In the United Kingdom, a concen­ trated liquid lactase preparation (Colief, 50 000 units/​g) is licensed for use in infants and children with symptomatic lactose intolerance. β-​galactosidase derived from Aspergillus oryzae (Lactrase), taken in tablet form immediately before challenge with lactose, is effective in children with late-​onset intolerance of lactose. Its cost, compared with dietary exclusion, may not be justified. More recently there has been a resurgence of the avid 19th-​century interest in the use of so-​ called prebiotic agents for a wide diversity of abdominal and other complaints; there have been claims of benefit in rotavirus infection and in the control of symptomatic lactose intolerance. At present, it is too early to decide whether these highly commercialized agents have any useful role in lactose intolerance but, despite their high cost, on balance some preparations may have a modest benefit in symptomatic control. In infants and young children with proven lactose intolerance, Farley’s Soya formula, Galactomin Formula 17, Isomil, SMA FF, Enfamil Lactofree, and other preparations provide protein and suitable carbohydrate in a powdered form so that adequate nutri­ tion can be maintained. For older children and severely ill adults with disaccharide intolerance, other preparations may be required (see ‘Asucrasia and starch intolerance’). In the future, microbial β-​galactosidases might be justified for food supplementation pro­ grammes in countries where lactose intolerance and nutritional de­ privation in the adult population are widespread. Therapeutic modulation of the intestinal microbiome A promising and innovative approach to the management of lactose intolerance and maldigestion is also being explored in the United States of America (see Azcarate-​Peril et al., in ‘Further reading’). The concept is based on an extensive preclinical programme carried out at Chapel Hill in which host factors such the intestinal microbiome have been explored experimentally in patients with lactose intoler­ ance and other conditions. The investigators have examined factors other than the constitutive nonpersistence of lactase and shown that the metabolism of residual lactose in the colon can be favourably altered by using oligosaccharides to modulate the bacterial popu­ lation so that lactose-​fermenting species are induced and appar­ ently favoured. Based on previous preclinical studies, a randomized double-​blind trial showed that oral administration of a short-​chain galactosaccharide (‘RP-​G28’) improved lactose digestion and toler­ ance in patients with hypolactasia. Accompanying these outcomes, analysis of bacterial diversity by 16S rRNA sequencing showed a change in the microbiome indicating a bifidogenic response with increased abundance of lactose-​fermenting Bifidobacterium spp., Faecalibacterium spp., and lactobacilli. Moreover, introduction of dietary lactose over a 30-​day period induced lactose-​fermenting roseburia. These findings confirm that the galacto-​oligosaccharide induced marked alterations in the faecal microbiome in lactose-​ intolerant individuals with increased relative abundance of lactose-​ metabolizing bacteria, and that this adaptive response by the endogenous microflora correlated with clinical outcomes of im­ proved lactose tolerance. If confirmed, these promising findings would immediately suggest alternative and apparently facile means for treating symptomatic lactase deficiency which may indeed synergise with probiotic therapies. Asucrasia and starch intolerance Complete absence of sucrase–​isomaltase activity in most patients with sucrose intolerance, together with the ubiquity of sucrose in modern diets, complicates symptom management. Modest re­ duction of amylopectin-​rich foods usually suffices to improve symptoms of starch intolerance, but complete avoidance of sucrose-​ containing foods can be difficult especially in infants and young chil­ dren. Powdered and liquid preparations such as Caloreen, Maxijul LE, Polycal liquid and powder, amongst others, may be needed for sucrase–​isomaltase deficiency. Glucose (or fructose) can be used as a sweetener. It has been reported that ingestion of dried brewer’s yeast (containing invertase or sucrase but little lactase activity) after food is effective in patients with sucrase–​isomaltase deficiency. However, dried yeast is rather unpalatable and not readily accepted by children. A high-​potency liquid preparation of invertase used in the industrial manufacture of fructose from unrefined sugar cane juice, yeast-​derived sacrosidase (Sucraid), is an oral preparation containing 8500 international units/​mL of β,d-​fructofuranoside fructohydrolase derived from baker’s yeast. It is approved by the Food and Drug Administration in the United States of America for patients with sucrase–​isomaltase deficiency. In a double-​blind ran­ domized controlled trial in patients with sucrase–​isomaltase defi­ ciency, given orally the agent was found to be safe, acceptable, and effective for the symptomatic treatment of the disease in patients al­ ready receiving a low-​starch diet. Although it is generally efficacious,

section 15  Gastroenterological disorders 2908 patients with allergies to yeast products, glycerine (glycerol), or pa­ pain may be intolerant and develop anaphylactic or other allergic reactions to sacrosidase. It is thus advised that the first dose be ad­ ministered in an environment that will allow severe allergic reac­ tions to be safely treated and where specific measures to resuscitate patients suffering acute anaphylaxis are available. The usual dosage is 1 to 2 ml of sacrosidase liquid given with each meal or snack; the enzyme preparation should be mixed with 60 to 120 ml of water, milk, or infant formula (and to avoid denaturation, no hotter than room temperature). Fruit juices are not recommended for delivery, because they usually contain abundant sucrose and fructose which attenuate the therapeutic effect. Since the agent enhances sugar ab­ sorption in the small intestine, patients with diabetes may encounter difficulties in postprandial blood glucose control when treatment is initiated. Half the dose of sacrosidase is best taken when food is first eaten, with the remainder ingested during consumption of the meal. Although it is licensed only for congenital sucrase–​isomaltase deficiency, the use of sacrosidase in postinfective and other sec­ ondary disaccharidase deficiencies has not been formally examined; together with appropriate dietary restriction, sacrosidase and ad­ junctive supplementation with β-​galactosidases may benefit patients with established disease of the small intestinal mucosa and remains to be explored. FURTHER READING Alfalah M, et  al. (2009). Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-​ isomaltase deficiency. Gastroenterology, 136, 883–​92. Arola H, et al. (1999). Low trehalase activity is associated with abdom­ inal symptoms caused by edible mushrooms. Scand J Gastroenterol, 34, 898–​903. Azcarate-​Peril MA, et  al. (2017). Impact of short-​chain galacto­ oligosaccharides on the gut microbiome of lactose-​intolerant indi­ viduals. Proc Natl Acad Sci USA, 114, E367–​75. Baudon JJ, et  al. (1996). Sucrase-​isomaltase deficiency:  changing pattern over two decades. J Pediatr Gastroenterol Nutr, 22, 284–​8. Bodé S, Gudmand-​Høyer E (1988). Incidence and clinical significance of lactose malabsorption in adult celiac disease. Scand J Gastroenterol, 23, 484–​8. Bolin TD, Davis AE, Duncombe VM (1982). A prospective study of persistent diarrhoea. Austral N Z J Med, 12, 22–​6. Clare H, Ruth M (1997). Phylogenetic analysis of the evolution of lac­ tose digestion in adults. Hum Biol, 69, 605–​28. Corazza GR, et al. (1992). Beta-​Galactosidase from Aspergillus niger in adult lactose malabsorption:  a double blind crossover study. Aliment Pharmacol Therapeut, 6, 61–​6. Di Stefano M, et al. (2002). Lactose malabsorption and intolerance and peak bone mass. Gastroenterology, 122, 1793–​9. Eadala P, et al. (2011). Association of lactose sensitivity with inflam­ matory bowel disease—​demonstrated by analysis of genetic poly­ morphism, breath gases and symptoms. Aliment Pharmacol Ther, 34, 735–​46. Ennatah NS, et al. (2002). Identification of a variant associated with adult-​type hypolactasia. Nat Genet, 30, 233–​7. Farnworth ER (2008). The evidence to support health claims for pro­ biotics. J Nutr, 138, 1250S–​54S. Gerbault P, et al. (2009). Impact of selection and demography on the diffusion of lactase persistence. PLoS One, 4, e6369. Gerbault P, et al. (2011). Evolution of lactase persistence: an example of human niche construction. Philos Trans R Soc Lond B Biol Sci, 366, 863–​77. Gray GM (1975). Carbohydrate digestion and absorption. Role of the small intestine. N Engl J Med, 292, 1225–​30. Gupta SK, Chong SK, Fitzgerald JF (1999). Disaccharidase activity in infants and comparison based on symptoms and histological changes. J Pediatr Gastroenterol Nutr, 28, 246–​51. Heyman MB (2006). Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics, 118, 1279–​86. Hoskova A, et al. (1980). Severe lactose intolerance with lactosuria and vomiting. Arch Dis Child, 55, 304–​16. Ingram CJ, et al. (2009). Lactose digestion and the evolutionary gen­ etics of lactase persistence. Hum Genet, 124, 579–​91. Kim SB, et al. (2019). Sucrase-isomaltase deficiency as a potential mas­ querader in irritable bowel syndrome. Dig Dis Sci. Sep 6. King CE, Toskes PP (1983). The use of breath tests in the study of malabsorption. Clin Gastroenterol, 12, 591–​610. Kuokkanen M, et al. (2006). Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. Am J Hum Genet, 78, 339–​44. Lewinsky, RH et  al. (2005). T-​13910 DNA variant associated with lactase persistence interacts with Oct-​1 and stimulates lactase pro­ moter activity in vitro. Hum Mol Genet, 15, 3945–​53. Liebert A, et al. (2017). World-​wide distributions of lactase persist­ ence alleles and the complex effects of recombination and selection. Human Genetics, 136, 1445–​53. Madzarovova-​Nohejlova J (1973). Trehalase deficiency in a family. Gastroenterology, 65, 130–​3. Marton A, et  al. (2012). Meta-​analysis:  the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests for predicting the North European lactase polymorphism C/​T-​13910. Aliment Pharmacol Ther, 35, 429–​40. Medow MS, et al. (1990). β-​Galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child, 144, 1261–​4. Misselwitz B, et al. (2019). Update on lactose malabsorption and in­ tolerance: pathogenesis, diagnosis and clinical management. Gut, Aug 19. pii: gutjnl-2019-318404. Montalto M, et al. (2005). Effect of exogenous beta-​galactosidase in patients with lactose malabsorption and intolerance: a crossover double-​blind placebo-​controlled study. Eur J Clin Nutr, 59, 489–​93. Murray IA, et al. (2000). Intestinal trehalase activity in a UK popula­ tion: establishing a normal range and the effect of disease. Br J Nutr, 83, 241–​5. Oak SJ, Jha R (2018). The effects of probiotics in lactose intoler­ ance: a systematic review. Crit Rev Food Sci Nutr. DOI: 10.1080/​ 10408398.2018.1425977 Plantinga TS, et al. (2012). Low prevalence of lactase persistence in Neolithic South-​West Europe. Eur J Hum Genet, 20, 778–​83. Pohl D, et  al. (2010). Excellent agreement between genetic and hydrogen breath tests for lactase deficiency and the role of extended symptom assessment. Br J Nutr, 104, 900–​7. Robayo-​Torres CC, et  al. (2009). 13C-​breath tests for sucrose diges­ tion in congenital sucrase isomaltase-​deficient and sacrosidase-​ supplemented patients. J Pediatr Gastroenterol Nutr, 48, 412–​8. Shaukat A, et  al. (2010). Systematic review:  effective management strategies for lactose intolerance. Ann Intern Med, 152, 797–​803. Sibley E (2004). Carbohydrate intolerance. Curr Opin Gastroenterol, 20, 162–​7. Simoons FJ (1978). The geographic hypothesis and lactose malabsorp­ tion. Am J Digest Dis, 23, 963–​80.

15.10.6 Whipple’s disease 2909

15.10.6 Whipple’s disease 2909

15.10.6  Whipple’s disease 2909 Swallow DM (2003). Genetics of lactase persistence and lactose in­ tolerance. Annual Reviews in Genetics, 37, 197–​219. Swallow DM (2006). DNA test for hypolactasia premature. Gut, 55, 131. Tori AJ, Carroll AE, Gupta SK (2007). Disaccharidase activity in in­ fants and comparison based on symptoms and histological changes. J Pediatr Gastroenterol Nutr, 45, 194–​8. Treem WR (1995). Congenital sucrase–​isomaltase deficiency. J Pediatr Gastroenterol Nutr, 21, 1–​14. Treem WR, et al. (1999). Sacrosidase therapy for congenital sucrase–​ isomaltase deficiency. J Pediatr Gastroenterol Nutr, 28, 137–​42. Tolonen S, et al. (2011). Lactase gene C/​T(-​13910) polymorphism, calcium intake, and pQCT bone traits in Finnish adults. Calcif Tissue Int, 88, 153–​61. Wang Y, et al. (1998). The genetically programmed down-​regulation of lactase in children. Gastroenterology, 114, 1230–​6. 15.10.6  Whipple’s disease Florence Fenollar and Didier Raoult ESSENTIALS Whipple’s disease is an uncommon infection caused by the actino- mycete Tropheryma whipplei, most commonly diagnosed when overt small intestinal disease leads to malabsorption, but with pro- tean other clinical manifestations (e.g. systemic, neurological, or cardiological). Diagnosis usually depends upon demonstration of classical histo- logical features in the small intestine, and positive identification of T. whipplei DNA by polymerase chain reaction. Treatment is with antibiotics, initially doxycycline and hydroxy­ chloroquine followed by long-​term therapy with doxycycline. Clinical improvement occurs within a few weeks, but prolonged treatment for at least a year is recommended. Relapse can occur, even after many years, especially when progressive central nervous system disease occurs in the absence of other systemic manifestations. Introduction When described in 1907, Whipple’s disease was considered to be a metabolic disorder. Tropheryma whipplei, the aetiological agent of Whipple’s disease, was first identified in 1998 using 16S rRNA polymerase chain reaction (PCR) coupled to sequencing, and the first successful culture was performed in 2000. Whipple’s disease, as described by Whipple, is a chronic systemic condition with pro­ tean manifestations that is ultimately fatal without specific antibiotic therapy, but this presentation is only the tip of the iceberg of the manifestations caused by T. whipplei. Aetiology and pathogenesis Humans are the only source of T. whipplei that has been clearly iden­ tified. The bacterium is most likely transmitted via the oral–​oral and the faecal–​oral routes, depending on the hygiene conditions. Although T. whipplei commonly infects humans, Whipple’s disease is rare. The higher prevalence of T. whipplei in certain populations is not associated with a higher prevalence of Whipple’s disease, sug­ gesting that only people with as yet unknown predisposing factors will develop this condition. Epidemiology There is asymptomatic carriage of T.  whipplei, mainly in faeces, the prevalence of which depends on age, exposure, and geograph­ ical area. The prevalence of T.  whipplei in faeces of European healthy adults has been estimated to be 3%, but faecal carriage is higher among populations with poor personal hygiene, such as homeless people, those in contact with faeces (e.g. sewer workers), and among the relatives of patients or chronic carriers in Europe (Table 15.10.6.1). The prevalence of asymptomatic carriage is higher in Africa and Asia than in Europe. The typical patient with classic Whipple’s disease is a Caucasian male of approximately 50  years of age. A national population-based study in the USA indicated a prevalence of 9.8 cases of Whipple’s disease per million people. Clinical features T. whipplei is involved in chronic infections and has also been re­ cently associated with acute infections such as gastroenteritis, pneu­ monia, and bacteraemia. Chronic infections include disseminated Whipple’s disease and localized infections. Classic Whipple’s disease is a systemic disease as T. whipplei is not only systematically detected in the intestinal tract, but the bac­ terium can be also observed in most of the organs: it can be detected in the blood, saliva, faeces, cerebrospinal fluid (even in the lack of neurological manifestations), brain, heart, eyes, and skin (even if no cutaneous abnormality is observed). No systemic involvement is ob­ served in chronic localized infections (saliva and faeces are mostly negative for T. whipplei), and the potential for relapse is not the same as in classic Whipple’s disease. These several differences suggest a Table 15.10.6.1  Prevalence of T. whipplei in faeces of healthy people depending on age, exposure, and geographical area Population Young children in France French general adult population Underground sewer workers in Europe Homeless people in France Adults in rural Gabon Adults in rural Senegal Relatives of T. whipplei patients or carriers (France) Children in rural Gabon Children in rural Senegal and Laos Prevalence <1% 3% ~12% 17.4% 38% ~48%

section 15  Gastroenterological disorders 2910 different susceptibility to T. whipplei between patients with classic Whipple’s disease and those with chronic localized infections, al­ though it has been recently shown that classic Whipple’s disease can appear among people who have been diagnosed and treated, years before, for localized T. whipplei endocarditis. Classic Whipple’s disease The typical patient, a Caucasian male (in approximately 80% of cases) of middle age (about 50 years old), initially complains of intermittent arthralgias (75%). Patients suffer also from chronic digestive troubles with diarrhoea (75%) and/​or weight loss (85%). The diagnosis is often made after the appearance of clinical manifestations such as weight loss or digestive troubles in patients treated with immuno­ suppressive therapy (about 4 months) for rheumatological disease, including corticosteroids and tumour necrosis factor antagonists. T. whipplei can nearly affect all organs and lead to many manifest­ ations. Patients can complain of nonspecific symptoms such as fever, fatigue, abdominal pain, cough, and myalgia. Lymphadenopathy, mainly mediastinal and mesenteric, can be detected. Various neuro­ logical manifestations can mimic almost all neurological diseases, the most frequently observed presentations include cognitive changes, ranging from memory impairment to dementia, as well as psychiatric disorder (e.g. personality changes, depression). Endocarditis, peri­ carditis, and myocarditis also occur in patients with classic Whipple’s disease. Eye and lung involvements are observed. Skin pigmentation was reported for many years, but now seems to be observed less fre­ quently, which may be attributable to earlier diagnosis. Chronic localized Whipple’s disease Many chronic localized T. whipplei infections without systemic and histological intestinal involvement have been observed. Endocarditis Endocarditis is the most frequent localized manifestation, the typical patient being an afebrile Caucasian male of approximately 60 years old, exhibiting mainly cardiac insufficiency or (less frequently) em­ bolic events. Localized T. whipplei endocarditis can transform sec­ ondarily into classic Whipple’s disease. Neurological The most common neurological symptoms in localized T. whipplei encephalitis are cognitive impairment, ataxia, and supranuclear ophthalmoplegia. An association of dementia, cerebellar ataxia, and weight gain has also been described. Ocular Chronic uveitis can be unilateral or bilateral, and posterior, inter­ mediate, and/​or anterior conditions that are resistant to or even worsened by corticosteroids. A correlation between the diagnosis of T. whipplei uveitis and a history of ocular surgery has been observed, suggesting potential nosocomial transmission of the bacterium or that use of corticosteroids during ocular surgery could activate la­ tent ocular infection. Differential diagnosis Whipple’s disease is in the differential diagnosis for a wide spectrum of diseases including inflammatory rheumatic diseases, diseases causing malabsorption, sarcoidosis, lymphoma, Addison’s disease, as well as a variety of neurological diseases. Clinical investigation The best molecular tool currently available to detect T. whipplei is a specific quantitative real-​time PCR test targeting repeated sequences of the bacterium. Rigorous criteria must be applied to interpret mo­ lecular assays, including the systematic use of positive and negative controls, and verification of the quality of DNA extracts. (a) (b) Fig. 15.10.6.1  Detection of Whipple’s disease by PAS staining and immunohistochemical analysis. PAS staining of a duodenal-​biopsy specimen shows reduced villous architecture and macrophages (magenta) in the lamina propria (a). Immunohistochemical staining with polyclonal rabbit anti-​T. whipplei antibody (at a dilution of 1:2000) and Mayer’s haemalum counterstaining show T. whipplei in a duodenal-​biopsy specimen (brown) (b). Images courtesy of Hubert Lepidi.

15.10.7 Effects of massive bowel resection 2911

15.10.7 Effects of massive bowel resection 2911

15.10.7  Effects of massive bowel resection 2911 T. whipplei DNA is detectable in various body fluids and tissues. Sampling should be performed depending on the clinical manifest­ ations: small-​bowel biopsies for digestive symptoms, synovial fluid and/​or biopsy for articular involvement, blood and/​or cardiac valve for endocarditis, cerebrospinal fluid for neurological manifestations, and aqueous humour for uveitis. When Whipple’s disease is suspected, screening may also be per­ formed on the basis of the combined analyses of saliva and faeces using specific quantitative real-​time PCR. If both were positive, the suspicion of Whipple’s disease is high, whereas if they are both nega­ tive, classic Whipple’s disease can be excluded. The diagnosis of classic Whipple’s disease is based on positive periodic acid–​Schiff (PAS) staining of duodenal biopsies (Fig. 15.10.6.1), but PAS staining can be positive in other circumstances, such as mycobacterium infection. Immunohistochemical analysis using specific antibodies allows the direct visualization of bacteria in samples and has sensitivity and specificity superior to those of PAS staining. 18F-​fluorodeoxyglucose positron emission tomography images demonstrating small-​bowel hypermetabolism seem to be associated with classic Whipple’s disease. Such images in an investigation of un­ explained weight loss, diarrhoea, or fever of unknown origin might suggest the need to consider and investigate for Whipple’s disease. Western blot serology can help differentiation of PCR-​positive asymptomatic carriers, who have a strong immune response, and patients with classic Whipple’s disease, who lack or have a low im­ mune response, but this technique is complex and can be performed only in the chapter authors’ laboratory. Culture of this fastidious bacterium from human specimens is currently also only performed in the authors’ laboratory. Management and prognosis Whipple’s disease is a lifelong disease. Failures, relapses, and rein­ fections caused by different T. whipplei strains have been observed in patients who have apparently been cured. Relapses have been also reported as late as 20 years after the initial diagnosis, and these may occur in organs other than those previously involved. Until recently, treatment was empirical, but the recent culture of T. whipplei has allowed antibiotic susceptibility testing to guide treatment protocols. Trimethoprim–​sulfamethoxazole, which for a long time was regarded as the mainstay of treatment, must be avoided due to its poor efficiency and its association with failures and relapses. Currently, for classic Whipple’s disease, on the basis of antibiotic susceptibilities and the follow-​up of patients, doxy­ cycline (200 mg/​day) and hydroxychloroquine (200 mg three times/​day) for 12 months is the best treatment. This should be fol­ lowed by long-​term (possibly lifelong) treatment with doxycycline because potentially fatal relapses can occur, as well as reinfections with new T. whipplei strains. For localized chronic infections, a combination of doxycycline and hydroxychloroquine for a duration of 12 to 18 months, followed by an extended follow-​up, has been proposed, but the recent obser­ vation of evolution of localized T. whipplei endocarditis into classic Whipple’s disease should also lead to consideration of longer treat­ ment for localized chronic infections. No specific treatments or recommendations are available for acute infections and chronic carriage. FURTHER READING Elchert JA, Mansoor E, Abou-Saleh M, Cooper GS (2019). Epidemiology of Whipple’s disease in the USA between 2012 and 2017: a population-based national study. Dig Dis Sci, 64, 1305–11. Fenollar F, Lagier JC, Raoult D (2014). Tropheryma whipplei and Whipple’s disease. J Infect, 69, 103–​12. Keita AK, et al. (2015). High prevalence of Tropheryma whipplei in Lao kindergarten children. PLoS Negl Trop Dis, 9, e0003538. Lagier JC, Cammilleri S, Raoult D (2016). Classic Whipple’s disease diagnosed by 18F-​fluorodeoxyglucose PET. Lancet Infect Dis, 16, 130. Lagier JC, et al. (2014). Treatment of classic Whipple’s disease: from in vitro results to clinical outcome. J Antimicrob Chemother, 69, 219–​27. Lagier JC, Raoult D (2018). Whipple’s disease and Tropheryma whipplei infections: when to suspect them and how to diagnose and treat them. Curr Opin Infect Dis, 31, 463–70. Ramharter M, et al. (2014). Prevalence and risk factor assessment of Tropheryma whipplei in a rural community in Gabon: a community-​ based cross-​sectional study. Clin Microbiol Infect, 20, 1189–​94. Vinnemeier CD, et al. (2016). Tropheryma whipplei in children with diarrhoea in rural Ghana. Clin Microbiol Infect, 22, 65.e1–​65.e3. 15.10.7  Effects of massive bowel resection Stephen J. Middleton, Simon M. Gabe,
and Raymond J. Playford ESSENTIALS Major vascular events involving the superior mesenteric artery and small-​bowel volvulus are the commonest reasons for adults to re- quire massive intestinal resection. The ability of the residual bowel to adapt after resection varies greatly between patients, but common postoperative problems include sepsis, diarrhoea (or high-​output stoma losses), fluid and electrolyte imbalance, malnourishment (protein–​energy malnutrition, mineral and vitamin deficiencies), gall- stones, renal stones, and psychological illness. Where appropriate, oral nutrition, initially consisting of low-​volume polymeric feeds administered by nasogastric or enteral tube, should be started within the first few days of surgery. Small-​volume, frequent, solid or semisolid meals with low long-​chain triglycerides and (when colon is in continuity) oxalate content should be introduced subsequently, and isotonic electrolyte solutions given as required. Oral multivitamin and mineral supplements are usually needed, and vitamin B12 injections may be required. There should be regular long-​term monitoring of fat-​ soluble vitamins (A and D), vitamin B12, folate, magnesium, zinc, and bone status. Long-​term intravenous nutrition is sometimes needed. Growth factor administration, especially glucagon-​like peptide-​2 analogues, may stimulate bowel adaptation. Small-bowel surgery can sometimes offer a modest increase in length for patients with dilated bowel. Those who are dependent on peripheral nutrition and develop complications such as loss of venous access or liver disease should be considered for intestinal transplantation.

section 15  Gastroenterological disorders 2912 Introduction Massive loss of the intestine occurs as a result of surgical resection leaving a residual length that is insufficient to support all aspects of nutrition adequately. These patients initially enter an acute phase with sudden loss of enteral function in association with a variety of other comorbidities either resulting from or being the cause of their intestinal catastrophe. If they survive this period they will enter a chronic phase of intestinal failure when their health and well-​being will depend upon careful nutritional support, which often includes intravenous feeding, as well as physical, psychological, and intestinal rehabilitation. During this phase, a plan for long-​term management is made, the aims of which will depend particularly upon the re­ habilitation potential of the remaining intestinal tract. The skills and facilities for effective management of the acute phase need to be widely available as patients usually present as emergencies to their nearest hospital. The chronic phase is often better managed in specialized centres. The management and prog­ nosis of patients is greatly influenced by the presence of the colon in continuity with the remaining small intestine. This chapter is pre­ dominantly concerned with adult patients, although much of it will also apply to paediatric patients. Aetiology The conditions that most frequently lead to sudden massive intes­ tinal surgical resection resulting in a short bowel in adults are mes­ enteric ischaemia and small-​bowel volvulus. Crohn’s disease is a common cause of short bowel, but this usually results from multiple segmental resections which lead incrementally to short-​bowel syn­ drome due to a combination of reduced length and reduced func­ tion within the remaining segments arising from factors such as mucosal fibrosis. Other causes include surgery to resect desmoid tumours and trauma. Lifestyle changes and medication to reduce ar­ terial disease, prudent limitation of surgical intervention in Crohn’s disease, and careful surgical technique to avoid subsequent volvulus after colectomy or bariatric surgery may help reduce the incidence of these events. In children, the main causes include necrotizing en­ terocolitis, gastroschisis, and intestinal volvulus. Pathophysiology Water and electrolyte depletion The consequences of intestinal resection are influenced by the re­ gion (or regions) of the gut that has been lost. Patients with short-​ bowel syndrome commonly fall into one of three groups based on their residual gastrointestinal anatomy (Fig. 15.10.7.1). The stomach may secrete 1 to 2 litres of acidic fluid each day, which is normally reabsorbed in the small bowel and colon. The proximal 100 cm of jejunum is net secretory, such that the water volume excreted via a stoma in this segment will be greater than that in an ingested meal. The sodium concentration of most meals varies between 10 and 40 mmol/​litre, and due to the contribution of gastro­ intestinal secretions this gradually increases to around 90 mmol/​ litre at the duodenojejunal flexure. On reaching the terminal ileum, the concentration has risen to about 140  mmol/​litre, largely due to water absorption in the more distal intestine. Compared to the ileum, the jejunum is less able to absorb water and sodium against a concentration gradient due to rapid back-​diffusion into the lumen to create an iso-​osmolar luminal fluid mixture. In contrast, the ileum is far less permeable and can mount a considerable concentration gradient across the mucosal surface. Furthermore, jejunal sodium absorption is coupled to glucose and amino acids, in contrast to the ileum which is free from these constraints and can also increase ab­ sorption in response to aldosterone. Taken in combination, these regional differences in intestinal function result in an adverse effect following loss of the distal small intestine that is greater than losing a similar amount of prox­ imal intestine. The presence of colon in continuity can compen­ sate to some degree for water and electrolyte losses and may also encourage adaptation (which includes increased villus height and crypt depth) of the remaining intestine to enhance absorption via mediators such as glucagon-​like peptide (GLP)-​2, which is released by colonic enterochromaffin L cells in response to malabsorbed nutrients. Changes in gut hormones, motility, and secretion Other potentially important pathophysiological changes include hypergastrinaemia. This is unlikely to cause gastric hypersecretion for more than a few weeks, although many patients benefit from treatment with a proton pump inhibitor in the longer term. Gastric emptying is often rapid in patients who have lost the colon and ileum, probably due to depletion of peptide tyrosine-​tyrosine (PYY)-​ releasing enterochromaffin cells. Pancreaticobiliary secretion is not greatly affected, but loss of more than 100 cm of terminal ileum leads to malabsorption of secondary bile acids. These act as secretagogues in the colon, increasing mucosal secretion, and fat malabsorption results from depletion of the bile acid pool. Patients with a jejunocolonic anastomosis frequently have rapid small bowel transit due to both reduced intestinal length and loss of the ileum, which has inherently slower transit. It is thought that the early arrival of liquid nutrients in the colon triggers a ‘colonic brake’, mediated by PYY, that reduces the transit rate of the solid meal components more proximally. Loss of the colon is associated (a) (b) (c) Fig. 15.10.7.1  The three types of patient with short bowel syndrome. (a) Jejunocolonic—​small intestine and proximal colon have been resected and the small bowel anastomosed to the colon with loss of the ileocaecal valve and some of the proximal colon. (b) Jejunostomy—​the small bowel has been shortened by resection(s) and the shortened small bowel ends in a jejunostomy. (c) Ileocolonic—​the small bowel has been shortened by resection(s) and the shortened small bowel is anastomosed to residual terminal ileum, leading to the large bowel through the ileocaecal valve in the normal way.

15.10.7  Effects of massive bowel resection 2913 with reduced intestinal adaptation due to lower levels of GLP-​2 and faster transit, probably caused by lower levels of PYY. Vitamins and micronutrients Loss of more than 50 cm of terminal ileum can result in vitamin B12 malabsorption and deficiency. Other important nutrients that are particularly prone to deficiency after small-​bowel resection include magnesium, zinc, iron, biotin, and selenium. Fat malabsorption is common and can lead to deficiency of essential fatty acids and the fat-​soluble vitamins (A, D, E, and K). Management Massive intestinal resection initially results in a high-​output state as gut motility returns in the early days after surgery. This acute phase predominantly requires urgent attention to water and electro­ lyte balance, control of sepsis, and establishment of safe nutrition. Subsequently the more insidious issue of progressive undernutrition, weight loss, and nutrient deficiencies may develop. Finally, with cor­ rect management, the major nutritional deficiencies are corrected and minor adjustments are needed to optimize long-​term outcome and symptoms control. The management can usefully be divided into acute and chronic phases. Acute phase Sepsis Following massive intestinal resection, patients are often critically ill and have uncontrolled sepsis. Adequate nutritional support will be impaired by the presence of sepsis, the source of which needs to be identified and resolved as a priority. Further surgical intervention should be avoided if possible until sepsis is controlled. Radiological drainage of infected fluid collections and appropriate antimicrobial treatment should be the mainstay of treatment. Infection of intra­ venous feeding lines is a common complication unless scrupulous care is maintained at all times. Specialist microbiological advice is advisable to select the best antibacterial and antifungal agents. Nutritional support During the first few weeks after massive intestinal resection, management of fluid and electrolyte balance is challenging (Table 15.10.7.1). Oral nutrition Oral or enteral nutrition should ideally be started within the first few days after surgery. Patients will usually have a nasogastric or other enteral feeding tube in place. A low-​volume polymeric feed is pref­ erable, which can be stopped when the patient is able to take oral nutrition. Subsequently, small-​volume, frequent, solid or semisolid meals should be introduced. The introduction of luminal nutrition tends to exacerbate diar­ rhoea or increase stomal output. Patients may enter a high-​output state and lose quantities in the region of 10 litres per day. Adequate fluid replacement depends upon accurate estimation of losses based on knowledge of those expected according to the remaining intes­ tine, and measured losses of water and electrolytes from the stoma, urine, and other sites such as abdominal drains and nasogastric tubes. Patients are often critically ill at this stage and abnormal renal losses may need to be identified and accounted for. Particular attention should be given to abnormal acid–​base balance, which is often insidious, as are magnesium and zinc defi­ ciencies. Early signs of hypomagnesaemia include cramps and par­ aesthesiae. This can be accentuated by proton pump inhibitors as these medications decrease magnesium absorption. Daily body weights are useful but may not be available in crit­ ically ill patients. Analysis of urine for sodium concentration and osmolality can assist in the estimation of sodium and water balance, but may be unreliable in the acutely ill patient due to acute kidney injury, and the therapeutic response to finding sodium depletion is inherently reactive rather than preventative. Clinical assessment is often made difficult as peripheral oedema may result from the acute illness rather than indicate intravascular volume overload. Thirst can be a useful guide, as can central venous and arterial blood pres­ sures. In practice, close observation and use of all these elements is usually adequate to provide enough information to institute an ef­ fective programme of water and electrolyte replacement. Oral hypotonic or hypertonic fluids should be restricted to 1 litre of hypotonic fluids and 1 litre of an electrolyte solution initially, increasing the restriction further if bowel/​stoma output remains high despite appropriate medical management. This is often difficult to achieve as patients commonly have an insatiable thirst, but con­ sumption of hypotonic fluids will lead to a net loss of water and so­ dium from the short bowel. For patients receiving enteral tube feeds, the sodium content can be increased by adding sodium chloride to achieve a sodium concentration of 90 to 100 mmol/​litre. Feeds with a high osmolality should also be avoided (e.g. elemental feeds). Stomal losses can be ameliorated with the use of proton pump inhibitors, H2 antagonists, loperamide, and codeine phosphate, limiting fluid intake, and drinking an electrolyte solution; taking food and drink separately can also help. Octreotide or its analogues can be used (but may increase the risk of gallstones and liver dys­ function) in patients with a particularly high output. Patients with an ileal remnant can occasionally benefit from fludrocortisone. In very high-​output states (>8 litres/​day), it is often necessary, in the initial 1 to 2 weeks, to restrict oral intake to sips of isotonic fluid (i.e. <200 ml per day) and administer nutritional support parenterally. Intravenous nutrition Following massive resection of the small bowel, the function of re­ maining intestine will be impaired due to the postoperative state, comorbidity such as sepsis, and it will not have had adequate time to start the process of adaptation. For these reasons, many patients will initially be rendered almost entirely dependent on parenteral nutritional support. Patients who are most likely to require paren­ teral support at this stage include those who are malnourished with little reserve, patients with a prolonged ileus, patients with a stomal Table 15.10.7.1  Management of a high-​output state Fluid intake Restrict hypo-​osmolar fluid Administer oral glucose-​saline solution Antimotility agents Loperamide Codeine phosphate Antisecretory agents Proton pump inhibitors Octreotide

section 15  Gastroenterological disorders 2914 output of more than 1.5 litres/​day, and patients with a short bowel (<100 cm to a jejunostomy or <50 cm to the colon). This can be started on the second or third postoperative day. Anatomy Having secured adequate nutritional support and sepsis control, attention can be refocused to establish the amount and nature of remaining intestine. This usually requires cross-​sectional imaging, contrast studies, and (sometimes) endoscopic examination to deter­ mine gut viability. Surgical procedures During the acute phase, only the most urgent surgery should be undertaken. Examples include the removal of dead gut or necrotic infected tissue that cannot be radiologically drained. Early recon­ structive surgery to bring the colon back into continuity with a je­ junal remnant should only be considered if conditions are ideal, which is rarely the case in the scenario of massive resection. Chronic phase Feeding and adaptation As the patient’s condition improves and becomes more stable, efforts should be made to minimize parenteral nutrition and maximize enteral and oral feeding to encourage intestinal adapta­ tion. Specific mixtures of electrolyte, sugar, and water which pro­ mote absorption can often be taken as drinks or given enterally (Table 15.10.7.2). Enteral tube feeding into stomach, jejunum, or via a mucus fistula into a portion of defunctioned distal intestine can be helpful from both the provision of nutrients and also to en­ courage intestinal adaptation. Hyperadaptation can be induced by the administration of ex­ ogenous growth factors such as GLP-​2 analogues. These were ini­ tially administered to patients who had already achieved an adapted steady state, but they are now being considered for use earlier in the adaptation process (Fig. 15.10.7.2). Nutritional requirements may reduce with time, due to adaptation, and overfeeding may occur if parenteral nutrition is not adjusted. Socialization The sudden loss of a large portion of the intestine is a cata­ strophic event with far reaching effects on patients’ social life and psychological well-​being. Psychological support is essential, and ef­ forts should be made to facilitate social contact. Education in self-​ directed care and patient engagement in clinical decision-​making are beneficial to long-​term outcome. Long-​term treatment plan After a period long enough to allow the maximum restoration of en­ teral nutrition, an assessment of the patient’s prognosis can be made. In some cases it may be immediately obvious that the intestinal remnant is too short to provide any prospect of independence from parenteral nutrition, but for others, increases in absorption due to adaptation can continue for about a year (Fig. 15.10.7.2). Bowel length measurements are taken from the duodenojejunal flexure. Patients may manage without parenteral nutrition if the jejunal remnant is longer than 50 cm with colon in continuity or greater than 100 cm to a jejunostomy. Isotonic electrolyte mixes (with a sodium concentration of about 100 mmol/​litre, approxi­ mating to the concentration in jejunostomy fluid) will be required according to the length and function of the remaining jejunum (Table 15.10.7.3). Patient involvement and education is vital to maximize the possibility of weaning from parenteral nutrition, and as with any chronic condition, assessment for psychiatric symp­ toms such as depression may be important. Gradual undernutrition (protein–​energy malnutrition) may occur during this period and can be insidious. Hypomagnesaemia Table 15.10.7.2  Electrolyte mixes commonly used in the United Kingdom Electrolyte solution Amount Measure Comments Concentration (mmol/​L) St Mark’s electrolyte solution Sodium bicarbonate 2.5 g 1 heaped 2.5-​ml spoonful Make up to 1 litre with water Flavourings are best added when it is being prepared Make up a fresh solution every day Keep chilled Na: 90 K: 0 Cl: 60 HCO3: 30 Glucose: 60 Glucose powder 20 g 6 level 5-​ml spoonfuls Sodium chloride 3.5 g 1 level 5-​ml spoonful Dioralyte solution (double usual strength) Sodium chloride 470 mg Amounts present in one sachet of Dioralyte Reconstitute 2 sachets with 200 ml of water (double usual strength) Make up a fresh solution every day Keep chilled Na: 120 K: 40 Cl: 120 Citrate: 20 Glucose: 180 Potassium chloride 300 mg Disodium hydrogen citrate 530 mg Glucose 3.56 g Early treatment Late treatment Hyperadaptation Accelerated adaptation Spontaneous adaptation Resection Bowel function 1 year 2 years 3 years Fig. 15.10.7.2  Intestinal adaptation following massive intestinal resection and the effects of early and late treatment with GLP-​2.

15.10.7  Effects of massive bowel resection 2915 is common and is treated with oral or intravenous magnesium supplements (intravenous: magnesium sulphate; oral: magnesium glycerophosphate or aspartate). Sodium depletion may require attention. Oral 1-​α-​hydroxycholecalciferol may be required for vitamin D deficiency. Bone health should be monitored and steps taken to prevent osteoporosis. Loss of the ileocaecal valve above residual colon and factors leading to small-​bowel stasis may result in small intestinal bacterial overgrowth. This may further impair nutrient absorption in general and is particularly associated with hypomagnesaemia and vitamin B12 deficiency. When long-​term parenteral nutrition is required, efforts should be made to provide this through a specialist centre. A dedicated single-​ lumen tunnelled intravenous feeding catheter should be placed with the tip situated at an appropriate high-​flow site (low superior vena cava or superior vena cava/​right atrial junction) to reduce the in­ cidence of line-​related venous thrombosis. Patients need rigorous training in line care if complications are to be avoided. Surgery Optimization of intestinal function Surgical restoration of intestinal continuity should be reconsidered when the patient is stable. This can enhance intestinal absorption and also encourage adaptation. Inclusion of the colon and/​or a seg­ ment of small intestine into the active digestive tract may greatly en­ hance fluid and electrolyte balance, which is often the most difficult element of intestinal function to restore. A few patients may be suitable for bowel lengthening proced­ ures: those with dilated intestinal remnants can be considered for procedures such as the STEP (serial transverse enteroplasty) and LILT-​Bianchi (longitudinal tailoring and lengthening) procedures, which should be performed only in highly specialized centres and after careful case selection. GLP-​2 analogues may be of use for those requiring minimal par­ enteral nutrition or only fluid and electrolytes, and can result in a significant reduction or removal of the need for intravenous sup­ port. Their current use is limited, but they have potential for more widespread application as clinical experience with them increases and costs fall. Treatment of small-​bowel bacterial overgrowth, which may com­ plicate short bowel, often leads to improved intestinal function. Transplantation Patients who have irreversible intestinal failure and complications of parenteral nutrition such as loss of venous access or intestinal failure-​associated liver disease may be candidates for intestinal trans­ plantation. Patient survival after isolated intestinal transplantation has greatly improved over the last 10 years and in well-​performing centres is now greater than 60% and in some centres greater than 85% at 5 years. The survival rate of patients undergoing multivisceral transplantation is lower, as in addition to the intestine, other organs such as the liver, pancreas, duodenum, and (often) stomach and kidney are transplanted in a cluster graft. Patients commonly have complex preoperative comorbidities and the operative procedure is much more complicated. The postoperative management of patients is particularly challenging and requires good cooperation between numerous medical and surgical specialists. Survival on parenteral nutrition remains better than after trans­ plantation in most centres, and is the best option for most patients. However, if the recent improvements in survival figures are sus­ tained at 10 years, transplantation will become a reasonable alter­ native to parenteral nutrition as the primary treatment for many patients during the next decade. Long-​term complications Colonic oxalate absorption is often increased due to malabsorbed fatty acids binding luminal calcium which would otherwise form insoluble calcium oxalate. Additionally, bile salt malabsorption in­ creases mucosal permeability to oxalate and bacterial degradation of oxalate is reduced. This may result in renal oxalate stones, which occur in about 25% of patients with jejunocolonic anastomosis. Strategies to avoid this include a low-​oxalate diet with restricted long-​chain triglycerides, and oral calcium supplements. Pigment gallstones are common (about 45% of patients with short small Table 15.10.7.3  Estimated long-​term fluid and nutritional supplements and common complications in patients with short bowel Jejunum-​colon Jejunostomy Length of remaining jejunum (cm): <50 Parenteral nutrition Parenteral nutrition and IV electrolyte solution <100 Oral/​enteral nutrition IV electrolyte solution ± parenteral nutrition <150 No supplement Nutritional supplement (oral/​enteral) and oral sodium/​glucose solutiona <200 No supplement Oral sodium/​glucose solutiona Renal calculi (calcium oxalate) 25% None Biliary calculi (pigment) 45% 45% d-​lactic acidosis Infrequent No Adaptation Yes No a Oral sodium/​glucose solutions are approximately iso-​osmolar. Note: estimates vary between individuals. Patients with jejunoileal anastomosis generally have fewer complications than jejunocolonic anastomosis. Patients with a high-​output enterocutaneous fistula can be considered in the same group as those with an end jejunostomy.

15.10.8 Malabsorption syndromes in the tropics 291

15.10.8 Malabsorption syndromes in the tropics 2916

section 15  Gastroenterological disorders 2916 intestine) and result from multiple factors, particularly stasis in the biliary tract due to low levels of gut hormones such as cholecysto­ kinin. d-​lactic acidosis occasionally occurs in patients with a short small intestine in continuity with colon. This is generated by colonic bacterial fermentation of malabsorbed carbohydrates, particularly mono-​ and oligosaccharides (Table 15.10.7.3). Patients requiring long-​term parenteral nutrition with a very short remaining intestinal remnant (<50 cm) are particularly likely to de­ velop intestinal failure-​associated liver disease. This usually presents as cholestatic liver disease, but it may be insidious and present late as cirrhosis. Recurrent sepsis promotes the condition, with the intra­ venous feeding line a common site. Osteoporosis is common in pa­ tients on parenteral nutrition and made more likely in the presence of liver disease and recurrent sepsis. FURTHER READING Carlson G (2001). Acute intestinal failure: surgical causes and manage­ ment. In: Nightingale J (ed) Intestinal failure, pp. 39–​49. Greenwich Medical Media Ltd, London. Jeejeebhoy KN (2008). The use of enteral nutrition in the adult with intestinal failure. In Langnas AN, et al. (eds) Intestinal failure: di- agnosis, management and transplantation, pp. 160–​66. Blackwell Publishing, Oxford. Middleton SJ, et al. (2011). Intestinal transplantation. In: Klein AK, Lewis CJ, Madsen LC (eds) Organ transplantation: a clinical guide, pp. 303–​11. Cambridge University Press, Cambridge. Nightingale J, et al. (2006). Guidelines for management of patients with a short bowel. Gut, 55 Suppl 4, iv1–​iv12. 15.10.8  Malabsorption syndromes in the tropics Vineet Ahuja and Govind K. Makharia ESSENTIALS Causes of secondary malabsorption that are most common in the tropics include (1) progressive wasting in people infected with HIV, which is known as ‘slim disease’; (2) various infections—​protozoal (e.g. Giardia lamblia, Cryptosporidium parvum), helminthic (e.g. Capillaria philippinensis, Strongyloides stercoralis), and bacterial (Mycobacterium tuberculosis); (3)  immunoproliferative small intestinal disease; and (4) hypolactasia. Coeliac disease and Crohn’s disease also occur. When patients with conditions that can cause secondary malabsorption are excluded, a group remains who have chronic diar- rhoea, malabsorption, and its nutritional sequelae. This primary or idiopathic malabsorption syndrome is called ‘tropical sprue’, which occurs against the background of tropical enteropathy (describing the fact that the morphology of the mucosa of normal gut is different in tropical preindustrialized countries from that in temperate-​zone industrialized countries). The aetiology of tropical sprue is not known: epidemiological data suggests an infective cause, but no causal agent has been identified. Presentation is typically with loose or watery stools lasting for several weeks or months, and with symptoms and signs of nutritional de- ficiency. Management involves symptomatic relief from diarrhoea, and correction of fluid and electrolyte abnormalities and nutritional deficiencies. Attempts at specific curative measures—​folic acid and tetracyclines—​are usually given for up to 6 months. Introduction Malabsorption in the tropics is considered an independent entity because of the distinctiveness of its causes as well as its public health significance in comparison to temperate areas. It comprises the primary malabsorption syndrome of tropical sprue, and various secondary causes, predominant of which are the protozoal, hel­ minthic, and mycobacterial infections that are much more prevalent in the tropics. The last two decades, however, have seen a decline in the incidence of tropical sprue and a perceptible shift towards cosmopolitization of the causes of chronic diarrhoea in the tropics. Generic descriptions of malabsorption syndrome in the tropics can be traced back to as early as 6 to 12 bc when in an Ayurvedic (Indian) medical treatise, ‘Charaka Samhita’, a condition charac­ terized by chronic diarrhoea was described as ‘Grahani Vyadhi’. In 1759, William Hillary published the first book in English on tropical diarrhoeal diseases and observed that these were more common in indigenous residents of Barbados than English settlers. William Twining gave the first accurate description of tropical sprue in 1818 from General Hospital, Kolkata, India. Manson in 1880 introduced the term ‘sprue’ for the wasting diarrhoeal illness common in the tropics. From 1962 onwards, investigators in Thailand, South India, Puerto Rico, Haiti, and Bangladesh noted a high incidence of malabsorption and histological evidence of chronic enteritis in asymptomatic ­apparently normal members of the native-​born population and coined the term tropical enteropathy. The mysticism associated with tropical enteropathy continues, and it has been renamed as ‘envir­ onmental enteropathy’ or ‘environmental enteric dysfunction’ in the last few years, suggesting that environmental factors are of more im­ portance than latitude or climate. Table 15.10.8.1 lists the various causes of malabsorption prevalent in the tropics. Noninfectious causes of tropical malabsorption Environmental (tropical) enteropathy Environmental enteropathy, previously known as ‘tropical enterop­ athy’, owes its origin to the finding of abnormal small intestinal mu­ cosal changes such as a decrease in the villous height, an increase in the crypt depth, and an increase in intraepithelial lymphocytes and lymphocytic infiltration of the lamina propria in adults from low-​ and middle-​income countries. Some of these individuals dem­ onstrate abnormal d-​xylose absorption, impaired fat and vitamin B12 absorption, and an increase in intestinal permeability. Despite these findings, many remain largely asymptomatic, revealing the

15.10.8  Malabsorption syndromes in the tropics 2917 subclinical nature of this enteropathy, the presence of which has been confirmed in infants as well as adults. Pathophysiology Environmental enteropathy is possibly an effect of repetitive ex­ posure to faeco–​oral contamination causing chronic mucosal im­ mune stimulation and resulting in morphological changes in the intestinal mucosa. The condition can be acquired and reversed: a 1971 study of United States of America Peace Corps volunteers posted in Pakistan showed that jejunal biopsies of some had villous blunting with chronic inflammation, along with abnormalities of carbohydrate malabsorption. Two to three years following migra­ tion back to the United States of America, there was a reversal of carbohydrate malabsorption and normalization of jejunal mucosal abnormalities in five of the volunteers who underwent jejunal bi­ opsy. Similarly, studies on asymptomatic Indian and Pakistani im­ migrants residing in New  York showed mucosal abnormalities within 2 years of migration and reversal of these abnormalities with an increased period of stay in the United States of America. Further evidence that these changes are environment dependent and not genetic was provided by a study from South India which showed that stillborn fetuses had normally elongated crypts, but enteropathic changes were demonstrated as early as 8 weeks after birth. A Zambian study noted jejunal mucosal abnormalities in 200 asymptomatic adults, with intestinal permeability changes that were more severe in lower than higher socioeconomic groups. Environmental enteropathy is absent in tropical locations such as Singapore and Qatar, which have a higher-​income population. Geographical variations have been shown in a large study involving asymptomatic adults from 14 countries across the world. Intestinal absorption and permeability aberrations were found in tropical ra­ ther than temperate countries, and there was a close correlation of the intestinal absorptive capacity of people in each country with national gross domestic product per capita, independent of cli­ mate, suggesting that socioeconomic factors may play a more significant role. Modifiable causes Environmental enteropathy has been linked to zinc deficiency; lack of proper water, sanitation, and hygiene (WASH) interven­ tions; and possibly altered gut microbiome. Zinc deficiency may be a consequence of impaired absorption and may be a poten­ tial driver of enteropathy through its effects on gut immunity and epithelial cell function. Faecal transplantation from malnourished Malawian children into germ-​free (gnotobiotic) mice resulted in the mice becoming malnourished, suggesting the importance of the microbiome. The presence of environmental enteropathy in developing countries has triggered public health problems of child­ hood stunting and anaemia, and is possibly the reason for the poor response to oral vaccines for polio and rotavirus. Tropical sprue Tropical sprue is an acquired intestinal malabsorption syndrome of unknown aetiology that affects residents and tourists of trop­ ical regions. It has been suggested that persistent infection may be responsible, hence it is also referred to as ‘postinfective tropical malabsorption’. European and American expatriate residents in the tropics were considered to be the primarily affected population until Baker and Mathan in South India suggested that the indigenous population was equally affected. Definition In 1970, Klipstein from Puerto Rico and Baker from Vellore, India, suggested that tropical sprue should be regarded as a syndrome which occurs among the indigenous population and visitors to cer­ tain tropical regions, and included in this syndrome would be all per­ sons who have malabsorption of two or more unrelated substances for which no aetiology can be ascertained. No single clinical mani­ festation or laboratory abnormality is diagnostic of tropical sprue. A present-​day working definition of tropical sprue includes (a)  compatible clinical presentation; (b)  demonstration of malabsorption of two or more unrelated substances; (c) abnormal small intestinal mucosal histology, which may be patchy; (d) exclu­ sion of other specific causes for malabsorption syndrome (except small intestinal bacterial overgrowth); and (e) response to treatment with folic acid and antibiotics such as tetracycline. Other terms used in this context have been ‘acute tropical sprue’ and ‘chronic tropical sprue’. Acute tropical sprue manifests as a rapid onset of diarrhoea and malabsorption and is observed either in expatriates visiting endemic areas or during epidemics in indi­ genous population. Chronic tropical sprue is an insidious onset of malabsorption symptoms seen in natives of sprue-​prone areas. Epidemiology Tropical sprue occurs in the warm and hot geographical regions located between the tropic of Cancer and the tropic of Capricorn Table 15.10.8.1  Causes of malabsorption in the tropics Noninfectious causes Infectious causes Tropical sprue Protozoal: Giardia intestinalis, Cryptosporidium parvum, cystoisosporiasis (Cystoisospora), Cyclospora cayetanensis, microsporidia (Enterocytozoon bieneusi and Encephalitozoon intestinalis) Coeliac disease Nematohelminthes: Strongyloides stercoralis, Capillaria philippinensis Small intestinal bacterial overgrowth Bacterial: Mycobacterium tuberculosis Crohn’s disease Viral: HIV enteropathy Immunoproliferative small intestinal disease (IPSID) Combined variable immunodeficiency disease (CVID) Idiopathic tropical pancreatitis Environmental enteropathy (also called tropical enteropathy)

section 15  Gastroenterological disorders 2918 on either side of the equator, but it has not been reported from all tropical countries. It is endemic in India, Puerto Rico, and Cuba; oc­ curs commonly in South and South-​East Asian countries including Myanmar, Sri Lanka, Vietnam, Indonesia, and the Philippines, and Middle-​East Asian countries; has been reported from Central American and South American countries such as Mexico, Venezuela, Colombia, Haiti, and the Dominican Republic; but it has not been reported from the tropical islands of Jamaica and Bahamas, or in most African countries. Tropical sprue occurs sporadically, although frequent epidemics have been reported. Household epidemics were recognized by Mathan from South India and Bahr in 1915, who described ‘sprue houses’ where successive tenants were attacked with sprue. Crombie described an epidemic of ‘Hill Diarrhea’ in Shimla in 1880, which possibly fitted the description of tropical sprue. Epidemic tropical sprue was reported following acute diarrhoea in prisoner of war camps, affecting both British and Indian soldiers in the Second World War, as well as from villages in South India. A documented study of an epidemic involving an estimated 100 000 people in 1961 in the North Arcot district in South India was done by Baker and Mathan. The highest incidence was ob­ served in the adults in the thirties to forties age group, with children showing a lower attack rate. An alarmingly high mortality rate of 40% was reported. Some cases remained symptomatic up to a year after disease onset. The public health importance of tropical sprue has decreased in recent years as epidemics of tropical sprue have not been reported since 1978. Improvements in WASH may be responsible for the de­ cline of sporadic cases. This has been documented in Puerto Rico, where studies by the United States of America army sprue team showed a decline in incidence from 7.4 to 0.3/​100 000 in the period 1953 to 1961. Similarly, a decline in the incidence from 2% in 1927 to 0.5% in 1957 has been reported from Cuba. Aetiology No single agent has been incriminated as causing tropical sprue. Most of the evidence suggests that it is caused either by enteric in­ fection or by poor nutrition, or a combination of both. Features favouring an infective aetiology include epidemic spread of the dis­ ease, intrafamilial spread, clustering in certain areas, acute onset of diarrhoeal illness, people affected in the first wave of an epidemic are not affected in the second wave, appearance of symptoms in vis­ itors to tropical areas within a few weeks to months, and response to antibiotics. Coliform toxin-​producing bacteria (Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae) have been isolated from the jejunum of patients with tropical sprue. Protozoa (Cryptosporidium parvum, Cystoisospora belli, Blastocystis homi- nis, and Cyclospora cayetanensis) have been identified in faecal samples and jejunal biopsies of patients with protracted diarrhoea in the tropics. Viral particles resembling orthomyxovirus and cor­ onaviruses (so-​called Grahani agents) have been demonstrated in the faeces of 90% of tropical sprue patients from South India, al­ though these viruses were also isolated from control subjects and children without diarrhoea. Tropical sprue in visitors to tropical countries may be due to persistent enteric infection with patho­ gens such as enteropathogenic E.  coli, Giardia intestinalis, or Cyclospora cayetanensis. Causative nutritional factors include protein malnutrition, folic acid deficiency, and high unsaturated fatty acid consumption. Folate deficiency has been suggested as it predisposes to bacterial over­ growth as well as impaired jejunal mucosal function. An experi­ mental study in a primate model of tropical sprue demonstrated development of symptoms within 2 months with a protein intake of 2%, as compared to 5 months in primates given a protein intake of 5%. Excessive dietary unsaturated fat may result in persistence of enteric bacterial contamination and has been suggested as a coaetiological agent in Puerto Rico and Haiti. Pathogenesis The hypothesized cascade of events leading to tropical sprue ­includes bacterial colonization, impaired small intestinal perme­ ability, ­alteration of gut immune responses, increased orocaecal transit time, unabsorbed fat triggering the ‘ileal brake’, bac­ terial overgrowth, and consequent mucosal inflammation and malabsorption in a self-​perpetuating cycle. Bacterial colonization causes altered enterocyte brush border integrity, disturbed mo­ tility, deconjugation of fatty acids, fatty acid malabsorption, and steatorrhoea. Ghoshal from Lucknow, India, has shown that in patients with tropical sprue, compared to controls, infusion of fat into the proximal small intestine inhibits antroduodenal motility, delays duodenocaecal transit time, and increases plasma levels of peptide tyrosine-​tyrosine and neurotensin. This leads to small-​bowel stasis, impaired small intestinal permeability and consequent bacterial overgrowth, resulting in passage of larger amounts of fluid into the colon, which should be compensated for by increased absorption. However, Ramakrishna from Vellore, India, has shown that colonic abnormality in tropical sprue prevents this compensatory mech­ anism, predisposing to occurrence of diarrhoea. The characteristic structural alteration of the intestine in tropical sprue includes involvement of both jejunum and ileum, as compared to sparing of the ileum in coeliac disease, and the predominance of involvement of the crypts is suggestive of an intestinal stem cell defect, rather than involvement of villi as seen in coeliac disease. Environmental enteropathy is not considered as a part of tropical sprue and the differences are shown in Table 15.10.8.2. Clinical features The temporal profile of symptoms in tropical sprue is an initial phase of acute or insidious onset of diarrhoea, with abdominal bloating, anorexia, and fatigue, which lingers on to the second phase of nu­ tritional deficiencies, and finally the third phase of severe anaemia. Adults are mostly affected, and a constellation of classic symptoms includes mild to severe chronic diarrhoea, pale, bulky, offensive odour stools suggestive of steatorrhoea, crampy abdominal pain, bloating, anorexia, and weakness. In some cases, malnutrition can occur even in the absence of diarrhoea. In visitors to tropical coun­ tries, acute diarrhoea associated with fever and malaise in the first week is the predominant symptom. Physical examination shows signs of nutritional deficiencies such as angular stomatitis, cheilitis, and glossitis due to vitamin B defi­ ciency; pallor due to folate and vitamin B12 deficiency causing meg­ aloblastic anaemia; peripheral oedema and hair changes secondary to hypoproteinaemia; hyperpigmentation of knuckles and buccal mucosa due to vitamin B12 deficiency causing increased melanin synthesis; and

15.10.8  Malabsorption syndromes in the tropics 2919 Table 15.10.8.2  Differences between tropical sprue and environmental (tropical) enteropathy Characteristics Tropical sprue Environmental (tropical) enteropathy Age group affected Mostly adults Adults as well as children Disease course Progressive course with occasional spontaneous remission Remission and relapses observed, depending on place of residence Symptoms and signs of malabsorption Present Absent or subclinical Tests of malabsorption Abnormal Abnormal in 50% of cases Small-​bowel histology Morphological alterations in the form of partial villous atrophy and chronic lymphocytic inflammation Morphological alterations in the form of partial villous atrophy and chronic lymphocytic inflammation Response to therapy Mostly a quick response, with normalization of intestinal function and morphological changes Response as seen in tropical sprue is not observed peripheral neuropathy. Folate deficiency is seen more often in India, while vitamin B12 deficiency predominates in some other places. A chronic malabsorption state may lead to deficiency of fat-​soluble vitamins (A, D, E, and K). Night blindness and corneal xerosis due to vitamin A deficiency may rarely occur. Uncommon manifestations include stupor and listlessness secondary to hypomagnesaemia and hypophosphataemia, and periodic paralysis due to hypokalaemia. The clinical course of tropical sprue is very variable: it can remit spontaneously or result in chronic malnutrition. Diagnosis and investigation The diagnostic steps involve demonstrating the presence of malabsorption and alterations in small-​bowel mucosal histology, and excluding secondary causes of malabsorption. Carbohydrate malabsorption (d-​xylose test—​although note the caveats expressed in Chapter 15.10.1), steatorrhoea (faecal fat test), and vitamin B12 and folate deficiency (decreased serum vitamin B12 and folate levels, and increased serum methylmalonic acid) should be checked for in every suspected case of tropical sprue. Two abnormal tests in an appropriate clinical context are consistent with a diagnosis of tropical sprue in the absence of other causes of malabsorption. In addition, investigations evaluating nutritional deficiencies should be performed to plan management. A confirmation of diagnosis is achieved by folate supplementation, which shows prompt resolution of clinical and laboratory abnormalities. An estimate of 5-​h urinary d-​xylose is made after administration of 5 g of d-​xylose and normal d-​xylose excretion is greater than 1.2 g at 5 h. Steatorrhoea is assessed by either the 24-​h faecal fat estima­ tion method of van de Kramer, or the more easily available test of the Sudan stain for fat globules in stool samples. Stool examinations for parasites should be performed. Other causes of malabsorption should be ruled out as outlined in Table 15.10.8.3. A contrast-​enhanced CT (enterography) scan of the abdomen will exclude abdominal lymphadenopathy and intestinal ulceroconstric­ tive lesions and is the preferred modality over small-​bowel barium series. Upper gastrointestinal endoscopy may show normal duodenal folds or scalloping of duodenal folds due to villous atrophy, and biopsy of distal duodenum should be taken. Partial villous atrophy is seen on mucosal biopsies. Normal duodenal crypt to villous ratio of 3:1 or 4:1 is reduced to 2: 1 or 1:1 (Figs. 15.10.8.1a and 15.10.8.1d–​15.10.8.1f). Villous fusion and an increase in lamina propria lymphocytes may also be seen. Management Treatment requires fluid and electrolyte supplementation, depending on the severity of diarrhoea, redressing nutritional de­ ficiencies, and a therapeutic trial with folate or a combination of antibiotics and folate. A  high-​calorie, high-​protein, and low-​fat diet, with restriction of long-​chain fatty acids, is advisable. Folic acid (10 mg daily) is given for a period of 6 months, and normalcy of appetite and weight gain has been observed within 2 weeks of its initiation. The addition of an antibiotic results in rapid re­ versal of intestinal histology and function. The standard antibac­ terial therapy consists of 1 g oral tetracycline given daily in divided doses, or 100 mg of oral doxycycline given twice daily, for a period of 4 to 8 weeks. In nonresponsive cases, antibiotics can be con­ tinued for a period of 6 months. Vitamin B12 supplementation, ini­ tially parenteral and thereafter oral, should be given if deficiency of vitamin B12 is documented. Coeliac disease Coeliac disease has been considered as a disease of temperate countries, but in the last decade it has been increasingly been rec­ ognized in tropical countries. Makharia from New Delhi, India, has shown a community prevalence of 1% in North India, which is akin to that in temperate countries. There is a remarkable overlap between clinical, haematological, and histological features in coeliac disease and tropical sprue. Complete villous atrophy occurs in coeliac disease and is not seen in tropical sprue (Figs. 15.10.8.1b and 15.10.8.1c). Tropical sprue is associated with a more prom­ inent eosinophilic infiltrate in the duodenum compared to coeliac disease. Crohn’s disease Malabsorption in Crohn’s disease is consequent to involvement of small intestine, small intestinal bacterial overgrowth secondary to stricturing disease, bile salt malabsorption due to terminal ileal involvement, short-​bowel syndrome due to repeated intestinal re­ section, and opportunistic enteric infections due to immunosup­ pressive medications. Traditionally, tropical regions have been considered as low-​prevalence areas for Crohn’s disease, but it is in­ creasingly being diagnosed. Phenotypically, there is an amazing re­ semblance between Crohn’s disease and intestinal tuberculosis, and differentiating one from the other is a perplexing challenge faced by physicians in these regions.

section 15  Gastroenterological disorders 2920 Primary immunodeficiency syndromes Common variable immunodeficiency is a genetic immune defect characterized by significantly decreased levels of IgG, IgA, and/​or IgM with poor or absent antibody production, with exclusion of other causes of hypogammaglobulinaemia. The main gastrointes­ tinal manifestation of common variable immunodeficiency is tran­ sient or persistent diarrhoea. Giardia lamblia is the most common offender; other infections include cytomegalovirus, Salmonella spp., Clostridium difficile, and Campylobacter jejuni. Endoscopic mucosal biopsies show nodular lymphoid hyperplasia and a characteristic ab­ sence of plasma cells, apart from villous blunting (Fig. 15.10.8.2d). Immunoproliferative small intestinal disease Immunoproliferative small intestinal disease (IPSID), while more commonly seen in the Mediterranean region, has also been reported from tropical countries. It is characterized by clonal proliferation of plasma cells in the small intestine that produce abnormal α heavy chain immunoglobulins, which is thought to be in response to chronic or recurrent enteric infections in childhood. Recently, IPSID was shown to be associated with Campylobacter jejuni infection. The disease is more common in the second and third decade of life. Diffuse involvement of intestinal mucosa leads to malabsorption, chronic diarrhoea, and abdominal pain. Clubbing of the fingers is often seen, and abdominal masses may be palpable. The diagnosis of IPSID should be suspected in patients with malabsorption who have abdominal pain and clubbing. Intestinal mucosal biopsies, which characteristically show dense cellular lymphoplasmacytic infiltrate in the lamina propria leading to ef­ facement of the crypts, confirm the diagnosis (Figs. 15.10.8.2a and 15.10.8.2b). High levels of α heavy chain in the jejunal fluid are seen. IPSID is a premalignant condition and progresses over a vari­ able time period to lymphoplasmacytic and immunoblastic lymphoma. All patients with IPSID should therefore undergo Table 15.10.8.3  Differentiating features of various causes of malabsorption in the tropics Differential diagnosis Differentiating features Coeliac disease • Coeliac serology will be positive in most cases • Duodenal histology—​complete villous atrophy may be seen in in coeliac disease, but not in tropical sprue • Gluten-​free diet—​response in coeliac disease Crohn’s disease • May have symptoms of bloody diarrhoea or recurrent partial bowel obstruction • CT abdomen may reveal evidence of stricturing or fistulizing disease • Colonoscopy may show colonic involvement Small intestinal bacterial overgrowth • Predisposing factors—​previous surgery, diabetes, scleroderma • No villous atrophy on duodenal biopsy Immunoproliferative small intestinal disease • Serum electrophoresis for α chain disease Tropical pancreatitis • Marked steatorrhoea and abdominal pain • Abdominal X-​ray—​pancreatic calcification • Ultrasonography—​ductal dilatation/​pancreatic atrophy Combined variable immunodeficiency • Past history of recurrent sinopulmonary infection • Serum immunoglobulin profile HIV enteropathy • HIV positive • Duodenal biopsy may show similar changes to those in tropical sprue Intestinal tuberculosis • Symptoms of partial bowel recurrent obstruction may be present • Tissue biopsy positive for acid-​fast bacilli stain and/​or culture • Caseating granulomas on tissue biopsy • Colon may be involved • Concomitant pulmonary tuberculosis may be present Giardiasis • Three stool specimens on 3 separate days for cysts and trophozoites • Faecal immunoassays Cryptosporidiosis • Multiple stool specimens for modified acid-​fast staining, direct fluorescent antibody (DFA) • Faecal enzyme immunoassays for detection of Cryptosporidium spp. antigens Cystoisosporiasis • Multiple stool specimens for modified acid-​fast staining Cyclospora • Multiple stool specimens for modified acid-​fast staining • Autofluorescent oocysts—​stool containing the parasite is viewed under an ultraviolet fluorescence microscope and the parasite appears blue or green against a black background Enterocytozoon bieneusi and Encephalitozoon intestinalis • Faecal smears stained with ‘quick-​hot gram chromotrope’ technique and viewed under light microscopy for spores • Immunofluorescent (IFA) assays Leishmaniasis • Serological tests • Bone marrow aspiration • Demonstration of amastigotes on duodenal biopsy Strongyloidiasis • Microscopic identification of larvae (rhabditiform and occasionally filariform) in the stool or duodenal fluid Capillariasis • Demonstration of eggs, larvae, and/​or adult worms in the stool or in intestinal biopsies.

15.10.8  Malabsorption syndromes in the tropics 2921 (a) (b) (c) (d) (e) (f) Fig. 15.10.8.1  Photomicrographs showing (a) normally oriented duodenal biopsy with a crypt-​to-​villous ratio of 1:3 (×100); (b) mild villous flattening (×100) and (c) marked villous flattening (×100) with hyperplastic crypts (arrows) are noted in coeliac disease; (d) duodenal biopsy in tropical sprue showing altered crypt-​to-​villous ratio and hyperplastic crypts (×100); (e) increased intraepithelial lymphocytes (arrows) (×200) and (f) macrocytosis of the epithelial cell nuclei (arrow) are also seen (×200). (a) (b) (c) (d) Fig. 15.10.8.2  (a, b) Duodenal biopsy in IPSID shows shorted and broadened villi with dense infiltrate of IgA-​positive plasma cells (arrow) in the lamina propria ((a) ×100; (b) ×100)); (c) giardia trophozoites (arrow) noted in a duodenal biopsy (×200); and (d) duodenal biopsy with shortened villi and large reactive lymphoid follicles (arrows) in the lamina propria in a case of combined variable immune deficiency (×40).

section 15  Gastroenterological disorders 2922 staging of the disease using laparoscopy or laparotomy prior to therapy. Patients with early disease can be treated with anti­ biotics such as tetracycline for a prolonged period (at least 1 year). Chemotherapy is recommended, together with antibiotics, for patients with advanced disease. Idiopathic tropical chronic pancreatitis A distinct nonalcoholic type of chronic pancreatitis of uncertain aetiology has been described exclusively from tropical areas, and this has been termed tropical chronic pancreatitis. Its prevalence is decreasing, and the idiopathic chronic pancreatitis as seen in Western countries is being recognized increasingly in tropical re­ gions. Classical features of tropical chronic pancreatitis are younger age at onset, large intraductal pancreatic calculi, accelerated dis­ ease course with steatorrhoea and insulin requiring diabetes, and a high susceptibility to pancreatic cancer. The recognized triad of tropical pancreatitis is presence of abdominal pain, steatorrhoea, and diabetes. Overt steatorrhoea is seen in approximately 20% of the patients and treated with low-​fat diet and pancreatic enzyme re­ placement therapy. Infectious causes of tropical malabsorption Protozoa Giardia intestinalis, Cryptosporidium parvum, cystoisosporiasis (Cystoisospora belli), Cyclospora cayetanensis, and the microsporidia (Enterocytozoon bieneusi and Encephalitozoon intestinalis) are common causes of prolonged diarrhoea and malabsorption. Giardia is a major cause of diarrhoea in children and in travellers. Malabsorption in giardiasis is due to diffuse shortening of microvilli, disruption of epithelial tight junctions, increased intestinal permeability, and deconjugation of bile salts. Severe, persistent, or recurrent giardiasis should lead to suspicion of asso­ ciated IgA deficiency. Giardia cysts can be observed in fresh smears (Fig. 15.10.8.3a), on formalin-​ethyl acetate, or permanent stained smear (Fig. 15.10.8.2c). Detection rates can be increased by testing for giardia antigen in stool. Modified acid-​fast stain of stool is used to demonstrate oocysts of cryptosporidia, cytoisospora, and cyclospora (Figs. 15.10.8.3b–​ 15.10.8.3d). In addition, the use of an enzyme immunoassay on stool specimens increases sensitivity and specificity of detection of cryptosporidia. Microscopic demonstration of large, typic­ ally shaped oocysts is the basis for diagnosis of cystoisosporiasis. Cyclospora oocysts stained by trichrome or modified acid-​fast stain are seen as refractile spheres with a central morula, resembling wrinkled cellophane. Microsporidial spores in stool are diagnosed by immunofluorescent assays or a recently developed ‘quick-​hot gram chromotrope’ staining technique (Fig. 15.10.8.3e). Table 15.10.8.4 shows the agents used to treat infectious causes of malabsorption. Nemathelminthes Strongyloides stercoralis can cause anaemia, chronic diarrhoea, and protein-​losing enteropathy. Hyperinfection occurs in the malnourished, patients on corticosteroids, and in those with coinfection with human T-​cell lymphotropic virus type 1. Multiple stool samples should be tested as the sensitivity of widely used diagnostic procedures, such as direct faecal smear, Baermann technique, and Koga agar plate culture is not satisfactory when (e) (f) (a) (b) (c) (d) Fig. 15.10.8.3  (a) Wet mount showing trophozoite of Giardia intestinalis; (b) modified acid-​fast (MAF) staining showing oocysts of Cryptosporidium parvum (size: 4–​6 µm); (c) MAF staining showing oocysts of Cyclospora cayetanensis (size: 8–​10 µm); (d) MAF staining showing oocysts of Cystoisospora belli (size: 20–​30 × 10 to 15 µm); (e) modified trichrome staining showing spores of microsporidia (size: 1–​2 µm); and (f) wet mount showing larva of Strongyloides stercoralis.

15.10.8  Malabsorption syndromes in the tropics 2923 used on a single stool specimen (Fig. 15.10.8.3f). Serology is a useful tool but has a low specificity. Intestinal capillariasis caused by Capillaria philippinensis is a common cause of malabsorption in South East Asia, chiefly Thailand and the Philippines. Patients present with chronic watery diarrhoea, steatorrhoea, chronic abdominal pain, and protein-​ losing enteropathy. It typically involves long segments of jejunum or ileum. Diagnosis is made either on stool examination, or from tissue obtained from jejunum or ileum by enteroscopy. Bacteria Intestinal tuberculosis caused by Mycobacterium tuberculosis can in­ volve any part of the gut and most commonly involves the ileocaecal area as an ulcerative or ulcerohypertrophic form. It can present as chronic diarrhoea, partial recurrent intestinal obstruction, or pro­ tein-​losing enteropathy. Loss of absorptive surface due to diffuse ulceration, bacterial overgrowth secondary to stricture formation, bile salt deconjugation, bile salt diarrhoea due to terminal ileal dis­ ease, and lymphatic obstruction are causes of malabsorption. In one study, biochemical evidence of malabsorption was found in 75% of patients with intestinal tuberculosis with intestinal obstruction, but in only 40% of patients without obstruction. The diagnosis is established by cross-​sectional imaging, small-​bowel or large-​bowel endoscopy, tissue biopsy, and acid-​fast bacilli stain and culture. Antitubercular therapy for 6 months is usually sufficient for treating the infection. Viruses HIV enteropathy can cause chronic diarrhoea and malabsorption in patients with AIDS, even in the absence of demonstrable opportunistic pathogen infection. Intestinal CD4 cells are preferen­ tially destroyed in HIV infection. Changing scenario of malabsorption syndrome in the tropics Until 10 years ago, tropical sprue was a leading cause of malabsorption in tropical countries. Socioeconomic improvement, better sanita­ tion, hygiene, and a decrease in water-​borne diseases in recent years have led to a decline in its incidence. Coeliac disease was initially thought to be a rare or uncommon disease in tropical countries, but it is now increasingly recognized in many tropical countries, including India. This may be because of the widespread diffusion of Western dietary habits, thus increasing consumption of gluten-​ containing cereals. Approach to a patient with malabsorption syndrome After routine clinical, haematological, and biochemical evaluation, tests for confirmation of malabsorption (d-​xylose, faecal fat esti­ mation, vitamin B12, folate, and serum methylmalonate) should be performed. The first line of investigation includes stool microscopy for parasites and ova, serological tests for HIV and coeliac disease, endoscopic examination, and duodenal biopsies. The next step is to check serum immunoglobulin levels, thyroid profile, glucose hydrogen breath test for bacterial overgrowth, and CT enterography (Fig. 15.10.8.4). Table 15.10.8.4  Therapeutic choices for infective causes of malabsorption Infective cause of malabsorption Therapy Giardia intestinalis Metronidazole 250–​400 mg three times daily orally for 5 days Or tinidazole 2 g single dose orally Or nitazoxanide 500 mg twice daily orally for 3 days Or albendazole 400 mg once daily orally for 5 days Cryptosporidium parvum Nitazoxanide 500 mg twice daily orally for 3 days Cystoisosporiasis (Cystoisospora) Trimethoprim/​sulfamethoxazole 160 mg/​800 mg two times daily orally for 10 days Immunocompromised patients: Trimethoprim/sulfamethoxazole 160 mg/800 mg four times daily orally for 10 days, followed by maintenance therapy 160 mg/​800 mg twice daily for 3 weeks Cyclospora cayetanensis Trimethoprim/​sulfamethoxazole 160 mg/​800 mg twice daily orally for 7 days Or ciprofloxacin 500 mg twice a day orally for 7 days Followed by maintenance therapy in patients with HIV: trimethoprim/​sulfamethoxazole 160/​ 800 mg three times a week for 10 weeks Or ciprofloxacin 500 mg three times a week for 10 weeks Enterocytozoon bieneusi Fumagillin 20 mg three times daily for 2 weeks Encephalitozoon intestinalis Albendazole 400 mg twice daily for 3 weeks Strongyloides stercoralis Ivermectin 200 μg/​kg single dose orally for 2 days May be extended to 5–​7 days in disseminated infection Capillaria philippinensis Albendazole 200 mg twice daily orally for 10 days Or mebendazole 200 mg twice daily orally for 20 days Mycobacterium tuberculosis Isoniazid, rifampicin, pyrazinamide, ethambutol for 2 months Followed by: Isoniazid and rifampicin for 4 months HIV enteropathy Antiretroviral therapy

section 15  Gastroenterological disorders 2924 FURTHER READING Baker SJ, Mathan VI (1971). Tropical sprue in Southern India. In: Wellcome Trust (ed) Tropical sprue and megaloblastic anemia, pp. 189–​260. Churchill Livingstone, Edinburgh. Brown IS, et al. (2014). Tropical sprue: revisiting an underrecognized disease. Am J Surg Pathol, 38, 666–​72. Cook GC (1984). Aetiology and pathogenesis of postinfective tropical malabsorption (tropical sprue). Lancet, 31, 721–​3. Ghoshal UC, et  al. (2003). Tropical sprue is associated with con­ tamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time. J Gastroenterol Hepatol, 18, 540–​7. Ghoshal UC, et al. (2014). Tropical sprue in 2014: the new face of an old disease. Curr Gastroenterol Rep, 16, 391. Ghoshal UC, Gwee KA (2017). Post-infectious IBS, tropical sprue and small intestinal bacterial overgrowth: the missing link. Nat Rev Gastroenterol Hepatol, 14, 435–41. Gorbach SL, et al. (1969). Bacterial contamination of the upper small bowel in tropical sprue. Lancet, 1, 74–​7. Klipstein FA, Baker SJ (1970). Regarding the definition of tropical sprue. Gastroenterology, 58, 717–​21. Klipstein FA, Samloff IM, Schenk EA (1966). Tropical sprue in Haiti. Ann Intern Med, 64, 575–​94. Korpe PS, Petri WA Jr (2012). Environmental enteropathy: critical implications of a poorly understood condition. Trends Mol Med, 18, 328–​36. Makharia GK, et al. (2014). Issues associated with the emergence of coeliac disease in the Asia–​Pacific region: a working party report of the World Gastroenterology Organization and the Asian Pacific Association of Gastroenterology. J Gastroenterol Hepatol, 29, 666–​77. Mathan VI, Baker SJ (1968). Epidemic tropical sprue and other epi­ demics of diarrhea in South Indian villages. Am J Clin Nutr, 21, 1077–​87. Ramakrishna BS, Mathan VI (1982). Water and electrolyte absorption by the colon in tropical sprue. Gut, 23, 843–​6. Sharma P, et al. (2019). Clinical, endoscopic, and histological differ­ entiation between celiac disease and tropical sprue: a systematic ­review. J Gastroenterol Hepatol, 34, 74–83. Fig. 15.10.8.4  An algorithmic approach to investigation of malabsorption in the tropics.

15.11 Crohn’s disease 2925

15.11 Crohn’s disease 2925

15.11 Crohn’s disease Miles Parkes and Tim Raine ESSENTIALS Crohn’s disease is a common form of chronic inflammatory bowel disease. Typically involving one or more of the terminal ileum, colon, and perineum, it causes patchy transmural inflammation character- ized microscopically by granulomata. Common complications in- clude fibrotic strictures, fistulas, and abscesses. The initiating trigger is unknown, but an unregulated mucosal immune response to commensal bacteria drives the chronic in- flammation. Variants in several genes involved in innate immunity are strongly associated, with NOD2, interleukin-​23, and autophagy pathways all implicated. Smoking also increases the risk. With a pattern of episodic flares, which are unpredictable in their timing and severity, Crohn’s disease confers significant morbidity but low mortality. Treatment of acute inflammatory disease is usually with cortico- steroids or (occasionally) therapeutic diets, the latter particularly in children. For steroid dependence, frequent relapse, or objective evi- dence of uncontrolled mucosal inflammation, immunosuppression is indicated with immunomodulator or biological therapy or a com- bination of the two. First-​line immunomodulators are azathioprine or 6-​mercaptopurine, with methotrexate used as second-​line therapy. Antitumour necrosis factor-​α (anti-​TNFα) antibody therapy can induce rapid remission of resistant disease and has a key role in maintaining remission in such cases. Newer monoclonal antibodies with a role in disease management include antibodies to IL12/23 and to integrins associated with intestinal lymphocyte trafficking. Despite increased use of immunosuppressants, 70 to 80% of patients require surgery in the long term, most commonly for ileal stricturing. Timely, conservative surgery is the key, minimizing the length of small-​bowel resected and using laparoscopic approaches where possible. For colonic disease requiring surgery, segmental col- ectomy or subtotal colectomy with ileorectal anastomosis are pre- ferred, but significant rectal or perianal involvement may require proctocolectomy and ileostomy. Perianal Crohn’s disease is treated medically with antibiotics, azathioprine, and anti-​TNF antibody therapy, and surgically with ab- scess drainage and placement of seton sutures through fistulas where possible. Some fistulas heal with intensive medical therapy. Others may warrant attempts at surgical repair if they produce unacceptable symptoms but success rates are not high. Introduction and history Crohn’s disease is a form of chronic, relapsing inflammatory bowel disease characterized by discontinuous segments of transmural in- flammation. It can affect any part of the gastrointestinal tract but most commonly involves the terminal ileum, colon, and perineum. The eponymous term ‘Crohn’s disease’ derives from the index de- scription of chronic ileal inflammation in young people in 1932 by Crohn, Ginzburg, and Oppenheimer. However, many much earlier reports describe what would now be called Crohn’s disease. Colonic Crohn’s disease was formally differentiated from ulcerative colitis by Lockhart-​Mummery and Morson in 1960, although recent gen- etic studies suggest, perhaps unsurprisingly, that they are closely related. Aetiology Precise pathogenic mechanisms are unknown, but Crohn’s disease evidently results from a complex interplay of genetic and envir- onmental factors producing an excessive, unregulated inflamma- tory response to luminal microflora in susceptible individuals. The trigger has not been identified. Susceptibility to the initial trigger may result from a defective mu- cosal barrier: either increased intestinal permeability, allowing lu- minal antigens to access the mucosal immune system, or aberrant innate immunity, which would increase risk of microbial invasion. Evidence from genetic studies increasingly implicates the latter in Crohn’s disease, the former perhaps being more relevant in ulcera- tive colitis. There may also be a primary contribution of microbial dysbiosis. Early failure to control microbial ingress leads to activa- tion of alternative, adaptive immune pathways mediated by CD4+ T cells. In Crohn’s disease, these are predominantly Th1 and Th17 cells, secreting signature cytokines interferon (IFN)-​γ/​interleukin (IL)-​2 and IL-​17 respectively, with tumour necrosis factor (TNF)-​α and IL-​ 23 also being critical mediators. Environmental factors The clearest environmental association is with smoking, which more than doubles the risk of developing Crohn’s disease while being protective against ulcerative colitis. The mechanism is unclear.

section 15  Gastroenterological disorders 2926 Use of nonsteroidal anti-​inflammatory drugs (NSAIDs) and the oral contraceptive pill are also associated, the former perhaps by increasing intestinal permeability—​well recognized to precede flares of Crohn’s disease. Interestingly, 10% of healthy first-​degree relatives of Crohn’s disease patients have increased intestinal perme- ability, suggesting a heritable basis. Many patients are concerned about dietary precipitants for Crohn’s disease. Excess refined sugar and lack of fibre have been noted in retrospective studies, but may reflect dietary accommoda- tion to early symptoms. Response to therapeutic diets also suggests food antigens are important but no single foodstuff is consistently associated. Microbiological determinants represent obvious potential trig- gers, and self-​limiting infections such as yersinia do precede Crohn’s disease in some instances. More contentiously, specific chronic in- fections might cause the persisting inflammation. Advocates of Mycobacteria paratuberculosis, which causes the granulomatous in- testinal inflammation of Johne’s disease in cattle, highlight detection of its DNA in Crohn’s ulceration in limited, poorly controlled studies. Furthermore, recent genetic studies have highlighted substantial overlap between Crohn’s disease susceptibility genes and those for leprosy and Mendelian susceptibility to mycobacterial disease. However, epidemiological evidence shows no clustering of Crohn’s disease in livestock farmers, and antituberculous therapy is not ef- fective in unselected patients with Crohn’s disease. The contribution of mycobacteria to disease aetiology thus remains speculative. A role for commensal bacteria appears more secure, particularly in perpetuating intestinal inflammation after the initial trigger. In nearly all murine models, intestinal inflammation is markedly at- tenuated in the absence of commensal flora or upon antibiotic treat- ment. Conversely, in some models, inflammation appears to be transmissible from genetically susceptible mice to wild-​type litter mate controls through cohousing and the sharing of dysbiotic flora. Clinical evidence comes from attenuation of Crohn’s disease in- flammation following diversion of the faecal stream with ileostomy. Commensal strains implicated include bacteroides and adherent invasive Escherichia coli, while others confer protection, including Faecalibacterium prausnitzii and ‘probiotic’ strains of lactobacilli and bifidobacter. Recent data have highlighted a potential role for viruses, with notable bacteriophage expansion in inflammatory bowel disease perhaps accounting for the loss of bacterial diversity that is a consistent feature. Disentangling cause–​effect relationships remains a challenge. Genetic determinants Although environmental influences are clearly important, it is gen- etic studies that have made most progress over the last decade. Each child of a Crohn’s disease-​affected individual has a 2 to 4% risk of developing Crohn’s disease, rising to approximately 30% where both parents are affected. The effect sizes for most confirmed sus- ceptibility genes are modest but they highlight critical molecular pathways predisposing to Crohn’s disease. A major theme that has emerged is the importance of the early host immune response to bacterial ingress—​particularly innate immunity. NOD2, the first Crohn’s disease gene identified, encodes an intra- cellular receptor for bacterial muramyl dipeptide. Upon ligand binding, NOD2 activates a range of downstream partners including NF-​κB (a transcription factor for several proinflammatory cytokines), caspase-​1 (which releases the active, proinflammatory form of IL-​1β), and mediators of autophagy (see later in this section). For NOD2 het- erozygotes, the risk of Crohn’s disease is doubled compared to wild type, while homozygotes have a 17-​fold increased risk. Interestingly there is significant heterogeneity, both for disease (NOD2 variants are specifically associated with ileal Crohn’s disease) and ethnicity (no NOD2 coding mutations are found in Japanese patients). Other signals identified by genome-​wide association scans in Crohn’s disease converge on two other key immune pathways. One is the activation of naive CD4+ T cells by IL-​23. Confirmed association with variants in genes for the IL-​23 receptor and IL-​12B (which en- codes a subunit common to IL-​12 and IL-​23) among other compo- nents of this pathway strongly corroborates functional experiments in mouse models, which also implicate IL-​23 in chronic intestinal inflammation. Another key component is autophagy. Replicated association at two separate genes, ATG16L1 and IRGM, first highlighted autophagy—​and NOD2 mutations are now known to disrupt this previously unsuspected pathway. Autophagy is the mechanism by which cells engulf, compartmentalize, and digest cytoplasmic debris and intracellular bacteria. Its disruption permits prolonged survival of several intracellular microorganisms—​perhaps important for the intracellular bacteria postulated to play a role in Crohn’s disease pathogenesis, including adherent invasive E. coli. The main disease-​associated polymorphisms in NOD2, IL23R, and ATG16L1 are coding variants associated with hypofunction. For most genetic signals identified by genome-​wide association studies in Crohn’s disease, which lie in nonprotein-​coding regions of the genome, aetiological understanding is at a more rudimentary stage, with presumed effects through changes in regulatory mechan- isms for gene expression. In which cells these genetic abnormalities have an effect remain unknown, but candidates include intestinal macrophages, dendritic cells, T cells, and epithelial cells. Indeed, it seems that the clinical phenotypes of Crohn’s disease may represent a final common pathway of immune-​mediated end-​organ damage resulting from not one but several potential underlying pathologies, including failure of epithelial barrier function, innate immune de- fects resulting in susceptibility to intracellular infection, inappro- priate activation of an adaptive immune response to commensal flora, and failure of immune regulation. Pathology Crohn’s disease can affect any part of the gastrointestinal tract but most commonly causes ileocaecal (40%), exclusively ileal (30%), or exclusively colonic (25%) inflammation with or without perianal in- volvement (25%). Diffuse small-​bowel, upper gut, or oral Crohn’s dis- ease are less frequent. Colonic disease often spares the rectum. These patterns typically remain stable in any given patient over time. Ulcers are usually present, with appearances varying from small aphthous lesions overlying lymphoid aggregates to scattered punched-​out, serpiginous, longitudinal, or pleomorphic ulcers (see Fig. 15.11.2). Inflammation is patchy, giving rise to ‘skip lesions’, and transmural—​ manifest as deep ulceration and cobblestoning endoscopically, and fat wrapping on cross-sectional imaging or at surgery. The bowel wall is usually thickened, often producing luminal stenosis, and the mes- entery oedematous with regional lymph node enlargement.

15.11  Crohn’s disease 2927 Histologically, Crohn’s disease is characterized by a patchy chronic transmural inflammatory infiltrate, maximal in the submucosa and lamina propria. This consists of lymphocytes, characteristically or- ganized as lymphoid aggregates, macrophages, and plasma cells. Acutely, neutrophils infiltrate around crypts producing cryptitis. Fissuring ulcers can penetrate deeply, sometimes to the serosal sur- face to produce fistulas, and noncaseating epithelioid granulomata formed from macrophages and giant cells may be found at any level in up to 60% of cases (Fig. 15.11.1). Typically in the colon there is preservation of goblet cell numbers and crypt architecture com- pared to ulcerative colitis. Epidemiology Crohn’s disease can affect people of any age but peak incidence oc- curs in early adulthood, with a smaller peak in the seventh decade. There is a marginal predominance in women and 15% of patients have an affected relative. Crude annual incidence in Western coun- tries ranges from 2 to 20 per 100 000, with a north–​south gradient (higher in the north) across Europe and North America. Incidence is highest in Ashkenazi Jews and low in Asia (0.5 per 100 000). The incidence and prevalence of Crohn’s disease appears to be rising in nearly all populations. This is especially apparent in non-​ Western societies, perhaps reflecting adoption of ‘Western’ lifestyles. Increased awareness and improved diagnostics have undoubtedly also contributed. Estimates of Crohn’s disease prevalence also vary significantly, in part according to ascertainment method. Population-​ and primary care-​based surveys in the United Kingdom put the prevalence as high as 140 to 210 per 100 000, while studies in secondary/​tertiary care are lower at 70 to 100 per 100 000. Either figure indicates that the burden of disease is substantial in terms of both morbidity and cost. Estimates of direct healthcare costs vary widely and are sig- nificantly impacted by country and disease severity, but recent ana- lyses suggest an average figure of £2000 to £4500/​patient-​year for Crohn’s disease. Clinical features The clinical presentation of Crohn’s disease varies from ‘classical’ to diagnostically challenging and nonspecific. Cardinal symptoms are the combination of abdominal pain, weight loss, and diarrhoea. With severe disease, patients may have systemic upset, with fever, tachycardia, and anaemia. More often, however, a modestly raised C-​reactive protein (CRP) and vague or irritable-​bowel-​like symp- toms may be the only clues mandating further investigation. Many patients report remitting and relapsing symptoms for months or years before the diagnosis is made. A family history of inflammatory bowel disease and smoking history should be sought. For patients with established disease, the Harvey–​Bradshaw index provides a simple assessment of activity, while the Crohn’s disease activity index requires symptom diaries plus laboratory data. In both cases, subjective elements may capture noninflammatory symptoms, leading to significant limitations. The Inflammatory Bowel Disease Questionnaire (IBDQ) is the best validated quality of life tool. Symptoms Symptoms are significantly determined by the site of intestinal inflammation and typically include lower abdominal pain, diar- rhoea, anorexia, and weight loss. Tiredness, malaise, sweats, and extraintestinal manifestations can be prominent. Abdominal pain reflects gut wall ulceration and mesenteric oe- dema, and often localizes to the right iliac fossa with ileocaecal disease. It may be constant, reflecting the presence of deep ulcer- ation, or colicky, exacerbated by eating and associated with other obstructive features such as vomiting or bloating as a consequence of luminal stricturing. Abdominal pain due to coincident gallstones or renal stones, both associated with Crohn’s disease, can cause confusion. Weight loss is common with active Crohn’s disease, particu- larly involving the small bowel, so patients should be weighed at each clinic visit. Contributory factors include food avoidance due to abdominal pain or mouth ulceration, intestinal protein loss, ca- tabolism induced by inflammation or sepsis, and malabsorption re- flecting the combination of diffuse small-​bowel disease, resection, and bacterial overgrowth. Most patients experience diarrhoea. Bowel frequency correlates with inflammatory activity, particularly in the colon, with bacterial overgrowth and ileal resection potentially contributing. Bleeding per rectum is less common than in ulcerative colitis, as is urgency—​ unless the rectum is involved or the anal sphincter damaged. An important point: many Crohn’s disease patients consider three to four semisolid bowel evacuations per day to be ‘normal’ and it is the change from baseline, including nocturnal frequency, which is im- portant in assessing disease activity. Perianal symptoms will occur in around 40%. Perianal pain may indicate an abscess or fissure formation, fistula discharge is common, and anal stricture may produce constipation or tenesmus. Fig. 15.11.1  Crohn’s disease affecting large bowel, showing fissuring ulceration (narrow arrow) and transmural inflammation with a ‘Crohn’s rosary’—​lymphoid aggregates studded along the outer border of the muscularis propria (broad arrow). Courtesy of Dr Vicki Save, Addenbrooke’s Hospital, Cambridge.

section 15  Gastroenterological disorders 2928 Fistulizing Crohn’s disease, with or without intra-​abdominal or pelvic abscess, is seen in around 40% of patients. It can be the presenting feature or evolve as a result of uncontrolled transmural inflammation. Typical fistulae include enteroenteric (often de- tected only on imaging, but may be associated with a mesenteric abscess), enterovesical (associated with pneumaturia and recurrent urinary tract infections), and rectovaginal. Perianal fistulae are more common than internal fistulae. Fertility is reduced in women with Crohn’s disease, and the miscarriage rate is higher, particularly with active disease during pregnancy. Signs Many patients with active Crohn’s disease appear deceptively well. A minority are anaemic or malnourished. A persisting tachycardia may point to dehydration, severe inflammation, or sepsis. The oral cavity should be inspected for ulceration and glossitis. The com- monest abnormal examination finding is right iliac fossa tenderness, often with associated fullness or a mass due to thickened and matted bowel loops. Equivalent findings may be found over any affected bowel segment. Anorectal examination may reveal various signs from violaceous fleshy or ‘woody’ skin tags to anal fissure, ulcer, abscess, and fistulae. Anal stenosis may be detected. Signs related to specific complications may be evident—​for ex- ample, fever and tachycardia with intra-​abdominal collection, dis- tension and high-​pitched bowel sounds with obstruction, and so on. Extraintestinal manifestations Extraintestinal manifestations of Crohn’s disease commonly affect the mouth, joints, skin, and eyes, and less commonly the liver and lungs. These are more frequent with colonic involvement and may precede intestinal symptoms. Oropharynx Aphthous ulcers are usually associated with active intestinal inflam- mation. These should be distinguished from haematinic deficiency (glossitis, angular cheilitis), oral candida, and (particularly) oropha- ryngeal Crohn’s disease, which usually causes fissuring and thick- ening of the lips but can present with deep sulcal ulceration and buccal cobblestoning. There is overlap with orofacial granulomatosis where 60% have asymptomatic intestinal lesions of Crohn’s disease. Both oral Crohn’s disease and orofacial granulomatosis can be successfully treated with a low-​benzoate, low-​cinnamon diet or topical steroids. Joints Involvement is seen in 10 to 20% of Crohn’s disease patients. This ranges from arthralgia to inflammatory arthritis (including anky- losing spondylitis). Inflammatory arthritis can be an asymmetric large-​joint arthropathy with pain and effusions prominent during flares of inflammatory bowel disease, or a symmetrical small-​joint arthropathy. Each has distinct genetic associations. Use of NSAIDs should be minimized as they increase gut permeability and can trigger a Crohn’s disease flare. Skin Eczema and psoriasis often flare with active Crohn’s disease, but the most common specific dermatological manifestation is erythema nodosum. Usually found at initial presentation, it settles with reso- lution of bowel inflammation and rarely recurs. Psoriasiform derma- toses have been reported with anti-​TNF treatment, necessitating drug withdrawal. An important but rare complication is pyoderma gangrenosum, a neutrophilic dermatosis. This is characterized by one or more painful, raised lesions, typically with a violaceous border. Treatment is with systemic corticosteroids or ciclosporin, or with anti-​TNF therapy. Eyes Inflammation usually presents as self-​limiting conjunctivitis or episcleritis, but it is important to differentiate this from more ser- ious scleritis or uveitis. Patients with Crohn’s disease who develop significant eye pain, visual disturbance, or photophobia should re- ceive emergency ophthalmic assessment. Liver Persistently abnormal liver function tests, particularly if cholestatic, should prompt investigation including magnetic resonance cholangi- ography for primary sclerosing cholangitis (see Chapter 15.23.3). Differential diagnosis The differential diagnosis of Crohn’s disease depends on its specific presentation. Acute ileitis in young patients closely mimics appendicitis, while chronic symptoms are often diagnosed as irritable bowel syn- drome. In older patients, colonic, particularly caecal, carcinoma must be considered. Clinicians often rely on a raised CRP or faecal calprotectin to identify patients with irritable bowel-​like symptoms needing further investigation. However, strong clinical suspicion (e.g. family history of Crohn’s disease) may warrant further investi- gation despite normal screening tests. Distinguishing acute inflammatory bowel disease from infection is a common challenge. Occasionally, the diagnosis of Crohn’s dis- ease cannot be confirmed until the second flare. In known Crohn’s disease patients, when abdominal symptoms recur, the challenge is distinguishing active inflammation from other causes. Most of the latter are discussed later (see ‘Complications’) but it is noteworthy that a history of inflammatory bowel disease increases susceptibility to infectious enterocolitis, and that irritable bowel syndrome is as common in individuals with Crohn’s disease as in the general popu- lation. Failure to appreciate these points can cause both diagnostic confusion and inappropriate treatment choices such as overuse of corticosteroids. Yersinia enterocolitica and Mycobacteria tuberculosis can mimic Crohn’s disease, sharing an ileocaecal predilection and causing acute and chronic inflammation respectively. However, the cause of most cases of acute ileitis is never determined and only a minority develop Crohn’s disease. Campylobacter, shigella, and salmonella cause an acute colitis usually with fever and sometimes with a reactive arth- ritis, and Clostridium difficile is increasingly found outside conven- tional risk groups. E. coli can cause colitis, with the 0157 serotype triggering haemolytic uraemic syndrome. Rarer causes of entero- colitis include amoebae, schistosomiasis, and cytomegalovirus, emphasizing the need for careful microbiological and histopatho- logical assessment. Rectal and perianal ulceration can be caused by

15.11  Crohn’s disease 2929 sexually transmitted infections such as gonorrhoea, syphilis, and lymphogranuloma venerium. Noninfectious mimics of Crohn’s disease include drugs, ischaemia, Behçet’s disease, lymphoma, small-​bowel carcinoma, solitary rectal ulcer, and radiotherapy. NSAIDs can produce intestinal inflam- mation and rarely ‘diaphragm’ strictures, and Fleet Phospho-​soda colonoscopy bowel preparation commonly causes rectal aphthoid ulceration with focal active colitis on histopathology. Nicorandil can produce oral and deep perianal ulceration, and mycophenolate mofetil occasionally causes right colonic ulceration. Ischaemic col- itis can mimic Crohn’s disease with segmental involvement and soli- tary rectal ulcers can be large and pleomorphic but histopathology discriminates. Diverticulitis can mimic Crohn’s disease clinically and histopathologically: colonoscopic biopsies from a diverticular segment must be labelled as such. For colonic inflammation, the major differential diagnosis for Crohn’s disease is ulcerative colitis. Differentiation is possible for about 95% of cases (Table 15.11.1), leaving 5% as indeterminate or, more accurately, unclassified due to equivocal appearances. Ulcerative colitis can mimic Crohn’s disease with a prominent caecal patch of inflammation well recognized in distal ulcerative colitis, or where inflammation becomes patchy on treatment. Clinical investigation Acute enterocolitis With any significant acute enterocolitis, excluding infection is critical. Three stool samples should be sent for microscopy, cul- ture, and C. difficile toxin assay. Serological tests for yersinia and polymerase chain reaction for cytomegalovirus should also be re- quested where appropriate. Routine laboratory tests For chronic symptoms, a few baseline tests provide important diag- nostic indicators. Faecal calprotectin is highly sensitive for intestinal inflammation. On blood tests an even modestly elevated CRP or ESR is consistent with active Crohn’s disease, sometimes accom- panied by elevated platelet and neutrophil counts and a low serum albumin. The latter reflects cytokine-​mediated downregulation of hepatic synthesis and intestinal protein loss. Anaemia is common, and multifactorial in origin; ferritin, vitamin B12, and folate should be checked. Liver and renal function tests and coeliac serology are advisable. Anti-​Saccharomyces cerevisiae antibody assays are posi- tive in 50 to 75% of established cases but add little to diagnosis and are not widely used. Where baseline tests indicate possible Crohn’s disease, the choice of the next investigation depends on the clinical context. Endoscopy Endoscopic examination remains the benchmark for mucosal visualization. Ileocolonoscopy with biopsies is highly sensitive for Crohn’s disease presenting with diarrhoea. Appearances vary, but Crohn’s disease hallmarks are segmental inflammation with pleomorphic ulceration and cobblestoning, most commonly ileocaecal (Fig. 15.11.2). Endoscopists should biopsy the rectum and intervening normal colon where inflammation is patchy to aid histopathological interpretation, and since histological findings in Crohn’s are often nonspecific, it is important that histology is inter- preted in the clinical context. The small bowel can be imaged using wireless capsule endoscopy and accessed by balloon enteroscopy, the latter usually being used to obtain biopsies where there is diag- nostic doubt or occasionally to dilate short strictures. Radiological imaging A range of imaging modalities are available to support the evalu- ation of Crohn’s disease. Plain abdominal radiography helps as- sessment of severe diarrhoea or possible obstruction, although increasingly CT is the investigation of choice for the latter. The use of conventional CT or CT enterography provides good def- inition of mucosal disease, as well as demonstrating extraluminal features such as fat wrapping and collections (Fig. 15.11.3). MRI enterography is increasingly available and provides similar infor- mation without exposure to ionizing radiation, as well as detecting subtle submucosal disease and affording precise definition of fistula Table 15.11.1  Features distinguishing Crohn’s disease from ulcerative colitis Crohn’s disease Ulcerative colitis Clinical features Bloody diarrhoea Uncommon Common Perianal disease Common Uncommon Abdominal mass Common Rare Endoscopy/​radiology Rectal inflammation Uncommon Defining feature Distribution Patchy Continuous Ulceration Pleomorphic, deep Superficial, fine Strictures/​fistulas Characteristic Rare Histology Depth Transmural Superficial Infiltrate Lymphocytes, macrophages, plasma cells Neutrophils, plasma cells, eosinophils Granulomas Characteristic Confined to ruptured crypts Fig. 15.11.2  Colonoscopic appearance of linear and pleomorphic ulceration of Crohn’s disease.

section 15  Gastroenterological disorders 2930 anatomy (Fig. 15.11.4). Small-​bowel ultrasonography is a highly operator-​dependent technique which can allow for sensitive, low-​ cost detection of small-​bowel disease (Fig. 15.11.5). Fistula anatomy should be defined using a combination of imaging (typically MRI) and, for perianal disease, examination under anaes- thesia. Perianal fistulae are classified by their complexity (simple, single track vs complex branching or multiple tracks) and their rela- tionship to the internal and external anal sphincters. Criteria for diagnosis No single feature is sufficient or necessary to diagnose Crohn’s dis- ease. Instead, diagnosis is based on cumulative clinical, laboratory, (a) (b) Fig. 15.11.3  Crohn’s disease with acute inflammation. CT enterography showing mural stratification of multiple segments of distal ileum. There is intense mucosal hyperenhancement (arrow in (b)) and enlargement and engorgement of the vasa recta (arrow in (a)), producing the ‘comb sign.’ An enhancing polypoid postinflammatory polyp is seen projecting into the distal ileal lumen (arrowhead). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. (a) (b) (c) Fig. 15.11.4  Crohn’s disease with active inflammation and stricturing. Magnetic resonance enterography shows marked mural thickening of a long segment of distal ileum. On MRI, mural thickening in active inflammation is of low signal intensity on T2 half-​Fourier-​acquisition single-​shot turbo spin-​echo (HASTE) (arrow in (a)); intermediate signal intensity on true fast imaging with steady-​state precession (TrueFISP) (b); and shows mural stratification with marked mucosal enhancement on the intravenous gadolinium-​enhanced volume interpolated breath-​hold examination (VIBE) image (arrow in (c)). Short strictures are present in the inflamed segment, and there is adjacent fibrofatty proliferation (asterisk). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.11  Crohn’s disease 2931 radiological, endoscopic, and histopathological evidence. This is usually straightforward, but the multidisciplinary team should carefully review the evidence when there is uncertainty. Management Management of Crohn’s disease must be tailored to the individual. Patients need a consistent medical approach underpinned by in- formation and support, for example, from specialist nurses and national patient organizations (see ‘Useful websites’). Nutritional deficits must be corrected, with medical therapy for active disease and timely surgery for refractory inflammation or complications. Treatment should be escalated according to disease severity and clinical progress. The ultimate goals of therapy are debated, and per- spectives may differ between physicians and patients. Although the long-​term avoidance of complications and maintenance of quality of life might be desired, very few clinical trials target these outcomes. Much recent emphasis has been placed on endoscopic evidence of mucosal healing as a treatment goal. This may indeed reduce the risk of complications, but at a cost to the patient and healthcare economy of a greatly increased need for immunosuppression. There remains a discordance in some patients between clinical symptoms and endo- scopic activity, which may complicate management decisions. The site of disease affects treatment choice, as does the patient’s previous experience and views regarding tolerability and risks versus benefits. Prospectively evaluated prognostic biomarkers are emerging but have yet to be adopted. Clinically, and based on some retrospective data, Crohn’s disease often behaves more aggressively in those with an early age of onset, diffuse disease or deep ulceration, marked peri- anal involvement, early requirement for steroids, and prominent extraintestinal manifestations. In such patients, and those with recur- rent relapse, maintenance immunosuppressive or biological therapy must be considered early. The clinician must synthesize all these strands in formulating an appropriate, individualized treatment plan. Smoking All Crohn’s disease patients who smoke should be advised to stop. This halves the risk of relapse, but even with focused interventions delivered in the context of a dedicated Crohn’s service, sustained ces- sation rates at 1 year are only around 30%. Diet and nutrition Dietetic assessment and advice is important, particularly in patients who have lost weight. Enteral supplements may be required, and specific deficiencies corrected. Parenteral nutrition is reserved for those with intestinal failure due to obstruction, high-​output fistula, or short-​bowel syndrome. For Crohn’s disease affecting the upper gastrointestinal tract and small bowel, therapeutic diets can—​by poorly understood ef- fects on mucosal immunity and gut flora—​suppress inflammation. Although meta-​analyses have suggested that such diets are less ef- fective than corticosteroids on an intention-​to-​treat basis, it appears that dietary therapy can perform well, leading to disease remission in 40 to 80% of those able to tolerate the feeds. Amino acid (‘elem- ental’), peptide, and protein-​based liquid feeds are equally effective, being nutritionally replete and used exclusive of all other foods for 2 to 4 weeks. Advantages of therapeutic diets include rapid nutritional res- titution and avoidance of corticosteroids—​limiting their adverse impact on growth (in children), osteoporosis, and superadded sepsis. Limitations mainly relate to palatability and frequency of early relapse. Specialist dietetic supervision, offering choice of fla- vour or preparation, and building gradually towards calculated nutritional requirements greatly increases adherence. Nasogastric or gastrostomy tube feeding are occasionally required. Successful transition to eating should start with a basic low-​fat, low-​fibre ex- clusion diet with phased reintroduction of normal foods over sev- eral weeks to identify specific dietary intolerances. This approach also deals with any superadded food intolerances that may con- tribute to symptoms, and can in itself produce prolonged remis- sion, although addition of immunomodulatory therapy is often required. Patients with a stricture should have a low-​residue diet to avoid bolus obstruction (avoiding sweetcorn, apple skins, etc.); and lactose intolerance is common in Crohn’s disease, requiring a lactose-​free diet with calcium supplementation. Oral Crohn’s disease often re- sponds to a low-​benzoate, low-​cinnamon diet. (a) (b) Fig. 15.11.5  Crohn’s disease with active inflammation in the ileum. Ultrasonography shows marked thickening and ulceration of an ileal segment (arrows in (a)). The normal sonographic layers of the bowel wall are preserved. On colour Doppler, there is hyperaemia of the segment. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2932 Medical therapies 5-​Aminosalicylates Mesalazine lacks efficacy in Crohn’s disease. Of six methodologic- ally rigorous trials, some indicated modest benefit, but this was not significant on meta-​analysis. There is a strong case for dropping mesalazine from the treatment algorithm of mild to moderately ac- tive Crohn’s disease. Mesalazine should also be abandoned as maintenance therapy following medically induced remission because of its demonstrated lack of efficacy, potential nephrotoxicity, and high cumulative cost. After many years on treatment, many patients may be resistant to the idea of stopping (indeed, may report symptom recurrence). A prag- matic approach is to try a slow wean. After surgical resection, maintenance mesalazine may confer some benefit, although the effect size is small (number needed to treat (NNT) = 11 to prevent one relapse at 12 months) and appears restricted to exclusively small-​bowel disease. Given the cost and in- convenience it should be reserved for selected cases, and only after more effective measures such smoking cessation. Antibiotics Antibiotics can successfully treat perianal abscesses, discharging fis- tulas, and small-​bowel bacterial overgrowth complicating Crohn’s disease. Metronidazole with or without ciprofloxacin is best and may be required for several weeks. Some clinicians recommend antibiotics for active Crohn’s colitis but supporting trials evidence is modest. A randomized controlled trial of antimycobacterial therapy for Crohn’s disease showed no benefit over placebo. Corticosteroids For most gastroenterologists, corticosteroids constitute the thera- peutic mainstay for induction of remission active Crohn’s disease. They induce symptomatic remission or satisfactory clinical response in 80% of patients with active disease. Typically given as a course of oral treatment reducing over 6 to 8 weeks, the conventional starting dose is prednisolone 40 mg/​day. Smaller starting doses appear less effective. Severe disease mandates hospital admission for intra- venous therapy with hydrocortisone (100 mg four times daily) or methyl prednisone (40 mg twice daily). Corticosteroid side effects can be mitigated by using oral budesonide, formulated for ileocaecal release. High first-​pass hep- atic metabolism ensures low systemic availability. Budesonide’s ef- ficacy approaches that of prednisolone. Where the latter is required (e.g. for more severe and extensive disease), calcium and vitamin D with or without oral bisphosphonate should be coprescribed to limit osteoporosis. Long-​term corticosteroid therapy is ineffective and should be avoided in Crohn’s disease. For the 35 to 40% of patients relapsing frequently off steroids (e.g. at least two relapses a year) or unable to wean without relapse, immunosuppressive or biological therapies are mandated. Immunosuppressants Azathioprine and 6-​mercaptopurine are the most commonly used immunosuppressants, with methotrexate second line and alterna- tives such as tacrolimus and thalidomide used rarely. Where re- mission is maintained, the vogue is towards increased duration of therapy—​driven by evidence of an increased risk of relapse on stop- ping even after many years in remission. Azathioprine and 6-​mercaptopurine The thiopurines azathioprine (2–​2.5 mg/​kg) and 6-​mercaptopurine (1.5 mg/​kg) are steroid sparing and effective in maintaining remis- sion in Crohn’s disease (NNT = 3). They inhibit purine synthesis via 6-​thioguanine triphosphate to prevent leucocyte proliferation and take up to 16 weeks to work; hence, they should be used along- side a more rapid strategy for induction of remission. Those with aggressive disease, severe perianal disease, or steroid dependence, or patients requiring two or more courses of corticosteroids per year are most likely to require azathioprine to maintain remission, though recent trials do not suggest a benefit of protocolized early introduction in these higher-​risk patients compared to treatment based upon clinical need alone. Immunomodulator therapy should continue for at least 4 years when effective and well tolerated—​and often longer. Some 20 to 30% of patients will be intolerant of thiopurines due to myalgias, nausea, rash, mild hepatitis, or cytopenias, and occasion- ally pancreatitis (2%). Risk of lymphoma is increased by a factor of 4, but remains rare particularly in young age groups. Patients should be warned of possible profound neutropenia and need regular monitoring of blood count and liver function, particularly following commencement or dose increase. Minor elevations of liver enzymes, lymphopenia, and macrocytosis are not significant. Variation in the thiopurine methyltransferase (TPMT) gene af- fects efficacy and safety of thiopurines. About 1 in 300 Europeans have negligible enzyme activity and risk severe neutropenia—​ preventable by measuring TPMT activity or genotype before starting therapy, although subsequent blood test monitoring is still required. TPMT heterozygotes are predisposed to thiopurine side effects including leucopenia, and usually respond to 50% of standard dose. Polymorphisms in the NUDT15 gene are also strongly associated with leukopenia. Where toxicity develops, switching from one thiopurine to the other often helps, despite their chemical similarity. For patients seemingly unresponsive or intolerant, doses can be increased to the limit of the dosing range or tolerability for 16 weeks before trying alternatives. Monitoring of thiopurine metabolites 6TGN (the active moiety) and 6MMP (a by-​product which can in- duce hepatotoxicity) can help to optimize therapy—​for example, checking compliance, increasing doses where 6TGN levels fall below the target range, or adding allopurinol and reducing ini- tial thiopurine doses by 75% in individuals who are preferential ‘shunters’ toward 6MMP (often indicated by abnormal liver func- tion tests on thiopurine therapy). Methotrexate Methotrexate is also effective for inducing and maintaining steroid-​ free remission in Crohn’s disease. The index randomized controlled trial used an induction dose of 25 mg/​week and 15 mg/​week main- tenance given intramuscularly. Many centres now use subcutaneous or oral methotrexate at these doses—​supported by retrospective evi- dence of efficacy. Nausea is common but reduced by prescribing a weekly dose of folic acid the day after the methotrexate. Blood test monitoring is again advised. Methotrexate is teratogenic and should be avoided in women of child-​bearing potential.

15.11  Crohn’s disease 2933 Other immunosuppressants Randomized trial evidence is lacking for other immunosuppres- sants. From available data, tacrolimus appears promising for refrac- tory inflammatory disease and closing fistulas, and thalidomide may have a short-​term role but is limited by toxicity. Oral ciclosporin is not effective. Biological therapies Anti-​TNF therapies The treatment of moderate or severe Crohn’s disease has been revolutionized by the demonstration that monoclonal antibodies targeting TNFα are clinically effective for both acute presenta- tions and long-​term maintenance. Infliximab, a chimeric human/​ mouse monoclonal antibody, was demonstrated in the landmark ACCENT 1 study to induce symptomatic improvement in 60% of patients with active luminal Crohn’s disease. Subsequent data dem- onstrated benefit in closing fistulas, healing ulcerated mucosa, and maintaining steroid-​free remission in 30 to 50% of patients re- sponding to initial induction and then given 8-​weekly infusions of infliximab. Improved quality of life and reduced hospitalization sig- nificantly offset treatment costs. Subsequent studies with alternative anti-​TNF antibody therapies such as adalimumab and certolizumab appear similarly effective, though only infliximab has been licensed for fistulizing disease. The benefits of anti-TNF therapy have been extended to increasing numbers of patients, particularly since expiry of original patents and the associated introduction of 'biosimilars', with corresponding reductions in drug costs. Anti-​TNF therapies are generally well tolerated and long-​term postmarketing registry data supports their use in a wide range of pa- tient populations. Major side effects include increased susceptibility to infection (sepsis must be controlled before treatment), reactiva- tion of tuberculosis (mandating screening), infusion reactions, and a possible slight increase in risk of lymphoma. Biologicals that affect lymphocyte trafficking More recently, monoclonal antibodies have been developed that target the surface receptors that direct lymphocyte trafficking to the gastrointestinal mucosa. The first of these, natalizumab, which tar- geted integrin α4, proved effective for Crohn’s disease, but it is now rarely used as associated inhibition of lymphocyte trafficking to the central nervous system leads to reactivation of JC virus and develop- ment of progressive multifocal leucoencephalopathy. Vedolizumab, which binds to the α4β7 heterodimer, inhibits lymphocyte trafficking more selectively to the gastrointestinal tract and has not been associated with development of progressive multifocal leucoencephalopathy. In the large-​scale GEMINI 2 and GEMINI 3 trials, vedolizumab showed significant benefits over pla- cebo in the maintenance of remission. It may also have a role in in- duction of remission, but the benefits in this regard are modest and it appears to be slow to take effect. Vedolizumab should thus be con- sidered a second-​line biological therapy in Crohn’s disease—​a useful treatment option for patients who have failed anti-​TNF therapy or in those who wish to maintain remission using an agent that avoids targeting systemic immunity. Ustekinumab Ustekinumab is a monoclonal anti­body targeting the p40 subunit common to IL-12 and IL-23. It has demonstrated efficacy in luminal Crohn's disease in both patients who have failed anti-TNF therapy and in those naive to anti-TNF therapy, and is licensed in both pa- tient groups. Data from other inflammatory disorders suggests a lower risk of infection than observed in patients on anti-TNF therapy. Biologicals in combination with other immunosuppressants A key question with all biological therapies is whether or not com- bination with other immunosuppressants provides a clinical benefit that can outweigh the increased side-​effect profile. For infliximab, use in combination with azathioprine has been shown in the SONIC trial to be more effective at maintaining remission than either therapy alone. Furthermore concomitant thiopurine therapy is known to re- duce immunogenicity (anti-drug antibody formation) and hence reduce secondary loss of response to anti-TNF therapy—which is a particular problem with infliximab. In contrast, the combination of infliximab with methotrexate at induction did not provide signifi- cant clinical benefit at 1 year in the COMMIT trial. Interestingly, in COMMIT rates of anti-​infliximab antibody development were lower in those receiving methotrexate, which might suggest the po- tential for clinical benefits beyond the 1-​year follow-​up of the study. The advantages of combinations of adalimumab with immuno- suppression are less clear cut and not born out by randomized clin- ical trials, although immunogenicity remains a problem for certain patient groups, including those with the HLA allele DQA1*05. Long term efficacy data for both vedolizumab and ustekinumab suggest that patients who achieve remission on either drug are likely to stay in remission on drug over a number of years. This may be related to low rates of immunogenicity observed with both agents. Trial data for these drugs in combination with immunosuppressants are limited to post-hoc analyses which do not suggest an observable benefit to com- bination therapy. Additional controversy comes with measuring and interpreting serum drug levels and levels of antidrug antibodies. These are par- ticularly helpful in individuals with secondary loss of response to anti-TNF therapy, where low drug levels and high antibody levels suggest the need to switch to an alternative anti-​TNF therapy, while high drug levels might suggest switching to a different drug class. It seems likely that such therapeutic drug monitoring will become rou- tine practice for both biological and immunomodulator therapies, helping to optimize and personalize these therapies. Duration of treatment An additional question for all maintenance therapies, but particu- larly pressing for biologicals given their higher cost, is how long to continue treatment for, and with what agent or combination of agents. Trials of drug cessation suggest approximately 50% risk of flare upon withdrawal of any maintenance therapy by two years, al- though as a general theme the risk appears lowest in those without clinical, biochemical, endoscopic or histological evidence of ongoing disease activity (so-​called deep remission). Response appears to be recaptured in nearly all cases when the drug is restarted. Other therapies Several novel therapies are currently being evaluated. These include oral and subcutaneous anti-​integrin agents and oral inhibitors of the Janus kinase family, involved in downstream signalling for several cytokines. Oral agents targeting lymphocyte trafficking through modulation of the sphingolipid receptor S1PR are also in late phase clinical trials.

section 15  Gastroenterological disorders 2934 Surgery The increased use of immunosuppression since the 1980s has cor- related with a reduced incidence of surgery, but nonetheless this is still required in up to 70 to 80% of patients with Crohn’s disease in the long term. The two main indications are refractory inflam- mation and complications of disease (the latter are discussed in the following section). Close collaboration between experienced supervising physicians and surgeons, and open discussion with the patient regarding treatment options, facilitates joined-​up clinical management. Surgery for refractory Crohn’s disease should be timely and conservative. In most cases laparoscopic approaches are used. Timeliness means patients not enduring medical therapies when it is clear they are not working, nor being propelled toward surgery before it is warranted (e.g. for radiologically severe but minimally symptomatic strictures). Patients should be involved in discussions regarding long-​term efficacy and safety of second-​line medical ther- apies versus the risks, benefits, and expected outcomes of surgery. Conservative surgery minimizes risk of long-​term harm, particu- larly short-​bowel syndrome. Thus strictureplasties (incising longitu- dinally and suturing vertically) effectively open short strictures and are favoured over small-​bowel resections where possible, while for resections only macroscopically involved bowel is removed. For co- lonic disease, panproctocolectomy carries the lowest risk of relapse but at the cost of permanent ileostomy. Segmental colectomy or sub- total colectomy with ileorectal anastomosis are usually preferred where possible. Surgery for perianal sepsis and fistulas usually in- volves drainage and placement of seton sutures, together with med- ical management, rather than more aggressive interventions which carry a high risk of nonhealing wounds or faecal incontinence. Optimization for surgery includes dietitian-​supervised correction of any malnutrition. Oral supplements are preferred but parenteral nutrition may be required. Corticosteroids should be minimized to limit adverse impact on wound healing—but evidence indicates that thiopurine therapy can safely be continued during the periopera- tive period. For anti-​TNF therapies the data are more varied, with a major, recent meta-​analysis suggesting a slight excess of septic complications perioperatively. For severe coloanal Crohn’s disease, a defunctioning ileostomy should be considered. Technically straight- forward, diverting the faecal stream usually settles coloanal inflam- mation, relieving symptoms and permitting subsequent elective panproctocolectomy on a clinically fit patient. Whether some pa- tients might avoid colectomy and be maintained in remission on stoma reversal if started on thiopurine or biological therapy is un- clear, but recent analyses suggest that this is unlikely for most. Approximately one-​half of patients requiring surgery for small-​ bowel Crohn’s disease require a repeat operation within 10 years, es- pecially smokers. Postoperative treatment with metronidazole and/​ or azathioprine has been shown to be associated with a lower risk of disease recurrence. The use of postoperative anti-​TNF therapy in high-​risk patients in the PREVENT study was associated with better endoscopic outcomes, but not with a detectable clinical benefit. In the POCER study, the use of endoscopic assessment at 6 months to guide treatment escalation/​de-​escalation was associated with im- proved clinical outcomes and reflects a sound evidence-​based ap- proach. Serial faecal calprotectin measurement offers a less invasive alternative to colonoscopy with a sensitivity for endoscopic recur- rence of around 90%. Pregnancy Most Crohn’s disease therapies, with the exceptions of methotrexate and thalidomide, are safe in pregnancy, but risks and benefits should be carefully discussed with patients. Acute flares should be treated with corticosteroids or dietary therapy (elemental or polymeric), and maintenance treatment with azathioprine and/​or anti-​TNF therapy (the latter until the third trimester) should usually be continued. Complications and their management The complications of Crohn’s disease confer significant morbidity and some mortality. Acute complications Intestinal Intestinal obstruction manifesting as colicky pain, vomiting, disten- sion, and absolute constipation presents acutely or subacutely and is due variably to food bolus, active inflammation (with mural oe- dema), adhesions, and fibrotic stenosis. Strictures usually affect the terminal ileum but can occur anywhere from oesophagus to anal canal. Inflammatory markers and abdominal CT or MRI consti- tute key investigations. Episodes usually resolve with conservative management: nil by mouth, intravenous fluids, corticosteroids, and nasogastric tube for pronounced vomiting. Recurrent episodes re- fractory to a low-​residue diet (exclusion of mushrooms, sweetcorn, vegetable skins, etc.) and increased immunosuppression (if evidence of inflammation) require endoscopic dilatation or surgical resec- tion/​strictureplasty. Intestinal perforation, caused by deep fissuring ulcers character- istic of Crohn’s disease, presents acutely as peritonitis, but symptoms may be considerably masked by corticosteroid therapy. Following diagnostic confirmation, usually on CT, urgent surgical resection is mandated. Fortunately, free perforation is rare as fibrotic serosal re- action and fat wrapping contain most leaks. Toxic megacolon is rare in Crohn’s disease, but those with acute se- vere colitis and systemic upset (fever, tachycardia, etc.) require close monitoring and serial abdominal radiographs. Where transverse colonic diameter is more than 6 cm at presentation and this persists despite 24 to 48 h of maximal medical therapy, or develops during such treatment, colectomy is mandated to prevent perforation. Severe bleeding is rare. After resuscitation, therapeutic options in- clude endoscopic haemostasis (adrenaline injection and clipping), angiographic occlusion, or surgical resection. Other medical Venous thromboembolism is common and potentially life-​ threatening, requiring vigilance and low molecular weight heparin during all hospital admissions. Subacute/​chronic complications Perianal fistulae Asymptomatic simple fistulae may not require specific treat- ment. Treating symptomatic perianal fistulae requires a joint medical and surgical approach. Medical management involves control of infection with antibiotics and control of disease with immunomodulators and/​or biological therapy. Surgical

15.11  Crohn’s disease 2935 approaches primarily include drainage of abscesses and keeping the fistula track open with noncutting setons. More definitive management may be attempted, for example, with instillation of fibrin glue, use of collagen plugs, or reconstructive approaches, but these are successful in less than 50% of cases. Emerging data using mesenchymal stem cells injected into the fistula tract have shown promise for improved healing rates, with one such therapy now li- censed. In severe disease, a defunctioning stoma may be required. Surgical complications Intra-​abdominal or pelvic abscesses can result from localized per- foration or internal fistulation. Symptoms include abdominal pain and marked weight loss, but can be surprisingly nonspecific and frequently mistaken for active luminal inflammation. Markedly elevated inflammatory markers indicate sepsis and mandate ab- dominal CT. Treatment options, decided by multidisciplinary review and depending on the patient’s clinical status, include antibiotics (metronidazole and ciprofloxacin) with radiological drainage and elemental diet or corticosteroids to suppress Crohn’s inflammation. Surgical drainage/​resection is usually best deferred while sepsis is thus controlled. Parenteral nutrition and intensive care may be required in severe cases. Symptomatic anal strictures should be dilated under anaesthetic, with benefit prolonged by using a dilator at home. Gallstones and renal stones are common, and symptoms may be confused with active Crohn’s disease. Conventional management is indicated. The risk of colon cancer is increased in Crohn’s disease affecting the colon. As with ulcerative colitis, risk correlates with disease ex- tent, activity, and duration. In one study, neoplasia was detected in 16% of patients over 20 years. Regular surveillance colonoscopy is warranted after 10 years’ extensive Crohn’s colitis, with biopsy series including any mucosal irregularities. The risk of small-​bowel car- cinoma increases 40-​fold compared to the general population, usu- ally within chronic strictures, but remains very rare. Medical and nutritional complications Short-​bowel syndrome following extensive resection is likely if there is less than 120 cm of small bowel ending in an ileostomy or 80 cm with colon in situ (colonic bacteria ‘scavenge’ calories by fermenta- tion, producing volatile fatty acids which are absorbed). Other patterns of malabsorption in Crohn’s disease include (1) vitamin B12 deficiency—​following ileal resection, levels should be monitored yearly and replaced parenterally where deficient; (2) iron deficiency—​oral iron preparations are frequently poorly tolerated or ineffective, hence intravenous iron sucrose/​iron dex- tran is often required; and (3) zinc, magnesium, and selenium defi- ciencies should be sought and treated. Ileal resection prevents resorption of bile acids in the entero- hepatic circulation. In the colon they can stimulate marked watery (choleretic) diarrhoea, which can be treated with colestyramine. Bacterial overgrowth of the small bowel results from stasis pro- duced by scarring and stricturing. Symptoms include diarrhoea, nausea, bloating, and flatulence. Treatment is with antibiotics (e.g. metronidazole, doxycycline, co-​amoxiclav); prolonged or rotating courses are often required. Osteoporosis occurs in approximately 12% of Crohn’s disease pa- tients, with increased fracture risk. Corticosteroid therapy, low body mass, poor dietary intake of calcium, smoking, hypogonadism, and uncontrolled inflammation all contribute. Regular bone densi- tometry is indicated, with calcium/​vitamin D supplements and bisphosphonates given as required. Growth failure is a major risk in adolescents, particularly with dis- ease activity around puberty. Height and weight must be monitored on growth charts. Acute relapse should be managed with dietary therapy (elemental/​polymeric) where possible. The priority is rapid induction of remission to restore growth, and infliximab or surgery may be required to achieve this. Long-​term corticosteroids must be avoided: azathioprine or infliximab are frequently used to maintain remission. Prognosis To a patient newly diagnosed with Crohn’s disease, the lack of a cure and uncertain future is understandably concerning. However, an aggressive or refractory course is unusual, and although morbidity during flares is substantial these are mostly short-​lived and usu- ally interspersed with long periods of remission with near-​normal quality of life. Although reliable prognostic markers are currently lacking, population-​based data from Denmark indicate 55% of patients to be in remission and 15% with mild disease only 1 year after diagnosis. Some 10 to 30% of patients relapse each year, less if immunomodulatory drugs are used. Up to 80% of Crohn’s disease patients require surgery in the long term. For ileal/​small-​bowel Crohn’s disease, surgery is required on average 8 years after diagnosis. Some 30 to 40% of patients experi- ence symptomatic relapse by 5 years postoperatively, with 30% re- quiring further surgery within 10 years. Smoking more than doubles this risk. Surgery is required less frequently for exclusively colonic disease. Risk of relapse following panproctocolectomy is low in such individuals. Large population-based studies have suggested slightly higher mortality rates in patients with Crohn's disease. Cause-​specific mortality includes an excess of colorectal cancer, but also ex- cess cardiovascular mortality, as well as acute complications including sepsis, pulmonary embolism, bowel perforation, and postoperative complications. Areas of controversy Key research priorities include identifying the precise role of specific microorganisms and the commensal gut flora in triggering and sus- taining the intestinal inflammation of Crohn’s disease. For patients requiring treatment escalation, we need data on optimal sequences of therapy with anti-TNF agents, vedolizumab or ustekinumab that produce the best overall results and best cost-effectiveness. For ­patients in remission, it will be important to understand better how long to continue with a given therapy, or combination of therapies, and to develop better risk models for considering drug-specific long-term risks and benefits. Likewise, more data are needed on optimal treatment algorithms, in particular the incorporation of therapeutic drug monitoring and endoscopic and biomarker moni- toring, and whether these result in improved clinical outcomes and are cost-effective?

section 15  Gastroenterological disorders 2936 Likely future developments In the near future, we expect to see the increased understanding of biomarkers that may be used to stratify patients. In particular, the use of genetic data and biomarkers at diagnosis and throughout treat- ment will help identify patients destined to run an aggressive disease course, with such patients targeted for more aggressive therapy. At the same time, progress in knowledge regarding pathogenic mech- anisms will feed development of new therapies, alongside progress in characterizing environmental triggers. Patients will continue to gain better access to biological and other novel immunotherapies. Increasing complexity of patient manage- ment will be supported with increasing use of specialist nurses and patient self-management. FURTHER READING Ananthakrishnan AN (2015). Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol, 12, 205–​17. Biedermann L, et al. (2012). Pregnancy and breastfeeding in inflam- matory bowel disease. Digestion, 86 Suppl 1, 45–​54. Colombel JF, et al. (2004). The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients. Gastroenterology, 126, 19–​31. Colombel JF, et al. (2010). Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med, 362, 1383–​95. Cosnes J, et al. (2001). Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology, 120, 1093–​9. Cosnes J, et al. (2005). Impact of the increasing use of immunosup- pressants in Crohn’s disease on the need for intestinal surgery. Gut, 54, 237–​41. Dignass A, et al. (2010). The second European evidence-​based con- sensus on the diagnosis and management of Crohn’s disease: cur- rent management. J Crohn’s Colitis, 4, 28–​62. Hanauer SB, et  al. (2002). Maintenance infliximab for Crohn’s dis- ease: the ACCENT I randomised trial. Lancet, 359, 1541–​9. Irving P (ed) et  al. (2011). Clinical dilemmas in inflammatory
bowel disease:  new challenges, 2nd edition. Wiley-​Blackwell, Chichester. Jostins L, et  al. (2012). Host-​microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491, 119–​24. Kostic AD, et al. (2014). The microbiome in inflammatory bowel dis- ease: current status and the future ahead. Gastroenterology, 146, 1489–​99. Lamb CA, et al. (2019). British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, Sep 27. pii: gutjnl-2019-318484. Prefontaine E, et  al. (2009). Azathioprine or 6-​mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev, 1, CD000067. Sandborn WJ, et al. (2013). Vedolizumab as induction and mainten- ance therapy for Crohn’s disease. N Engl J Med, 369, 711–​21. Sandborn WJ, Feagan BG, Lichtenstein GR (2007). Medical manage- ment of mild to moderate Crohn’s disease: evidence-​based treat- ment algorithms for induction and maintenance of remission. Sandborn W, et al. (2012). Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med, 367, 1519–28. Useful websites Crohn’s and Colitis Foundation of America: http://​www.ccfa.org Crohn’s and Colitis UK: http://​www.crohnsandcolitis.org.uk International IBD Genetics Consortium: http://​www.ibdgenetics.org/

15.12 Ulcerative colitis 2937

15.12 Ulcerative colitis 2937

ESSENTIALS Ulcerative colitis is a chronic relapsing and remitting disease in which chronic inflammation affects the rectum and extends proximally to a variable extent. The precise aetiology remains unknown but involves an interplay between reduced diversity in the gut microbiota and a genetically dysregulated gut immune system and epithelial barrier. Typical presentation of mild or moderate disease is with a gradual onset of symptoms including diarrhoea, rectal bleeding, and the pas- sage of mucus. Severe disease is characterized by anorexia, nausea, weight loss, and severe diarrhoea (more than six motions daily), with the patient likely to look unwell with fever, tachycardia, and other signs of volume depletion, and the abdomen may be distended and tympanitic, with reduced bowel sounds and marked colonic tender- ness. Complications of acute disease include acute dilatation and perforation, and those of long-​standing disease include carcinoma. Extraintestinal manifestations are common, with some related to colitic activity (e.g. oral aphthous ulceration, erythema nodosum, and peripheral arthropathy) but others not (e.g. sacroiliitis and pri- mary sclerosing cholangitis). Diagnosis is usually made on the basis of exclusion of infective colitis by stool culture and the finding of typical diffuse inflammation in the rectum and above at sigmoidoscopy. Management requires rapid control of symptoms with induction therapy followed by maintenance of remission. Mild disease is typ- ically treated with 5-​aminosalicyclic acid delivered both orally and by enema, and moderate disease by 5-​aminosalicyclic acid and ster- oids. Patients with severe disease require hospital admission, intra- venous steroids, and daily review by both a physician and a surgeon experienced in the management of ulcerative colitis. Ciclosporin or infliximab are used as rescue therapies for steroid-​resistant acute se- vere ulcerative colitis, but colectomy should not be delayed when this is required. Maintenance therapy with immunomodulators, small molecules and biological therapies are both effective at maintaining remission, and several new drugs are in clinical trials. Introduction Ulcerative colitis is a chronic inflammatory disease of the colon, of uncertain cause. It almost always affects the rectum and extends proximally to involve the colon to a variable extent. It is character- ized by a relapsing and remitting course. The disease was first described in 1859 by Samuel Wilks, a physician at Guy’s Hospital, London, who recognized that ‘simple, idiopathic colitis’ could be distinguished from other forms of colitis, mainly bac- terial dysentery. It took many years for the concept to be accepted, but in 1931, Sir Arthur Hurst was able to give a complete description of the disease, including the sigmoidoscopic appearances. Nevertheless, he still considered the disease to be primarily infective, even though its chronic nature might be induced secondarily by other factors. Over recent decades, a greater understanding of disease pathogenesis has emerged, as for many other chronic inflammatory conditions, with ulcerative colitis thought to result from a dysregulated immune response to components of commensal gut bacteria with strong gen- etic and environmental influences in this interaction. Epidemiology Ulcerative colitis is a worldwide disease, although it may be difficult to diagnose in areas where infective colitis is prevalent. Published rates for incidence and prevalence vary considerably and while the disease remains most common in Westernized countries, it is in- creasingly apparent worldwide. Hence, annual incidence rates in Europe are as high as 30 per 100 000 population with similar rates reported in North America. An increase in incidence over the past three decades has been reported most for Asian populations while the condition is also becoming more common in South America and Africa. A north–​south gradient in incidence is well recognized in Europe where countries with a higher latitude such as Scandinavia report 15.12 Ulcerative colitis Jeremy Sanderson and Peter Irving Acknowledgement: the authors and editors gratefully acknowledge the inclusion in this chapter of material contributed to previous editions of the Oxford Textbook of Medicine by Emeritus Professor D.P. Jewell.

section 15  Gastroenterological disorders 2938 higher incidences than those closer to the Mediterranean. While this is likely to be multifactorial, the gradient has been used as an indicator for a role of vitamin D in disease pathogenesis. Both in North America and South Africa, Jewish individuals appear three to four times more prone to ulcerative colitis than those who are non-​Jewish. Within Israel, Ashkenazi Jews have a higher incidence than Sephardim Jews, but it is still less than the incidence in Jewish individ- uals in North America or, indeed, than the European incidence. This highlights the likely role of environmental factors in addition to genetic factors in pathogenesis. This is emphasized even more by studies of mi- gration which consistently show a higher incidence in second-​ as op- posed to first-​generation immigrants to areas of higher prevalence, best studied in migration from Asia to Europe. On the other hand, differences in incidence between urban as opposed to rural communities, or be- tween different socioeconomic groups, have been slight and inconstant. The age of onset peaks between 20 and 40 years, but the disease may present at all ages from the first few months of life to the eighties. Some series show a second peak of onset in the 60-​ to 70-​year-​old age group, but more recent studies suggest this has disappeared. Nonetheless, there are differences in course of disease at differing age of onset, with dis- ease severity, extension of disease, and likelihood of surgery all greater in those with a young age of onset. Earlier series suggested a female predominance of the disease but more recent studies show little sex difference. Aetiology The precise cause or causes of ulcerative colitis remain unknown. However, as outlined later in this section, a much greater under- standing of the pathogenesis of the disease has developed from re- search over the last 10 to 15 years, combining data from immunology, genetics, and molecular microbiology. The overarching theory pro- poses that ulcerative colitis represents a dysregulated gut immune response directed most likely at commensal bacteria resident in the gut lumen, with a loss of integrity in the epithelial barrier contrib- uting to this interaction. While there are associations with true auto- immune diseases, the concept of ulcerative colitis as an ‘autoimmune’ condition has largely been abandoned. External influences such as diet, smoking, psychological stress, and medication are important as secondary influences but unlikely to be primary triggers. Genetic factors The familial incidence of ulcerative colitis has long been recognized, with 2 to 14% of patients likely to have at least one other family member affected with inflammatory bowel disease, usually ulcerative colitis but occasionally Crohn’s disease. Most of this familial associ- ation is within first-​degree relatives. Within a multiply affected family, there is a high degree of concordance for disease characteristics (e.g. extent, severity, and presence of extraintestinal manifestations). Familial incidence may, of course, reflect that family members are often exposed to common environmental factors. However, the higher concordance in monozygotic compared to dizygotic twins provides strong evidence that genetic factors play a role in determining disease susceptibility. Nonetheless, the concordance rate for ulcerative colitis in monozygotic twins is still quite low at 6 to 12%, suggesting that the genetic component of an individual’s risk of developing the disease is much less than it is for Crohn’s disease, where the concordance rate for identical twins is 35 to 45%. Ulcerative colitis (and Crohn’s disease) is viewed as a polygenic disorder in which the influence of a considerable number of low-​risk alleles combine to promote the chances of an individual developing the disease. However, a monogenic model may explain some cases of early-​onset (<5 years old) or very early-​onset (<2 years old) disease. The most recent large genome-​wide association studies of inflamma- tory bowel diseases have expanded the number of genomic regions of interest to 241. Of these, most confer a risk of both ulcerative col- itis and Crohn’s disease. Contrary to earlier expectations, most of the variants identified are noncoding in nature and hence considered to be somehow involved in modulation of expression of genes at other sites. This fits well with the concept that epigenetic influences on gene expression are an important part of the genetic susceptibility to inflammatory bowel disease, occurring through mechanisms such as altered methylation or via microRNAs. At present, the cellular influence of such genetic variation in ulcerative colitis appears to be focused partly on gut immune cells and, interestingly, on the gut epithelial cell, supporting the concept that the disease occurs as a result of a dyregulated immune response, most likely to components of the gut microbiota but promoted by a loss of integrity in the epi- thelial barrier. Host genetics also has an influence on the phenotype of ulcera- tive colitis. For example, the occurrence of extraintestinal manifest- ations also appears to be related to genetic make-​up. For example, specific HLA variants confer altered risk to arthropathy, and eye and skin complications, and genome-​wide association studies have iden- tified separate genetic loci conferring a risk of primary sclerosing cholangitis. Microbial factors Earlier concepts in which the pathogenesis of ulcerative colitis in- volved certain pathogenic bacteria have now largely been aban- doned in favour of a more broad involvement of bacteria present in the gut. One compelling argument for this has been the consistent demonstration that most animal models of colitis are ameliorated by a germ-​free environment and augmented once re-​exposed to lu- minal bacteria. Likewise, as indicated in the following paragraphs, the various early-​age epidemiological factors thought to promote the development of colitis are likely to have their effect primarily through alterations in the gut bacteria. The gut microbiota in health comprises a vast number of bacterial species—​as many as 800—​most of which are unculturable and form a complex, balanced ecosystem which plays a key role in shaping host immune responses through interaction with the gut immune system. Importantly, through 16s ribosomal RNA-​based analysis, a loss of diversity in the gut microbiota has been consistently demon- strated in patients with ulcerative colitis. This loss of diversity alone is thought to allow a variety of proinflammatory bacteria, for ex- ample, Bacteroides spp., greater access to immune cells (including the epithelium) while the anti-​inflammatory effects of other bacteria (e.g. bifidobacteria) are diminished. An increase in certain types of bacteria may have more specific influences. For example, sulphate-​reducing bacteria are found more commonly in those with colitis. These possess the capacity to reduce sulphate to sulphide which, in turn, inhibits butyrate oxidation, a key energy reaction in epithelial cells. Hence, altered bacteria may have a direct effect on epithelial integrity. Manipulation of the microbiota in the gut is likely to represent a novel therapeutic area in ulcerative colitis in coming years. Fascinating recent trials confirm the efficacy

15.12  Ulcerative colitis 2939 of faecal microbiota transplantation in some patients with ulcerative colitis and, whilst this may be thought of as a rather blunt instru- ment in terms of manipulation of the microbiome, it strongly sug- gests that this is an important area to explore therapeutically. Diet In contrast to Crohn’s disease, dietary factors have generally been considered to play little role in the aetiology or course of ulcerative colitis. The failure of active colitis to respond either to avoidance of oral food by intravenous nutrition, or to faecal diversion by means of a split ileostomy, are key examples of this. Nonetheless, many pa- tients report improvement on specific diets, particularly those redu- cing certain carbohydrates, which may be genuinely due to influence on factors involved in pathogenesis, particularly microbial factors, or be related to alteration of functional gut symptoms which exist frequently in patients with ulcerative colitis. Accordingly, interest is growing in investigating the role of diet in ulcerative colitis. Other environmental factors As well as microbial and dietary factors, smoking and certain drugs have an important influence on the development and course of the disease. The use of nonsteroidal anti-​inflammatory drugs (NSAIDs) is well established as a risk factor for ulcerative colitis, particularly as a trigger for disease flares. The risk is particularly evident at higher doses and appears to be related to nonselective cyclooxygenase in- hibition as selective cyclooxygenase-​2 inhibitors carry a lower risk. Patients with ulcerative colitis should therefore be advised generally to avoid NSAIDs where possible. The role of other medications such as oral contraceptives is more debatable. Smoking is clearly an important modifying factor in the patho- genesis of ulcerative colitis. Interestingly, in contrast to the strong negative influence on the course of Crohn’s disease, the effect on ul- cerative colitis is in the opposite direction. Numerous studies have shown that ulcerative colitis is more common in nonsmokers than smokers, with a relative risk of 2 to 6. Ex-​smokers have a particularly high incidence, and this is highest for former heavy smokers com- pared with light smokers. There is also evidence that smokers have a less aggressive disease course. Appendicectomy, or perhaps appendicitis, also appears protective against ulcerative colitis, particularly when undertaken at a young age. As for smoking, the influence of appendicectomy appears op- posite to the effect on Crohn’s disease. The mechanism of this effect remains unclear. Hygiene hypothesis Along with allergic disorders, both ulcerative colitis and Crohn’s disease are evolving as classic conditions which fit the hygiene hy- pothesis. Numerous studies have associated a risk of developing ulcerative colitis (and Crohn’s disease) with nonvaginal delivery, lack of breastfeeding, early antibiotic use, sibling count, and various other parameters. The underlying explanation for these associations is uncertain, but almost certainly demonstrates the critical import- ance of the gut microbiota in the pathogenesis of ulcerative colitis. One intriguing extension to the hygiene hypothesis proposes that inflammatory bowel disease is more prevalent in the West as a result of reduced helminthic infection rather than primarily altered bac- terial influences. Indeed, treatment with nonpathogenic helminths, proposed to promote a more regulatory T helper (Th)-​2 cell gut im- mune response, have shown clinical benefit in some studies. Immunopathogenesis In active ulcerative colitis, there is an intense infiltration of the in- flamed mucosa with neutrophils, plasma cells, B and T lymphocytes, and macrophages. The stimulus to this broad-​ranging immune ac- tivation is clearly complex and involves some primary immune re- sponses but undoubtedly a range of secondary immune activation as a consequence of the inflammation and disrupted get mucosa. While all components of the gut immune system are involved, the inflammation in ulcerative colitis, and Crohn’s disease, is predom- inantly T-​cell driven. The antigenic trigger to T-​cell-​driven inflam- mation arises from increased exposure to various bacterial antigens, either as a result of a breached epithelial barrier or a relative increase in proinflammatory bacteria arising from reduced microbial diver- sity in the gut microbiota. Until fairly recently, ulcerative colitis was felt to demonstrate a Th2 pattern of immune activation based on cytokine profiles, in contrast to Crohn’s disease, in which a more typ- ical Th1 profile was seen. However, with lessons learnt from inflam- matory bowel disease genetics research, this paradigm has changed with the emergence of the Th17/​IL-​23 pathway as a key component of the immune activation seen in both types of inflammatory bowel disease. In ulcerative colitis, evidence supports a role for each of these pathways. Hence, contrary to earlier studies, increased pro- duction of the Th1 cytokine, tumour necrosis factor (TNF)-​α, has been demonstrated, and anti-​TNFα antibody therapy has become an important treatment for refractory disease. The concept of differing T-​cell pathways is a rapidly evolving area of research. Hence, recently discovered T-​cell subsets may be important in ulcerative colitis, particularly Th9 cells, considered important in al- lergic disorders. Likewise, regulatory T cells (Tregs) are also likely to play an important role: they have an immunosuppressive influence, act as an important balance to control the otherwise proinflammatory response, and may emerge as an important therapeutic target in future. Several other pathways designed to contain the immune response and to avoid excessive tissue damage are also likely to be impaired in ul- cerative colitis and help explain chronic persistent inflammation. Elements of autoimmunity may play a role in ulcerative col- itis, a concept that would fit with the association with other clas- sical autoimmune conditions such as thyroid disease and diabetes. Likewise, the presence of antibodies to epithelial cell components and, for example, the consistent presence of circulating perinuclear antineutrophil cytoplasmic antibodies in ulcerative colitis, and not Crohn’s disease, support this concept. Pathology Macroscopic features Ulcerative colitis almost always involves the rectum, but in about 40% of patients the disease is limited to the rectum (proctitis) or rectum and sigmoid (proctosigmoiditis). In adults, only about 20% will have the whole colon involved (pancolitis), but this proportion rises to about 50% in cases of childhood-​onset ulcerative colitis. In mild disease, the mucosa is hyperaemic and granular, with oe- dema hiding the normal vascular pattern. Small punctate ulcers ap- pear as the disease becomes more marked, which may then enlarge and extend deeply into the lamina propria. In severe disease, the ul- ceration may become linear along the line of the taeniae coli and the

section 15  Gastroenterological disorders 2940 mucosa can become intensely haemorrhagic. In long-​standing dis- ease, scarring and atrophy can be present, sometimes shortening the colon. Inflammatory polyps (pseudopolyps) may also develop in long-​ standing disease. While sometimes somewhat dramatic in appearance, these polyps have no malignant potential. When the disease goes into remission, the colonic appearance returns to normal in many cases, but—​especially in patients who have had recurrent or severe attacks—​the mucosa may become atrophic and featureless. There is often narrowing and shortening of the bowel. However, fibrous strictures complicating long-​standing disease are rare and should always raise the possibility of Crohn’s disease or malignant transformation. In acute severe disease, due to disruption of the muscle layer of the colon, acute colonic dilatation can occur and the bowel becomes thin and congested. There is usually severe ulceration, with only small islands of mucosa remaining, and the risk of colonic perforation is high. Microscopic features In ulcerative colitis, the inflammation is largely confined to the mucosa (in contrast to the transmural inflammation seen in Crohn’s disease). The lamina propria becomes oedematous, with dilated and congested capillaries, and extravasation of red blood cells. There is a mixed cellular infiltrate of acute and chronic inflammatory cells including neutrophils, lymphocytes, plasma cells, macrophages, mast cells, and eosinophils. Neutrophils invade the epithelium, often in the glandular crypts, giving rise to a cryptitis or crypt abscesses, a pathological hallmark of the disease. Damage to the crypts leads to increased epithelial cell turnover and discharge of mucus from goblet cells. With increasing inflammation, the surface epithelial cells become flattened and ir- regular, and eventually ulcerate. In severe disease, deeper ulcers may extend into the lamina propria, leading to inflammatory changes in the submucosa that creates the pathological setting for acute dilata- tion or perforation. Many of the acute changes of ulcerative colitis are nonspecific and may also be seen in infective colitis. However, the diagnosis of ul- cerative colitis can be made with some accuracy (>80% probability) if features of a chronic inflammatory process are present. These in- clude distorted crypt architecture, crypt atrophy, basal lymphoid ag- gregates, and a chronic inflammatory infiltrate. Histological appearances may return to normal once the disease has gone into remission, but there is frequently evidence of bifid or shortened crypts, hyperplasia of the muscularis mucosae, neuronal hypertrophy, and Paneth-​cell metaplasia at the base of the crypts. Cytomegalovirus (CMV) inclusions may be seen on occasions. In the setting of an acute flare in a patient receiving immunosup- pressive therapy, CMV-​colitis complicating ulcerative colitis needs to be considered as appropriate antiviral therapy may be effective and prevent colectomy. Clinical features Patients usually present with a gradual onset of symptoms, often intermittent, but becoming progressively more severe. Occasionally, ulcerative colitis can present much more rapidly and may mimic an infective colitis. Indeed, some patients begin with a genuine docu- mented acute infection such as campylobacter or salmonella enter- itis which then develops into more typical ulcerative colitis. The principal symptoms include diarrhoea, rectal bleeding, the passage of mucus, and—​less frequently—​abdominal pain. When the inflammation is confined to the rectum (proctitis), patients often pass fresh blood and mucus, which is often separate to a normal stool. Indeed, patients with proctitis can often complain of consti- pation rather than diarrhoea and, on clinical symptoms alone, may be mistakenly diagnosed as suffering from haemorrhoids. When the inflammation extends beyond the rectum, there is usually diarrhoea with mucus and a variable amount of blood. The diarrhoea is often accompanied by considerable urgency and tenesmus, and patients can be incontinent. Nocturnal diarrhoea is a common symptom in the presence of severe inflammation. Patients with severe ulcerative colitis affecting most or all of the colon are often anorexic and nauseated, and may have lost weight. They usually have severe diarrhoea (more than six motions daily) mixed with pus, and blood. In all presentations of ulcerative colitis, including proctitis, pa- tients may also complain of fatigue and may have symptoms re- ferable to some of the extraintestinal manifestations, especially recurrent oral aphthous ulceration. On examination, patients with mild or moderate attacks usually look well and exhibit few abnormal physical signs. Weight should al- ways be recorded and, for children and adolescents, both height and weight should be noted on growth charts. Abdominal examination may reveal a tender colon but is often normal. Bowel sounds are normal and rectal examination is also usually normal, but may reveal blood. Patients with a severe attack may also look deceptively well, with tachycardia or a tender colon sometimes the only abnormal signs. However, many of these patients are ob- viously unwell, with fever, salt and water depletion, anaemia, and evidence of weight loss. There may be oral candidiasis, aphthous ulceration, signs of iron deficiency, and finger clubbing. Rarely, the skin changes of hypoalbuminaemia and dependent oedema may occur. The abdomen may be distended and tympanitic, with reduced bowel sounds and marked colonic tenderness. Minor perianal disease, such as a fissure, may occur in patients with active ulcerative colitis, but this is never as severe as is seen in patients with Crohn’s disease. Investigation and diagnosis The diagnosis of ulcerative colitis is made on the basis of the history, the absence of faecal pathogens, and the endoscopic and histological appearances of the colon. Blood markers of inflammation Active disease is often accompanied by a neutrophil leucocytosis, thrombocytosis, and a rise in acute-​phase proteins (e.g. C-​reactive protein (CRP)) and in ESR). There may also be a fall in haemoglobin and albumin levels. Although the CRP is perhaps the most com- monly used marker, any of these markers of active inflammation can be measured serially during the course of treatment as an indicator of disease activity. This may be daily during the course of a severe attack requiring hospitalization, or intermittently during outpatient assessment and treatment. Patients with proctitis rarely have a rise in CRP unless the inflam- mation is particularly severe, hence symptom scoring is the main guide to activity in this setting.

15.12  Ulcerative colitis 2941 Faecal markers Faecal calprotectin or lactoferrin, both released from neutrophils present in the gut lumen as a consequence of gut mucosal inflam- mation, are excellent noninvasive markers of active gut inflamma- tion even in the absence of symptoms. They are useful in differential diagnosis (particularly between inflammatory bowel disease and irritable bowel syndrome) and are especially useful to monitor the response to therapy without the need for endoscopic assessment. Faecal samples for microbiological analysis should be obtained from all patients presenting for the first time and, ideally, all those presenting with a flare of established disease. This should include testing for Clostridium difficile toxin as well as for standard bacterial and other pathogens according to the clinical setting. For example, opportunistic infection should be considered in immunodeficiency syndromes and lymphogranuloma venereum should be tested (rectal swab) in men with proctitis who have sex with men. Sigmoidoscopy and colonoscopy Rigid sigmoidoscopy is considered safe, even in patients with a se- vere attack, and not only confirms rectal inflammation but also al- lows a biopsy specimen to be taken and an assessment of severity to be undertaken. An unprepared flexible sigmoidoscopy is preferable where available, but full colonoscopy is rarely necessary during an acute attack although many regard this procedure as safe despite the theoretical increased risk of perforation. The earliest signs of colitis on sigmoidoscopy are blurring of the vascular pattern associated with hyperaemia and oedema, leading to blunting of the valves of Houston. With increasing severity, the mucosa becomes granular and then friable. With more severe in- flammation, the mucosa shows spontaneous bleeding and ulcer- ation (Fig. 15.12.1). These changes begin in the rectum and extend proximally in a continuous manner to affect a variable length of the colon. The disease can, however, be associated with relative rectal sparing. The reason for this is not known, but the finding can be wrongly used to diagnose Crohn’s disease of the colon. Pseudopolyps (inflammatory polyps) often occur in patients with long-​standing disease and tend to be colonic rather than rectal: they have no ma- lignant potential and may even regress over many years if the disease remains in remission. Colonoscopy with multiple biopsies is important for assessing the full extent of disease. It is not critical at presentation (where sig- moidoscopy will often suffice in order to commence treatment), but it should be undertaken at some point early in the course of the dis- ease, particularly to exclude Crohn’s disease and ensure the treat- ment plan is appropriate. Colonoscopy is mandatory for patients with a colonic stricture. It is also required for cancer surveillance in long-​standing ulcerative colitis (see ‘Colorectal carcinoma’). Preparation of the colon should follow the normal methods, with osmotic laxative being the most satisfactory, but a gentler approach is needed if colonoscopy is done in the presence of severe inflamma- tion, but this is rarely indicated (unprepared flexible sigmoidoscopy should nearly always suffice in this setting). Biopsy specimens should always be taken at sigmoidoscopy or colonoscopy to permit accurate histological assessment which con- tributes to grading of severity as well as to the differential diagnosis. In the setting of acute severe colitis, biopsies should be processed urgently to look for CMV inclusion bodies which should be supple- mented by immunohistochemistry. Capsule endoscopy targetting the colon is available but not yet widely used in the management of ulcerative colitis. Radiology All patients with a severe attack must have a plain abdominal radio- graph. Not only does this exclude a dilated colon, but it may pro- vide some prognostic information (mucosal islands, distended small-​bowel loops) and demonstrate the extent of the disease. An abnormal haustral pattern, thickening of the bowel wall, and mu- cosal oedema can be detected on a plain film (Fig. 15.12.2). An in- flamed colon does not hold faecal material, hence the presence of faecal matter in the ascending or transverse colon usually indicates that the inflammation is distal. Plain abdominal radiographs should be repeated daily or every other day when severe colitis persists des- pite ongoing therapy. Fig. 15.12.1  Sigmoidoscopic appearances of severe ulcerative colitis showing spontaneous bleeding and ulceration. Fig. 15.12.2  Plain abdominal radiograph of a 24-​year-​old man presenting with severe ulcerative colitis. The ascending and transverse colon are grossly oedematous and diseased, with loss of the normal haustral pattern. In addition, there are multiple loops of dilated small intestine.

section 15  Gastroenterological disorders 2942 Barium studies have been superseded by colonoscopy. However, in settings where colonoscopy is unavailable, double-​contrast barium enema can safely be given to patients with less severe disease, but the colon must not be overdistended and the procedure should be stopped if the patient complains of pain (Fig. 15.12.3). Cross-​sectional imaging is not used routinely for diagnosis in ulcerative colitis but has a role in the exclusion of complications (Figs. 15.12.4 and 15.12.5). In particular, an abdominal CT scan should be undertaken if there is clinical suspicion of perforation during severe colitis. The threshold for CT should be reasonably low in this setting as high-​dose steroid therapy can often mask the symptoms and signs of peritonitis. Ultrasound is increasingly used in some parts of the world both as a diagnostic tool and also to monitor disease activity. Other laboratory data Anaemia is common, particularly in more extensive active disease, and is often a mixture of chronic disorder and iron deficiency. Iron loss is common as a result of chronic blood loss; this can be exacer- bated by a severe attack, in which 0.5 g of elemental iron can be lost, hence a hypochromic, microcytic anaemia is frequently present. Biochemical abnormalities are rare in mild or moderate attacks, but hypokalaemia, hypoalbuminaemia, and a rise in gammaglobulin frequently accompany a severe attack. Minor elevations of the aspar- tate transaminase or alkaline phosphatase concentrations are also frequently seen in patients with a severe attack, but they return to normal when the disease goes into remission. Persistent elevation, however, may indicate underlying chronic liver disease, particularly primary sclerosing cholangitis, and needs investigating. Assessment of disease severity The severity of ulcerative colitis can be graded in a number of ways—​ clinically, biochemically, and endoscopically—​each providing an important guide to the treatment required and a marker of disease activity that can be followed over time in order to assess response. Many activity indices have been devised for the purpose of clinical trials, but these are rarely used in day-​to-​day practice apart from the following simple guide. Clinical grading In simple terms, it is useful to grade the clinical severity of ulcerative colitis according to the symptoms into mild, moderate, and severe: • Mild disease—​fewer than four stools daily, with or without blood, with no systemic disturbance Fig. 15.12.3  A double-​contrast barium enema in a patient with active ulcerative colitis. The figure is a close-​up view of the splenic flexure showing extensive mucosal ulceration, loss of haustration, and narrowing of the colon. The patient also has diverticula in the descending colon. Fig. 15.12.4  Acute ulcerative colitis: CT findings. Section through the rectosigmoid reveals a diffusely inflamed and thickened mucosa. The oedematous submucosal layer (arrows) is paralleled by the external layer of muscularis propria and the internal layer of submucosa, both of which have higher attenuation. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.12.5  Chronic ulcerative colitis: CT features. Sagittal reformatted image of the descending colon shows narrowing of the lumen and a thickened submucosa infiltrated by fat (arrow), producing a ‘target’ sign. The splenic flexure appears normal in calibre and mural thickness. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.12  Ulcerative colitis 2943 • Moderate disease—​four to six stools daily • Severe disease—​at least six stools daily, with bleeding, and evi- dence of systemic illness as shown by fever and tachycardia Even in the clinic, it is useful to capture this into an objective clin- ical score, particularly for the purpose of monitoring the efficacy of treatment, and the Simple Clinical Colitis Activity Index represents a good way of doing this routinely, although many variations on a theme of this can be used (Table 15.12.1). Differential diagnosis Symptoms of gradual onset If the patient has a history of slow onset of symptoms, including blood and mucus, and has diffuse inflammation on sigmoidoscopy, a diagnosis of ulcerative colitis is highly probable. The main differen- tial diagnosis is Crohn’s disease (see Chapter 15.11). In some cases, a definite distinction is not possible, but if clinical, radiological, endo- scopic, and histological information are considered together, less than 10% of patients fall into the category of indeterminate colitis, a term originally used to describe an uncertain colitis based on the examination of a colectomy specimen and therefore inappropriate when only biopsy specimens are available. Hence, the recommended term is ‘inflammatory bowel disease—​unclassified’. Collagenous colitis usually has normal appearance at colono­ scopy and is diagnosed on the basis of a thickened subepithelial col- lagen band (wider than 15 μm) seen in a mucosal biopsy specimen. Microscopic or lymphocytic colitis has a normal endoscopic ap- pearance but shows a diffuse infiltration of the lamina propria with lymphocytes and eosinophils on histological examination. Although ischaemic colitis classically occurs around the splenic flexure, it may occur in the rectum, especially in older individuals, and frequently has typical histological features. Drugs can induce colitis. Those that have been implicated include NSAIDs, gold, penicillamine, and chemotherapy agents particularly the increasingly used checkpoint inhibitors which are frequently as- sociated with colonic inflammation which may be life threatening. Interestingly, 5-​aminosalicylic acid may also cause an allergic colitis, causing diagnostic confusion in patients beginning treatment for a recent diagnosis of ulcerative colitis. A careful history will usually identify this problem. Chronic infection mimicking colitis is rare. Occasionally, schistosomal colitis is seen with uniform inflammation, and travel to an endemic area should prompt careful histological examination for characteristic schistosomal lesions. Mycobacterial infections gener- ally mimic Crohn’s disease rather than ulcerative colitis. Radiation damage to the rectum may occur, especially in men who have had radiotherapy to the prostate. Occasionally, solitary rectal ulcer syndrome presents as circumferential inflammation mimicking ulcerative proctitis, but typical histology should avoid confusion. Symptoms of acute onset For those patients presenting with a much more abrupt onset, in- fective forms of colitis must be excluded by stool culture. A sudden onset of symptoms, the predominance of abdominal pain, the inges- tion of potentially infected food (chicken, shellfish), history of travel, and evidence of diarrhoeal disease in contacts are potential pointers towards infection. Sigmoidoscopic appearances can be very similar to ulcerative colitis, but histology can be useful in distinguishing an infective from a more chronic ulcerative colitis. Hence, the presence of a chronic inflammatory infiltrate, architectural disturbances of the glands, and basal lymphoid aggregates favour ulcerative colitis. The common organisms causing an infective colitis are salmon- ella, shigella, and campylobacter. Yersinial infections may also cause colitis and can pursue a chronic course over many months before resolving. Special culture conditions may isolate the organism from stool, but a rising titre of serum antibody is often the more reliable Table 15.12.1  Simple Clinical Colitis Activity Index (SCCAI) descriptors, threshold, and kappa statistic (a measure of interobserver variation in rating, with a value of 1.0 indicating perfect concordance) Descriptor Level Kappa (95% CI) Bowel frequency (day) 0.83 (0.78 to 0.88) 1–​3 0 4–​6 1 7–​9 2

9 3 Bowel frequency (night) 0.89 (0.81 to 0.97) 1–​3 0 4–​6 1 Urgency of defecation 0.76 (0.71 to 0.81) Nil 0 Hurry 1 Immediately 2 Incontinence 3 Blood in stool 0.77 (0.72 to 0.83) No 0 Trace 1 Occasionally frank 2 Usually frank 3 General well-​being 0.88 (0.83 to 0.94) Very well 0 Slightly below par 1 Poor 2 Very poor 3 Terrible 4 Extracolonic features 1 (per manifestation) 0.25 (0.18 to 0.32) Thresholds Remission ≤2 Mild 3 to 5 Moderate 6 to 11 Severe ≥12 Total score (Range 0–​19) 0.75 (0.70 to 0.81) CI, confidence interval. Components of the Simple Clinical Colitis Activity Index (SCCAI), indicating thresholds used to categorize into remission, mild, moderate, and severe disease activity. From Walsh AJ, et al. (2014). Comparing disease activity indices in ulcerative colitis. J Crohns Colitis, 8, 318–​25, by permission of Oxford University Press.

section 15  Gastroenterological disorders 2944 method of identifying the infection. Escherichia coli 0157 is a recog- nized cause of an acute colitis, especially in institutions, and massive bleeding is often a characteristic feature. Children may develop a haemolytic uraemic syndrome. For patients who have travelled in endemic areas, amoebic colitis should be considered; stool exam- ination and histological demonstration of amoebae in rectal biopsy specimens make the diagnosis. An antibiotic history must be taken, but a pseudomembranous colitis secondary to C. difficile can occur in the absence of antibiotic usage, especially in older people. Furthermore, C. difficile infection is a relatively common cause of a flare of ulcerative colitis, hence testing all patients admitted to hospital with suspected acute colitis is best practice in this setting. Other causes of infective colitis can occur in immunosuppressed patients and include CMV and herpes simplex. Although these or- ganisms usually cause more focal discontinuous colonic inflamma- tion, they can be associated with a diffuse pattern of inflammation. As previously mentioned, CMV can be seen as a superimposed in- fection in patients with acute ulcerative colitis on high-​dose steroids and should always be looked for in a rectal biopsy in those failing to settle on treatment. While abrupt in onset, sexually transmitted causes of proctitis (gonorrhoea, chlamydia, lymphogranuloma) do not usually cause diarrhoea and, especially with gonorrhoea, are as- sociated with the passage of watery pus. Exclusion of sexually trans- mitted infection is often best managed by referral to the appropriate acute clinic as testing is more thorough and effective. Extraintestinal manifestations The extraintestinal manifestations of ulcerative colitis are listed in Box 15.12.1. Skin Erythema nodosum occurs in about 2 to 4% of patients and is usu- ally associated with active disease. The lesions occur most com- monly on the anterior aspect of the lower legs. Inflammatory joint and eye disease often coexist with erythema nodosum. Pyoderma gangrenosum is rare (1–​2%) and usually seen in pa- tients with active disease, but occasionally persists despite inactive colitis. The lesions usually begin as sterile pustules, most commonly on the limbs, which break down as they enlarge and finally coalesce. Ulceration leads to necrosis and the lesions become surrounded by a black, necrotic margin. Treatment of the colitis is usually followed by regression of the skin lesions, but pyoderma can be very resistant to therapy, including anti-​TNF agents, and may even persist following colectomy. Indeed, because of the predilection of pyoderma for sites of skin trauma, troublesome lesions can occur in laparotomy wounds and in the skin close to an ileostomy. Mouth Crops of aphthous ulcers are common in patients with active dis- ease. A sore tongue and angular stomatitis often accompany chronic iron deficiency. Focal ulceration on the lateral aspects of the tongue is a rare colitis-​associated lesion, as is a vivid gingivitis known as pyostomatitis vegetans. Eyes Episcleritis or anterior uveitis occurs in 5 to 8% of patients. Local cor- ticosteroids and treatment of active colitis usually lead to resolution. Joints An acute arthropathy occurs in 10 to 15% of patients with active dis- ease. It affects the larger joints (knees, hips, ankles, wrists, elbows) and is usually asymmetrical. It is a nonerosive condition and settles as the colitis goes into remission. A less common joint complication is a symmetrical small-​joint polyarthropathy, which is seronegative and is unrelated to the activity of the colitis. Low back pain and early morning stiffness is a common symptom and usually due to sacroiliitis, which can be seen by plain radiology in 12 to 15% of patients and in 30 to 35% by MRI. It is unrelated to the activity of the colitis, and is not strongly associated with HLA B27. Ankylosing spondylitis, conversely, occurs in only 1 to 2% of patients, more often men, with 60% having the HLA B27 pheno- type. Spondylitis may present before the colitis becomes apparent or may follow the intestinal symptoms. The natural history is inde- pendent to that of the colitis and the condition needs various treat- ment approaches under the guidance of a rheumatologist. NSAIDs are frequently required but need to be used cautiously because of the risk of flaring the colitis. Anti-​TNF agents are highly effective in relieving the pain and stiffness of both sacroiliitis and ankylosing spondylitis. Liver disease Patients with severe attacks of ulcerative colitis often have minor ele- vations of alkaline phosphatase or transaminases. The cause of these enzyme rises is probably multifactorial, including malnutrition, sepsis, and hepatic steatosis (fatty liver), which occurs in up to 60% of patients undergoing urgent colectomy. The liver enzymes return to normal when remission is achieved, but there may be persistent abnormalities in liver enzymes in about 3% of patients, usually a rise in alkaline phosphatase. The overwhelming majority of these patients will have primary sclerosing cholangitis when the bile duct is visualized by endoscopic cholangiography (see Chapter 15.22.4). Histologically, liver biopsy specimens show evidence of chronic liver disease, but the spectrum of appearances ranges from those of an autoimmune hepatitis to the classic picture of concentric periductular fibrosis with obliteration of bile ducts. Box 15.12.1  Extraintestinal manifestations of ulcerative colitis Related to activity of colitis • Oral aphthous ulceration • Fatty liver (hepatic steatosis) • Erythema nodosum • Peripheral arthropathy • Episcleritis • Anterior uveitis • Pyoderma gangrenosum (sometimes unrelated to disease activity) Unrelated to activity of colitis • Unrelated to colitis • Sacroiliitis • Ankylosing spondylitis • Primary sclerosing cholangitis • Cholangiocarcinoma

15.12  Ulcerative colitis 2945 Many patients with ulcerative colitis and sclerosing cholangitis remain well for many years. The colitis frequently runs a relatively mild course, though often affects the whole colon, but the liver dis- ease is progressive and ultimately leads to portal hypertension and liver failure. Sclerosing cholangitis is a premalignant condition and explains the well-​recognized association between ulcerative colitis and cholangiocarcinoma. Furthermore, there is a high incidence of colorectal cancer, especially of the right colon, in these patients. Colonoscopic surveillance is therefore mandatory. The mild nature of the colonic inflammation despite extensive disease, the frequently observed rectal sparing, and the right-​sided cancers have called into question whether the colonic disease is really the same as ulcerative colitis. Rare associations Pericarditis with or without an effusion has been described in associ- ation with an acute attack of colitis, but a true association is not proven. Autoimmune haemolytic anaemia has been reported in ulcerative col- itis and may recur when the colonic disease becomes active. Amyloid rarely occurs in ulcerative colitis and is much more likely to be asso- ciated with Crohn’s disease. A rapidly progressing bronchiectasis has also been described in some patients with ulcerative colitis. Medical management Optimal treatment of ulcerative colitis requires rapid control of symptoms with induction therapy followed by maintenance of re- mission. There is a move towards treating more aggressively, perhaps aiming for complete mucosal or even histological healing, although this remains controversial. Ensuring appropriate timing of surgical intervention remains a cornerstone of the management of ulcerative colitis. It is also important that patients are encouraged to be involved in their management where possible; self-​management protocols and access to patient support groups should be encouraged. There are several guidelines to support management, with only minor differences between them. The European Crohn’s and Colitis Organisation guidelines are generally representative and up to date. Induction of remission Proctitis Proctitis refers to disease limited to the rectum. This accounts for about a third of patients with ulcerative colitis and tends to pre- sent with rectal bleeding, frequency, and tenesmus, often without diarrhoea. Despite its limited extent, proctitis can be very difficult to treat. Initial treatment with 5-​aminosalicylic acid is best given topically and is most effective when combined with oral therapy. Suppositories may treat the rectum more effectively than enemas. Topical steroids can also be used but are less effective than 5-​ aminosalicylic acid, although the combination of the two is often used in refractory cases. When disease remains refractory to these treatments, systemic steroids, immunomodulators, and biological drugs are all appropriate and, on occasion, colectomy is required. Proximal constipation should be considered in patients with proctitis, particularly those who are refractory to treatment and in whom abdominal pain and bloating are prominent. Treatment with osmotic laxatives not only treats the constipation, but is often asso- ciated with improvement in rectal inflammation. It is also important to consider disease extension in patients whose proctitis is refrac- tory to treatment as this is often associated with a worse prognosis. Left-​sided and extensive ulcerative colitis Mild disease The most effective initial treatment is with 5-​aminosalicyclic acid delivered both orally and through an enema. Once-​daily dosing of 5-​aminosalicyclic acid is as effective as multiple-​daily dosing. Where 5-​aminosalicyclic acid is ineffective, topical steroids may be used instead. For refractory disease, systemic steroids in the form of prednisolone starting at 40 mg per day, decreasing gradually over 8 weeks, is appropriate. Moderate disease While initial treatment with 5-​aminosalicylic acid at doses greater than 2 g per day is an appropriate first-​line treatment, more pa- tients with moderate disease end up needing systemic steroids and these are sometimes used first line. Prevention of steroid-​induced bone thinning should be considered with, for example, calcium and vitamin D. When steroids are used first line, 5-​aminosalicyclic acid should also be given, although it is important to remember that a few patients experience worsening of symptoms with 5-​aminosalicyclic acid (see ‘Differential diagnosis’). Steroid-​refractory disease In those with severe symptoms (stool frequency of more than six per day with blood), failure to respond to oral prednisolone should prompt admission to hospital for treatment with intravenous steroids or escalation to biological therapy to induce remission. Treatment with thiopurines (mercaptopurine or azathioprine) is in- appropriate in this situation due to their slow onset of action. Three different anti-​TNF agents have been shown to be effective at inducing and maintaining remission in treatment-​refractory ulcera- tive colitis. Infliximab, adalimumab, and golimumab have all been shown to be superior to placebo in this setting. Unfortunately there are no head-​to-​head trials that directly compare their efficacy, and due to differences in trial design and in the subjects enrolled, it is dif- ficult to draw conclusions about which, if any, is the most effective. As with many drugs used in inflammatory bowel disease, real-​ world effectiveness of anti-​TNF in ulcerative colitis appears to be better than the efficacy demonstrated in the registration trials. The role of anti-​TNF drug level and antidrug antibody testing is likely to be of benefit in some scenarios, particularly in patients who are losing response, and, at least for infliximab, combining treatment with a thiopurine has been shown in a high-​quality randomized controlled trial to be more effective than using either drug alone. Screening for transmissible infections as well as for latent tubercu- losis with a chest radiograph and an interferon-​γ release assay or PPD test is regarded as good practice. Vedolizumab is an antibody to α4β7, an integrin expressed on white blood cells which home to the gut. It has been shown to be superior to placebo in treatment-​resistant ulcerative colitis although the effects are less marked in patients who have previously been ex- posed to anti-​TNF therapy. Its gut specificity means that the risk of systemic infection seen with nontargeted therapies appears to

section 15  Gastroenterological disorders 2946 be reduced. A recent trial comparing vedolizumab and anti-​TNF showed that adalimumab was less effective than vedolizumab in patients with moderate to severe ulcerative colitis. As more head- to-head studies become available, our understanding of treatment positioning will increase. Tofacitinib, an inhibitor of janus kinase, is an orally administered treatment that has recently been licensed for the treatment of ul- cerative colitis. It appears to be at least as effective as the available biological therapies. Early experience suggests that it may be the pre- ferred choice in patients who have failed biologics although it is also undoubtedly effective in biologic-naive patients. A whole host of biologic and non-biologic therapies are currently going through early and late phase trials with those targeting the Il-12/23 axis being the next to arrive on the market. Pharmaco­ economic considerations will undoubtedly influence treatment choice in many parts of the world particularly as patents expire allowing cheaper versions of new therapies to become available. Tacrolimus has also been used in patients who are refractory to oral corticosteroids. A randomized controlled trial demonstrated that response was more likely in tacrolimus-​treated patients than in those who received placebo. Overall, it must be remembered that a significant proportion of patients fail to respond to any of these therapies, in which case sur- gery remains an appropriate option. Steroid-​dependent disease Patients who fail to withdraw steroids without relapsing or who re- quire recurrent courses of steroids in quick succession are deemed steroid dependent. Because of the multiplicity of adverse outcomes associated with long-​term steroid use, as well as the inability of ster- oids to maintain remission, steroid-​sparing agents are introduced in steroid-​dependent patients. As a rule of thumb, up to one course of systemic steroids a year is thought to be acceptable. The options for steroid-​dependent patients include anti-​TNF therapy, anti-​integrin therapy and tofacitinib. However, as such pa- tients may not have active disease, it is also appropriate to consider using thiopurines. A Cochrane meta-​analysis has shown that these are effective steroid-​sparing agents in ulcerative colitis. They are usually initially given at a weight-​based dose of 1 to 1.5 mg/​kg of mercaptopurine or 2 to 2.5 mg/​kg of its prodrug azathioprine. Approximately one-​third of patients treated with thiopurines de- velop side effects that limit their use. Myelosuppression and liver dys- function can normally be identified with prospective monitoring of blood tests, unlike flu-​like symptoms and pancreatitis. Thiopurines are known to increase the risk of non-​Hodgkin’s lymphoma and nonmelanoma skin cancer although the absolute risk in patients aged under 50  years remains extremely low. Pharmacogenetic markers that allow prospective identification of patients who are more likely to develop side effects have been studied in recent years. One such pharmacogenetic marker has now entered routine clin- ical practice; measurement of the activity of the enzyme thiopurine methyltransferase (or genotypic assessment of TPMT) allows iden- tification of the 1 in 300 people with extremely low TPMT activity. Such patients are at extremely high risk of bone marrow suppres- sion if treated with thiopurines and should not receive azathioprine or mercaptopurine. However, equally importantly, approximately 1 in 10 people have intermediate activity of TPMT. While also at an increased risk of myelosuppression, they are also more likely to develop some of the other side effects commonly associated with thiopurines, such as flu-​like symptoms. Reduced dosing to ap- proximately 50% of the standard dose allows successful treatment in most of these patients. Thus, while TPMT testing is suggested in many guidelines, it is important to note that knowledge of TPMT phenotype or genotype does not negate the need for white blood cell count monitoring as non-​TPMT related myelosuppression also occurs. Another pharmacogenetic marker identifying non-TPMT related myelsuppression has recently been discovered such that NUDT15 genotyping may also soon enter clinical practice. In add- ition, whilst a recently identified marker for thiopurine-related pan- creatitis may not have great clinical utility, there is ongoing interest in pharmacogenetics in this field which may allow further person- alisation of therapy. Therapeutic drug monitoring with measure- ment of thiopurine metabolites such as the thioguanine nucleotides and methylated metabolites allows optimization of therapy, as well as identifying thiopurine-​resistant patients, and is becoming more widely used. Methotrexate has occasionally been used as an alternative immuno­ modulator to thiopurines although, unlike in Crohn’s disease, there is limited high-​quality evidence to support its use. Indeed, recent ran- domized controlled trials failed to reach their primary endpoints and with increasing alternative treatments available, the use of metho- trexate in this condition is likely to disappear. Severe disease The presence of more than six bloody stools a day in combination with any systemic systems such as fever, tachycardia, anaemia, or an ESR of more than 30 mm/​h defines severe disease and should prompt admission to hospital. Intercurrent infection is common and should be excluded by sending stool samples for microscopy and culture as well as for C. difficile toxin. A flexible sigmoidos- copy should be performed to confirm the diagnosis and to ex- clude intercurrent infection with cytomegalovirus. Treatment with high-​dose intravenous steroids, for example, 100 mg of hydrocortisone four times daily or 60 mg of methylprednisolone per day, should be initiated along with thromboprophylaxis with low molecular weight heparin as the risk of deep vein thrombosis and pulmonary embolism is greatly increased with active disease. The presence of rectal bleeding should not be used as a reason not to use thromboprophylaxis. Fluid and electrolytes should be replaced with particular attention being paid to potassium levels which are often low. Antibiotics are only needed if infection is considered likely. Nutritional supplementation should be given to malnourished patients. Patients should be reviewed daily by both a physician and a sur- geon experienced in the management of ulcerative colitis. After 3 days of treatment with intravenous steroids, an assessment of re- sponse should be undertaken. For those that are responding, who will have improvement in their stool frequency and rectal bleeding with an absence of systemic features, substituting the intravenous ster- oids with oral prednisolone is appropriate after 5 to 7 days. However, patients who have either more than eight stools a day, or who have three to eight stools per day and a CRP of greater than 45 mg/​litre after 72 h of intravenous steroids, have an 85% chance of requiring urgent surgery. Accordingly, colectomy or rescue therapy should be considered. The decision between ongoing medical therapy and sur- gery should involve a careful and thorough discussion between the

15.12  Ulcerative colitis 2947 patient, their physician, and the surgeon. Numerous factors weigh into this including the potential risks of each of the options, the quality of life experienced prior to the current attack, which thera- peutic options for maintenance of remission remain should rescue therapy be successful, and the patient’s personal preference. Rescue therapy Randomized controlled trial evidence supports the use of either ciclosporin or infliximab as rescue therapies for steroid-​resistant acute severe ulcerative colitis. Ciclosporin Ciclosporin should be given at a dose of 2 mg/​kg per day, usually as an intravenous infusion. Higher doses (e.g. 4 mg/​kg as was used in the original trial) are no more effective but are likely to be asso- ciated with a greater risk of side effects. Hypomagnesaemia should be corrected prior to use, and intravenous ciclosporin should be avoided in the presence of hypocholesterolaemia. An alternative in this situation may be to use oral ciclosporin (5 mg/​kg) which may be just as effective as the intravenous preparation having excellent bioavailability. Response should be assessed over 4 to 7 days. In the short term, response rates are in the region of 80%, although the likelihood of avoiding colectomy in the long term may be as low as 50% over 5 years. Infliximab Infliximab is more effective than placebo in patients with steroid-​ resistant acute severe colitis. While the initial trial demonstrating this used a single infusion of 5 mg/​kg, it has subsequently become apparent that the optimal regimen requires higher dosing. Indeed, preliminary data suggests that levels of infliximab can drop rapidly after dosing in acute severe colitis, perhaps due to loss into the bowel lumen, such that doses higher than 5 mg/​kg at weeks 0, 2, and 6 (the standard regimen for ulcerative colitis) may be needed to maximize the response. Poor response is associated with low serum albumin levels. While not supported by data in this setting, it is likely that in the longer term, the response to infliximab is likely to be improved when it is combined with a thiopurine, albeit at a higher risk of side effects. As for ciclosporin, of those patients that respond, many undergo colectomy over the ensuing years and patients should be made aware of this fact when deciding whether to receive rescue therapy or not. Ciclosporin or infliximab? Two randomized controlled trials have compared the use of ciclosporin and infliximab in patients with acute severe ulcerative colitis. One used a combined clinical endpoint, while the other had a quality-​adjusted outcome as its primary measure. Neither demon- strated a significant advantage of one drug over the other. Currently, the convenience of administering infliximab is probably its greatest advantage over ciclosporin. Whereas previously the lack of main- tenance options in azathioprine-​experienced patients drove the use of infliximab in this patient group, the advent of newer maintenance therapies makes this decision less clear. While it is unclear whether one drug is superior to the other in the setting of acute severe ulcerative colitis, case series suggest that sequential use of infliximab and ciclosporin or vice versa is inappropriate, being associated with an increased risk of morbidity and mortality. For patients who do not respond to rescue therapy after 4 to 7 days, or for those who deteriorate despite treatment, subtotal col- ectomy is mandated. Inappropriately delaying surgery is dangerous and best avoided by ensuring that decisions are taken at appropriate time points using a multidisciplinary approach. Maintenance therapy Once remission is achieved with 5-​aminosalicylic acid, mainten- ance is with continued treatment. Sulfasalazine was the first 5-​ aminosalicyic acid-​containing drug to be used in ulcerative colitis. Its use is limited by side effects related to the sulfapyridine component, which is released once the drug reaches the colon where bacteria act on the azo-​bond linking it to 5-​aminosalicylic acid. Common side effects include nausea and headache, but more serious side effects include agranulocytosis and reversible male infertility. Sulfasalazine, however, maintains a role in patients with coexistent enteropathic arthropathy, which may respond well to this drug. For most patients, however, newer preparations of 5-​aminosalicylic acid are available. As the drug is partially absorbed in the upper gastrointestinal tract, preparations which either delay its release until the distal small bowel or rely on bacteria to release the active com- ponent in the colon are generally used. Tolerance is usually excel- lent. Rare but serious side effects include pancreatitis and interstitial nephritis, which can lead to end-​stage renal failure. Accordingly, monitoring of renal function should be performed in patients taking 5-​aminosalicylic acid with the serum creatinine measured soon after starting and yearly thereafter. However, the most frequent side effect limiting its use is worsening of diarrhoea, which may occur in up to 10% of patients. Whichever preparation is used, once-​daily therapy has been shown to be at least as effective as multiple-​daily dosing and is likely to improve adherence. There is limited evidence to suggest that one preparation is better than another, although swapping to alterna- tive release preparation can on occasion be successful in cases of nonresponse. For patients with proctitis, topical maintenance therapy with sup- positories can be extremely effective and often does not necessarily require daily dosing. Maintenance therapy with steroids is inappropriate and as- sociated with a wide range of side effects. As described earlier, immunomodulators and biological therapies are both effective at maintaining remission. The cost associated with newer agents has been the greatest barrier to expanding use of these agents as mainten- ance therapy although the advent of biosimilar versions of anti-TNF has greatly decreased the economic burden associated with their use. The effectiveness as maintenance agents of biologics and tofacitinib and their long-​term safety profile (albeit limited for tofacitinib) ap- pears to be at worst comparable with immunomodulators. Thus, withdrawal of therapy is an area of increasing interest. Limited data are available for anti-​TNF withdrawal in ulcerative colitis where the greatest risk of stopping treatment probably relates to the risk of antibody production which may compromise subsequent reintro- duction. By comparison, withdrawal of thiopurine is probably suc- cessful in about half of patients who have been in remission in the long term; reassuringly, reintroduction of thiopurines is normally effective in patients who relapse.

section 15  Gastroenterological disorders 2948 Surgical management The need for surgery in patients with ulcerative colitis is driven by one of several scenarios: first, patients with acute severe colitis not responding to medical therapy; second, in the context of complica- tions of severe colitis such as toxic megacolon; third, patients with chronic disease activity; and, fourth, patients who have dysplasia or cancer. Particularly in the setting of active disease, a subtotal colectomy is usually performed initially. Restorative proctocolectomy with for- mation of an ileoanal pouch may then be offered. The J-​pouch is the preferred configuration as it involves a shorter operation time and has similar long-​term outcomes in terms of pouch function compared to larger-​volume configurations. Either a stapled pouch-​ anal anastomosis leaving a short cuff of rectal mucosa, or a hand-​ sewn pouch in association with a mucosectomy, can be performed (Fig. 15.12.6). In general, the former is associated with better con- tinence, although the latter prevents recurrence of dysplasia and the possibility of developing cuffitis. There is an increasing vogue for performing colectomy and pouch surgery using minimal access techniques resulting in an improved cosmetic appearance and a shorter length of stay. Pouch surgery is associated with a decrease in fecundity among females and with a risk of impotence and ejaculatory dysfunction in men. On rare occasions, ileorectal anastomosis is performed, although careful surveillance of the remnant rectum is required. Pouch function is generally good in most patients, with better outcomes being associated with high-​volume pouch centres. On average, patients with pouches open their bowels between four and six times a day and often once at night. Complications after pouch surgery include small-​bowel obstruction, which occurs in up to 30% of patients but usually responds to conservative management. Pouchitis occurs in approximately half of patients over a 10-​year period. Endoscopic assessment helps to exclude other conditions such as irritable pouches, cuffitis, ischaemia, Crohn’s disease, or in- fection. In assessing the pouch endoscopically, it is also important to inspect the prepouch ileum for inflammation or stenosis. Pouchitis normally responds to antibiotics such as ciprofloxacin and metronidazole, although long-​term treatment is sometimes needed. There is some evidence that VSL#3, a probiotic, is able to improve maintenance of antibiotic-​induced remission in patients with pouchitis. Approximately 5% of patients experience pouch failure resulting in a long-​term nonfunctioning pouch, pouch excision and per- manent end ileostomy, or a redo pouch operation. Prognosis/​outcome The outcome of ulcerative colitis is varied. A few patients have a single attack which responds to treatment without any subsequent relapses. At the other end of the spectrum, approximately 5% of pa- tients will have a severe attack at presentation necessitating colec- tomy. The remainder have a disease course somewhere in between. Most patients relapse within their first year after diagnosis and then go on to have regular relapses, but with a frequency of less than once per year. Approximately 10% will have more than one relapse per year and some have unremitting disease activity. Active inflammation, even in the absence of symptoms is a pre- dictive factor for future relapse. In addition, both macroscopic and microscopic inflammation are known to drive the risk of dysplasia and cancer. It is also likely that chronically active disease contrib- utes to the colonic dysfunction that is characteristic of long-​standing ‘burnt-​out’ colitis. The risk of requiring colectomy is difficult to determine but is probably in the region of 10%. Having extensive disease or disease extension is known to increase the risk of colectomy, and admission to hospital with an attack of acute severe colitis increases the like- lihood of subsequent colectomy fivefold. By comparison, patients with proctitis have a much lower risk of colectomy. Whether the ad- vent of new therapeutic options will dramatically alter the long-​term requirement for colectomy remains to be seen. Complications Acute complications Toxic dilatation Acute severe colitis can be associated with toxic dilatation of the colon, also known as toxic megacolon. It occurs in approximately 5% of cases of acute severe colitis and is recognized by radio- logical dilatation of the colon to 5.5 cm associated with signs of systemic toxicity. The use of antimotility drugs and opiates may precipitate toxic dilatation, as may electrolyte disturbances such as hypokalaemia and hypomagnesaemia. While patients who pre- sent with dilatation may respond to medical therapy, failure to re- spond within 24 h of intensive medical therapy or the development (a) (b) Fig. 15.12.6  Different methods to fashion an ileal pouch anal anastomosis. A double-​stapled technique leaves the anal transition zone intact and may be associated with better pouch function (a). A mucosectomy and hand-​sewn anastomosis removes all the colonic mucosa, is felt to reduce the long-​term risk of cancer in the rectal stump, but may be associated with an increased likelihood of faecal leakage (b). Reproduced from MacKay GJ, Dorrance HR, Molloy RG, O'Dwyer PJ (eds) (2010). Colorectal surgery (Oxford Specialist Handbooks in Surgery) with permission from Oxford University Press.

15.12  Ulcerative colitis 2949 of dilatation in the context of intensive therapy requires surgical intervention. Perforation Perforation is, fortunately, rare in the context of appropriately man- aged acute severe ulcerative colitis but can occur in the absence of toxic dilatation. It carries a high risk of mortality and can be the result of inappropriately delayed surgery. As the vast majority of patients who experience perforation are on high-​dose steroids to manage their colitis, it is important to remember that steroids can mask the signs of peritonitis. Colectomy is mandatory in the setting of ulcerative colitis-​associated perforation. Massive haemorrhage Uncontrollable colonic blood loss is rare in patients with ulcerative colitis. However, when it does occur, if medical therapy and resusci- tation fails, surgical intervention is required. Thromboembolism Pulmonary embolism remains an important cause of mortality in patients with ulcerative colitis. The risk is highest in patients who are hospitalized with acute colitis and those undergoing surgery. A wide range of venous and arterial thromboses are reported in association with ulcerative colitis, highlighting the importance of adequate thromboprophylaxis in this setting. Long-​term complications Colonic structural effects Strictures rarely form in people with chronic ulcerative colitis. They are associated with an increased risk of colorectal carcinoma and, if severe, prevent adequate colorectal cancer surveillance. Similarly, extensive pseudopolyp formation may make cancer surveillance more challenging. Patients who develop strictures or who have ex- tensive pseudopolyp formation should have a discussion about the risk:benefit balance of surveillance and colectomy. Colonic functional effects Chronic active disease is associated with colonic dysfunction. The typical appearance of a ‘lead pipe’ colon with a lack of haustration and a tubular structure provides a visual illustration of the effects of chronic activity on colonic function. Impaired motility and a lack of compliance can have devastating effects on colonic function, ex- plaining the greatly increased risk of faecal incontinence in patients with ulcerative colitis. Colorectal carcinoma There is a clear association between long-​standing ulcerative colitis and an increased risk of colorectal cancer, except in patients with proctitis. The risk is low during the first 8 years of disease, apart from in patients with specific risk factors such as primary sclerosing chol- angitis, advanced age, or a strong family history. Disease activity is probably the biggest risk factor and there is some evidence that the use of medications decreases the risk of colitis-​associated cancer. Estimates of the risk of developing cancer vary widely, but for pa- tients with extensive disease, the risk is probably lower than previ- ously thought; one of the original meta-​analyses suggested the risk of colorectal cancer was as high as 18% at 30 years, whereas more recent estimates have been as low as 2% at the same time point. Because of the risk of colitis-​associated colorectal cancer, screening is recommended. Current guidelines suggest that an index colonoscopy should be performed approximately 8  years after diagnosis to define microscopic and macroscopic disease ex- tent. It is important to note, however, that up to one in five colitis-​ associated cancers present before this time point. Subsequent colonoscopy should be performed at an interval of 1 to 5 years, depending on risk factors such as inflammation, family history, and disease extent. Patients with concomitant primary sclerosing cholangitis are at particularly high risk of developing colorectal cancer and should have an annual colonoscopy from the time of diagnosis of primary sclerosing cholangitis. Patients with proc- titis (and no past history of more extensive disease) do not re- quire screening. The presence of pseudopolyps makes screening more challenging and should be taken into consideration when determining the screening interval, or even the possibility of prophylactic colectomy. Screening colonoscopy is best performed by experienced colonoscopists familiar with techniques to enhance the detection of dysplasia. For example, chromoendoscopy employing pancolonic dye spray with targeted biopsies is now regarded as the gold standard. However, where this is not available, four random biop- sies taken every 10 cm has been shown to increase the chance of detecting dysplasia. Special circumstances Ulcerative colitis in pregnancy Fertility is unaffected by ulcerative colitis although voluntary child- lessness is increased in inflammatory bowel disease. Women who conceive while in remission are no more likely to relapse than nonpregnant women. However, if conception occurs during an ac- tive disease flare, this is associated with an increased risk of active disease throughout pregnancy. Most medications used to treat ulcerative colitis are considered low risk in pregnancy; the risk of active disease is greater than that associated with medication use with the exception of metho- trexate, which is teratogenic, and vedolizumab and tofacitinib, where there is not yet enough data to understand the risks of its use. 5-​aminosalicyclic acid, steroids, thiopurines, and anti-​TNF therapy are all used in pregnancy. The risk to the infant of infection in the first year of life associated with maternal anti-​TNF exposure ap- pears to be very small if, indeed, it exists. Nevertheless, because of the fact that anti-​TNF is actively transported across the pla- centa, therapy is sometimes withdrawn towards the end of the second trimester, although the risks of drug withdrawal need to be considered in this situation. Anti-​TNF-​exposed babies should not receive live vaccines until their serum levels of anti-​TNF have dropped. Ulcerative colitis does not necessitate caesarean section, although the presence of an ileoanal pouch is a relative contraindication to vaginal delivery. Breastfeeding is considered safe with standard ul- cerative colitis medications. Ulcerative colitis in childhood Onset of ulcerative colitis before the age of 10 years is unusual. However, when it does present in children, it probably has a more

section 15  Gastroenterological disorders 2950 severe phenotype than that seen in adults. Extensive disease is more common, accounting for up to 80% of colitis in children. Furthermore, failure to respond to steroids is more frequently encountered than in adult onset ulcerative colitis. It is probably for this reason that colectomy rates are significantly higher in children than in adults, reportedly being as high as 40% after 10 years of disease. Treatment principles are similar to adult-​onset ulcerative colitis although particular attention to steroid exposure and its effects on growth are required. Due to the higher incidence of steroid resist- ance, exposure to immunomodulating and/​or biological therapies is increased in childhood-​onset ulcerative colitis; dose adjustments may be necessary depending on the preparations used. Future developments The treatment of ulcerative colitis has been through a marked change over recent years. The availability of treatments with new modes of action as well as adaptation of traditional treatments to improve their effectiveness and tolerability has improved our ability to treat the condition. Several new treatments are likely to become available over the next few years. Accordingly, there is a need to identify ways in which patients can be profiled in order to treat them with the most effective medication. Such personaliza- tion of medicine is one of the ways in which the ever-​increasing challenges of the pharmacoeconomic impact of new, often ex- pensive, drugs can be addressed. Similarly, with increasing recog- nition of the relevance of mucosal healing and the possibility of long-​term complications arising from chronically active disease, it is imperative that research addresses long-​term benefits and safety, as well as the cost-​effectiveness, of more aggressive treat- ment strategies. FURTHER READING Duijvestein M, et al. (2018). Novel therapies and treatment strategies for patients with inflammatory bowel disease. Curr Treat Options Gastroenterol, 16, 129–​46. Harbord M, et al. (2017). Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management. Journal of Crohn’s and Colitis, 11, 769–84. Imdad A, et al. (2018). Fecal transplantation for treatment of inflam- matory bowel disease. Cochrane Database Syst Rev, 11, CD012774. Khalili H, et al. (2018). The role of diet in the aetiopathogenesis of inflammatory bowel. Nat Rev Gastroenterol Hepatol, 15, 525–35. Lamb CA, et al. (2019). British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, Sep 27. pii: gutjnl-2019-318484. Lee SH, Kwon JE, Cho ML (2018). Immunological pathogenesis of inflammatory bowel disease. Intest Res, 16, 26–​42. Limketkai BN, Wolf A, Parian AM (2018). Nutritional interventions in the patient with inflammatory bowel disease. Gastroenterol Clin North Am, 47, 155–​77. Magro F, et al. (2017). Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1:
Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. Journal of Crohn’s and Colitis, 11, 649–70. Matsuoka K, et al. (2018). Evidence-​based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol, 53, 305–​53. Mosli MH, et al. (2017). Histologic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Database Syst Rev, 5, CD011256. NG SC, et al. (2018). Worldwide incidence and prevalence of inflam- matory bowel disease in the 21st century: a systematic review of population-​based studies. Lancet, 23, 390, 2769–​78. Singh S, et al. (2019). AGA Technical Review on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology, 156, 769–808.

15.13 Irritable bowel syndrome 2951

15.13 Irritable bowel syndrome 2951

ESSENTIALS Symptoms suggestive of disturbed lower gastrointestinal func- tion without adequate explanation are very common in adults in the Western world, up to 15% of whom experience such symp- toms at any one time, although most do not seek medical advice. It is not clear whether the symptoms of those individuals who
do seek medical help have a different pathophysiological basis from those who do not, and whether the seeking of medical advice is more an indication of a worried individual than of disturbed gut function. The currently used terms are best viewed as an attempt to pro- vide some clinically useful, rather than pathophysiologically ac- curate, categorization of patients and their symptoms based on disordered gut–​brain interactions. Irritable bowel syndrome is defined according to the Rome IV criteria as recurrent abdominal pain associated with a change in frequency or form of stool that is related to defecation for at least 3 months. Many subtypes are recognized. Routine haematological and biochemical screening is usually performed on the assumption that it will be normal. Features that raise the suspicion of organic disease and indicate a need for fur- ther investigation include the onset of symptoms in middle-​aged or older individuals, weight loss, or blood in the stool. Management remains empirical:  no single pharmacological agent or group of agents has ever been found to be consistently effective. The principal task of the physician is to provide explan- ation and reassurance (sometimes supplemented by psychological treatments), but particular symptoms are often treated as follows:
(1) constipation—​defecation may be eased by supplementary dietary fibre and poorly absorbed fermentable carbohydrates which in- crease faecal bulk and soften the stool; osmotic laxatives and enemas are used for the severely constipated patient, as well as more novel agents; (2) diarrhoea—​attention to diet is often helpful, as are simple antidiarrhoeal agents; and (3)  abdominal pain—​ antispasmodics (e.g. hyoscine butyl bromide) are frequently used, as are antidepressants. Introduction The functional gastrointestinal (GI) disorders are a heterogeneous group of syndromes, which can be defined as ‘variable combin- ations of chronic or recurrent gastrointestinal symptoms which are not explained by structural or biochemical abnormalities’. These disorders are common, accounting for more than 40% of all new referrals to secondary care gastroenterological clinics, although the overwhelming majority of patients are managed in primary care. However, the multifaceted pathophysiology that underpins symptom genesis and maintenance in functional GI disorders is incompletely understood. As a result, there is a relative paucity of efficacious treatments and long-​term patient outcomes are sub- optimal. It is therefore not surprising that the socioeconomic impact is considerable, with healthcare costs estimated to be in the order of $34 billion per annum in the seven largest Western healthcare economies, notwithstanding the impact in terms of the reduction in quality of life. The most commonly encountered functional GI disorder in clin- ical practice is irritable bowel syndrome (IBS), although a variety of terms have been used to describe this disorder in the past such as ‘nervous colitis’ and ‘spastic colon’. Despite a considerable research effort towards identification of objective biomarkers, IBS remains a symptom-​based diagnosis in the absence of another ‘organic’ cause. The Rome foundation, an international committee of experts, has sought to systematize the diagnosis of IBS with a focus to improve homogeneity within both the research and clinical spheres. In order to separate IBS from transient gut symptoms, the current diagnostic criteria place an emphasis upon the chronic relapsing–​remitting nature of the disorder. IBS is defined according to Rome IV criteria as recurrent abdominal pain associated with a change in frequency or form of stool that is related to defecation for at least 3 months (Box 15.13.1). Despite the Rome classification, it is often helpful to summarize the symptoms of IBS using the ABC mnemonic (Fig. 15.13.1). Considering that abdominal pain and/​or discomfort remains a central defining feature of IBS, it is not unsurprising that it is 15.13 Irritable bowel syndrome Adam D. Farmer and Qasim Aziz

section 15  Gastroenterological disorders 2952 the symptom most likely to prompt medical consultation, yet it re- mains challenging to manage effectively. IBS accounts for between 40 and 60% of outpatient referrals to gastroenterology clinics and thus, with such a considerable burden of disease, the development of a complete understanding of the underlying pathophysiology of this complex disorder remains the prerequisite step on the road to the development of efficacious treatments. Although this under- standing is in its nascent stages, the last two decades have wit- nessed remarkable progress in unravelling the complexities of this disorder. Pathogenesis and aetiology The pathoaetiology of IBS is complex and multifactorial. A useful approach is to consider it in terms of a construct referred to as the brain–​gut axis. This refers to circuitous communication between the GI tract and the brain, which has gained widespread accept- ance as helpful for providing an explanation of both normal GI function, and acute and chronic perturbations thereof. The model has also provided a useful framework to conceptualize the various pathoaetiological factors of IBS, whether they are biological, psy- chological, or social in nature (Fig. 15.13.2). Genetic influences Within families, a number of studies have reported clustering of IBS, and twin studies demonstrate heritability in the order of 40%. Many candidate genes have been investigated in IBS, including those encoding the serotonin transporter SLC6A4, 5-​hydroxytryptamine 2A (5-​HT2A) receptor, norepinephrine transporter, alpha2A and 2C-​adrenergic receptor, and the β3 subunit G protein. However, the results from these studies have been largely disappointing since reproducibility across different cohorts is lacking, most likely re- flecting the problem of these initial underpowered small studies. To combat these limitations, large population-​based genome-​ wide association studies (GWASs) represent one of the most exciting potential avenues. A recently published GWAS of more than 500 IBS cases and 5000 healthy controls has revealed that a locus at 7p22.1 was consistently associated with IBS. This locus includes coding regions for the KDEL endoplasmic reticulum protein retention receptor 2 (KDELR2) and glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein, although the functional significance of these in IBS remains to be fully explored. Another potential application of the GWAS approach is its poten- tial to predict treatment using pharmacogenetic profiles. Although such an approach is in its infancy, a European collaborative has re- cently been set up to improve homogeneity in sampling and tech- nical methods, from which it is hoped that significant progress will be made (GENes in Irritable Bowel Syndrome Research Network EURope, http://​www.GENIEUR.eu). Infection IBS can occur after an enteric infection, where it is termed postinfectious IBS. Although most individuals who develop an infectious gastroenteritis have self-​limiting symptoms, approxi- mately 25% develop IBS-​like symptoms that outlast the initial infection. Specific personality traits, such as neuroticism and anx- iety, are independent risk factors for postinfectious IBS, which has been documented to occur after infections with a variety of enteric pathogens including campylobacter, salmonella, shigella, and Escherichia coli. Notably, community outbreaks of water-​borne infections, such as was seen in Walkerton, Ontario, Canada, when the town’s water supply was contaminated with E. coli, have pro- vided the opportunity to prospectively examine the pathophysi- ology and natural history of the postinfectious condition. The outcome of these studies has highlighted the deficiency of ubi- quitous pathophysiological features across patients, suggesting marked intraindividual variability. Visceral hypersensitivity Currently, the favoured hypothesis to account for chronic abdom- inal pain and discomfort in IBS is visceral hypersensitivity. Some patients with IBS have a heightened sensitivity to mechanical disten- sion of the rectum, which is referred to as ‘visceral hypersensitivity’ (Fig. 15.13.3). This epiphenomenon has resulted in a considerable research effort aimed at identifying the underlying causative mech- anisms. For instance, sensitization of the peripheral and central nervous system, psychological factors, and dysfunction within the stress response systems, namely the autonomic nervous system and the hypothalamic pituitary adrenal axis, have been implicated as co- variant factors. However, testing of rectal distension lacks the pre- requisite sensitivity and specificity for it to become a routine clinical diagnostic test. Psychological factors Psychological comorbidities such as somatization, anxiety, depres- sion, and hypochondriasis have been linked with IBS. In addition, Box 15.13.1  Rome IV Criteria for the diagnosis of Irritable Bowel Syndrome Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months, associated with 2 or more of the following criteria: • Related to defecation • Associated with a change in frequency or form of stool • Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis Bloating Change in bowel habit Abdominal pain or discomfort Fig. 15.13.1  The ABC of IBS. The characteristic symptoms are abdominal pain or discomfort, bloating, and change in bowel habit.

15.13  Irritable bowel syndrome 2953 Genetics Internal factors Hypothalamic- pituitary- adrenal axis response Bidirectional communcation Bidirectional communcation Autonomic nervous system response Gastrointestinal Tract Sensory modulation Neuroendocrine response Emotion, feeling arousal, vigilance External factors Inflammation Infection Adverse life events Fig. 15.13.2  The construct of the brain–​gut axis is useful for ‘conceptualizing’ the pathoaetiological factors in IBS. IBS patients report first sensation and pain at lower distension volumes than healthy controls IBS patients Rectal balloon distension Healthy controls Fig. 15.13.3  Visceral hypersensitivity in IBS. Patients with IBS, in general, report first sensation and pain at lower levels of rectal balloon distension compared with healthy controls.

section 15  Gastroenterological disorders 2954 adverse life events, such as sexual and physical abuse, are linked with the disorder. Increased levels of psychiatric comorbidity are seen in tertiary care IBS clinics compared to community populations. Gut microbiota Advances in culture-​independent techniques have facilitated both quantification and qualitative evaluation of the microbiological population residing within the GI tract, hereinafter referred to as the GI microbiota. The GI microbiota is a diverse ecosystem that inhabits the entire length of the GI tract, with microbial cells outnumbering human cells by approximately 10 to 1. Most of the microbiota resides within the colon (approximately 1014 organisms). Prior to birth, the GI tract is largely sterile, but is vertically in- oculated from the mother’s vagina during delivery, with subsequent establishment of the diverse microbiota ecosystem during the first year of life. During early life, the GI microbiota becomes increas- ingly diverse and is influenced by the external environment, dietary components, genetic factors, and ethnicity. The relationship between the GI tract and the microbiota is complex and symbiotic. While arguably the main function of the GI microbiota is to protect against external pathogens, it has also been shown that it influences and modulates cognition, including learning and memory. Studies have demonstrated that germ-​free animals, inoculated with the GI microbiota from IBS patients, can induce a state of visceral hypersensitivity and alterations in GI transit. Moreover, recent studies in IBS patients have demonstrated two species-​specific subtypes of IBS, which were independent of symptom-​based/​Rome classifications. The first of these showed a microbial composition similar to normal, while the second was characterized by an increase in firmicutes-​associated taxa, with a relative depletion of bacteroides-​related taxa. The implication of these data suggests GI microbial enterotyping may facilitate strati- fication of IBS subpopulations, which may lead to individualization of treatment. However, such techniques remain resource intensive, thereby limiting their utility in routine clinical practice. Recent data have suggested that nonabsorbable antibiotics, such as rifaximin, are associated with a moderate improvement in global symptoms and also abdominal pain and bloating. Further studies are needed to replicate these initial findings and to ascer- tain whether patients need regular retreatment to maintain the therapeutic effect. Faecal microbiota transplantation has received considerable attention recently, particularly in the treatment of pseudomem- branous colitis caused by Clostridium difficile. It has been shown to be more effective for the treatment of recurrent C. difficile infection than the use of oral antimicrobials, such as vancomycin. Given the role of the microbiota in IBS, a number of preliminary case reports and retrospective studies examining the efficacy of faecal microbiota transplantation in the treatment of IBS have been reported. These have shown promising results, although to date there are no pro- spective, randomized, double-​blinded, placebo-​controlled trials. Epidemiology Worldwide, IBS affects approximately 5 to 20% of individuals, depending on the definition of IBS used. One large United Kingdom-​ based study of 580 000 primary care patients has estimated that the incidence of IBS is approximately four new cases per 1000 population per annum, with the peak occurring in the 18 to 34 years age group, declining with increasing age thereafter. The prevalence is around 25 times that of the incidence, hence IBS can be regarded as a chronic disorder. Several risk factors have been identified, the most reprodu- cible of which is female sex, with an odds ratio of 1.67. IBS is frequently associated with other disorders including gastro-​oesophageal reflux disease, functional dyspepsia, and psy- chiatric comorbidity such as anxiety, depression, and somatiza- tion. Furthermore, IBS is also associated with other medically unexplained disorders/​functional somatic syndromes such as fibro- myalgia, chronic fatigue syndrome, and migraine. Clinical features Current guidelines recommend that the diagnosis of IBS should be positively made, based on characteristic symptoms, rather than by exclusion based on a battery of (negative) investigations. While there is no clinically applicable biomarker for IBS, the diagnosis is based upon the patient fulfilling the diagnostic criteria in conjunc- tion with a small number of targeted investigations. The central defining clinical features of IBS are recurrent ab- dominal discomfort and/​or pain associated with a change in in stool frequency or consistency (Fig. 15.13.4). In many patients, the abdominal discomfort is sometimes relieved following defe- cation. IBS is frequently associated with a plethora of extra-​GI manifestations including tiredness, headache, dysmenorrhoea, and dyspareunia in females. While symptoms characteristically change over time, patients typically report pain or discomfort on approximately 3 days per week, frequently occurring in clusters. Although IBS is currently subdivided based upon predominant bowel habit, patients frequently move from one subtype to an- other over time. IBS with diarrhoea (IBS-​D) is reportedly the 100 75 50 25 0 0 25 50 Percentage time of loose/watery stool IBS-C IBS-M IBS-D IBS-U Percentage time of hard/lumpy stool 75 100 Fig. 15.13.4  The different subtypes of IBS are classified according to the predominant bowel habit. IBS with constipation (IBS-​C), IBS with diarrhoea (IBS-​D), IBS with mixed bowel habit (IBS-​M), and IBS unclassified (IBS-​U).

15.13  Irritable bowel syndrome 2955 commonest subtype, accounting for approximately 40% of cases, with mixed IBS (with alternating constipation and diarrhoea; IBS-​M) being the least common. IBS with constipation (IBS-​C) is significantly more common in women, and IBS-​D has been dem- onstrated to be more common in men. IBS is associated with a re- duction in health-​related quality life, increased absenteeism from work, as well as a diminution in productivity. By definition, the physical examination in IBS is normal, although it should be undertaken to reassure the patient as well as to help exclude other organic diseases. For instance, a rectal examination is often helpful to identify patients with disordered defecation syn- dromes such as dyssynergic defecation. Differential diagnosis and investigations Patients displaying the typical features of IBS, in the absence of alarm or red flag symptoms (Box 15.13.2), can be confidently diagnosed with IBS. Given the relative lack of specificity of symp- toms in IBS, the differential diagnosis is broad and includes lac- tose intolerance, small intestinal bacterial overgrowth, coeliac disease, inflammatory bowel disease, bile acid malabsorption, and food allergies. Screening investigations typically include a full blood count, inflammatory markers (such as ESR and/​or C-​reactive protein), serum ferritin and vitamin B12, thyroid function tests, serological testing for coeliac disease (antitissue transglutaminase antibodies), and consideration of testing CA125 in women. Recent evidence has shown that a faecal calprotectin concentration of less than 40 μg/​g and a C-​reactive protein concentration of less than 0.5 mg/​dl can confidently exclude inflammatory bowel disease in patients with IBS symptoms. Stool microscopy may be helpful in diagnosing chronic enteric in- fections such as giardiasis, although these are uncommon in western IBS patients. In elderly patients, endoscopic imaging of the colon is required in order to exclude microscopic colitis, which is common and can account for up to 20% of unexplained diarrhoea in patients aged over 70 years. Bile acid malabsorption is also an important differential diag- nosis of IBS with diarrhoea, since the clinical response to bile acid sequestrants, such as cholestyramine, is good. A recent meta-​ analysis reported that 28.7% of those meeting the criteria for IBS with diarrhoea had bile acid malabsorption, which can be diagnosed using 75SeHCAT testing. In patients with watery diarrhoea, the diag- noses of small intestinal bacterial overgrowth and lactose intoler- ance should also be considered. Further testing is not required in most cases of IBS, although if alarm symptoms are present, or if there is diagnostic uncertainty regarding an inflammatory disorder, then colonoscopy can be con- sidered. In patients presenting with diarrhoea, colonic biopsies should be taken at colonoscopy to exclude microscopic colitis, espe- cially in females over 50 years old. In patients with severe constipa- tion, further investigation directed at assessing colonic motility may be performed, for instance, a transit study, or evaluating anorectal anatomy and physiology, such as a colonic marker study, anorectal manometry or proctography. In patients presenting with severe pain and other red flag symptoms, further investigations such as cross-​ sectional imaging should be considered. Figure 15.13.5 shows a sug- gested diagnostic algorithm for the patient presenting with IBS-​like symptoms. Box 15.13.2  Alarm symptoms that should prompt further investigation • Abnormalities on clinical examination • Weight loss • Rectal bleeding or masses • Nocturnal symptoms • History of recent antibiotic use • Raised inflammatory markers • Family history of colorectal carcinoma or ovarian cancer Fig. 15.13.5  Suggested diagnostic algorithm for IBS. CRP, C-​reactive protein; ESR, erythrocyte sedimentation rate; FBC, full blood count; TFTs, thyroid functions tests; tTG, tissue transglutaminase.

section 15  Gastroenterological disorders 2956 Management: general approaches Given the incomplete understanding of the pathophysiology of IBS, treatment is directed towards the predominant or most bothersome symptom(s). Central to a successful outcome is the doctor–​patient relationship. In particular, validation of a patient’s symptoms in a supportive environment is an absolute corner- stone of management. It is not uncommon to encounter patients who have experienced negative attitudes towards their symptoms from healthcare professionals, a situation compounded by the current lack of an objective diagnostic biomarker. Such negative attitudes result in a breakdown of the therapeutic relationship and thus patients are often disenfranchised. Reassurance and education are required, and the underlying rationale of treat- ment should be discussed in detail with the patient when this is initiated. The clinician and the patient should also agree upon, and set, reasonable treatment goals in the context of regular outpatient re- views. In this context, it is important not to underestimate the role of the wider multidisciplinary team, such as colleagues in psych- iatry, psychology, and dietetics. The frequency and regularity of such reviews may be limited by local service provision, but they do permit definition of response or nonresponse, facilitate earlier es- calation of intervention as appropriate, and importantly also leave patients with a sense of confidence that their symptoms are being taken seriously. Although such an approach is resource intensive, over the long term it is likely to be cost-​effective, and most IBS pa- tients will not need such an intensive approach. In addition to these general approaches, various interventions have been suggested as being beneficial, including lifestyle measures and pharmacological and psychological treatments. The National Institute for Health and Care Excellence has recently published up- dated clinical guidelines on the management of IBS. A central aspect of pharmacological management is the stratification of patients into the predominant subtype of IBS, which aids in directing therapeutics towards the most problematic symptoms. A management algorithm is shown in Fig. 15.13.6. Lifestyle and dietary interventions There are numerous lifestyle aspects that can be modified, and which frequently result in symptomatic improvement. For example, patients should be given written information emphasizing the im- portance of self-​help measures such as taking exercise and creating time to relax. General advice includes taking regular meals, drinking at least eight cups of fluid per day, and limiting caffeinated drinks. Patients often report that certain dietary components can both precipitate and exacerbate symptoms, hence their diet and nutrition should be assessed. The role of avoidance of certain dietary com- ponents has generated considerable interest in the role of ferment- able oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) in the symptomology of IBS. FODMAPs are ferment- able carbohydrates, which provide substrate to the GI microbiota, resulting in enhanced colonic fermentation and the production of intraluminal gaseous distension in addition to exerting a direct os- motic effect. The net result is colonic distension, which may mani- fest as bloating, distension, and abdominal pain. Foods high in Establish therapeutic relationship, reassurance, and education Establish IBS subtype/predominant bowel habit All management undertaken in the context of regular review IBS-constipation IBS-diarrhoea First-line pharmacology Antispasmodics Simple laxatives First-line pharmacology Antispasmodics Loperamide Second-line pharmacology Linaclotide Low-dose SSRI* Second-line pharmacology Low-dose TCA* Consider ondansetron* For patients unresponsive to standard therapies consider: Referral to psychiatrist with expertise in managing IBS Psychological interventions such as hypnotherapy or cognitive behavioural therapy Antibiotics, probiotics Exercise Increase fluid intake Dietary advice Consider dietician referral for low-FODMAP diet Fig. 15.13.6  A suggested management approach for IBS.

15.13  Irritable bowel syndrome 2957 FODMAPs include fruits such as apples, peaches, and nectarines, lactose-​containing substances, legumes, and artificial sweeteners such as those containing sorbitol (Fig. 15.13.7). A randomized con- trolled crossover trial reported that patients with IBS had a reduc- tion in bloating, abdominal pain, and flatus, with greater satisfaction with stool consistency, with a diet low in FODMAPs. Furthermore, a recent study has reported that dietitian-​led FODMAP group educa- tion is clinically effective and may represent significant cost savings over individually administered advice. Pharmacotherapy Elucidation of optimum pharmacotherapy has proved difficult in IBS, not least due to a particularly high placebo response rate, which is approximately 40%. This means that to demonstrate the ef- ficacy of a novel compound, over and above the placebo response rate, the recruitment of large numbers of participants is necessary. Nevertheless, there are a variety of pharmacological options, which are included in most recent United Kingdom clinical guidelines, al- though the absolute evidence base for many of these is limited. Antispasmodic drugs Antispasmodic drugs largely compete with acetylcholine at post- ganglionic vagal nerve endings and therefore reduce the strength of smooth muscle contraction, reducing abdominal pain. A recent Cochrane database system review has highlighted cimetropium/​ dicyclomine, peppermint oil, pinaverium, and trimebutine to be beneficial in reducing IBS symptoms (Table 15.13.1). Low-​dose antidepressants Low-​dose tricyclic antidepressants are recommended as second-​line treatment for those patients in whom laxatives, loperamide, or anti- spasmodics have not reduced symptoms. The exact mechanisms by which they exert their analgesic effects within the viscera are yet to be completely understood, although they modulate both ascending Lactose Fructans/frutose FODMAPs Gas distension Osmotic effect Increased abdominal pain and distension Polyols Fig. 15.13.7  A schematic detailing the mechanism of action of foods that are high in FODMAPs on symptom production in IBS. Lactose (e.g. milk, yoghurt, custard, ice cream), fructans/​fructose (e.g. apples, garlic, onions, wheat) and polyol (e.g. plums, peach, pear, watermelons) components of food are high in FODMAPs and cause a gaseous and osmotic distension effect. In patients with IBS, this can lead to increased abdominal pain and distension. Table 15.13.1  The relative risk of improvement in abdominal pain, global assessment, and symptom score using antispasmodics in patients with IBS IBS symptom Relative risk 95% confidence interval Numbers needed to treat Improvement in abdominal pain 1.32 1.12–​1.55 7 Improvement in global assessment 1.49 1.25–​1.77 5 Improvement in symptom score 1.86 1.26–​2.76 3

section 15  Gastroenterological disorders 2958 visceral sensory afferents and central transmission, slow GI transit, and treat comorbid anxiety and depression. Tricyclic antidepres- sants reduce persisting IBS symptoms by an odds ratio of 0.68. It is important to present the rationale for using tricyclic antidepres- sants in patients with IBS and to communicate potential side effects including tiredness, dry mouth, and constipation. Considering that constipation is a side effect, it is recommended that amitriptyline be avoided in patients with IBS-​C. Selective serotonin reuptake inhibitors are thought to select- ively block the presynaptic serotonin reuptake transporter, thereby increasing the quantity of serotonin within the synaptic space. Citalopram has been shown to reduce abdominal pain in com- parison to placebo in IBS patients, an effect that was independent of drug-​induced changes in anxiety and depression. Selective sero- tonin reuptake inhibitors can cause diarrhoea and are therefore gen- erally best avoided in patients with IBS-​D. Psychological and psychiatric therapies In IBS, psychological treatments as a class of interventions per se are effective in reducing symptom burden and treating coexistent psychiatric pathology. Behavioural therapies, including cognitive behavioural therapy, dynamic psychotherapy, and hypnotherapy, all alleviate symptoms associated with IBS. For example, gut-​focused hypnotherapy, whereby the aim is to reassure the patient regarding their symptoms with the aid of hypnosis, improves GI symptoms through cognitive changes and has been demonstrated to signifi- cantly improve abdominal pain and quality of life in a cohort of pa- tients with drug-​refractory IBS. The role of the psychiatrist with an interest in functional GI disorders is a critical facet of management of IBS patients, and in particular those in whom symptoms are recalcitrant to standard therapies. In such patients, there may be coexistent psychiatric diag- noses that warrant expert evaluation and treatment. Manipulation of the microbiota Considering that the microbiota is a burgeoning area of research in the field, a considerable effort has been afforded to studying both probiotics and antibiotics. Although the quality of evidence for probiotics is limited, a large placebo-​controlled trial of rifaximin, a nonabsorbable antibiotic, observed symptomatic improvement, al- though the numbers needed to treat were relatively high. Given con- cerns around antimicrobial resistance, further work is needed to stratify patients who may preferentially benefit from this intervention. Management: specific types of irritable
bowel syndrome Constipation predominant IBS In those with IBS-​C, simple laxatives such as senna and docusate are often effective in managing symptoms, in addition to lifestyle measures. Lactulose is often poorly tolerated, due to worsening of bloating, and is therefore not advocated. Linaclotide is a minimally absorbed peptide guanylate cyclase-​C agonist and recommended as second-​line therapy in patients who have symptoms for longer than 12 months. Its mechanism of action is shown in Fig. 15.13.8a. Notably, linaclotide has an important ef- fect on colonic nociceptors, which is a central feature of IBS-​C, and two randomized controlled trials have shown it to be effective in re- ducing abdominal pain, bloating, and constipation symptoms. The 5-​hydroxytryptamine (serotonin) type 4 (5-​HT4) agonists such as tegaserod have been demonstrated to be effective, although this particular compound was withdrawn due to an excess of cardio- vascular side effects in comparison to placebo. The results from trials of newer agents, such as prucalopride and naronapride, with a more favourable side-​effect profile, are awaited. The mechanism of action of 5-​HT4 agonists is shown in Fig. 15.13.8b. Linaclotide (a) (b) Lumen Increased 5-HT Enterochromaffin cells Mucosa Lumen 5-HT4 agonist Submucosal plexus Circular muscle Myenteric plexus Increased contractions and prokinetic effect Serosa Afferent pain fibres Enterocyte CFTR P GC-C + GTP cGMP PKGII + Fig. 15.13.8  Mechanism of action of guanylate cyclase-​C (GC-​C) agonists and 5-​HT4 agonists. (a) Intraluminal linaclotide binds to the GC-​C receptor stimulating the production of cyclic GMP (cGMP) leading to activation of protein kinase II (PKGII) and phosphorylation (P) of the cystic fibrosis transmembrane conductance regulator (CFTR) and secretion of chloride (Cl−) and bicarbonate (HCO3 −) into the lumen which is followed by sodium (Na+) and water (H2O). The overall effect is to increase/​accelerate intestinal transit. cGMP also inhibits the afferent pain fibres leading to analgesia. (b) Circulatory 5-​HT4 agonists activate 5-​HT4 receptors on enterochromaffin cells within the GI tract causing direct activation of the enteric nervous system leading to increased frequency and strength of contractions within the circular muscle in the GI tract leading to a prokinetic effect.

15.13  Irritable bowel syndrome 2959 Diarrhoea-​predominant IBS Loperamide exerts an antidiarrhoeal effect through the inhibition of peristalsis, leading to prolongation of gut transit time through its action as a mu (μ)-​opioid receptor agonist. It does not cross the blood–​brain barrier and is frequently used as a first-​line agent in IBS-​D. Although loperamide has no benefit on overall symptoms in IBS, it does reduce stool frequency and defecatory urgency and im- proves stool consistency. 5-​HT3 receptor antagonists may be effective in the management of treatment IBS-​D symptoms, given serotonin is a major mediator of afferent nerve signalling and prokinetic activity within the GI tract. Previously, the 5-​HT3 receptor antagonist aldosterone was ap- proved for use as a second-​line agent in IBS-​D, although it has been withdrawn due to the rare complication of ischaemic colitis. Since this withdrawal other 5-​HT3 receptor antagonists have been studied. A recent placebo-​controlled crossover trial of ondansetron in 120 IBS-​D patients has shown significant improvement in IBS symp- toms, including reduced urgency within 7 days of treatment. Given that ondansetron has a well-​established safety profile from its use as an antiemetic agent for many years, these initial findings warrant further investigation. Conclusions and future directions IBS remains a prevalent, multifactorial, and enigmatic disorder. Its diagnosis relies on the identification of a characteristic symptom pattern coupled with the exclusion of other organic disorders. In reality, however, it is likely that IBS represents a number of distinct pathophysiological processes that culminate in identical clinical phenotypes. While the diverse management options available offer the potential to improve symptoms, further work is warranted on the individualization of therapeutic interventions. Nevertheless, despite the clinical burden of IBS, it remains a fruitful area of gastro- enterological practice and clinical research. The pharmacotherapeutic pipeline for IBS is a fruitful area of development with a number of novel compounds in active phase II and III development. In IBS-​C, plecanatide, another guanylate cyclase-​C agonist, and A3309, an ileal bile acid transporter inhibitor, are demonstrating promise in early-​phase clinical trials. Phase III studies of eluxadoline, a locally active, mixed μ-​opioid receptor agonist/​delta (δ)-​opioid receptor antagonist, have shown moderate efficacy in the treatment of IBS-​D. FURTHER READING Canavan C, West J, Card T (2014). Review article: the economic im- pact of the irritable bowel syndrome. Aliment Pharmacol Ther, 40, 1023–​34. Chang L, Lembo A, Sultan S (2014). American gastroenterological association institute technical review on the pharmacological management of irritable bowel syndrome. Gastroenterology, 147, 1149–​72.e2. Chey WD, et  al. (2012). Linaclotide for irritable bowel syndrome with constipation: a 26-​week, randomized, double-​blind, placebo-​ controlled trial to evaluate efficacy and safety. Am J Gastroenterol, 107, 1702–​12. Ford AC, et al. (2009). Efficacy of antidepressants and psychological therapies in irritable bowel syndrome:  systematic review and meta-​analysis. Gut, 58, 367–​78. Jeffery IB, et al. (2012). An irritable bowel syndrome subtype de- fined by species-​specific alterations in faecal microbiota. Gut, 61, 997–​1006. Mearin F, et al. (2016). Bowel Disorders. Gastroenterology, pii: S0016- 5085(16)00222-5. doi: 10.1053/j.gastro.2016.02.031. Simren M, et al. (2013). Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut, 62, 159–​76.

15.14 Colonic diverticular disease 2960

15.14 Colonic diverticular disease 2960

ESSENTIALS Colonic diverticula are herniations of mucosa through the bowel musculature. They are seen most often in the sigmoid and descending colon, with a prevalence of up to 65% in people over the age of 80 in European populations. They are uncommon in African and Asian countries, where the prevalence is only 0.2%. A lifelong diet deficient in dietary fibre is associated with their development, but it is not known why some diverticula become symptomatic. Diverticula are usually discovered incidentally, but symptoms which are attributable to diverticular disease include colicky abdom- inal pain and bloating, often accompanied by a change in bowel habit with the passage of broken, pellety stools after considerable straining. All patients with such presentation should be investigated to exclude rectal or sigmoid carcinoma. Treatment is with reassurance that there is no serious underlying disease, a high-​fibre diet, and—​for patients with pain—​antispasmodics such as mebeverine. Elective resection may be indicated in the few patients who have repeated severe attacks. Complications of diverticular disease include diverticulitis, pericolic abscess formation, peritonitis, intestinal obstruction, haem- orrhage, and fistula formation. Acute diverticulitis typically presents with pain and tenderness over the left lower abdomen, and the pa- tient may have pyrexia, malaise, anorexia, and nausea. Treatment is with rest, broad-​spectrum antibiotics, and analgesia. Resection of the sigmoid colon may be necessary if symptoms fail to resolve or recur, or for patients with complications (peritonitis, fistula, obstruc- tion). Overall, percutaneous drainage, antibiotic treatment, and ex- pectant policies have reduced the need for both acute and elective surgical treatment. Epidemiology The term diverticular disease was first described in the medical literature at the turn of the 20th century. The first case of resec- tion for a complication of diverticular disease was documented by Mayo in 1907. Autopsy studies in the United Kingdom and Australia have shown that the prevalence of colonic diverticula increases with age. It is less than 5% at the age of 40 years, at the age of 60 it is 30%, and it rises to 65% by the age of 80. In Edinburgh, 23% of all barium enemas demonstrated diverticula. The annual incidence increased from 0.17 in 1000 in those under 45 years to 5.7 in 1000 in those over 75 years of age. Subtle sex differences have been observed: women were affected more than men. A study in eastern England measured the incidence of perforation sec- ondary to diverticular disease. They observed that there was in- crease in perforation with age and after adjusting for age there was a higher incidence in males (5.1 in 100 000/​year in males and 3.6 in 100 000/​year in females). In spite of the introduction of high-​fibre diets, there is no evidence that the incidence of diverticular disease is declining. A recent review has observed a slight rise in the preva- lence of perforated diverticular disease in Western countries from 2.4 in 100 000 in 1986 to 3.8 in 100 000 in 2000. By contrast, colonic diverticulosis is very rare in African and Asian countries where the prevalence is 0.2%. Interestingly, in a re- view of 600 Japanese patients with diverticular disease, right-​sided colonic disease was demonstrated in 70%. This geographical distri- bution is not simply due to genetic factors and race, as Asian and African migrants moving to the United Kingdom or the United States of America have acquired the prevalence of disease seen in the native white population, which suggests an environmental risk factor, thought to be dietary. This is in agreement with the observa- tion that patients presenting with complicated diverticular disease have a low intake of dietary fibre, and vegetarians have a low inci- dence of the disease. Multiple other factors have also been impli- cated in the development of diverticular disease, including lack of physical exercise, obesity, smoking, and immunosuppression. Aetiology Diverticular disease is said to be a disease of the 20th century and in the United Kingdom there is a correlation between the rising in- cidence at the beginning of the 20th century and an increased con- sumption of refined flour and sugar. Sugar consumption has trebled since 1860, and in the late 1870s the stone grinding of flour was re- placed by roller milling, which removes more fibre. Modern white bread and some brown breads contain little fibre compared with the 15.14 Colonic diverticular disease Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and Neil J.McC. Mortensen

15.14  Colonic diverticular disease 2961 amount in wholemeal bread, which was previously a staple part of the diet. The development of diverticula may be heavily influenced by a lifelong diet deficient in dietary fibre. A high-​fibre diet is related to reduced gut transit times, with less strain on the colon. Modern, fibre-​deficient diets on the other hand give rise to stiff, viscous stools that need high intracolonic pressures to propel them. High luminal pressures cause a protrusion of the mucosa through vul- nerable points in the sigmoid and descending colon. These usually occur at sites where colonic blood vessels penetrate the wall. This hypothesis is supported by the observation that, although basal intracolonic pressures are similar in health and diverticular disease, when the diseased colon is activated by emotion, eating, mechanical stimuli, or drugs such as morphine or prostigmine, high pressures are generated in those segments that have diverticula. This is due to hypersegmentation by the colonic smooth muscle, and the dif- ference has been recorded in the earliest stage of disease and may explain its progressive nature. In symptomatic patients, an increase in dietary fibre causes a relief of symptoms in many cases. Changes in the colon wall also play a part. With age, and fol- lowing episodes of diverticulitis, the colonic wall becomes stiff and less distensible, aggravating the effects of raised intracolonic pres- sure. An increase in elastin and changes in collagen have been re- ported. Diabetic patients are prone to diverticular disease at an earlier stage, suggesting a defect in glycosylation of colonic collagen with advancing age. In those with connective tissue disorders such as Ehlers–​Danlos syndrome or Marfan’s disease, diverticula are also seen at an unusually early age. Pathogenesis of diverticular complications The distinction between symptomatic and asymptomatic diver- ticular disease is important, for although something is known about the formation of diverticula, it is not known why some diverticula become symptomatic. A large American cohort study has shown that high red meat in- take and a diet deficient in fruit and vegetables multiplied the risk of developing symptomatic diverticular disease threefold. The benefits of fibre are thought to be secondary to their effect in reducing gut transit times and colonic segmentation. Secondly, there may be a symbiotic effect related to the formation of short-​chain fatty acids, which are released after bacterial action on fibre. On the other hand, certain chemicals in cooked meat such as heterocyclic amines are thought to trigger cytotoxicity of colonocytes. The pathogenesis of diverticular perforation is not clear. However, rises in intradiverticular pressure are thought to play a role. This may be secondary to a blockage of the mouth of a diverticulum with faecal material or colonic segmentation. Once the pressure rises over a critical threshold, focal ischaemia leading to necrosis occurs. This would then allow the passage of luminal bacteria into the local pericolic tissue. With time, this would mature into a local abscess. In cases of failure of local tissue to contain the infection, there may be a progression to a faecal peritonitis. This spectrum of diverticular complications can be classified into the four stages as proposed by Hinchey (Table 15.14.1). More recently, a practical classification based on CT findings has been proposed, which is effectively a modified Hinchey classification (Table 15.14.2). The sigmoid colon, which is less compliant than other colonic segments, is where intraluminal colonic pressures are highest. This reflects the observation that the sigmoid colon is the commonest area in the colon to develop diverticular disease and also sec- ondary complications such as perforation. It has also been noted that diverticula are very distensible and other factors are thought to play a role in whether complications such as perforation occur. Pathology reveals that diverticula consist mainly of a mucosal layer and any factor that results in changes of the integrity of the mu- cosal barrier will result in alteration of the ability microbial popu- lation to pass into the local tissues. This can be divided into factors affecting: • the microbial flora (antibiotics and fibre deficiency) • mucin secretion (nonsteroidal anti-​inflammatory drugs (NSAIDs) and fibre) • epithelial cell insult (NSAIDs) • immune activity in the colonic wall (age, drugs such as cortico- steroids and immunosuppressants) There is a growing body of evidence that NSAIDs have a role to play in complicated diverticular disease. Two prospective case–​control studies have shown patients with complications of diverticular disease were more likely to be taking NSAIDs than age-​matched controls. Another study compared 115 cases with complicated di- verticular disease with 77 with uncomplicated disease. NSAIDs and corticosteroids were found to be associated with development of peritonitis and abscess formation. Also, a large American co- hort study following over 35 000 male health professionals showed that individuals on NSAIDS had a relative risk of 2.2 of developing symptoms of abdominal pain, bleeding, or change in bowel habit secondary to diverticular disease. The action of NSAIDs may be sec- ondary to a reduction in mucosal blood flow as a result of modula- tion of prostaglandin levels. Table 15.14.1  Hinchey classification of sepsis/​contamination in diverticulitis Stage Characteristics I Pericolic abscess II Contained pelvic, retroperitoneal, or distant intraperitoneal abscess III Generalized purulent peritonitis, no communication with bowel lumen IV Generalized faecal peritonitis, communication with bowel lumen Table 15.14.2  Modified Hinchey classification in diverticulitis Stage Characteristics 0 Mild clinical diverticulitis Ia Ib Confined pericolic inflammation—​phlegmon Confined pericolic abscess II Pelvic, or distant intra-​abdominal, or retroperitoneal abscess III Generalized purulent peritonitis IV Faecal peritonitis

section 15  Gastroenterological disorders 2962 Pathology A diverticulum consists of a herniation of mucosa through the co- lonic musculature. As it enlarges, its muscular covering atrophies, so that the fully developed diverticulum consists of mucosa, connective tissue, and peritoneum, making it strictly a false diverticulum. The striking abnormality is in the thickening of the circular and longitu- dinal muscle, which both narrows the colonic lumen and shortens the sigmoid like a concertina to give a ‘sawtooth’ appearance on barium enema. The diverticula occur as slit-​like apertures between the muscle clefts. Inflammation in diverticular disease is the result of infection around diverticula, which spreads within the pericolic fat to form a dissecting abscess. Usually a single diverticulum is the cause of a pericolic abscess, perhaps initiated by the presence of a faecolith. Involvement of the peritoneum results in local peritonitis, which may become generalized in the event of a perforation. This may also give rise to intra-​abdominal abscesses or fistulas to the bladder, small bowel, vagina, or uterus. Repeated episodes of diverticulitis lead to a contracted, narrowed sigmoid colon surrounded by fibrous tissue. Bleeding in diverticular disease can often be traced to an in- fected diverticulum. This may cause either the erosion of a vessel in its wall or the formation of granulation tissue inside the diver- ticulum, which then bleeds. Clinical features, investigation, and management Only 15 to 25% of cases of diverticular disease result in symptoms, of which 75% develop diverticulitis. They are usually discovered in- cidentally. The symptoms usually result from disordered motility ra- ther than secondary complications of the disease. Uncomplicated diverticular disease Symptoms which are attributable to diverticular disease include col- icky abdominal pain and bloating. Pain can be felt along the course of the colon, particularly over the sigmoid, and is often accompanied by a change in bowel habit with the passage of broken, pellety stools after considerable straining. Examination may reveal some tender- ness over the sigmoid colon without guarding or evidence of sys- temic upset. These symptoms may be indistinguishable from those of the irritable bowel syndrome. The passage of blood with an un- formed stool needs to be investigated thoroughly to exclude more sinister pathology. All patients should have a CT colonography or flexible sigmoidos- copy to exclude a rectal or sigmoid carcinoma (Fig. 15.14.1). Once diagnosed, patients should be reassured that there is no serious underlying disease and a high-​fibre diet should be recommended. Exercise and high dietary fibre have been shown to prevent the devel- opment of diverticular disease in prospective studies. However, evi- dence for the efficacy of dietary fibre for the treatment of established diverticular disease is not conclusive, as shown by two random- ized controlled trials where only one showed improved symptoms. Current dietary recommendations include wholemeal bread, whole- wheat breakfast cereals, rough porridge, or muesli, and fresh fruit and vegetables daily. Fibre increases stool bulk in three ways—​by holding water, by proliferation of bacteria, and from the by-​products of bacterial fermentation. The coarser the fibre, the greater is the faecal bulk, but also the greater the unpalatability. Although cooking bran improves its taste, it reduces its water-​holding capacity. A good clinical response is usually achieved by including two tablespoons of bran with the morning cereal, but about one-​half of patients will experience gaseous distension or cramps on starting the high-​fibre diet. It is worth warning them that this is likely to happen and that it will resolve within a month or so if they persist with the diet. More recent studies looking at pharmacological agents have shown some benefit with rifaximin (a derivative of rifamycin), pro- biotics, and fibre. Mesalazine has also been associated with a de- creased recurrence of symptoms over placebo. However, this study also showed that abdominal pain was more common in the treat- ment group. A case–​control study has shown that mesalazine is as- sociated with reduced intracolonic pressure and a reduction in the perforation rate. A reduction in perforation rate was also observed with the use of calcium channel blockers. This is thought to act via the mechanism of reducing intracolonic pressure. Long-​term use of opioids may be detrimental in such patients, resulting in an in- creased risk of developing perforation. In patients with pain, antispasmodics such as mebeverine may be useful. In a minority with repeated severe attacks, an elective laparo- scopic resection might be indicated (Table 15.14.3). This is probably more effective than sigmoid myotomy, an operation that became popular in the mid 1960s. In this procedure, the circular muscle is divided with a longitudinal incision to widen the colonic lumen. The incision is made through the taenia so as to avoid opening diver- ticula, and is deepened until the mucosa is just seen. The operation Table 15.14.3  Indications for surgery in diverticular disease Sepsis Purulent peritonitis Faecal peritonitis Nondrainable pelvic or pericolic abscess Colonic obstruction Inflammatory stricture Fibrotic stricture Suspected malignancy Fistulae Colovesical Colovaginal Ileocolic Major haemorrhage Fig. 15.14.1  Barium enema showing a narrowed sigmoid colon with a few diverticula. This appearance can be confused with that of a carcinoma and colonoscopy would be indicated to clarify the diagnosis.

15.14  Colonic diverticular disease 2963 lowers the sigmoid intraluminal pressures and improves symptoms but, after 3 years, pressures return to their former levels. The use of myotomy has declined and the procedure is now rarely, if ever, performed. The current gold standard is a laparoscopic sigmoid resection. Complicated diverticular disease Complications of diverticular disease include diverticulitis, which can be subdivided into uncomplicated and complicated attacks. The latter subgroup includes patients with pericolic abscess for- mation, peritonitis, fistula formation, intestinal obstruction, and haemorrhage. Complicated diverticular disease results in significant morbidity and mortality. This has obvious cost implications in terms of expend- iture in health services across the Western world. It is important to distinguish the minority of patients who suffer from a febrile attack with left iliac fossa peritonism, sometimes called left-​sided appendi- citis, from those with chronic pain and diarrhoea. The inflammation may settle with minimal symptoms, or develop into a pericolic ab- scess or peritonitis. Clinical assessment alone for the diagnosis of diverticulitis (or its complications) is not precise enough. CT is highly accurate and should be performed. Ultrasonography or MRI can be used as an al- ternative to diagnose acute diverticulitis, with the choice depending mainly on local preferences and experience. There is no role for col- onoscopy in the acute phase. Acute diverticulitis Pain is felt over the left lower abdomen, and the patient may have pyrexia, malaise, anorexia, and nausea which is evidence of sys- temic upset. The neutrophil count and C-​reactive protein level are raised. This is as a result of localized bacterial infection in the colonic wall causing an inflammatory infiltrate thus resulting in systemic manifestations. In some cases, right iliac fossa tender- ness may be present due to sigmoid colon looping to the right side of the abdomen. This may be diagnosed at laparoscopy for right iliac pain. The generally recommended treatment is with rest, antibiotics, usually co-​amoxiclav 1.2 g and metronidazole 500 mg 8-​hourly (ef- fective against Gram-​negative bacteria and anaerobes), and anal- gesia. Most patients with an uncomplicated attack can be treated as outpatients. It is noteworthy, however, that a recent randomized trial showed that antibiotic treatment for acute uncomplicated diverticu- litis did not accelerate recovery, also that antibiotics did not pre- vent complications or recurrence. Regardless of the treatment, most cases settle within a few days and the diagnosis can be confirmed after 6 to 8 weeks with imaging or endoscopy. A narrow segment can sometimes be difficult to distinguish from a carcinoma and any doubtful cases can be clarified by subsequent careful colonoscopy (Fig. 15.14.2). Routine intraluminal imaging following an episode of CT-​ or ultrasonography-​diagnosed acute diverticulitis is recom- mended to exclude the occasional synchronous cancer. If symptoms fail to resolve, or recur, laparoscopic resection of the sigmoid colon may be necessary. When it is necessary to resect an acutely inflamed and unprepared colon, a Hartmann’s operation may be safer than a sigmoid colectomy as the former avoids an anastomosis, although recent studies have shown the feasibility and safety of primary anastomosis in these circumstances. Complications will normally develop during the primary episode, with further episodes having less inflammatory sequelae. The risk of recurrence after the first episode ranges from 7 to 60%. Elective surgery after uncomplicated diverticulitis may be indicated by the presence of persistent symptoms, and the frequency and severity of attacks. It would also be reasonable to discuss surgery in a patient under the age of 50 years presenting with severe, complicated di- verticulitis for the first time. However, this needs to be tempered by the observation from a population-​based study that only 25% of patients with perforated diverticulitis actually had a previous his- tory of diverticular disease. This is in agreement with other studies which puts the range at 3 to 30%. Furthermore, following elective operation, 10% develop recurrent diverticulitis. Patients being con- sented for elective operations therefore need to be fully informed of the potential risks and benefits. Current guidelines do not suggest the routine indication for elective surgery following uncomplicated diverticulitis. There is little evidence to support a different management strategy in younger patients compared to older ones. However, earlier elective surgery might be justified in immunocompromised patients because of an increased risk of complications in this population. For recur- rent diverticulitis operated electively, a primary anastomosis would be ideal. Diverticular abscess Acute diverticulitis can lead to a local peritonitis with abscess forma- tion, either in the paracolic or pelvic area. There may be a palpable mass and a swinging fever. When in doubt, the diagnosis should be confirmed by spiral CT scanning with rectal contrast (Fig. 15.14.3). The latter investigation is excellent at demonstrating bowel wall thickening, abscess formation, and extraluminal disease. The speci- ficity is high (>97%). The size of the abscess can be measured. Small abscesses less than 5 cm in size can be treated with antibiotics with good outcome. Those less than 2 cm in size can be treated with anti- biotics in the community. It is wise to let an abscess localize while treating the patient with rest, antibiotics, and analgesia. Some abscesses will be amenable to Fig. 15.14.2  The typical appearance of diverticula seen at colonoscopy. Note the muscular haustra and the mouths of diverticula—​one with a faecolith. From the Slide atlas of gastroenterology, Gower Medical Publishing, London, with permission.

section 15  Gastroenterological disorders 2964 drainage by direct incision, either over them or via the rectum or va- gina. More complicated collections, especially in the pelvis, are best drained by CT-​guided aspiration or drain placement. There is rarely any need to do a proximal transverse colostomy. If drainage persists, an elective laparoscopic sigmoid colectomy with primary anasto- mosis can be done at a later date. Even when an abscess is localized, there is a risk of rupture into the peritoneal cavity with subsequent generalized peritonitis. Perforated diverticulitis Acute diverticulitis can be complicated by generalized purulent peri- tonitis, either by direct spread from the inflamed colon or by rupture of a peridiverticular abscess. Purulent peritonitis carries a mortality of around 15%. The clinical picture is of severe intraperitoneal sepsis with toxaemia, ileus, and abdominal pain, and generalized sepsis will often follow. Before surgery, such patients need to be intensively resuscitated with intravenous fluids together with administration of systemic antibiotics. Once stabilized, they require emergency laparotomy. Other causes of the acute abdomen that may not require surgery should be excluded, including pelvic inflammatory disease, ureteric calculus, and even pulmonary embolus. In these circumstances, spiral CT scanning is invaluable. Surgical options include: • laparoscopic lavage with drainage • defunctioning transverse loop colostomy • Hartmann’s procedure—​removing the diseased sigmoid, over- sewing the distal rectum, and bringing out an end colostomy • colonic resection and primary anastomosis Laparoscopic washout has been shown to be an effective option in selected cases where there is no evidence of widespread faecal con- tamination, but its use remains controversial. Drains are routinely left in place at the end of the procedure. An elective laparoscopic sigmoid resection is advised at least 12 weeks after the initial attack. Defunctioning stomas are associated with complications of ongoing sepsis secondary to residual faecal material that is still pre- sent within the septic colon. Historically, complicated diverticular disease was managed in three stages in which initially the sepsis was drained together with the formation of transverse loop colostomy. This was then followed by resection of the diseased segment and end colostomy followed by reversal. However, this required three hospital admissions and resulted in considerable morbidity. The reduction to a two-​stage (Hartmann’s) procedure resulted in a drop in mortality rates. More recent studies suggest that in a selected case group a one-​ stage process involving primary anastomosis is not associated with increased mortality rates. This has the added advantages of reducing hospital readmissions, although there is a risk of potential leak, and most patients with a primary anastomosis require a defunctioning ileostomy There has been a shift away from the more conservative procedures in this situation due to the residual ‘septic colon’ and the further problem of the unsuspected carcinoma within the inflam- matory mass. For these reasons, experienced colorectal surgeons tend to perform colonic resections. Hartmann’s operation is still the procedure most frequently used (Fig. 15.14.4). Hartmann’s procedure is safe and effective and removes the postoperative risk of anastomotic leak, although subsequent (a) (b) Fig. 15.14.4  (a) The area of sigmoid colon resected for perforated diverticular disease. (b) Hartmann’s operation—​the sigmoid colon has been resected, the rectum oversewn, and a left iliac fossa colostomy fashioned. Fig. 15.14.3  CT of the pelvis in a patient with acute diverticulitis. The sigmoid colon is grossly thickened, the lumen narrowed, and pockets of air are seen in the diverticular disease.

15.14  Colonic diverticular disease 2965 reconnection involves a major operation in older patients. A signifi- cant proportion of patients (up to 40%) do not undergo reversal, thus adding weight to the argument for the one-​stage procedure in selected and stable cases. Faecal peritonitis This is a catastrophic complication with a mortality approaching 50% in patients over the age of 80 years. A diverticulum ruptures, often with little or no inflammation, liberating quantities of faeces into the peritoneal cavity. Rapid and severe septic shock ensues. Energetic resuscitation is necessary, followed promptly by sur- gery and a Hartmann’s operation. These patients often need to be stabilized in an intensive care unit postoperatively. Intestinal obstruction Recurrent inflammation with fibrosis and muscular hypertrophy can lead to progressive stenosis and colonic obstruction, which is usually chronic but may present acutely. Conservative treatment is worth trying at first, provided a carcinoma has been excluded. With the aid of a stool softener, the symptoms may resolve and the stric- ture gradually dilate. If these measures fail, the bowel should be prepared for a laparoscopic segmental colonic resection, with care taken not to aggravate the obstruction. A surgical resection is also indicated if a carcinoma cannot be excluded. Small-​bowel obstruction is sometimes a complication of acute diverticulitis, as the bowel may adhere to the inflammatory mass. It usually resolves as the inflammation subsides but on occasion, surgery is required for division of adhesions or even a small-​bowel resection. Colonic fistulas A colovesical fistula usually presents with recurrent urinary tract in- fections, together with pneumaturia or faecuria. The fistula arises in the sigmoid, which has often folded over into the pouch of Douglas, and adheres to the apex of the bladder. This is the most frequent cause of colovesical fistula, but carcinoma and Crohn’s disease should be excluded. In women, this condition is usually seen after hysterectomy. Fistulas may also occur between the sigmoid and vagina, uterus, ureter, and ileum. They seldom heal spontaneously but do not always give rise to disabling symptoms and so represent a relative indication for surgery. Sigmoid colectomy as a one-​stage procedure is the best option, and colostomy is rarely required. A fistula into the bladder is simply closed. Urethral catheter drainage is continued for a week, and can be removed after a cystogram has excluded a urinary leak. Haemorrhage Major haemorrhage is an uncommon but well-​recognized compli- cation. Bleeding from the colon only accounts for 20% of gastro- intestinal haemorrhages, of which 50% are diverticular in origin. It is important that other more common causes for bleeding such as polyps and angiodysplasia are excluded by angiographic studies or CT angiography and colonoscopy. Most patients tend to be eld- erly. Massive bleeding is defined when over 40% of blood volume is lost. This can be catastrophic in older patients who have a reduced physiological capacity to maintain vital organ perfusions. Massive bleeds tend to present as fresh rectal bleeding. Up to 80% will settle down spontaneously and require only transfusion and supportive measures. The initial management of these patients in- cludes oxygen therapy with adequate venous access. Disorders of coagulation need to be identified and corrected during the ongoing resuscitation process. It is important to exclude upper gastrointes- tinal bleeding by way of endoscopy. Colonoscopy in the immediate aftermath of a bleed can be difficult but in experienced hands the diagnostic yield can be high as 70%. The endoscope needs to have a wide-​bore suction channel and excessive insufflation needs to be avoided due to the risk of causing a rebleed. In units with access to vascular services, mesenteric angiography can be performed. An ongoing minimum bleeding rate of 1 to 1.5 ml/​min is required to accurately localize the lesion. Therapeutic interventions that are available include vasopressin injection and selective embolization, though this carries a risk of colonic ischaemia. Radiolabelling is usually reserved for patients who are haemo- dynamically stable, with no access to vascular radiology and failure to establish a diagnosis during endoscopy. However, in circum- stances where there is accelerated transit of blood, localization can be poor. As the haemorrhage can be from any part of the colon, good localization is an essential prelude to any operation. Blind colonic resections have a particularly poor record and if the site of bleeding has still not been located, on-​table colonic lavage via the appendix stump and intraoperative colonoscopy will usually target the bleeding segment. A study published in The New England Journal of Medicine re- ported the results of urgent colonoscopy in bleeding diverticular disease. Instead of the traditional conservative measures, pa- tients were given bowel preparation and colonoscoped within 12 h. Bleeding sites thus identified were treated by colonoscopic diathermy and the number of major bleeds, blood transfusions, and operations was reduced together with length of hospital stay. It remains to be seen whether this will result in a major shift of emphasis in management. However, the main objective in these patients should be proper monitoring and prompt investigation after admission with colonic bleeding. FURTHER READING Angenete E, et al. (2014). Laparoscopic lavage is feasible and safe for the treatment of perforated diverticulitis with purulent periton- itis: the first results from the randomized controlled trial DILALA. Ann Surg, 263, 117–​22. Biondo S, et al. (2002). Acute colonic diverticulitis in patients under 50 years of age. Br J Surg, 89, 1137–​41. Boulos BP, et al. (1984). Is colonoscopy necessary in diverticular dis- ease? Lancet, i, 95–​6. Brodribb AJ (1977). Treatment of symptomatic diverticular disease with a high fibre diet. Lancet, i, 644–​66. Campbell K, Steele RJ (1991). Non-​steroidal anti-​inflammatory drugs, and complicated diverticular disease: a case-​control study. Br J Surg, 78, 190–​1. Buchs NC, et al. (2013). Assessment of recurrence and complications following uncomplicated diverticulitis. Br J Surg, 100, 976–​9. Chabok A, et al. (2012). Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. Br J Surg, 99, 532–​9. Cirocchi R, et al. (2013). Treatment of Hinchey stage III-​IV diverticu- litis: a systematic review and meta-​analysis. Int J Colorectal Dis, 28, 447–​57.

section 15  Gastroenterological disorders 2966 Eastwood MA, et al. (1977). Variation in the incidence of diverticular disease within the city of Edinburgh. Gut, 18, 571–​4. Eastwood MA, et al. (1978). Comparison of bran, ispaghula and lac- tulose on colon function in diverticular disease. Gut, 19, 1144–​7. Feingold D, et al. (2014). Practice parameters for the treatment of sig- moid diverticulitis. Dis Colon Rectum, 57, 284–​94. Fozard JBJ, et al. (2011). ACPGBI position statement on elective resec- tion for diverticulitis. Colorectal Dis, 13 Suppl 3, 1–​11. Gear JSS, et al. (1979). Symptomless diverticular disease and intake of dietary fibre. Lancet, i, 511–​14. Gianfranco JA, Abcarian H (1982). Pitfalls in the treatment of gastro- intestinal bleeding with blind subtotal colectomy. Dis Colon Rect, 25, 441–​5. Grief JM, Fried DO, McSherry CK (1980). Surgical treatment of per- forated diverticulitis of the sigmoid colon. Dis Colon Rect, 23, 483–​7. Heaton KW (1985). Diet and diverticulosis—​new leads. Gut, 26, 541–​3. Hughes LE (1969). Postmortem survey of diverticular disease of the colon. Gut, 10, 336–​51. Hyland JMP, Taylor I (1980). Does a high fibre diet prevent the compli- cations of diverticular disease? Br J Surg, 67, 77–​9. Janes SEJ, Meagher A, Frizelle FA (2006). Management of diverticu- litis. BMJ, 332, 271–​5. Jensen DM, et al. (2000). Urgent colonoscopy for the diagnosis and treatment of severe diverticular haemorrhage. N Engl J Med, 342, 78–​82. Jones OM, et al. (2008). Laparoscopic resection for diverticular dis- ease: follow-​up of 500 consecutive patients. Ann Surg, 248, 1092–​7. Kaiser AM, et al. (2005). The management of complicated diverticu- litis and the role of computed tomography. Am J Gastroenterol, 100, 910–​17. Kettlewell MGW, Moloney GE (1977). Combined horizontal and lon- gitudinal colomyotomy for diverticular disease: preliminary report. Dis Colon Rect, 20, 24–​8. Krukowski ZH, Koruth NM, Mattheson NA (1985). Evolving practice in acute diverticulitis. Br J Surg, 72, 684–​6. Krukowski ZH, Mattheson NA (1985). Emergency surgery for diver- ticular disease complicated by generalised and faecal peritonitis: a review. Br J Surg, 71, 921–​7. Morris CR, et al. (2002). Epidemiology of perforated colonic diver- ticular disease. Postgrad Med J, 78, 654–​9. Myers E, et al. (2008). Laparoscopic peritoneal lavage for generalised peritonitis due to perforated diverticulitis. Br J Surg, 95, 97–​101. Oberkofler CE, et al. (2012). A multicentre randomized clinical trial of primary anastomosis or Hartmann’s procedure for perforated left colonic diverticulitis with purulent or faecal peritonitis. Ann Surg, 256, 819–​26. Ornstein MH, et al. (1981). Are fibre supplements really necessary in diverticular disease of the colon? A controlled clinical trial. BMJ, 282, 1353–​6. Painter NS (1975). Diverticular disease of the colon. Heinemann Medical, London. Papi C, et al. (1995). Efficacy of rifaximin in the treatment of symptom- atic diverticular disease of the colon: a multi-​centre double-​blind placebo-​controlled trial. Aliment Pharmacol Ther, 9, 33–​9. Reilly M (1966). Sigmoid myotomy. Br J Surg, 53, 859–​63. Smith AN, et  al. (1969). Clinical and manometric results one year after sigmoid myotomy for diverticular disease. Br J Surg, 56, 895–​9. Vennix S, et al. (2014). Systematic review of evidences and consensus on diverticulitis: an analysis of national and international guidelines. Colorectal Dis, 16, 866–​78. Whiteway J, Morson BC (1985). Elastosis in diverticular disease of the sigmoid colon. Gut, 26, 258–​66. Wilson RG, Smith AN, Macintyre IM (1990). Complications of diver- ticular disease and non-​steroidal anti-​inflammatory drugs: a pro- spective study. Br J Surg, 77, 1103–​4.

15.15 Congenital abnormalities of the gastrointest

15.15 Congenital abnormalities of the gastrointestinal tract 2967

ESSENTIALS Congenital abnormalities of the gastrointestinal tract can be divided into macroscopic anatomical abnormalities and single gene high- penetrance functional defects that present either directly postnatally or during the first few months of life. On occasion, symptoms may be delayed for months or years even in patients with substantial ana- tomical defects. Anatomical and structural abnormalities can affect any part of the gut. These include oesophageal atresia and tracheo-​oesophageal fis- tula, anterior abdominal wall defects, congenital pyloric stenosis, atresia and stenosis of the small intestine, duplication of the gastrointestinal tract, small intestinal malrotation with or without volvulus, small intes- tinal lymphangiectasia, Meckel’s diverticulum, congenital short intes- tine syndrome, colonic atresia, Hirschsprung’s disease, and imperforate anus. Meconium ileus is an intestinal obstruction that develops in utero, often associated with subsequent structural abnormalities. The widespread use of ultrasonography allows many abnormal- ities to be recognized prenatally. Presentation of structural congenital abnormalities of the gastrointestinal tract in adult life is uncommon, but small intestinal lymphangiectasia, Meckel’s diverticulum, or small intestinal obstruction can present beyond childhood. Functional congenital abnormalities include multiple genetic defects that cause congenital diarrhoea due to malabsorption and maldigestion, defects in enterocyte and enterochromaffin cell de- velopment, and autoimmune enteropathies. In addition, there is a group of genetic defects that predispose to development of extreme early infantile onset of inflammatory bowel disease. An interdisciplinary approach is required for the optimal manage- ment of children with complex congenital abnormalities. Congenital structural abnormalities Oesophageal abnormalities Oesophageal atresia and tracheo-​oesophageal fistula The incidence of this condition is approximately 1 in 2500 to 1 in 4500 live births. The occurrence is typically sporadic. In about 85% of cases, the upper oesophagus ends in a blind pouch and the lower oesophagus communicates with the trachea via a tracheo-​ oesophageal fistula. In addition, there are other anatomical vari- ations as indicated in Fig. 15.15.1. Clinical features In some children, the combination of polyhydramnios and absent gastric bubble can suggest an oesophageal atresia during prenatal ultrasonographic scans. About 40% of infants with oesophageal atresia are born prematurely and some are small for gestational age. Shortly after birth, copious amounts of frothy saliva dribble from the mouth, associated with choking, dyspnoea, and cyanotic episodes. Frequent suction is required to keep the airway clear. The infant with a tracheo-​oesophageal fistula without associated oesophageal atresia coughs, chokes, and becomes cyanosed during feeds. As air escapes through the fistula into the oesophagus, gaseous distension of the abdomen is frequently present. Aspiration of feed into the airway results in pulmonary collapse and consolidation. In children with lower tracheo-​oesophageal fistulas, acidic stomach secretions can reach the lungs and contribute to complications. Over 80% of infants with oesophageal atresia have cardiac, ano- rectal, urogenital, or skeletal anomalies (or combinations such as VACTERL association). Cardiac anomalies occur in up to 60%, with ventricular septal defects and tetralogy of Fallot being most common. 15.15 Congenital abnormalities of
the gastrointestinal tract Holm H. Uhlig 85% 2% <1% 8% 4% Fig. 15.15.1  Anatomical variations of oesophageal atresia and tracheo-​ oesophageal fistula with their relative frequencies indicated.

section 15  Gastroenterological disorders 2968 Survival of infants with oesophageal atresia is high (95%) but depends on specialized care and risk factors such as low birth weight, associated congenital abnormalities, and complications (pneumonia). Diagnosis When oesophageal atresia is suspected, a size 10 or 12 FG catheter is passed through the mouth and into the oesophagus. If the oe- sophagus is obstructed, the catheter meets a resistance 9 to 12 cm from the gum margin. A smaller catheter may curl up in the ob- structed oesophagus. Contrast studies of the oesophagus are rarely necessary. A chest and abdominal radiograph will show the position of a radio-​opaque tube in the upper oesophagus. The presence of gas in the bowel despite an oesophageal atresia indicates a tracheo-​ oesophageal fistula. Complete absence of gas in the abdomen is diagnostic of an oesophageal atresia without a distal tracheo-​ oesophageal fistula. The radiograph will also reveal abnormalities of ribs or vertebrae, signs of pneumonia, and may provide evidence of an associated cardiac abnormality. In isolated tracheo-​oesophageal fistula, very contrast studies of the oesophagus may demonstrate the fistula, but endoscopic exam- ination of the trachea and oesophagus is usually diagnostic. Management Early division of the tracheo-​oesophageal fistula and anastomosis of the oesophagus are possible in most cases. A primary anastomosis may not be feasible in oesophageal atresia with a long gap, extreme prematurity, or where the infant’s general condition is poor. A gas- trostomy or a transanastomotic nasogastric tube is usually used for feeding after operation. In case of long-​gap oesophageal atresia, sev- eral surgical and thoracoscopic procedures aim to elongate the oe- sophagus and adjust the ends of the atretic oesophagus to provide continuity. Postoperative complications include anastomotic leaks, gastro-​oesophageal reflux, anastomotic strictures (30–​40%), and oe- sophageal dysmotility. Anterior abdominal wall defects Exomphalos The incidence of exomphalos is approximately 1 in 5000 births. An exomphalos occurs when the abdominal contents, in particular liver and intestine, herniate through the umbilical ring into the base of the umbilical cord. Clinical features The herniated abdominal contents are covered by a translucent membrane composed of peritoneum and amnion. The diagnosis is often already made on a prenatal ultrasonographic scan. The le- sion will be obvious at birth. Occasionally, the membrane will rup- ture during, or shortly after delivery. In about 30 to 50% of cases, other abnormalities are associated, particularly chromosomal tri- somy 18 (but also 13 and 21), cardiac anomalies, and the Beckwith–​ Wiedemann syndrome. The Beckwith–​Wiedemann syndrome, also termed the exomphalos macroglossia gigantism syndrome, usually presents as a large-​for-​date infant with hemihypertrophy and exomphalos. It is due to defects in the epigenetic control of imprinted loci on chromosome 11 that control fetal and postnatal growth via genes such as H19, IGF2, KCNQ1OT1, and CDKN1C. The tongue is strikingly large, there are frequently ridges in the earlobes, and a prominent naevus flammeus on the forehead. Hypoglycaemia as a result of hyperinsulinism produced by islet cell hyperplasia is treated using standard neonatal hypoglycaemia protocols. In 20% of children, hypoglycaemia persists beyond the first week or even the neonatal period and might require sustained tube feeding, medication, or rarely subtotal pancreatectomy. In the long term, children with this syndrome have an increased incidence of solid tumours, particularly nephroblastoma (Wilms’ tumour) and hepatoblastoma. Management The prenatal ultrasound examination is key to assess the extent of the anatomical problem, to differentiate exomphalos minor (<5 cm defect and no liver in sac) from exomphalos major (>5 cm defect or liver in sac), and to detect associated abnormalities. If a diaphrag- matic hernia is detected before birth, a fetal MRI scan may help to determine residual lung volume. A caesarean section can prevent birth trauma in children with exomphalos major. After birth, a nasogastric tube is passed to decompress the bowel. The sac can be very satisfactorily covered and supported by wrap- ping plastic film around the exomphalos and the baby’s trunk. Preoperative plain radiographs of chest and abdomen may help to assess the intestinal gas pattern, and investigate a diaphragmatic hernia. Primary closure will be performed if the contents of the sac can be reduced into the peritoneal cavity. If closure of all layers of the abdominal wall is impossible, skin closure alone may be used, or a synthetic material is used to enclose the sac or to build a silo. Gradual reduction of the contents into the peritoneal cavity is then possible. If gradual closure is required, application of antiseptic so- lutions or silver-​based solution or cream onto the membrane can produce a granulating surface that epithelializes. Postoperatively, ventilatory support may be necessary. Parenteral nutrition will be necessary if oral feeds cannot be given. Survival is related to the size of the lesion and the severity of any associated abnormalities. Gastroschisis The incidence of gastroschisis is approximately 1 in 2500 births. Incidence is increasing and young maternal age as well as primi- gravida status and low socioeconomic status are risk factors. In gastroschisis, there is a full-​thickness defect in the anterior abdom- inal wall, usually to the right of the umbilical cord. The defect is small, but most of the gastrointestinal tract may be extruded through it. In contrast to exomphalos, other abdominal organs are rarely eviscer- ated and abnormalities outside the gastrointestinal tract are unusual. Prenatal diagnosis on an ultrasonographic scan is common. Labour is often induced at 37 weeks’ gestation to reduce complications such as sepsis or bowel damage. Clinical features After delivery, hypothermia and hypoproteinaemia due to the ex- posed bowel are common problems. The small size of the defect in the anterior abdominal wall and the often narrow pedicle from which the bowel is suspended may impair the blood supply and result in infarction of the extruded intestine. Atresia may have oc- curred because of intrauterine impairment of the blood supply.

15.15  Congenital abnormalities of the gastrointestinal tract 2969 Management A nasogastric tube is passed and the bowel decompressed. The bowel should be enclosed in plastic wrap (cling film) around the baby’s trunk. This keeps the bowel moist and prevents excessive heat loss. Antibiotics are commenced preoperatively and management of hypoproteinaemia and hypovolaemia is important. At operation, primary abdominal wall closure is aimed for, but this is not possible in some cases and a plastic sheet is used to form an artificial silo to enclose the intestine (often Silastic or Gor-​Tex sheets, increas- ingly preformed manufactured silos). The size of the silo is gradually reduced over some days, squeezing the bowel back into the peri- toneal cavity until closure of the abdominal wall becomes feasible. Ventilatory support postoperatively is often necessary. Parenteral nutrition is essential and may need to continue until gastrointestinal motility and absorption are adequate. About one-​fifth of children have complex gastroschisis with intes- tinal atresia or complications such as gangrene, closing gastroschisis, perforation, strictures or volvulus leading to sepsis, necrotizing en- terocolitis, prolonged parenteral nutrition, and short-​gut syndrome. Abnormalities of the bowel Congenital pyloric stenosis Congenital hypertrophic pyloric stenosis is a disorder character- ized by hypertrophy of the circular muscle of the pylorus causing obstruction to the gastric outlet. The incidence is 2 per 1000 live births. The aetiology is unknown. Theories include primary muscle hypertrophy, abnormalities of the maturation of ganglion cells, ab- sence of a certain type of ganglion cell, or a response to abnormally high concentrations of circulating gastrin. Genetic and environ- mental factors play an important part. There is an increased inci- dence of pyloric stenosis in siblings of an affected child and in the offspring of a woman who has had the condition. Nonbreastfeeding also increases the risk. In any large series, the male-​to-​female ratio is 3 or 4:1. Clinical features The onset of symptoms is usually between 3 and 6 weeks of age, but may present shortly after birth. Vomiting of increasing severity is the cardinal symptom, eventually occurring after most feeds and becoming projectile. The vomitus is milk and mucus, and may con- tain altered blood suggesting an oesophagitis or gastritis, but bile is never present. The baby stops gaining weight and becomes consti- pated. Characteristically the baby is alert, anxious, and hungry. If diagnosis is delayed, severe malnutrition may develop. Due to the loss of gastric acid, a hypochloraemic, hypokalaemic metabolic al- kalosis might be found, but fluid loss can lead to subsequent meta- bolic acidosis. Examination reveals evidence of weight loss and in advanced cases, signs of dehydration will be present. After feeding, waves of peristalsis travelling from left to right in the epigastrium will be seen (visible peristalsis). The thickened pylorus is felt as an olive-​sized tumour lying deep to the edge of the right rectus and is often most easily palpable when the stomach is empty. The diagnosis is largely supported by clinical symptoms, but ultra- sonography is the standard diagnostic technique with pyloric length more than 1.2 cm and pyloric wall thickness of more than 3 mm sup- porting the diagnosis. If ultrasonography is not available, a barium meal is diagnostic when the ‘string’ sign of the elongated pylorus and accumulation of contrast in the prepyloric antrum is demonstrated. Management Preoperative correction of water and electrolyte deficits is essential. The pyloromyotomy described by Ramstedt splits the hypertro- phied muscle longitudinally allowing the mucosa to bulge through the defect, thus enlarging the pyloric canal. The laparoscopic pyloromyotomy has increasingly replaced classical laparotomy. Postoperatively, various feeding regimens are advocated to achieve enteral feeding within 24 h. Ad libitum feeding is as safe as a regi- mented feeding protocol. The prognosis is excellent. Atresia and stenosis of the small intestine An intrinsic obstruction may produce either complete (atresia) or partial obliteration (stenosis) of the bowel lumen. Complete oblit- eration may be due to a gap between the two ends of the small in- testine, with or without a connecting band between these ends, or a complete mucosal diaphragm. Small intestinal atresia is a more common finding than is stenosis. The duodenum is most often af- fected, followed by jejunum, and ileum. Associated abnormalities of the gastrointestinal tract include malrotation, oesophageal atresia, imperforate anus, biliary atresia, and annular pancreas. Intrinsic ob- struction of the small intestine of congenital origin presents most often in the neonatal period. When the obstruction is partial, it may first present even in infancy and childhood. Congenital intrinsic duodenal and jejunoileal obstruction Congenital intrinsic duodenal obstruction may be accompanied by an annular pancreas; this is a sign of failure of duodenal develop- ment rather than an obstructive lesion per se. Congenital intrinsic duodenal obstruction is not, in general, associated with multiple atresias in the remainder of the small intestine, but there may be obstruction at two levels in the duodenum. Associated abnormal- ities include Down’s syndrome where duodenal lesions occur in 10% of cases. In patients with multiple intestinal atresia, recessive defects in the gene TTC7A have been described, causing a variable combination of severe intestinal epithelial cell polarization defects, multiple intes- tinal atresia, and severe combined immunodeficiency (SCID)-​like immunodeficiency. Subsequent intestinal inflammation develops in some patients. The substantial epithelial component of the defect is illustrated by the finding that haematopoietic stem cell transplant- ation does not cure the intestinal defect. Clinical features When duodenal obstruction is complete, bilious vomiting usually occurs within a few hours of birth and is bile stained unless the ob- struction is proximal to the ampulla of Vater. Meconium may be passed normally and there may be obvious epigastric distension. When obstruction is incomplete, the symptoms may be intermittent and the diagnosis delayed. In jejunoileal obstruction, bile-​stained vomiting and abdominal distension usually occur within the first 2 days of life. Meconium may or may not be passed. When obstruction is incomplete, the diagnosis may again be delayed and the child may present with intermittent vomiting, abdominal distension, and even with features of malabsorption.

section 15  Gastroenterological disorders 2970 Antenatal ultrasonography may guide diagnosis by showing di- lated proximal bowel loops associated with polyhydramnios. Plain radiographs of the abdomen are usually diagnostic in symptom- atic infants who present with a complete obstruction. In duodenal atresia, there is the characteristic ‘double bubble’ (Fig. 15.15.2) and in jejunal atresia a ‘triple bubble’ may be found. When duodenal ob- struction is incomplete, there may be small amounts of air in the lower bowel. A  contrast study may be necessary to demonstrate the obstruction and may suggest an associated malrotation. When there is complete jejunoileal obstruction, there are usually multiple dilated loops of intestine. A contrast enema may reveal an unused microcolon. When obstruction is incomplete, a contrast follow-​ through may be needed to establish the diagnosis. Management A nasogastric tube is passed to empty the stomach and allow ac- curate measurement of gastric losses. Fluid and electrolyte disturb- ances should be corrected. In duodenal obstruction, the operation of choice is duodenoduodenostomy. In jejunoileal lesions, adequate re- section of the proximal dilated gut reduces the great discrepancy in size between the two blind ends and can facilitate end-​to-​end anas- tomosis, allowing better peristalsis of the nondilated prestenotic gut and preventing delay in establishing enteral feeds. Considerable loss of intestinal length may occur as a direct result of the atresia and surgical correction will result in further loss. Loss of considerable lengths of jejunum is well tolerated. Every effort is made to preserve some ileum and the ileocaecal valve to prevent sec- ondary complications caused by malabsorption and problems in the enterohepatic circulation. Duplication of gastrointestinal tract Duplications are cystic or tubular structures whose lumen is lined by a mucous membrane, usually supported by smooth muscle. They occur most often within the dorsal mesentery of the gut. Duplications may occur anywhere along the alimentary tract but they are found most often in relation to the small intestine, particu- larly the ileum. They may not communicate with the main lumen of the gastrointestinal tract. Duplications may be found in association with intestinal atresias. Small intestinal duplication may contain ec- topic gastric mucosa causing peptic ulceration of the adjacent small intestinal mucosa with bleeding and perforation. Clinical features Duplications often present in infancy as a small-​bowel obstruction, or a small cystic duplication may form the lead point of an intus- susception. A palpable abdominal mass in infancy, as well as rectal bleeding and volvulus, may also be modes of presentation. The clin- ical diagnosis is often difficult, and although ultrasonography and MRI can be supportive, and a technetium scan may be helpful by demonstrating ectopic gastric mucosa, sometimes diagnostic lapar- oscopy or laparotomy is required. Initial presentation may be a posterior mediastinal cystic mass, possibly associated with cervical or upper thoracic vertebral abnor- malities. The mass is likely to communicate through the diaphragm with an intestinal duplication. Management Excision of a cystic duplication, with or without the adjacent intes- tine, is usually straightforward. Any associated thoracic cyst will also need excision. Short tubular duplications can be excised with the adjacent intestine. Long tubular duplications can be opened longi- tudinally and the mucosa stripped out, leaving the common muscle wall and preserving the intestinal length. Small intestinal malrotation with or without volvulus Malrotation of the small intestine is due to disordered movement of the intestine around the superior mesenteric artery during the course of intrauterine development. It affects up to 1 in 1200 births. Several genetic defects have been identified that cause malrotation, including mutations in the forkhead transcription factor gene FOXF1 and several genes that affect left–​right pattern and cause complex intrauterine development defects including intestinal malrotation (CFC1, ZIC3, NKX2–​5, ACVR2B, LEFTY2). There are two main abnormalities. First, there is a gross narrowing of the base of the mesentery, which may allow the midgut to twist around and cause a volvulus. This may occur acutely, causing com- plete obstruction, or it may occur intermittently, producing bouts of partial or complete obstruction. Secondly, there may be partial duo- denal obstruction from extrinsic compression of the small intestine by peritoneal bands (Ladd’s bands) that extend from the caecum to the subhepatic region. Clinical features Malrotation may be associated with intestinal atresia or stenosis. It is also found in association with diaphragmatic hernia, omphalocele, and gastroschisis. Malrotation may be asymptomatic and is some- times discovered only as an incidental finding on a barium study (Fig. 15.15.3). Most children who develop symptoms related to malrotation do so within the neonatal period, presenting with features of complete or incomplete intestinal obstruction. Obstruction to the blood supply Fig. 15.15.2  Plain radiograph of the abdomen of an infant with duodenal atresia showing the characteristic ‘double bubble’.

15.15  Congenital abnormalities of the gastrointestinal tract 2971 to the bowel will lead to extensive gangrene of the small bowel. Bloody stools may present as an early sign of this complication. Intermittent and incomplete obstruction may present later in childhood with episodes of (bile-​stained) vomiting and abdominal pain, but also malabsorption. Intestinal stasis may cause bacterial overgrowth in the lumen of the small intestine and steatorrhoea may be caused by protein-​losing enteropathy due to obstruction of the mesenteric lymphatics. Plain radiographs of the abdomen may reveal an air-​filled stomach with some gas scattered through the lower part of the abdomen. A contrast study can reveal the presence of malrotation by failure of the duodenal passage to cross to the left of the vertebral bodies. Management Surgical intervention is indicated when a firm diagnosis is estab- lished. Ladd’s operation is usually the procedure of choice. This in- volves, in general, the placement of the colon on the left and the small intestine on the right, having divided any bands and adhesions between the duodenum and large bowel, and, by dissection, broad- ened the base of the mesentery as much as possible. Although bowel necrosis after a volvulus is untreatable, severe bowel ischaemia can be reversible and a ‘second-​look’ laparotomy may allow necrotic tissue to be differentiated from ischaemic tissue and recovered intes- tinal tissue to be preserved. Meckel’s diverticulum This diverticulum is the vestigial remnant of the vitellointestinal duct. Although most people who have such a diverticulum are asymp- tomatic, complications may arise due to the presence of ectopic gastric or pancreatic tissue in the diverticulum. The diverticulum is located antimesenterically in the distal ileum within 100 cm of the ileocaecal valve. Rectal bleeding is the main symptom. This is usually the passage of bright blood rather than tarry melaena stools. Typically, the stool is at first dark in colour but later bright red. Bleeding may be acute, with shock requiring urgent blood transfusion, or it may be chronic. In any child who has a massive, painless rectal bleed, a Meckel’s di- verticulum is a likely differential diagnosis. Most often bleeding from a Meckel’s diverticulum is associated with ulceration of the small bowel adjacent to ectopic gastric or pancreatic mucosa. Small intestinal obstruction may occur due to volvulus, or an intussuscep- tion with the diverticulum as the lead point. Acute diverticulitis may produce a picture indistinguishable from acute appendicitis. A technetium scan is usually the most important investigation. The radionuclide 99mTc concentrates in the gastric mucosa and ec- topic gastric mucosa appears as an abnormal abdominal localization on scintigraphy. This allows detection of a Meckel’s diverticulum with ectopic gastric mucosa, or indeed any duplication with such ectopic tissue. When rectal bleeding occurs, investigation includes colonoscopy to exclude polyps, intestinal vascular malformation, or ulceration. An upper gastrointestinal endoscopy may exclude peptic ulceration or oesophagitis, but upper gastrointestinal bleeding often presents with haematemesis. Angiography or red blood cell scintigraphy (Fig. 15.15.4) might be considered in cases of severe bleeding, but a diagnostic laparoscopy or laparotomy is typically required. Meconium ileus Meconium ileus affects about 10 to 20% of children with cystic fi- brosis during the neonatal period, and a similar syndrome in older children and young adults with cystic fibrosis may occur—​the meconium ileus equivalent. The meconium of abnormally viscid consistency adheres to the mucosa and cannot be propelled along the bowel, causing small intestinal obstruction in the distal ileum. The abnormal consistency may result from several factors including the lack of pancreatic enzymes during fetal life and reduced secre- tion of water and electrolytes in such infants. Fig. 15.15.3  Intestinal malrotation. Barium examination of the small bowel shows the duodenum and small bowel on the right and the colon (arrows) on the left. The duodenum does not cross the midline and the ligament of Treitz is absent. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.15.4  Bleeding Meckel’s diverticulum. Fused images of a technetium red blood cell scan obtained by single-​photon emission computed tomography show bleeding (arrows) in the right lower abdomen surgically proven to stem from within a Meckel’s diverticulum. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2972 Over 1000 mutations in the CFTR gene have been described in cystic fibrosis. The ΔF508 CFTR mutation is most common. Meconium ileus is enriched in patients with severe loss-​of-​function mutations in the CFTR gene (such as the ΔF508 mutation). Clinical features If not already suspected on antenatal ultrasonographic scans by white-​appearing guts, the neonate with meconium ileus usually de- velops signs of intestinal obstruction within the first 24 to 48 h of life. Classical signs are bile-​stained vomiting, progressive abdom- inal distension, and failure to pass meconium. In some cases, meco- nium may just cause obstruction, but meconium ileus may also be complicated by perforation of the gut. When this occurs in utero, intraperitoneal calcification may be observed on a plain radio- graph of the abdomen, providing evidence of meconium peritonitis. Perforation may also occur in the neonatal period. In simple meconium ileus, the plain radiograph of the abdomen may show dilated bowel but few fluid levels. Sometimes there is the appearance of bubbly meconium in the right lower quadrant. Bowel loops may be palpable. If a contrast enema is performed, a microcolon, a consequence of disease, will be demonstrated. Atresia associated with meconium ileus is frequently indistinguishable radiologically from an atresia of ischaemic origin. Management Initial nasogastric tube decompression, application of antibiotics, and intravenous hydration will stabilize the child. Hyperosmolar enemas (such as Gastrografin, dilution 3:1) can resolve the meco- nium plug in about one-​third of cases, but care is required to avoid them inducing dehydration. Enemas should not be used until a plain radiograph of the abdomen or ultrasonography has excluded the possibility of complicated meconium ileus with perforation. Additional application of N-​acetylcysteine via nasogastric tube or enema to resolve the mucus plug has been suggested by some centres, but evidence of efficacy is not clear. When meconium ileus is complicated by atresia or perforation, gangrene, peritonitis, or associated volvulus, surgical intervention is essential. Surgical options include the formation of an ileostoma with decompression or resection with an immediate end-​to-​end anastomosis. The diagnosis of cystic fibrosis should be confirmed by sweat elec- trolyte estimations (concentrations of sweat sodium >60 mmol/​litre are likely diagnostic) and genetic testing of the CFTR gene. Congenital short-​bowel syndrome Congenital short-​bowel syndrome is characterized by substantial reduction of small-​bowel length due to mutations in the CLMP or FLNA genes. Compared to the 250 cm short-​bowel length of a term baby, patients with congenital short-​bowel syndrome present with approximately 50 cm length, associated with mal-​ or nonrotation of the intestine. Pyloric hypertrophy has been found in some patients. Patients present shortly after birth with bile-​stained vomiting as well as diarrhoea and failure to thrive. They initially require parental nutrition and substitution of vitamins and trace elements. Although historically the prognosis is poor, the condition can be managed when sepsis episodes and liver failure can be avoided. Over time, there is some improvement in absorption capacity and food is often tolerated within 1 or 2 years of age. Colonic atresia Atresia of the large intestine affects approximately 1 child among 20 000 live births. The baby presents in the first 24 to 48 h with marked abdominal distension, vomiting, and failure to pass meco- nium. Abdominal radiographs reveal multiple dilated loops of bowel with fluid levels; the position of the loops may suggest a large-​bowel obstruction. A contrast enema can help to define the position of the atresia/​stenosis. Nasogastric suction and intravenous fluids are commenced pre- operatively. At laparotomy, the lesion may be an isolated atresia or associated with multiple atresias of the small and large bowel. If the atresia is solitary and right sided, it may be possible to perform a resection and primary anastomosis. Frequently a colocolic anasto- mosis and a covering enterostomy are required to allow the dilated proximal bowel to recover. Hirschsprung’s disease Intestinal innervation is key for autonomic bowel movement. The ganglion cells of the gut lie in the submucosa and intermyenteric plane. Ectodermal in origin, they migrate caudally along the length of the gut. Failure of migration of ganglionic cells down to the in- ternal sphincter of the anal canal results in an aganglionic seg- ment causing Hirschsprung’s disease. The distal rectum is always aganglionic and the aganglionosis extends proximally for a vari- able distance. In 70% of cases, the rectosigmoid is involved, in 20% the aganglionosis extends proximal to the sigmoid for a variable distance up the colon, and in 10% the aganglionosis extends into the small intestine. The aganglionic bowel is incapable of coordin- ated peristalsis and passively constricts, resulting in a mechanical obstruction. The incidence is approximately 1 in 5000 births. There is a clear male dominance (male-​to-​female ratio of approximately 4:1). Hirschsprung’s disease is a polygenic disorder, some patients carry mutations in the RET gene. Additional genes are implicated by the association with Down’s syndrome as well as other syndromal associations including Mowat–​Wilson syndrome (ZEB2 gene), Waardenburg syndrome type 4 (EDNRB, EDN3, or SOX10 gene), or Goldberg–​Shprintzen syndrome (KIAA1279 gene). Clinical features Symptoms of Hirschsprung’s disease are present in the first 2 days of life in almost all cases, although exceptionally a baby will have no symptoms during the early neonatal period. The major symp- toms are failure to pass meconium within 24 h of birth, abdominal distension, vomiting, and poor feeding, which may occur singly or in combination. Frequently, a rectal examination will relieve the ob- struction by passively dilating the aganglionic segment. However, later presentation with constipation that dates back to the neonatal period and failure to thrive is not uncommon. Hirschsprung’s enterocolitis is a serious complication presenting with abdominal distension, profuse diarrhoea, and circulatory collapse. The infant is gravely ill and the mortality is up to 20%. The incidence of enterocolitis can be reduced if the diagnosis of Hirschsprung’s disease is made in the first week of life. In the neonatal period, a plain abdominal radiograph will reveal distension of small and large bowel. Water-​soluble contrast enema may show the narrow aganglionic bowel with dilated proximal

15.15  Congenital abnormalities of the gastrointestinal tract 2973 bowel (Fig. 15.15.5), but a normal contrast enema does not exclude Hirschsprung’s disease. If the sigmoid diameter is larger than the rectum diameter, Hirschsprung’s disease should be suspected in a symptomatic child. The definitive diagnostic procedure is a suction or full-​thickness rectal biopsy. Endoscopic biopsies are not suffi- ciently deep to capture the intermyenteric plexus. Suction biopsy that can be taken at the bedside enable the pathologist to assess ganglion cells in the submucosal plexus with high sensitivity and specificity. Full-​thickness biopsy provides the intermyenteric plexus as well. In Hirschsprung’s disease, ganglion cells are absent, hyper- trophic nerve trunks are present, and histochemical stain for acetyl- cholinesterase activity reveals increased staining in the bowel wall. Anorectal manometry shows failure of relaxation of the internal sphincter in response to rectal distension in Hirschsprung’s disease, but this method is unreliable in the neonatal period and is not part of the routine diagnostic method. Management Following diagnosis, either definitive surgery is carried out or a col- ostomy is fashioned in ganglionic bowel and definitive surgery de- ferred for a period of time. Definitive surgery consists of excision of aganglionic bowel with a ‘pull-​through’ procedure, enabling an anastomosis to be made between the anus and ganglionic colon. The three operations most often performed are those described by Swenson, Duhamel, and Soave. Increasingly, laparoscopic tech- niques are used. Compared with transabdominal approaches, the transanal technique decreases operative times, length of hospital- ization, and offers improved continence and reduced constipation. Provided that the surgery is uncomplicated, the long-​term compli- cations, which include faecal and urinary incontinence, and impo- tence, should be low. Bowel control is likely to be imperfect for a number of years, with soiling as a major problem, but good bowel control will be achieved in most patients treated by experienced surgeons. Imperforate anus The incidence is approximately 1 in 5000 births. The basic clas- sification differentiates between high and low abnormalities. In high anomalies, the bowel terminates above the pelvic floor and the bowel often communicates with the urethra in the male (a rectourethral fistula) and the vagina or vestibule in the fe- male (a rectovaginal/​vestibular fistula). In low anomalies, the bowel passes through the pelvic floor and either opens onto the perineum in an ectopic position, or lies just beneath the skin-​covered anus. More boys than girls present with an imper- forate anus. Associated anomalies of the urogenital tract, oe- sophagus, heart, and skeletal system are common (VACTERL association). Clinical features Examination of the perineum will establish the presence of an anorectal anomaly. In boys, the presence of meconium on the perineum usually indicates a low anomaly. In girls, careful inspec- tion is necessary to differentiate meconium being passed per vag- inum, indicating a high anomaly, from meconium emerging from a perineal site, suggesting a low anomaly. If in doubt, the precise anatomy of the anomaly may be resolved by contrast studies. In boys, a cystourethrogram can demonstrate a rectourethral fistula in a high proportion of cases, but is rarely necessary as an ini- tial diagnostic procedure. Having defined the nature of the ano- rectal anomaly, evidence of any associated abnormality should be sought by careful clinical examination and radiographs of chest, abdomen, and the vertebral column. Management In case of a low anomaly, dilatation of the opening alone may suffice, but in most cases an anoplasty produces a sufficient re- sult. A high anomaly necessitates a defunctioning colostomy in the neonatal period. Definitive surgery involves division of any fistula and positioning the bowel accurately within the pelvic floor and sphincter muscles. Delay in achieving bowel control is common and a number of secondary operations designed to improve control have been advocated. A permanent colostomy should rarely be necessary. The high incidence of associated genitourinary abnormalities makes it mandatory to investigate carefully the urinary tract at an early stage. Functional congenital abnormalities Small intestinal lymphangiectasia Primary intestinal lymphangiectasia is a rare disorder that pre- sents with protein-​losing enteropathy, lymphopenia, hypo­ gammaglobulinaemia, hypoalbuminaemia, or chylous ascites as a consequence of dilated intestinal lacteals and submucosal or subserosal lymphatic vessels resulting in lymph leakage. Small intestinal lymphangiectasia (Waldmann’s disease) is a primary congenital abnormality that needs to be differenti- ated from secondary manifestations of other disease processes such as constrictive pericarditis, Crohn’s disease, or intestinal tuberculosis. Several syndromic forms and lymphangiectasia-​causing genes have been identified. These include Hennekam’s syndrome char- acterized by the association of lymphoedema, intestinal lym­ phangiectasia, intellectual deficit, and facial dysmorphism caused Fig. 15.15.5  Barium enema in Hirschsprung’s disease illustrating a narrow aganglionic rectum with dilation proximally.

section 15  Gastroenterological disorders 2974 by mutations in CCBE1 and FAT4. Intestinal lymphangiectasia has also been found in a patient with HOIP deficiency and patients with von Recklinghausen’s, Turner’s, Noonan’s, or Klippel–​Trenaunay syndrome. The condition can present throughout life, but most often in the first 2 years with diarrhoea and failure to thrive as well as oe- dema with hypoproteinaemia (serum albumin and serum IgG). There is lymphopenia in the presence of normal bone marrow lymphopoiesis. Malabsorption may cause steatorrhoea, fat-​soluble vitamin deficiency, as well as hypocalcaemia. Diagnosis is made by endoscopy and capsule endoscopy showing the characteristic lymphatic abnormality with multiple, white, swollen lymphatic lacteals. Single-​ or double-​balloon enteroscopy might be required to assess distal jejunal or ileal lesions. As a noninvasive laboratory method, increased faecal α-​1-​antitrypsin levels suggest intestinal lymphatic protein loss. Lymphangiectasia is rarely localized enough to allow surgical excision of a segment and offer a permanent cure. Dietetic inter- vention to reduce the amount of long-​chain fatty acids in the diet and adding medium-​chain triglycerides can be helpful. A formula containing medium-​chain triglyceride may be used, and medium-​ chain triglyceride oil may be added during cooking. Dietary inter- vention leads to sustained improvement of oedema and growth rates. Fat-​soluble vitamin and electrolyte supplements might be required. Albumin infusions are of little value in management as their benefit is transitory. Congenital diarrhoeal disorders: noninflammatory enteropathies Congenital diarrhoea is a group of disorders caused by multiple monogenic defects that lead to osmotic or secretory diarrhoea. Several mechanisms contribute to the pathogenesis, including de- fects in absorption, transport of nutrients and electrolytes due to defective enzymes and membrane carriers or absent pancre- atic enzymes, enterocyte differentiation and polarization, and enteroendocrine cells differentiation. In addition to those dis- orders that primarily affect absorption and digestion, autoimmune enteropathies that cause destruction of enterocyte, Paneth cell, or enterochromaffin cell function can present in this group. A sum- mary of multiple mechanisms, diseases, and related gene defects is provided in Table 15.15.1. A systematic approach is required to differentiate underlying defects. Response to fasting allows differentiation between os- motic (stop after fasting) and secretory forms of diarrhoea (persist despite fasting). Clues to particular diagnoses can come from a range of blood, urine, and stool tests that include measurement of faecal ion concentrations (sodium and chloride-​losing diarrhoea), faecal reducing substances (carbo- hydrate malabsorption), blood gas, blood glucose, albumin (protein-​losing enteropathy), triglycerides and cholesterol (abetalipoproteinaemia), aminoaciduria (lysinuric diarrhoea), stool pancreatic elastase (pancreatic insufficiency), and sweat test (cystic fibrosis). Structural enterocyte defects (such as tufting enteropathy, microvillus inclusion disease, and pri- mary or autoimmune polyglandular syndrome-​associated loss of enterochromaffin cells) and the presence of intestinal inflam- mation can be discerned by gastroduodenoscopy and biopsy evaluation using routine microscopy (haematoxylin and eosin stain, periodic acid–​Schiff reagent, immunostaining) and electron microscopy. Autoantibodies towards enterocytes can be found in immunodysregulation polyendocrinopathy enter- opathy X-​linked syndrome (IPEX), and autoantibodies against other intestinal antigens (antiparietal cell H+/​K+-​ATPase anti- bodies, anti-​intrinsic factor, antitryptophan hydroxylase) are found in autoimmune polyglandular syndrome 1. Treatment depends on the underlying condition. Nutritional therapy, in particular exclusion diets and special formulae, will overcome osmotic diarrhoea and improve the condition in some absorption defects (such as lactose-​free feeding in patients with lactase deficiency or fructose-​based formulas in patients with Table 15.15.1  Causes of congenital noninflammatory diarrhoea Disease group/​disease Gene Defects in absorption and transport of nutrients and electrolytes Abetalipoproteinaemia MTTP Acrodermatitis enteropathica SLC39A4 Chylomicron retention disease SAR1B Congenital chloride diarrhoea SLC26A3 Congenital lactase deficiency LCT Congenital sodium diarrhoea SPINT2, SLC9A3 Diarrhoea-​associated DGAT1 mutation DGAT1 Enterokinase deficiency TMPRSS15 Familial diarrhoea syndrome GLUCY2C Fanconi–​Bickel syndrome SLC2A2 Glucose–​galactose malabsorption SLC5A1 Abetalipoproteinaemia APOB Lysinuric protein intolerance SLC7A7 Maltase–​glucoamylase deficiency MGAM Primary bile acid diarrhoea SLC10A2 Sucrase–​isomaltase deficiency SI Defects in enterocyte structure Congenital tufting enteropathy EPCAM, SPINT2 Microvillous inclusion disease MYO5B, STX3 Trichohepatoenteric syndrome
(syndromic diarrhoea) TTC37, SKIV2L Defects in enteroendocrine cell differentiation Enteric anendocrinosis NEUROG3 Mitchell–​Riley syndrome RFX6 Proprotein convertase 1/​3 deficiency PCSK1 X-​linked lissencephaly with abnormal genitalia ARX Autoimmune enteropathy Autoimmune polyglandular syndrome 1 AIRE IPEX syndrome FOXP3 IPEX-​like enteropathy IL2RA, STAT5B, STAT1, ITCH Adapted by permission from Springer Nature: Canani RB, Castaldo G, Bacchetta R, Martin MG, Goulet O (2015). Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. Nat Rev Gastroenterol Hepatol, 12, 293–​302.

15.15  Congenital abnormalities of the gastrointestinal tract 2975 glucose–​galactose malabsorption). Nutritional deficits need to be compensated for by oral or parenteral substitution of nutri- ents. Defects that cause enterocyte structure defects might require total parenteral nutrition and intestinal transplantation. Immune-​ mediated disorders require a range of immunosuppressive and immunomodulatory medications. Monogenic forms of inflammatory bowel disease Among the functional defects that can present with very early-​ onset and even infantile inflammatory bowel disease, there is a spectrum of more than 50 monogenic disorders. IL-​10 signalling defects due to loss-​of-​function mutations in IL10 or its re- ceptor (IL10RA and IL10RB genes) present with infantile onset of intestinal inflammation. There is a large group of diseases that present as immunodeficiency, such as defects in bacterial handling as well as immune dysregulation. Immunodeficiencies and immune dysregulation defects should be considered in par- ticular in children under 2 years of age at onset of inflammatory bowel disease. The age of onset in monogenic conditions is sig- nificantly younger compared to polygenic inflammatory bowel disease, which has a peak incidence between 20 and 40 years of age. Monogenic diseases are associated with increased morbidity and mortality. Children often present with diarrhoea, in particular bloody diarrhoea and failure to thrive. Endoscopy shows frequently a pancolitis. Common causes of intestinal inflammation such as cow’s milk protein allergy, coeliac disease, or uncomplicated in- fections need to be excluded. Twelve features that should raise sus- picion of a monogenic cause include (1) very Young Age of onset, (2) Multiple family members and consanguinity, (3) Autoimmunity, (4) failure to Thrive, (5) Treatment with conventional medication fails, (6) Endocrine concerns, (7) Recurrent infections or unex- plained fever, (8) Severe perianal disease, (9) Macrophage activa- tion syndrome and haemophagocytic lymphohistiocytosis, (10) Obstruction and atresia of intestine, (11) Skin lesions and dental and hair abnormalities, and (12) Tumours that can be summar- ized as ‘YOUNG AGE MATTERS MOST’. Monogenic disorders that can present with very early-​onset intestinal inflammation are shown in Table 15.15.2. Careful phenotyping can often suggest a genetic candidate de- fect. The introduction of multiplex sequencing technologies such as targeted gene panel sequencing, whole-​exome sequencing, or whole-​genome sequencing has already revolutionized the diag- nostic approach of such disorders since it allows the diagnosis to be established in patients with atypical presentations or before the full phenotypic characteristics have emerged. Many established anti-​inflammatory and immunosuppressive therapy options are used in both monogenic and conventional in- flammatory bowel disease. However, it is important to establish a genetic diagnosis since some disorders require very specific treat- ments. Haematopoietic stem cell transplantation is the established curative approach in a number of defects that affect haematopoietic cell lineages (such as IL-​10 signalling defects). The establishment of an early genetic diagnosis and appropriate curative approach via such transplantation can avoid repeated surgery, including colec- tomy in some patients. Anti-​IL-​1 targeting treatments can resolve Table 15.15.2  Monogenic disorders that can present with very early-​onset intestinal inflammation Disease group/​disease Gene Epithelial barrier Dystrophic epidermolysis bullosa COL7A1 Kindler syndrome FERMT1 X-​linked ectodermal dysplasia and immunodeficiency IKBKG TTC7A deficiency TTC7A ADAM17 deficiency ADAM17 Familial diarrhoea GUCY2C Phagocyte defects Chronic granulomatous disease CYBB, CYBA, NCF1, NCF2, NCF4 Glycogen storage disease type 1b SLC37A4 Congenital neutropenia G6PC3 Leucocyte adhesion deficiency 1 ITGB2 hyper-​ and autoinflammatory Mevalonate kinase deficiency MVK Phospholipase Cγ2 defects PLCG2 NLRC4 NLRC4 Familial Mediterranean fever MEFV Familial haemophagocytic lymphohistiocytosis type 5 STXBP2 X-​linked lymphoproliferative syndrome 2 (XLP2) XIAP X-​linked lymphoproliferative syndrome 1 (XLP1) SH2D1A Hermansky–​Pudlak syndrome HPS1, HPS4, HPS6 T-​ and B-​cell selection and differentiation defects Combined variable immunodeficiency ICOS, LRBA IL-​21 deficiency IL21 CTLA4 deficiency CTLA4 Agammaglobulinaemia BTK, PIK3R1 Hyper-​IgM syndrome CD40LG, AICDA Wiskott–​Aldrich syndrome WAS Atypical SCID/​Omenn syndrome DCLRE1C, ZAP70, RAG1, RAG2, IL2RG, LIG4, ADA, CD3γ Hoyeraal–​Hreidarsson syndrome DKC1, RTEL1 Loeys–​Dietz syndrome TGFBR1, TGFBR2 PI3K hyperactivation PIK3R1, PTEN FOXP3 regulatory T-​cell immundysregulation, autoimmune enteropathy IPEX syndrome FOXP3 IPEX-​like syndrome IL2RA, STAT1, STAT3 IL-​10 signalling defects IL-​10 and receptor defects IL10RA, IL10RB, IL10 Other MASP2-​deficiency MASP2 Trichohepatoenteric syndrome SKIV2L, TTC37 Adapted from Gastroenterology, Vol. 147, Uhlig HH, et al., The diagnostic approach to monogenic very early onset inflammatory bowel disease, pp. 990–​1007, Copyright © 2014, with permission from Elsevier.

section 15  Gastroenterological disorders 2976 intestinal inflammation in autoinflammatory disorders such as mevalonate kinase defects. FURTHER READING Congenital structural abnormalities Burkardt DD, et al. (2014). Advances in Hirschsprung disease genetics and treatment strategies: an update for the primary care pediatri- cian. Clin Pediatr (Phila), 53, 71–​81. Celli J (2014). Genetics of gastrointestinal atresias. Eur J Med Genet, 57, 424–​39. Gamba P, Midrio P (2014). Abdominal wall defects: prenatal diagnosis, newborn management, and long-​term outcomes. Semin Pediatr Surg, 23, 283–​90. Herman RS, Teitelbaum DH (2012). Anorectal malformations. Clin Perinatol, 39, 403–​22. Lakshminarayanan B, Lakhoo K (2014). Abdominal wall defects. Early Hum Dev, 90, 917–​20. Martin V, Shaw-​Smith C (2010). Review of genetic factors in intestinal malrotation. Pediatr Surg Int, 26, 769–​81. Peters B, et al. (2014). Advances in infantile hypertrophic pyloric sten- osis. Expert Rev Gastroenterol Hepatol, 8, 533–​41. Peeters B, Benninga MA, Hennekam RC (2012). Infantile hypertrophic pyloric stenosis-​-​genetics and syndromes. Nat Rev Gastroenterol Hepatol, 9, 646–​60. van der Werf CS, et al. (2015). Congenital short bowel syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation. Biochim Biophys Acta, 1852, 2352–​61. Functional congenital abnormalities Boisson B, et al. (2015). Human HOIP and LUBAC deficiency under- lies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med, 212, 939–​51. Canani RB, et al. (2015). Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. Nat Rev Gastroenterol Hepatol, 12, 293–​302. Ingle SB, Hinge Ingle CR (2014). Primary intestinal lymphangiectasia: minireview. World J Clin Cases, 2, 528–​33. Pazmandi J, Kalinichenko A, Ardy RC, Boztug K (2019). Early-onset in- flammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunol Rev, 287(1), 162–85. Sullivan KE, Conrad M, Kelsen JR (2018). Very early-onset inflamma- tory bowel disease: an integrated approach. Curr Opin Allergy Clin Immunol, 18(6), 459–69. Terrin G, et  al. (2012). Congenital diarrheal disorders:  an updated diagnostic approach. Int J Mol Sci, 13, 4168–​85. Thiagarajah JR, et  al. (2018). Advances in Evaluation of Chronic Diarrhea in Infants. Gastroenterology, 154(8), 2045–59. Uhlig HH (2013). Monogenic diseases associated with intestinal in- flammation:  implications for the understanding of inflammatory bowel disease. Gut, 62, 1795–​805. Uhlig HH, et al. (2014). The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology, 147, 990–​1007. Uhlig HH, Muise AM (2017). Clinical Genomics in Inflammatory Bowel Disease. Trends Genet, 33(9), 629–41. Vignes S, Bellanger J (2008). Primary intestinal lymphangiectasia (Waldmann’s disease). Orphanet J Rare Dis, 3, 5.

15.16 Cancers of the gastrointestinal tract 2977

15.16 Cancers of the gastrointestinal tract 2977

ESSENTIALS Cancers of the gastrointestinal tract are one of the most rewarding interfaces in translational medicine, leading to greater understanding of the genetic mechanisms leading to cancer and the development of novel targeted therapies. Diagnosis of gastrointestinal tract cancers is usually made or suspected at endoscopy and confirmed by biopsy. Oesophageal cancer A common cancer, usually of squamous cell histology, that is particu- larly prevalent in East Asia and Southeast Africa. Typical presentation is with dysphagia. Staging investigations include contrast-​enhanced CT, 2-​[18F] fluoro-​2-​deoxy-​d-​glucose positron emission tomography CT (FDG PET-​CT), and endoscopic ultrasonography. In patients who are fit and suitable for surgery, neoadjuvant chemotherapy improves survival, but most patients are elderly with comorbid disease and un- suitable for curative surgery, and many others present with advanced disease such that palliation with or without systemic therapy is the only option. Overall survival at 5 years is 15%. Stomach cancer Usually adenocarcinoma, this is particularly prevalent in East Asia, Eastern Europe, and Western South America. Predisposing factors include Helicobacter pylori infection, low socioeconomic status, to- bacco smoking, heavy alcohol use, and diet. Dysphagia, early satiety, and anaemia are common presenting features, with weight loss being an indication of advanced disease. Tumour staging is by CT with or without FDG PET-​CT. Best treatment, when appropriate and when possible, is by surgery with extensive nodal resection combined with perioperative chemotherapy with or without adjuvant radiotherapy. Patients with advanced disease require palliation. Overall survival at 5 years is 18.9%. Colorectal cancer This is the third most common cancer in men and second most common in women worldwide, and is predisposed to by a Western diet. Most cases arise by transformation of an adenoma to a car- cinoma by sequential inherited and acquired mutations. Typical presentations of left-​sided tumours are alteration in bowel habit, obstruction, or overt bleeding, whereas right-​sided tumours often present with iron-​deficiency anaemia. Patients are staged by CT, supplemented by liver MRI if there is doubt about hepatic spread, and pelvic MRI for rectal cancers. Surgical resection is the primary treatment and potentially curative. Neoadjuvant therapies are used in high-​risk rectal cancers and adjuvant chemotherapy in colon can- cers. Colonic stenting can relieve bowel obstruction. Overall survival at 5 years is now almost 60%. Introduction Cancers of the gastrointestinal tract provide a paradigm for the in- vestigation and treatment of cancer. The relationship between de- velopments in basic research and progress in clinical management has generated one of the most rewarding interfaces in translational medicine, particularly with respect to novel targeted therapies. This has occurred on the background of an increasing understanding of the genetic predisposition to cancer, in particular the influence of common, low-​penetrance susceptibility alleles in conferring pre- disposition to neoplasia. Examples of this include sporadic colo- rectal carcinoma as well as better understood genetic syndromes (Table 15.16.1). There is also increasing interest in the influence of genetic polymorphisms that predict toxicity from systemic treatments. For example, UGT1A1 codes for UDP-​glucuronyl transferase which is normally responsible for the conversion of unconjugated bilirubin into conjugated bilirubin but is also known to convert the breakdown products of irinotecan to their inactive form (SN-​ 38 to SN-​38G). Certain polymorphisms in this gene have been shown to be associated with a greater risk of irinotecan toxicity (diarrhoea, neutropenia) and response to therapy in metastatic colorectal cancer. Another example is the microsatellite instability pathway, which involves deficiency of the nucleotide mismatch re- pair (MMR) system. This deficiency occurs in 12 to 15% of spor- adic colorectal cancers and is associated with a more favourable prognosis than patients with intact MMR pathways. Evidence suggests that patients with stage II deficient MMR colon cancers do not benefit from adjuvant 5-​fluorouracil (5-​FU) and are best treated with surgery alone. More recently deficient MMR has been shown to define a cohort of advanced disease patients who respond to checkpoint inhibition. 15.16 Cancers of the gastrointestinal tract Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira

section 15  Gastroenterological disorders 2978 The potential benefits of such approaches to the diagnosis and treatment of gastrointestinal tumours cannot be overstated. Although much of the translational work and trials using novel tar- geted agents to date have been in colorectal cancer, they are of poten- tial relevance to all types of gastrointestinal malignancy. Oesophageal cancer Epidemiology Oesophageal cancer is the eighth most common cancer worldwide with over 450 000 new cases per annum (Fig. 15.16.1). Mortality rates parallel incidence and, despite progress in diagnosis and treat- ment, there has been little overall impact on survival. The overall trends in incidence vary significantly by country and sex, with the highest rates found in East Asia and Southeast Africa. Worldwide, there is a 21-​fold variation in the incidence rates be- tween different regions and a three to fourfold higher incidence in men compared to women. In the United Kingdom, between 2005 and 2015, age-​standardized incidence rates remained stable. Marked variation between ethnic groups has also been reported, although results are conflicting depending on the ethnic groups studied and the country in which the studied populations reside. Geographical location and ethnicity are likely to affect predisposing genetic and environmental risk factors. Squamous cell carcinoma (SCC) is the more common histological subtype in East Asia and is more closely linked to smoking and to- bacco use. Conversely, adenocarcinoma of the oesophagus is more common in the United States of America and Europe and is more closely associated with obesity, gastro-​oesophageal reflux disease (GORD), and Barrett’s oesophagus. Predisposing factors Environmental The vast majority of cases of oesophageal cancer are sporadic and related to environmental factors. Environmental risk factors for oesophageal SCC include smoking (fivefold risk increase), alcohol, chewing tobacco and betel nuts, and certain micronutrient defi- ciencies. Risk factors for oesophageal adenocarcinoma include GORD and Barrett’s oesophagus (6–​14% of patients with GORD will develop Barrett’s oesophagus, and up to 1% of these will de- velop oesophageal cancer), obesity, smoking, and diets low in fibre, fruits, and vegetables. Other risk factors include achalasia, oesophageal strictures due to ingestion of corrosives, radiotherapy, and coeliac disease. Plummer–​ Vinson syndrome, characterized by the triad of iron deficiency anaemia, dysphagia, and oesophageal webs, is associated with oe- sophageal SCC in 2 to 5% of cases. Genetic There are some rare recognized genetic syndromes. Tylosis palmoplantaris is an autosomal dominant syndrome characterized by hyperkeratosis of the palms and soles and a 40-​fold increased risk of SCC of the oesophagus; a mutation in RHBDF2 on chromosome 17q25 codes for an inactive protein (iRHOM2) that normally plays a role in epidermal growth factor receptor (EGFR) signalling. For an affected family member, the estimated lifetime risk of cancer is 95% by age 65. Up to 7% of cases of Barrett’s oesophagus and oesopha- geal adenocarcinomas occur in family clusters, although the genetic basis behind this observation remains unclear. Pathology Middle and upper oesophageal cancers are more likely to be SCC, whereas those in the lower oesophagus are more commonly adeno- carcinoma. SCC and adenocarcinoma account for most oesophageal cancers, with less than 2% being other histological types such as sar- coma, small-​cell cancer, or lymphoma. Clinical features and investigation Patients classically present with progressive dysphagia, initially to solids and then to liquids. Other late symptoms such as dyspnoea, a hoarse voice, pain, and weight loss suggest advanced disease and confer a poor prognosis. Initial diagnosis is made at upper Table 15.16.1  Gastrointestinal cancer syndromes, their molecular defects, and cancer risk Clinical syndrome Cancer risk Gene Normal gene function Cowden syndrome 9–​16% PTEN Multifunctional tumour suppressor enzyme Familial adenomatous polyposis (FAP) 100% (69% in attenuated FAP) APC Tumour suppressor protein that acts as an antagonist in the WNT signalling pathway Juvenile polyposis 38–​68% BMPR1A Transmembrane receptor that binds to ligands involved in TGFβ pathway, leading to activation of SMAD proteins SMAD4 Transcription factor and tumour suppressor Lynch’s syndrome (HNPCC) M: 27–​74% F: 22–​61% MLH1/​MSH2 DNA MMR M: 22–​69% F: 10–​30% MSH6 DNA MMR M: 20% F:15% PMS2 DNA MMR MUTYH-​associated polyposis 43–​100% MUTYH DNA base excision repair (corrects A–​G base pair mismatches) Peutz–​Jeghers syndrome 39% STK11 Tumour suppressor enzyme involved in polarization and apoptosis F, female; M, male. Adapted from Syngal S, et al. (2015). ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol, 110, 223–​62.

15.16  Cancers of the gastrointestinal tract 2979 gastrointestinal endoscopy (Fig. 15.16.2a) or occasionally by con- trast radiology, and confirmed by endoscopic biopsy. Standard sta- ging investigations include contrast-​enhanced CT (Fig. 15.16.3), 2-​[18F] fluoro-​2-​deoxy-​d-​glucose positron emission tomography (FDG PET-​CT) to exclude distant disease, and endoscopic ultrason- ography (EUS) in selected cases (Fig. 15.16.2b) to better stage the primary tumour in anticipation of surgery. Management Curative-​intent treatment For most patients with operable disease and an adequate perform- ance status, the preferred treatment is surgery combined with neoadjuvant chemotherapy or chemoradiotherapy. The surgical ap- proach depends on the site of the tumour and can be open, minimally invasive, or a combination of the two. Preoperative chemotherapy has been shown to confer an improved overall survival compared to surgery alone, with no difference in morbidity or postoperative mortality. Preoperative chemoradiotherapy leads to improved overall survival and disease-​free survival and no difference in com- plications such as anastomotic leak, but worse rates of treatment-​re- lated mortality. For early-​stage (T1aN0) disease, endoscopic mucosal resec- tion provides similar overall survival to oesophagectomy. Radical chemoradiotherapy can also be considered for selected patients with T1bN0 disease. Male Eastern Asia (a) Southern Africa Eastern Africa Less developed regions World Northern Europe South-Central Asia South America Western Europe More developed regions Australia/New Zealand Northern America Central and Eastern Europe Middle Africa Caribbean Western Asia Melanesia South-Eastern Asia Northern Africa Southern Europe Micronesia Polynesia Central America Western Africa 20 15 10 5 0 5 10 15 20 Female Incidence Mortality Fig. 15.16.1  (a) Estimated age-​standardized incidence and mortality rates per 100 000 for oesophageal cancer worldwide by sex, 2012 estimates. (b) Trends in age-​standardized incidence of oesophageal cancer in men in selected countries per 100 000 population, 2012. (c) Trends in age-​standardized incidence of oesophageal cancer in women in selected countries per 100 000 population, 2012. Reproduced with permission from Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://​gco.iarc. fr/​today/​home, accessed on 23 May 2018.

section 15  Gastroenterological disorders 2980 Palliative treatment Many patients with oesophageal cancer are of an advanced age with comorbidities that often make them unsuitable candidates for curative-​ intent treatment. In inoperable nonmetastatic oesophageal cancer, chemoradiotherapy confers a better overall survival than radiotherapy alone, although if high-​dose radiotherapy is not possible (e.g. the tumour cannot fit within the radiotherapy field) then chemotherapy, local treat- ments (e.g. stenting), or palliative dose radiotherapy can be considered. 15 (b) 10 5 0 15 10 5 0 1975

15.16  Cancers of the gastrointestinal tract 2981 In patients with metastatic disease and an adequate perform- ance status, first-​line chemotherapy consists of a combination of two or three agents, typically including 5-​FU or capecitabine with a platinum-​based agent. In patients with HER2-​positive adeno- carcinoma of the gastro-​oesophageal junction, the anti-​HER2 monoclonal antibody trastuzumab may be used in addition to double-​agent chemotherapy. Second-​line chemotherapy can be con- sidered in selected patients, where both taxane and irinotecan based schedules are modestly effective. Several local treatments are available for the palliative manage- ment of dysphagia. Metal stenting provides immediate relief, al- though external beam radiotherapy is associated with a greater overall survival (+77 days). However, external beam radiotherapy often temporarily worsens dysphagia and so is not always suitable as a primary treatment (although it can be offered poststenting). If external beam radiotherapy is not possible, brachytherapy can be considered if available. Other treatment options such as laser, balloon dilatation, and photodynamic therapy are possible but not widely used in clinical practice. Prognosis Despite an improvement in survival over the last four decades, overall age-​standardized 5-​year overall survival is currently 15% in the United Kingdom. The Surveillance, Epidemiology, and End Results (SEER) cancer statistics review (1975–​2014) from the National Cancer Institute (United States of America) reported a 5-​year overall survival from diagnosis of 38.5%, 20.7%, and 3.9% for local, regional, and distant disease, respectively. Stomach cancer Epidemiology Like oesophageal cancer, stomach cancer occurs mainly in older people and has a striking variation in worldwide incidence (Figs. 15.16.4a and 15.16.4b). There are an estimated 952  000 cases per annum globally, with 60% of cases occurring in just three countries—​China, Japan, and Korea. However, there has been a marked change from historical rates; 40 years ago, stomach cancer was the most common neoplasm globally, whereas now it is the fifth most common. In the United Kingdom, the incidence of stomach cancer has reduced from 31.8 per 100 000 in 1971 to 11.3 per 100 000, with a peak incidence in the ninth decade. International vari- ation is thought to be due to a combination of dietary differences, salt consumption and the prevalence and virulence of Helicobacter pylori infections in different regions. Predisposing factors Environmental Environmental risk factors are variable depending on the site of stomach cancer. Noncardia stomach cancers are associated with H. pylori infection, low socioeconomic status, high intake of smoked and salted food, and low consumption of fruit and veget- ables. Cancers of the cardia, such as oesophagogastric tumours, are associated with obesity and GORD. Risk factors common to both sites are age, male sex, smoking, heavy alcohol consumption, family history, radiation exposure, low fibre intake, and low physical ac- tivity. Ethnic differences are likely to be driven by environmental exposures; first-​generation Japanese expatriates in the United States of America have the same risk of stomach cancer as the domestic Japanese population, but their grandchildren have the same risk as their American Caucasian counterparts. Genetic Whole-​genome association studies in East Asian populations have identified several single-​nucleotide polymorphisms associ- ated with gastric cancer; these include prostate stem cell antigen (PSCA, possibly has a tumour suppressor function in the stomach), Mucin-​1 (MUC1, a membrane-​bound protein providing a barrier function), and PLCE1 (phospholipase C epsilon 1, linked to mul- tiple pathways and processes for cell survival and growth). Although the vast majority of cases are sporadic, genetic syn- dromes account for 1 to 3% of cases of stomach cancer. Hereditary diffuse gastric cancer is an autosomal dominant disorder Fig. 15.16.3  Axial CT image demonstrating circumferential thickening of the upper oesophagus (arrow), consistent with oesophageal carcinoma. Case courtesy of Dr Roberto Schubert, Radiopaedia.org. (b) (a) Fig. 15.16.2  (a) Mass arising from a Barrett’s oesophagus segment at endoscopy. Note the abnormal epithelium which lies distally and around the mass. (b) Endoscopic ultrasound examination demonstrating the mass that has not penetrated the wall of the oesophagus (short arrow) and an associated enlarged lymph node (long arrow).

section 15  Gastroenterological disorders 2982 < 3.4 3.4–5.2 5.2–7.4 7.4–10.9 ≥ 10.9 (a) No data Not applicable All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement. © International Agency for Research on Cancer 2018 Data source: GLOBOCAN 2012 Map production: IARC (http://gco.iarc.fr/today) World Health Organization Fig. 15.16.4  (a) Estimated age-​standardized incidence rates per 100 000 for stomach cancer worldwide, 2012 estimates. (b) Trends in age-​standardized incidence of stomach cancer in men in selected countries per 100 000 population, 2012. (c) Trends in age-​standardized incidence of stomach cancer in women in selected countries per 100 000 population, 2012. (a) Reproduced with permission from Ervik M, Lam F, Ferlay J, Mery L, Soerjomataram I, Bray F (2016). Cancer Today. Lyon, France: International Agency for Research on Cancer. Cancer Today. Available from:
http://​gco.iarc.fr/​today, accessed on 23 May 2018. (b) and (c) Reproduced with permission from Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://​gco.iarc.fr/​today/​home, accessed on 23 May 2018.

15.16  Cancers of the gastrointestinal tract 2983 80 (b) 70 60 50 40 30 20 10 0 1975

40 (c) 30 20 10 0 1975

section 15  Gastroenterological disorders 2984 characterized by reduced expression of E-​cadherin (25% of fam- ilies with this condition have a mutation in the CDH1 gene that codes for cadherin) and development of a highly invasive form of diffuse gastric cancer. Hereditary diffuse gastric cancer confers a lifetime risk of stomach cancer of over 80% by age 80, with a me- dian age at diagnosis of 38. Other hereditary syndromes that increase the risk of gastric cancer are familial adenomatous polyposis (FAP), Peutz–​Jeghers syndrome, and Lynch’s syndrome (see Table 15.16.1 and ‘The polyp- osis syndromes’ below). Although there have been historical claims that the French emperor Napoléon Bonaparte’s stomach cancer was familial, a 2007 analysis suggested that his cancer was more likely sporadic with his main risk factor being H. pylori infection. Pathology Most stomach cancers (90–​95%) are adenocarcinomas, with the remaining cancers usually being lymphomas, gastrointestinal stromal tumours (GISTs), or carcinoid tumours. Macroscopically, the Borrmann classification describes gastric tumours as polypoid, fungating, ulcerating, or diffusely infiltrating. The last of these is known clinically as linitis plastica (histologically a signet-​ring cell carcinoma that is associated with poorer survival). The Lauren classification has been used for the last 50 years and divides gastric adenocarcinoma into intestinal type (54%), diffuse type (32%), and indeterminate type (15%). Intestinal type is more commonly associated with H. pylori infection and diffuse type is more common in female and younger patients. The World Health Organization classification (2010) for gastric adenocarcinoma sub- divides into four major (papillary, tubular, mucinous, signet ring cell and other poorly cohesive carcinomas) and many rarer histological variants. Clinical features and investigation Dysphagia, early satiety, and anaemia are common presenting fea- tures, with weight loss being an indication of advanced disease. Gross haematemesis is unusual. An epigastric mass is palpable in about 30% of patients, and palpable lymphadenopathy in the left supraclavicular fossa (Virchow’s node/​Troisier sign) may be present. Metastasis occurs to the peritoneum (with ascites and ovarian in- volvement known as Krukenberg’s tumour), to the liver, and in later stages to the lung and other sites. Gastric cancer is the most common malignancy to be associated with dermatomyositis or acanthosis nigricans. Diagnosis is usually made by upper gastrointestinal endos- copy (Fig. 15.16.5) and biopsy. Tumour staging is by CT scan. Patients require careful assessment to determine fitness for surgery. Occasionally, staging laparoscopy or FDG PET-​CT is used to deter- mine resectability. Management Curative-​intent treatment Radical surgery (total or subtotal gastrectomy) with lymphadenectomy can offer cure for localized gastric cancer. Depending on the tumour site, D2 lymphadenectomy (removal of all perigastric nodes and nodes surrounding major arterial trunks) has a marginal benefit in overall survival compared to D1 lymphadenectomy (removal of perigastric nodes only). Complete surgical removal plays a critical role in overall survival; patients with a negative resection margin (R0) have a greater overall survival than patients with a positive resection margin (R1), even if attempts are then made to convert the R1 to an R0 resection by extending the surgical margin (Fig. 15.16.6). Due to the high risk of locoregional and metastatic recurrence, several randomized controlled trials have investigated the role of neoadjuvant, adjuvant, and perioperative (both neoadjuvant and adjuvant) chemotherapy, with or without radiotherapy. Compared to surgery alone, there is evidence that overall survival is improved by perioperative and adjuvant chemotherapy but not neoadjuvant chemotherapy alone. Adjuvant chemoradiotherapy improves overall survival compared to adjuvant chemotherapy, but with a high risk of treatment morbidity. Based on the available evidence, the current National Institute for Health and Care Excellence (NICE) guidelines recommend offering perioperative chemotherapy for patients undergoing curative-​intent resection. If no neoadjuvant treatment was given preoperatively, patients should be offered adjuvant chemotherapy or chemoradiotherapy. Fig. 15.16.5  Endoscopic images of gastric cancer. From Jahng J, et al. (2012). Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability. World J Gastroenterol, 18, 3571–​7.

15.16  Cancers of the gastrointestinal tract 2985 Palliative treatment Palliation of proximal gastric obstruction and palliative chemo- therapy is similar to that for oesophageal cancers, including deter- mination of HER2 status and use of trastuzumab. Malignant gastric outlet obstruction can be palliated with stenting, although this is less successful (there is a 25% stent migration or fracture rate) than for stents placed more proximally. Surgical bypass is an option for patients who are sufficiently fit, but postsurgical gastroparesis is common, particularly in those with metastatic disease. Prognosis Despite an improvement in survival over the last four decades, overall age-​standardized 5-​year overall survival is currently 18.9% in the United Kingdom. The SEER cancer statistics review (1975–​2014) reported a 5-​year overall survival from diagnosis of 63.6%, 28.0%, and 4.3% for local, regional, and distant disease respectively. Small bowel cancers Epidemiology and pathology Small-​bowel cancers are rare; in the United States of America they represent 3% of gastrointestinal malignancies and 0.6% of all can- cers. Although rare in the United Kingdom (1500 cases per annum), the incidence of small-​bowel cancer has more than doubled in the last 25 years (Fig. 15.16.7). Common histological subtypes are adenocarcinoma (40%, most often in the duodenum), neuroendocrine tumours (NETs) (40%, most often carcinoid tumours in the ileum or appendix), and lymphomas (10%, most often found in the jejunum). Predisposing factors Environmental risk factors for small-​bowel adenocarcinoma in- clude alcohol consumption, smoking, and high consumption of sugar, refined carbohydrates, red meat, and smoked food. 1.0 0.8 0.6 0.4 0.2 0.0 0 Total 447 48 25 271 27 17 167 18 10 116 8 4 83 6 2 58 p=0.l4 p=0.02 PS-R1 (n = 25) FS-R1-to-PS-R0 (n = 48) PS-R0 (n = 447) 5 1 PS-R0 FS-R1-to-PS-R0 PS-R1 1 yr 2 yrs 3 yrs 4 yrs 5 yrs 12 24 36 Time (months) Overall Survival Proportion Surviving 48 60 72 Fig. 15.16.6  The effect of proximal margin status on overall survival following curative-​intent surgery for gastric cancer. PS-​R0, permanent section R0; FS-​R1-​to-​PS-​R0, frozen section R1 to permanent section R0; PS-​R1, permanent section R1. R1 margin status confers a survival disadvantage, even if attempts to extend the margin to achieve complete clearance (R0) are made. Reprinted by permission from Springer Nature: Squires MH, et al. (2014). Utility of the proximal margin frozen section for resection of gastric adenocarcinoma: A 7-​institution study of the US gastric cancer collaborative. Ann Surg Oncol, 21, 4202–​10. 3.0 2.5 2.0 1.5 1.0 Year of Diagnosis Incidence Rate per 100,000 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2014 2013 2015 Males Persons Females Fig. 15.16.7  Age-​standardized incidence rates of small bowel cancer in the UK, 1993 to 2015. Cancer Research UK (http://​www.cancerresearchuk.org/​).

section 15  Gastroenterological disorders 2986 Chronic inflammation of the small intestine also predisposes to carcinogenesis. Crohn’s disease increases the risk of small-​bowel adenocarcinoma with an estimated cumulative risk of 2.2% after 25 years. Coeliac disease is associated with both adenocarcinoma and small-​bowel lymphoma. A United Kingdom study reporting on 395 new cases of small-​bowel cancer (1998–​2000) found that 39% of new diagnoses of small-​bowel lymphoma and 13% of small-​ bowel adenocarcinoma patients had a prior diagnosis of coeliac disease. Small bowel adenocarcinoma is also associated with FAP, Lynch’s syndrome, and Peutz–​Jeghers syndrome. Although historically the primary cause of death of patients with FAP was colorectal cancer, due to improved screening and prophylactic proctocolectomy, duodenal adenocarcinoma is now the leading cause of cancer-​ related mortality in these patients. FAP patients are normally en- rolled in a duodenal surveillance programme undergoing regular duodenoscopies to monitor for duodenal polyps. Lynch’s syndrome, caused by a germline mutation of a DNA MMR gene, confers a 1% risk of small bowel adenocarcinoma. Peutz–​Jeghers syndrome, char- acterized by widespread hamartomatous polyposis and oral hyper- pigmentation, confers a 500-​fold increased risk of small-​bowel adenocarcinoma. Clinical features and investigation Symptoms are typically nonspecific and include intermittent ab- dominal pain, weight loss, nausea and vomiting, gastrointestinal bleeding, change in bowel habit, and anaemia. More distal tumours may present with small-​bowel obstruction. The diagnosis is usually made by upper gastrointestinal endos- copy or during surgery, in part due to the inaccuracy and low sensi- tivity of abdominal CT in detecting such lesions (47%). Newer and more accurate noninvasive investigations with greater diagnostic accuracy than conventional abdominal CT include CT enteroclysis, magnetic resonance enteroclysis, and capsule endoscopy. Management Localized adenocarcinomas, NETs, and GISTs are best treated with surgery, which may be as limited as a wide local excision in the distal small bowel but as extensive as a pancreaticoduodenectomy in the case of duodenal adenocarcinoma. There is a paucity of data and trials to support the use of adjuvant or palliative chemotherapy in small-​bowel tumours, although this is likely due to the impracticality of recruiting enough patients for adequately powered trials rather than a true lack of treatment ef- fect. Of note, most GISTs (>85%) have a mutation in the KIT proto-​ oncogene and the adjuvant use of the tyrosine kinase inhibitor imatinib was shown in the SSG XVIII trial to improve relapse-​free survival (66% vs 48%) and 5-​year overall survival (92% vs 82%) in high-​risk GISTs. Imatinib and other tyrosine kinase inhibitors are also used in the palliative setting, although development of treatment resistance re- mains an issue. As carcinoid metastases are often hypervascular, liver metastases are sometimes amenable to hepatic artery-​based therapies such as embolization. Somatostatin analogues may pro- vide symptomatic control of hormonally active carcinoid tumours, although this does not reduce the tumour burden. Small-​bowel lymphomas are best treated with chemotherapy. Prognosis Although complete surgical excision can achieve long-​term survival, most patients are diagnosed with advanced disease due to the nonspecific nature of symptoms. Despite this, survival is more favourable than oesophageal or stomach cancers. The SEER data- base (2007–​2013, all histological subtypes) reported a 5-​year overall survival from diagnosis of 85.3%, 73.6%, and 42.2% for local, re- gional, and distant disease, respectively. Colorectal cancer Epidemiology Colorectal cancer is the third most common cancer in men and the second most common in women worldwide. There is a 10-​fold vari- ation in incidence globally, with the highest rates in Australia and New Zealand and the lowest rates in Western Africa (Fig. 15.16.8a). In the United Kingdom, colorectal cancer is the fourth most common cancer with approximately 42  000 people diagnosed every year. The incidence rate in the United Kingdom has remained stable since the early 1990s and survival has more than doubled from 22% in 1975 to 57% in 2010 to 2011 (Fig. 15.16.8b). The peak incidence of the disease is in people aged 85 to 89, with less than 6% of cases diagnosed under the age of 50 years. Predisposing factors Environmental and dietary factors There several well-​established environmental risk factors for colorectal cancer (Fig. 15.16.9). A  high body mass index ap- pears to pose a higher risk to men than women, and it has been proposed that this may be secondary to differences in fat dis- tribution and central adiposity between males and females. Smoking and the consumption of red meat also increase the risk of colorectal cancer, although the relationship with smoking is not linear. Protective environmental factors include increased phys- ical activity and the consumption of fibre, fruit, and vegetables. Other factors include alcohol consumption (increased risk), pro- cessed meats (increased risk), hormone replacement therapy in postmenopausal women (reduced risk), and the use of aspirin and nonsteroidal anti-​inflammatory medication (reduced risk). Many of these factors are associated with a Westernized diet (e.g. high red meat and low fruit and vegetable consumption) which is thought to account in part for the global differences seen in inci- dence. Data from several population studies support this theory; for example, an analysis of census data from Canada found that the risk of colorectal cancer in the recently immigrated popula- tion was roughly half that of the Canadian-​born population (odds ratio 0.48 for men and 0.54 for women) but their risk converged as their years since migration increased, matching the Canadian-​ born population after 50 to 60 years. Medical conditions Type 2 diabetes has been shown in several meta-​analyses to increase the risk of colorectal cancer by 22 to 30% compared with nondiabetics. Due to the effect of chronic inflammation, inflammatory bowel

15.16  Cancers of the gastrointestinal tract 2987 < 4.9 4.9–8.5 8.5–14.4 14.4–26.3 ≥ 26.3 No data Not applicable (a) All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement. Data source: GLOBOCAN 2012 Map production: IARC (http://gco.iarc.fr/today) World Health Organization © International Agency for Research on Cancer 2018 100 (b) 90 80 70 60 50 40 30 20 10 0 1980–1981 1980–1991 2000–2001 Period of Diagnosis Net Survival (%) 2005–2006 2010–2011 1971–1972 Men Women Adults Fig. 15.16.8  (a) Estimated age-​standardized incidence rates per 100 000 for colorectal cancer worldwide, 2012 estimates. (b) Trends in age-​standardized 10-​year net survival from colorectal cancer in the UK, 2010 to 2011. (a) Reproduced with permission from Ervik M, Lam F, Ferlay J, Mery L, Soerjomataram I, Bray F (2016). Cancer Today. Lyon, France: International Agency for Research on Cancer. Cancer Today. Available from: http://​gco.iarc.fr/​today, accessed on 23 May 2018. (b) Cancer Research UK: http://​www.cancerresearchuk.org/​.

section 15  Gastroenterological disorders 2988 disease confers a 70% increased risk of colorectal cancer compared to the normal population; the risk is the same for both ulcerative colitis and Crohn’s colitis. The risk increases with the duration and extent of disease. For all patients with Crohn’s colitis or ulcerative colitis, the cumulative risk of colorectal cancer after the first, second, and third decade of disease is 0.7%, 2.6%, and 6.6% respectively. In patients with extensive colitis, this risk increases to 2%, 12%, and 21% respectively. Genetic factors After excluding patients with FAP and Lynch’s syndrome, roughly one in five cases of colorectal cancer can be attributed to hereditary 16 .9 .6 .7 .8 .8 .9 1 .8 .9 1 .9 1 1.1 1.4 1.9 2.4 2.9 1 1.1 1.2 1.3 1.4 1 1.2 Relative Risk Relative Risk Relative Risk Relative Risk Relative Risk Relative Risk 1.4 1.6 0 0 5 10 Red Meat (servings/wk) 15 20 0 2 4 Fruit (servings/day) 6 8 10 20 40 Smoking (pack-yr) 60 80 0 2 4 Vegetable (servings/day) Standardized PA Score 6 8 0 2 3 4 5 18 20 22 24 26 28 Referent Adjusted BMI (kg/m2) 30 32 34 36 38 40 42 44 46 CRC Colon Overall RR Overall RR Cohort CC, colon CC, CRC Overall RR M, CRC M, colon F/B, CRC F/B, colon Overall RR Overall RR Overall RR (a) (b) (c) (d) (e) (f) Fig. 15.16.9  Relative risk of developing colon cancer in relation to: (a) body mass index (BMI); (b) physical activity (PA); (c) cigarette smoking; (d) vegetable consumption; (e) consumption of red meat; (f) fruit consumption. CC, case–​control studies; CRC, colorectal cancer; F/​B, female/​both sexes; M, male; RR, relative risk. Adapted by permission from Springer Nature: Johnson CM, et al. (2013). Meta-​analyses of colorectal cancer risk factors. Cancer Causes Control, 24, 1207–​22.

15.16  Cancers of the gastrointestinal tract 2989 factors. Having a family history of colorectal cancer in a first-​ degree relative more than doubles an individual’s risk (pooled risk of 2.24 in one meta-​analysis). Women under the age of 50 with BRCA1 mutations have a 4.8-​fold increased risk of colorectal cancer compared to the normal population. Polymorphisms in some genes have also been linked to increased colorectal cancer risk (e.g. SMAD7 and CYP2E1). The polyposis syndromes The known polyposis syndromes, many of which have some pre- disposition to malignancy, are listed in Table 15.16.2. Polyps can arise from either parenchymal or stromal cells within the colon, and many of the syndromes listed have a mixture or predominant polyp types rather than being exclusively featuring one type of polyp. Familial adenomatous polyposis FAP, although the most common of the polyposis syndromes, is re- sponsible for less than 1% of all colorectal cancers, but it is likely that this figure will continue to decrease due to improved disease detection and prophylactic colectomies in affected patients. FAP has a reported prevalence of 1 in 6850 to 1 in 3250 live births, with no major differences in incidence either globally or between males and females. The principal feature of the condition is the presence of hun- dreds to thousands of adenomatous polyps throughout the colon (Fig. 15.16.10). It is inherited as an autosomal dominant condition, although about one-​third of cases arise without a family history, demonstrating a high rate of de novo mutations. The gene respon- sible for FAP—​the adenomatous polyposis coli (APC) gene—​is Table 15.16.2  Polyps and polyposis syndromes affecting the colon Polyp type Polyposis syndrome Colorectal cancer risk Adenoma Familial adenomatous polyposis (FAP) 93% by age 50 Attenuated FAP 69% by age 80 MUTYH-​associated polyposis 43% by age 50 Serrated polyposis syndrome Up to 50% lifetime risk Hamartoma Peutz–​Jeghers syndrome 39% by age 64 Juvenile polyposis syndrome 68% by age 60 Cronkhite–​Canada syndrome 25% of cases PTEN hamartoma tumour syndromes (including Cowden syndrome,
Bannayan–​Riley–​Ruvalcaba syndrome and Lhermitte–​Duclos disease) 9–​16% lifetime risk Inflammatory Inflammatory polyposis of IBD Up to 21% after 30 years of active disease Mucosal prolapse syndrome No increased risk Neural Neurofibromatosis type I No evidence of increased risk Multiple endocrine neoplasia type 2B No evidence of increased risk Lymphoid Nodular lymphoid hyperplasia N/​A (lymphoproliferative disorder) Multiple lymphomatous polyposis N/​A (lymphoma) Other/​mixed Hereditary mixed polyposis syndrome Unknown IBD, inflammatory bowel disease; N/​APTEN, phosphatase and tensin homolog. Data sources: Burt RW, Jasperson KW (2016). Polyposis syndromes. In: Podolsky DK, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC (eds). Yamada’s textbook of gastroenterology, 6th edition. Chichester: Blackwell, pp. 1583–​607; Oh SH, Lee JH, Namgung H (2012). A case of rectal cancer in a patient with neurofibromatosis type 1.
J Korean Soc Coloproctol, 28, 170–​3. (a) (b) Fig. 15.16.10  Familial adenomatous polyposis: endoscopic (left) and pathological (right) appearance. Images courtesy of the National Cancer Institute, Miguel Rodriguez-​Bigas, MD, University of Texas, MD Anderson Cancer Center (Photographer).

section 15  Gastroenterological disorders 2990 located on chromosome 5q21 and normally acts as a tumour sup- pressor. Most mutations are nonsense mutations, resulting in a trun- cated protein of less than the predicted 310-​kDa (2843 amino acids) wild-​type APC protein. The site of the mutation correlates with the phenotypic manifestations of FAP, such as congenital hypertrophy of retinal pigment epithelium, desmoids, and the severity of polyp- osis (Fig. 15.16.11). As well as colonic polyps, most patients will also have adenomas in the duodenum, stomach, and elsewhere in the small intestine. Patients normally undergo prophylactic surgery by the age of 25 and are entered into upper gastrointestinal endoscopy surveillance programmes by the age of 30. Lynch’s syndrome (hereditary nonpolyposis colorectal cancer) Lynch’s syndrome, historically known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most commonly inherited her- editary colon cancer syndrome and accounts for up to 4% of all cases of colon cancer and up to 10% of cases diagnosed before the age of 50. Compared to sporadic colon cancer with a median age at diagnosis of 69 for men and 73 for women, this decreases to 61 years in patients with Lynch’s syndrome. Colon cancer typically arises from an adenoma in the right hemicolon with an excess incidence of synchronous colorectal cancer at diagnosis. Lynch’s syndrome is also associated with a number of extracolonic malignancies with increased lifetime risks, including endometrium (60%), pancreatobiliary (18%), brain (1.2–​2.4%), urothelial tract (2.6–​4%), and small bowel (1–​4%). The Muir–​Torre variant of Lynch’s syndrome is characterized by the occurrence of one or more sebaceous neoplasms, such as sebaceous adenomas, sebaceous adenocarcinomas, keratoacanthomas, or squamous cell cancers. Patients who are suspected of having Lynch’s syndrome are iden- tified using the Amsterdam II criteria (Box 15.16.1), but it is im- portant to note that not all patients with Lynch’s syndrome will fulfil the criteria. The condition arises as a result of a germline mutation of at least one of the DNA MMR genes:  MLH1, MSH2, MSH6, or PMS2. MLH1, and MSH2 mutations account for 70% of the mutations seen in Lynch’s syndrome. The normal function of the MMR genes is to encode proteins that repair DNA base–​base mismatches arising as a result of replication errors. Replication errors are more common in regions of DNA known as microsatellites, where multiple short nucleotide repeat sequences occur. Loss of DNA repair function leads to the so-​called microsatellite instability of these regions, such that the allele sizes of microsatellites are different in tumours than in normal cells from the same individual. Genetic processes and pathology Our understanding of the molecular pathogenesis of colorectal cancer has exponentially increased since Fearon and Vogelstein de- scribed their genetic model for the adenoma–​carcinoma sequence for colorectal cancer in 1990. Although colorectal carcinogenesis was previously thought to occur following stepwise progressive ac- cumulation of primarily genetic mutations (such as the APC gene in the early stages of development and KRAS and TP53 in the later stages), it is now appreciated to be a much more complex process involving chromosomal instability, microsatellite instability, and epigenetic changes as well as genetic mutations. At present, four established pathway-​orientated models for spor- adic colorectal cancer have been described (Fig. 15.16.12): 157 Codon Extracolonic phenotype CHRPE Attenuated FAP Intermediate FAP Profuse FAP Desmoid tumours 412 1595 1464 1250 Fig. 15.16.11  Diagrammatic representation of the APC gene. The FAP phenotype (i.e. severity of polyposis) varies depending on the site of mutation; mutations between codons 1250 and 1464 result in severe FAP, whereas attenuated and intermediate FAP occurs following mutations outside of this region. Related extracolonic manifestations, such as desmoid tumours and congenital hypertrophy of the retinal pigment epithelium (CHRPE), are also associated with mutations in particular regions of the APC gene. CHRPE, congenital hypertrophy of the retinal pigment epithelium; FAP, familial adenomatous polyposis. Adapted from Burt RW, Jasperson KW (2016). Polyposis syndromes. In: Podolsky DK, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC (eds). Yamada’s textbook of gastroenterology, 6th edition. Chichester: Blackwell. pp. 1583–​607. Box 15.16.1  Amsterdam II criteria for the diagnosis of Lynch’s syndrome • At least three relatives with an HNPCC-​associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) • One must be a first-​degree relative of the other two • At least two successive generations should be affected • At least one should be diagnosed before the age of 50 • FAP should be excluded in the colorectal cancer case(s) if any • Tumours should be verified by histopathological examination Adapted from Vasen HFA, Watson P, Mecklin JP, Lynch HT (1999). New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology, 116, 1453–​6.

15.16  Cancers of the gastrointestinal tract 2991 • The traditional pathway—​this accounts for 70% of cases and fol- lows the Fearon and Vogelstein model; normal mucosa develops into colonic adenomas via gene mutations in APC and KRAS, re- sulting in tumours in the distal colon with TP53 mutations and chromosomal instability. Their prognosis is considered average. • The serrated pathway—​this accounts for 10 to 20% of cases of colo- rectal cancer; serrated adenomas and polyps form from normal mucosa due to BRAF mutations and global hypermethylation of CpG islands resulting in the silencing of several tumour suppressor genes (this is known as the CpG island methylator phenotype). Resultant tumours are found to have loss of expression of MLH1 and are characterized by high microsatellite instability. Usually found in the proximal colon, they have a favourable prognosis. • The alternative pathway—​this accounts for 10 to 30% of colorectal cancer, is less homogeneous than the traditional or serrated path- ways, and can have mutations in KRAS, APC, or BRAF and do not feature CpG hypermethylation or microsatellite instability. These tumours confer a poor prognosis and have a poor response to chemotherapy. • The ‘de novo’ pathway—​very rarely, tumours can develop without precursor lesions; these are characterized by APC and TP53 gene mutations as well as loss of heterozygosity at chromosome 3p, but rarely have KRAS mutations. Anatomically, colorectal cancers can arise in any part of the large bowel or rectum, but are most frequent in the rectum, sigmoid colon, and caecum (Fig. 15.16.13). Clinical features and investigation The site of a colorectal cancer influences the symptoms that it is likely to produce. The stool becomes more solid as it passes through the colon, hence obstruction and overt bleeding are increasingly likely with distal lesions. Blood is typically dark and mixed in with the stool, in contrast to the fresh or dripping bleeding that is often (50%–70%) (10%–30%) (10%–20%) Tubular adenoma CIN Villous adenoma SSA/P TSA CIMP-L CIMP-L CIMP-H (very rare) SSA/P MSI-L Adenocarcinoma in situ Adenocarcinoma in situ Adenocarcinoma in situ Adenocarcinoma invasive and metastatic Adenocarcinoma invasive and metastatic Adenocarcinoma invasive and metastatic Adenocarcinoma invasive and metastatic Distal colon Poor prognosis Poor response to chemotherapy Proximal colon Good prognosis Adenocarcinoma in situ Mucosa Submucosa Muscularis Propria Normal mucosa APC KRAS TP53 TGF-β β–catenin EMT Loss of E-cadherin EMT Loss of E-cadherin EMT KRAS APC BRAF MLH1 MSI-H APC TP53 LOH at chr 3p BRAF Normal mucosa Normal mucosa Normal mucosa Fig. 15.16.12  Molecular pathogenesis of colorectal cancer. APC, adenomatous polyposis coli; BRAF, B-​Raf proto-​oncogene, serine/​threonine kinase; CIMP-​H, CpG island methylator phenotype—​high; CIMP-​L, CpG island methylator phenotype—​low; CIN, chromosomal instability; EMT, epithelial-​mesenchymal transition; KRAS, Kirsten rat sarcoma viral oncogene homolog; LOH, loss of heterozygosity; MLH1, MutL homolog 1; MSI-​H, microsatellite instability—​high; MSI-​L, microsatellite instability—​low; SSA/​P, sessile serrated adenomas/​polyps; TGF-​β, transforming growth factor beta; TP53, tumour protein 53; TSA, traditional serrated adenomas. From Yamagishi H, Kuroda H, Imai Y, Hiraishi H (2016). Molecular pathogenesis of sporadic colorectal cancers. Chin J Cancer, 3, 4. © Yamagishi et al. 2016.

section 15  Gastroenterological disorders 2992 caused by haemorrhoids. Alteration of bowel habit may be in terms of frequency or increased constipation where the flow of solid stool is obstructed, which is particularly likely with left-​sided lesions. Tumours can grow to a considerable size in the right colon without affecting faecal flow, often leading to presentation with iron defi- ciency anaemia as a consequence of long-​standing but occult blood loss. Pain in a patient with colorectal cancer suggests obstructive disease or invasion, and weight loss is a late symptom suggesting advanced disease and poor prognosis. Digital rectal examination is an essential part of the physical examination of any patient with symptoms that might be attribut- able to colorectal cancer. The finding of an enlarged, irregular, hard liver clearly suggests metastatic disease. Routine laboratory investigation may reveal iron deficiency an- aemia and abnormal liver blood tests, but specific investigations focus on the bowel. Patients with suspected colorectal cancer should have a colonoscopy with biopsy unless contraindicated. In patients with comorbidities, alternative investigations are CT colonography or flexible sigmoidoscopy followed by barium/​ water-​soluble contrast enema. Box 15.16.2 summarizes current referral criteria in the United Kingdom for adults with suspected colorectal cancer. Staging Once a diagnosis of colorectal cancer is confirmed, patients require a staging CT scan to assess the extent of disease. Further local staging of rectal cancer is performed by pelvic MRI (or endorectal ultra- sonography if MRI is contraindicated). In patients with metastatic disease only located in the liver, further imaging such as MRI liver or FDG PET-​CT may be used to determine resectability. Although Dukes’ classification was historically used to stage colorectal car- cinoma, this has now been superseded by the more detailed TNM staging system (Table 15.16.3). Management Surgery Surgical resection is the primary treatment and potentially cura- tive. Colon cancers are usually treated with hemicolectomy, upper and middle rectal tumours with anterior resection, and low rectal tumours with abdominoperineal resection. Rectal cancer surgery is performed with total mesorectal excision as this reduces local recur- rence rates and improves survival. Patients with very early (T1N0) rectal cancer can be managed with transanal endoscopic microsur- gery as an alternative to major surgery in selected cases. Occasionally patients with operable left-​sided colonic tumours present with acute large-​bowel obstruction. As emergency colo- rectal cancer surgery is associated with much higher morbidity and mortality (10–​20%) than elective surgery, some patients can be ini- tially managed with a colonic stent to relieve obstruction, allowing for elective surgery following resuscitation. However, this option is not suitable for low rectal tumours, right-​sided tumours, or in pa- tients with evidence of peritonitis or perforation. Neoadjuvant treatment Although approximately 75% of patients have no evidence of metas- tases at diagnosis, 30 to 40% of patients who undergo curative-​intent surgery will develop recurrent disease. Neoadjuvant treatment for rectal cancer is guided by the pre- dicted risk of local recurrence based on the preoperative MRI find- ings. Patients with low-​risk operable rectal cancer proceed straight to surgery, moderate-​risk patients can be offered short-​course radio- therapy followed by immediate surgery, and high-​risk patients (if fit) are offered chemoradiotherapy with an interval to allow for tumour regression prior to surgery. The value of neoadjuvant chemotherapy in advanced colon cancer is not established. A recent retrospective analysis from the National Cancer Database (USA) of 27 575 patients with nonmetastatic T3 or T4 colon cancer treated with either adjuvant chemotherapy or neoadjuvant chemotherapy found that neoadjuvant chemotherapy reduced risk of death at 3 years by 23% compared to patients having adjuvant chemotherapy in patients with T4b disease (but not in pa- tients with T3 or T4a disease). Prospective trials are needed. 15% Unspecified Rectum 29% Sigmoid colon 18% Descending colon 2% Splenic flexure 2% Transverse colon 4% Hepatic flexure 2% Ascending colon 5% Caecum 13% Appendix 1% Anus 2% Rectosigmoid juction 7% Fig. 15.16.13  Anatomical distribution of adenocarcinoma within the large bowel. Box 15.16.2  Referral criteria for suspected colorectal cancer • Make urgent (within 2 weeks) referral for patients who: — are aged 40 or over with unexplained weight loss and abdominal pain — are aged 50 or over with unexplained rectal bleeding — are aged 60 or over with: • iron deficiency anaemia, or • change in bowel habit — have a positive faecal occult blood test • Consider urgent referral for patients who: — have a palpable rectal or abdominal mass — are aged under 50 with rectal bleeding and any of the following unexplained symptoms or findings: • abdominal pain • change in bowel habit • weight loss • iron deficiency anaemia • Offer faecal occult blood test to assess for colorectal cancer in adults without rectal bleeding or who have unexplained symptoms but do not meet the above-​listed criteria for referral Source:  National Institute for Health and Care Excellence (NICE) (2015). Suspected cancer:  recognition and referral (NICE guideline NG12). London: NICE [updated July 2017].

15.16  Cancers of the gastrointestinal tract 2993 Adjuvant treatment Moertel and colleagues published a seminal paper in 1990 demonstrating that adjuvant 5-​FU for stage III and high-​risk stage II colon cancer reduced disease recurrence by 41% and risk of death by 33% compared to observation alone. Further trials found that the addition of oxaliplatin to 5-​FU and folinic acid (FOLFOX regimen) significantly improved disease-​free survival and overall survival in stage II/​III colon cancer. The combination of a fluoropyrimidine with oxaliplatin is now the established standard of care, with capecitabine monotherapy being another option for patients who cannot tolerate FOLFOX. The evidence for the use of adjuvant chemotherapy is less well es- tablished for rectal cancer. A systematic review in 2015 did not find a survival benefit from adjuvant chemotherapy with 5-​FU if patients have undergone neoadjuvant radiotherapy or chemoradiotherapy. The addition of oxaliplatin, although possibly associated with an improvement in disease-​free survival, does not improve overall survival. Adjuvant chemoradiotherapy is only indicated in selected cases, such as patients with a high risk of local recurrence when no neoadjuvant radiotherapy has been given. Current NICE guidelines advise to consider offering adjuvant chemotherapy to high-​risk stage II and stage III rectal cancer to reduce the risk of local and sys- temic recurrence. Advanced disease Unlike metastatic disease in other cancers of the gastrointestinal tract, stage IV colorectal cancer is sometimes amenable to resec- tion of the primary tumour and metastatic deposits with a chance Table 15.16.3  Tumour, node, metastasis (TNM) staging of colorectal carcinoma T—​primary tumour Tx Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ (invasion of lamina propria) T1 Tumour invades submucosa T2 Tumour invades muscularis propria T3 Tumour invades subserosa or into non peritonealized pericolic or perirectal tissues T4 Tumour directly invades other organs or structures and/​or perforates visceral peritoneum: T4a: tumour perforates visceral peritoneum T4b: tumour directly invades other organs or structures N—​regional lymph nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1–​3 regional lymph nodes: N1a: metastasis in 1 regional lymph node N1b: metastasis in 2–​3 regional lymph nodes N1c: tumour deposit(s), i.e. satellites, in the subserosa, or in nonperitonealized pericolic or perirectal soft tissue without regional lymph node metastasis N2 Metastasis in 4 or more regional lymph nodes: N2a: metastasis in 4–​6 regional lymph nodes N2b: metastasis in 7 or more regional lymph nodes M—​distant metastasis M0 No distant metastasis M1 Distant metastasis: M1a: metastasis confined to one organ (liver, lung, ovary, nonregional lymph node(s)) without peritoneal metastases M1b: metastasis in more than one organ M1c: metastasis to the peritoneum with or without other organ involvement Stagea 0 Tis N0 M0 I T1, T2 N0 M0 II T3, T4 N0 M0 III Any T N1, N2 M0 IV Any T Any N M1 a Stage simplified for clarity. Adapted from Brierley J, Gospodarowicz M, Wittekind C (eds) (2017). TNM classification of malignant tumours, 8th edition. Chichester: John Wiley & Sons, Ltd.

section 15  Gastroenterological disorders 2994 of long-​term survival. Neoadjuvant therapy and surgery for liver metastases has been shown to improve disease-​free survival. Other ablative techniques for liver metastases such as selective internal radiotherapy and radiofrequency ablation, as well as surgical resec- tion of isolated lung metastases, are having an impact on the long-​ term survival of patients once thought to have incurable disease. Fluoropyrimidines, in combination with both oxaliplatin and irinotecan, can improve survival in patients with unresectable dis- ease. Oral fluoropyrimidines such as capecitabine have been shown to be as effective as 5-​FU but incur more toxicity. Biological ther- apies are also available; for example, the anti-​EGFR antibody cetuximab can be used in EGFR-​expressing, RAS wild-​type meta- static colorectal cancer. Patients with MMR deficiency respond well to immune modulation with antiprogrammed cell death (anti-​PD-​

  1. receptor monoclonal antibodies. The molecular genotyping of pa- tients is likely to play an increasing role in future treatment decisions as our ability to characterize individual patients’ tumours leads to individualized care. Colonic stenting is an effective technique for symptoms of left-​sided bowel obstruction. Octreotide may also improve symp- toms in those with disease at multiple sites precluding stenting or surgery. Screening and prevention Four randomized controlled trials (1993–​2007) and a Cochrane re- view (2007) found that bowel cancer screening using the faecal oc- cult blood test reduced colorectal cancer mortality by 16% and also reduced colorectal cancer incidence, presumably due to the removal of benign polyps that would otherwise have progressed to malig- nancy. Biennial faecal occult blood testing (using a home testing kit) is currently offered to all adults aged 60 to 74, and on request to adults aged 75 and over. In 2010, the United Kingdom Flexible Sigmoidoscopy Screening randomized controlled trial assigned over 170 000 patients to either a single flexible sigmoidoscopy (between the ages of 55 and 64) or no intervention. Over a median follow-​up period of 11.2 years, colo- rectal cancer incidence in the screened group was reduced by 23% and colorectal cancer mortality by 31%. This benefit was confirmed in a follow-​up study of the same cohort published in 2017 (median follow-​up 17.11 years), demonstrating that screening reduced colo- rectal cancer incidence by 26% and colorectal cancer mortality by 30%. Due to these results, one-​off flexible sigmoidoscopy screening for adults at age 55 is currently being implemented across the United Kingdom. Prognosis Bowel cancer survival has more than doubled in the United Kingdom in the last 40 years, due to a combination of improved de- tection through screening, improved surgical techniques, and the establishment of evidence-​based neoadjuvant, adjuvant, and pallia- tive therapies. Five-​year overall survival, although now approaching 60%, is heavily influenced by the stage at diagnosis (Fig. 15.16.14). Tumours that occur throughout the gastrointestinal tract Several types of malignancy can occur throughout the gastrointes- tinal tract. Initial symptoms may be related to the mass effect that occurs within that site; for instance, a caecal B-​cell lymphoma may present with obstruction and a right iliac fossa mass. Initial manage- ment should be emergency surgery, as for all obstructing tumours of the caecum, but subsequent treatment should be based on the path- ology rather than the anatomy. Lymphomas should be treated as a haematological malignancy rather than as the much more common cause of obstruction, an adenocarcinoma. Exceptions are neuro- endocrine malignancies that have specific management determined by their primary site. 100 110 90 80 70 Relative Survival (%) Stage I Stage II Stage III Stage IV Stage at Diagnosis All Stages Stage Not Known 60 50 40 30 20 10 0 Men Women Fig. 15.16.14  Five-​year relative survival (%) of colorectal cancer by stage. Source: Cancer Research UK. Bowel cancer survival statistic [internet]. CRUK 2018. Available from: http://​www. cancerresearchuk.org/​ [Accessed 2018 Mar 26].

15.16  Cancers of the gastrointestinal tract 2995 Gastrointestinal lymphoma Primary lymphomas are rare, accounting for only 1 to 4% of all gastrointestinal malignancies. There are two commonly occurring lymphomas of the gastrointestinal tract, mucosa-​associated lymphoid tissue lymphoma and diffuse large B-​cell lymphoma, the latter being managed with a combination of surgery and chemo- therapy. See Chapter 15.10.4 for further discussion. Gastrointestinal stromal tumour GISTs arise from the interstitial cells of Cajal, thought to be the pacemaker cells for enteric contraction. They occur throughout the gastrointestinal tract, and gastric GIST (the most common type) frequently grows to a significant size before there are any local symptoms. Most (88%) are associated with mutations of the KIT gene, leading to constitutive activation and oncogenic devel- opment. Treatment options were limited to surgery and the prog- nosis was poor before the introduction of imatinib, a small molecule that inhibits tyrosine kinase domains of the KIT and platelet-​ derived growth factor (PDGF) receptors. Median survival is now approaching 12 years with a 5-​year overall survival of almost 80%. Unlike chemotherapy, responses can occur many months into treat- ment. Patients with KIT exon 11 mutations have a higher rate of ob- jective response (84%) than patients with exon 9 mutations (48%) or no mutations in the KIT or PDGFR receptor (0%). GISTs are typ- ically responsive before the development of novel mutations in fur- ther KIT domains, responsible also for primary nonresponsiveness. Salvage therapies include other kinase inhibitors or surgery. Gastrointestinal melanoma Primary gastrointestinal melanoma occurs throughout the gastro- intestinal tract but is most commonly found in the anorectum (54%), oropharynx (33%), and oesophagus (5.9%). Whenever a melanoma is found in the bowel, care must be taken to exclude an occult skin cancer, as the vast majority of cases of intestinal mel- anoma are metastases from a cutaneous primary. Surgery is often the first treatment, but there is no evidence-​based management algo- rithm. Staging and treatment is usually based on that for cutaneous melanoma. Signet-​ring cell carcinoma (linitis plastica) Although over 95% of cases of linitis plastica occur in the stomach, it can also occur in the colon and rectum, gallbladder, and pancreas. Such cases must be carefully differentiated from the more common scenario of a linitis plastica of the stomach with peritoneal spread. Neuroendocrine tumours NETs are a group of neoplasms arising from neuroendocrine cells of the diffuse endocrine system. They comprise approximately 2% of all malignant tumours of the gastrointestinal tract and are usually sporadic, but they may occur as part of multiple endocrine neoplasia syndromes, von Hippel–​Lindau syndrome, neurofibromatosis, and tuberous sclerosis. Most have relatively slow tumour growth but have malignant potential, and most are diagnosed when distant (mainly liver) metastases have developed. Gastroenteropancreatic (GEP) NETs make up the majority, and these can be subdivided into carcinoid tumours of the luminal tract and pancreatic NETs (traditionally called islet-​cell carcinomas). Surgery of the primary and metastases, where possible, remains the only chance of cure. As NETs are usually hypervascular, locoregional therapies for liver metastases such as selective internal radiotherapy and transarterial chemoembolization have a role. Systemic (pal- liative) therapies include somatostatin analogues for symptom control in functional tumours, peptide receptor radionuclide treat- ment, low-​dose interferon, biological therapies (e.g. bevacizumab, everolimus, and sunitinib), and chemotherapy. See Chapters 15.9.2 and 15.26.3 for further information. Sarcomas Sarcomas of the gastrointestinal tract are exceedingly rare, with leiomyosarcomas of the stomach and small bowel being the most common. Management should be as for all other sarcomas. Small-​cell carcinoma Small-​cell carcinomas have been described in all parts of the gastro- intestinal tract. Treatment is as for primary small-​cell carcinoma of the lung, but prognosis is poor. Metastasis Metastases from cancer of the gastrointestinal tract occur commonly in the liver (see Chapter 15.24.6) due to haematological spread via the portal venous system. Rectal tumours can metastasize directly to the lungs from haematological spread via the portosystemic rectal veins. Other patterns of spread include transcoelomic (more common in mucinous and signet-​cell ring adenocarcinomas) and lymphatic. The liver is the most common site of metastatic presen- tation for carcinoma of unknown primary, and metastasis must be suspected in patients with a history of prior malignancy. Biopsy and comparison with prior histopathology is essential to confirm the diagnosis where there is clinical doubt and the overall condition of the patient makes this appropriate. FURTHER READING André T, et al. (2004). Oxaliplatin, fluorouracil, and leucovorin as ad- juvant treatment for colon cancer. N Eng J Med, 350, 2343–​51. Aparicio T, et al. (2014). Small bowel adenocarcinoma: epidemiology, risk factors, diagnosis and treatment. Dig Liver Dis, 46, 97–​104. Arnal MJD, Arenas AF, Arbeloa AL (2015). Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol, 21, 7933–​43. Atkin W, et  al. (2017). Long-​term effects of once-​only flexible sig- moidoscopy screening after 17 years of follow-​up: the UK flexible sigmoidoscopy screening randomised controlled trial. Lancet, 389, 1299–​311. Atkin WS, et al. (2010). Once-​only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised con- trolled trial. Lancet, 375, 1624–​33. Brenner B, et al. (2004). Small-​cell carcinoma of the gastrointestinal tract: a retrospective study of 64 cases. Br J Cancer, 90, 1720–​6. Breugom AJ, et al. (2015). Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-​analysis of individual patient data. Lancet Oncol, 16, 200–​7.

section 15  Gastroenterological disorders 2996 Brierley J, Gospodarowicz M, Wittekind C (eds) (2017). TNM classi- fication of malignant tumours, 8th edition. John Wiley & Sons, Ltd, Chichester. Burt RW, Jasperson KW (2016). Polyposis syndromes. In: Podolsky DK, et al. (eds) Yamada’s textbook of gastroenterology, 6th edition, pp. 1583–​607. Blackwell, Chichester. Cairns SR, et al. (2010). Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut, 59, 666–​90. Call J, et  al. (2012). Survival of gastrointestinal stromal tumor pa- tients in the imatinib era: life raft group observational registry. BMC Cancer, 12, 90. Cancer Research UK (2018). Bowel cancer risk factors. http://​www. cancerresearchuk.org/​health-​professional/​cancer-​statistics/​ statistics-​by-​cancer-​type/​bowel-​cancer/​risk-​factors Cancer Research UK (2018). Cancer statistics for the UK. http://​www.cancerresearchuk.org/​health-​professional/​ cancer-​statistics-​for-​the-​uk Cusack JC, Overman MJ, Kunitake H (2018). Treatment of small bowel neoplasms. UpToDate Inc. https://​www.uptodate.com/​contents/​ treatment-​of-​small-​bowel-​neoplasms Ellis A, et al. (2015). Tylosis with oesophageal cancer: diagnosis, man- agement and molecular mechanisms. Orphanet J Rare Dis, 10, 126. Fearon ER, Vogelstein B (1990). A genetic model for colorectal tumori- genesis. Cell, 61, 759–​67. Ferlay J, et  al. (2013). GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer, Lyon. http://​globocan.iarc.fr Glynne-​Jones R, et al. (2017). Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-​up. Ann Oncol, 28 Suppl 4, iv22–​iv40. Hewitson P, et al. (2007). Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev, 1, CD001216. Howlader N, et  al. (eds). SEER cancer statistics review, 1975–​2014. National Cancer Institute, Bethesda, MD. https://​seer.cancer.gov/​ csr/​1975_​2014/​ Hu B, et al. (2012). Gastric cancer: classification, histology and applica- tion of molecular pathology. J Gastrointest Oncol, 3, 251–​61. Jain S, Dhingra S (2017). Pathology of esophageal cancer and Barrett’s esophagus. Ann Cardiothorac Surg, 6, 99–​109. Jang E, Chung DC (2010). Hereditary colon cancer: Lynch syndrome. Gut Liver, 4, 151–​60. Johnson CM, et al. (2013). Meta-​analyses of colorectal cancer risk fac- tors. Cancer Causes Control, 24, 1207–​22. Le DT, et al. (2015). PD-​1 blockade in tumors with mismatch-​repair deficiency. N Eng J Med, 372, 2509–​20. Napier KJ, Scheerer M, Misra S (2014). Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol, 6, 112–​20. National Institute for Health and Care Excellence (NICE) (2006). Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes’ C) colon cancer Technology appraisal guidance. NICE, London. National Institute for Health and Care Excellence (NICE) (2010). Imatinib for the treatment of unresectable and/​or metastatic gastro-​ intestinal stromal tumours. Technology appraisal guidance. NICE, London. National Institute for Health and Care Excellence (NICE) (2011). Colorectal cancer:  diagnosis and management. Clinical guideline. NICE, London. National Institute for Health and Care Excellence (NICE) (2014). Imatinib for the adjuvant treatment of gastrointestinal stromal tumours. Technology appraisal guidance. NICE, London. National Institute for Health and Care Excellence (NICE) (2018). Oesophago-​gastric cancer:  assessment and management in adults. NICE guideline. NICE, London. National Institute for Health and Care Excellence (NICE) (2015). Suspected cancer: recognition and referral. NICE guideline. NICE, London. Oronsky B, Ma PC, Morgensztern D, Carter CA (2017). Nothing but NET:  a review of neuroendocrine tumors and carcinomas. Neoplasia, 19, 991–​1002. Siegel R, DeSantis C, Jemal A (2014). Cancer statistics, 2014. CA Cancer J Clin, 64, 104–​117. Siegel RL, Miller KD, Jemal A (2018). Cancer statistics, 2018. CA Cancer J Clin, 68, 7–​30. Syngal S, et  al. (2015). ACG clinical guideline:  genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol, 110, 223–​62. Vasen HFA, et  al. (1999). New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) pro- posed by the International Collaborative Group on HNPCC. Gastroenterology, 116, 1453–​6. Yamagishi H, et al. (2016). Molecular pathogenesis of sporadic colo- rectal cancers. Chin J Cancer, 35, 4.

15.17 Vascular disorders of the gastrointestinal t

15.17 Vascular disorders of the gastrointestinal tract 2997

ESSENTIALS A wide range of vascular disorders and vasculitides may affect the gastrointestinal tract. Most are quite uncommon, but presentations are often dramatic with intestinal bleeding or gangrene. Intestinal ischaemia is most commonly due to atherosclerosis or thrombosis causing arterial or venous mesenteric vascular oc- clusion. There are four primary syndromes. (1) Ischaemic colitis—​ presents with abdominal pain, nausea, vomiting, and tenderness followed by passage of loose bloody stool. Supportive manage- ment is usually sufficient, but a key challenge is early identification of patients with severe injury who are likely to progress to transmural ulceration and perforation. (2) Acute mesenteric ischaemia—​typic- ally presents with sudden abdominal pain, initially without localizing signs such that diagnosis is often delayed. Priorities of management are resuscitation, exclusion of other causes of apparent abdominal catastrophe, and prompt laparotomy to resect ischaemic bowel. (3) Chronic mesenteric ischaemia—​most often caused by athero- sclerotic disease and presents with severe and poorly localized cramping abdominal pain after eating. Diagnosis requires evidence of vascular occlusion on imaging, and revascularization is the defini- tive management strategy. (4) Mesenteric venous thrombosis—​diag- nosis is most commonly via cross-​sectional imaging. The mainstay of treatment is supportive, as well as anticoagulation and a search for predisposing factors. Vasculitides affecting the intestine may be primary (e.g. polyarteritis nodosa, Henoch–​Schönlein purpura, and antineutrophil cytoplasmic antibody-​associated vasculitis) or secondary (related to underlying infection, exposure to drugs, or a connective tissue disorder such as systemic lupus erythematosus or rheumatoid arthritis). Abdominal symptoms rarely dominate the clinical picture. Vascular lesions of the gastrointestinal tract may present with acute haemorrhage, chronic iron deficiency anaemia, or obstruc- tion. Lesions include angiodysplasias, telangiectasias, haemangi- omas, Dieulafoy lesions, and gastric antral vascular ectasia. These lesions may occur in isolation or as part of a syndrome (e.g. heredi- tary haemorrhagic telangiectasia). Intestinal ischaemia Intestinal ischaemia most commonly occurs due to arterial or venous mesenteric vessel occlusion from atherosclerosis or embolism. Although uncommon, intestinal ischaemia is associated with high mortality and has an increasing incidence, which is rising in par- allel with an ageing population and the incidence of atherosclerosis. These conditions lead to a range of clinical syndromes and present a diagnostic challenge due to their nonspecific clinical features. Vascular anatomy A basic understanding of the vascular anatomy of the gastrointes- tinal (GI) tract is required (Figs. 15.17.1 and 15.17.2). The main blood supply derives from three branches of the abdominal aorta—​ the coeliac trunk, the superior mesenteric artery (SMA), and the in- ferior mesenteric artery (IMA). The arteries arising from the coeliac trunk supply the stomach, proximal duodenum, liver, and pancreas. SMA branches supply the distal duodenum, jejunum, and ileum through vascular arcades that terminate in straight end arteries (the vasa recta). Branches of the SMA and IMA anastomose at regular intervals to supply the colon—​the right colon by the ileocolic and right colic branches, the transverse colon by the middle colic branch, and the left colon by branches of the IMA. Limited collaterals from the IMA and SMA create a watershed area at the splenic flexure (Griffith’s point) which is susceptible to ischaemia during low-​flow states. The rectosigmoid junction is another potential watershed area (Sudeck’s point). The lower rectum is supplied by both the su- perior rectal artery (a continuation of the IMA) and vessels arising out of the internal iliac artery. This dual blood supply means the lower rectum is often spared from ischaemic episodes. Duodenal venous drainage follows the arterial arcades through to the portal vein. The superior mesenteric vein drains the small bowel and right colon and the inferior mesenteric vein drains the left colon. Pathophysiology Two main mechanisms damage the intestine after vascular occlu- sion. First, cellular dysfunction and necrosis results from direct 15.17 Vascular disorders of
the gastrointestinal tract Ray Boyapati

section 15  Gastroenterological disorders 2998 deprivation of oxygen and nutrients. Second, once oxygenation is restored, reperfusion injury may exacerbate intestinal damage. Reperfusion injury is a complex and incompletely understood in- flammatory response. Reactive oxygen metabolites (including superoxide, hydrogen peroxide, and hydroxyl radicals) and lib- erated proinflammatory intracellular components play key roles. Vasoactive mediators are released into the circulation, intestinal barrier integrity is lost, and bacterial translocation, septic shock, and multiorgan failure may occur. Venous obstruction increases mesenteric venous bed resistance resulting in diminished perfusion, venous congestion, and intestinal wall oedema. Capillary rupture ensues with increasing oedema, and chronically dilated collaterals may bleed. Bowel infarction occurs with complete occlusion of venous return. Various complex and interacting homeostatic mechanisms pro- tect the GI tract from ischaemic injury. Intrinsic processes of splanchnic blood flow autoregulation (including reactive hyper- aemia, pressure–​flow autoregulation, and hypoxic vasodilation) help prevent intestinal ischaemia. In addition, collateral vessels tem- porarily dilate and allow for continued perfusion if an abrupt ob- struction to the blood supply occurs. Clinical syndromes Intestinal ischaemia is classified into distinct syndromes based on clinical presentation and the GI tract segment involved. Any one clinical syndrome may have multiple aetiologies (e.g. acute mes- enteric ischaemia can result from both embolic and atherosclerotic disease). Acute ischaemia threatens intestinal viability, whereas the less common chronic ischaemia occurs when compromised blood supply cannot support the functional needs of the GI tract. Ischaemic colitis Ischaemic colitis is the most common form of intestinal ischaemia and the cause of up to 1 in 2000 hospital admissions. The true in- cidence is uncertain as many mild cases go unrecognized due to transient symptoms. Most cases occur in patients aged 60 years or older. Intestinal ischaemia commonly complicates aortic valve and abdominal aortic aneurysm repair surgery. Other risk factors in- clude vasculitis, coagulation disorders, and drug use (e.g. cocaine, digoxin, sumatriptans, and nonsteroidal anti-​inflammatory agents (NSAIDs)). The colon is more susceptible to ischaemia than the small bowel due to its less well-​developed microcirculation. In addition, dis- tension of the colon may impair blood flow. Ischaemic colitis may therefore occur in the segment of intestine immediately proximal to an obstructing lesion or with colonic pseudo-​obstruction. Ischaemic colitis may affect any part of the large intestine, al- though the lower rectum is usually spared because of its dual blood supply. The left colon is most frequently affected, especially the watershed areas of the splenic flexure and rectosigmoid junction. However, the right colon is also susceptible to ischaemia because the vasa recta is less well developed. The spectrum of tissue damage is broad, and ranges from mild, superficial, and patchy changes to extensive necrosis. Patients present with abdominal pain, tenderness, nausea, and vomiting, progressing to urgency and bright red or maroon stool. Supportive management is usually sufficient because most cases Middle colic artery Right colic artery Ileal branches Ileocolic artery Superior mesenteric artery Fig. 15.17.1  Anatomy of the superior mesenteric artery. From MacKay GJ, Dorrance HR, Molloy RG, O’Dwyer PJ (eds) (2010). Colorectal surgery (Oxford specialist handbooks in surgery). By permission of Oxford University Press. Middle colic Marginal artery of Drummond Inferior mesenteric Left colic Middle and inferior rectal Superior rectal Superior mesenteric Ileocolic Right colic Appendicular Fig. 15.17.2  Blood supply to the colon. From MacKay GJ, Dorrance HR, Molloy RG, O’Dwyer PJ (eds) (2010). Colorectal surgery (Oxford specialist handbooks in surgery). By permission of Oxford University Press.

15.17  Vascular disorders of the gastrointestinal tract 2999 spontaneously resolve. The key challenges for the clinician are to dif- ferentiate ischaemic colitis from inflammatory bowel disease (endo- scopic and histological appearances can be similar) and promptly identify those patients with severe injury who are likely to progress to transmural ulceration and perforation. Initial plain films and laboratory tests are nonspecific but may be diagnostic and are useful in identifying other causes for symp- toms. Colonoscopy with minimal insufflation in an unprepared colon should be organized within 48 h. Findings include oedema, erosions, and ulcers with segmental or circumferential submucosal haemorrhages (Fig. 15.17.3). Planned follow-​up colonoscopy is per- formed to ensure improvement. CT and CT angiography often show nonspecific bowel wall thickening and are helpful to exclude other causes, especially if acute mesenteric ischaemia is being considered (Fig. 15.17.4). Supportive treatment is with intravenous fluids, broad-​spectrum antibiotics, and bowel rest. Urgent laparotomy may be required if gangrene or perforation occurs. Colonic strictures may develop fol- lowing recovery, although these rarely require intervention. Acute mesenteric ischaemia Acute mesenteric ischaemia is a syndrome caused by an abrupt interruption of mesenteric blood flow that leads to intestinal is- chaemia, inflammation, and eventually, infarction. It is relatively rare (approximately 0.1% of hospital admissions). Risk factors in- clude those related to embolic disease (e.g. atrial fibrillation, recent acute myocardial infarction, and valvular heart disease) and athero- sclerotic disease (e.g. increasing age, diabetes, smoking, and high cholesterol). For younger patients, risk factors include underlying thrombophilia, and cocaine, amphetamine, and vasoactive medica- tion use. Mortality remains at 30 to 70% despite improvements in investigation and management. Acute mesenteric ischaemia may be due to embolic, thrombotic, or nonocclusive processes. Emboli cause up to a third of episodes and arise from the heart in 80% of cases, hence the condition is most common in patients with primary cardiac conditions such as atrial fibrillation, bacterial endocarditis, or recent myocardial infarction with left ventricular thrombus. Uncommon causes include paradox- ical embolism through a patent foramen ovale and embolism from aortic mural thrombi. Emboli lodge preferentially just distal to the origin of the middle colic artery from the SMA. Acute mesenteric arterial thrombosis is caused by plaque rupture in the setting of severe atherosclerosis, most commonly near the origin of the SMA. Extensive compensatory collateral circulation has usually developed due to the gradual nature of atherosclerosis. This collateral formation (and the rich, redundant nature of the in- testinal blood supply) means that at least two major mesenteric ves- sels are generally affected before infarction occurs. Rarely, all three vessels may be occluded without visceral damage. Nonocclusive mesenteric ischaemia is responsible for around 20% of cases of acute mesenteric ischaemia. This occurs due to dispro- portionate splanchnic vasoconstriction resulting from a sustained state of hypoperfusion, most often in settings of elderly patients with severe low-​output cardiac failure, patients requiring haemodialysis, and patients with shock requiring intensive care therapy (including those who have had cardiopulmonary bypass surgery). A variety of Fig. 15.17.3  Endoscopic appearances of ischaemic colitis with changes ranging from patchy erythema to frank ulceration in a sharply defined segment of involvement. Reproduced from www.gastrointestinalatlas.com. (a) (b) Fig. 15.17.4  Ischaemic colitis—​CT features. Axial (a) and coronal reformatted (b) images demonstrate mural thickening with submucosal oedema (arrows) of the transverse colon and both colonic flexures in a 34-​year-​old woman with systemic lupus erythematosus. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 3000 often interrelated factors are implicated, including medications (par- ticularly vasopressors and digoxin), cardiovascular events, and pre-​ existing atherosclerosis. For elective cardiac surgery patients, risk factors include older patients, renal insufficiency, diuretic therapy, need for intra-​aortic balloon pump support, and postoperative high serum lactate. Acute mesenteric ischaemia from any cause may cause a spectrum of intestinal tissue damage ranging from self-​limiting and transient superficial injury to life-​threatening transmural necrosis. There is wide variability in clinical features, which depend on the extent of is- chaemic damage. The classic presentation is of acute, severe abdom- inal pain, colicky in the early stages but progressing to constant and unremitting, that lasts longer than a few hours. This presentation of overwhelming distress with relatively unimpressive clinical signs makes early diagnosis challenging. Clinical features are nonspecific and include nausea, vomiting, diarrhoea with or without blood, ab- dominal distension, and hyperactive bowel sounds. With progres- sion to transmural infarction, peritonitis and cardiovascular collapse may occur. A preceding history of weeks or months of postprandial abdominal pain, nausea, and weight loss suggests SMA thrombosis. Initial investigations include routine blood tests for evaluation of abdominal pain and coagulation profile, arterial blood gas, lac- tate, and lipase. There are no reliable early serum markers for acute mesenteric ischaemia. Leucocytosis is common, but often only pre- sents late in the disease course. There may be a metabolic acidosis, although early profound vomiting may cause a metabolic alkalosis. Electrocardiogram findings of an arrhythmia might suggest an em- bolic source and help raise the index of suspicion for mesenteric ischaemia. After resuscitation, further initial investigations are per- formed mainly to exclude other courses of severe abdominal pain. Abdominal plain films are often normal early on but may show small-​bowel and/​or right colon thumbprinting indicating bowel wall oedema (Fig. 15.17.5), nonspecific dilatation of the small bowel with fluid levels, mesenteric vascular gas, or free intraperitoneal air. CT angiography has now become the initial investigation of choice because it can be performed expeditiously and is less time-​consuming and invasive than the historical gold standard of mesenteric angiography. It has high sensitivity and spe- cificity in identifying occlusive SMA disease but is less accurate for nonocclusive mesenteric ischaemia (Fig. 15.17.6). Magnetic resonance angiography (MRA) is often difficult to perform quickly and is limited by lower spatial resolution and slower acquisition times compared to CT angiography. Once gangrene develops (Fig. 15.17.7), the mortality rate of acute mesenteric ischaemia may be as high as 90%, highlighting the im- portance of avoiding delays in proceeding to definitive therapy. Initial management includes aggressive resuscitation (critical to combat further hypotension-​related hypoperfusion), hospitaliza- tion, bowel rest, empirical broad-​spectrum antibiotics, intensive monitoring, avoidance of vasoconstrictive medications, urgent se- nior surgical review, and prompt laparotomy to resect the ischaemic bowel and restore blood flow. Treatment decisions should ideally involve a multidisciplinary team approach with gastroenterol- ogists, general and vascular surgeons, radiologists, anaesthetists, Fig. 15.17.5  Plain abdominal radiograph of a man presenting with acute abdominal pain and rectal bleeding. There is thumbprinting (arrow) in the region of the splenic flexure, and the small bowel is dilated. Image reproduced with permission from Medscape Drugs & Diseases (https://​ emedicine.medscape.com/​), Ischemic Colitis Imaging, 2016, available at: https://​ emedicine.medscape.com/​article/​366808-​overview. Fig. 15.17.6  Acute arterial occlusive mesenteric ischaemia. CT images during intravenous contrast in early arterial phase in a patient with proximal thrombotic occlusion of the superior mesenteric artery show portal venous gas (arrow on left image), mesenteric venous gas (arrow on right image), pneumatosis intestinalis, and a diffuse lack of bowel wall enhancement in keeping with bowel infarction. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.17  Vascular disorders of the gastrointestinal tract 3001 and intensivists. Any sign of peritonism mandates immediate lapar- otomy. Perioperative mesenteric angiography allows for the plan- ning of surgical resection and infusion of vasodilators and has been shown to improve outcomes. Depending on local interventional radiological expertise, aspiration embolectomy, thrombolysis, and endovascular stenting may be alternatives to laparotomy. If there is any doubt over the viability of residual intestine, a repeat lapar- otomy 12 to 24 h later is indicated. With nonocclusive mesenteric ischaemia, infiltration of the SMA with vasodilators during angiog- raphy may help relieve the obstruction. Chronic mesenteric ischaemia Chronic mesenteric ischaemia occurs when the physiological re- quirements of the GI tract cannot be met. It is less common than acute mesenteric ischaemia and accounts for less than 5% of all cases of intestinal ischaemia. Atherosclerotic disease is the cause in over 95% of cases, with the proximal regions of the coeliac artery, SMA, or IMA usually affected (hence the term ‘intestinal angina’). Uncommon causes include mesenteric vasculitis, fibromuscular dysplasia, and radiation. Risk factors are those associated with atherosclerosis. The nonspecific clinical features and lack of specific diagnostic tests make this a challenging diagnosis. The classic presentation is of severe, poorly localized, cramping abdominal pain occurring 20 to 60 min after eating that resolves within a few hours. The postprandial symptomatology may be due to atherosclerosis limiting the higher blood flow requirements, or from a ‘steal’ phenomenon (diversion of blood flow from intestinal to gastric circulation when food enters the stomach). Patients often present with a fear of eating and weight loss. Physical signs such as an abdominal bruit are nonspecific and clinically unhelpful. Common investigations for abdominal pain such as abdominal plain films, CT, and endoscopy are usually normal. CT angiog- raphy, MRA, duplex ultrasonography, or invasive catheter angiog- raphy may identify flow disturbances or occlusion. The diagnosis relies on a combination of clinical features consistent with chronic mesenteric ischaemia, exclusion of other causes of abdominal pain, and radiological evidence of occlusion in at least two of the three major mesenteric arteries. However, due to the high incidence of asymptomatic mesenteric atherosclerotic disease with collateral for- mation, radiological evidence of obstruction in two or even three mesenteric arteries supports the diagnosis, but is insufficient in itself to prove it. Chronic mesenteric ischaemia may be a harbinger of significant atherosclerosis elsewhere and diagnosis should initiate cardiac in- vestigations. General treatment measures include management of atherosclerosis, including statins, weight loss, exercise, and cessation of smoking. Depending on local expertise and in selected cases with short segments of occlusion, endovascular stenting can have good long-​term success rates. Stenotic lesions most commonly occur at the aortic origins of the vessels so definitive management at lapar- otomy with mesenteric reconstruction may be very rewarding. Mesenteric venous thrombosis Mesenteric venous thrombosis is less common than arterial oc- clusion. This condition affects younger people (mean age between 40 and 60  years) and has a male predominance. The superior mesenteric vein is far more commonly involved than the inferior mesenteric vein. Mesenteric venous thrombosis usually occurs in thrombophilias which are inherited (e.g. antithrombin III deficiency and pro- tein C or S deficiency) or acquired (e.g. polycythemia rubra vera, thrombocythaemia, and antiphospholipid antibody syndrome), systemic disorders causing a hypercoagulable state (e.g. cancer and nephrotic syndrome), a local abdominal process (e.g. pancreatitis and postsplenectomy, inflammatory bowel diseases), or stasis (e.g. congestive heart failure and portal hypertension). A clear precipitant cannot be found in 20 to 40% of cases. Presentation may be acute or chronic. The acute presentation has clinical features of acute mesenteric ischaemia and accounts for between 5 and 10% of such presentations. In the chronic presenta- tion, bowel infarction is less common and patients may present with (a) (b) Fig. 15.17.7  Colonic infarction—​CT features. (a) Axial image obtained at the pelvic brim shows pneumatosis intestinalis of the ascending (arrow) and descending colon. Both the small bowel and colon are dilated and fluid filled. (b) A scan at the level of the liver demonstrates extensive intrahepatic portal venous gas. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 3002 vague abdominal pain, nausea, and vomiting. The condition is often asymptomatic until complications of portal hypertension develop (e.g. varices or ascites). As with acute mesenteric ischaemia, initial investigations are nonspecific. Acid–​base abnormalities and leucocytosis may be pre- sent, and plain abdominal films may show dilated loops of bowel, mucosal oedema with thumbprinting, or features of perforation. CT with contrast is usually the imaging modality of choice and is highly accurate in demonstrating thrombi in the superior mesen- teric vein and portal veins. Abdominal Doppler ultrasonography may also be used but is less sensitive for smaller thrombi. Imaging may also show complications of portal hypertension such as varices and ascites. Nowadays, diagnosis seldom requires invasive mesen- teric angiography. Treatment is aimed at preventing bowel infarction by reperfusion of the intestine. For the acute presentation, management includes supportive therapy and immediate anticoagulation, which should generally continue for at least 6 months (or longer if there is an underlying thrombophilia). A systematic search for any underlying predisposing factors should be performed. Patients who pre- sent chronically may require management of portal hypertensive bleeding from varices with banding and/​or transjugular intrahepatic portosystemic shunt. Vasculitides affecting the intestine Several vasculitides affect the GI tract, although involvement is usually part of a systemic process and rarely dominates the clinical picture. Vasculitis can affect any splanchnic blood vessel, including arteries, arterioles, veins, venules, and the vasa recta. Inflammation of these vessels drives regional ischaemia, resulting in disruption of blood flow and eventually ischaemic damage to the intestine or other organs such as the pancreas and liver. Overall, the most common forms of intestinal vasculitis en- countered are those associated with polyarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, and Henoch–​Schönlein purpura. Intestinal involvement can lead to the full spectrum of tissue damage, from self-​limiting superficial injury to perforation. Intestinal vasculitis may occur through a primary autoimmune process (‘primary’ vasculitis) or as part of a systemic process such as an underlying connective tissue disorder, infection, malig- nancy, or exposure to drugs (‘secondary’ vasculitis). This chapter will focus on the approach to patients with vasculitis affecting the intestine:  the classification, pathophysiology, clinical features, and treatment of specific vasculitides are covered elsewhere (see Chapters 19.11.6, 19.11.7, 19.11.8, 19.11.9, and 19.11.10). Clinical presentation Patients with known systemic vasculitis or connective
tissue disease Most patients with GI involvement of primary or secondary vascu- litis have other clinical features related to the underlying systemic vasculitis or connective tissue disease. Indeed, diagnosis of intestinal vasculitis commonly relies on the systemic features and laboratory findings of the underlying illness, rather than the often nonspecific abdominal complications. In reality, most patients will already have been diagnosed with vasculitis, and the challenge for the clinician is to promptly identify GI involvement when present. Involvement of multiple specialty teams and interdisciplinary meetings are often required. The clinical features reflect the underlying vessels involved and depend on the extent and severity of disease in the affected intes- tine. Patients can present with any of the features of mesenteric ischaemia. The acute presentation of GI vasculitis is indistinguish- able from acute mesenteric ischaemia, including severe abdominal pain, a relative lack of clinical signs, and progression to peritonitis and shock, but vasculitis accounts for only around 2% of all causes of intestinal infarction. The chronic presentation is indistinguish- able from chronic mesenteric ischaemia due to atherosclerosis, with intestinal angina, fear of eating, and progressive weight loss. Vasculitis of the intestine can lead to protein-​losing enteropathy and subsequent cachexia, peripheral oedema, and ascites. Nonspecific symptoms of nausea, vomiting, weight loss, abdominal pain, and diarrhoea are often present. GI bleeding can result from ischaemic damage or rupture of a mesenteric aneurysm. Patients may uncom- monly present with small-​bowel obstruction from stricturing dis- ease, which can be difficult to distinguish from NSAID-​induced enteropathy or Crohn’s disease. More severe disease is suggested by intussusception, perforation, or infarction. Ischaemic hepatitis, oe- sophagitis, gastritis, pancreatitis, appendicitis, and cholecystitis may also occur. In patients with a pre-​existing diagnosis of systemic vasculitis or connective tissue disorder, presentation with symptoms in keeping with acute or chronic mesenteric ischaemia, but without an obvious source of embolism, should prompt further investigation for GI involvement. Patients not known to have systemic disease In the absence of an existing diagnosis of vasculitis or connective tissue disease, when should clinicians consider vasculitis of the GI tract as a cause for abdominal symptoms? Unexplained abdom- inal pain, diarrhoea, bleeding, weight loss, and anorexia with or without fevers should prompt the usual investigations for these symptoms, including laboratory tests, abdominal imaging, and en- doscopy. If these investigations fail to reveal a diagnosis, the less common differentials such as occult malignancy, occult infection, or intestinal vasculitis should be entertained. Abdominal symptoms occurring with other features of systemic vasculitis or connective tissue disease may provide the critical clinical clue. Occasionally, clinicians may encounter a patient who has had multiple courses of empiric corticosteroids for relief of GI symptoms without careful exclusion of intestinal vasculitis. Primary vasculitides Any systemic vasculitis can theoretically affect the mesenteric circulation. There is variable GI tract involvement depending on the specific primary vasculitis involved. Table 15.17.1 outlines the various vasculitides, the frequency of GI tract involvement, and associated GI features. Vasculitides affecting only the large to medium-​sized arteries such as giant cell arteritis and Takayasu’s ar- teritis have low rates of clinically significant GI tract involvement due to the marked redundancy of the mesenteric circulation. In general, GI involvement in primary vasculitis indicates more severe disease and poorer prognosis.

15.17  Vascular disorders of the gastrointestinal tract 3003 In two types of vasculitis, intestinal involvement is reflected in the American College of Rheumatology (ACR) diagnostic criteria. ACR criteria for polyarteritis nodosa include weight loss, which is prob- ably due to common involvement of the superior mesenteric artery. ACR criteria for Henoch–​Schönlein purpura include postprandial abdominal pain or bowel ischaemia, usually associated with bloody diarrhoea. Rare syndromes of localized small-​bowel vasculitis have been reported. Cryptogenic, multifocal ulcerating stenosing enteritis (CMUSE) is a rare localized vasculitis that leads to small-​bowel ulcers, strictures, and obstructive symptoms. After bone marrow transplantation, there are case reports of jejunal vasculitis causing protein-​losing enteropathy. Secondary vasculitis related to collagen vascular diseases Mesenteric vasculitis should be considered in patients with collagen vascular diseases and GI symptoms (Table 15.17.2). Patients with these conditions often have GI symptoms such as abdominal pain, diarrhoea, dyspepsia, dysphagia, and gastro-​oesophageal reflux, but it is important to note that most GI symptoms in these patients are due to causes other than mesenteric vasculitis. In fact, possibly the most common cause of GI symptoms and pathology in patients with collagen vascular disorders is as a complication of treatment. NSAIDs are commonly used and lead to many GI manifestations including peptic ulcer disease, enteropathy, intestinal strictures, and secondary vasculitis. Prednisolone, also commonly used to treat these conditions, may contribute to peptic ulcer disease or GI infections. GI symptoms may result from a process related to the primary collagen vascular disorder itself. For example, dysmotility in sys- temic sclerosis due to overproduction of collagen and subsequent fibrosis may cause dysphagia, delayed gastric emptying, colonic in- ertia, or small intestinal stasis with bacterial overgrowth. Mesenteric vasculitis in systemic lupus erythematosus is relatively uncommon (2–​15%) but has a high mortality rate. The Systemic Table 15.17.1  Gastrointestinal involvement of primary vasculitides Disease GI tract features Approximate frequency of
GI involvement Polyarteritis nodosa Small bowel and gallbladder most commonly affected. Rarely complicated by perforation and infarction. Association with hepatitis B. Other: cholecystitis, appendicitis, pancreatitis 30–​60% Henoch–​Schönlein purpura May present with acute abdomen without typical palpable purpura. GI bleeding is common. Small bowel most frequently involved. Rarely complicated by intussusception, perforation, and infarction. Other: gallbladder hydrops, pancreatitis 50–​70% (5–​20% at disease presentation) Antineutrophil cytoplasmic antibody associated: Granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) GI tract ulceration (oesophageal, intestinal). Less commonly: infarction, cholecystitis, pancreatitis 5–​20% Eosinophilic granulomatosis with polyangiitis (formerly known as Churg–​Strauss syndrome) 30–​45% Microscopic polyangiitis 5–​10% Degos’s disease Peritonitis secondary to bowel perforation is the most common cause of death 50% Behçet’s disease Ileocaecal region most frequently involved. Also can affect oesophagus, transverse and ascending colon. Can mimic inflammatory bowel disease with mucosal ulceration, and may also have similar extraintestinal findings. Other: pancreatitis 5–​25% Kawasaki’s disease 5% have acute abdomen at initial presentation. May present with paralytic ileus, gallbladder hydrops, appendicitis, or intestinal ischaemia 5–​10% Buerger’s disease –​ Case reports Giant cell arteritis –​ Case reports Takayasu’s arteritis Mesenteric vessels involved in up to 12% on angiography but only rarely symptomatic Case reports Cryoglobulinaemic vasculitis Association with hepatitis C Case reports Table 15.17.2  Gastrointestinal manifestations and mesenteric vasculitis in collagen vascular disorders Disease Approximate frequency
of mesenteric vasculitis Common GI symptoms (from disease or side effects of medications) Rheumatoid arthritis 0.5–​1% Heartburn, dysphagia, diarrhoea Systemic lupus erythematosus 0.2–​10% Abdominal pain, nausea, vomiting, anorexia in 30–​50%. Relatively common: heartburn and diarrhoea. Less frequent: dysphagia, abdominal pain, distension due to ascites, and GI bleeding Systemic sclerosis Rare Most frequent: progressive dysphagia. Heartburn, stricture formation, poor gastric emptying, bacterial overgrowth causing diarrhoea and malabsorption, progressive constipation due to impaired colonic motility Sjögren’s syndrome Rare Symptoms relatively rare: abdominal pain, nausea, constipation, diarrhoea, and malabsorption

section 15  Gastroenterological disorders 3004 Lupus International Collaborating Clinics (SLICC)/​ACR Damage Index includes scores for mesenteric insufficiency and intestinal infarction or resection. Acute mesenteric ischaemia in systemic lupus erythematosus may be caused by either thrombosis related to antiphospholipid antibodies or mesenteric vasculitis. This distinc- tion is important as treatment will be with anticoagulation rather than immunosuppression. Investigation It is preferable to investigate vasculitis affecting the GI tract prior to specific treatment being instituted, although this is sometimes not possible. Acute presentation with severe abdominal pain should be investigated as described previously. Investigations including inflammatory markers, serological markers of autoimmunity, and angiography may be helpful. The erythrocyte sedimentation rate is almost always elevated in active vasculitis and, although it lacks specificity, may be used as an initial screening test and to monitor progress. In the presence of mesenteric ischaemia, serum lactate is often raised, although this is neither sensitive nor specific enough to be used for diagnosis. Other systemic features of vasculitis may be found with careful clinical examination and basic investigations such as chest radiography and urinalysis. Screening with mesenteric angiography or CT angiography is the most revealing test and should be performed if there is significant clinical concern. However, the findings of different vasculitides can overlap considerably and hence this test rarely determines the spe- cific diagnosis in isolation. Up to two-​thirds of cases of polyarteritis nodosa have recognizable aneurysms of mesenteric and renal vessels on mesenteric angiography (Fig. 15.17.8). Although multiple mesen- teric circulation microaneurysms are a characteristic of polyarteritis nodosa, these can be found in other vasculitides. Furthermore, fibromuscular dysplasia may have similar angiographic appearances. CT angiography can help exclude thrombotic or embolic causes of mesenteric ischaemia. Up to 12% of patients with Takayasu’s arteritis (medium and large vessels affected) will have findings of mesenteric involvement on angiography, but most will not have symptomatic intestinal vasculitis. In systemic lupus erythematosus, CT angi- ography may show bowel wall thickening, dilated loops, ascites, lymphadenopathy, and dilated mesenteric veins. Intestinal tissue biopsy has a low sensitivity in diagnosing GI tract vasculitis and tissue diagnosis can usually be made from alternative, more accessible sites. Management Treatment of vasculitis affecting the GI tract depends on the underlying systemic disease. General treatment measures such as bowel rest, total parenteral nutrition, antibiotics, and corticoster- oids are often required. Corticosteroids at high doses are effective for all vasculitides. Other treatments such as cyclophosphamide, azathioprine, methotrexate, immunoglobulins, and biologics de- pend on the specific diagnosis. Early involvement of senior surgical colleagues is warranted when patients present acutely as with acute mesenteric ischaemia. Patients with stricturing disease may also re- quire surgical resection. Vascular lesions of the intestine Vascular lesions of the intestine are not uncommon and may be con- genital or acquired. They may present at any age, although some le- sions are more likely in certain age groups (e.g. caecal angiodysplasias in elderly patients). This section focuses on primary vascular lesions of the intestine and does not cover the many disorders which may secondarily affect blood vessels of the GI tract, such as peptic ulcers, diverticular disease, aortoenteric fistulas, malignancy, and portal hypertensive bleeding. The clinical presentation of vascular lesions of the intestine is varied and includes acute, sometimes life-​threatening haemorrhage, chronic iron deficiency anaemia, and obstruction. If the lesions are part of an underlying disorder, there may be other associated clin- ical features (e.g. epistaxis in patients with hereditary haemorrhagic telangiectasia). Investigation is often difficult, especially when lesions are not ac- cessible via gastroscopy or colonoscopy. In such cases, video capsule endoscopy, CT angiography, and MRA can help identify the location of haemorrhage. Double-​balloon enteroscopy, radiographic embol- ization, or surgery may be required to treat lesions inaccessible by routine gastroscopy, enteroscopy, or colonoscopy. In acute haemorrhage, urgent endoscopy is required, with haemo- stasis achieved through a combination of one or more strategies, including injection of adrenaline, banding, clipping, and application of heat or nonthermal coagulation methods such as argon plasma coagulation. If endoscopic treatment is unsuccessful, surgical over- sewing or resection is required. Angiodysplasias Angiodysplasias (alternative names include angioectasias, vascular dysplasias, and vascular ectasias) are acquired arteriovenous mal- formations. They are usually small degenerative lesions of previous healthy blood vessels and histologically comprise dilated vessels Fig. 15.17.8  Arteriography showing multiple renal artery stenoses and microaneurysms (arrows) with an inferior kidney pole infarction in a patient with polyarteritis nodosa. From Ball GV, Fessler BJ, Bridges, Jr. SL (eds) (2014). Oxford textbook of vasculitis, 3rd edition. By permission of Oxford University Press.

15.17  Vascular disorders of the gastrointestinal tract 3005 in the mucosa and submucosa. They may be singular or multiple and can occur throughout the GI tract. Up to 80% are found in the caecum and ascending colon, around 15% are in the jejunum and ileum, and the remainder are elsewhere. Angiodysplasias are the most common GI tract vascular abnor- mality, present in around 1% of asymptomatic individuals. There is an increasing prevalence with age, and in patients over 60 years they are second only to diverticular disease as the most common cause of lower GI bleeding. Small-​bowel angiodysplasias may account for up to 40% of occult GI bleeding. Bleeding from angiodysplasias is more common in patients on antiplatelet agents or therapeutic anticoagulation, and those who have conditions with a bleeding diathesis such as chronic renal in- sufficiency and end-​stage liver disease. There is a higher rate of GI bleeding from angiodysplasias in the presence of aortic stenosis (Heyde’s syndrome), although the cause of this remains uncertain. Presentation may be with iron deficiency anaemia or acute lower GI haemorrhage, particularly from right-​sided colonic lesions. Direct visualization of the intestinal mucosa with endoscopy or video capsule endoscopy are the investigations of choice. The classic appearance is of one or more small (<10 mm), cherry red, arborizing lesion(s) (Fig. 15.17.9). In the acute setting, CT, MRA, or standard angiography may demonstrate a bleeding point (Fig. 15.17.10). If incidentally found on endoscopy, there is no indication to treat these lesions. If, however, the lesion is thought to be the cause of symptoms, treatment with direct application of heat or nonthermal coagulation is often sufficient. Argon plasma coagulation is gaining favour as the modality of choice. Some patients may require mul- tiple endoscopic procedures to treat difficult lesions. Local resection or arterial embolization may be necessary if lesions are inaccessible via endoscopy, too widespread, or resistant to repeat endoscopic therapy. Arterial embolization of the small bowel carries a substan- tial risk of intestinal ischaemia. Pharmacological treatments with thalidomide or octreotide are reserved for transfusion-​dependent and treatment-​resistant cases. Telangiectasias Telangiectasias are dilated venules and most commonly occur in the GI tract as part of hereditary haemorrhagic telangiectasia (also known as Osler–​Weber–​Rendu disease). Hereditary haemorrhagic telangiectasia is an uncommon, multisystem, autosomal dominant disease with telangiectasias and arteriovenous malformations affecting the nasal passages, skin, GI tract, lungs, liver, and brain (Fig. 15.17.11). After epistaxis, GI haemorrhage is the most frequent form of bleeding, occurring in up to one-​third of these patients. Gut telangiectasias are most commonly found in the stomach and prox- imal small bowel. Presentation may be with iron deficiency anaemia Fig. 15.17.9  Small-​bowel enteroscopy showing angiodysplasia. From Jolly E, Fry A, Chaudhry A (eds) (2016). Training in medicine. By permission of Oxford University Press. (a) (b) (c) Fig. 15.17.10  (a) Angiodysplastic lesion in the caecum: superior mesenteric angiogram in a 53-​year-​old man with anaemia for 20 years (no lesion found at previous operations). Vascular lake in caecum (arrowed). (b) Angiodysplastic lesion in the caecum: superior mesenteric angiogram in a 53-​year-​old man with anaemia for 20 years (no lesion found at previous operations). Capillary phase, showing early filling vein arising from lesion. (c) Angiodysplastic lesion in the caecum: superior mesenteric angiogram in a 53-​year-​old man with anaemia for 20 years (no lesion found at previous operations). Injected specimen magnified ×30. Courtesy of Dr D J Allison, Royal Postgraduate Medical School; previously published in Br J Hosp Med (1980), 23, 358.

section 15  Gastroenterological disorders 3006 or overt GI bleeding. Typically, there are numerous lesions making endoscopic therapy difficult. Often regular cauterization is required. Haemangiomas Intestinal haemangiomas are uncommon, benign vascular lesions that occur as single or multiple lesions anywhere in the GI tract. They most commonly occur in the small bowel, and in particular the jejunum. The rectosigmoid is the most common colonic site. When occurring as multiple lesions, haemangiomas may occur as part of a syndrome (Table 15.17.3). Patients may present at any age with oc- cult or overt GI haemorrhage, obstruction, or intussusception. Haemangiomas have solid characteristics of tumours and are classified as cavernous, capillary, or mixed. The capillary subtype is a proliferation of capillaries surrounded by a lining of endothelial (a) (b) (c) Fig. 15.17.11  Hereditary haemorrhagic telangiectasia. (a) Characteristic tiny dilated vascular lesions on the cheek in a middle-​aged woman. (b) Red maculopapular lesions on tongue and lower lip in a 55-​year-​old woman. (c) Endoscopic image of right nasal cavity showing telangiectasias on the anterior septum and inferior turbinate in a 59-​year-​old man. From Mulliken JB, Burrows PE, Fishman SJ (eds) (2013). Mulliken and Young’s vascular anomalies: hemangiomas and malformations. By permission of Oxford University Press. Table 15.17.3  Syndromes associated with GI vascular lesions Syndrome Vascular lesion in the GI tract Most common location of GI involvement Turner’s syndrome Telangiectasia Angiodysplasias Haemangiomas Small bowel Hereditary haemorrhagic telangiectasia Telangiectasias Stomach and proximal small bowel Blue rubber bleb nevus syndrome Haemangiomas Small bowel Klippel–​Trenaunay and Parkes–​Weber syndromes Haemangiomas Distal colon Systemic sclerosis and CREST Telangiectasias Anywhere throughout the GI tract; may have GAVE in the stomach Peutz–​Jeghers syndrome Hamartomatous polyposis Jejunal and ileal

15.17  Vascular disorders of the gastrointestinal tract 3007 cells and occurs as single lesions, predominantly in the perianal skin but also the appendix and small bowel. Cavernous haemangiomas comprise large blood-​filled cavities lined by endothelial cells, and present the greatest clinical risk as they are generally larger, have a higher propensity to bleed, and may consume platelets leading to thrombocytopenia. The endoscopic appearance of the cavernous type is as a sessile, polypoid lesion which can be distinguished from adenomatous polyps by their bluish colour, poorly defined margins, and typically submucosal location. Endoscopic therapy or angio- graphic embolization may arrest bleeding. Dieulafoy’s lesions A Dieulafoy’s lesion represents a small submucosal defect overlying a large-​calibre and tortuous arteriole. It is the reported cause of 1 to 2% of cases of acute GI bleeding. Diagnosis can be a challenge because identification often relies on stigmata of recent bleeding or active bleeding during endoscopy (Fig. 15.17.12), and ‘missed’ Dieulafoy’s lesions are likely to be the cause of many cases of un- identified GI bleeding. Most lesions occur in the upper stomach but they may occur anywhere along the GI tract. Advances in endoscopy have dramatically reduced mortality from these lesions, with pro- cedures successful in over 90% of cases. Gastric antral vascular ectasia Gastric antral vascular ectasia (GAVE) is an incompletely under- stood condition that causes up to 4% of cases of GI bleeding. The characteristic endoscopic appearance is of erythematous stripes along the antral rugal folds which represent ectatic vessels (thus the alternative name, ‘watermelon stomach’) (Fig. 15.17.13). GAVE is associated with several comorbid conditions such as primary biliary cholangitis, systemic sclerosis and renal failure. The treatment of choice is endoscopic cautery, usually with argon plasma coagulation and often requiring multiple treatments. Pharmacological treat- ments such as oral oestrogen and progesterone, octreotide, tranex- amic acid, and thalidomide have been reported in small series and should be reserved for transfusion-​dependent patients. Resistant disease may require surgical antrectomy. FURTHER READING Bala M, et al. (2017). Acute mesenteric ischemia: guidelines of the World Society of Emergency Surgery. World J Emerg Surg, 12, 38. Garcia-​Porrua C, et al. (2006). Localised vasculitis of the gastrointes- tinal tract. Seminar Arthritis Rheum, 35, 403–​6. Lara LF, et al. (2010). Dieulafoy lesions of the GI tract: localization and therapeutic outcomes. Dig Dis Sci, 55, 3436–​41. Oglat A, Quigley EM (2017). Colonic ischemia: usual and unusual presentations and their management. Curr Opin Gastroenterol, 33, 34–​40. Thomas A, et al. (2018). An analysis of the clinical, laboratory, and histological features of striped, punctate, and nodular gastric antral vascular ectasia. Dig Dis Soc, 63, 966–​73. van Dijk LJ, van Petersen AS, Moelker A (2017). Vascular imaging of the mesenteric vasculature. Best Pract Res Clin Gastroenterol, 31, 3–​14. Fig. 15.17.12  Endoscopic image of a spurting Dieulafoy’s lesion. Reproduced from www.gastrointestinalatlas.com. Fig. 15.17.13  GAVE. Note the linear aggregates of red markings in the antrum and the absence of an underlying mosaic-​like pattern. From Hauser SC (ed) (2014). Mayo Clinic gastroenterology and hepatology board review, 5th edition. By permission of Oxford University Press.

15.18 Gastrointestinal infections 3008

15.18 Gastrointestinal infections 3008

ESSENTIALS Gastrointestinal infections, especially diarrhoea and vomiting, are responsible for substantial morbidity, mortality, and socioeconomic penalties worldwide. In poor countries, the greatest burden of dis- ease is borne by infants and young children, although older people and immunocompromised patients are also at great risk of severe and complicated disease. Poor sanitation, inadequate water supplies, and globalization of food production, processing, and retailing in- crease the risk of large epidemics of food-​ and waterborne outbreaks of gastrointestinal disease. Clinical syndromes Acute diarrhoea can be caused by pathogens ranging from toxin-​ producing strains of Escherichia coli to rotavirus and Giardia spp. Gastrointestinal pathogens usually cause three principal syn- dromes: acute watery diarrhoea, acute bloody diarrhoea (inflamma- tory diarrhoea or dysentery), and persistent diarrhoea. They can also cause systemic disease. Patients who do not have high fever (>38.5°C), systemic illness, tenesmus, bloody diarrhoea, a prolonged course (>2 weeks), or de- hydration require neither investigation nor treatment. Investigation is required in patients with any of these features, with faecal spe- cimens examined by culture (bacterial pathogens and some protozoa), microscopy (ova, cysts, and parasites), immunoassays (some protozoa and viruses), and molecular methods, usually poly- merase chain reaction (PCR) or reverse transcriptase PCR (bacterial toxin genes and viruses). A specific laboratory diagnosis is useful epidemiologically and therapeutically, especially for invasive patho- gens and diarrhoea in high-​risk patients such as the very young, eld- erly, or immunocompromised. Management Oral rehydration therapy is the priority for patients with mild to moderate diarrhoea as long as vomiting is not a major feature, and it can also follow initial parenteral rehydration in severely de- hydrated patients. Antimicrobial therapy is not recommended or usually required for uncomplicated diarrhoea, but antibiotic treat- ment is beneficial for cholera, giardiasis, cyclosporiasis, shigellosis, symptomatic traveller’s diarrhoea, Clostridium difficile diarrhoea, and typhoid. Antimotility drugs are useful in controlling moderate to se- vere diarrhoea in adults but they are not generally recommended for infants and young children under the age of 4 years. Prevention Strict attention to food and water precautions and hand washing helps reduce the risk of gastrointestinal infections. Immunization has not yet proved successful for combating many gastrointestinal pathogens, with the notable exception of rotavirus. Introduction On a global scale, diarrhoeal diseases are among the top 10 leading causes of death, killing an estimated 1.5 million people in 2012. In the infectious diseases category, which collectively cause around 23% of deaths worldwide, diarrhoeal diseases lie in second place (jointly with HIV/​AIDS) behind the estimated 3.1  million deaths from lower respiratory tract infections. The impact is greatest in low-​ and middle-​income countries. As well as killing people, gastrointestinal infections can exert a toll as major causes of chronic ill health through, for example, their contribution to malnutrition. There can also be serious systemic sequelae such as chronic kidney disease requiring long-​term renal replacement therapy following haemolytic uraemic syndrome (HUS) caused by enterohaemorrhagic Escherichia coli (EHEC), and Guillain–​Barré syndrome (GBS) following infection with Campylobacter spp. Aetiological agents A wide variety of bacteria, viruses, and parasites cause gastro- intestinal infections (Tables  15.18.1–​15.18.3), usually by gaining entry directly via the gastrointestinal tract. Exceptions to this in- clude hookworm (Ancylostoma spp. and Necator americanus), which burrows through the skin, usually of the foot, and even- tually migrates to the intestine via the bloodstream, lymphatics, and lungs. 15.18 Gastrointestinal infections Sarah O’Brien

15.18  Gastrointestinal infections 3009 Table 15.18.1  Aetiology of gastrointestinal infection: major bacterial pathogens Organism Typical incubation period Typical symptoms Typical duration Bacillus cereus Emetic type: 30 min–​6 h Nausea and vomiting 24 h Diarrhoeal type: 6–​15 h Cramping abdominal pain, acute watery diarrhoea Campylobacter spp. 2–​5 days Cramping abdominal pain, fever, acute watery and/​or acute bloody diarrhoea 2–​10 days Clostridium botulinum 12–​36 h after ingesting toxin Early signs and symptoms include striking lethargy, weakness, and vertigo, normally followed by blurred or double vision and increasing problems with talking and swallowing. If untreated, symptoms may progress to descending paralysis—​ arms, trunk (including respiratory muscles), legs Months Clostridium difficile Unclear but could be up to 7 days Severe abdominal pain, anorexia, fever, acute watery or, rarely, bloody diarrhoea 7–​10 days; around 25% of patients relapse, typically 3 days–​3 weeks post cessation of treatment Clostridium perfringens 10–​12 h Mild cramping abdominal pain, acute watery diarrhoea 12–​24 h Diffusely adherent Escherichia coli (DAEC) 6–​48 h Mild, acute watery diarrhoea Days Enteroaggregative E. coli (EAggEC) 8–​18 h Acute watery diarrhoea, which turns bloody in approximately a third of cases Days Enterohaemorrhagic E. coli (EHEC) 3–​4 days Range from asymptomatic to mild diarrhoea to haemorrhagic colitis, which presents as severe cramping abdominal pain, nausea or vomiting, and frequent episodes of diarrhoea that becomes obviously bloody. Fever is usually absent or low grade 2–​9 days in the absence of complications Enteroinvasive E. coli (EIEC) 12–​72 h Abdominal cramping pain, acute bloody diarrhoea, vomiting, fever 5–​7 days Enteropathogenic E. coli (EPEC) 4–​12 h Profuse acute watery diarrhoea, vomiting, low-​ grade fever 21–​120 days Enterotoxigenic E. coli (ETEC) 8–​44 h Acute watery diarrhoea, cramping abdominal pain, low-​grade fever, nausea Up to 20 days Listeria monocytogenes Invasive disease: 3 days to 3 months Headache, stiff neck, photophobia, confusion, vertigo, and convulsions Days to weeks Nontyphoidal Salmonella spp. 6–​72 h Headache, fever, nausea, vomiting, cramping abdominal pain, acute watery or bloody diarrhoea 4–​7 days Salmonella Paratyphi 1–​10 days Anorexia, headache, high fever, lassitude; abdominal pain, diarrhoea or constipation. In severe cases, signs of Gram-​negative septicaemia 1–​2 weeks S. Typhi 8–​14 days Anorexia, headache, high fever, lassitude, abdominal pain, diarrhoea or constipation, skin rash of flat, rose-​coloured spots on the trunk. In severe cases, signs of Gram-​negative septicaemia 7–​10 days on appropriate treatment; 3 months if untreated; 3–​5% become chronic carriers Shigella spp. 8–​50 h Cramping abdominal pain, fever, acute bloody diarrhoea, tenesmus 5–​7 days Staphylococcus aureus 1–​7 h Acute onset of nausea, cramping abdominal pain, vomiting, and watery diarrhoea Up to 1 day Vibrio cholera Serogroups O1 and O139: 2–​3 days Vomiting, mild to severe acute watery diarrhoea Days to weeks Serogroups other than O1 and O139: 12–​24 h Fever, cramping abdominal pain, acute watery diarrhoea 7 days Vibrio parahaemolyticus 4–​90 h Cramping abdominal pain, nausea, vomiting, fever, acute watery or bloody diarrhoea 2–​6 days Yersinia enterocolitica 1–​11 days Fever, abdominal pain that can be confused with appendicitis, diarrhoea and/​or vomiting Up to 3 weeks

section 15  Gastroenterological disorders 3010 Table 15.18.2  Aetiology of gastrointestinal infection: major viral pathogens Organism Typical incubation period Typical symptoms Typical duration Adenovirus 40/​41 3–​10 days Abdominal pain, fever, vomiting and acute watery diarrhoea Up to 10 days Astrovirus 3–​4 days Anorexia, abdominal pain, fever, acute watery diarrhoea 2–​3 days Hepatitis A 15–​50 days Anorexia, nausea, vomiting, fever, diarrhoea, myalgia, jaundice. Jaundice occurs 5–​7 days after onset of gastrointestinal symptoms 1–​2 weeks Hepatitis E 3–​8 weeks Anorexia, abdominal pain, arthralgia, fever, malaise, jaundice, vomiting 2 weeks Norovirus 12–​24 h Explosive, projectile vomiting, acute watery diarrhoea, headache, low-​grade fever, myalgia 24–​48 h Rotavirus 24–​72 h High fever, vomiting, acute watery diarrhoea 3–​7 days Sapovirus 1–​3 days Nausea, vomiting, acute watery diarrhoea, myalgia 2–​3 days Table 15.18.3  Aetiology of gastrointestinal infection: major parasites Organism Typical incubation period Typical symptoms Typical duration Protozoa Balantidium coli 3–​4 days Can be asymptomatic but also causes acute bloody diarrhoea, nausea, vomiting, headache If treated 5–​20 days depending upon therapy chosen Cryptosporidium hominis 7–​10 days Cramping abdominal pain, nausea and vomiting copious acute watery diarrhoea 2–​14 days in immunocompetent people but may become chronic in the immunocompromised Cryptosporidium parvum 7–​10 days Cramping abdominal pain, nausea and vomiting, copious acute watery diarrhoea 2–​14 days in immunocompetent people but may become chronic in the immunocompromised Cyclospora cayetanesis 7–​10 days Anorexia, weight loss, cramping abdominal pain, bloating, acute watery and explosive diarrhoea Days to months Cystoisospora belli 3–​14 days Cramping abdominal pain, acute watery diarrhoea, malabsorption and weight loss Weeks to months if untreated Dientamoeba fragilis 1–​2 weeks Abdominal pain and watery diarrhoea 1–​2 weeks unless infection becomes chronic Entamoeba histolytica 2–​4 weeks Abdominal distension, mild diarrhoea to severe acute bloody diarrhoea A few days to several weeks Giardia intestinalis 1–​2 weeks Cramping abdominal pain, malaise, flatulence, foul-​ smelling diarrhoea, weight loss 2–​6 weeks unless infections becomes chronic Toxoplasma gondii 5–​23 days Acute toxoplasmosis; sore lymph nodes, myalgia, flu-​like symptoms. Ocular toxoplasmosis; blurred or reduced vision, increased production of tears, eye redness and pain, photophobia Several weeks Trichinella spp. 1–​4 weeks Abdominal discomfort, diarrhoea, myalgia, weakness, fever, muscle pain, facial swelling Weeks to months Helminths Ascaris lumbricoides 4–​8 weeks Often asymptomatic, unless the patients spots a worm in their faeces, or, occasionally, when a worm escapes through the mouth, nose, or anus. Heavy infestations can cause abdominal pain and distension, nausea, anorexia, vomiting, self-​limiting pneumonia, intestinal obstruction 1–​2 years unless treated Anisakis simplex and Pseudoterranova decipiens 24 h–​2 weeks Noninvasive anisakiasis; no symptoms or coughing up a nematode after a tingling sensation in the throat 3 weeks to several months Invasive anisakiasis; nausea, vomiting, severe abdominal pain, diarrhoea, mild to strong allergic response Ancylostoma duodenale 5–​8 weeks Epigastric pain, abnormal peristalsis, iron-​deficiency anaemia Up to 1 year if untreated Diphyllobothrium latum 15 days Abdominal discomfort, altered appetite, mild diarrhoea, vitamin B12 deficiency in prolonged or heavy infestations, rarely intestinal obstruction Up to 25 years if left untreated Dipylidium caninum 21–​28 days Mostly asymptomatic but can cause abdominal distension, restlessness, diarrhoea Following treatment: follow-​up at 1 and 3 months

15.18  Gastrointestinal infections 3011 Bacteria Important bacteria causing diarrhoeal disease include the following: • Bacillus cereus—​Gram-​positive, spore-​forming rod that produces two enterotoxins:  a heat-​stable emetic toxin that is formed in highly contaminated food and a heat-​labile diarrhoeal toxin that forms in the small intestine. • Campylobacter spp.—​Gram-​negative, spiral-​shaped rods, are the most frequent bacterial cause of diarrhoeal disease in high-​income countries where infection is often associated with consumption of undercooked contaminated poultry. Seroepidemiological studies show that exposure to Campylobacter spp. is very common but does not necessarily lead to protective immunity. Rare but serious sequelae include GBS and reactive arthritis. It also causes mesen- teric adenitis, which can be confused with acute appendicitis. • Clostridium difficile—​a Gram-​positive, spore-​forming drumstick (or spindle)-​shaped rod, is an important healthcare-​associated, or nosocomial, infection in high-​income countries, although spread within the community outside healthcare settings is increasingly recognized. It colonizes the gastrointestinal tract after perturba- tions of the healthy gut microbiome, usually following treatment with broad-​spectrum antibiotics. It commonly affects the elderly. • Clostridium perfringens type A  strains—​Gram-​positive, spore-​ forming rods, are major causes of classical food poisoning resulting in acute watery diarrhoea following enterotoxin production. • E.  coli spp.—​Gram-​negative rods, commonly found in diar- rhoea cases in low-​ and middle-​income countries where they are leading cause of hospital admission for infectious diarrhoea. There are six major categories of E. coli that cause diarrhoea—​ enteroaggregative E. coli (EAggEC), EHEC, enteroinvasive E. coli (EIEC), enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), and diffusely adherent E. coli (DAEC). The role of DAEC as a diarrhoeal pathogen has been disputed because in many studies it has been found as frequently in asymptomatic controls as in cases. However, DAEC are gaining acceptance as a cause of diarrhoea in preschool children in low-​ and middle-​income coun- tries and in travellers. • Salmonella spp.—​Gram-​negative rods, cause typhoid fever (S. Typhi), paratyphoid fever (S. Paratyphi), and foodborne dis- ease (nontyphoidal Salmonella spp.). Salmonellas are found worldwide in warm-​blooded and cold-​blooded animals, and in the environment. • Shigella spp.—​Gram-​negative rods, classically cause dysentery. HUS is an occasional, but severe, complication. • Staphylococcus aureus—​a Gram-​positive coccus, is another clas- sical food poisoning organism. Food handlers who are carriers of enterotoxin-​producing S. aureus or who have visible purulent skin lesions, especially on their hands, can contaminate food. S. aureus produces various emetic enterotoxins, but staphylococcal entero- toxin A is most often implicated in staphylococcal food poisoning worldwide. • Vibrio spp.—​Gram-​negative bacilli, cause cholera (V.  cholerae serogroups O1 and O139), acute gastroenteritis (V. parahaemo- lyticus and V. cholerae serogroups other than O1 and O139), and septicaemia (V. vulnificus). • Yersinia enterocolitica—​a Gram-​negative bacillus, is associated with eating pork meat or pig intestine (chitterlings). Pathogenic Y.  enterocolitica biotype 4 (serotype 3)  strains predominate in Europe and the United States of America. Extraintestinal mani- festations include mesenteric adenitis, mimicking acute appendi- citis, and erythema nodosum and reactive arthritis are recognized postinfectious complications. Viruses Important viruses, which are the commonest causes of acute watery diarrhoea globally, include the following: • Adenovirus subgroup F (types 40 and 41)—​a well-​known cause of acute gastroenteritis in very young children (<6  months of age). Organism Typical incubation period Typical symptoms Typical duration Enterobius vermicularis and E. gregorii 1–​2 months Intense pruritus ani and perineal pruritus 2 weeks if treated Hymenolepis nana 2–​4 weeks Mainly asymptomatic but can cause abdominal pain nausea, weakness, anorexia, diarrhoea Following treatment: follow-​up at 2 weeks and 3 months Necator americanicus 35–​40 days (for gastrointestinal symptoms to appear) Itching and a localized rash at the entry site. Heavy infection can produce abdominal pain, anorexia, weight loss, fatigue, diarrhoea, and anaemia Up to 1 year if untreated Schistosoma spp. 6–​8 weeks Abdominal pain, fatigue, fever, headache, generalized myalgia, vertigo, vomiting, bloody diarrhoea If untreated 20–​30 years Strongyloides stercoralis 14–​30 days Many infections are asymptomatic. When symptoms occur they include abdominal pain, heartburn, bloating, alternating diarrhoea and constipation, dry cough, rash Up to 30 years if untreated Taenia spp. 2–​4 months Often asymptomatic but can lead to cause abdominal pain, nausea, anorexia, diarrhoea Years unless treated Trichiuris trichiuria Up to 3 months Light infections are mostly asymptomatic. Moderate to heavy infections produce abdominal pain, nausea, vomiting, bloody diarrhoea, anaemia, and rectal prolapse 1–​2 years if left untreated Table 15.18.3  Continued

section 15  Gastroenterological disorders 3012 • Astrovirus—​accounts for between 2% and 9% of all acute child- hood nonbacterial gastroenteritis worldwide. It is a common cause of outbreaks in day-​care settings and nurseries. The illness is usually self-​limiting but severe, systemic infections can occur in immunocompromised and elderly patients. • Norovirus—​responsible for approximately 18% of all cases of acute gastroenteritis globally and the leading cause of acute epidemic gastroenteritis. It poses a major problem in closed and semiclosed settings such as schools, hospitals, and cruise ships, where it can result in explosive outbreaks. Outbreaks are often identified using Kaplan’s criteria (Box 15.18.1) because the short-​lived nature of the illness means that most infections are unconfirmed by labora- tory testing. Most of the noroviruses that infect humans belong to genogroups GI and GII. Periodically, new strains emerge and spread around the world very rapidly. Susceptibility to norovirus infection appears to be linked with the expression of human histoblood group antigens. • Rotavirus—​until recently this was the leading cause of viral gastro- enteritis and diarrhoeal deaths worldwide. It led to approximately 2 million hospital admissions and around 0.5 million deaths an- nually in children less than 2  years of age. However, rotavirus vaccination appears to have reduced substantially the burden of community-​acquired and hospital-​acquired cases in countries with high vaccine uptake. • Sapovirus—​this is from the same family of viruses as norovirus (the Calciviridae). Alongside norovirus, sapoviruses of geno­ groups GI, GII, GIV, and GV are the most common causes of acute viral gastroenteritis in adults. However, unlike noroviruses, sapoviruses tend to cause only mild illness in young children. In a community-​based study of infectious diarrhoea in the United Kingdom, sapovirus was found to be the second most commonly identified agent after norovirus. Although many pathogens cause diarrhoea and vomiting, some agents gaining entry via the gastrointestinal tract cause extraintestinal symptoms. For example, Listeria monocytogenes rarely causes diarrhoea (<1% of reported cases) but is associated with invasive disease—​meningitis and septicaemia. Similarly, V. vulnificus infection, which is associated with the consumption of raw or undercooked shellfish, results in septicaemia in immuno- compromised people or patients with liver disease. Parasites The burden of parasitic infections varies geographically. In high-​ income countries, protozoa are much more common causes of illness than intestinal helminths. By contrast, in low-​income countries in- testinal helminths are among the most prevalent infections in hu- mans. Principal parasitic causes of gastrointestinal infection include the following: • Cryptosporidium spp.—​a protozoan parasite that leads to acute watery diarrhoea in healthy people but can cause pro- longed, chronic diarrhoea in immunocompromised people. The main pathogens for humans are C. parvum and C. homi- nis but other species can also produce disease in people. Outbreaks have been associated with contaminated drinking water and, rarely, contaminated food. The cysts are not des- troyed by the levels of chlorine used to disinfect drinking water supplies. • Cyclospora cayetanensis—​a protozoan parasite causing watery diarrhoea, weight loss, anorexia, bloating, nausea, vomiting, muscle aches, and persistent fatigue. It is endemic in many low-​ and middle-​income countries. Illness may last from a week to a month or longer if it is left untreated. It is one of the few gastro- intestinal infections for which there is specific antimicrobial therapy. • Entamoeba histolytica—​a protozoan parasite affecting an esti- mated 40 to 50 million people globally, leading to approximately 40 000 deaths. Symptoms range in severity from mild diarrhoea to severe dysentery. • Giardia lamblia—​a flagellate protozoan parasite resulting in both epidemic and sporadic disease. A variety of intestinal symptoms follow infection including abdominal cramps, flatulence, and chronic diarrhoea leading to weight loss and fatigue. Illness can extend to months or years if it is undiagnosed. • Soil-​transmitted helminths—​with the exception of Strongyloides stercoralis, these do not often cause diarrhoea. Hyperinfection with S.  stercoralis can occur in immunocompromised pa- tients and the resulting heavy worm burdens can lead to se- vere complications such as intestinal obstruction. Infestations with hookworms and whipworm tend to cause extraintestinal manifestations. Certain organisms exhibit marked seasonal patterns, for ex- ample, norovirus, which is classically described as causing ‘winter vomiting,’ rotavirus, which also peaks during the cold winter months, Campylobacter spp. with a marked late spring peak in temperate climates, and nontyphoidal Salmonella spp., which tend to peak in late summer. For organisms such as nontyphoidal Salmonella spp. that can multiply outside the main reservoir (e.g. in or on food), it has been suggested that climate change might in- crease their impact in future. The time that elapses between exposure to an infectious agent and onset of symptoms or signs is called the incubation period. Each gastrointestinal infection has a typical incubation period that requires multiplication of the infectious agent to a threshold necessary to produce symptoms or laboratory evidence of infection. The incubation can vary according to the infectious dose, the replication rate of the organism and underlying host factors such as age, sex, and genetic susceptibility. The infectious dose can vary considerably from pathogen to pathogen as shown in Table 15.18.4. Box 15.18.1  Kaplan’s criteria for diagnosis of a norovirus outbreak • A mean (or median) illness duration of 12 to 60 h and • A mean (or median) incubation period of 24 to 48 h and • More than 50% of people with vomiting and • No bacterial agent found on stool examination. After Kaplan JE, et al. (1982). Epidemiology of Norwalk gastroenteritis and the role of Norwalk virus in outbreaks of acute nonbacterial gastroenteritis. Ann Intern Med, 96, 756–​61.

15.18  Gastrointestinal infections 3013 Epidemiology and spread Susceptibility Susceptibility to most gastrointestinal pathogens is general, but young children, the elderly, and the immunocompromised are rec- ognized as being at higher risk of developing infection and may suffer a more severe illness. Rates of gastrointestinal infection tend to be higher in children under the age of 5 years than in any other age group. Children ex- perience higher rates of EHEC infections than adults and are also at increased risk of developing severe complications such as HUS. Indeed, in high-​income countries HUS is the most common cause of acute kidney injury in young children. The elderly are at increased risk of developing another complication of EHEC infection, namely thrombotic thrombocytopenic purpura, with its associated high mortality. Listeria monocytogenes, which is ubiquitous and grows on food held at refrigerator temperature, is an important cause of fetal loss, and of invasive disease (meningitis and/​or septicaemia) in the eld- erly. Elderly men have recently been group identified as being at highest risk for hepatitis E virus infection. Underlying medical conditions and drug treatment (e.g. proton pump inhibitors to reduce stomach acid), may increase the predis- position to acquiring gastrointestinal infection. Moreover, chronic infection with certain pathogens (e.g. Cryptosporidium spp.), may herald the onset of AIDS in patients infected with HIV. Transmission The major transmission routes for gastrointestinal infection are person-​to-​person spread via the faecal-​oral route, ingesting faecally contaminated food or drinking water, or direct spread from infected animals or the environment, which has become contaminated with pathogens. Transmission can also occur through inhalation of aero- sols containing gastrointestinal pathogens, sexual transmission, vertical transmission from mother to unborn child, and through a contaminated blood transfusion supply. Tables 15.18.5 to 15.18.7 summarize the principal reservoirs and transmission routes. Person-​to-​person spread Many gastrointestinal pathogens are transmitted from person to person via the faecal-​oral route. The faecal–​oral route (also referred to as the oral–​faecal route or orofaecal route) means that patho- gens in faeces voided by one person pass to the mouth of another (Fig. 15.18.1). The so-​called F-​diagram was designed deliberately to be memorable, showing that faecal–​oral transmission occurs via ‘fingers, flies, fields, foods, and fluids’ (i.e. polluted drinking water, surface water, or groundwater). It also illustrates where control measures can be implemented to prevent transmission. Food-​borne spread The substantial impact of food-​borne disease is sobering. The World Health Organization (WHO) recently produced the first es- timates of their global burden. Altogether, a total of 31 global food-​ borne hazards were found to cause around 600 million food-​borne illnesses and 420 000 deaths in 2010. The most frequently recognized causes were diarrhoeal disease pathogens, especially norovirus and Campylobacter spp. Foodborne diarrhoeal diseases accounted for approximately 230  000 deaths. Major causes were nontyphoidal Salmonella spp., S. Typhi, Taenia solium, and hepatitis A virus. Forty per cent of the food-​borne disease burden occurred in children under the age of 5 years. There was also marked regional variation, with the highest burdens witnessed in Africa, South-​East Asia, and parts of the Eastern Mediterranean. Food can become contaminated at source during primary pro- duction (i.e. in the fields—​crops or food-​producing animals), during processing, transportation, at retail level, and/​or in the hospitality sector or the domestic setting. Increasing globaliza- tion of the food supply spreads organisms rapidly worldwide. A classic example of this was the large outbreaks of Cyclospora cayetenensis in North America from contaminated raspberries imported from central America. Transporting food long distances is also a means of spreading antimicrobial resistance, such as a na- tionwide outbreak of multidrug-​resistant Salmonella Heidelberg infections in the United States of America associated with con- sumption of ground turkey meat. Food handlers with poor per- sonal hygiene can also contaminate food. This is well recognized for bacterial pathogens and increasingly so for viral pathogens such as norovirus. Waterborne spread Ensuring the safety of the drinking water supply by separating sewage from it, the so-​called sanitary revolution, has been described as the greatest medical advance since 1840. Yet poor water quality remains a major hazard to human health in many parts of the world. Nearly 60% of the global total of 1.5 million deaths from diarrhoeal diseases arises from unsafe water supplies, and inadequate sani- tation and hygiene. An estimated 361 000 of these 842 000 water-​ related deaths occur in children under 5 years of age, primarily in low-​ and middle-​income countries. Vibrio cholerae is a classical waterborne pathogen in low-​and middle-​income countries, where epidemics and pandemics are strongly associated with drinking unsafe water or eating food that has been prepared using unsafe water. Mass migration following man-​made or natural disasters and overcrowded refugee camps provide the perfect conditions for the rapid spread of cholera out- breaks. Case fatality rates in these circumstances are often high. Cryptosporidium spp. are more commonly associated with water- borne outbreaks in high-​income countries. Table 15.18.4  Infectious dose for selected gastrointestinal pathogens Organism Infectious dose (organisms) Escherichia coli (other than EHEC) 106–​108 Vibrio cholera 104–​106 Nontyphoidal salmonellas

105 Campylobacter spp. 100s Cryptosporidium parvum 10–​30 oocysts Shigella spp. 10s Norovirus 1–​10 virus particles EHEC ≤10

section 15  Gastroenterological disorders 3014 Table 15.18.5  Principal reservoirs and transmission pathways for gastrointestinal bacteria Organism Reservoirs Person-​to-​person Food-​borne Waterborne Zoonotic Environment-​to-​person Bacillus cereus Soil and environment ✘ ✓✓ ✘ ✘ ✘ Campylobacter spp. Food-​producing animals (including poultry) and domestic pets ✘ ✓✓ ✘ ✘ ✘ Clostridium botulinum Spores in soil, honey, animal and fish guts ✘ ✓✓ ✘ ✘ ✘ Clostridium difficile Humans ✓✓ (✓) ✘ ✘ ✓ Clostridium perfringens Humans and animals ✘ ✓✓ ✘ ✘ ✘ Diffusely adherent Escherichia coli (DAEC) Humans ✓ ✓✓ ✓✓ ✘ ✘ Enteroaggregative E. coli (EAggEC) Humans ✓ ✓✓ ✓✓ ✘ ✘ Enterohaemorrhagic E. coli (EHEC) Cattle ✓✓ ✓✓ ✓✓ ✓✓ ✓✓ Enteroinvasive E. coli (EIEC) Humans ✘ ✓✓ ✓✓ ✘ ✘ Enteropathogenic E. coli (EPEC) Humans ✓ ✓✓ ✓✓ ✘ ✓ Enterotoxigenic E. coli (ETEC) Humans (✓) ✓✓ ✓ ✘ ✘ Listeria monocytogenes Soil, water, mud, silage, domestic and wild animals, birds, humans ✓ ✓✓ ✘ (✓) (✓) Nontyphoidal Salmonella spp. Domestic and wild animals (including poultry) ✓ ✓✓ ✓ ✓ (✓) Salmonella Paratyphi Humans ✓ ✓✓ ✓✓ ✘ ✘ Salmonella Typhi Humans ✓ ✓✓ ✓✓ ✘ ✘ Shigella spp. Humans ✓✓ ✓ ✓ ✘ ✘ Staphylococcus aureus Humans, cattle, dogs, birds ✘ ✓✓ ✘ ✘ ✘ Vibrio cholera Humans ✓✓ ✓✓ ✓✓ ✘ ✘ Vibrio parahaemolyticus Marine coastal environment ✘ ✓✓ ✘ ✘ ✘ Yersinia enterocolitica Pigs, sheep, cattle, goats ✓ ✓✓ ✓✓ ✓ ✘ ✓✓, major route; ✓, minor route; (✓), rarely reported; ✘, not reported. Table 15.18.6  Principal reservoirs and transmission pathways for gastrointestinal viruses Organism Reservoirs Person-​to-​person Food-​borne Waterborne Zoonotic Environment-​to-​person Adenovirus 40/​41 Humans ✓✓ ✘ ✓ ✘ ✓ Astrovirus Humans ✓✓ ✘ ✘ ✘ ✘ Hepatitis A Humans ✓✓ ✓ ✓ ✘ ✘ Hepatitis E Humans, pigs ✓✓ ✓ ✓ ✘ ✘ Norovirus Humans ✓ ✓ ✓ ✘ ✓ Rotavirus Humans ✓✓ ✘ (✓) ✘ ✘ Sapovirus Humans, pigs ✓✓ (✓) (✓) ✘ (✓) ✓✓, major route; ✓, minor route; (✓), rarely reported; ✘, not reported.

15.18  Gastrointestinal infections 3015 Zoonotic spread Several bacteria, including Campylobacter spp., EHEC, nontyphoidal Salmonella spp., and Yersinia entercolitica, and protozoa, including Cryptosporidium parvum and Giardia intestinalis, are zoonotic, that is, their main reservoir is in animals, notably domestic livestock and companion animals (pets). As well as contaminating the food or water supply, these organisms can also spread to humans via direct contact with the animal source. Outbreaks of EHEC among small children visiting petting zoos, city farms, and open farms are now well documented. Environment-​to-​person spread Soil-​transmitted helminths are classic examples of infections acquired directly from the environment. Roundworm (Ascaris lumbricoides), whipworm (Trichiuris trichiuria), and hookworms (Ancylostoma duodenale and Necator americanicus) are common in tropical and subtropical regions of low-​income countries where water and sanitation facilities are inadequate. Recently it has been estimated that A. lumbricoides affects more than a billion people globally, T. trichiura around 795 million people, and hookworms approximately 740 million people. Norovirus can also be transmitted from the environment. Virus particles aerosolized during explosive diarrhoea and vomiting can settle on hard surfaces or soft furnishings where they can survive for long periods of time before being picked up by another person who touches the contaminated surfaces days or even weeks later. In practice, many gastrointestinal pathogens can be spread via more than one route as is illustrated for Campylobacter spp. in Fig. 15.18.2. Table 15.18.7  Principal reservoirs and transmission pathways for gastrointestinal parasites Organism Reservoirs Person-​to-​person Food-​borne Waterborne Zoonotic Environment-​to-​person Protozoa Balantidium coli Pigs ✓✓ ✘ ✓ ✘ ✘ Cryptosporidium hominis Humans ✘ ✘ ✓✓ ✘ ✘ Cryptosporidium parvum Livestock (cattle, sheep goats), humans ✓✓ ✓✓ ✓✓ ✓✓ ✓ Cyclospora cayetanesis Humans ✓ ✓✓ ✓ ✘ ✘ Cystoisospora belli Humans ✘ ✓✓ ✓✓ ✘ ✘ Dientamoeba fragilis Humans ✓✓ ✘ ✘ ✘ ✘ Entamoeba histolytica Humans ✘ ✓✓ ✓✓ ✘ ✘ Giardia intestinalis Humans, beavers, cats, dogs, cattle, deer ✓✓ ✓ ✓ ✘ ✓ Toxoplasma gondii Cat (✓) ✓✓ ✘ ✓✓ ✘ Trichinella spp. Pigs, dogs, cats, horses, rats, wild animals ✘ ✓✓ ✘ ✘ ✘ Helminths Ascaris lumbricoides Humans ✘ ✓✓ ✘ ✘ ✓✓ Anisakis simplex and Pseudoterranova decipiens Crustaceans, squid, octopus, fish ✘ ✓✓ ✘ ✘ ✘ Ancylostoma duodenale Humans ✘ ✓ ✘ ✘ ✓✓ Diphyllobothrium latum Fish ✘ ✓✓ ✘ ✘ ✘ Dipylidium caninum Dogs, cats ✘ ✘ ✘ ✓✓ ✘ Enterobius vermicularis and E. gregorii Humans ✓✓ ✘ ✘ ✘ ✓✓ Hymenolepis nana Humans,?mice ✓✓ ✓✓ ✓✓ ✘ ✓✓ Necator americanicus Humans ✘ ✘ ✘ ✘ ✓✓ Schistosoma spp. Humans (S. mansoni and S. haematobium); humans, dogs, cats, pigs, cattle, water buffalo, wild rodents (S. japonicum) ✘ ✘ ✓✓ ✘ ✘ Strongyloides stercoralis Humans (✓) ✘ ✘ ✘ ✓✓ Taenia spp. Cattle (T. saginata), pigs (T. solium), humans and pigs (T. asiatica) ✘ ✓✓ ✘ ✘ ✘ Trichiuris trichiuria Humans ✘ ✓✓ ✘ ✘ ✓✓ ✓✓. major route; ✓. minor route; (✓). rarely reported; ✘. not reported

section 15  Gastroenterological disorders 3016 Other transmission routes As well as the five conventional pathways described previously, gastrointestinal infections can also spread via other routes including: • sexual contact, for example, Shigella spp. and hepatitis E virus are now recognized as causing outbreaks among men who have sex with men • blood transfusion, for example, hepatitis A virus and hepatitis E virus during the viraemic phase of the illness • vertical transmission from mother to fetus, for example, listeriosis • solid organ transplant and xenotransplantation—​hepatitis E Fig. 15.18.1  The ‘F-​diagram’ illustrating the transmission routes for gastrointestinal infections. Source: UNICEF Philippines and Luis Gatmaitan/​2014/​Gilbert F. Lavides. Human infection and disease Meat Calves Weaned calves Heifers (and steers?) Milking cows Dry cows Pasture contamination Human behaviours Environmental ‘reservoirs’ Invertebrate vectors (beetles and flies) Invertebrates (beetles and flies) Human behaviours (beetles and flies) Waste Human behaviours Equipment Equipment Invertebrates Chicken Infection Human Infection and disease Likely control points Wild mammals and birds Equipment and buildings (fomites) Soil and water Protozoa and algae Pasture contamination Human behaviours Climate/ seasonal changes Pasture contamination Human behaviours Contamination of feed Contamination of feed Milk Fig. 15.18.2  The multiple transmission routes for Campylobacter infection.

15.18  Gastrointestinal infections 3017 Pathogenesis/​pathology The complex interplay between agent and host is involved in de- velopment of disease. Features of organisms that assist in causing disease are toxin production, adherence to the gut mucosa, and invasion. Features of the host that help to repel gastrointes- tinal infections include physical barriers, immunity, and the gut microbiome. Organism factors Toxin production Many gastrointestinal bacteria produce enterotoxins. These toxins can be preformed on contaminated food, for example, Bacillus ce- reus and S. aureus emetic toxins, or, like cholera toxin, they can exert their action directly on intestinal epithelial cells. C. difficile produces two toxins. Toxin A is generally termed the enterotoxin although it also has some cytotoxic activity, and toxin B, which is a potent cytotoxin. Both are important in causing symptoms of antibiotic-​associated diarrhoea and a significant complica- tion, namely pseudomembranous colitis. Shigella spp. produce two enterotoxins. These are shigella enterotoxin 1 (ShET-​1) and shigella enterotoxin 2 (ShET-​2), which occurs in many (but not all) shigellae and in EIEC. Each has a different mechanism of ac- tion on the gut. Adherence Enteropathogens can use various mechanisms to stick to the gut mucosa. V. cholerae uses a toxin-​coregulated pilus, which is a fim- brial colonization factor. EPEC, EAggEC, and DAEC exhibit char- acteristic patterns of adherence to cultured epithelial cells. EPEC strains demonstrate a pattern called localized adherence. EAggEC isolates bind in an aggregative adherence pattern, which looks like stacked bricks on the surfaces of the cells. DAEC strains exhibit dif- fuse adherence, where the bacteria uniformly cover the entire cell surface. Giardia lamblia adheres to the gut lining using a ventral disc, also known as a sucking or adhesive disc. Invasion Invasive enteropathogens such as Campylobacter spp., Shigella spp., nontyphoidal Salmonella spp., and Yersinia spp. invade the mucosal surface of the large bowel, particularly the distal ileum and colon. They infect epithelial cells, or translocate into mesenteric lymph nodes and the bloodstream. Histological examination shows mu- cosal ulceration with acute inflammation in the lamina propria. Shigella dysenteriae produces Shiga toxin, which causes cell damage in a manner similar to ricin, and EHEC strains produce similar Shiga-​like toxins, which act on the vascular endothelium of small blood vessels, particularly in the colon and renal glomeruli. The ensuing kidney destruction leads to HUS, which is a leading cause of acute kidney injury in children in high-​income countries. Host factors Physical barriers The gastrointestinal tract has a series of physical barriers to repel or remove harmful pathogens. These include stomach acid, pan- creatic enzymes, bile, and intestinal secretions. Peristalsis and the normal process of shedding epithelial cells that line the gut are also important natural barriers to infection. The pH of gastric acid in the human stomach is around 1.5 to 3.5. Its main function is to kill off ingested microbes so that they never reach the small intestine. The proton pump H+/​K+-​ATPase maintains stomach acidity, and diseases such as atrophic gastritis, or drugs such as proton pump inhibitors that suppress gastric acid secretion, increase the risk of gastrointestinal infection. Epithelial cells in the small intestine are covered in a glycocalyx of mucins and other glycoproteins that can entrap bacteria. Defensins, which are secreted by Paneth cells localized at the bottom of the in- testinal crypts, also possess antimicrobial properties. Immune system The gastrointestinal immune system is challenged constantly through a combination of its resident microbiome, the antigen load in food, and the presence of potential pathogens. Immune mechan- isms to protect against disease are found in lymphoid tissue and in intraepithelial and lamina propria lymphocytes. Gut-​associated lymphoid tissue Peyer’s patches and mesenteric lymph nodes comprise major com- ponents of the lymphoid tissues in the gut. The mucosal epithelium and underlying lamina propria are the effector sites. They contain various types of immune cells such as activated T cells, plasma cells, mast cells, dendritic cells, and macrophages. These cells are pre- sent in normal circumstances and are kept under control by various powerful regulatory mechanisms. Immune response Epithelial cells act as microbial sensors. Responding to bacterial in- cursion, they secrete several factors including IL-​6, IL-​8, RANTES, TNFα, and MCP-​1. In turn, neutrophils, eosinophils, monocytes, phagocytic macrophages, and T cells are used to stimulate protective immunity. The inflamed intestine contains various specific immune cells such as CD4+ and CD8+ T cells, γδT cells, regulatory T cells, and IgA-​secreting plasma cells. Microbiome Host–​microbe interactions appear to influence immune functions at all levels from the initial innate defences to complex acquired responses. The microflora of the small intestine is relatively scant, but the large intestine has a richly diverse microflora amounting to around 1012 bacteria per gram of luminal contents. Under normal circumstances, conditions in the large bowel are largely anaerobic and favour the Bacteroidetes and Firmicutes phyla. Regardless of causative organism, during an episode of acute diarrhoea the rapid passage of intestinal contents means that the environment in the colon becomes less anaerobic; hence, strict anaerobes reduce in number while coliforms increase. The pathogen itself dominates and is, therefore, detected on microbiological testing. The immune system must learn to cope with the commensal microflora while mounting an appropriate response to pathogens. Commensal bacteria and pathogens share many factors, which can be detected by pathogen recognition receptors such as toll-​like re- ceptors. It seems that commensals fail to trigger inflammatory re- sponses through a number of different mechanisms:

section 15  Gastroenterological disorders 3018 • Modulation of gut macrophage innate activating receptors such as CD89 and CD14 • Training of local cells by immunomodulatory factors (retinoic acid, TGFβ, IL-​10, thymic stromal lymphopoietin), which are pro- duced in large quantities • Decreased function of toll-​like receptors in intestinal dendritic cells • The noninvasive nature of commensal organisms. Commensal bacteria only breach the epithelium after being taken up by local dendritic cells from whence they are transported to the mesen- teric lymph nodes and stopped in their tracks. Secretory IgA is produced in the gut, which restricts the number of commensals, and regulatory T cells reduce inflammatory responses. On the rare occasion that commensals breach all these barriers then they are engulfed and killed by local, noninflammatory macrophages Clinical features Most gastrointestinal infections cause symptoms of diarrhoea and vomiting but some present with extraintestinal manifestations such as meningitis, septicaemia, or jaundice. Diarrhoea The WHO defines diarrhoea as three or more loose or liquid stools in a day. For people who typically open their bowels less than once a day, diarrhoea is defined as the more frequent passage of loose or liquid stools than is normal for the individual. There are three main clinical presentations for diarrhoeal diseases. These are acute watery diarrhoea, acute bloody diarrhoea (inflammatory diarrhoea or dys- entery), and persistent diarrhoea, but it should be noted that these categories are not mutually exclusive. For example, a patient with Campylobacter spp. might complain initially of acute watery diar- rhoea but develop acute bloody diarrhoea as the illness progresses. The main clinical features produced by different pathogens are sum- marized in Tables 15.18.1 to 15.18.3. Acute watery diarrhoea Acute watery diarrhoea is characterized by passing large-​volume, watery stools very frequently. This can happen as many as 10 to 20 times in a 24-​h period. Patients can become dehydrated very rap- idly because of the high rate and volume of bowel movements. Acute watery diarrhoea is further split into two groups. Secretory diarrhoea In secretory diarrhoea, ion transport across the gut mucosa is al- tered. This leads to increased secretion and decreased absorption of fluids and electrolytes from the gut, particularly in the small bowel. Classically, organisms that produce enterotoxins cause secretory diarrhoea. These include V.  cholerae, S.  aureus, Clostridium per- fringens, and ETEC. Secretory diarrhoea tends to be unaffected by withholding food. Osmotic diarrhoea Osmotic diarrhoea happens when unabsorbed or poorly absorbed solute in the small bowel promotes fluid secretion into the gut lumen. The volume of stools is fairly small compared with secretory diarrhoea and symptoms tend to improve or subside with fasting. There are two types of osmotic diarrhoea. These are malabsorption, which happens when bacterial overgrowth occurs in the small bowel, and maldigestion, for example, lactose intolerance following acute diarrhoea. Acute watery diarrhoea is a common clinical feature of infection with viruses such as rotavirus and norovirus, V. cholera, and travel- lers’ diarrhoea-​causing organisms such as ETEC. Acute watery diar- rhoea tends to last several hours or days and is caused by organisms that target the small intestine. Accompanying symptoms include an- orexia, nausea, vomiting, cramping abdominal pain, bloating, and a low-​grade fever. If acute watery diarrhoea is left untreated, the associated fluid and electrolyte losses can lead to rapid dehydration and associated meta- bolic disturbance. Cholera, a classical cause of acute watery diar- rhoea, can produce profound dehydration leading to death as little as 3 to 4 h after symptom onset. Three levels are used to describe the extent of dehydration. There are no overt symptoms or clinical signs associated with early dehy- dration. Thirst, restlessness, and irritability, decreased skin turgor, and sunken eyes are features of moderate dehydration. Severe dehy- dration occurs when these symptoms worsen and lead to hypovol- aemic shock. If body fluids and electrolytes are not replaced urgently then the patient will die. Acute bloody diarrhoea Acute bloody diarrhoea (dysentery) is caused by invasive enteropathogens such as Campylobacter spp., C.  difficile, EHEC, Entamoeba histolytica, Shigella spp., nontyphoidal Salmonella spp., V.  parahaemolyticus and Yersinia entercolitica. These organisms mainly affect the colon. Acute bloody diarrhoea is often preceded by acute watery diarrhoea but, as the illness progresses, the volume of liquid stools produced might actually reduce as blood and mucus appear in the stools. Severe cramping lower abdominal pain and fever often accompany acute bloody diarrhoea. Three hypotheses have been developed to explain the mechanism of fluid production in acute bloody diarrhoea. Firstly, that an en- terotoxin stimulates fluid production. For example, the B subunit of ShET-​1 is known to affect the transport of fluid and electrolytes into the small bowel. Secondly, that invading enteropathogens cause intense inflammation at the invasion site, leading to fluid secretion and diarrhoea. For example, ShET-​2 is an enterotoxin haemolysin that elicits a profound inflammatory response during mucosal in- vasion. Thirdly, that physical damage to the epithelium might stop fluids from being reabsorbed so that a net build-​up of fluid in the lumen of the bowel leads to diarrhoea. Persistent diarrhoea Persistent, or chronic, diarrhoea is defined by passing three or more loose stools per day for more than 4 weeks. Pathogens that affect the small intestine can cause persistent diarrhoea, with Giardia intestinalis the commonest infectious cause. Accompanying symp- toms include anorexia, bloating, weight loss, and steatorrhoea. Cryptosporidium spp. can lead to chronic diarrhoea in immunocom- promised patients, particularly those with AIDS. Up to 3% of travellers returning from low-​ or middle-​income countries can experience persistent diarrhoea lasting for a month or more. Various pathogens, including Giardia and Cyclospora cayeten- ensis, are implicated but often the cause is not identified.

15.18  Gastrointestinal infections 3019 Other clinical manifestations Invasive disease Salmonella Typhi and Listeria monocytogenes both cause septicaemia. L.  monocytogenes is also a relatively rare but important cause of meningoencephalitis. Neonates, the elderly, immunocompromised individuals, and people with alcoholic liver disease, cirrhosis and diabetes are all at increased risk of invasive listeriosis. Cronobacter sakazakii is a rare cause of bacteraemia, meningitis, and necrotizing enterocolitis. Infection happens when vulnerable people, chiefly infants and immunocompromised adults, eat con- taminated food. It has caused outbreaks in neonatal units because of its ability to survive for prolonged periods in low-​moisture foods such as powdered infant formula. The case-​fatality rate is very high. Occasionally, as well as causing septicaemia, nontyphoidal Salmonella spp. can present with focal infection at body sites dis- tant from the gut, such as septic arthritis, cholecystitis, endocarditis, pericarditis, or pyelonephritis. Jaundice Hepatitis A and hepatitis E both cause acute jaundice in adults not previously exposed to the viruses in childhood, when infection may be asymptomatic or very mild. Malnutrition Diarrhoeal diseases are recognized as both causes and consequences of malnutrition, especially in young children. Similarly, the illness burden associated with intestinal helminths is mainly due to the chronic and deleterious effects on the nutritional status and health of the people afflicted. Paralysis Clostridium botulinum produces one of the most potent neurotoxins known to man. Symptoms of botulism occur following the inges- tion of preformed toxin in food. C. botulinum can produce seven different types of toxin, of which four affect humans (types A, B, E, and, rarely, F). It classically causes a descending paralysis (not to be confused with the ascending paralysis of GBS). Intestinal botulism Intestinal botulism (also known as infant botulism) is very rare, but usually occurs in infants under 2 months of age, although it may affect infants up to 12 months of age. Intestinal botulism hap- pens when they eat food, such as honey, that contains spores of C. botulinum. The spores then germinate, colonize, and produce neurotoxin in the infant’s gut. This can lead to constipation and a floppy baby. Differential diagnosis Acute diarrhoea The differential diagnosis of acute diarrhoea usually includes con- sideration of the likely causative organism based on symptom- atology and incubation period. The differential diagnosis of acute diarrhoea is long and includes inflammatory bowel disease, bowel ischaemia, radiation injury, adverse drug reactions, heavy metal poisoning, toxin-​mediated shellfish poisoning (ciguatera shellfish poisoning, paralytic shellfish poisoning, neurotoxic shellfish poi- soning, diarrhoetic shellfish poisoning, amnesic shellfish poisoning, puffer fish poisoning, azaspiracid poisoning), scombrotoxin (hista- mine) poisoning, mushroom poisoning, thyrotoxicosis, Addison’s disease, carcinoid, medullary tumour of the thyroid and vasoactive intestinal peptide-​secreting adenomas. Persistent diarrhoea The differential diagnosis of persistent diarrhoea is very long and includes bowel cancer, coeliac disease, inflammatory bowel disease, chronic pancreatitis, diverticular disease, adverse drug reactions, Whipple’s disease, and short-​gut syndrome. The diagnosis of irrit- able bowel syndrome should be made on positive clinical grounds, but is often a diagnosis of exclusion once other causes of persistent diarrhoea have been investigated and ruled out. Typhoid fever There is a very large differential diagnosis during the early stages of typhoid fever. Depending on the context, infectious possibil- ities include brucellosis, malaria, tuberculosis, and Gram-​positive septicaemia. Clinical investigation Expert bodies such as the National Institute for Health and Care Excellence, the British Society for Gastroenterology, the American Academy of Family Physicians, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, the European Society for Pediatric Infectious Diseases, and the WHO have all produced guidelines on the clinical evaluation and management of acute and persistent diarrhoea. The mainstay of clinical investigations for diarrhoea remains searching for an aetiological agent (organisms and/​or toxins) using microbiological methods that involve stool examination by culture (for bacterial pathogens and some protozoa), microscopy (for ova, cysts, and parasites), immunoassays (for some protozoa and vir- uses), and molecular methods, usually polymerase chain reaction (PCR) or reverse transcriptase PCR (for bacterial toxin genes and viruses). Despite thorough examination of stool samples, the diag- nostic gap is large—​more than 50% of diarrhoeal samples may not yield a pathogen. Culture usually produces a positive result in 24 to 48 h. Negative results will not usually be reported until 72 h after the plates were started to be sure that the sample really is negative. Culturing an organism is still regarded as the gold standard test, but the rapidly expanding range of nonculture-​based methods, which can provide an accurate answer within the working day, is likely to change the diagnostic landscape in future. Although the physician managing a case of acute gastrointestinal infection does not necessarily need to know the precise identity of the causative pathogen because in many cases it will not alter their clinical management plan, knowing the aetiology is very important from a public health point of view. The public health investigation and management of a case of cryptosporidiosis is quite different from that of a case of salmonellosis. For most patients, especially in high-​income settings, symptoms of acute diarrhoea may resolve without clinical investigation since

section 15  Gastroenterological disorders 3020 many illnesses tend to be short lived. Indeed, patients might never contact the healthcare system. In the United Kingdom, for example, only a few people with acute diarrhoea ever present to their primary care physician. When they do it is often because of the presence of blood in the stools or because of persistent diarrhoea. Both these symptoms require further investigation. If symptoms persist after an infectious diagnosis has been ruled out then further, more in- vasive investigations might be required, for example, colonoscopy. Investigations for suspected typhoid fever must include drawing blood for blood films, a malaria rapid diagnostic test, and blood cultures. Investigation of suspected botulism may involve ruling out other potential causes of muscle weakness such as myasthenia gravis. Management Supportive care Oral rehydration salts The mainstay of treatment for acute gastroenteritis is restoring and maintaining adequate fluid and electrolyte balance. In children, in the main this will be achieved using oral rehydration salts. The WHO and UNICEF published a joint statement on the clinical management of acute diarrhoea (http://​www.unicef.org/​publica- tions/​files/​ENAcute_​Diarrhoea_​reprint.pdf), which describes the recommended composition of reduced osmolarity oral rehydra- tion salts (Table 15.18.8). It needs to be administered frequently, in small amounts, and on a continuous basis until symptoms have subsided. Adults with mild diarrhoea do not often need to use formal pre- parations of oral rehydration salts. Instead, they can be encouraged to increase their fluid intake using products that contain sodium (e.g. soups), potassium (e.g. fruit juice), and glucose. As soon as the patient can eat and drink properly they can start eating food again. Some patients may experience secondary lactose intolerance, which initiates diarrhoea again, so temporarily changing to a diet excluding milk or dairy products, or using lactose-​free milk, deals with the symptoms. Zinc supplements There is good evidence that using zinc supplements reduces both the duration and severity of diarrhoea. Zinc supplementation also lessens the odds of subsequent gastrointestinal infections for 2 to 3 months. The WHO therefore recommends their use in conjunc- tion with oral rehydration salts: 20 mg zinc supplements daily for 10 to 14 days in children with acute diarrhoea (10 mg daily for infants <6 months old). Dietary zinc deficiency is particularly common in low-​income countries. Intravenous rehydration Where diarrhoea and vomiting are severe, or where a patient shows clinical evidence of severe dehydration, then intravenous rehydra- tion must be used. Early intravenous hydration with isotonic saline also appears to decrease the risk of oligoanuric acute kidney injury in children with diarrhoea who are at risk of developing HUS. Antidiarrhoeal medication Antimotility agents, which bind to opioid receptors in the gastro- intestinal tract, delay intestinal transit. Loperamide does not cross the blood–​brain barrier readily. They are most useful for adult trav- ellers who have no alternative but to continue their journey while they are symptomatic. They are not recommended for use in infants and young children under the age of 4 years where they can mask the severity of diarrhoea and thus the extent of dehydration. Specific treatments Antimicrobials Antimicrobial therapy is not recommended or usually required for uncomplicated diarrhoea. The decision to treat should ideally be made after the results of a stool examination are available and in discussion with a microbiologist. Growing levels of antimicrobial resistance among gastrointestinal pathogens means that, should therapy be required, it needs to be administered taking into account the context of local antimicrobial resistance patterns. Antimicrobials are used to treat pseudomembranous colitis asso- ciated with C. difficile and may also be indicated in persistent diar- rhoea. They are required to treat typhoid fever and other invasive gastrointestinal infections. They are not generally recommended to treat EHEC infection because there is some, albeit mixed, evidence that using antibiotics may precipitate HUS. Patients with underlying medical conditions, especially con- ditions that lead to immune compromise, require treatment with antimicrobials, with the treatment plan guided by the causative or- ganism and local antibiotic sensitivity patterns. Faecal microbiota transplant Faecal microbiota transplantation, also known as faecal transplant, is quickly gaining acceptance as a safe, viable, and effective treatment for recurrent C. difficile infection. It can be administered in several different ways—​into the proximal colon using a colonoscope, into the distal colon via an enema/​rectal tube, or into the upper gastro- intestinal tract by means of a nasogastric tube. Cure rates of 90% and greater are reported. Table 15.18.8  The reduced osmolality oral rehydration solution recommended by WHO and UNICEF Reduced osmolarity ORS g/​litres Sodium chloride 2.6 Glucose, anhydrous 13.5 Potassium chloride 1.5 Trisodium citrate, dihydrate 2.9 Total weight 20.5 Reduced osmolarity ORS mmol/​litre Sodium 75 Chloride 65 Glucose, anhydrous 75 Potassium 20 Citrate 10 Total osmolarity 245 ORS, oral rehydration solution.

15.18  Gastrointestinal infections 3021 Mass drug administration for soil-​transmitted helminths The WHO’s strategy for controlling soil-​transmitted helminth in- fections is to prevent and control morbidity by periodic treatment of at-​risk populations who live in endemic areas. The intention of treating the whole of the at-​risk population is to diminish the worm burden and reduce morbidity. The WHO defines people at risk as being preschool-​aged children, school-​aged children, and women of childbearing age. The treatment regimen is based on the preva- lence of soil-​transmitted helminths in the community and is as fol- lows: once per annum when the prevalence exceeds 20%; twice per annum when the prevalence exceeds 50%. Botulinum antitoxin Suspected botulism is a clinical and public health emergency. Early diagnosis and treatment are absolutely critical. Botulinum antitoxin should be given as soon as possible. Although it does not reverse paralysis, botulinum antitoxin does stop its progression. The patient will almost certainly require intensive care with close observation of respiratory function. Severe cases may need 2 to 8 weeks of mech- anical ventilation. Patients eventually recover when new neuromus- cular connections have been generated. Prognosis Most cases of uncomplicated diarrhoea in high-​income countries recover completely with no lasting after-​effects. In low-​income and middle-​income settings, the picture is very different, and it is sobering to think that in the 21st century diarrhoeal diseases still kill 1.5 million people each year, exacting a particular toll on children. Listeriosis is a potentially lethal infection with a case-​fatality rate of around 30% in neonates and over 60% in the elderly. The case fatality rate of botulism in high-​income countries is between 5 and 10%, and around 1% of children affected by intestinal botulism die from it. Typhoid fever is estimated to cause around 600 000 deaths annually in low-​ and middle-​income countries. Special circumstances/​complications HUS and thrombotic thrombocytopenic purpura Approximately 10% of children with EHEC infection develop HUS, which has a case-​fatality rate ranging from 3 to 5%. Neurological complications (e.g. seizure, stroke, and coma) occur in up to 25% of HUS patients, and chronic renal sequelae, which are often mild, affect around 50% of survivors. In the elderly, the case-​fatality rate for thrombotic thrombocytopenic purpura, another complication of EHEC infection, is at least 50%. Guillain–​Barré syndrome GBS is a recognized late complication of Campylobacter infection. This ascending paralysis (not to be confused with the descending paralysis of botulism) is estimated to occur in around 1 in 2000 cases of Campylobacter infection. The mechanism appears to be molecular mimicry. In these patients, the immune system produces IgG anti- bodies to lipo-​oligosaccharides in the bacterial cell wall that cross-​ react with human nerve cell gangliosides. A quarter of people with GBS develop weakness of the respira- tory muscles leading to respiratory failure and requiring mechanical ventilation. Despite the best care, approximately 5% of GBS cases will die. For people who recover, the extent to which they get better is variable. GBS prognosis hinges on age (worse in those >40 years of age) and symptom severity after 2 weeks. Campylobacter-​associated GBS can leave people severely disabled 1 year post onset. Irritable bowel syndrome Postinfectious irritable bowel syndrome develops in up to a third of people with recent gastrointestinal infection. It has been described following infection with Campylobacter spp., Salmonella spp., diarrhoeagenic strains of Escherichia coli, Shigella spp., and, more recently, norovirus. Typically patients complain of recurrent diar- rhoea. Management is as for other causes of the condition. Joint complications Two types of joint complications are recognized after gastrointes- tinal infection: reactive arthritis and septic arthritis. Reactive arthritis characteristically starts 2 to 4 weeks after in- fection with a triggering organism such as Campylobacter spp., nontyphoidal Salmonella spp., Shigella spp., and Yersinia spp. People who express HLA B27 are at increased risk of developing reactive arthritis. Most people make a full recovery and can resume normal activities a few months after the initial presentation, although their symptoms may last up to a year. Between 15 and 50% of patients experience symptoms again after the initial flare has abated and it is postulated that these relapses occur as a result of reinfection. Septic arthritis is a rare complication of infection with Salmonella spp. that usually affects the large joints. The onset of septic arthritis typically occurs 2 to 7 weeks after acute gastroenteritis in 0.2 to 2.5% of patients with nontyphoidal Salmonella spp. Prevention Important and effective ways of preventing gastrointestinal infec- tion are sanitation, hygiene, vaccination, prevention of secondary spread, and ensuring food safety. Sanitation Separating sewage from drinking water to maintain a safe supply of drinking water is critical for good health and well-​being, yet 1.1 billion people worldwide still defecate in the open. Open defeca- tion happens most often in low-​income countries where childhood mortality from diarrhoeal disease is very high. Added to this, an estimated 90% of wastewater in developing countries is discharged either untreated or partially treated. The WHO has declared that eliminating open defecation by increasing levels of access to ad- equate sanitation would reduce cases of diarrhoea in children under the age of 5 years by a third. Hygiene Where access to a safe supply of potable water has been secured, the next similarly effective measure in reducing the spread of diarrhoeal disease is washing hands with soap and water. There is good evi- dence from randomized controlled trials and from a Cochrane sys- tematic review that washing hands properly reduces the incidence of diarrhoea by around a third. What is much less clear is how to help people to maintain good hand washing habits lifelong.

section 15  Gastroenterological disorders 3022 In healthcare settings in high-​income countries, alcohol-​based hand gels have been introduced to help reduce the incidence of healthcare-​associated infections such as meticillin-​resistant S.  aureus. However, these gels are ineffective against norovirus, Cryptosporidium spp., and C.  difficile so that, for preventing the spread of gastrointestinal infection, washing hands with soap and water still remains the best advice. Vaccination There are relatively few vaccines directed towards gastrointestinal pathogens. Typhoid There are two widely used typhoid vaccines. The Ty21a vaccine is a live, orally administered vaccine, a three-​dose schedule of which prevents 35 to 58% of cases of typhoid fever in the first 2 years after vaccination. The Vi capsular polysaccharide vaccine, which is sub- unit vaccine administered by a single injection, prevents around 69% of cases in the first year after administration. A new conjugate form of the Vi capsular polysaccharide vaccine, called Vi-​rEPA, ap- pears to have similar or even superior efficacy and might induce longer-​term immunity. Cholera There are two types of oral cholera vaccine, both preventing over 50% of cholera cases for up to 2 years in vaccinated endemic popula- tions. The monovalent vaccine is based on formalin and heat-​killed whole cells of V. cholerae serogroup O1 (classical and El Tor, Inaba, and Ogawa strains) coupled with a recombinant cholera toxin B subunit. Since cholera toxin B resembles the heat-​labile toxin of ETEC functionally and structurally, and the two toxins cross-​react, Dukoral also helps to prevent ETEC infection. The bivalent cholera vaccine provides protection against V. cholerae serogroups O1 and O139 but does not prevent infection with ETEC since it does not contain the cholera toxin B subunit. Rotavirus Mass vaccination with rotavirus vaccine has been hugely successful in countries around the globe following its implementation in na- tional vaccination programmes. There are two live, attenuated rota- virus vaccines that can be administered orally, and they are highly effective (>85%) at preventing severe rotavirus gastroenteritis in children under 2  years of age in high-​income countries. In low-​ income countries, vaccine efficacy in children under 2 years is lower (>40%). Nevertheless, because the overall burden of rotavirus dis- ease is much higher in low-​income countries, the absolute benefit of vaccination is actually greater than in high-​income countries. Hepatitis A There are three highly effective vaccines that can be used to prevent hepatitis A  infections. Indications for vaccination include inter- national travel to an endemic country and occupational exposure to hepatitis A. Vaccination of food-​producing animals As well as vaccinating the population there are examples of vaccinating food-​producing animals that yield benefits for public health. A potent illustration of this occurred in the United Kingdom. Following a prolonged epidemic of nontyphoidal Salmonella spp. due to S. Enteritidis phage type 4, which was linked to the consump- tion of contaminated, undercooked poultry and hens’ eggs, a vac- cine was developed and administered to broiler-​breeder and laying poultry flocks. It has produced a dramatic and sustained reduction in nontyphoidal Salmonella spp. in people in the United Kingdom. Preventing secondary spread Many public health departments produce guidelines for reducing the secondary spread of gastrointestinal infections. There are spe- cial considerations for people working in the food and hospitality industries (food handlers), healthcare workers, children aged less than 5 years, and people who find it difficult to practise good hy- giene. Stipulations may include exclusion from nursery, school, or work until symptom free for at least 48 h when, in general, the risk of onward transmission lessens. Depending on the causative organism and the occupation, some groups may also need to provide consecu- tive negative stool samples before they can return to work. Various pathogens or clinical syndromes, like food poisoning, are statutorily notifiable. This means that the clinician who suspects that a patient is suffering a notifiable disease is obliged, by law, to report it to the competent public health authority. The purpose of notifi- cation is to allow public health agencies to investigate and control the spread of infection. For example, a single case of botulism con- stitutes both a medical and public health emergency. Swift action is required to trace a contaminated food and prevent anyone else from eating it. If a diagnosis of food-​borne botulism is suspected it is imperative that public health authorities trace people who might have shared the same meal as the index case as quickly as possible to ascertain their welfare. The list of notifiable diseases can vary by country so clinicians should familiarize themselves with the locally relevant list and make sure that they comply with the law on notification. Food safety Delivering a safe and secure supply of food is very important for good health and well-​being. This means either keeping patho- gens out of food, or controlling their growth, right along the chain from ‘farm to fork’. Food safety is everybody’s responsibility from primary production, through processing and retail, to the com- mercial or domestic kitchen. Safe handling of food in the kitchen is often summarized as the so-​called four Cs. These are adequate Cooking; proper Cleaning of food preparation utensils, surfaces and hands; correct use of Cooling (refrigeration); and avoiding Cross-​ contamination (i.e. transferring pathogens from raw to cooked or ready-​to-​eat foods). Intestinal botulism can be avoided by not giving honey to children less than 1 year of age and by washing fruit and vegetables with pot- able water before feeding them to infants. Uncertainty, controversy,
and future developments Uncertainty There are a great many organisms that are shed in faeces but, given the current state of knowledge, their relevance as causes of human illness is still doubtful.

15.18  Gastrointestinal infections 3023 Several viruses falling into this category of doubtful pathogenicity include aichi virus, bocavirus, cardiovirus, cosavirus, klassevirus, picobirnavirus, and torovirus. Controversy More than half of all antibiotics used worldwide are delivered to live- stock to treat or prevent infections and as growth promoters, hence a very real threat to human health arises from antimicrobial resistant organisms that are transmitted through the food chain. Indeed, it has been suggested that over 1500 deaths each year in the European Union are directly associated with antibiotic use in poultry. The emergence of colistin resistance in E. coli in China, thought to be associated with intensive pig production, is very bad news in- deed. This is the antibiotic of last resort for treatment of severe in- fections in humans. Even worse is the news that colistin resistance is plasmid mediated. This mechanism has previously spread resistance determinants around the globe very rapidly. There is every reason to think that this will also happen with colistin resistance. The burden of antimicrobial resistance in animals is compounded by the fact that only around 50% of the antibiotics prescribed in hu- mans are for bacterial infections. They are used too frequently for patients who turn out to have viral or parasitic infections against which they are ineffective. There is good evidence that antimicrobial resistance can be curtailed or even reversed. In Australia, where the use of fluoro­ quinolones was banned in animal husbandry, resistance in food-​ borne pathogens and in people is very low. Similarly, in northern Europe there have been steep and swift drops in the levels of resistant bacteria in livestock in countries where antibiotic use in animal husbandry has been reduced. Ever since the 1960s, medical and veterinary practitioners have argued about who is to blame for antimicrobial resistant infections in humans. In the absence of new classes of antimicrobials (and even if they are developed), the only solution to this apocalyptic threat is responsible prescribing by both professions. Future developments Nonculture diagnostics, next-​generation sequencing,
and metagenomics New methods for diagnosing and characterizing microorganisms are set to revolutionize our understanding of gastrointestinal in- fections. These methods are sensitive, quick, can detect multiple pathogens at once and, increasingly, can be performed at the point of care. The challenge will be to interpret the results in a situation when mixed infections may appear to occur much more often. In conjunction with metagenomics our understanding of the com- plex interplay between pathogens and the microbiome should increase, hence it is likely that these technological advances will unlock much more information about the ecology of the gut in health and disease. Vaccines in development There are several vaccine candidates against pathogens that cause acute gastroenteritis, including norovirus, Campylobacter jejuni, EHEC, ETEC, nontyphoidal Salmonella spp., and Shigella spp. Some of these are at a very early stage of development and it remains to be seen whether or not they make it all the way to market. FURTHER READING Burden of illness Havelaar AH, et al. (2015). World Health Organization global esti- mates and regional comparisons of the burden of foodborne disease in 2010. PLoS Med, 12, e1001923. Kotloff KL, et al. (2013). Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS):  a prospective, case-​control study. Lancet, 382, 209–​22. Liu L, et al. (2012). Global, regional, and national causes of child mor- tality: an updated systematic analysis for 2010 with time trends since 2000. Lancet, 379, 2151–​61. Tam CC, et al. (2012). Longitudinal study of infectious intestinal dis- ease in the UK (IID2 study): incidence in the community and pre- senting to general practice. Gut, 61, 69–​77. Torgerson PR, et al. (2015). World Health Organization estimates of the global and regional disease burden of 11 foodborne parasitic diseases, 2010: a data synthesis. PLoS Med, 12, e1001920. Clinical guidelines Barr W, Smith A (2014). Acute diarrhea in adults. Am Fam Physician, 89, 180–​9. Guarino A, et al. (2014). European Society for Pediatric Gastroentero­ logy, Hepatology, and Nutrition/​European Society for Pediatric Infectious Diseases evidence-​based guidelines for the management of acute gastroenteritis in children in europe: update 2014. J Pediatr Gastroenterol Nutr, 59, 132–​52. Surawicz CM, et al. (2013). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol, 108, 478–​9. Vecchio AL, et al. (2016). Comparison of recommendations in clin- ical practice guidelines for acute gastroenteritis in children. J Pediatr Gastroenterol Nutr, 63, 226–​35. Microbiome Prakash S, et al. (2011). Gut microbiota: next frontier in understanding human health and development of biotherapeutics. Biologics, 5, 71–​86. Shreiner AB, Kao JY, Young VB (2015). The gut microbiome in health and in disease. Curr Opin Gastroenterol, 31, 69–​75. Management Allen SJ, et al. (2010). Probiotics for treating acute infectious diar- rhoea. Cochrane Database Syst Rev, 11, CD003048. Applegate JA, et  al. (2013). Systematic review of probiotics for the treatment of community-​acquired acute diarrhea in children. BMC Public Health, 13 Suppl 3, S16. Carter B, Fedorowicz Z (2012). Antiemetic treatment for acute gastro- enteritis in children: an updated Cochrane systematic review with meta-​analysis and mixed treatment comparison in a Bayesian framework. BMJ Open, 2, e000622. Freedman SB, et al. (2015). Gastroenteritis therapies in developed coun- tries: systematic review and meta-​analysis. PLoS One, 10, e0128754. Hartling L, et  al. (2006). Oral versus intravenous rehydration for treating dehydration due to gastroenteritis in children. Cochrane Database Syst Rev, 3, CD004390. Kelly CR, et al. (2015). Update on fecal microbiota transplantation 2015:  indications, methodologies, mechanisms, and outlook. Gastroenterology, 149, 223–​37.

section 15  Gastroenterological disorders 3024 Lazzerini M, Ronfani L (2013). Oral zinc for treating diarrhoea in chil- dren. Cochrane Database Syst Rev, 1, CD005436. Prevention Ejemot RI, et  al. (2008). Hand washing for preventing diarrhoea. Cochrane Database Syst Rev, 1, CD004265. Ejemot-​Nwadiaro RI, et  al. (2015). Hand washing promotion for preventing diarrhoea. Cochrane Database Syst Rev, 9, CD004265. Madhi SA, et al. (2010). Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med, 362, 289–​98. O’Ryan M, et al. (2015). Vaccines for viral and bacterial pathogens causing acute gastroenteritis. Part I: overview, vaccines for enteric viruses and Vibrio cholerae. Hum Vaccin Immunother, 11, 584–​600. O’Ryan M, et  al. (2015). Vaccines for viral and bacterial patho- gens causing acute gastroenteritis. Part II: vaccines for Shigella, Salmonella, enterotoxigenic E.  coli (ETEC) enterohemorragic E. coli (EHEC) and Campylobacter jejuni. Hum Vaccin Immunother, 11, 601–​19. Rheingans R, et al. (2014). Systematic review of the economic value of diarrheal vaccines. Hum Vaccin Immunother, 10, 1582–​94.

15.19 Miscellaneous disorders of the bowel 3025

15.19 Miscellaneous disorders of the bowel 3025

ESSENTIALS A wide range of miscellaneous disorders can affect the bowel. Those discussed in this chapter include cystic disorders, protein-​losing enteropathy, vascular disorders of the intestine, intestinal pseudo-​ obstruction, various disorders of the colon and rectum (including microscopic, collagenous and lymphocytic colitis, solitary rectal ulcer syndrome), peritoneal disorders, and endometriosis. Cystic disorders of the bowel Colitis cystica profunda First described by Stark in 1766 and then by Virchow as colitis cystica polyposa in 1863, the disorder is characterized by submucosal mucin-​filled cysts. They may be single or multiple, within 12 cm of the anal verge, and are more common in younger men. It may represent a subgroup of the solitary rectal ulcer/​rectal prolapse syn- drome but has also been associated with Crohn’s disease. The cysts are seen at colonoscopy as a submucosal mass covered by normal rectal mucosa that may occasionally be hyperaemic, polypoid, or ul- cerated. Diagnosis can be made with transrectal ultrasound, MRI, or colonoscopy, as it is important to exclude malignancy. Treatment is with bulking agents and laxative, re-​education to avoid straining at stool, and surgery only if there is associated rectal prolapse. Pneumatosis cystoides intestinalis Gas-​filled cysts within the small or large bowel are rare and can de- velop in a wide range of conditions. Some are primary, asymptom- atic, often in the left colon, and with no apparent cause. Others are secondary, involve the ileum and right colon, and can be associated with chronic obstructive pulmonary disease, intestinal obstruction, severe colonic inflammation (pseudomembranous colitis, necro- tizing enterocolitis), connective tissue disease (systemic sclerosis, mixed connective tissue disease), amyloidosis, endoscopy, or CT colography. Pneumatosis cystoides intestinalis has recently been described in patients receiving α-​glucosidase inhibitors. The sub- mucosal or subserosal cysts are lined by histiocytes and giant cells and, although easy to diagnose on resection, specimens can be dif- ficult with biopsies. Symptoms, where present, may include diarrhoea, vague abdom- inal discomfort, blood per rectum, and weight loss. The air-​filled spaces may be seen on abdominal films, but CT is best to diagnose them (Fig. 15.19.1). They appear as submucosal masses on colonos- copy. Rarely, portal venous gas can also be visualized, which implies associated bowel infarction. In some primary cases, a conservative approach is possible, but when symptomatic treatment is with high-​flow oxygen therapy (55–​75% O2), aiming for a Pao2 greater than 200 mmHg for 4 to 10  days or, avoiding oxygen toxicity, with hyperbaric oxygen. If colonic integrity is compromised, or there is evidence of systemic sepsis or bowel perforation, broad-​spectrum antibiotics and sur- gery are required. 15.19 Miscellaneous disorders of the bowel Alexander Gimson Fig. 15.19.1  CT image showing linear pneumatosis intestinalis (arrows) in the ascending and descending colon. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 3026 Protein-​losing enteropathy This is a syndrome due to excessive loss of protein from the gastrointestinal tract. It should be considered in any case where hypoproteinaemia or a low albumin cannot be explained by renal loss (nephritic syndrome) or reduced hepatic synthesis. The cardinal features are peripheral oedema, occasionally diarrhoea and weight loss. There is a low albumin (occasional falling to very low levels, <15 g/​dl), and reduced immunoglobulins, caeruloplasmin, and fibrinogen. Gastrointestinal protein loss may be due to a wide range of causes (Box 15.19.1). Increased interstitial pressure within the intestine can lead to protein loss due to lymphangiectasia (Waldmann’s disease, lymphoedema–​lymphangiectasia–​intellectual disability, Hennekam’s syndrome), chronic lymphatic obstruction due to tuberculosis, sarcoidosis, lymphoma, retroperitoneal fibrosis, or in association with an elevated right-​sided heart pressure (con- strictive pericarditis, following Fontan’s procedure). Various ul- cerative disorders of the gastrointestinal tract include severe erosive gastritis, Crohn’s disease, pseudomembranous colitis, and acute graft-​versus-​host disease. Finally, it has been associated with Ménétrier’s disease, bacterial overgrowth of the small bowel, Whipple’s disease, eosinophilic gastroenteritis, coeliac disease, and tropical sprue. A number of radioisotopes have been used for diagnosis, with 51Cr-​labelled albumen being most commonly used. Stool α1-​antitrypsin levels are also used, as this protein is not broken down within the gut. Treatment should be aimed at raising the serum albumin level and management for each specific cause of the protein loss. Miscellaneous vascular disorders of the intestine Spontaneous intramural haemorrhage Spontaneous bleeding into the bowel wall may occur following trauma; during excessive anticoagulation with warfarin; in patients with coagulation disorders, particularly haemophilia; and in vascu- litis. It may present as pain, symptoms of partial intestinal obstruc- tion, intussusception, and rarely intestinal haemorrhage. The main differential diagnosis is with acute mesenteric ischaemia. CT may not be able to distinguish between these two diagnoses although intramural haemorrhage is more commonly associated with pro- longed INR. Treatment is usually conservative with correction of the coagulation deficit and transfusion. Aortoenteric fistulas Aortoenteric fistulas are rare but serious conditions that may arise as a complication following abdominal aortic surgery or rarely spon- taneously. Clinical symptoms range from occult, recurrent gastro- intestinal bleeding and intermittent, unexplained fever attacks to dramatic, massive intestinal blood loss with shock. The fistula is usu- ally in the second or third part of the duodenum and may be diag- nosed by CT with contrast or angiography (Fig. 15.19.2). Treatment is by surgery although recently endoluminal aortic stents have been successfully used. Mortality remains high. Intestinal pseudo-​obstruction Acute colonic pseudo-​obstruction Acute massive dilatation of the caecum and right colon, sometimes extending into the transverse and left side of the colon, can occur following intra-​abdominal surgery for any cause as well as in any critically ill patient with severe sepsis, or respiratory or cardiac dis- ease. In Ogilvie’s original report, two patients had retroperitoneal malignancy, currently an exceptionally rare cause for this syndrome. Most patients have constant dull pain with marked abdominal distension associated with vomiting. There is constipation, but many patients continue to pass wind and some occasionally have diarrhoea despite the colonic dilatation. Bowel sounds are variable in pitch and frequency but are absent only rarely. The diagnosis is made on a plain radiograph of the abdomen, which can be undertaken to monitor the risk of colonic perforation—​ the main risk from this disorder. The differential diagnosis includes toxic megacolon (a complication of inflammatory bowel disease or Clostridium difficile infection), caecal volvulus (Fig. 15.19.3), and mechanical colonic obstruction. Treatment is with intravenous fluids and electrolytes, together with nasogastric suction, and any drugs that might be implicated in reduced colonic motility (e.g. opioids, tricyclic antidepressants, or anticholinergic agents) should be stopped. Pharmacological stimulation has been recommended with neostigmine (an acetyl- cholinesterase inhibitor), and a meta-​analysis of trials has been positive. Decompression of the colon with a rectal tube or with colonoscopy is occasionally needed, although the long-​term value has been contested. Very rarely, surgical decompression with a caecostomy may be warranted if the colon is more than 12 cm in Box 15.19.1  Causes of a protein-​losing enteropathy Inflammatory conditions • Inflammatory bowel disease—​Crohn’s disease • Gastric cancer • Intestinal lymphoma • α-​Chain disease Lymphatic obstruction • Intestinal lymphangiectasia • Right-​sided heart failure • Congestive cardiac failure • Constrictive pericarditis • Fontan procedure for single ventricle • Hepatic venous outflow obstruction • Mesenteric tuberculosis or sarcoidosis • Intestinal lymphoma Increased permeability without ulceration • Coeliac disease • Tropical sprue • Ménétrier’s disease • Amyloidosis • Bacterial overgrowth of small bowel • Connective tissue diseases • Allergic gastroenteropathy • Eosinophilic gastroenteropathy

15.19  Miscellaneous disorders of the bowel 3027 diameter, and may be accompanied by resection if there is evi- dence of obvious colonic ischaemia. Chronic intestinal pseudo-​obstruction This is a rare syndrome associated with symptoms and signs sug- gesting mechanical obstruction of the large or small bowel in the absence of any obstructive lesion. A similar disorder of the intes- tine but without features of obstruction or bowel dilatation has been termed ‘chronic intestinal dysmotility’. The main features are of nausea, repeated vomiting, and ab- dominal pain. There may be significant bowel distension and constipation or occasionally diarrhoea. Bowel sounds are usually hyperactive. There are a number of causes (Box 15.19.2) which include familial visceral neuropathies and myopathies, which may present in infancy or adulthood; collagen vascular disorders; neuromuscular disorders and endocrinopathies; infections; and some drugs. The diagnosis requires features of colonic or small-​bowel dila- tation and may require specific electrophysiological studies or full-​thickness bowel biopsy at laparotomy. Treatment is directed at the underlying disease, or the use of prokinetic agents. Rarely, surgery may be needed for isolated sections of affected bowel, or substantial sections if symptoms are severe and chronic. Some cases have done well following small-​bowel transplantation. Fig. 15.19.2  Aortoenteric fistula in a patient with an aortobifemoral graft who was admitted with fever and upper gastrointestinal bleeding. The arterial phase of intravenous contrast enhancement shows extravasation of contrast material from the aorta into the duodenum (arrows). Extensive soft tissue surrounds the aorta. At surgery, a mycotic aneurysm was found. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.19.3  Plain abdominal X-​ray showing a prominent focal loop of air-​distended large bowel with its axis extending from the right lower quadrant to the left upper quadrant in a case of caecal volvulus. From Abujudeh HH (ed) (2014). Emergency radiology cases. By permission of Oxford University Press.

section 15  Gastroenterological disorders 3028 Miscellaneous disorders of the colon and rectum Microscopic colitis This syndrome is characterized by the triad of watery diarrhoea, a normal macroscopic colonoscopy, and specific histology showing either lymphocytic colitis or collagenous colitis. Although usually considered together as microscopic colitis, there are some distinct epidemiological, histological, and therapeutic differences between the two types. There is an annual incidence rate of 10/​100  000 with lymphocytic colitis being marginally the most common. It is five times more common over the age of 65 years and in women. There have been associations with coeliac disease, hypothyroidism, a family history of inflammatory bowel disease, and more recently drugs including selective serotonin reuptake inhibitors, H2 antagon- ists, and nonsteroidal anti-​inflammatory drugs. Collagenous colitis This was first recognized by Lindström in 1976. Patients, mostly women, usually present in the fifth and sixth decade, but the disease can occur in young adults as well as in older people. Watery diar- rhoea accompanied by occasional abdominal cramps, wind, disten- sion, and some nausea are usual. Diarrhoea can be severe and may seem secretory in nature. There may be some mucus, but bleeding per rectum does not occur. Despite such severe symptoms the pa- tients look well, with a good appetite, and they do not lose weight. There are no abnormal physical signs and on colonoscopy the mucosa looks normal, although it may seem somewhat granular and hyperaemic. Such endoscopic changes can occur throughout the colon but are usually patchy and never severe. The diagnosis is made on the appearance of the biopsy, where there is a thickened band of subepithelial collagen extending 15 µm compared with a normal thickness of 2 to 6 µm. The collagen band is widest in the right colon and tends to become thinner more distally. Immunohistochemical studies have shown that the abnormal tissue consists predominantly of collagen type 3, and there is a patchy variable inflammatory infil- trate in the lamina propria consisting of lymphocytes, plasma cells, and some neutrophils. The disease is confined to the colon and is distinct from collagenous sprue. Regarding treatment, a Cochrane review in 2017 found low-​ quality evidence suggesting that budesonide may be effective for inducing and maintaining clinical and histological responses, but concluded that bismuth subsalicylate, Boswellia serrata extract, mesalazine with or without cholestyramine, prednisolone, and pro- biotics required further study. Lymphocytic colitis The clinical symptoms are similar to collagenous colitis but the mucosa always looks normal at colonoscopy. Histological examin- ation shows a diffuse inflammatory cell infiltrate throughout the lamina propria with no architectural changes to the glands. The infiltrate is predominantly lymphocytes but there may also be eo- sinophils and a characteristic feature is the marked increase in intraepithelial lymphocytes, which clearly distinguishes it from ul- cerative colitis where they are normal or reduced. In some cases of microscopic colitis there may be spontaneous remissions and symptoms may have been preceded by some infec- tious trigger, including Campylobacter jejuni, Clostridium difficile, or yersinia infection. In cases that do not resolve, treatment is now more rational as recent meta-​analyses have demonstrated signifi- cant improvement with budesonide, which is now generally used as first-​line therapy, although there are also reports of improvements with mesalazine, cholestyramine, bismuth, or just simply with loperamide. Malakoplakia This is a rare, chronic granulomatous condition, most commonly affecting the genitourinary tract, skin, lung, bone, or brain; within the gastrointestinal tract it is most common in the sigmoid colon or rectum. It is observed in two clusters: in children and older people. It is more common in diabetic, immunosuppressed, or immunocom- promised patients, including those with hypogammaglobulinaemia, HIV infection, or after organ transplantation. Yellowish soft plaques 1 to 20 mm in diameter show a histiocytic infiltrate with eosino- phils and characteristic basophilic, laminated, calcium-​containing Michaelis–​Guttman bodies. In the bowel, it may occur with isolated rectosigmoid involve- ment, as diffuse colonic involvement, or as a focal lesion associated with a polyp or cancer. It is usually considered to be a granuloma- tous reaction to a chronic infection: Escherichia coli, klebsiella, and proteus have been implicated. Treatment is with antibiotic therapy (quinolone and co-​trimoxazole–​trimethoprim) and by minimizing immunosuppression. Solitary rectal ulcer syndrome The solitary rectal ulcer syndrome is somewhat misnamed as it may occasionally occur above the rectum and be multiple or circumfer- ential. It occurs across the age spectrum and is seen into the ninth decade. The ulcer may be at one end of the spectrum of clinical dis- orders associated with rectal mucosal prolapse and is caused in most cases by mucosal ischaemia and infarction. Presentation is with blood per rectum in 90% of cases, and less frequently with abdominal pain, mucus per rectum, straining at defecation, diarrhoea, and constipation. Patients are commonly an- aemic, and the symptoms have a serious impact on the quality of life. The ulcers may be located anteriorly (70%), posteriorly, or cir- cumferentially, and are multiple in one-​third of cases. At colonos- copy, the ulcer may be surrounded by a minimal area of inflamed mucosa, or it may be at the end of a polypoid lesion simulating a carcinoma. Biopsy is crucial to rule out that diagnosis. Histology Box 15.19.2  Causes of chronic intestinal pseudo-​obstruction • Familial visceral myopathy • Familial visceral neuropathy • Paraneoplastic neuropathy • Scleroderma • Dermatomyositis/​polymyositis • Mixed connective tissue disease • Diabetic neuropathy • Spinal cord injury • Neurofibromatosis • Myotonic dystrophy • Amyloidosis • Hypothyroidism • Hypoparathyroidism

15.19  Miscellaneous disorders of the bowel 3029 usually shows evidence of ischaemia, but the characteristic feature is hypertrophy of the muscularis mucosae with smooth muscle fibres extending between the crypts and down into the epithelium. Treatment is commonly difficult but should be centred on cor- rection of constipation with bulking agents (with or without lactu- lose), and patients should be warned not to strain at stool. Topical treatments with 5-​aminosalicylic acid or corticosteroids have been helpful in small series, but as these ulcers can remit spontaneously, it is difficult to be sure whether treatment has been effective in an individual patient. For patients with continuing disabling symp- toms, anorectal physiological measurements should be considered because there may be evidence of impaired pelvic floor muscle in- novation. A defecating proctogram may determine whether the ano- rectal angle changes when the patient attempts to empty the rectum and record the degree of mucosal prolapse. Surgical therapy with a rectopexy may be helpful in some cases. Stercoral ulcers These occur in association with faecal impaction and are most commonly found in the rectosigmoid area. The patients are usu- ally elderly, but these ulcers can occur at any age in severely con- stipated individuals, including patients with a neurological cause for constipation. The common symptoms are those associated with constipation—​nausea, abdominal distension, pain, and anorexia. The ulcers are frequently asymptomatic but may be the cause of an- aemia from chronic bowel loss. The differential diagnosis includes other ulcers within the colon, particularly those with an infectious cause (tuberculosis and amoebiasis) as well as malignancy. Isolated ulcers of the large intestine not associated with underlying colitis are rare but may be an incidental finding on screening col- onoscopy or present with abdominal pain, acute blood per rectum bleeding, or chronic gastrointestinal blood loss. A common cause, particularly when the ulcers are caecal or right sided, is the use of nonsteroidal anti-​inflammatory drugs. Complications of parenteral nutrition
and intestinal failure A number of complications of parenteral nutrition have been de- scribed relating to vascular thrombosis and catheter-​related sepsis, but metabolic complications and the development of a cholestatic liver disease are the most important. Metabolic dysfunction includes hyperglycaemia, dyslipidaemia, manganese toxicity, oxalate renal stones, osteoporosis, and a refeeding syndrome which includes hypophosphataemia, hypernatraemia, and hypokalaemia shortly after starting nutrition in a malnourished patient. Hepatobiliary disease includes cholelithiasis and a progressive cholestasis resulting in liver failure. This progressive liver disease is more common in children with intestinal failure (due, for instance, to necrotizing enterocolitis) but may also occur in adults. In larger cohort studies, about 25% of cases receiving total parenteral nutri- tion will have significantly abnormal liver blood tests with up to 5% showing evidence of fibrosis leading to cirrhosis. The liver dis- ease may be driven by the total parenteral nutrition itself and result from nutrient excess, deficiency, or toxicity, and is suggested by the dramatic improvements in liver function that can occur with ma- nipulation of the contents of the nutrition support. On the other hand, it may also be related to the accompanying bowel resection. Bacterial overgrowth, increased permeability of the bowel wall due to intestinal atrophy, gut-​derived endotoxins, and lithocholic acid with a reduced circulating bile salt pool and bile flow promoting cholestasis have all been suggested. The development of a similar liver disease in patients following a jejunoileal bypass and other forms of bariatric surgery and the fact that liver dysfunction is less common in patients with an intact colon or who can maintain small amounts of enteral feeding are evidence in favour of the gut being a major driver of the liver pathology. Management of these cases should be centralized in intestinal failure units experienced in the complex management of nutrition support and scrupulous catheter care. A  careful balance in lipid composition, where both too much and too little must be avoided as well as too much carbohydrate, is important. Cyclical feeding and wherever possible maintaining at least some enteral nutrition are recommended. Ursodeoxycholic acid, as a choleretic, has been shown to prevent liver dysfunction and antibiotics to prevent bac- terial overgrowth in children but there is less evidence of their ef- ficacy in adults. Supplementation with choline and taurine are also important. Bowel-​lengthening surgical techniques in children are still unproven but there is increasing evidence of the benefit of trans- plantation of the small bowel (with or without a liver) and 50% 5-​ year survival is now being recorded. Disorders of the peritoneum A number of rare disorders can specifically affect the peritoneum and serosal surfaces of the large and small bowel (Box 15.19.3). Their importance is firstly as a differential diagnosis for diffuse ma- lignant infiltration of the peritoneum, by far the commonest cause of widespread peritoneal deposits seen on cross-​sectional imaging, but also because they may require specific therapy. Disseminated malignancy is common, with ovarian and adeno- carcinoma most prevalent. Patients present with abdominal swelling, ascites, pain, and weight loss. CT scanning will reveal peritoneal deposits and biopsy is mandatory in order to tailor chemotherapy to specific cancers (Fig. 15.19.4). Primary peritoneal mesothelioma presents in a similar manner with a slightly better Box 15.19.3  Diffuse disorders of the peritoneum • Malignancy: —​ Primary: mesothelioma, leiomyosarcoma, solitary fibrous tumour —​ Secondary: ovary, stomach, colon, kidney —​ Pseudomyxoma peritonei —​ Desmoid tumours • Erdheim–​Chester disease • Sarcoidosis • Amyloidosis • Tuberculosis • Retractile mesenteritis • Leiomyomatosis peritonealis disseminate

section 15  Gastroenterological disorders 3030 prognosis. A clue to synchronous peritoneal carcinomatosis may be an elevated level of CA19-​9. It is associated with poor survival and reduced quality of life. The benefits of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with disseminated ovarian cancer, gastric cancer, and peritoneal meso- thelioma remain unproven. Desmoid tumours (aggressive fibromatosis) are rare benign neoplasms of fibroblastic origin that can be either extra-​ or intra-​ abdominal (mesenteric fibromatosis). They are locally invasive, with high recurrence rates. It occurs as a sporadic form and is associated with familial neoplastic syndromes including Gardner’s syndrome and familial adenomatous polyposis (FAP). Sporadic cases may have mutations in the adenomatous polyposis coli (APC) or β-​catenin (CTNNB1) genes. In FAP, tumours carry biallelic APC mutations. Overall, desmoids can occur in up to 15% of FAP cases rising to 65% after abdominal surgery in those with 3′ APC mutations. They are a leading cause of death after colectomy. Symptoms include pain, fea- tures of intestinal obstruction, and often a palpable mass. Treatment remains unsatisfactory and includes surgery, nonsteroidal anti-​ inflammatory drugs, and tamoxifen. Pseudomyxoma peritonei has been linked to peritoneal spread of appendiceal and ovarian mucinous tumours (Fig. 15.19.5). Erdheim–​Chester disease is a multisystem xanthomatosis with histiocytic proliferation similar to Langerhans cell histiocytosis but with a different immunohistochemical profile. Mutations in the BRAF proto-​oncogene occur in the majority of cases. Sheets of foamy histiocytes can involve lung, skin, brain, adrenals, renal tract, liver, and peritoneum. Treatment is unsatisfactory but pegylated interferon-​α is recommended as first-​line therapy. The syndrome of retractile mesenteritis (sometimes referred to as sclerosing mesenteritis or mesenteric panniculitis) may pre- sent with abdominal discomfort, pain, diarrhoea, and weight loss. Chronic fibrosing inflammation involves the root of the mesentery and small bowel. In some cases it has been associated with retroperi- toneal fibrosis, a desmoid or carcinoid tumour of the small bowel. It is more common in males and may have a prolonged debilitating course. Treatment is with tamoxifen and corticosteroids. Leiomyomatosis peritonealis disseminata is an uncommon condition characterized by subperitoneal proliferation of benign nodules composed of smooth muscle cells. It is most common in premenopausal women and hormonal influences may play a role in its pathogenesis. The macroscopic appearance mimics peritoneal carcinomatosis but the clinical course is benign and may regress with stopping hormone therapies. (a) (b) Fig. 15.19.4  Intravenous and oral contrast-​enhanced CT images showing enhancing tumour nodules in the greater omentum (arrows in (a)), ascites, and nodular thickening of the pelvic peritoneum (arrow in (b)) in a case of metastatic colon cancer. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. (a) (b) Fig. 15.19.5  Intravenous contrast-​enhanced CT showing low-​attenuation mucinous ascites scalloping the liver margin (arrow in (a)). The spleen is engulfed by mucin, which contains areas of calcification (arrowhead in (a)). Large amounts of mucin are evident in (b). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.19  Miscellaneous disorders of the bowel 3031 Endometriosis Endometriosis is defined as the presence of endometrium and stroma outside the uterine cavity and myometrium was first described by von Rokitansky in 1860. It is commonly asymptomatic and occurs in up to 15% of menstruating women. Involvement of the bowel is much less common and only rarely causes symptoms, but when they do occur they are often debilitating and may take years to be diag- nosed. The pathogenesis is considered to be retrograde passage of endometrial tissue into the pelvic organs and subsequent spread by haematogenous or lymphatic dissemination. When implanted, the tissue continues to be hormonally modulated. It is most commonly left-​sided within the abdomen in the rectosigmoid region (80%) fol- lowed by ileum, caecum, and appendix. Small serosal endometriotic nodules rarely cause symptoms, but large collections and those in a subserosal location may result in vague abdominal and back pain, diarrhoea, constipation, and abdominal bloating, symptoms that closely mimic the irritable bowel syndrome. Rectal bleeding may occur, but symptoms are not often cyclical. Symptomatic endomet- riosis is found in women of childbearing age and is uncommon be- fore age of 20 years. It is important to consider the diagnosis in any women with prolonged symptoms suggestive of the irritable bowel syndrome who does not respond to initial therapies and in those whose pain is not relieved by defecation. Nevertheless, diagnosis may be difficult as symptoms can be multiple and diffuse especially if the lesions are widespread. Imaging is the mainstay of diagnosis and includes transvaginal ultrasonography, double-​contrast barium enemas, and colonoscopy, but endometriosis is increasingly being identified with MRI. The presence of methaemoglobin from a re- current haemorrhage within the lesion causes hyperintense T1-​ weighted images and hypointensity on T2. Old endometriotic lesions with significant fibrosis are less well identified on MRI, and CT scans may be necessary. Some cases are only diagnosed at lapar- otomy or laparoscopic examination of the bowel. Management must be individualized and distinguish between peritoneal and deep infiltrating endometriosis. In some, a solely expectant and conser- vative approach or medical therapy is appropriate. Few trials have been performed. Inducing a pseudo-​pregnancy state with low-​dose oestrogen–​progestogen is not recommended for intestinal disease, and agents that are effective in pelvic endometriosis including the synthetic androgen danazol or gonadotrophin-​releasing hormone agonists may not be appropriate in bowel endometriosis as they may promote fibrosis. A cautious trial of therapy as a first line may be indicated but laparoscopy or surgery will be needed in those with severe symptoms or partial bowel obstruction. FURTHER READING Boland K, Nguyen GC (2017). Microscopic colitis:  a review of collagenous and lymphocytic colitis. Gastroenterol Hepatol (NY), 13, 671–​7. Cameron IC, et al. (1995). Intestinal endometriosis: presentation, in- vestigation, and surgical management. Int J Colorectal Dis, 10, 83–​6. Cipolletta L, et  al. (1995). Malakoplakia of the colon. Gastrointest Endosc, 41, 225–​8. Gagliardi G, et al. (1996). Pneumatosis coli: a proposed pathogenesis based on study of 25 cases and review of the literature. Int J Colorectal Dis, 11, 111–​18. Kelly D (2006). Intestinal failure associated liver disease—​what do we know today? Gastroenterology, 130, 870–​7. Nyhlin N, et al. (2006). Systematic review: microscopic colitis. Aliment Pharmacol Ther, 23, 1525–​34.

15.2 Symptoms of gastrointestinal disease 2727

15.2 Symptoms of gastrointestinal disease 2727

ESSENTIALS The skilful analysis of symptoms indicating disorders of the digestive system is an integral part of the practice of internal medicine. Many patients with abdominal symptoms do not have easily defined or- ganic conditions. The traditional skills of taking a careful history and examining the patient thoroughly are invaluable in managing patients who have functional disorders such as ‘irritable bowel’, nonulcer dys- pepsia, nonspecific diarrhoea, recurrent abdominal pain, and soma- tization disorder. The enormous advances in endoscopy, scanning, and other inves- tigative techniques have not made clinical diagnosis less important. Most gastrointestinal disorders are minor self-​limited conditions of uncertain cause or are ‘functional’ in nature, thereby often eluding definition even if extensive diagnostic procedures are (fruitlessly) em- ployed. At the other extreme, the early suspicion of life-​threatening disease and prompt referral of patients for investigation depends on clinical judgement. The nature of gastrointestinal symptoms Symptoms arising from the gastrointestinal tract are common and the lay terminology used to describe them can be misleading. Characteristic patterns of symptoms can be associated with normal test results and classified as ‘functional’ rather than ‘organic’ in na- ture. Functional gastrointestinal disorders comprise more than 60% of a gastroenterologist’s outpatient workload, and it is best to con- sider such conditions as ‘disorders of brain and gut interaction’ ra- ther than originating solely in one or other of these organs. There is a risk that, with increasing reliance on diagnostic tests, the lack of positive findings can lead to a breakdown in trust and the relationship between patient and clinician. Patients’ lives may be blighted by symptoms that affect their ability to socialize, sleep, leave the house, or work, and the lack of positive test results and a label (for instance) of ‘irritable bowel syndrome’ may lead to pejorative disbe- lief from relatives, friends, and employers that confounds the situ- ation further. It is essential that the clinician is able to recognize such symptoms and provide a diagnosis without embarking on a lengthy diagnostic trail littered with false-​positive findings and negative consequences, and compassionately manage the patient’s symptoms, their understanding of the condition, and their expectations. Gastrointestinal symptoms are amplified by emotional echoes linked to the primacy of food and feeding in our evolutionary past. Eating or drinking together, bringing and sharing food, and ‘going out’ for a meal are representative of the way in which food has long been the glue of society. Psychosocial consequences of gastrointes- tinal symptoms can become symptoms in their own right: the social embarrassment of refusing food that has been offered; of noises and smells generated by the intestinal tract; of vomiting at the table; of urgency to defecate after mealtimes; of faecal incontinence; of having to plan your day by the presence of toilet facilities; of having a stoma that empties unpredictably—​to name just a few. Clinicians need to be aware that such symptoms may be so embarrassing that patients may be reluctant to even mention them in consultation. Upper gastrointestinal tract symptoms Orofacial symptoms from a gastrointestinal perspective The gastroenterologist is rarely consulted for isolated oral symp- toms. Minor aphthous ulceration is common and rarely her- alds an underlying gastrointestinal disorder although it can be associated with underlying nutrient deficiency, which may relate to malabsorption. Such deficiencies may result also in fissuring and erythema of the tongue and inflammation of the corners of the mouth (angular cheilitis). The latter symptom is more commonly found in the elderly due to superficial infection of an intertriginous skin fold. Deeper fissuring ulcers of the gingival mucosa and tongue may be associated with inflammatory conditions such as Behçet’s disease or Crohn’s disease—​in the latter case, lip swelling can be disfiguring, and can be indistinguishable from that seen with orofacial granulomatosis. Referred pain in the jaw is experienced as an unpleasant ache, for instance, as a result of myocardial ischaemia or oesophageal reflux or spasm. In the latter case, it may be associated with pain referred to the tip of the tongue and salivation. Gastro-​oesophageal reflux can also lead to burning discomfort in the mouth, predominantly 15.2 Symptoms of gastrointestinal disease Jeremy Woodward

SECTION 15   Gastroenterologica l disorder 2728 in the oropharynx, a ‘metallic’ or ‘acid’ taste, and changes in the quality of the voice. It is important to distinguish the poorly understood ‘burning mouth’ syndrome in which the patient describes very unpleasant sensory symptoms of the tongue or entire oral cavity with no vis- ible diagnostic features and in the absence of significant gastro-​ oesophageal reflux. This entity often responds to drugs used for treating neuropathic pain. Dysphagia and odynophagia Difficulty in swallowing (dysphagia) is considered an ‘alarm’ symptom and to have a good predictive value for oesophagogastric cancer. However, the overall rate of cancer diagnosis in patients re- ferred with dysphagia is around 3 to 5%. Patients are often able to point to the level on the sternum at which they feel the food is sticking. This most accurately pinpoints the site of pathology when a lower level is identified—​with higher symptoms the cause could be at that site, or be the result of proximal pooling of food and fluid from a more distal obstruction. Careful questioning can discriminate different patterns of problems with swallowing in those with high dysphagia (Table 15.2.1). High dysphagia needs to be carefully distinguished from the common feeling of a ‘lump in the throat’—​an awareness at the back of the throat, around the level of cricopharyngeus, that can be constantly present and lead to a per- ception of difficulty with swallowing. This symptom, long known as ‘globus hystericus’, is associated with stress and anxiety and is a classic example of a functional gastrointestinal symptom accentu- ated by fear of underlying disease. Simple reassurance may suffice but the symptom usually evaporates after a negative nasendoscopic examination. The pooling of nasal secretions in the pharynx due to a postnasal drip can lead to a similar sensation. Low dysphagia, at the sternoxiphisternal level, is most frequently the result of reflux oesophagitis even in the absence of endoscop- ically noted stricture and can settle quickly with acid suppression using a proton pump inhibitor. Acid reflux can also lead to the ap- pearance of a fibrostenotic ‘Schatzki’ ring which may result in dys- phagia out of proportion to the narrowing of the lumen. Conversely, fibrotic, benign peptic strictures can produce surprisingly little dys- phagia despite considerable constriction of the lumen. Similarly, oe- sophageal tumours may present with dysphagia at a remarkably late phase of encroachment. Obstructing lesions of the oesophagus will usually lead to better tolerance of liquid ingesta than solids. Achalasia of the cardia leading to impaired relaxation of the distal oesophagus results in prolonged dysphagia usually (but not always) without pain and predominantly for solids in the earlier stages. The gradual progression of dysphagia in achalasia can lead to signifi- cant weight loss, arousing suspicion of malignancy. In only a small number of instances is this the case, due to infiltration of the oe- sophageal wall with metastatic cells causing ‘pseudoachalasia’ or secondary to paraneoplastic antineuronal antibodies. Other mano- metric patterns of oesophageal dysmotility—​such as hypertensive oesophagus, diffuse oesophageal spasm, and nonspecific motor disorders—​tend to present with dysphagia (in about two-​thirds of cases) associated with severe retrosternal pain that can be confused with myocardial ischaemia and refer in a similar pattern to the jaw, shoulder, or arm. These symptoms may last for up to an hour and respond similarly to sublingual nitrates. In addition, they tend to be intermittent and may occur weeks apart without any obvious trigger. Food bolus obstruction (‘steakhouse syndrome’) is the sudden, unexpected complete obstruction of the oesophagus while eating and presents a quite different pattern from progressive dysphagia—​ it is indeed rarely seen with conditions such as carcinoma or acha- lasia and patients may describe no prior symptoms of dysphagia. Patients may experience extreme distress and may be unable to swallow their own saliva, and if left obstructed in this fashion are at risk of oesophageal perforation and pulmonary aspiration of pooled ingesta and secretions. The culprit lesion may even be difficult to de- tect on endoscopy although about 50% of cases are associated with a Schatzki ring or peptic stricture. Poorly masticated fatty meat such as beef or pork is the usual cause but it is important to exclude inad- vertent foreign object ingestion as well. The other common cause of food bolus impaction, especially in young adults, is eosinophilic oesophagitis. In this condition, most likely a manifestation of hypersensitivity to unknown food antigens, patients may experience unpredictable and intermittent symptoms of dysphagia. Patients may describe food sticking at different levels in the oesophagus, including the mid sternum, rather than the cricopharyngeal or lower sternal edge as for most other causes. Dysphagia needs to be discriminated from pain on swallowing (odynophagia). In the oropharynx, odynophagia may be related to Table 15.2.1  High dysphagia Symptom Associations Sensation of awareness at the back of the throat worse with swallowing liquids or solids and not obstructing the passage of food Common. ‘Globus’ symptom may be associated with anxiety and stress Swallowing difficulty associated with pain Local infective or inflammatory causes such as tonsillitis, pharyngitis, oropharyngeal candidiasis, mucosal ulceration, or tumour Difficulty forming a food bolus and moving it around the mouth Dry mouth—​anxiety, medications (i.e. antihistamines, tricyclic antidepressants, diuretics, antihypertensives), Sjögren’s syndrome, IgG4 disease Neurological impairment—​i.e. bulbar/​pseudobulbar palsy, Parkinson’s disease, motor neuron disease, multiple sclerosis Advanced dementia Choking, coughing, and/​or nasal regurgitation, worse with fluids than solids while swallowing Neurological dysphagia—​as above including small vessel ischaemia, large territory cortical infarcts, and brainstem damage Choking, coughing after swallowing with inability to clear bolus Local high obstructive causes including pharyngeal pouch, cricopharyngeal spasm, postcricoid web, cervical spine osteophytes, tumour, dysphagia lusorum (aberrant aortic origin of right subclavian artery)

15.2  Symptoms of gastrointestinal disease 2729 local causes such as oral candidal infection, tonsillitis, viral pharyn- gitis, or ulceration. Painful sensations associated with the passage of food in the lower oesophagus experienced behind the sternum should be distinguished from a heightened awareness of the passage of food and fluids that is a common manifestation of visceral hyper- sensitivity, especially with hot or cold fluids. Odynophagia in this location is most commonly related to reflux oesophagitis, but may occur along with dysphagia in mechanical obstruction due to oe- sophageal dysmotility or strictures. Isolated odynophagia is rarely reported in malignancy without associated dysphagia, possibly as a result of patients changing the consistency of their dietary intake to avoid obstruction. Heartburn A distinctive and familiar symptom, heartburn can be difficult for patients to describe. However, the ‘burning’ nature of the discomfort and the central location with upwards radiation are characteristic of a symptom that is almost always associated with gastro-​oesophageal reflux. With such a common symptom it is important to be aware of variants, which include radiation across the chest or into the jaw and tongue, left scapula, or centre of the back. Patients may describe a bad taste in their mouth or the presence of clear fluid. Heartburn and reflux may be associated with eating, or just experienced at night or on bending or lying down. It may be relieved by drinking water, milk, or antacids but not invariably so. It is important for patients and clinicians not to confuse heartburn with myocardial ischaemia. It is also important for clinicians to realize that acid reflux does not always cause heartburn. It is frequently asymptomatic and in over half of those experiencing symptoms, the only feature is a localizing pain high in the epigastrium behind the xiphisternum. ‘Dyspepsia’ and ‘indigestion’ These terms are synonymous and relate to a lay perception of upper abdominal symptoms being related to the inability to digest food. ‘Indigestion’ is used to describe a variety of different postprandial symptoms that have little to do with digestion but may include post- prandial fullness, heartburn, dysphagia, upper abdominal pain, bloating, distension, belching, and nausea. ‘Dyspepsia’ has been used in criteria to try to define a stomach origin of upper gastrointes- tinal symptoms as differentiated from ‘heartburn’ arising from the oesophagus. While dyspepsia can be due to significant underlying pathology such as gastroduodenal ulceration or malignancy, the majority of patients with ‘dyspepsia’ have normal gastroscopic ap- pearances such that endoscopy is not recommended in the United Kingdom for those under 55 years without the ‘alarm’ features of weight loss, persistent vomiting, or anaemia. Minor endoscopic appearances of erythema or gastritis are rarely responsible for ‘dys- peptic’ symptoms. However, when Helicobacter pylori is present, its eradication leads to resolution of symptoms in up to 40% of cases of dyspepsia without ulceration. Hiccups Hiccups are caused by a sudden reflex contraction of the dia- phragm, usually unilateral, with the characteristic sound produced by glottic closure against the inflow of air. Normally self-​limiting and with no known purpose, hiccups can be caused by gastric dis- tension, gastro-​oesophageal reflux, pericarditis, subphrenic collec- tions, intrathoracic tumours, or metabolic derangements (uraemia, alcohol excess). A  significant underlying cause is more likely if present for more than 48 h. Stimulation of the nasopharynx with iced water or lemon juice, or altering respiratory function by breath holding or the Valsalva technique will resolve the symptom in the majority of cases. Belching Eructation, persistent burping or belching, can be associated with anxiety and is a common accompaniment of gastro-​oesophageal re- flux. The excess gas is usually due to air swallowed by an increased frequency of dry swallowing as a learnt response to reflux episodes. Acid suppression with proton pump inhibitors significantly reduces the symptom (and swallowing frequency) when associated with acid reflux, but it may require breathing exercises or psychological approaches in other cases. Halitosis or foul smells associated with burping may be due to gastric stasis or food fermenting in a gastric or oesophageal diverticulum. Nausea Nausea is perhaps the most diffuse and difficult gastrointestinal symptom to evaluate. Derived from a Greek word for ‘ship’, it is most easily associated with motion (or sea-​) sickness and is induced centrally by a wide variety of different triggers with vomiting as the linked effector component. It probably evolved as a reflex means of voiding potentially toxic food substances. The afferent limb arises from chemoreceptors in the stomach and upper intestine as well as visceral stretch receptors predominantly in the stomach, and chemoreceptors outside the blood–​brain barrier in the medulla oblongata. Nausea has a strong learned component in order to lead to conditioned food aversion and prevent repeated ingestion of toxins. This memory for chemical stimuli leads to subjective nausea with sensory triggers such as sight, sound, or smell. An evolutionary advantage for motion sickness is unclear unless to expel neuro- toxins leading to disequilibrium, such as natural alcohols. Nausea arising from stomach mechanoreceptor activation can be relieved by emptying the stomach and explains the relief that can arise with vomiting, but also the significant benefit achieved in nausea associ- ated with (e.g. malignant bowel obstruction) using a Ryle’s tube or venting gastrostomy. Vomiting Vomiting is the forceful ejection of gastric contents by sudden con- traction of the abdominal and gastric musculature with relaxation of the gastro-​oesophageal junction, usually preceded by nausea. Different patterns of vomiting can be discerned relating to the underlying pathology—​patients with self-​limiting acute, repetitive vomiting usually have a toxic or viral gastroenteritic cause. Patients with mechanical obstruction of the pylorus or proximal duodenum due to tumour, scarring, or oedema associated with peptic ulcer- ation, or ‘groove’ pancreatitis, may eat normally and then experience large-​volume vomits without warning including evidence of meals eaten much earlier. Bile-​stained or feculent vomits may provide a clue to the level of obstruction. Some patients vomit after eating or drinking very small quantities such that the gastric sensation or chemoreception may be sufficient to trigger a learnt vomiting reflex. In around 40% of cases, this reflex can be suppressed using psychological approaches. This symptom is prominent in patients with gastric dysmotility, often young females.

SECTION 15   Gastroenterologica l disorder 2730 Frequently the patient describes vomiting everything they eat or drink shortly afterwards, yet maintain their weight and hydration, presumably only vomiting a small proportion of their intake. This pattern of vomiting may correspond to a reflex contraction of ab- dominal wall muscles known as ‘rumination’ syndrome. There is a strong psychogenic component to nausea and vomiting, including a response to altered eating behaviour such as anorexia or bulimia nervosa where patients may self-​induce vomiting by pha- ryngeal stimulation prior to learning to vomit spontaneously. A condition previously only recognized in children of ‘cyclical vomiting syndrome’ is poorly understood but results in repeated stereotypical episodes of vomiting with a prodrome reminiscent of migraine. Early satiety and postprandial fullness Patients with gastric outlet obstruction or gastroparesis may com- plain of a feeling of fullness when eating and may only be able to manage small meals. However, gastric emptying can be normal or fast with symptoms of early satiety which may arise from impaired fundic relaxation after eating—​a ‘functional’ dyspepsia. Rapid gastric emptying, due to neuromuscular discoordination or surgically altered gastroduodenal anatomy, can lead to postpran- dial fullness and bloating, associated with sweating or fainting. This ‘dumping’ syndrome is due to both delivery of a high osmolar load into the intestine and a lack of integrated neurohormonal feedback. The latter can also result in a delayed postprandial hypoglycaemia or ‘late dumping’. Avoiding taking liquid and solids within half an hour of each other and regular eating of small quantities (‘grazing’) can help to manage dumping symptoms. Abdominal pain The acute abdomen Sudden onset of pain, often well localized and associated with fea- tures of peritonism, such as exacerbation with breathing or move- ment, guarding, and rebound or percussion tenderness, signifies an acute abdomen and warrants urgent cross-​sectional imaging and surgical review (see Chapter  15.4.1 for further discussion). Metabolic disorders that can masquerade as a surgical acute ab- domen include diabetic ketoacidosis and lactic acidosis. The latter should raise concern about the possibility of underlying visceral ischaemia regardless of risk factors for arterial vascular disease as it can occur at any age as a result of prothrombotic disorders (ar- terial or venous thromboses) or congenital malrotation of the gut. First presentation of a familial periodic fever or acute porphyria may rarely present with an acute abdomen. Approach to chronic or recurrent abdominal pain Chronic abdominal pain (Table 15.2.2, Fig. 15.2.1) can present a significant challenge. Often the duration of the symptoms indicate a benign condition and there may be no obvious abnormality on ini- tial investigations, leading to a functional diagnosis. Chronic abdominal pain due to ‘visceral hypersensitivity’ may be initiated by an acute initial pathology which it might mimic in nature and location. Such pain can usually be identified as func- tional if the underlying cause is removed—​after appendicectomy or cholecystectomy, for instance. An understanding of such sec- ondary functional visceral hypersensitivity aids the clinician greatly Table 15.2.2  Considerations in diagnosis of chronic abdominal pain Feature Considerations Duration • Long-​standing symptoms without progression are unlikely to signify serious underlying pathology • It may be possible to identify a change in diet or lifestyle at the time the pain started Temporal pattern • Frequent intermittent pain occurring only some days a week with long periods of respite is common with functional disorders • Rare, infrequent episodes may be due to functional disorders but consideration of other pathologies such as biliary colic, recurrent acute pancreatitis, intermittent volvulus, or acute diverticulitis should be considered • Spasmodic pain in the early morning may arise from the colon due to the diurnal pattern of migrating motor complexes • Pain associated with fermentative gas bloating may get worse during the day and ease overnight • Functional colonic pain may be affected by the menstrual cycle Location and radiation • Pain that appears in different places around the abdomen is most likely to be of functional colonic origin rather than a fixed pain of localized pathology • Pain localized (with one finger) to a specific point is more likely of abdominal wall (musculoskeletal) origin than visceral • See Fig. 15.2.1 for chronic pain localizations Nature of the pain • Spasmodic (cramping) pain may be described as ‘twisting’ or ‘vice like’ and usually signifies hollow organ origin • Constant deep aching pain should lead to exclusion of localized inflammation—​for instance, associated with diverticulitis or ileocaecal Crohn’s disease but may still be functional in origin • ‘Knife like’ through to back is a common description of pancreatic pain (rather than radiating around to the back) Exacerbating and relieving factors • Position—​pain triggered by movement is most likely of musculoskeletal origin but changes in position can exacerbate or relieve functional pains, particularly associated with bloating (right iliac fossa pain due to bloating is often worse when sitting or driving). Movement of the right hip can be painful with transmural ileocaecal inflammation associated with Crohn’s disease. Pain due to gastro-​oesophageal reflux can be worse when lying on one side (usually the left) • Eating—​exacerbation of a severe upper abdominal pain with eating may indicate gastroduodenal ulceration or a pancreaticobiliary origin. However, pain arising from anywhere in the gastrointestinaly tract can be triggered by eating due to the stimulation of motility • Defecation—​pain eased or exacerbated by opening the bowels usually implicates a colonic origin • Breathing—​may indicate a musculoskeletal origin, but can exacerbate capsular pain from the liver or spleen Associated symptoms • Bloating and loud borborygmi associated with chronic pain may indicate a stricture, but more commonly represent colonic fermentation of dietary substrate or as a result of malabsorption (i.e. bacterial overgrowth, coeliac disease) • Nausea may be a secondary response to pain, but vomiting could implicate a gastroduodenal or pancreaticobiliary origin • Altered bowel function at the time of the pain or an alternating bowel habit would usually indicate a functional colonic origin

15.2  Symptoms of gastrointestinal disease 2731 in the management of conditions such as chronic pancreatitis where ongoing pain may not arise from the pancreas itself and may be ex- acerbated by long-​term use of opiate analgesia. Altered bowel function Normal bowel function varies significantly and although the bowel operates to a diurnal motility rhythm, a daily bowel motion is passed by only around a third of the population (Fig. 15.2.2). It is essential to clarify the patient’s description of their bowel habit in terms of frequency and consistency—​some patients describe faecal incontinence or the passage of mucus as ‘diarrhoea’ and ‘constipa- tion’ may be used variably to describe the passage of hard stools, infrequent passage of stools (of any consistency), or having to strain to pass a motion regardless of frequency or form. The Bristol stool chart can be helpful for patients to describe the form of their stool (Fig. 15.2.3). A persistent change in bowel habit (>6 weeks) in pa- tients over 60 years is considered an indication for urgent referral in the United Kingdom to exclude colorectal cancer. Diarrhoea Diarrhoea is best considered as the more frequent passage of looser motions than usual, rather than an objective definition of more than 200 g of stool per day. Paradoxical ‘overflow’ diarrhoea due to faecal impaction should be excluded in very elderly or infirm pa- tients by rectal examination. A variety of medications—​including nonsteroidal anti-​inflammatory drugs, selective serotonin reuptake inhibitors, proton pump inhibitors, and metformin—​can cause diar- rhoea. The duration of a diarrhoeal episode and the appearance of the stools often help to define the cause. Acute self-​limiting diarrhoea is usually of infectious origin and may be bloody (dysenteric) in the case of ischaemic colitis, cytomegaloviral, bacterial, or amoebic in- fection, and can be prolonged (up to 3–​4 weeks). Diarrhoea due to idiopathic inflammatory bowel disease (most commonly ulcerative or Crohn’s colitis) is usually frequent, bloody, and small volume and may be associated with fever, tenesmus, and systemic symp- toms. Fatty diarrhoea (steatorrhoea) can be detected by the pale colour, unpleasant odour, and fatty globules and is a specific sign of fat malabsorption but is only present in about one-​third of cases. Common causes include pancreatic exocrine deficiency, giardiasis, small intestinal bacterial overgrowth, and coeliac disease—​the lack of obvious fatty change in the stools should not exclude these diagnoses. Chronic watery diarrhoea may be due to unabsorbed osmoles, for instance, sugar alcohols such as xylitol, or magne- sium, phosphate, or sulphate ions present in laxatives. Nonabsorbed Gastro-oesophageal reflux Isolated epigastric or radiating upwards Functional colonic pain (locations may change) Chronic cholecystitis (to right scapula) Biliary colic (to back and epigastrium) Pancreatic pain Pain from small intestine, i.e. mesenteric angina Ileocaecal inflammation Crohn’s, tuberculosis Liver capsule pain Fig. 15.2.1  Anatomical considerations of chronic abdominal pain. 0 5 10 15 20 25 30 35 40 <1 2 3 4 5 6 7 8 10 11 12 13 14 15 16 17 18 19 20 21>21 Percentage of population Number of bowel motions per week Men Women Fig. 15.2.2  Normal bowel frequency. Data from Heaton KW, et al. (1992). Defecation frequency and timing, and stool form in the general population: a prospective study. Gut, 33, 818–​24.

SECTION 15   Gastroenterologica l disorder 2732 carbohydrates, such as lactose or fructose, or complex polysacchar- ides as excess dietary fibre cause osmotic diarrhoea due to bacterial fermentation to short-​chain fatty acids and an acidic stool (pH <6) often associated with bloating or passage of wind. Secretory causes can be differentiated from osmotic causes of profuse watery diar- rhoea by persistence during fasting, and commonly signifies bile salt malabsorption or forms of microscopic colitis. Gastrointestinal neuroendocrine tumours (carcinoid, vasoactive intestinal peptide-​ producing tumour) account for less than 1% of cases, and classically gastrinoma results in steatorrhoea due to acid inactivation of pan- creatic enzymes. Constipation A common problem that increases with age and immobility, con- stipation affects up to 70% of elderly patients in nursing or residen- tial care homes. Careful questioning can distinguish patients who have obstructed defecation as a result of pelvic floor dysfunction from patients with slow-​transit constipation. The latter is frequently related to voluntary withholding of stool, often dating from ad- verse experiences in childhood or adolescence, or due to painful defecation due to anal causes such as fissure. Insufficient fluid or dietary fibre intake may be causative. Many medications lead to constipation, including opioids, antidepressants, serotonin re- ceptor blockers, diuretics, and calcium channel blockers. Significant underlying causes are uncommon but include hypothyroidism, coeliac disease, Parkinson’s disease, and hypercalcaemia. Motor dys- function of the gut due to neuromuscular disorders can result in a variety of presentations—​Hirschsprung’s disease can result in severe constipation in neonates and young infants but in its short segment form may not be diagnosed until adulthood with a ‘mega rectum’. Chronic idiopathic intestinal pseudo-​obstruction is the term given to the clinical presentation of various smooth muscle and enteric neuronal pathologies and may be heralded by profound constipa- tion and abdominal distension. Alternating pattern Alternating diarrhoea and constipation should be clearly distin- guished from either symptom in isolation and usually signifies a benign functional disturbance that frequently responds to dietary fibre supplementation. Patients may only report the symptom (ei- ther constipation or diarrhoea) that is most troublesome and it can require careful questioning to uncover the alternating pattern. ‘Irritable bowel syndrome’ This term implies abdominal pain or discomfort, bloating, and a change in bowel habit and has been defined by a number of different criteria (Table 15.2.3). It is often separated as diarrhoea, constipa- tion, or alternating pattern predominant. Specified criteria should be seen as tools for research and not diagnostic tests that require strict fulfilment as a prerequisite for the diagnosis of a functional disorder. While it can be reassuring, the use of the term ‘irritable bowel syndrome’ can have detrimental consequences. Clinicians may consider this to be the end of their engagement with the patient (having ruled out ‘serious’ pathology), whereas it should instead be the start of managing and treating their symptoms. Possibly as a result of such attitudes, the term carries lay undertones of trivi- alization which some patients may find difficult to accept. Indeed, it may be that (in common with many gastrointestinal symptoms) the overuse of the term ‘irritable bowel syndrome’ has led to such misunderstanding and decrease in its utility that it should be used sparingly or even replaced by a narrative diagnosis of a ‘disorder of brain-gut interaction’. Bristol Stool Chart Type 1 Separate hard lumps, like nuts (hard to pass) Sausage-shaped but lumpy Like a sausage but with cracks on the surface Like a sausage or snake, smooth and soft Soft blobs with clear-cut edges Fluffy pieces with ragged edges, a mushy stool Watery, no solid pieces. Entirely Liquid Type 2 Type 3 Type 4 Type 5 Type 6 Type 7 Fig. 15.2.3  Bristol Stool Chart. Copyright 2000 Rome Foundation, Inc. All rights reserved. Table 15.2.3  Definitions for irritable bowel syndrome ‘Rome IV’ criteria, 2016 Recurrent abdominal pain or discomfort experienced on average at least one day a week over the last 3 months associated with two or more of the following (with onset at least 6 months prior to diagnosis): • Association with defecation • Onset associated with a change in bowel frequency • Onset associated with a change in stool appearance ‘Manning’ criteria, 1978 (the more positive criteria, the greater likelihood of irritable bowel syndrome) • Onset of pain linked to more frequent bowel movements • Looser stools associated with onset of pain • Pain relieved by passage of stool • Noticeable abdominal bloating • Sensation of incomplete evacuation >5% of the time • Diarrhoea with mucus >25% of the time

15.2  Symptoms of gastrointestinal disease 2733 Anorectal symptoms Bright red bleeding arising from the anus is a frequent accom- paniment of hard stools and may be noticed only on wiping. Such bleeding can arise from the distal rectum in proctitis, without asso- ciated diarrhoea. While patients may report profuse bleeding from haemorrhoids, this is usually more worrying in its appearance and rarely sufficient to cause significant blood loss or iron deficiency. Rectal bleeding as a result of pelvic radiotherapy can be profuse and troublesome, and associated with reduced rectal compliance leading to urgency and frequent small stools. The latter may equally accom- pany chronic rectal involvement with inflammatory bowel disease. Prolapse of haemorrhoidal tissue (‘piles’) can be associated with straining at stool and is usually only painful when associated with thrombosis. More significant prolapse of the anterior rectal wall can be due to pelvic floor weakness (usually in females and often relating to childbirth), and can result in traumatic ‘solitary rectal ulcer syndrome’ that can be confused with proctitis but shows a distinctive histology. Rectal pain on defecation is usually due to an anal fissure and can be accompanied with bleeding and lead to secondary constipation by voluntary avoidance of passing stool. Superficial perianal fistulae may be isolated but when complex or deep are usually associated with Crohn’s disease and may not always be associated with symp- toms of colonic involvement. A symptom of intense, deep rectal pain—​‘proctalgia fugax’—​ is common, fleeting, and of unknown origin and rarely signifies underlying pathology. A more chronic form of similar rectal pain—​ ‘levator ani syndrome’—​can be identified by pain felt on the left side approximately 5 cm inside the rectum. FURTHER READING Abdel Jalil AA, Katzka DA, Castell DO (2015). Approach to the pa- tient with dysphagia. Am J Med, 128, 1138.e17–​23. Bellini M, et al. (2015). Irritable bowel syndrome and chronic consti- pation: fact and fiction. World J Gastroenterol, 21, 11362–​70. Drossman DA, Hasler WL (2016). Rome IV – Functional GI dis- orders: Disorders of Gut-Brain Interaction. Gastroenterology, 150(6), 1257–61. Gunnarsson J, Simren M (2008). Efficient diagnosis of suspected func- tional bowel disorders. Nat Clin Pract Gastroenterol Hepatol, 5, 498–​507. Heaton KW, et  al. (1992). Defecation frequency and timing, and stool form in the general population: a prospective study. Gut, 33, 818–​24. Levy RL, et al. (2006). Psychosocial aspects of the functional gastro- intestinal disorders. Gastroenterology, 130, 1447–​68. Longstreth GF, et al. (2006). Functional bowel disorders. Gastroenterology, 130, 1480–​91. National Institute for Health and Care Excellence (2014). Gastro-​ oesophageal reflux disease and dyspepsia in adults: investigation and management. Clinical guideline. http://​www.nice.org.uk/​guidance/​ cg184 National Institute for Health and Care Excellence (2017). Clinical knowledge summaries: hiccups. http://​cks.nice.org.uk/​hiccups Sweetser S (2012). Evaluating the patient with diarrhea: a case-​based approach. Mayo Clin Proc, 87, 596–​602. Talley NJ, Ford AC (2015). Functional dyspepsia. N Engl J Med, 373, 1853–​63. Talley NJ, et al. (1990). Diagnostic value of the Manning criteria in ir- ritable bowel syndrome. Gut, 31, 77–​81.

15.20 Structure and function of the liver, biliary

15.20 Structure and function of the liver, biliary tract, and pancreas 3032

ESSENTIALS Liver and biliary tract The liver, sited in the right upper quadrant of the abdomen, com- prises eight segments, each of which is a complete functional unit with a single portal pedicle and a hepatic vein. Within the functional segments, the structural unit is the hepatic lobule, a polyhedron sur- rounded by four to six portal tracts containing hepatic arterial and portal venous branches from which blood perfuses through sinus- oids, surrounded by walls of hepatocytes that are a single cell thick and lined by specialized endothelial cells with ‘windows’ (fenestrae), to the centrilobular region and the central hepatic veins. Bile se- creted through the canalicular membrane of the hepatocyte collects in biliary canaliculi, from which it passes through the biliary tract into the gut. The liver secretes bile, which aids digestion by emulsifying lipids, and has a central role in metabolism of (1) bilirubin, from haem; (2) bile salts, the principal mechanism for clearance of cholesterol; (3) carbohydrates; (4) amino acids and ammonia; (5) proteins, most circulating plasma proteins being produced by hepatocytes; and (6) lipid and lipoproteins. Pancreas The pancreas lies in the retroperitoneum and is composed of (1)  an exocrine portion centred on acini, producing an alkaline secretion containing digestive enzymes including serine prote- ases, exopeptidases, and lipolytic enzymes, draining through a ductal system into the duodenum; and (2) the islets of Langerhans, which secrete insulin (also glucagon, somatostatin, and pancreatic polypeptide). Liver and biliary tract The hepatic diverticulum originates from the foregut (duodenum) at week 3 to 4 of gestation and then subdivides into hepatic and biliary buds. The hepatic bud contains bipotential progenitor cells that differentiate into hepatocytes and biliary cells. Liver structure is produced by progressive subdivisions of the hepatic bud. The biliary bud forms the gallbladder. Ingrowing capillary plexuses ultimately form sinusoids. Kupffer cells derive from circulating macrophages and stellate cells from submesothelial cells located beneath the surface of the developing liver. The adult liver weighs 1.2 to 1.5 kg and has a highly vascular archi- tecture. The classic descriptions of liver anatomy demonstrating the complexity of different parenchymal and nonparenchymal elements have a long history, but only recently have they been united with an increasing understanding of the intricate functional organization and physiological compartmentalization of liver structure. This has had a profound effect on our understanding of the control of physiological processes and the development of liver surgery. A grasp of the hepatic anatomy is key to an appreciation of these complex functional arrangements. Morphological anatomy This describes the classic structure of the liver into two lobes, right and left, and the accompanying vascular structures, lymphatics, and biliary tract (Fig. 15.20.1). The liver, situated in the right upper quadrant of the abdomen, is covered by Glisson’s capsule, a visceral continuation of the peri- toneum. Three ligaments attach to surrounding structures—​the falciform ligament anterior and superiorly, and the two posterior triangular ligaments which enclose the retrohepatic vena cava and the small bare area of the liver. Inferiorly, Glisson’s capsule attaches to the lesser curve of the stomach and at the hepatic hilus encases the hepatic pedicle consisting of hepatic artery, portal vein, and common hepatic bile duct. Hepatic lobes The two major lobes, right and left, and two accessory lobes, quadrate and caudate, are defined by points of surface anatomy. The larger right lobe comprises the dome of the liver under the diaphragm and is limited anteriorly and medially by the falciform ligament and posteriorly by the right border of the inferior vena cava. The quadrate lobe inferiorly abuts on to the antrum of the stomach and first part of the duodenum and is bor- dered by the posterior transverse hilar fissure, the gallbladder 15.20 Structure and function of the liver,
biliary tract, and pancreas William Gelson and Alexander Gimson

15.20  Structure and function of the liver, biliary tract, and pancreas 3033 fossa laterally, and the umbilical fissure medially. The caudate lobe lies posterior and superior to the quadrate lobe limited by the vena cava and the ligamentum venosum. Finally, the left lobe has the umbilical fissure medially and the falciform ligament anteriorly. Vascular anatomy The portal vein, hepatic duct, and hepatic artery form the hep- atic pedicle with the bile duct anterior in the free edge of the lesser omentum and the portal vein posteriorly (Fig. 15.20.1c). The latter is formed by the confluence of the superior mesenteric vein and the splenic veins running posteriorly in the pedicle, dividing into left and right branches to supply each lobe (Fig. 15.20.2). The left gas- tric vein also drains into the portal vein and may, in the presence of portal hypertension, be a major feeding vessel for gastro-​oesophageal varices. The portal vein is anatomically unique as it drains into the liver, not the heart. The hepatic artery arises from the coeliac axis as the common hepatic artery before dividing into a gastroduodenal and the main hepatic artery. There are several common anatomical vari- ants of the arterial supply of the liver, which are of no functional significance but which are of importance in liver transplantation and during surgical resection. The standard division into single left and right hepatic arteries is present in approximately 70% of cases (Figs. 15.20.1c and 15.20.2), but common variants include a separate second right hepatic artery (10%), separate right and left hepatic arteries (8%), and origin of the main hepatic artery off the superior mesenteric artery (2.5%). Variants of the left hepatic (a) Orientation Liver Oesophagus Stomach Spleen Pancreas Colon Rectum Appendix Large bowel Biliary tree Duodenum Jejunum Ileum Anus Small bowel

Umbilical fissure Inferior view Anterior view Superior view Right lobe (b) Caudate lobe Right triangular ligament Porta hepatis Inferior vena cava Ligamentum venosum Left lobe Gallbladder fossa Falciform ligament Left lobe Inferior vena cava Right lobe Right triangular ligament Left triangular ligament Right triangular ligament Left triangular ligament IVC Bare area Right lobe Coronary ligament Falciform ligament Left lobe Caudate lobe Right hepatic duct (c) Cystic artery Cystic duct Gallbladder Common bile duct Accessory duct of Santorini Ampulla of Vater Superior mesenteric vein Pancreatic duct Splenic vein Gastroduodenal artery Common hepatic artery Left gastric vein Left hepatic duct Pancreas Duodenum Fig. 15.20.1  (a) Orientation of the liver; (b) lobar anatomy and relations of the liver; (c) hilar, portal biliary tract, and pancreatic anatomy.

section 15  Gastroenterological disorders 3034 arterial supply also occur, with a separate left hepatic artery arising from the left gastric artery in 10% of cases. Venous drainage of the liver is through the three main hepatic veins, right, left, and middle, the latter two coalescing before joining the inferior vena cava. The caudate lobe drains separately through an array of small spigelian veins directly into the inferior vena cava. The functional anatomy of the liver (see ‘Functional anatomy) de- scribes the relationship between the main divisions of the portal vein and their draining hepatic veins running in the right, left, and main scissures (Fig. 15.20.3). Biliary anatomy Biliary canaliculi drain into left and right hepatic bile ducts forming the common hepatic duct until entry of the cystic duct, after which it is designated the common bile duct and has a diameter of less than 8 mm. The left hepatic duct follows a nearly horizontal course, par- tially extrahepatic. Anatomical variants are again quite frequent, and are surgically important, the most common being drainage of the cystic duct directly into the right hepatic duct. The common bile duct passes behind the first part of the duodenum, through pancre- atic tissue to the ampulla of Vater, joining drainage of the pancreatic duct (Fig. 15.20.1c). The gallbladder lies in a shallow depression in the underside of the liver, may contain up to 50 ml of bile, and is con- nected to the cystic duct with a spiral valve. Lymphatics The liver has a high blood flow (25% of cardiac output) and a highly permeable microcirculation. The consequent production of intersti- tial fluid, intrahepatic lymph, is formed in the perisinusoidal space of Disse between the hepatocytes and sinusoidal lining endothe- lium. Lymphatic vessels drain via the portal tracts, closely applied to the hepatic arterial branches, to the hilum and thence to the thor- acic duct. A smaller proportion drains with the hepatic veins and some interstitial fluid drains through Glisson’s capsule into the peri- toneum. Lymph flow acts to drain from the liver the interstitial fluid and protein that forms inevitably through microvascular filtration. The lymph flow rate in mammalian liver is approximately 0.5 ml/​ kg of liver per minute, making up 25 to 50% of thoracic duct lymph flow, and may be increased either by elevated microvascular pressure (hydrostatic pressure) through increased hepatic venous pressure or increased inflow pressure, or by reduced transcapillary oncotic pressure. Nervous system Both sympathetic and parasympathetic efferent innervation of the liver are described, an anterior plexus around the hepatic artery and posterior plexus around the portal vein. Sympathetic stimulation increases glucose release and glycogenolysis, and reduces oxygen consumption, ammonia uptake, and bile formation. Hepatic vas- cular resistance also rises as does portal pressure and there is rapid expulsion of blood out of the liver into the systemic circulation. An intrinsic nervous system with a wide variety of neurotransmitters, including noradrenaline, prostanoids, neuropeptide Y, substance P, and vasoactive intestinal peptide, is closely located to smooth muscle cells, fibroblasts, endothelial lining cells, and biliary epithe- lium within the liver and may be involved in chemoreception and osmoreception. Extrinsic nervous regulation of hepatic physiological processes seems to be of minor importance as there is no apparent impair- ment of liver metabolism or bile formation following orthotopic liver transplantation. It may be more relevant during pathophysio- logical stress: the existence of a hepatorenal reflex in patients with cirrhosis has been postulated whereby an increase in sinusoidal pressure is associated with increased efferent renal sympathetic ac- tivity and reduced renal blood flow. In animal models of chronic liver disease, the metabolic consequences of sympathetic nerve stimulation are impaired but the haemodynamic responses are exaggerated. Venous anatomy Arterial anatomy VENOUS OUTFLOW: VENOUS INFLOW: right, middle and left hepatic veins into IVC PORTAL VEIN Liver middle colic right colic ileocaecal site of portosystemic anastomosis - lower oesophagus, anal canal, bare area of liver, spleen - also periumbilical and retroperitoneal Aorta Coeliac trunk Superior mesenteric artery

15.20  Structure and function of the liver, biliary tract, and pancreas 3035 Functional anatomy Following the initial descriptions by Cantlie in 1898, there has been an increasing appreciation of the importance of the functional anatomy of the liver, the culmination of which was the description by Couinaud of the present eight liver segments that underpins all modern hepatic surgery. Each segment is a complete functional unit with a single portal pedicle and a hepatic vein (Fig. 15.20.3). There are four portal pedicles, two for each lobe, each supplying a sector of the liver, divided from each other by the three hepatic veins lying in a right, middle, and left scissure. This separates the liver into a right and left liver, different from lobes, with inde- pendent vascular supply and biliary drainage. Within each sector of the liver there are further subdivisions into segments. The caudate lobe (segment 1) has its own venous drainage, manifest during the Budd–​Chiari syndrome with thrombosis of hepatic veins when all venous drainage attempts to pass through this segment with conse- quent lobar hypertrophy. The left liver consists of the left posterior sector of segment 2 alone, and a left anterior sector of segment 3 medially and segment 4 laterally separated by the umbilical fissure. The right liver comprises a posterior sector of segment 7 superiorly and segment 6 inferiorly and an anterior sector of segment 5 inferiorly and segment 8, being most of the dome of the liver, superiorly. Structural organization Within the functional segments of the liver, the structural unit is the hepatic lobule, a polyhedron (2 × 0.7 mm) surrounded by four to six portal tracts containing hepatic arterial and portal venous branches from which blood perfuses through sinusoids, surrounded by walls of hepatocytes that are a single cell thick and lined by specialized endothelial cells with ‘windows’ (fenestrae), to the centrilobular re- gion and the central hepatic veins (Fig. 15.20.4). The portal vein branches give off numerous terminal portal ven- ules that run around the lobules in the interlobular septa accom- panied by arterioles and bile ductules, and subsequently branch into inlet venules which each supply a hepatic microcirculatory subunit consisting at the base of numerous interconnected sinusoids and, at the apex, the central vein (Fig. 15.20.4). Sinusoids Sinusoids are specialized capillaries without a basement membrane and lined with endothelial lining cells through which proteins of low molecular weight may percolate into the space of Disse. The sinusoidal membrane of the surrounding hepatocytes is covered by microvilli that increase the surface area sixfold (Fig. 15.20.5). Within the sinusoids, Kupffer cells and liver-​associated lympho- cytes may be found, and within the space of Disse, the hepatic Hepatic vein Input to portal tracts (from portal vein: blue, hepatic artery: red) and output from portal tract (to biliary tree: green) Central vein (drains to hepatic vein) Sinusoids Hepatocytes Biliary canaliculus Lobules Central veins Portal tracts Lobule Inlet venule Central vein Portal vein Terminal portal vein Hepatic microcirculatory subunit Fig. 15.20.4  Liver microanatomy. Arterial and venous blood mixes in sinuosoids and flows to a central vein, which sits in the centre of a hexagonal lobule and ultimately supplies the corresponding hepatic vein. Bile flows in the opposite direction to blood along canaliculi that form biliary ductules, which make up portal triads along with the hepatic arterial and portal venous branches.

section 15  Gastroenterological disorders 3036 stellate cells (also called Ito, fat storage, or perisinusoidal cells), which respectively make up 2%, 0.2%, and 1.4% of the lobular par- enchyma (Table 15.20.1). Biliary canaliculi Bile secreted through the canalicular membrane of the hepatocyte collects in biliary canaliculi, which pass around hepatocytes until draining through the short canal of Hering into the bile ductule. Cholangioles are lined by three or four cells that eventually become cuboidal epithelium. The volume and flow rate of bile are low; secretion into the duo- denum is controlled by gallbladder contraction and sphincter of Oddi tone. Agents that cause gallbladder contraction, including cholecystokinin, secretin, and motilin, also relax the sphincter of Oddi (Table 15.20.2). Factors modulating biliary motility have re- ceived increased attention recently with the realization that the syn- drome of biliary dysmotility may be the cause of biliary-​type pain in some cases. Changes in gallbladder motility may also be important in gallstone pathogenesis. Cellular elements Hepatocytes Hepatocytes are arranged in unicellular plates (Remak’s plates) that branch and divide around sinusoids, and are covered by spe- cific membranes at each surface: sinusoidal (70% of surface area) for exchange of material between the Disse space and intracellular compartment (endo-​ and exocytosis); canalicular membrane (15%) for exchange with the smallest of biliary canaliculi or hemicanals; and lateral membrane (15%) separated from the former by tight junctions and involved in intercellular transport between hepato- cytes. There is abundant smooth and rough endoplasmic reticulum, numerous mitochondria, glycogen stores, and an extensive cyto- skeleton. The metabolic functions of hepatocytes are discussed in ‘Metabolic processes’. Hepatocytes have an immense regenerative capacity and will proliferate in the face of loss due to necrosis, apoptosis, or iat- rogenic surgical resection. If proliferative capacity is lost due to exhaustion or damage, hepatocytes may be derived from pro- genitor cells located in the canals of Hering and nearby small bile ductules. Other cell types Other cells making up 6% of all parenchyma include sinusoidal lining endothelial cells, Kupffer cells, lymphocytes, hepatic stel- late cells (Ito cells, fat-​storing cells), and pit cells (intrahepatic lymphocytes) (Table 15.20.1). These cells each differ in morph- ology, patterns of function, reactions to stimuli and disease, and expression of surface molecules and receptors. Interplay between these cells is critical, with communication via tight junctions al- lowing complex modulation of hepatocyte growth and function by sinusoidal lining cells. Parenchymal cells may clear mediators, including cytokines, secreted by endothelial lining and Kupffer cells. Waves of cellular activity may pass down the length of si- nusoids. Importantly, some cells show heterogeneity of function relative to their zonal location. Periportal hepatocytes differ from Table 15.20.1  Hepatic parenchymal cellular elements and physiological functions Cell type Percentage of parenchyma Surface receptors Cellular functions Hepatocytes 94 Asialoglycoprotein receptors,
IL-​6, cytokine receptors, albumin, transferrin, mannose, annexin,
MHC class 1, Fas ligand Maintain glucose, amino acid, ammonia, and bicarbonate homeostasis. Bile acid synthesis and transport. Synthesis of most plasma proteins. Processing of absorbed nutrient fuels and xenobiotics. Lipoprotein metabolism. Processing of hormones and signal mediators Endothelial lining cells 2.5 Scavenger receptor, Fc IgM, MHC class II (CD4), CD58, thrombospondin receptor Acts as physical barrier lining to sinusoids allowing passage of molecules via fenestrations up to 100 nm or numerous pinocytotic vesicles. Receptor-​mediated uptake of HDL, LDL by scavenger receptor. May express numerous adhesion molecules marginating leucocytes and lymphocytes to sites of inflammation Kupffer cells 2 KP-​1, (CD68), Fc and complement receptors, VCAM, ICAM-​1 Phagocytosis of numerous particles including cellular debris, denatured albumin, bacteria, complement. After stimulation, release inflammatory mediators: oxygen radical species, nitric oxide, proteases, TNFα, IL-​1, IL-​6, IL-​10, TGFβ, prostanoids, interferons Stellate, fat storage, or Ito cells 1.4 Retinoid, cytokine receptors, platelet-​derived growth factor,
TGFβ, endothelin receptor Vitamin A storage. Under a wide range of stimuli, including TNFα, TGFβ, acetaldehyde, CCL4, prostanoids, cytokines, and oxygen species, transform into myofibroblasts. Secrete extracellular matrix proteins after activation (collagen, fibronectin, laminin, chondroitin sulphate, hyaluronic acid) resulting in fibrogenesis. Activated transformed stellate cells control sinusoidal blood flow Pit cells 0.1 CD2, CD18 Natural killer cell activity that may be directed against tumour cells and virus-​ infected cells and occurs without prior activation Tight Endothelial cell process Kupffer cell Basolateral hepatocyte membrane with microvili junction Stellate cell Lateral membrane Endothelial lining cell Disse space Fig. 15.20.5  Hepatic sinusoid, sinusoidal cells, and functional spaces.

15.20  Structure and function of the liver, biliary tract, and pancreas 3037 perivenous cells in both the direction of carbohydrate metabolism and ammonia/​glutamine synthesis. Ito cells show zonal differ- ences in desmin and cytokeratin staining, vitamin A storage, and α-​smooth muscle actin. Endothelial lining cells These cells are central to the processes that control entry and exit trafficking of molecules from the sinusoidal flow into the Disse space. Fenestrae with a diameter of 100 nm, occupying up to 8% of the sinusoidal surface, act as a physical barrier to access of par- enchymal cells by large molecules including lipids, cholesterol, vitamin A, and possibly some viruses. Endothelial cells also pos- sess numerous specialized endocytotic mechanisms, some linked to specific receptors including mannose, transferrin, caeruloplasmin, modified high-​density lipoprotein (HDL), low-​density lipoprotein (LDL), glucosaminoglycans, and hyaluronic acid. Nonspecific endo- cytosis of molecules and small particles up to 0.1 µm also occurs. Endothelial cells are also capable of expressing a range of surface adhesion molecules including E-​ and P-​selectins, intercellular ad- hesion molecule 1 (ICAM-​1), and lymphocyte function-​associated antigen-​4 (LFA-​4) that enhance polymorphonuclear leucocyte and lymphocyte adherence, activation, and migration towards sites of inflammation. Kupffer cells These cells represent part of the mononuclear phagocyte system and are adherent to the sinusoidal surface of endothelial lining cells, predominantly in a periportal distribution. Covered with nu- merous microvilli and with a number of intracytoplasmic vesicles, their main function is to phagocytose a range of particulate ma- terial including cellular debris, senescent red blood cells, parasites, bacteria, endotoxin, and tumour cells. Phagocytosis is via a range of mechanisms including coated pits, macropinocytotic vesicles, and phagosomes aided by opsonization of particles by fibronectin or opsonin. Kupffer cells may be activated by molecules including Escherichia coli endotoxin, interferon-​γ, tumour necrosis factor-​ α (TNFα), and arachidonic acid as well as zymosan and phorbol myristate to release a range of inflammatory mediators that include oxygen radical species, nitric oxide, proteases, TNFα, interleukins 1, 6, and 10 (IL-​1, -​6, -​10), transforming growth factor-​β (TGFβ), prostanoids, and interferon-​α and -​γ. Some of these may act in an autocrine or paracrine loop to further activate other Kupffer cells. These inflammatory products have a range of effects including sig- nificant modulation of parenchymal cell function (downregulation of albumin synthesis and upregulation of acute-​phase protein gene expression), and induction of adherence of polymorphonuclear leucocytes and lymphocytes to endothelial lining cells due to en- hanced expression of endothelial adhesion molecules. Lymphocytes Lymphocytes are present in large numbers in the normal human liver. All subsets are represented (NK, NKT, CD4+, and CD8+ cells). Some are terminally differentiated and others naïve, traf- ficking through the liver in search of antigens. In inflammatory disease processes, lymphocyte recruitment increases. The pattern of recruitment is variable and provides distinct inflammatory pat- terns. For example, portal-​based inflammation in primary biliary cholangitis and primary sclerosing cholangitis, and parenchymal inflammation in autoimmune hepatitis and infection with hepa- titis viruses. Hepatic stellate cells Stellate cells (Ito cells, fat-​storing cells) have a similar morphology to fibroblasts with the addition of fat droplets, and are located within the Disse space. A fine branching array of cytoplasmic processes circle sinusoids under the endothelial cells. Stellate cells contain most of the body’s stores of vitamin A. Retinoids are taken up from chylo- microns by specific receptors on hepatocytes and stellate cells and stored within the latter. These cells are central to the process of hep- atic fibrogenesis, responding to mediators released by parenchymal and Kupffer cells, causing transformation into myofibroblasts. TGFβ initiates this process, stimulating production by the transformed stellate cell of extracellular matrix products (collagen types I, III, and IV, fibronectin, laminin, chondroitin sulphate, and hyaluronic acid) in addition to products for matrix degradation (collagenase, metalloproteinase, and its inhibitor TIMP-​1). Activation of stellate cells is also an important mechanism for control of sinusoidal perfu- sion, through cytoskeletal actin within branching cellular processes beneath the endothelium. Pit cells Similar to large granular lymphocytes and located in clefts within endothelial lining cells, pit cells have natural killer cell properties with spontaneous activity against tumour cells in the absence of prior activation. They may also play a role in hepatic regeneration. Physiological processes Hepatic blood flow The liver receives approximately 25% of cardiac output, one-​third from the hepatic artery and two-​thirds from the portal vein with a plasma flow at rest of 1600 ml/​min in women and 1800 ml/​min in men. Hepatic blood flow increases after feeding and with expir- ation and decreases with standing, inspiration, and sleep. In con- trast to other organs, metabolic autoregulation of blood flow is not observed. Changes in hepatic oxygen consumption do not seem to control hepatic blood flow. Vascular autoregulation of hepatic Table 15.20.2  Physiological effects of neurotransmitters and hormones on biliary function Contraction Relaxation Gallbladder motility Acetylcholine Secretin Cholecystokinin Glucagon Motilin Vasoactive intestinal peptide β-​Adrenergic agents Pancreatic polypeptide Endorphins Sphincter of Oddi Secretin Cholecystokinin Motilin Vasoactive intestinal peptide β-​Adrenergic agents Pancreatic polypeptide

section 15  Gastroenterological disorders 3038 arterial blood flow mediated by adenosine is present, but may not be of great physiological importance. Hepatic arterial resistance in- creases with increasing hepatic venous pressure due to a stepwise myogenic response in the hepatic artery to increased pressure. There is an important reciprocity between portal venous and hep- atic arterial flow with a reduction in portal venous input being asso- ciated with a significant compensatory decrease in hepatic arterial resistance and rise in arterial flow. The mechanism for this relation- ship is unproven but may be due to adenosine-​mediated arterial vasodilatation. The portal venous system is passive, without pressure-​dependent autoregulation, and the major physiological factors controlling flow are those modulating supply to the intestines and spleen. The sites of portal venous resistance are not fully defined in humans but may be at sinusoidal or postsinusoidal levels. The significant capacitance of the hepatic circulation, with blood comprising up to 20% of liver volume, is reflected in the important role of the liver and splanchnic circulation in acting as a blood reservoir. Sympathetic nerve stimulation may reduce hepatic blood volume by up to 50%. Sinusoidal perfusion Blood pressure in sinusoids ranges from 4.8 to 1.7 mmHg, with flows of 270 to 410 ml/​s. There is likely to be considerable hetero- geneity of the unidirectional sinusoidal flow, control for which can be considered as either passive (haemodynamic) or active. Passive control mechanisms include (1) the arterial input pressure and flow at the level of the arteriosinous twig at the origin of the sinusoid; and (2) changes in right atrial pressure, central venous pressure, and hepatic venous pressure that are transmitted to the sinusoid from the centrilobular veins. Active control mechanisms include (1) the presence of ‘functional’ sphincters at the inlet and outlet of the sinusoid due to indentations by the cell bodies of si- nusoidal lining cells, which under different physiological stimuli may change dimension and alter sinusoidal perfusion; (2) plug- ging by leucocytes, which are less compressible than erythrocytes and may under physiological stimuli adhere to endothelial lining cells; (3) activation of Kupffer cells within sinusoids and release of other vasoactive mediators including nitric oxide, cytokines, and prostanoids; and (4) transformation of hepatic stellate cells into activated contractile myofibroblasts that constrict the sinusoidal lumen. Sinusoidal flow will also affect the transendothelial traffic into and out of the Disse space by the processes of forced sieving and endothelial massage that may affect, respectively, the passage of lipoprotein particles and the appropriate mixing of the inter- stitial fluid. Therefore, sinusoidal flow is likely to have a profound effect on numerous hepatic metabolic functions and clearance of xenobiotics. Bile formation The formation of bile by hepatocytes and its modification by bile ductular epithelium serves many functions (Table 15.20.3). In hu- mans, the daily production of 600 ml of bile is made up of 75% of canalicular origin and 25% from ductules. Bile is formed by osmotic filtration, with the secretion of the two primary bile salt anions, taurine and glycine conjugates of cholic acid and chenodeoxycholic acid, across the canalicular membrane by an active transport mech- anism against a concentration gradient of 5000:1 (Fig. 15.20.6). Negatively charged intercellular tight junctions prevent back diffu- sion of these anions, allowing the selective passage of cations, pre- dominantly sodium, and to a smaller extent potassium, calcium, and magnesium, followed by the passive transit of water, transcellularly Table 15.20.3  Physiological functions of bile Digestion Neutralization of duodenal pH Bile salt activation of lipase, formation of micelles Emulsification, lipolysis, and solubilization of fat Absorption of fat-​soluble substances Excretion, including xenobiotics Cholesterol Bilirubin Drugs Environmental toxins Heavy metals Mucosal immunity Secretory IgA Cholic acid Cholesterol Bilirubin glucuronide Organic cations Phospholipid NTCP Basolateral membrane Conjugated bile salts Glutathione Chenodeoxycholic acid OATP GSHT MDR3 MDR1 BSEP cMOAT Enterohepatic circulation Canalicular membrane Conjugated bile salts Bacterial action Ileum and colon Lithocolic acid Deoxycholic acid Fig. 15.20.6  Bile salt metabolism and enterohepatic pathway. ATP-​ dependent bile export—​bile salt-​dependent bile flow; BSEP, bile salt export pump; GSHT, glutathione transporter—​glutathione transport independent of bile flow; MDR1, multidrug resistance—​organic cation, xenobiotic export; MDR2, bilirubin glucuronide export—​bile salt-​ independent bile flow; MDR3, multidrug resistance—​translocation of phosphatidylcholine; NTCP, Na-​taurocholate cotransporters—​conjugated bile salt uptake from portal blood; OATP, organic anion transporter—​bile salt, organic anion, and amphipathic solutes uptake.

15.20  Structure and function of the liver, biliary tract, and pancreas 3039 or between cells. The resulting bile salt-​dependent bile flow makes up 50% of canalicular bile flow, with the remaining bile salt-​ independent flow resulting from the active secretion of bicarbonate and glutathione. Bile in biliary ductules is further modified by reabsorption of glucose, amino acids, and bile salts, as well as active secretion. Reabsorption of bile salts, the cholehepatic shunt pathway, occurs after their protonation in bile with the generation of further bicar- bonate into bile stimulating bile flow. Active secretion of bicarbonate and chloride within ductules is mediated by the secretin receptor and the cystic fibrosis transmembrane receptor. Gallbladder epithe- lium further modifies and concentrates bile by an active anion trans- port process. Bile salt conjugates secreted from hepatocytes into bile are deconjugated in the jejunum and ileum with reabsorption and re- uptake by the liver—​this enterohepatic circulation conserves bile acids and maintains their high concentration within bile. The 5% of bile acids passing through the ileocaecal valve are fully deconjugated by colonic bacteria and reabsorbed as the secondary bile acids deoxycholic acid and lithocholic acid, which are in turn secreted as taurine and glycine conjugates. Metabolic processes Hepatic metabolic processes have a central role in protein, carbohy- drate, and lipid metabolism and fuel economy, orchestrating a di- verse interplay between central splanchnic and peripheral organs. Interruption to these processes results in the major metabolic con- sequences of acute and chronic liver disease. Modulation of these metabolic processes can occur at a number of levels. Transport of molecules across membranes and through cells is an important control mechanism as are rate-​limiting enzyme levels, controlled at a number of transcriptional and translational points. There is im- portant zonal heterogeneity of hepatocyte function, with periportal zone 1 cells with a higher oxidative capacity and larger mitochondria involved in gluconeogenesis, β-​oxidation of fatty acids, amino acid catabolism, ureagenesis, cholesterol synthesis, and bile secretion, whereas perivenular cells are more involved with glycolysis, lipo- genesis, ammonia clearance with glutamine synthesis, detoxifica- tion, and biotransformation. Bilirubin metabolism The first step in the production of bilirubin is the formation of biliverdin IXa by the action of haem oxidase on haem-​containing proteins including catalases, cytochromes, as well as haemo- globin in senescent red cells, with the release of carbon monoxide and Fe2+. Biliverdin convertase within the cytosol reduces bili- verdin to unconjugated bilirubin (Fig. 15.20.7). Both biliverdin convertase and haem oxidase are predominantly found within reticuloendothelial cells. Bilirubin is transported within plasma bound with high affinity to albumin. A few substances may displace bilirubin from albumin, including sulphonamides and fatty acids. Unbound bilirubin, which is insoluble in water, is present only in nanogram quantities but may cause significant cellular toxicity in neonates and in the Crigler–​Najjar syndrome. Bilirubin uptake by hepatocytes occurs via an organic anion-​ binding protein receptor. Within the hepatocyte, the unbound bilirubin is transported by organelles and a number of transport proteins including glutathione-​S-​transferase (ligandin) to the endo- plasmic reticulum. This reduces back diffusion into sinusoids of the lipid-​soluble unbound bilirubin. Glucuronidation to the mono-​ and diglucuronides renders bilirubin water soluble. Secretion across the canalicular membrane occurs at the canalicular multispecific membrane organic anion transporter. Bile salt metabolism In addition to their role in digestion, bile acids are the principal mechanism for clearance and metabolism of cholesterol, which acts as a substrate for their synthesis and in turn promotes biliary cholesterol secretion as lamellar vesicles. The first step in bile acid synthesis is rate limiting and involves cholesterol 7α-​hydroxylase. Transcriptional control of the cholesterol 7α-​hydroxylase gene has been demonstrated with thyroxine and glucocorticoids increasing, and glucagon decreasing, gene expression. Preformed (nondietary) cholesterol and bile acids may also control this enzyme. The close association between bile acid and cholesterol metabolism is reflected in the often parallel activation of 7α-​hydroxylase and HMG-​CoA reductase, which is of critical importance in bile acid synthesis. The two major bile acids, cholic acid (60% of bile acid pool) and chenodeoxycholic acid, are secreted into bile as taurine and glycine conjugates. The transport receptors for both uptake into hepato- cytes and transport across the canalicular membrane are controlled at both transcriptional and post-​transcriptional levels by multiple factors including bile acids, cytokines, and hormones. Nuclear re- ceptors such as the farnesoid X and liver X receptor also regulate transcription. Carbohydrate metabolism The liver has a central role in maintaining blood glucose within a narrow margin. During fasting, hepatic glucose release is contrib- uted to by both glycogenolysis (33%) and gluconeogenesis (67%) Fig. 15.20.7  Metabolism of haem and bilirubin with clearance through canalicular membrane to bile.

section 15  Gastroenterological disorders 3040 from lactate, pyruvate, glycerol, and the glucogenic amino acids alanine and glutamine (Fig. 15.20.8). This process is regulated by at least four levels: (1) hormonal control, with glucagon accounting for up to two-​thirds of basal fasted glucose output, and cortisol, growth hormone, and catecholamines also contributing; (2)  the supply of substrates, fatty acids, lactate, pyruvate, and amino acids for hepatic gluconeogenesis; (3) metabolic regulation of hepatic en- zyme activity; and (4) the degree of hepatocellular hydration. The direction of gluconeogenesis or glycogenolysis is controlled at the level of three paired enzyme cycles—​glucose/​glucose 6-​phosphate, fructose 6-​phosphate/​fructose 1,6-​bisphosphate, and pyruvate/​ phosphoenolpyruvate. In contrast, after a glucose load, insulin sup- presses hepatic glucose release and activates glucose synthetase, while autoregulation of hepatic glucose extraction by glucose itself within the portal venous circulation is an important factor in con- trolling the distribution of the load between liver and peripheral tissues. Amino acid and ammonia metabolism The liver is the most important organ in controlling the plasma concentration of amino acids. During prolonged starvation, hep- atic proteolysis stimulated by glucagon increases splanchnic export of amino acids, whereas during the postprandial absorptive state, amino acid uptake is significantly increased. The gluconeogenic amino acids are preferentially extracted and metabolized, whereas the branched-​chain amino acids valine, leucine, and isoleucine are only cleared in the liver for protein synthesis and are catabolized in the muscle. During sepsis and under the influence of cytokines IL-​1, IL-​6, and TNFα, the liver may significantly enhance gluconeogenesis and protein synthesis of acute-​phase reactants (C-​reactive protein, serum amyloid A). The liver has a critical role in clearing portal venous ammonia generated within the gut lumen, by both formation of carbamoyl phosphate and entry into the urea cycle in periportal hepatocytes, and glutamine synthetase-​driven glutamine synthesis in perivenous hepatocytes. Protein synthesis Most circulating plasma proteins with the exception of immuno- globulins and von Willebrand factor are produced by hepatocytes. The major controlling factors for this constitutive protein secretion are substrate delivery and the degree of hydration of hepatocytes. Acute-​phase protein secretion is also specifically controlled by cyto- kines with a reciprocal relationship to albumin and other carrier protein synthesis. Lipid and lipoprotein metabolism Figure 15.20.9 gives a simplified picture of lipoprotein metab- olism. Plasma lipoproteins are particles with an outer layer of cholesterol, phospholipids, and apoproteins and an inner core of cholesterol esters and triglycerides. The various lipoproteins differ in the relative proportions of these elements. Dietary-​derived chylomicrons, consisting of more than 90% triglyceride, are pro- cessed within muscle and adipose tissue by lipoprotein lipase, ex- tracting free fatty acids and the remnant, enriched in cholesterol, are extracted by the liver—​an exogenous lipid pathway. During carbohydrate feeding, free fatty acids formed within the liver are exported as very low-​density lipoprotein (VLDL) and taken up by muscle and adipose tissue with extraction of free fatty acids, leaving intermediate-​density lipoprotein and subsequently LDL. Specific LDL receptors on hepatocytes or scavenger receptors on Kupffer cells remove LDL where cholesterol may be utilized for bile salt metabolism or excreted into bile. Peripheral LDL receptors in Glut-2 Transporter Glucose Alanine Glycogen Mitochondria Glucose 6-phosphate Fructose 6-phosphate Fructose 1,6-phosphate Phosphoenolpyruvate Glucose 1-phosphate Lactate Pyruvate Oxaloacetae Pyruvate Oxaloacetae Fig. 15.20.8  Carbohydrate metabolism and pathways for glycolysis and glycogenesis. Lipoprotein lipase Bile acids/cholesterol LDL receptor Dietary fat Intestine Oxidized LDL VLDL Free fatty acid MUSCLE and ADIPOSE TISSUE IDL Chylomicrons Remnant receptor LDL receptor Chylomicron remnants Scavenger receptor LDL Scavenger receptor HDL Lecithin; cholesterol acyltransferase (LCAT) EXTRAHEPATIC TISSUES Fig. 15.20.9  Lipoprotein metabolism.

15.20  Structure and function of the liver, biliary tract, and pancreas 3041 extrahepatic tissues also extract cholesterol. Export of cholesterol from peripheral tissues in HDL is modified in plasma by lecithin; cholesterol acyltransferase and LDL is formed for further recircu- lation. Further details can be found in Chapter 12.6. Pancreas Structure and function A retroperitoneal organ receiving arterial supply from splenic, su- perior mesenteric, and gastroduodenal arteries, the pancreas is com- posed of an exocrine portion centred on acini producing digestive enzymes draining through a ductal system into the duodenum, and the islets of Langerhans which make up 1 to 2% of the whole volume and are predominantly located along arterioles. Development and congenital anomalies The pancreas develops from ventral and dorsal buds of the primitive duodenum. With rotation around the duodenum, the two portions fuse together and the duct originating from the dorsal portion (duct of Santorini) forms the accessory duct while the main drainage of the gland is through the duct of Wirsung to the ampulla of Vater. Failure of ductal fusion, pancreas divisum, in which most of the gland drains through the duct of Santorini to the minor papilla, occurs in approximately 8% of the population, and in a small pro- portion may lead to recurrent acute pancreatitis. Annular pancreas results from pancreatic tissue remaining wrapped around the duo- denum during rotation of the ventral portion. Ectopic pancreatic tissue may occur in a submucosal location within the stomach and duodenum. Exocrine pancreas The pancreas secretes up to 2 litres of fluid per day although resting secretion rates are very low (0.3 ml/​min). Acini are located in lob- ules draining into extralobular ducts. Cells lining the ducts se- crete bicarbonate, the major anion within pancreatic juice. The acinar cells are pyramidal with the nucleus and endoplasmic re- ticulum towards the base and zymogen storage granules towards the apex and draining duct. Two classes of proteolytic enzymes are secreted—​the serine proteases and the exopeptidases. Serine proteases all require activation either by intestinal endopep- tidase in the case of trypsinogen or by trypsin itself in the case of chymotrypsin, elastase, and protease E. Serine protease act at various cleavage points whereas the carboxypeptidases A and B (exopeptidases) cleave C-​terminal amino acids. The lipolytic en- zymes include phospholipase A2, lipase, and carboxylesterase. Other proteins found in pancreatic secretions include lysosomal proteins, ribonucleases, and amylase. Control of the secretory process involves hormones as well as sympathetic and parasympathetic nerve fibres. Secretin is the main stimulus to ductal bicarbonate secretion, whereas cholecystokinin, acetylcholine, and to a lesser extent gastrin and neurotensin stimu- late zymogen release of digestive enzymes at the apical membrane. Although often described as having cephalic, gastric, and intestinal phases to indicate the origin of the pancreatic stimulus, this dis- tinction is physiologically artificial since the phases run concur- rently. Somatostatin and glucagon inhibit pancreatic proenzyme secretion. Endocrine pancreas The islets of Langerhans represent an endocrine organ consisting of four cell types: α cells secreting glucagon, β cells secreting insulin, δ cells secreting somatostatin, and PP cells secreting pancreatic poly- peptide. The β cells constitute 80% of islet volume and form the cen- tral core around which the others cells form a mantle. The principal physiological function of these cells is to maintain stable glucose concentration irrespective of substrate delivery. The β cells act as a sensor of glucose concentration over a wide range, with rapid equilibration of glucose levels across the cell membrane by the GLUT-​2 transporter. The molecular basis for this sensor is considered to be glucokinase, the activity of which closely follows glucose levels. Enhanced glucose metabolism in- creases ATP/​ADP ratios, which in turn blocks potassium ion channels, and the subsequent change in membrane potential allows an influx of calcium that promotes exocytosis of insulin-​ containing granules. Many other hormones, neuropeptides, and neurotransmitters also modulate glucose-​dependent insulin se- cretion (Table 15.20.4). Table 15.20.4  Source and metabolic control of pancreatic endocrine function Source Stimuli for release Inhibitors of release Physiological role Insulin B cells Glucose, leucine, inosine, sulphonylureas Secondary stimuli: free fatty acids, arginine, alanine, acetylcholine, glucagon, GIP Hypoglycaemia, adrenaline, noradrenaline, somatostatin, insulin-​like growth factor Increases rate of transport of glucose across cell membrane Enhances glycogen synthesis and inhibits gluconeogenesis; increases protein, triglyceride, and VLDL synthesis in hepatocytes Enhances protein and glycogen synthesis in muscle cells Enhances triglyceride deposition and inhibits lipolysis in adipocytes Glucagon A cells Glucose, catecholamines Secondary stimuli: glutamine, alanine, arginine, vasoactive intestinal peptide Insulin, somatostatin Stimulates glycogenolysis. Promotes gluconeogenesis from amino acids. Increases lipolysis in adipose tissue Somatostatin D cells Glucose, arginine, GIP, glucagon, sulphonylureas Sympathetic nerve stimulation Suppresses pancreatic exocrine release of insulin and glucagon Reduces gastric motility Inhibits growth hormone-​releasing hormone Pancreatic polypeptide PP cells Protein intake, sympathetic nerve stimulation ? Probable inhibition of pancreatic acinar and ductal secretion GIP, glucose-​dependent insulinotropic polypeptide.

section 15  Gastroenterological disorders 3042 FURTHER READING Balabaud C, et al. (1988). Light and transmission electron microscopy of sinusoids in human liver. In: Bioulac Sage P, Balabaud C (eds) Sinusoids in human liver; health and disease, pp. 87–​110. Kupffer Cell Foundation, Rijswik. Erlinger S (1993). Intracellular events in bile acid transport by the liver. In: Tavoloni N, Berk PD (eds) Hepatic transport and bile se- cretion: physiology and pathophysiology, pp. 467–​75. Raven Press, New York. Fiorucci S, Distrutti E (2019). The pharmacology of bile acids and their receptors. Handb Exp Pharmacol, doi: 10.1007/164_2019_238. Gumucio JJ (1999). Functional organisation of the liver. In: Bircher J, et al. Oxford textbook of clinical hepatology, pp. 437–​46. Oxford University Press, Oxford. Kang S, Davis RA (2000). Cholesterol and hepatic lipoprotein assembly and secretion. Biochim Biophys Acta, 1529, 223–​30. Knook DL, Wisse E (eds) (1982). Sinusoidal liver cells. Elsevier, Amsterdam. Lefkowitch J (2018). Anatomy and function. In:  Dooley JS, et  al.
(eds) Sherlock’s diseases of the liver and biliary system, 13th edition, pp. 1–​16. Wiley-​Blackwell, Chichester. Tukey RH, Strassburg CP (2000). Human UDP-​glucuronosyltransferases: metabolism, expression, and disease. Ann Rev Pharmacol Toxicol, 40, 581–​616.

15.21 Pathobiology of chronic liver disease 3043 W

15.21 Pathobiology of chronic liver disease 3043 Wajahat Z. Mehal

ESSENTIALS Chronic liver disease is responsible for most of the clinical burden of liver disease. Chronic liver injury can occur via a variety of mech- anisms, including sterile inflammation and activation of innate and adaptive immunity. Despite the diversity of disease aetiologies and the ability of the liver to regenerate, a significant minority of patients with chronic liver disease proceed to liver fibrosis and eventually cir- rhosis, which is defined histologically by regenerative hepatocyte nodules surrounded by fibrous bands of matrix. Ongoing liver injury stimulates the development of a myofibroblast cell type which is responsible for matrix remodelling, haemodynamic changes, and immune cell regulation. This typically results in repair without significant modification of the basic liver structure. In a few subjects, this repair process results in alterations of the basic structure of the liver with loss of hepatocyte mass, deposition of collagen, and the development of hypertension in the portal venous system. Although cirrhosis is well defined histologically, there is a spec- trum of severity. In early cirrhosis, patients are asymptomatic but with increasing derangement in hepatic function and portal hypertension, patients can decompensate and develop ascites, coagulopathy, en- cephalopathy, jaundice, renal failure, oesophageal varices, and spon- taneous bacterial infections. Management is focused on removing or reducing ongoing liver injury, and managing cirrhosis-​related complications by the use of low-​salt diets, diuretics, β-​blockers, endoscopic therapy, vasopres- sors, and antibiotics. There is, as yet, no definite role for antifibrotic medications. Introduction The clinically relevant outcomes of chronic injury to the liver paren- chyma are directly dependent on the development of liver cirrhosis or hepatocellular cancer, which is usually secondary to the develop- ment of cirrhosis. Chronic parenchymal injury to the liver stimu- lates a number of adaptive changes including ongoing hepatocyte proliferation, immune cell infiltration and activation, myofibroblast differentiation, and matrix remodelling. These adaptive changes appear universal, but result in the development of cirrhosis in approximately 20% of patients. The aetiology, severity, and duration of the injury are important, as are poorly defined genetic factors, and the presence of more than one insult seems to accelerate the rate of disease progression. Therapies for cirrhosis are under development, some targeting the individual diseases and others seeking to prevent or modify fibrosis. Removal of scar tissue from a fibrotic organ would still leave a dam- aged organ, but the liver may be uniquely suited for antifibrotic ther- apies due to its well-​known capacity to regenerate. For hepatocellular cancer, reducing the burden of cirrhosis is likely the best preventa- tive approach, but current therapies are focused primarily on man- agement after hepatocellular cancer has developed, rather than reducing the risk of hepatocellular cancer development. Aetiology and pathogenesis of liver injury Globally the major aetiological factors for chronic liver disease are viral hepatitis (B and C), alcoholic steatohepatitis, and nonalcoholic steatohepatitis (NASH). Analysis of chronic liver injury by hepatitis B virus (HBV) and hepatitis C virus (HCV) is an exercise in simi- larities and differences. The contrasts are that most adults infected by HBV mount an effective immune response and clear viraemia within 6 months, whereas for HCV chronic infection is typical. After loss of HBV viraemia, subjects maintain a replication capable strand of HBV DNA in the hepatocyte nucleus, but loss of HCV viraemia can result in a total loss of virus. Of relevance to liver injury, both vir- uses are not cytopathic, and liver injury and subsequent adaptive re- sponses are due to the immune response initiated by viral infection. Liver injury in chronic HBV infection In addition to not being cytopathic, HBV also has a low ability to initiate innate immune responses (natural killer (NK) and nat- ural killer T (NKT) cells). In most patients, however, there is a multispecific CD8+ and CD4+ T-​cell response, and also the produc- tion of neutralizing autoantibodies. In the absence of neutralizing antibodies, there is chronic infection and usually the persistence of some degree of a T-​cell response. The CD4+ T-​cell response is important in maintaining a CD8+ and B-​cell response, and the CD8+ T-​cell response is key to the production of antiviral cytokines (predominantly interferon (IFN)-​γ), and crucially cytotoxicity 15.21 Pathobiology of chronic liver disease Wajahat Z. Mehal

section 15  Gastroenterological disorders 3044 towards hepatocytes. The scale of the anti-​HBV T-​cell response is modified by a number of viral components, including the hepa- titis B surface antigen and hepatitis B envelope antigen. The site of priming of the CD8+ T cells determines functional capacity of the activated CD8+ T cell, with antigen presentation by nonprofessional antigen-​presenting cells such as hepatocytes resulting in a low level of cytotoxicity, generically referred to as exhaustion. A sig- nificant mechanism in the exhausted phenotype is the absence of costimulatory molecules such as programmed cell death 1 (PD1) on the antigen-​presenting cell. CD8+ T cells have a key role in clearing HBV from infected hep- atocytes via cytolytic and noncytolytic means, and are likely the drivers of liver injury in chronic HBV infection. CD8+ T cells spe- cific for viral antigens temporarily stop in the sinusoids using plate- lets as an intermediaries to bind to the sinusoidal endothelium. From this position they can make contact with multiple hepatocytes and sample if individual hepatocytes are expressing an antigen/​major histocompatibility complex with affinity for their T-​cell receptor. An adequate recognition will result in the production of IFN-​γ and possible hepatocyte death. An important implication of this is that loss of endothelial fenestration, as occurs in chronic liver injury, may limit the ability of CD8+ T cells to clear HBV-​infected hepatocytes. Liver injury in chronic HCV infection HCV shares the lack of cytolytic action with HBV but contrasts with it in stimulating a more diverse immune response, which is subverted from being fully effective in multiple ways. One reason for this pleotropic response is that HCV is highly mutable, and mu- tants that are not targeted by the current immune response become dominant. Hepatocytes generate predominantly a type III IFN re- sponse via stimulation of a variety of nucleic acid receptors. HCV has developed multiple strategies to inhibit the production of these immune responses, including inhibition of cellular translation, degradation of signalling molecules, blocking of Toll-​like receptor (TLR)-​3 signalling, and upregulation of anti-​inflammatory path- ways. HCV infection also results in dysfunction of many immune cells, including dendritic cells, by uncharacterized pathways. There are multiple reports of HCV infection altering the function of innate immune cells such as NK and NKT cells, but a consensus has not developed. An indirect effect of modulating NK cells’ function by HCV is on liver fibrosis. For example, reduction of IFN-​γ is expected to reduce liver injury, but promote fibrogenesis. There is a HCV-​specific T-​cell response after infection, and the strength and scope of this response is a key determinant of reso- lution of infection. CD4+ and CD8+ T cells are both needed for viral clearance, and as for HBV CD4+ T cells provide a stimula- tory role for CD8+ T cells, which are responsible for cytotoxicity towards hepatocytes. In the absence of clearing acute infection, the prolonged antigenic stimulation of CD8+ T cells results in a state of functional hyporeactivity. In contrast to a clear role for CD8+ T cells in liver injury, the universally present B-​cell response results in the development of antibodies which are usually not neutralizing, and appear to have no role in the development of liver injury. Alcoholic and nonalcoholic steatohepatitis Alcoholic and nonalcoholic hepatitis are characterized by hepatocyte steatosis, ballooning, liver inflammation, and fibrosis. Nonalcoholic hepatitis is typically due to overnutrition and obesity. Both share many features, and central to the development of the disease pheno- type appears to be the presence of chronic metabolic and oxidative stress in hepatocytes, resulting in hepatocyte death. A crucial feature of the disease is the development of an inflammatory response. Such inflammation that occurs after cell death, in the absence of patho- gens, is termed sterile inflammation, and the cellular circuit respon- sible for it has been identified (Fig. 15.21.1). The term ‘damage-​associated molecular patterns’ (DAMPs) is broadly applied to self-​molecules which have the ability to ac- tivate inflammation, and these are proposed to explain immune responses to tissue injury. A large and varied number of DAMPs have been identified (Table 15.21.1). Two contrasting types of cell death are the programmed death termed apoptosis in which there is nuclear degradation and sequestration of cellular contents within plasma membrane blebs, and the unexpected and unregu- lated cell death termed necrosis in which cellular contents are ii: Damage-associated molecular patterns (damps) i: Dying cell Sensing immune cell vi: Immune- mediated injury v: Sterile inflammatory response Healthy cell iv: Inflammatory cytokines iii: DAMP receptor Fig. 15.21.1  Pathological cell death results in the production and release of DAMPs which activate specific receptors on immune cells and initiate release of inflammatory cytokines. This results in a sterile inflammatory response that exacerbates tissue injury. Table 15.21.1  Molecules associated with damage, their receptors, and potential therapies Molecule Receptor Therapy ATP P2X7 Receptor antagonists, Apyrase Cytochrome c Unknown γ-​Tocotrienol Defensins CCR6, TLR4 Antagonists and antibodies HMGB1 TLR4, RAGE Neutralizing antibodies HSP TLR4, CD14, CD91 Anti-​HSP antibodies Hyaluronic acid TLR2, TLR4 Antagonists Hyaluronidase Mitochondrial DNA TLR9, NLRP3 TLR9 antagonists DNAses Nuclear DNA TLR9 TLR9 antagonists DNAses N-​formylated peptides FPR and FPRL1 Antibodies NFPs in combination with TFAM RAGE and TLR9 TLR9 antagonists S100 proteins RAGE Blocking antibodies Uric acid Nonreceptor Xanthine oxidase inhibitor HSP, heat shock protein; RAGE, receptor for advanced glycation endproducts; TFAM, mitochondrial transcription factor.

15.21  Pathobiology of chronic liver disease 3045 relatively intact and extravasate due to disruption of the plasma membrane. In addition to physical retention of DAMPs in apop- totic plasma membrane blebs, several active processes such as deg- radation of nucleic acids and inactivation of high mobility group box (HMGB)-​1 by oxidation limit DAMP activity during apop- tosis. Immunologically silent cell death by apoptosis is dependent on the removal of apoptotic bodies by phagocytosis. In its absence, apoptotic bodies undergo secondary necrosis and lose their integ- rity with spillage of their contents including DAMPs into the extra- cellular environment. Tissue injury is frequently a combination of apoptosis and necrosis. Many DAMPs activate pattern recognition receptors (PRRs), of which TLRs are the best characterized. The function of these re- ceptors is best studied on immune cells, but they are expressed very broadly in the liver with important functions on parenchymal cells. Among the immune cells, Kupffer cells and infiltrating monocytes are key players in this inflammatory response. The inflammasome is a cytosolic multiprotein complex that is vital for the activation of caspase-​1 and initiation of many inflammatory responses. Full activation of the inflammasome machinery requires two distinct signals (Fig. 15.21.2). The first signal results in transcriptional upregulation of many molecules, including inflammasome com- ponents and (importantly) the procytokines pro-​IL-​1β and pro-​ IL-​18. This is provided by TLRs and other receptors with the MyD88 signalling domain via a NF-​κB pathway. In the absence of additional signals, the pro-​IL-​1β produced is inactive and re- mains inside the cell. A diverse range of signals can provide signal 2, including ATP via the P2X7 receptor, and reactive oxygen spe- cies. This results in caspase-​1 activation, which in turn activates by cleavage of the inflammatory procytokines pro-​IL-​1β and pro-​ IL-​18 and results in their secretion from the cell. Identification of the important role of the inflammasome has also identified down- stream pathways such as IL1-​R as key therapeutic targets in sterile liver inflammation. Pathophysiology of cirrhosis The processes resulting in liver injury described in the previous section are diverse, yet after chronic liver injury there develops a common phenotype of fibrosis and cirrhosis. Liver cirrhosis is de- fined histologically by regenerative hepatocyte nodules surrounded by fibrous bands of matrix. Traditionally, cirrhosis was also con- sidered to be irreversible, but fortunately the regenerative capaci- ties of the liver can extend to remodelling liver tissue even after the development of some types of cirrhosis. This has become evi- dent with increasing numbers of patients receiving treatment for HCV, and after weight loss in patients with NASH. It is uncertain at what point cirrhosis becomes irreversible, but irreversibility be- comes more likely as the scar thickens, becomes more acellular, and is chemically cross-​linked, all of which are associated with long-​ standing cirrhosis. Cirrhosis likely has a number of stages, but it is unclear how these can be identified and classified. The successes in demonstrating fibrosis regression, even in patients with cirrhosis, indicate that the liver has the capacity to regress scar, increasing optimism that this can be manipulated therapeutically. Understanding of the development of liver fibrosis was greatly advanced by the isolation and characterization of hepatic stellate cells (HSCs). This allowed for identification of their activation, a transdifferentiation process which converts them from vitamin A-​storing cells to proliferative myofibroblasts, resulting in their acquisition of a range of functions. Primary among these is the deposition of extracellular matrix, including collagen, during par- enchymal liver diseases. HSC activation unfolds progressively in sequential stages. The ‘initiation’ phase refers to early events that render the quiescent stellate cell responsive to a range of growth factors. Rapid induction of β-​platelet-​derived growth factor re- ceptor, development of a contractile and fibrogenic phenotype, and modulation of growth factor signalling are the cardinal features of this response. Signal-1 Transcription NLRP ASC Pro-caspase-1 Signal-2 Active caspase-1 Pro-IL-1β IL-1β IL-1β Nucleus TLR Ligand ATP P2X7 Fig. 15.21.2  Inflammasome activation requires a two-​signal process. Signal 1 results in transcriptional upregulation of procytokines and inflammasome components. Signal 2 results in assembly of the inflammasome, cleavage of caspase-​1, and activation and secretion of cytokines.

section 15  Gastroenterological disorders 3046 Initiation and progression of for HSC activation The key event in HSC activation is injury to hepatocytes or bil- iary epithelium, subsequent to which many of the factors that are known to activate immune cells can also activate HSC. These include many DAMPs, reactive oxygen species, and hedgehog ligands. The changes initiated by HSC activation can then further provide signals to maintain HSC activation, for example, the enhanced density of the extracellular matrix leads to increasing matrix stiffness, which is a significant stimulus to stellate cell activation in part through in- tegrin signalling. After initiation of activation, HSCs can then re- spond to a number of cytokines and growth factors to which they were previously inert. These signals combine to enhance HSC prolif- eration, contractility, fibrogenesis, matrix remodelling, and increase proinflammatory signalling. Despite significant overlap there are disease-​specific pathways of fibrogenesis, but details of the sequence of activation of these pathways is not yet known. Resolution of liver fibrosis Reduction in the number of activated HSCs is critical to the re- versibility of fibrosis, and activated HSCs are known to be removed by at least three processes: apoptosis, senescence, and reversion to an inactivated phenotype. The apoptosis of activated stellate cells has been documented in a rodent experimental fibrosis model, and surprisingly is a feature even during ongoing fibrosis. With removal of the injury insult, the degree of apoptosis increases. Cellular sen- escence is a genetically controlled programme preventing cell div- ision once cells exceed a finite proliferative capacity, and can also occur as a regulated process in response to the loss of proliferative signals. HSCs undergo senescence and then accumulate in experi- mental hepatic fibrosis. Senescent HSCs are also targeted by NK cells for clearance in vivo, thereby linking senescence to HSC apop- tosis. There is also evidence of reversion of activated stellate cells to a more inactivated state in rodent models of fibrosis. Although these reverted HSCs lose many of the features of activation, they have an enhanced capacity to reactivate upon re-​exposure to fibrogenic stimuli. The relative contribution of each of these pathways of re- duction of HSC number is unclear, but reversion is thought to be the dominant one. Immune regulation of liver fibrosis The innate and adaptive immune responses are central to the de- velopment of liver injury in many types of chronic liver diseases, and they also significantly modify the development of fibrosis (Fig. 15.21.3). Among the innate cell population, liver macrophages have been most thoroughly investigated and have key functions in fibrogenesis and fibrinolysis. Resident liver macrophages (Kupffer cells) are present at birth and are self-​renewing. After injury, they ini- tiate a fibrotic response via recruitment of additional innate immune cells, including large numbers of inflammatory blood monocytes. The infiltrating monocytes undergo a phenotypic change such that they resemble Kupffer cells and have the capacity to produce a wide range of cytokines, many of which have potent proinflammatory or direct profibrotic actions on activated HSCs, such as TNFα and IL-​1β, and transforming growth factor (TGF)-​β1 and PDGF-​BB, re- spectively. They also express a range of chemokines, for example, C-​ C motif ligands, which recruit myofibroblasts and other leucocytes. Due to their important role in fibrosis these ligands are great can- didates for antifibrotic therapy, indeed several strategies that try to block TGFβ1 activity have demonstrated efficacy in rodent models of liver fibrosis. These include a fully humanized anti-​TGFβ1 anti- body, soluble TGFβ1 receptors, blocking peptides, and small mol- ecules to block downstream receptor-​like kinase activity. Similarly, inhibition of several chemokines and their receptors have demon- strated antifibrotic efficacy, although these mediators affect different cell types and are involved in many process including angiogenesis, cellular proliferation, and differentiation, and their inhibition may have significant off-​target effects. When liver injury stops, liver macrophage populations that have been vital for fibrogenesis undergo a major phenotypic switch, with enhanced production of the extracellular metalloproteinase Activation Proliferation Apoptosis Profibrogenic macrophage (Ly6Chi) Proresolution macrophage (Ly6Clow) Phenotype switch Quiescent Activated Myofibroblast Apoptotic myofibroblast Natural killer cells TGFβ IL-1β Galectin 3 PDGF TRAIL MMP9 Th2/Th17 Th1 IL-13 (TGFβ) IL-4 IL-17 IFN-γ IL-12 HSC HSC Platelets TRAIL Granzyme Perforin Fig. 15.21.3  HSCs undergo activation, proliferation, and apoptosis. Many immune-​mediated factors regulate the transition between these stages.

15.21  Pathobiology of chronic liver disease 3047 enzymes to degrade the excess extracellular matrix and release of proapoptotic ligands which can induce activated HSC apop- tosis. For established fibrosis, enabling this phenotypic switch and enhancing the number of proresolution macrophages is an attractive antifibrotic approach. The relative balance of the T-​helper (Th)-​1 and Th2 T-​cell pheno- type is also an important determinant of fibrosis for innate immune and T cells. The classically proinflammatory Th1 cytokines IFN-​γ and IL-​12 are typically antifibrotic/​fibrolytic, whereas the Th2 cyto- kines IL-​4 and IL-​13 are profibrogenic. Macrophages show analo- gous M1 and M2 polarization, which is induced by similar cytokines to those responsible for Th1 versus Th2 polarization. However, there are several subtypes of M2 macrophages, with some of them possibly exhibiting antifibrotic effects, complicating simple Th1/​M1 versus Th2/​M2 polarizing approaches using cytokine blockade. Skewing towards Th1 and M1 is more attractive than general inhibition of the Th2/​M2 pathway, although this may enhance classical inflammation and tissue destruction. The two related innate immune cell populations, NK and NKT cells, have opposite effects. NK cells can limit fibrosis by inducing cell cycle arrest and apoptosis of activated HSC. Conversely, deple- tion and adoptive transfer experiments suggest that NKT cells can promote fibrogenesis, but the mechanism of their profibrotic action is not well characterized. Clinical manifestations of cirrhosis Most cirrhosis is subclinical or affects the quality of life with nonspecific symptoms such as malaise, fatigue, insomnia, and re- duced concentration that are not easily attributed to liver disease. Characteristic symptoms develop after cirrhosis has advanced to a significant degree, but there is great variability in their presenta- tion. The development of jaundice (which also occurs in acute liver injury) is the clearest indicator of liver disease and occurs when hepatocyte excretory function is severely compromised. This is vis- ible as a yellow dislocation of the skin, conjunctiva, and mucous membranes. There is a poor correlation between serum conjugated hyperbilirubinaemia and jaundice. Spider angiomas may be visible as small reddish spots, typically on the face and upper trunk, which on closer examination are a conflu- ence of dilated vessels that are fed by a single arteriole. They are due to reduced degradation of oestradiol by the cirrhotic liver. Palmar erythema is also due to this hormonal imbalance and is identified by a relative increase in erythema of the thenar and hypothenar prom- inences, compared to the central palm. On abdominal examination, percussion may reveal a reduced area of liver dullness, although this is very variable. In lean patients, the liver edge may be felt to be hard, but it is usually not tender. The development of severe portal hypertension is associated with a number of physical findings. Splenomegaly is very common but usually not clinically detectable. The development of ascites is a marker of decompensation in cirrhosis and is clinically evident as a shifting dullness on percussion or the presence of a fluid thrill. Clinical examination, however, has poor sensitivity for mild ascites, with reliable detection only when the volume is greater than 1 to 2 litres. With long-​standing, severe portal hypertension, prominent veins may been seen radiating from the umbilicus (caput medusa). Diagnosis There is a significant need for diagnostic tools for cirrhosis because pathognomonic signs are only present very late in disease. This ques- tion typically arises when the diagnosis of a liver disease has been made (e.g. HCV infection, NASH, etc.). The definitive, although still imperfect, test is the liver biopsy. The definition of cirrhosis is histo- logical, and if the tissue sample size is adequate, this is the current gold standard. Its two weak points are the very small sampling size, and the fact that doing the test is very invasive. To overcome these limitations, several noninvasive tests have been developed. These can be broadly categorized as serological or radiological. In general, these noninvasive tests have high sensitivity and specificity to dis- tinguish between normal and cirrhotic livers, but poor accuracy to differentiate between moderate and severe fibrosis. The serological markers utilize surrogates for hepatic function, or turnover of the extracellular matrix. Most have a high accuracy to distinguish between normal and cirrhotic livers, and approxi- mately 80% accuracy for distinguishing mild from moderate fi- brosis. The established radiological tests such as ultrasonography, CT, and MRI have low sensitivity, but in the presence of certain features (an enlarged caudate lobe, inhomogeneous hepatic tex- ture or surface, splenomegaly, or collateral vessels) the specificity is high. Ultrasonography is the most widely used test and can provide valuable information about gross hepatic architecture, atrophy and hypertrophy of hepatic lobes, and thrombosis in the portal system. A technique that quantifies the degree of stiffness of the liver based on the velocity of an elastic wave via an intercostally placed transmitter has been a valuable addition in assessing the degree of liver fibrosis. The velocity of a pressure wave is determined by pulse ultrasonography and correlates with liver stiffness. This test is fre- quently limited, especially in NASH patients, by morbid obesity, ascites, and small intercostal spaces, but has a higher degree of sen- sitivity and specificity for quantifying fibrosis than serological tests. Prognosis There have been many attempts at developing prognostic scoring systems and one of the earliest scoring systems—​the Child–​Pugh–​ Turcotte (CPT)—​provides fairly good prognostic information and is widely used because of its simplicity (encephalopathy, ascites, bili- rubin, albumin, and INR). It classifies cirrhotic patients into three stages, with 1-​year survival for stage A approximately 100%, stage B 80%, and stage C 45%. The more objective Model for End-​Stage Liver Disease (MELD) system (creatinine, bilirubin, INR) provides prognostic information over 3 months and is used for prioritizing for liver transplantation. Both scores are affected by medical interven- tions: CPT by management of encephalopathy and ascites, MELD by changes in creatinine, and both by infusion of albumin. The ability to treat the underlying condition clearly has the greatest impact on the prognosis of a cirrhotic patient. The other factor which is significantly associated with prognosis is obesity. In many industrially developed countries, the prevalence of obesity is around 25% and is even higher in patients with liver dis- ease. The presence of obesity is associated with faster progression to cirrhosis in HCV infection and NASH, and is also associated with a

section 15  Gastroenterological disorders 3048 greater likelihood of developing HCC, even in some precirrhotic pa- tients. Importantly, in a prospectively followed, well-​defined cohort, obesity had a deleterious effect on the evolution of compensated cirrhosis of all aetiologies, independent of portal pressure and liver function, with clinical decompensation occurring in 43% and 31% of obese and overweight patients, respectively, compared with 15% of patients with normal body mass index after a median follow-​up of 59 months. The ability of weight loss to delay the development of de- compensation in obese patients has not been proven, but it has been shown that weight loss in patients with NASH can reverse all the histological features, including fibrosis and cirrhosis in some cases. It is particularly encouraging that the weight does not need to return to the ideal, and a loss of approximately 10% is sufficient to see histo- logical improvement. Future developments One of the most active areas is the development of antifibrotic therapeutics. Approaches to antifibrotics range across a wide area of biology, from agents that limit the original injury to those that directly limit the deposition or increase the removal of fibrotic scar tissue. It is known that the extracellular matrix undergoes remodelling even after the development of cirrhosis, and the im- provement in cirrhosis after loss of liver injury by treatment of HCV or weight loss in NASH has demonstrated that cirrhosis is a dynamic state that is amenable to improvement. The great expansion in our understanding of the biology of fibrogenesis has greatly enriched the field of antifibrotic therapeutics and many antifibrotic approaches are being pursued (Table 15.21.2). These are also of much interest in other areas, and two drugs have been approved for idiopathic pulmonary fibrosis. The major limitation to progress in relation to liver fibrosis, however, is the problem of identification of valid end-​points for clinical trials: disease progres- sion occurs relatively slowly, repeated sampling by liver biopsy is not practicable, and there is no consensus on noninvasive surro- gates for liver biopsy. FURTHER READING Arulanandan A, Loomba R (2015). Non-​invasive testing for NASH and NASH with advanced fibrosis: are we there yet? Curr Hepatol Rep, 14, 109–​18. Mehal WZ (2014). The inflammasome in liver injury and non-​ alcoholic fatty liver disease. Dig Dis, 32, 507–​15. Mehal WZ, Schuppan D (2015). Antifibrotic therapies in the liver. Semin Liver Dis, 35, 184–​98. Tsochatzis EA, Bosch J, Burroughs AK (2014). Liver cirrhosis. Lancet, 383, 1749–​61. Table 15.21.2  Strategies for antifibrotic drugs Reduce HSC proliferation Immunosuppressants HMG-​CoA-​reductase inhibitors Angiogenesis inhibitors PDG-​β receptor antagonism Reduce HSC activation Inhibitors of phosphodiesterase Cytokine regulators: IFN-​α, TGFβ modulators, integrin αvβ6 antagonists PPARα, PPARγ agonists Farnesoid X receptor antagonists Histone deacetylase inhibitors

15.22 Presentations and management of liver diseas

15.22 Presentations and management of liver disease 3049

15.22.1 Investigation and management of jaundice 3

15.22.1 Investigation and management of jaundice 3049

CONTENTS 15.22.1 Investigation and management of jaundice  3049 Jane Collier 15.22.2 Cirrhosis and ascites  3058 Javier Fernández and Vicente Arroyo 15.22.3 Portal hypertension and variceal bleeding  3068 Marcus Robertson and Peter Hayes 15.22.4 Hepatic encephalopathy  3080 Paul K. Middleton and Debbie L. Shawcross 15.22.5 Liver failure  3089 Jane Macnaughtan and Rajiv Jalan 15.22.6 Liver transplantation  3100 John G. O’Grady 15.22.1  Investigation and management of jaundice Jane Collier ESSENTIALS Physiology of bilirubin Haem molecules are degraded in macrophages to biliverdin and then to bilirubin, which is selectively removed by hepatocytes from sinusoidal blood and conjugated, chiefly with two glucuronic acid moieties. Conjugated bilirubin is excreted into the bile, but in many liver diseases it refluxes back into blood from which some is filtered into and darkens the urine (choluria). In the distal intestine, conju- gated bilirubin is deconjugated and reduced to a series of uro-​ and stercobilinogens that give the normal colour to faeces. Clinical approach Jaundice is the clinical sign of hyperbilirubinaemia and usually in- dicates disease of the liver or biliary tree. Dark urine and pale stools indicate cholestasis. Stigmata of chronic liver disease do not define the cause of jaundice. Unconjugated hyperbilirubinaemia—​presents with raised serum bili- rubin levels and normal other liver-​related blood tests. Causes include haemolysis and benign inherited unconjugated hyperbilirubinaemia (i.e. Gilbert’s syndrome). Conjugated hyperbilirubinaemia—​routine liver-​related blood tests cannot alone differentiate between intra-​ and extrahepatic causes
of jaundice although high levels of transferases suggests hepa- titis (e.g. viral, autoimmune) or hepatic necrosis (e.g. paracetamol). Alcohol and drug histories are needed in those with both elevated alkaline phosphatase and transferases. Extrahepatic cholestasis should be sought by abdominal ultrasonography to detect a di- lated intra-​ and/​or extrahepatic biliary tree (and often also to reveal its cause, e.g. gallstones, tumour). Further investigation depends on the clinical context:  (1) likely large bile duct disease—​endo- scopic retrograde cholangiopancreatography, magnetic reson- ance cholangiography, and endoscopic ultrasonography; (2) likely intrahepatic cholestasis—​autoantibodies, immunoglobulins, and liver biopsy. Introduction The commonest cause of jaundice varies geographically. Biliary ob- struction due to common bile duct stones or malignancy followed by liver injury due to alcohol are the commonest reasons for jaun- dice presenting in adults in the United Kingdom in both primary and secondary care. The five key components to identifying the cause of jaundice are the history, presence or absence of hepatosplenomegaly, pattern of liver function tests, chronic liver disease screen, and ultrasound examination. 15.22 Presentations and management
of liver disease

section 15  Gastroenterological disorders 3050 Physiology of bilirubin All haem molecules in haemoglobin or cytochrome enzymes are degraded in macrophages, especially in the spleen and liver, via bili- verdin to bilirubin. Haem oxygenase breaks open the asymmetric tetrapyrrole haem molecule specifically at the α-​methene bridge, releasing carbon monoxide and iron, and forming biliverdin (Fig. 15.22.1.1). The excretion of carbon monoxide in breath can be used quantitatively to determine the breakdown of haem to bili- rubin, of which 200 to 350 mg (340–​600 µmol) is produced daily. Biliverdin is green and is directly excreted in bile by birds, am- phibians, and reptiles, but not by mammals in which biliverdin is reduced by the macrophage cytosolic enzyme biliverdin reductase, chiefly to the yellow bilirubin IXα, which has then to be excreted. Bilirubin is surprisingly lipid soluble due to internal hydrogen bonding in the molecule so that it forms a tight, nonpolar, nonlinear structure. After release from macrophages, it is firmly bound to plasma albumin, so that none enters the urine. At high concen- trations in the blood, it slowly diffuses into tissues, where it can be toxic, particularly in the neonatal brain (kernicterus) or the kidney. Jaundice is less obvious in unconjugated than in conju- gated hyperbilirubinaemia since its diffusion into the tissues is more limited. Bilirubin is readily oxidized back to biliverdin, hence the green vomit of intestinal obstruction. The normal circulating pool of bilirubin in the plasma (approxi- mately 100 µmol) is almost all unconjugated. The normal range of plasma bilirubin is wide (approximately 5–​19 µmol/​litre), reflecting wide variations in the rate of conjugation in the liver. The distribu- tion of values is Gaussian, so that the true upper limit of normal is arbitrary (see ‘Hereditary hyperbilirubinaemia’). Hepatic enzyme-​ inducing drugs, such as barbiturates, reduce the plasma level by increasing the rate of conjugation in hepatocytes and hence the plasma clearance of bilirubin. Bilirubin is selectively removed by hepatocytes from sinusoidal blood, where its uptake is facilitated by the direct contact of plasma with hepatocytes in the interstitial space of Disse through fenestra- tions in the endothelium of hepatic blood capillaries. Although up- take and excretion predominate, dynamic studies show that there is also considerable reflux of bilirubin out of the cell back into the plasma. Within the hepatocyte, bilirubin is principally conjugated by one of the two specific isoforms of the microsomal enzyme uridine 5'-​ diphosphate-​glucuronosyltransferase (UGT1A1), chiefly with two glucuronic acid moieties. Minor quantities of bilirubin are conju- gated with one glucuronic acid molecule (monoglucuronide) or with combinations of related sugars (xylose, glucose); a small amount of unconjugated bilirubin also appears in bile. The physical and chemical properties of the conjugated molecules are quite different from those of unconjugated bilirubin, for they lose the internal hydrogen bonding of bilirubin and become more linear, fully water-​soluble molecules that are efficiently excreted in bile. In many liver diseases, conjugated bilirubin readily refluxes back into blood and, since it is water soluble and less firmly bound to albumin than unconjugated bilirubin, about 1% is filtered across the glomerular membrane and darkens the urine (choluria). Hepatocytes have at least six specific active transporters at their apex for the excretion into the canaliculi of the major components of bile. Conjugated bilirubin is excreted out of the endoplasmic reticulum and then across the apical microvillous intercellular canalicular membrane into bile by the anionic conjugate transporter protein MRP2 (multidrug resistance-​associated protein 2). MRP2 also transports other multivalent anionic drugs into bile, and is also present in the renal tubule and proximal small intestine. MRP3, and probably MRP1, transport conjugated bilirubin, bile acids, and drugs back out across the basolateral sinusoidal hepatocyte mem- brane into blood, and are upregulated by increased intracellular con- centrations of bilirubin. Hence, in cholestasis, conjugated bilirubin and drugs are safely excreted into urine. The urinary excretion of conjugated bilirubin is increased by the bile acids that also accumulate in cholestasis. If renal function is normal, this renal excretion of bilirubin eventually matches its normal rate of production when conjugated bilirubin levels in the plasma reach about 600 µmol/​litre. With renal failure, or haemolysis, plasma levels rise higher little bilirubin, even if conjugated, diffuses through renal dialysis membranes. Deconjugated bilirubin can undergo a substantial enterohepatic circulation; it is absorbed from the colon, particularly when there is bile acid malabsorption and hence the concentration of bile acids in the colon is increased, for example, as a result of disease or resection of the ileum. This reabsorption then increases the concentration of bilirubin re-​excreted in bile, and may in part explain the increased incidence of pigment gallstones in patients with ileal disease. Oral ursodeoxycholic acid also increases the enterohepatic recycling of bilirubin, perhaps by solubilizing bilirubin in the intestinal lumen, or by impairing the reabsorption of other bile acids in the ileum. This may explain the rim of calcification in an outer pigment layer of cholesterol gallstones during their treatment with ursodeoxycholic acid, and thus their frequent resistance to such dissolution therapy. Similarly, fasting increases unconjugated bilirubin levels in the plasma by increasing the reabsorption of bilirubin because it reduces intestinal motility and improves absorption. HAEM Haemoglobin and other haem proteins e.g. cytochromes, myoglobin (haem oxygenase) Iron, carbon monoxide Biliverdin Bilirubin Bilirubin conjugates (glucuronyl transferase) (biliverdin reductase) Protoporphyrin IX Protoporphyrinogen IX Coporphyrinogen Ill Uroporphyrinogen Ill Porphobilinogen (PBG) δ-Aminolaevulinic acid (ALA) Glycine+ succinyI CoA Fig. 15.22.1.1  The porphyrin–​bilirubin pathway.

15.22.1  Investigation and management of jaundice 3051 In the distal intestine, conjugated bilirubin is deconjugated and reduced to a series of uro-​ and stercobilinogens that give the normal colour to faeces. Some colourless urobilinogen is nor- mally absorbed from the colon and undergoes an enterohepatic circulation, with a small amount being excreted in urine. If this biliary excretion is impaired in liver disease, or increased in haemolysis, then excess urobilinogen is excreted in urine, where it can oxidize on standing to dark brown urobilins. Urobilinogen is easily detected by routine clinical ‘stix’. Ehrlich’s aldehyde re- agent was at one time used; urine containing excess urobilinogen turns red with this reagent and the urobilinogen pigment can then be extracted into an organic solvent, such as chloroform. This is unlike the similar pigment formed from the more polar porphobilinogen adduct in acute porphyria, which remains in the upper aqueous phase. Aetiology A useful approach to investigation and managing jaundice is to think of the cause as either prehepatic, hepatic, or posthepatic (Table 15.22.1.1). Prehepatic jaundice The hallmark of prehepatic jaundice is that alanine aminotrans­ ferase (ALT) or aspartate aminotransferase (AST) and alka- line phos­phatase (ALP) levels will all be normal. Unconjugated hyperbilirubinaemia is commonest, caused by haemolysis or Gilbert’s syndrome, which is the commonest of the hereditary hyperbilirubinaemia syndromes. Haemolysis Haemolysis due to haemolytic anaemias can be differentiated from Gilbert’s syndrome by the presence of anaemia, splenomegaly, and an elevated reticulocyte count. Patients with haemolytic anaemias can also develop pigmented gallstones. Worsening of jaundice in a patient with known haemo- lytic anaemia associated with an elevated ALP level or serum trans- aminases and pain should prompt investigations to exclude bile duct stones. Other causes of haemolysis causing an unconjugated hyperbilirubinaemia include causes of a rapid breakdown in red blood cells releasing haemoglobin and saturation of bilirubin conju- gation in the liver, for example, massive blood transfusion and inef- fective erythropoiesis due to vitamin B12 deficiency. Hereditary hyperbilirubinaemia Causes of hereditary hyperbilirubinaemia are shown in Table 15.22.1.2. Gilbert’s syndrome is recessively inherited and due to reduced bilirubin conjugation by UGT in hepatocytes. Low enzyme levels are due to a variant in the TATAA box in the UGT1A1 gene promotor which is found in 8% of the population. Genetic tests are available, although the diagnosis can usually be made confidently in the presence of an isolated unconjugated bili- rubin level in the absence of haemolysis. Bilirubin levels rarely exceed 70 μmol/​litre and often increase following periods of starva- tion or with intercurrent illnesses. Crigler–​Najjar syndrome is a rarer condition, presenting with jaundice in the neonate where there is either complete absence of the UGT enzyme (type 1) or less than 10% present (type 2). The former is often fatal due to kernicterus (bilirubin encephalopathy). Dubin–​Johnson syndrome is a rarer, recessively inherited hyperbilirubinaemia where the bilirubin, unlike Gilbert’s syndrome, is predominately conjugated. It is due to a mutation in the MRP2 gene (ABCC2) encoding a canalicular transport protein for con- jugated bilirubin. Bilirubin levels can be higher than in Gilbert’s syndrome and it leads to a ‘black’ liver due to deposition of melanin-​ like pigment seen on liver histology. Some conjugated bilirubin is also transported back across the sinusoidal membrane into blood and then reabsorbed into the hepatocyte, where it is stored be- fore being secreted into the canaliculus. The inability to reabsorb this conjugated bilirubin, possibly due to mutations in the organic anion transport proteins (OATP), can also lead to a conjugated hyperbilirubinaemia. This condition is rarer than Dubin–​Johnson syndrome and is known as Rotor’s syndrome. Hepatic jaundice Causes include acute liver injury, chronic liver disease, and hep- atic infiltration. Acute liver injury such as viral hepatitis can lead (if severe) to acute liver failure with hepatic encephalopathy and coagulopathy. Pre-​existing chronic liver injury such as cirrhosis can also present with jaundice, either due to progression of the underlying condition such as chronic hepatitis C, or due to an add- itional liver injury as seen with superimposed alcoholic hepatitis on a background of alcoholic cirrhosis. This explains why jaundice is a common presentation of previously undiagnosed alcoholic liver disease. Chronic biliary disease such as primary biliary cholangitis (pre- viously known as primary biliary cirrhosis) and primary sclerosing Table 15.22.1.1  Approach to diagnosing the cause of jaundice Type of jaundice Diagnoses to consider Prehepatic Unconjugated hyperbilirubinaemia Hereditary: Gilbert’s syndrome Increased production: haemolysis Decreased uptake by hepatocytes: drugs Conjugated hyperbilirubinaemia Hereditary: Dubin–​Johnson syndrome Hepatic Acute Chronic Infiltration Drugs Viral hepatitis, i.e. A to E, CMV, EBV Autoimmune hepatitis Alcoholic hepatitisa Ischaemic hepatitis Alcohol Viral hepatitis B, C, and delta (D) Biliary disease; PBC and PSC NAFLDb Hereditary; haemochromatosisb, Wilson’s disease, α1-​antitrypsin deficiencyb Metastases; lymphoma; amyloid Posthepatic Bile duct stones Chronic pancreatitis Obstruction from malignancy IgG4 disease a Although present acutely with hepatic inflammation, 80% cases will have cirrhosis. b Jaundice uncommon until end-​stage liver disease. CMV, cytomegalovirus; EBV, Epstein–​Barr virus; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cholangitis (previously known as primary biliary cirrhosis); PSC, primary sclerosing cholangitis.

section 15  Gastroenterological disorders 3052 cholangitis may present with jaundice before the development of other complications of cirrhosis such as ascites or hepatic encephal- opathy. This is due to relatively preserved hepatocyte function, con- trasting with disease directed at hepatocytes such as hepatitis C. In contrast, jaundice is a very late symptom of end-​stage liver disease in chronic liver disease due to haemochromatosis, α1-​antitrypsin defi- ciency, and nonalcoholic fatty liver disease. Jaundice from acute-​on-​chronic liver injury can also be caused by hepatocellular carcinoma or hepatotoxic drugs. In Wilson’s disease, haemolysis may contribute to hyperbilirubinaemia in the presence of cirrhosis and lead to the clinical presentation. Posthepatic jaundice This leads to biliary obstruction and classically is associated with high ALP levels. The commonest causes are bile duct stones and malignant obstruction anywhere within the bile duct. Malignant obstruction includes cancer of the ampulla of Vater or pancreas, cholangiocarcinomas of the common bile duct or biliary hilum, ma- lignant lymph nodes at the hepatic hilum, and (rarely) intrahepatic metastases. Stones in the cystic duct can also cause external com- pression of the common bile duct, known as a Mirizzi’s syndrome. Benign causes of biliary obstruction include chronic pancrea- titis, IgG4 disease, primary sclerosing cholangitis, and (rarely) surgical injury to the bile duct as a result of laparoscopic chole- cystectomy. Biliary obstruction in primary sclerosing cholan- gitis can be due to dominant biliary structures, development of a cholangiocarcinoma, or small biliary stones, but jaundice can also occur due to progression in intrahepatic biliary disease. Other Systemic infections can be complicated by jaundice, including mal- aria and leptospirosis. Low platelets, fever, and recent travel history to an endemic area are key to the former, whereas exposure to rat-​ infested water, conjunctival erythema, and early renal dysfunction can be key to the latter. Severe systemic bacterial infections can lead to the syndrome of intrahepatic cholestasis of sepsis in which endotoxin, tumour necrosis factor, and other factors affect biliary transport pro- teins on the sinusoidal and canalicular membrane of hepatocytes, leading to jaundice associated with high ALP levels. Other sys- temic illnesses that have been associated with jaundice include untreated severe thyrotoxicosis, polymyalgia rheumatica, and sys- temic vasculitis. Clinical features History Key features from the history in determining the cause of jaundice are summarized in Table 15.22.1.3. Dark urine and pale stools are usually present in posthepatic ob- structive jaundice but can also occur in severe liver injury. The pres- ence of epigastric or right upper quadrant pain as opposed to mild abdominal discomfort is highly suggestive of common bile duct stones and is one of the most important symptoms in differentiating the cause of jaundice. Fever suggests cholangitis due to common bile duct stones, par- ticularly in the presence of rigors. A high temperature can also be seen in hepatic infiltration from lymphoma but is usually low grade in acute viral A to E hepatitis. A sore throat with systemic viral symptoms suggests Epstein–​Barr virus infection. Primary cyto- megalovirus infection can be seen in both immunosuppressed and nonimmunosuppressed adults and may be associated with diar- rhoea, high fever, and contact with young children. Weight loss is seen both in obstructive jaundice due to malig- nancy or chronic pancreatitis as a result of malabsorption, and in the catabolic state of chronic liver disease. Itching that precedes jaundice is very suggestive of chronic injury to small intrahepatic bile ducts such as occurs in primary biliary cholangitis or primary sclerosing cholangitis. Table 15.22.1.2  Causes of hereditary hyperbilirubinaemias Gilbert’s syndrome Dubin–​Johnson syndrome Rotor’s syndrome Genetic basis UGT1A1 Chromosome 2 ABCC2 Chromosome 2 SLCO1B1 and -​B3 Chromosome 2 Mechanism Low levels of hepatocyte UGT Unable to conjugate bilirubin Deficiency in the canalicular transport of nonbile acid organic anions Defective hepatic storage of conjugated bilirubin Bilirubin Fluctuating Unconjugated Usually <100 μmol/​litre Fluctuating Conjugated 50–​100 μmol/​litre but can be much higher Fluctuating Conjugated Liver histology Normal No injury Black pigment No injury Precipitants Fasting Pregnancy Oral contraceptive Oral contraceptive Diagnosis Unconjugated bilirubin in absence of haemolysis or genetic testing Urine coproporphyrins: high level of coproporphyrin type 1 Increased urine total coproporphyrins Prognosis No itching Good No itching Good No itching Good Crigler–​Najjar syndrome type 1, unlike Gilbert’s syndrome, is often fatal and is the complete inability to conjugate bilirubin by glucuronidation. ABCC2 gene encoding the canalicular export pump MRP2 (multidrug resistance-​associated protein 2); SCL01B1 and -​B3, genes encoding the sinusoidal organic acid transport proteins OATPB1 and OATPB3; UGT, uridine-​diphosphate-​5-​gluconysyltransferase.

15.22.1  Investigation and management of jaundice 3053 Drugs A detailed drug history is very important, including over-​the-​ counter medications such as nonprescribed herbal remedies and anabolic steroids which can be bought over the Internet and can cause acute liver injury. Although many drugs can cause idiosyn- cratic liver injury, common culprits include antibiotics such as co-​ amoxiclav, rifampicin/​isoniazid, nonsteroidal anti-​inflammatory drugs, antivirals such as efavirenz, immunosuppressants such as azathioprine, and high-​dose statins. Oestrogens/​progesterone at the lower doses now typically used in the oral contraceptive pill rarely cause cholestatic liver injury. The exception are individuals who carry mutations in the canalicular bil- iary transporter proteins, bile salt export pump (BSEP) or MRP3, where there is often a history of itching during pregnancy. The former is also known as benign recurrent cholestasis. Co-​amoxiclav drug-​induced jaundice differs from other drug-​ induced injury in that it can occur 4 to 6 weeks after stopping the drug. There are a few drugs where drug-​induced liver injury can occur after many months after a drug has started (e.g. tetracyclines and nitrofurantoin). These drugs cause liver injury that mimics autoimmune liver disease. Paracetamol is an example of a drug which can cause acute liver failure. Jaundice is a relatively late symptom, preceded by a marked coagulopathy and encephalopathy. The pattern of liver injury with drugs varies from cholestatic liver function tests (high ALP concentrations) to hepatitic liver function tests (high ALT concentrations) or a mixed picture, em- phasizing the importance of a drug history when investigating jaundice. Drugs can also exacerbate pre-​existing undiagnosed liver disease. Drug history should also include recent use of immunosuppressive agents. Immunosuppression with drugs such as cyclophosphamide and rituximab in the presence of chronic hepatitis B infection leads to a rise in hepatitis B virus DNA, and when immunosuppression stops and immune function improves, liver failure and jaundice can occur. Prednisolone can also lead to a flare in inflammation in chronic hepatitis B, resulting in acute-​on-​chronic liver failure. Alcohol Alcoholic liver disease is unlikely to be the only cause for jaundice in men who drink less than 50 units/​week and women who drink less than 35 units/​week for less than 5 years. However, other cofac- tors such as hepatitis C, hepatitis B, and nonalcoholic fatty liver dis- ease may pre-​exist, contributing to chronic liver disease at a lower threshold. The average alcohol intake of those presenting with alco- holic hepatitis is greater than 100 units/​week. Sexual history Unprotected sexual activity can lead to acute hepatitis B and in men who have sex with men hepatitis C can also be transmitted sexu- ally and present acutely. Travel history and history of vaccinations is important in identifying hepatitis A and E and other infections such as malaria. Intravenous drug use is a risk factor for hepatitis B, delta, and C. Other Table 15.22.1.4 lists some of the other rare causes of liver disease leading to jaundice in specific patient groups, including pregnancy and following bone marrow transplantation. Examination Clinical hepatomegaly suggests cirrhosis, hepatic infiltration, or hepatic venous outflow obstruction. The causes of hepatic infiltra- tion include hepatic metastases, primary liver cancer, lymphoma, and amyloid. The liver may be small or enlarged in cirrhosis. Stigmata of chronic liver disease such as spider naevi are often present in cirrhosis, particularly in alcoholic liver disease, but club- bing is rare. Splenomegaly may indicate portal hypertension from chronic liver disease but will also be present in haemolytic anaemia and in rarer infiltrative liver diseases such as amyloid or lymphoma. In chronic liver disease, splenomegaly is often easier to identify by ultrasonography than by palpation. Ascites may be due to malignancy or a block to venous out- flow from the liver resulting in portal hypertension. The common Table 15.22.1.3  Hints from the history and examination in the diagnosis of jaundice History Abnormal liver
function test Possible diagnosis Inflammatory bowel disease Diarrhoea ALP PSC Ethnicity/​country of birth ALT/​AST Hepatitis B/​C IV drug use/​unscreened blood transfusions ALT/​AST Hepatitis B/​C Alcohol ALT/​mixed Alcoholic disease Recent new drugs ALP or ALT Drug induced Recent immunosuppression ALT ALT/​mixed Hepatitis E CMV Travel history ALT Hepatitis A, E Sexual history ALT Hepatitis B Other autoimmune disease ALT Autoimmune hepatitis Family history ± knee/​metacarpophalangeal joint pain ± emphysema ± difficulty writing/​ concentration Haemochromatosis α1-​Antitrypsin Wilson’s disease Table 15.22.1.4  Jaundice in specific clinical contexts Clinical context Diagnoses to consider Bone marrow transplantation Hepatic veno-​occlusive disease Reactivation of hepatitis B Graft-​versus-​host disease Pregnancy (third trimester) Intrahepatic cholestasis of pregnancy Acute fatty liver disease of pregnancy HELLP/​pre-​eclampsia Bile duct stones Intensive care Intrahepatic cholestasis of sepsis Ischaemic cholangiopathy Ischaemic hepatitis Total parenteral nutrition HIV Immune reconstitution Indinavir/​ritonavir Efavirenz HELLP, haemolysis, elevated liver enzymes, and a low platelet count.

section 15  Gastroenterological disorders 3054 causes of malignant ascites associated with jaundice are gastrointes- tinal malignancies such as pancreatic cancer and gastric cancer, ei- ther through peritoneal deposits or large-​volume liver metastases which can cause portal hypertension. Ascites will be exudative in the former and transudative in the latter. Associated jaundice will be due to either biliary obstruction from the primary tumour or ma- lignant lymph nodes at the porta hepatis, or liver metastases with or without biliary obstruction. Hepatic venous outflow obstruction can be due to right heart failure or obliteration of the hepatic veins. Sinusoidal obstructive syndrome is the name given to obliteration of the hepatic veins and includes occlusion of the large hepatic veins, usually with clots (Budd–​Chiari syndrome), and obliteration of the small hepatic veins (known as veno-​occlusive disease). The latter is a complica- tion of bone marrow transplantation and other chemotherapeutic drugs. Budd–​Chiari syndrome classically presents with sudden onset of ascites and hepatomegaly and mild to moderate elevations in bilirubin. Investigation Blood tests Liver functions tests It is helpful to differentiate hepatitic liver function tests where the transaminases are differentially elevated from cholestatic liver function tests where the ALP is the main abnormal liver blood test. Hepatitic liver function tests Table 15.22.1.5 summarizes the differential diagnosis of jaundice with hepatitic liver function tests. The most important differential is between acute viral hepatitis, drug-​induced liver injury, and auto- immune liver disease. Very high ALT concentrations (often >10  000 IU/​litre) sug- gest either paracetamol overdose or ischaemic hepatitis. In para- cetamol poisoning which presents with jaundice, paracetamol has usually been taken longer than 48 h before and is undetectable in serum, and the development of liver failure is indicated by a rising prothrombin time. Ischaemic hepatitis is seen with hypo- tension in the setting of right heart failure. In both conditions, the ALT falls with time after the initial injury and is paralleled by worsening jaundice. High ALT concentrations (usually >1000 IU/​litre) suggest auto- immune liver disease, acute viral hepatitis, or drug injury. Hepatitis E is now recognized as a cause of endemic acute viral hepatitis in Northern Europe and the United States of America in the absence of a travel history. In the presence of chronic hepatitis B, superinfection with hepatitis D should be excluded. In autoimmune liver disease, as well as positive antinuclear anti- bodies and/​or smooth muscle antibodies, the IgG levels are often greater than 30 g/​litre. A liver biopsy showing plasma cells is re- quired to confirm the diagnosis. In alcoholic liver disease, there is often an elevated ALP, with AST and ALT levels rarely above 250 IU/​litre, even in the pres- ence of alcoholic hepatitis. This inflammatory response to al- cohol commonly causes jaundice but requires a liver biopsy to differentiate it from end-​stage alcoholic cirrhosis. Higher levels of ALT suggest co-​existent liver injury such as inadvertent para- cetamol toxicity. Persistently minor elevations in ALT levels (i.e. <100 IU/​litre) are common in chronic hepatitis C and B, haemochromatosis, and nonalcoholic fatty liver disease. Although jaundice in these causes of chronic liver diseases is a late symptom of cirrhosis, they can coexist with alcoholic-​induced liver disease and so should be considered in a patient with jaundice who may have cirrhosis. Haemochromatosis should be excluded by both a ferritin and a transferrin saturation, which is usually greater than 55%. The caveat is that transferrin is produced by the liver so in cirrhosis, transferrin saturation can be artificially elevated without signifi- cant iron overload. Alcohol can also increase the serum ferritin level, which falls on abstinence. The diagnosis of haemochroma- tosis is confirmed by genetic testing for the common HFE gene mutations. It is important to recognize, however, that ferritin is an acute-​phase protein and the level will be very high in patients with acute liver failure, hence it rarely helps diagnosis if the ALT con- centration is greater than 1000 IU/​litre. Nonalcoholic fatty liver disease is the commonest cause of ab- normal liver function tests in the presence of a negative chronic liver disease screen (Table 15.22.1.5), and in the absence of jaun- dice the key is to differentiate simple fatty liver disease (steatosis or nonalcoholic fatty liver disease), which is nonprogressive, from nonalcoholic steatohepatitis, which can progress to cirrhosis:  an AST level greater than the ALT level in the presence of diabetes and hypertension suggests nonalcoholic fatty liver disease. An AST/​ ALT ratio is consequently incorporated into several serological Table 15.22.1.5  Hepatitic liver function tests and the chronic liver disease screen ALT >10 000 IU/​litre Consider: Ischaemic hepatitis Paracetamol overdose ALT >500 IU/​litre Consider acute viral hepatitis: Hepatitis A IgM Hepatitis B surface antigen Monospot for Epstein–​Barr virus infection Cytomegalovirus IgM Hepatitis E IgM Consider autoimmune hepatitis: Liver autoantibodies (antinuclear antibody, smooth muscle antibody, soluble liver antigen) IgG Consider: Drug-​induced liver injury ALT< 500 IU/​litre Chronic liver disease screena Hepatitis B surface antigen Hepatitis C antibody Ferritin + transferrin saturation Liver autoantibodies (antinuclear antibody and smooth muscle antibody) Immunoglobulins α1-​antitrypsin Copper/​caeruloplasmin (if age <40)b AMAa ALT< 250 IU/​litre Chronic liver disease as above Also consider alcohol a If ALP level is elevated. b Wilson’s disease; often ALP low or normal and also haemolysis.

15.22.1  Investigation and management of jaundice 3055 noninvasive methods of assessing liver fibrosis, which are useful in assessing liver fibrosis when investigating cause of abnormal liver blood tests in the absence of jaundice. Cholestatic liver function tests (high ALP) Liver-​related causes of elevated ALP and their investigation are shown in Table 15.22.1.6. Large duct biliary obstruction is the commonest cause of cholestatic liver function tests, followed by intrahepatic biliary in- jury affecting the small intrahepatic bile ducts. Hepatic infiltration due to compression of the sinusoids also causes high ALP levels. In contrast to high ALT levels, high ALP levels are also frequently seen in extrahepatic systemic conditions such as rheumatoid arthritis and polymyalgia rheumatic, but accompanying jaundice is unusual. Bile duct stones are usually associated with pain, but they can occur without symptoms, particularly if the bile duct is very dilated. Cholangitis is a frequent associated complication which can mani- fest just as confusion in the elderly. Rigors are common as Gram-​ negative organisms usually cause sepsis. In the absence of extrahepatic biliary obstruction an anti­ mitochondrial antibody (AMA) test should be performed to ex- clude primary biliary cholangitis. This is positive in 90% of cases of primary biliary cholangitis, who are usually female. In AMA-​ negative individuals, magnetic resonance cholangiopancreatography (MRCP) should be done to exclude intrahepatic biliary disease such as primary sclerosing cholangitis, followed by a liver biopsy if the diagnosis remains unclear. Other autoantibodies such as gp210 and sp100 can be positive in the 10% of patients with primary biliary cholangitis who are AMA negative. IgG4 systemic disease is a recently recognized condition which can cause a sclerosing cholangitis picture on MRCP and occasionally mimic a hilar cholangiocarcinoma or inflammation of the pancreas (autoimmune pancreatitis) leading to a distal bile duct stricture. The diagnosis is made by the finding of IgG4 plasma cells on histology and/​or elevated IgG4 in serum. Intrahepatic cholestasis of sepsis and ischaemic cholangiopathy should also be considered in patients with jaundice and high ALP levels in the intensive care setting. Intrahepatic cholestasis of sepsis is probably mediated through the effect of endotoxin on the biliary transported proteins on the canalicular and sinusoidal hepato- cyte membrane. Ischaemic cholangiopathy is rarer, but sometimes arises because the biliary system is dependent on blood flow from the hepatic artery, and prolonged hypotension can lead to necrosis of bile duct epithelium which sloughs off into the lumen causing biliary obstruction. This condition should be considered particu- larly in jaundiced patients who have had a high inotropic require- ment in cardiac intensive care units. Total parenteral nutrition is also associated with cholestatic liver function tests, which are com- moner following prolonged nutrition and where the lipid compo- nent is high. γ-​Glutamyl transferase adds little to the investigation of jaun- dice, except in oestrogen or pregnancy-​associated intrahepatic cholestasis. γ-​Glutamyl transferase may differentiate between mu- tations in the ABCB11 gene encoding BSEP from mutations in ABCB4 encoding MDR3, both canalicular transport proteins, as it is normal in the former. Chronic liver disease screen Components of the chronic liver disease screen are shown in Table 15.22.1.5. Synthetic liver function tests A key to acute liver injury is a normal albumin. In posthepatic biliary obstruction, due to malabsorption of vitamin K from a lack of bile salts in the gut lumen, the prolonged prothrombin time will correct with intravenous vitamin K. The degree of elevation of prothrombin time in acute and chronic liver injury does not predict increased bleeding but is an important prognostic marker (Table 15.22.1.7). The triad of low platelets (due to reduced production as a result of low hepatic thrombopoietin production and increased consump- tion due to splenomegaly), prolonged prothrombin time, and low albumin suggests cirrhosis. Jaundiced patients with cirrhosis may have only mildly elevated ALP and ALT levels, and occasionally these can be normal, but the presence of a low albumin, platelets, and high prothrombin time will then differentiate cirrhosis from prehepatic jaundice. Ascitic tap A 10 to 20-​ml sample of ascites should be sent for cytology, ascitic white cell count, bacterial culture, protein, and albumin (Table 15.22.1.8). The last of these will help distinguish exuda- tive from transudative ascites. A serum–​ascitic albumin gradient (SAAG) of greater than 11 indicates a transudate. An ascitic pro- tein level is also helpful as in hepatic venous outflow obstruction, including right heart failure, although the ascites is a transudate it will have a high protein, helping to differentiate it from cirrhosis. Radiology Figure 15.22.1.2 summarizes the pivotal role of ultrasonography and biliary imaging in identifying causes of jaundice. Ultrasound examination This is the key investigation in excluding posthepatic jaundice. Dilated intrahepatic ducts indicate obstruction at the liver hilum, either due to cholangiocarcinoma or lymph node metastases. Gallbladder stones in a patient with biliary pain, even in the absence Table 15.22.1.6  Liver-​related causes of elevated ALP and their investigation Condition Investigation Bile duct obstruction Ultrasonography ± IgG4 ± blood culture Intrahepatic biliary disease Primary biliary cholangitis Primary sclerosing cholangitis Drugs Intrahepatic cholestasis of sepsis Total parenteral nutrition AMA/sp100/​gp210 antibody MRCP History History History Hepatic infiltration: Lymphoma Acute leukaemia Metastatic cancer Hepatocellular carcinoma Liver biopsy Blood film Liver biopsy/​CT scan α-​Fetoprotein/​CT scan/​liver biopsy Note: high ALP (usually < 1000 IU/​litre) can be seen in alcoholic liver disease (cirrhosis and alcoholic hepatitis).

section 15  Gastroenterological disorders 3056 of a dilated biliary system, suggest common bile duct stones, only 30% of which will be seen on ultrasonography. In acute liver injury, the ultrasound examination will be normal. The presence of splenomegaly and/​or abnormal liver texture sug- gests underlying chronic liver disease. Classical nodular liver is not always seen on ultrasonography in the presence of cirrhosis. The hepatic veins can also be seen using Doppler ultrasonog- raphy, and in the presence of ascites this is important to exclude both hepatic venous outflow obstruction and portal vein occlusion, which can complicate cirrhosis or be caused by a complicating tu- mour. Hepatic infiltration from a tumour such as lymphoma or diffuse liver metastases can be difficult to see on ultrasonography. A CT scan is needed and should be considered when there is hepato- megaly and high ALP levels. Biliary imaging MRCP remains the diagnostic investigation of choice for identifying the cause of biliary obstruction. It may identify bile duct and cystic duct stones not seen on ultrasonography, although it can miss small gallbladder stones which are best seen by ultrasonography. It is also useful in mapping the extent of biliary obstruction in bile duct cancers, particularly hilar cholangiocarcinomas, to help in deciding if stenting will improve jaundice and decide between endoscopic and percutaneous approach. MRCP will also identify chronic pancreatitis and swollen pancreas typical of IgG4 disease. Endoscopic retrograde cholangiopancreatography (ERCP) is also used to confirm diagnosis and for therapy. Pancreatic CT is needed before endoscopic stenting to stage/​assess operability of ampullary, pancreatic, or bile duct cancers because further assessment of oper- ability is impossible if post-​ERCP pancreatitis occurs (1 in 20 risk). Liver biopsy Liver histology is often needed once posthepatic biliary obstruction and acute viral hepatitis have been excluded, to stage the degree of liver injury, to differentiate acute from chronic liver damage, and to aid diagnosis. It is a major component of the diagnostic criteria for autoimmune liver disease and is often needed to make a diagnosis in the presence of a hepatitic liver function test once acute viral hepa- titis has been excluded serologically. Percutaneous liver biopsy has a 0.5% risk of bleeding and a small risk of pneumothorax. Other rare complications include intrahepatic arteriovenous fistulae and haemobilia. Transjugular liver biopsy is indicated in the presence of ascites, a platelet count less than 50 × 109/​litre, and a prolonged prothrombin time. Noninvasive markers of liver fibrosis such as FibroScan are less useful in the presence of jaundice as inflammation can increase FibroScan scores, incorrectly suggesting cirrhosis. Ascites also re- duces the sensitivity and specificity of FibroScan. Other tests In a patient with cirrhosis less than 40 years of age and with haem- olysis, particularly in the presence of a normal or low ALP, Wilson’s disease should be considered and examination for Kayser–​Fleischer rings with a slit lamp should be performed. Table 15.22.1.8  Investigation of ascites Parameter Comment Serum–​ascitic albumin gradient (SAAG) <11 = exudate

11 = transudate Protein High in hepatic venous outflow obstruction despite SAAG >11 suggesting transudate Neutrophil count 250 cells/​mm3 in spontaneous bacterial peritonitis Cytology High yield in ovarian cancer Amylase Pancreatic duct leak in chronic pancreatitis from pancreatic injury Rarely associated with jaundice from biliary obstruction Table 15.22.1.7  Scoring systems for liver disease severity Score components Bilirubin PT Creatinine Sodium Complications Other Acute liver failure Kings criteria: paracetamol Yes Yes Encephalopathy Kings criteria: nonparacetamol Yes Yes Age Cause Time to jaundice Chronic liver failure Child–​Pugh Yes Yes Ascites Encephalopathy MELD Yes Yes Yes MELD-​Na Yes Yes Yes Yes UKELD Yes Yes Yes Yes Maddreya Yes Yes a Used for alcoholic hepatitis. MELD, Model for End-​Stage Liver Disease; Na, sodium; PT, prothrombin time; UKELD, United Kingdom model for end-​stage liver disease.

15.22.1  Investigation and management of jaundice 3057 Management All potentially hepatotoxic drugs, including recently started medi- cation, should be stopped. Vitamin K will reverse abnormal coagu- lation in patients with posthepatic obstructive jaundice, allowing biliary intervention at ERCP, including sphincterotomy. Drugs that may adversely affect renal function, which is already compromised in cirrhosis and acute liver failure, should be avoided. High levels of bilirubin are also toxic to renal tubules. Itching due to large duct biliary obstruction can be difficult to palliate if the cause cannot be treated, but may respond to antihistamines and aqueous cream with 1% menthol. Treatments effective for itching due to intrahepatic biliary disease such as primary sclerosing cholangitis in- clude colestyramine, rifampicin, or naltrexone. Itching in patients with intrahepatic cholestasis of pregnancy responds to ursodeoxycholic acid. Although treating cholangitis associated with biliary obstruction may lead to improvements in both jaundice and liver function tests, investigation of the underlying cause should still be undertaken. In drug-​induced jaundice, after stopping the causative drug, cholestatic liver function tests can take months to return to normal, whereas following hepatitic drug injury, liver function tests will often normalize within weeks. Further management is dependent on the cause identified fol- lowing blood tests and imaging (Fig. 15.22.1.2). Practice management guidelines are available through the websites of the European Associa­ tion for the Study of the Liver (http://​www.easl.eu) and American Association for the Study of the Liver (http://​www.aasld.org). FURTHER READING Buchman AI, Iyer K, Fryer J (2006). Parenteral nutrition-​associated liver disease and role for intestinal and intestinal/​liver transplant- ation. Hepatology, 43, 9–​19. Bunchorntavakal C, Reddy KR (2013). Review article; herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther, 37, 3–​17. Chalasani N, et al. (2008). Causes, clinical features and outcome from a prospective study of drug-​induced liver injury in the United States. Gastroenterology, 135, 1924–​34. Chand N, Sanyal AJ (2007). Sepsis induced cholestasis. Hepatology, 45, 230–​41. Erlinger S, Arias IM, Dhumeaux D (2014). Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology, 146, 1625–​38. Halilbasic E, Claudel T, Trauner M (2013). Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol, 56, 156–​68. Hennes EM, et al. (2008). Simplified criteria for the diagnosis of auto- immune hepatitis. Hepatology, 48, 169–​76. Lok AS, et al. (2012). Reactivation of hepatitis B during immunosup- pressive therapy: potentially fatal yet preventable. Ann Intern Med, 156, 743–​5. Martinez SM, et al. (2011). Non-​invasive assessment of liver fibrosis. Hepatology, 53, 325–​35. Purcell RH, Emerson SU (2008). Hepatitis E: an emerging awareness of an old disease. J Hepatol, 48, 494–​503. Rockey DC, et al. (2009). Liver biopsy. Hepatology, 49, 1017–​44. JAUNDICE Normal ALT/ALP Normal albumin/platelets* Abnormal ALP/ALT Ultrasound scan Dilated CBD Undilated CBD**/* High ALT
High ALP MRCP/ERCP **If pain and gallbladder stones and elevated ALP or ALT <1000 needs MRCP to exclude bile duct stones
• Suggestion of cirrhosis; splenomegaly/low platelets No evidence of haemolysis Unconjugated bilirubin Gilbert’s syndrome See Table 15.22.1.5 No cause identified Liver biopsy (diagnosis/staging) Exclude drugs AMA MRCP to exclude PSC Fig. 15.22.1.2  Summary of the investigation of jaundice. AMA, antimitochondrial antibody; CBD, common bile duct; PSC, primary sclerosing cholangitis.

15.22.2 Cirrhosis and ascites 3058

15.22.2 Cirrhosis and ascites 3058

section 15  Gastroenterological disorders 3058 15.22.2  Cirrhosis and ascites Javier Fernández and Vicente Arroyo ESSENTIALS Ascites is the accumulation of fluid in the peritoneal cavity and the most common complication of cirrhosis, when it is associated with a poor prognosis. It occurs only when portal hypertension has de- veloped and is mainly due to renal sodium retention secondary to splanchnic arterial vasodilation that leads to homeostatic activation of vasoconstrictor and sodium-​retaining systems. Clinical presentation is with abdominal distension. Patients with tense ascites can also complain of backache or abdominal pain. Investigation The initial evaluation of a patient with ascites must include (1) history and physical examination; (2) liver and renal function tests including serum and urine electrolytes; (3) analysis of ascitic fluid (diagnostic paracentesis) for cell count and culture, and protein/​albumin con- centration; other tests such as cytology (suspicion of malignancy), amylase (pancreatic disease), and polymerase chain reaction and culture for mycobacteria (tuberculosis) should be done only when the diagnosis is unclear; (4) abdominal ultrasonography for evidence of cirrhosis, portal hypertension, or malignancy. Management First-​line manoeuvres include dietary salt restriction (80–​120 mmol/​ day), and therapeutic or total paracentesis. Water restriction is only recommended if there is severe dilutional hyponatraemia. Refractory ascites is managed by repeated paracentesis or insertion of a transjugular intrahepatic portosystemic shunt. Cirrhotic patients with ascites should be considered for liver transplantation. Complications All patients with cirrhosis and ascites are at risk of spontaneous bacterial peritonitis. Typical symptoms are abdominal pain and fever, but the condition may be asymptomatic. The gut is the most frequent source of organisms (bacterial translocation from intestinal lumen). Treatment with appropriate antibiotics (tailored according to the local epidemiological pattern of antibiotic re- sistance) should be started as soon as a presumptive diagnosis is made following diagnostic paracentesis (polymorphonuclear neutrophil count ≥250/​mm3). Prophylactic norfloxacin reduces the risk of recurrent episodes. Mortality is around 10% for the acute episode and 75% at 1 year; hence (unless contraindicated), all patients with spontaneous bacterial peritonitis should be con- sidered for liver transplantation. Patients with cirrhosis and ascites are also at high risk of other complications: (1) refractory ascites, (2) hyponatraemia, (3) hepatorenal syndrome, (4) paraumbilical hernia, and (5) pleural effusion. Introduction Ascites is the accumulation of fluid in the peritoneal cavity. Studies on its pathogenesis began in the 17th century when Richard Lower (1631–​1691), a physician based in Oxford, demonstrated that ascites developed in dogs following ligation of the inferior vena cava. Ernest Henry Starling (1866–​1927), a physiologist based at University College London, made a major contribution to the study of oedema formation with the demonstration that both hydrostatic forces and oncotic forces were involved, and that the increase in thoracic lymph flow following obstruction of the in- ferior vena cava is mainly derived from the liver. Aetiology Ascites is the most common complication of cirrhosis and indicates the presence of portal hypertension and hepatic decompensation. It occurs in at least 50% of patients within 10 years of the diagnosis of cirrhosis, which accounts for over 75% of cases presenting with ascites. Ascites may also be caused by malignancy, pancreatitis, tuber- culosis, cardiac failure, myxoedema, or other rarer causes, each of which may also occur in patients with cirrhosis (Table 15.22.2.1). Although ascites commonly occurs in patients with cardiac failure, it is rarely a presenting feature. Ascites does not occur in patients with portal vein thrombosis and is infrequent in other forms of noncirrhotic intrahepatic portal hypertension such as idiopathic portal hypertension. It frequently occurs in patients with the Budd–​Chiari syndrome, severe alcoholic hepatitis, and subacute liver failure. Other (rare) causes of ascites include constrictive pericar- ditis, veno-​occlusive disease, malnutrition, hypoalbuminemia (nephrotic syndrome and protein-​losing enteropathy), stromal tumours and Meigs’ syndrome, hypothyroidism, lymphatic leak (chylous ascites), autoimmune inflammatory conditions (e.g. sys- temic lupus erythematosus), or Whipple disease. Rare infections include candidiasis, brucellosis, and filariasis. Granulomatous liver disease such as sarcoidosis may cause portal hyperten­ sion and (occasionally) ascites. Ascites may also occur in the Acknowledgement: the authors and editors gratefully acknowledge the in- clusion in this chapter of material contributed to previous editions of the Oxford Textbook of Medicine by Professor Kevin Moore. Table 15.22.2.1  Underlying causes of patients presenting with ascites in the United States of America Cause % Total Cirrhosis (alcoholic liver disease) 65 Cirrhosis (viral) 10 Cirrhosis (other)   6 Malignancy 10 Heart failure   3 Tuberculosis   2 Pancreatic disease   1 Other causes   3

15.22.2  Cirrhosis and ascites 3059 ovarian hyperstimulation syndrome in women undergoing fer- tility treatment. Epidemiology Cirrhosis is the fifth leading cause of death in the United Kingdom. It heralds the beginning of a usually rapid decline of liver func- tion, with about half of patients dying within 2 years of the onset of ascites. Pathogenesis Ascites Until recently, the most widely accepted explanation for the patho- genesis of ascites and renal failure in cirrhosis has been based on the peripheral arterial vasodilation and the forward hypotheses of ascites formation proposed by Schrier et al. in 1988. This holds that the primary event stimulating renal sodium and water reten- tion in cirrhosis is splanchnic arterial vasodilation caused by a massive release of local vasodilators (i.e. nitric oxide) secondary to portal hypertension. In the initial phases of cirrhosis, compensa- tion occurs through the development of hyperdynamic circulation (high plasma volume, cardiac index, and heart rate). As cirrhosis progresses and splanchnic arterial vasodilation increases, this compensatory mechanism is insufficient to maintain circulatory homeostasis. Arterial pressure decreases, leading to stimulation of baroreceptors, homeostatic activation of the sympathetic ner- vous system (SNS) and the renin–​angiotensin–​aldosterone system (RAAS), and production of antidiuretic hormone (ADH, or vaso- pressin), all leading to renal sodium and water retention. Within the splanchnic microcirculation, the forward increase in capillary pressure and permeability from the greatly increased inflow of blood at high pressure into the splanchnic capillaries leads to the leakage of fluid into the abdominal cavity. The peripheral arterial vasodilation hypothesis has been revisited. Firstly, several studies have shown that cardiac function is increased in early stages of cirrhosis and ascites, but declines with the pro- gression of the disease, being frequently normal in patients with hepatorenal syndrome. Hence, progression of circulatory dysfunc- tion, the stimulation of the RAAS and the SNS, ADH production, and impairment of renal function in cirrhosis are caused by both progressive splanchnic arterial vasodilation and primary impair- ment in cardiac function (Fig. 15.22.2.1). Secondly, the peripheral arterial vasodilation hypothesis does not provide an explanation for the fact that patients with advanced cirrhosis frequently develop multiorgan failure (acute-​on-​chronic liver failure), a syndrome characterized by systemic inflammation and high short-​term mor- tality. According to a new hypothesis, systemic inflammation could also contribute to the major clinical manifestations of advanced cir- rhosis (Fig. 15.22.2.2). The sustained activation of the innate im- mune system caused by an abnormal translocation of bacteria and bacterial products from the intestinal lumen (pathogen-​associated molecular patterns) could lead to the persistent activation of the innate pattern recognition receptors and subsequent chronic inflammation. Proinflammatory cytokines and oxidative stress could accentuate circulatory dysfunction (by enhancing arterial vasodilation and cardiac dysfunction) and damage the kidneys and other organs, worsening their function. Renal dysfunction Renal function abnormalities (reduced ability to excrete sodium and free water and decreased renal perfusion and glomerular filtration rate) follow a progressive course in cirrhosis. Impairment of renal sodium handling can already be detected before the development of ascites, when cirrhosis is still compensated. In this phase, patients have subtle abnormalities in renal sodium excretion, for example, reduced natriuretic response to the acute administration of sodium chloride, and abnormal natriuretic responses to changes in posture. As cirrhosis progresses, patients become unable to excrete their regular sodium intake. Sodium is then retained together with water and fluid accumulates in the abdominal cavity as ascites. In the early phase, sodium retention is unrelated to the activation of the RAAS or of the SNS. However, when sodium retention is in- tense (urinary sodium excretion <10 mEq/​day), the plasma renin activity and the plasma concentrations of aldosterone and nor- adrenaline are invariably increased. Aldosterone increases sodium reabsorption in the distal and collecting tubules, and increased renal SNS activity stimulates sodium reabsorption in the proximal tu- bule and loop of Henle. Sodium retention in this phase is therefore caused by increased sodium reabsorption throughout the nephron. Dilutional hyponatraemia (serum sodium concentration of <130 mEq/​litre) develops in later phases when electrolyte-​free water clearance is severely reduced. Finally, patients develop functional acute kidney injury secondary to intense renal hypoperfusion (type 2 hepatorenal syndrome). The degree of sodium retention in these patients is very intense and most of them do not respond to diuretics and have refractory ascites. Free water clearance is also markedly Cardiac output Effective arterial hypovolemia Normal effective blood volume Splanchnic arterial vasodilation Systemic vascular resistance Extra-splanchnic vasoconstriction Degree of activation of RAAS, SNS, ADH Compensated cirrhosis Changes Ascites Time (years) Hyponatremia Type-2 HRS Fig. 15.22.2.1  Pathogenesis of circulatory and renal dysfunction in cirrhosis (peripheral vasodilation hypothesis). ADH, antidiuretic hormone; HRS, hepatorenal syndrome; RAAS, renin–​angiotensin–​ aldosterone system; SNS, sympathetic nervous system. Reprinted from Journal of Hepatology, Vol. 63, Bernardi M, et al., Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis, Pages 1272–​84, Copyright © 2015 European Association for the Study of the Liver, with permission from Elsevier.

section 15  Gastroenterological disorders 3060 reduced and most patients have significant hyponatraemia. Patients with type 2 hepatorenal syndrome are at increased risk of type 1 hepatorenal syndrome, a rapidly progressive acute kidney injury that frequently occurs in association with the failure of other organs and systems (acute-​on-​chronic liver failure). Clinical features Ascites is graded 1 to 3 depending on its severity. Grade 1 ascites is mild, and only detectable by ultrasound examination; grade 2 ascites is moderate, and is manifest by moderate symmetrical distension of the abdomen; and grade 3 ascites is large or gross, with marked abdominal distension. A grade 2 ascites is most easily detected by a shifting dullness. Grade 3 ascites is usually tense and easily de- tected by the presence of a fluid thrill on palpation. Aside from an unpleasant feeling of abdominal distension and/​or abdominal pain, many patients will complain of backache. There is often divarication of the rectus abdominis muscles, and prominent veins may be evi- dent on the abdominal wall (Fig. 15.22.2.3). Paraumbilical hernias develop in about 20% of patients with ascites, an incidence that in- creases to up to 70% in those with long-​standing recurrent tense as- cites, with the main risks being rupture and strangulation. Pleural effusions (hepatic hydrothorax) develop in about 5% of patients with cirrhosis and may develop in patients with no dis- cernible ascites. The pleural effusions are right-​sided in 85% of cases, left-​sided in 13%, and bilateral in 2%. Laboratory diagnosis The cause of ascites is often obvious. Where there are no obvious clues to its aetiology, tests must be directed both at diagnosing the presumed cause of liver disease and at excluding other causes of as- cites such as malignancy or tuberculosis. Other causes of abdom- inal distension such as huge masses, Meigs’ syndrome, or pregnancy should be considered. The essential investigations on admission of a patient to hospital include the following: • Liver and renal function tests, including serum and urine electrolytes—​patients with cirrhosis and ascites are prone to hyponatraemia or renal impairment, either spontaneously or fol- lowing diuretic therapy. • Analysis of ascitic fluid (diagnostic paracentesis) for cell count, determination of protein concentration, and culture to confirm or exclude spontaneous bacterial peritonitis (SBP). A  Gram stain is informative in patients with secondary peritonitis (polymicrobial). Cytology, amylase measurement, and poly- merase chain reaction and culture for mycobacteria should be done when there is suspicion of other potential diagnosis (ma- lignancy, pancreatic disease, and tuberculosis, respectively). • Abdominal ultrasonography is needed to evaluate liver appear- ance (nodular in cirrhosis; congested in congestive cardiac failure), provide data on portal hypertension (splenomegaly, portal vein dilation, collaterals), portal vein flow (thrombosis is present in 8% of patients with cirrhosis), the presence of liver tumour(s) (hepatocellular carcinoma or metastases), and to semiquantify the amount of ascites. Compensated cirrhosis Early decompensated cirrhosis Decompensated cirrhosis Acute-on-chronic liver failure Mild/moderate BT Moderate SAV compensated by increased CO No systemic or organ inflammation Significant SAV No further increase in CO Moderate systemic and organ inflammation Severe SAV Decreased CO Significant systemic and organ inflammation Extreme circulatory and cardiac dysfunction Organ hypoperfusion Severe organ inflammation and oxidative stress Organ damage Organ failures Acute-on-chronic liver failure Marked effective hypovolaemia organ dysfunction Renal failure Effective hypovolaemia Organ dysfunction No organ failure No effective hypovolaemia No organ dysfunction Significant BT Severe BT Bacterial infection Acute sterile inflammation Severe burst of BT Fig. 15.22.2.2  The systemic inflammation hypothesis of decompensation and acute-​on-​chronic liver failure in cirrhosis. Bacterial translocation (BT) progressively impacts the natural course of cirrhosis causing circulatory and cardiac dysfunction and finally acute-​on-​chronic liver failure. CO, cardiac output; SAV, splanchnic arterial vasodilation. Modified from Journal of Hepatology, Vol. 63, Bernardi M, et al., Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis, Pages 1272–​84, Copyright © 2015 European Association for the Study of the Liver, with permission from Elsevier. Fig. 15.22.2.3  Alcoholic cirrhosis with ascites is often associated with marked anorexia and malnutrition.

15.22.2  Cirrhosis and ascites 3061 Paracentesis An ascitic tap is performed for either diagnostic purposes or for the removal of large volumes of ascites. The most common site for para- centesis is about 15 cm left lateral to the umbilicus (approximately 5 cm superior and medial to the left anterior superior iliac spine), with care being taken to avoid an enlarged spleen. The epigastric ar- teries run just lateral to the umbilicus towards the midinguinal point and should be avoided. For diagnostic purposes, 20 ml of ascitic fluid should be with- drawn, and 5 to 15 ml placed under aseptic conditions (i.e. the needle changed) into each of two blood culture bottles. A 2-​ to 5-​ml ali- quot of fluid should also be sent in a plastic container (containing ethylenediaminetetraacetic acid (EDTA) if the sample has a ten- dency to clot) to the lab for cell count (polymorphonuclear neutrophil (PMN) or lymphocyte count) and ascitic fluid protein determination. Cytological examination requires 20 to 50 ml of ascitic fluid. Ascitic fluid investigations A diagnostic paracentesis should be performed in all patients with new-​onset grade 2 or 3 ascites, and in all patients hospitalized for worsening of ascites or any other complication of cirrhosis, in order to rule out SBP. An appropriate ascitic fluid analysis must include cell count and the determination of total protein concentration. Ascitic protein concentration and serum–​ascites
albumin gradient Conventionally, ascites is described as being an exudate or a transu- date depending on whether ascitic protein concentration is respect- ively more or less than 25 g/​litre, the purpose of this subdivision being to narrow the differential diagnosis of its cause. The causes of transudative and exudative ascites are given in Table 15.22.2.2. Cardiac ascites, malignancy, and tuberculous peritonitis usually have a high ascitic protein content. However, 20% of patients with a malignancy and 30% of those with tuberculosis have low-​protein ascites. Ascites in cirrhosis is normally a transudate (85%), but about 15% of cases of cirrhotic ascites have an ascitic protein level of more than 25 g/​litre. Measuring the difference between serum and ascites albumin levels (high gradient, >11 g/​litre vs low gradient, <11 g/​ litre) considerably improves the capacity to subdivide exudative or transudative causes. The overall accuracy of this method is high, although its actual impact in day-​to-​day clinical practice is small (Table 15.22.2.3). In patients with cirrhosis, a very low ascitic protein level (<10–​15 g/​litre) is associated with an increased risk of SBP. Moreover, pro- tein concentration in ascites (>10 g/​litre) has been suggested as a criterion to distinguish between spontaneous and secondary peri- tonitis (Runyon’s criteria). Ascitic amylase The ascitic fluid amylase level should always be measured in pa- tients with an exudative or unexplained ascites. A very high value is obtained when ascitic fluid results from a pancreatic pseudocyst. Patients with secondary peritonitis due to gut perforation also pre- sent high levels of amylase and bilirubin in ascitic fluid. Ascitic fluid cell count An ascitic neutrophil count of at least 250 PMNs/​mm3 is diagnostic of SBP. An elevated lymphocyte count should raise the possibility of tuberculous peritonitis or malignancy. Excess red blood cells are most commonly due to a traumatic tap, but should also raise the pos- sibility of malignancy (i.e. haemoperitoneum due to hepatocellular carcinoma in cirrhosis). Ascitic fluid culture Ascitic fluid must be processed in the same way as blood cultures, and ascitic fluid inoculated directly into blood culture bottles at the bedside. This policy doubles the positive culture rate. If an ascitic cell count is reported as showing less than 250 PMNs/​mm3 but sub- sequent culture is positive (bacterascites), then the ascitic tap should be repeated since the patient may have developed SBP and thus re- quire treatment with antibiotics and albumin. Ascitic fluid cytology Ascitic cytology should involve liaison with the cytopathologist so that the index of suspicion and type of potential tumour are dis- cussed. A 20-​ to 50-​ml sample of ascitic fluid is required to produce a cell concentrate for cytology—​obtained by centrifuging the ascites fluid, removing supernatant, and resuspending the cells. A sample of the concentrate then undergoes a cytospin to deposit cells on to microscope slides, following which the cells are stained. Typical stains include the Papanicolaou and May–​Grünwald–​Giemsa stain. Ascitic volume Ascitic volume is not usually determined in clinical practice. It can, however, be quantified radiologically or by indicator-​dilution (radiolabelled 99Tc-​macroalbumin). As a rough guide, patients with barely detectable ascites usually harbour between 1 and 4 litres, Table 15.22.2.2  Subdivision into exudative and transudative ascites Exudative ascites
(protein>25 g/​litre) Transudative ascites
(protein <25 g/​litre) Malignancy (80%) Cirrhosis (85%) Tuberculosis (70%) Malignancy (20%) Congestive cardiac failure Protein-​losing enteropathy Cirrhosis (15% of cases) Tuberculosis (30%) Pancreatitis Budd–​Chiari syndrome Myxoedema Constrictive pericarditis Nephrotic syndrome Table 15.22.2.3  Subdivision of patients into high and low ascitic albumin gradient Serum–​ascites albumin
gradient <11 g/​litre (low gradient) Serum–​ascites albumin
gradient >11 g/​litre (high gradient) Malignancy Cirrhosis Tuberculosis Cardiac failure Pancreatic Budd–​Chiari syndrome Biliary Myxoedema Nephrotic syndrome Connective tissue disease

section 15  Gastroenterological disorders 3062 those with moderate ascites 4 to 8 litres, and those with marked as- cites more than 8 litres of fluid. Management Patients with ascites can be divided into those who are easy to treat and those who are difficult. In general, patients with their first pres- entation of ascites and normal renal function, who have a spot urine sodium concentration of greater than 20 mmol/​litre, or an identifi- able source of dietary sodium excess, respond well to simple meas- ures. Likewise, when ascites has developed as a consequence of bleeding or infection, it usually resolves more readily. The treatment of ascites is summarized in Box 15.22.2.1. Bed rest There is no evidence to recommend bed rest as part of the treatment of ascites. Moreover, bed rest accentuates muscle atrophy, a very sig- nificant problem in advanced cirrhosis. Dietary salt restriction There is a consensus that dietary salt restriction is an important component of the management of patients with cirrhosis and ascites. Standard practice is to restrict sodium intake to 80 to 120 mmol/​day, which in effect is equivalent to a ‘no added salt’ diet with avoidance of preprepared meals. A greater reduction in so- dium intake interferes with nutrition and is not advisable. In most cases, however, urinary sodium excretion is very low, and a negative sodium balance cannot be achieved without diuretics. Even in these cases, sodium restriction is important because it reduces diuretic requirements. Water restriction As a general recommendation There are no data to support fluid restriction in patients with ascites and normal serum sodium concentration. It is well known that water follows salt, hence fluid loss will occur if a patient achieves negative sodium balance with dietary salt restriction and/​or diuretics. In patients with hyponatraemia Dilutional hyponatraemia in cirrhosis is related to severely impaired renal free water excretion, due mainly to ADH hypersecretion. Other mechanisms involved are impaired renal production of pros- taglandin E2 (a powerful antagonist of the tubular effect of ADH), and reduced sodium and water delivery to the ascending limb of the loop of Henle and the distal convoluted tubule, where urinary dilu- tion occurs. Treatment of dilutional hyponatraemia in cirrhosis with ascites should, therefore, be directed towards reducing total body water. The administration of sodium may produce a transient in- crease in serum sodium, but at the expense of increasing the rate of ascites formation. Fluid restriction has been the standard of care in patients with severe hyponatraemia, but is rarely effective in improving serum so- dium concentration, although it can be helpful in preventing a fur- ther decrease in serum sodium level. The lack of efficacy is probably due to the fact that in clinical practice total daily fluid intake cannot be restricted to less than 1 litre/​day. A more recent approach has been the use of highly selective vasopressin V2 antagonists (vaptans) with the aim of improving serum sodium concentration by increasing solute-​free water ex- cretion. These drugs produce a rapid and marked increase in urine volume with a reduction in urine osmolality and an increase in serum osmolality and serum sodium concentration. They have consistently been demonstrated to improve control of ascites and serum sodium in the short term, but seem to increase mortality in phase III studies. Diuretics Furosemide and spironolactone are the diuretics most commonly used in the treatment of ascites in cirrhosis. Spironolactone is the preferred drug, because—​in contrast to healthy subjects—​it is gen- erally more effective than furosemide. Cirrhotic patients with ascites and marked hyperaldosteronism (50% of patients with ascites) do not respond to furosemide, whereas most will respond to spirono- lactone. Patients with normal or slightly increased plasma aldos- terone concentration respond to low doses of spironolactone (100 to 150 mg/​day), but as much as 300 to 400 mg/​day may be required in those with marked hyperaldosteronism. The goal of treatment is to maintain patients free of ascites with the minimum dose of diuretics. Thus, once the ascites has largely resolved, the dose of diuretic should be reduced to the minimum, or discontinued if possible. The safe upper limit of the rate of weight loss is unclear, but most experts agree that the diuretic dose should be adjusted to achieve a rate of weight loss below an average of 500 g per day in patients without peripheral oedema, or 1 kg per day in those with peripheral oedema. Patients not responding to 400 mg/​ day of spironolactone and 160 mg/​day of furosemide will not re- spond to higher diuretic doses. Spironolactone Spironolactone is an aldosterone antagonist, acting mainly on the distal tubules to increase natriuresis and conserve potas- sium. Natriuretic effect occurs between the third and the fifth day. The main problem with clinical use in men is the develop- ment of gynaecomastia, which is often painful. Other side effects of spironolactone include hyponatraemia, impotence, menstrual disturbance (although most ascitic patients are amenorrhoeic), and osteomalacia. Eplerenone is a useful alternative for patients who develop gynaecomastia and other sex-​related adverse effects on spironolactone. It binds specifically to mineralocorticoid re- ceptors and less to progesterone and androgen receptors than spironolactone, hence it has a much lower propensity to induce these side effects. Box 15.22.2.1  Summary of treatment of ascites • Sodium restriction to 80 to 120 mmol/​day • Diuretic therapy should use spironolactone as the first-​line drug • Water restriction should only be used in severely hyponatraemic pa- tients with caution • Total paracentesis should initially be carried out on patients with marked ascites • Shunts (TIPS) may be used in those with refractory ascites in whom recurrent paracentesis is too frequent or poorly tolerated, or in those with a hepatic hydrothorax

15.22.2  Cirrhosis and ascites 3063 Amiloride Amiloride, a diuretic acting in the collecting duct, is less effective than aldosterone antagonists and should only be used in those pa- tients who do not tolerate spironolactone. Furosemide Furosemide is a loop diuretic generally used as an adjunct to spir- onolactone treatment. The simultaneous administration of both agents increases their natriuretic effect and reduces the incidence of hypo-​ or hyperkalaemia that may be observed when these drugs are given alone. Complications and benefits of diuretic therapy Diuretic therapy generally improves morbidity and well-​being, since it leads to resolution or amelioration of ascites, allows a more liberal diet, decreases portal pressure, and increases the opsonic activity of ascitic fluid, thereby decreasing the risk of SBP. However, diuretic use in cirrhosis often leads to complications (Box 15.22.2.2), particu- larly in patients requiring high diuretic doses. Approximately 20% develop significant renal impairment, which is usually moderate and reversible after diuretic withdrawal. Hyponatraemia secondary to a decrease in the renal ability to excrete free water also occurs in approximately 20% of these patients. The most severe complication related to diuretic treatment is hepatic encephalopathy, which oc- curs in approximately 25% of those who are hospitalized with tense ascites and treated with high doses of diuretics. Therapeutic paracentesis Large-​volume paracentesis has been in use for at least 2000 years, and was widely used in the earlier part of the last century. When diur- etics first became available in the 1940s, the practice declined, but it was still used as an adjunct to therapy until the early 1960s, when it gradually fell into disrepute with the recognition that repeated para- centesis resulted in salt depletion and oliguria, and became virtually banned as a treatment. However, it re-​emerged in the mid 1980s when several controlled clinical studies demonstrated that (1) large-​volume paracentesis combined with albumin infusion was more effective and associated with fewer complications (hyponatraemia, renal impair- ment, and hepatic encephalopathy) than diuretic therapy in patients with grade 3 ascites; (2) it shortened hospital stay; and (3) it was a safe procedure with a very low rate of local complications. Total paracentesis is a rapid, effective, and safe treatment of as- cites in cirrhosis and is the treatment of choice for tense ascites. The mobilization of ascites by paracentesis is associated with a deterior- ation of circulatory function, as manifested by a marked increase in plasma renin activity and aldosterone concentration, in 60 to 70% of patients. This impairment in circulatory function results from accentuation of the arterial vasodilation already present in these patients, but the incidence of this complication is reduced to 30 to 40% if paracentesis is followed by plasma volume expansion with synthetic plasma volume expanders (dextran 70 or polygeline), and to only 18% if it is accompanied by plasma volume expansion with albumin (8 g per litre of ascitic fluid removed). Practical aspects Paracentesis cannulas should have multiple side perforations to avoid obstruction by omentum. All ascitic fluid should be drained in a single session as rapidly as possible over 1 to 4 h. The old dogma that rapid paracentesis causes marked hypotension is false. There is an immediate fall in right atrial pressure (within 30 min), due to a decrease in intra-​abdominal pressure and a decrease in compression of the right atrium. There is a rapid decrease in systemic vascular re- sistance and increase in cardiac output that peaks at 3 h. Pulmonary capillary wedge pressure remains constant for 6 h (in the absence of colloid), and decreases after this interval in the absence of colloid replacement. Mean arterial pressure decreases by about 8 mmHg. These changes are shown in Fig. 15.22.2.4. The drainage system should never be left in place overnight since this carries a high risk of infection and bleeding complications. Colloid replacement As commented before, it is very important that colloid replacement is given following large-​volume paracentesis to prevent circulatory dysfunction. After total paracentesis, synthetic plasma expanders may be used if the volume of ascites removed is less than 5 litres, but albumin should be used when more than 5 litres is removed. All or most trials have used albumin at a dose of 8 g/​litre of ascites Box 15.22.2.2  Complications of diuretics in the management of ascites • Hyponatraemia (20–​30%) • Hyperkalaemia (spironolactone) or hypokalaemia (loop diuretics) • Hepatic encephalopathy (secondary to electrolyte disturbance) • Renal impairment • Hyperuricaemia (30%) • Gynaecomastia, osteomalacia, and mild metabolic acidosis with spironolactone Mean arterial pressure (mmHg) Cardiac output (litres/min) Right atrial pressure (mmHg) PCWP (mmHg) 13 12 11 10 9 8 7 6 Time (h) Time (h) 24 48 11 6 3 2 1 100 90 80 70 60 Time (h) 0 0.5 24 48 6 3 2 1 0 0.5 24 48 6 3 2 1 0 0.5 24 48 6 3 2 1 0 0.5 10 9 8 7 6 5 Time (h) 10 9 8 7 6 Fig. 15.22.2.4  Haemodynamic changes following acute total paracentesis of approximately 10 litres of ascites over 1 h. Paracentesis was commenced at time 0 h and sequential changes were monitored by a Swan–​Ganz catheter, without albumin replacement. PCWP, pulmonary capillary wedge pressure. Modified from Panos MZ, et al. (1990). Single, total paracentesis for tense ascites: sequential haemodynamic changes and right atrial size. Hepatology, 11, 662–​7.

section 15  Gastroenterological disorders 3064 removed: there are no data on whether smaller amounts of albumin have differing degrees of efficacy. A recent meta-​analysis shows that albumin administration improves survival in patients receiving large-​volume paracentesis. Colloids should be given after paracen- tesis has been completed. Benefits Paracentesis most obviously provides immediate relief from as- cites and a tense abdomen, but also a number of other benefits, including (1) relief of respiratory muscles—​tense ascites clearly re- stricts breathing, and increases both the workload of respiration and energy expenditure, with paracentesis providing immediate relief; (2) reduction in resting energy expenditure, which is increased by ascites; and (3) enhanced salt and water excretion—​due to acute re- duction of renal venous pressure and consequent increase in renal perfusion, also an acute decrease in plasma ADH levels, which are directly related to intrathoracic or intra-​abdominal pressure, with both of these perhaps making patients more responsive to diuretic therapy. Contraindications It is generally agreed that there are no contraindications to para- centesis, although studies to date have excluded several subsets of patients, primarily because of inadequate data. In practice, some clinicians have concerns about carrying out paracentesis in patients who have a severe coagulopathy or marked thrombocytopenia in case localized bleeding complications arise, but there are no data to support this view. Patients with severe thrombocytopenia usually re- ceive platelet transfusion before large-​volume paracentesis. Intravenous albumin infusion There is clear evidence that the infusion of albumin is beneficial to patients with cirrhosis. It has a useful role in relation to large-​volume paracentesis (see ‘Therapeutic paracentesis’), prevents hepatorenal syndrome, improves short-​term survival in SBP (see SBP ‘Prognosis and management’ section), and is essential in the treatment of type 1 hepatorenal syndrome together with vasoconstrictors (mainly terlipressin). Some studies have demonstrated that periodic albumin admin- istration improves the response to diuretics in patients with as- cites. A  recent randomized controlled trial showed that regular albumin administration (40 g every week) prevented renal failure, hyponatraemia, and SBP, decreased the need for repeated large-​ volume paracentesis and hospital readmissions and improved long- term survival in patients with cirrhosis and ascites. Management of refractory ascites Refractory ascites is defined as ascites that cannot be mobilized, or early recurrence of ascites after paracentesis which cannot be pre- vented because of lack of response to maximal diuretic therapy and salt restriction (<80–​120 mmol salt/​day), or when there is inability to reach an effective diuretic dose because of side effects. Assessment of the response of patients with ascites to diuretic therapy and salt restriction should only be made in stable patients without associated complications such as bleeding or infection. Five to ten per cent do not respond adequately. This may be because the diuretics induce an electrolyte disturbance or encephalopathy, necessitating a temporary and recurrent withdrawal of medication, or alternatively the patient may be genuinely resistant. In both these groups, there is invariably significant renal dysfunction when as- sessed by creatinine clearance or other techniques measuring glom- erular filtration rate. The mainstay of treatment for these patients is repeated large-​volume paracentesis or insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Shunts Transjugular intrahepatic portosystemic shunts TIPS is the most recent treatment introduced for the management of portal hypertension. It works as a side-​to-​side portacaval shunt and is extremely effective in improving circulatory and kidney function, and reducing ascites. TIPS induces a marked increase in cardiac output, a decrease in systemic vascular resistance, an elevation in right atrial pressure and pulmonary wedge pressure, and a signifi- cant reduction in the plasma levels of renin, aldosterone, noradren- aline, and ADH, indicating an improvement in effective arterial blood volume. The improvement in circulatory function induces a rapid increase in urinary sodium excretion, which occurs within the first 1 to 2 weeks. Significant increases in serum sodium con- centration and glomerular filtration rate are also observed over 1 to 3 months, indicating improved renal perfusion and free water clear- ance. The improvement in systemic and splanchnic haemodynamics is associated with a complete disappearance of ascites or a partial response (sufficient improvement so that paracentesis is no longer required) in most patients. Only 10% of patients fail to respond to TIPS. Ascites characteristically resolves very slowly (1–​3 months), but continuous diuretic treatment at lower doses is required in more than 90% of cases, either for the treatment of ascites or to reduce the peripheral oedema. Hepatic encephalopathy is the most important complication, seen in more than 40% of cirrhotic patients with refractory ascites treated by TIPS. In most instances, it responds to standard therapy. Peritoneovenous shunts (Le Veen shunts or Denver shunts) Peritoneovenous shunting became very popular in the 1970s, with numerous publications on its benefits to renal function and reso- lution of ascites. However, it soon became apparent that many shunts became blocked or infected and caused scarring of the peritoneum, which can make liver transplantation difficult. This old technique offers no survival advantage over medical therapy, TIPS, or repeated paracentesis and has been abandoned. Prognosis The occurrence of ascites in patients with cirrhosis is associated with a poor prognosis, and patients with ascites may have a much worse prognosis than currently reflected in the Model for End-​Stage Liver Disease (MELD) or United Kingdom Model for End-​Stage Liver Disease (UKELD) score system, commonly used in organ allocation for liver transplantation. Survival rates are around 50% at 1 to 2 years, but somewhat better in alcoholic patients with ascites who stop drinking. The develop- ment of SBP in patients with ascites is associated with a mortality of 75% at 1  year, hence the development of this complication is

15.22.2  Cirrhosis and ascites 3065 associated with an overall poor prognosis and, unless contraindi- cated, all patients should be considered for liver transplantation. Complications The complications of ascites are shown in Box 15.22.2.3. Spontaneous bacterial peritonitis Diagnosis and epidemiology The diagnosis of SBP is based on clinical suspicion and on ascitic fluid analysis. It is defined as an ascitic fluid PMN count of at least 250 cells/​mm3 (independently of the results of the ascitic fluid and blood cultures), with no evident intra-​abdominal source of infec- tion. In patients with haemorrhagic ascites, a subtraction of 1 PMN per 250 red blood cells should be made. Ascitic fluid cell count is generally performed manually, although automated cell counts may give comparable results. The measurement of lactic dehydrogenase concentration, glucose levels, and total protein concentration in ascitic fluid is important to establish a differential diagnosis between spontaneous and sec- ondary peritonitis. A secondary peritonitis must be suspected when at least two of the following features are present in ascitic fluid: glu- cose levels less than 50 mg/​dl, protein concentration greater than 10 g/​litre, or lactic dehydrogenase concentration greater than normal serum levels. Gram’s stain is frequently negative in SBP but may identify patients with ascites and gut perforation (polymicrobial). Patients with gut perforation also present with high levels of amylase and bilirubin in ascitic fluid. Prompt CT scanning and surgical inter- vention are required in patients with secondary peritonitis. Culture of ascitic fluid directly into blood culture bottles (aerobic and anaerobic media) at the bedside is positive in 40 to 60% of cases of SBP. Moreover, blood cultures are positive in many patients. The most common organisms isolated are shown in Table 15.22.2.4. About 11% of patients presenting with ascites will develop SBP within 1 year, and 15% within 3 years. For patients admitted to hos- pital with ascites, with or without other complications (e.g. bleeding), the incidence of SBP on admission is about 10%. Pathogenesis The pathogenesis of SBP is shown in Fig. 15.22.2.5. Most organisms causing this infection are Gram-​negative bacteria of enteric origin, and colonization of ascitic fluid is presumed to occur following an episode of bacteraemia. Two major alterations are involved in the development of SBP: intestinal bacterial overgrowth and transloca- tion of bacteria from the intestinal lumen to the systemic circula- tion. Patients with advanced cirrhosis also have alterations in the innate immune system that facilitate bacterial translocation, prolong bacteraemia, and decrease their capacity to eliminate bacteria from the blood and ascitic fluid. Risk factors The risk factors for the development of SBP are summarized in Box 15.22.2.4. Decreased opsonic activity Patients with a low protein content (<10–​15 g/​litre) have an in- creased risk of developing SBP compared to those with a high ascitic protein content. Consequently, patients with cirrhotic and nephrotic ascites are prone to infection, whereas those with malignant ascites or cardiac ascites are not. For those cirrhotic patients with an as- citic protein level less than 10 g/​litre, the risk is 24% within 3 years, increasing to 60% at 1 year in patients with poor liver and/​or renal function. When bacteria enter ascitic fluid they may be lysed by the ac- tivity of complement or coated with opsonins. Complement defi- ciency also predisposes to infection. The opsonic activity of ascitic fluid correlates with the total protein, as well as that of CH100 (total haemolytic complement), C3, and C4 concentration. These concentrations may be increased by diuretics, thus decreasing the risk of SBP. Recent instrumentation A high degree of instrumentation increases the risk of secondary bacteraemia and potentially of SBP, but the risk is not increased by large-​volume paracentesis. Upper gastrointestinal haemorrhage Upper gastrointestinal haemorrhage increases the risk of SBP and other infections during or immediately after the bleeding episode (first 5–​7 days), with an incidence ranging between 16% (compen- sated cirrhosis) and 66% (advanced cirrhosis). Bacterial infections Box 15.22.2.3  Complications of ascites • SBP • Hepatorenal syndrome • Pleural effusion • Respiratory difficulties • Paraumbilical hernia • Hypercatabolic state Table 15.22.2.4  Organisms causing spontaneous bacterial peritonitis Enteric organisms (75–​80%) Escherichia coli (55%) Klebsiella spp. (15%) Enterobacter spp. (4%) Enterococcus faecalis (6%) Anaerobes (<1%) Nonenteric organisms (20–​25%) Gram-​positive cocci:   Streptococcus pneumoniae (10%)   Other Streptococcus spp. (5–​10%)   Staphylococcus spp. (2–​4%)   Others (2%) Box 15.22.2.4  Risk factors for SBP • Upper gastrointestinal haemorrhage • Previous SBP • Low protein ascites (<10–​15 g/​litre: decreased opsonic activity) • Instrumentation

section 15  Gastroenterological disorders 3066 in this setting increase the probability of failure to control bleeding, rebleeding, and hospital mortality. Antibiotic prophylaxis re- duces the mean incidence of in-​hospital infections, including SBP, rebleeding and improves survival. Previous SBP The recurrence rate for SBP is 47% at 6 months and 69% at 1 year. Patients recovering from a previous episode of SBP should receive antibiotic prophylaxis (norfloxacin 400 mg/​day or ciprofloxacin 500 mg/​day). Clinical features The clinical presentation of SBP depends on the stage at which the infection is diagnosed. Most patients present signs or symptoms clearly suggestive of peritoneal infection, although SBP may be asymptomatic, especially in the initial stages. Abdominal pain and fever are the most characteristic symptoms (Box 15.22.2.5). Other signs and symptoms are vomiting, ileus, diarrhoea, hepatic enceph- alopathy, gastrointestinal bleeding, renal impairment, septic shock, and hypothermia. Early diagnosis of SBP relies on the performance of diagnostic paracentesis at hospital admission in all cirrhotic patients with ascites and in hospitalized patients with ascites whenever they deteriorate. Prognosis and management The mortality associated with SBP is now about 10%. Adequate anti- biotics must be started as soon as a presumptive diagnosis is made following diagnostic paracentesis. For patients with bacterascites but no rise in the neutrophil count, the ascitic tap should be repeated. The treatment of SBP is summarized in Box 15.22.2.6. Empirical antibiotic schedules must be adapted to the site of acquisition of infection and to the local epidemiological pattern of antibiotic re- sistance given the higher rate of infections caused by multidrug-​ resistant bacteria in nosocomial infections (e.g. β-​lactams in community-​acquired infections and carbapenems ± glycopeptide in nosocomial infections). Treatment is continued until complete resolution of all signs of infection and the ascitic neutrophil count decreases to within the normal range, which is generally achieved within a week. The ad- ministration of albumin at a dose of 1.5 g/​kg at the time of diagnosis and 1 g/​kg on day 3 decreases the incidence of renal dysfunction and decreases mortality from 29 to 10%. Prevention Antibiotic prophylaxis in cirrhosis must be restricted to selected pa- tients at a very high risk of SBP in order to prevent the development ENTERIC BACTERIA BACTERIAL TRANSLOCATION TO MLN SBP BACTERAEMIA PORTAL VEIN Intestinal bacterial overgrowth Increased gut permeability RES dysfunction Portosystemic shunts Alterations in mucocutaneous barriers Decreased systemic clearance capacity Alterations in antimicrobial activity in ascites COLONIZATION OF ASCITIC FLUID NON-ENTERIC BACTERIA Fig. 15.22.2.5  Pathogenesis of SBP. Enterobacteria translocate from the intestinal lumen to the systemic circulation through the mesenteric lymph nodes (MLN). Bacteria reach ascites after sustained bacteraemia. If local host defence is poor, bacteria colonize ascitic fluid and cause SBP. RES, reticuloendothelial system. Box 15.22.2.5  Symptoms of SBP • Asymptomatic: 10% • Abdominal pain: 70% • Abdominal tenderness: 10% • Fever: 50% • Encephalopathy: 10% • Shock: <5% Box 15.22.2.6  Management of SBP 1 Diagnosis of SBP on ascitic fluid cell count (≥250 PMNs/​mm3) 2 Initiate appropriate intravenous antibiotics tailored according to the local epidemiological pattern of antibiotic resistance 3 Infuse albumin at 1.5 g/​kg at diagnosis and 1 g/​kg on day 3 4 Treat with antibiotics until 1 to 2 days after confirming resolution (repeated paracentesis) 5 Commence prophylaxis against future SBP (norfloxacin 400 mg/​day or ciprofloxacin 500 mg/​day) 6 Consider liver transplantation as 1-​year mortality is 75%

15.22.2  Cirrhosis and ascites 3067 of antibiotic resistance. Current indications of antibiotic prophylaxis are (1) upper gastrointestinal bleeding, (2) previous episode of SBP, and (3) low protein ascites (<15 g/​litre) and advanced cirrhosis (poor liver and/​or renal function). Hepatorenal syndrome Hepatorenal syndrome is the development of functional acute kidney injury in patients with advanced cirrhosis in the absence of any pathological cause of renal failure. It is due to a reduction of renal blood flow in the setting of a marked activation of the RAAS and the SNS. Systemic inflammation is also a major factor involved in pathogenesis. See Chapter 21.5 for further discussion. Pleural effusion Pleural effusions (hepatic hydrothorax) develop in about 5% of pa- tients with cirrhosis. Fluid tracks up into the pleural cavity via de- fects in the diaphragm (e.g. holes or blebs), which occasionally close spontaneously. Hepatic hydrothorax may develop in patients with no discernible ascites. The pleural effusions are right-​sided in 85% of cases and bilateral in 2% of cases. Management is as for conven- tional ascites unless it is unresponsive and causing severe dyspnoea, in which case a TIPS could be inserted. Respiratory difficulties Increasing abdominal distension due to the accumulation of peri- toneal fluid increases the effort required for breathing. Occasionally this may precipitate extreme difficulty in breathing that should be treated by rapid large-​volume paracentesis. Paraumbilical hernia Paraumbilical hernias develop in about 20% of patients with ascites, an incidence that increases up to 70% in those with long-​standing recurrent tense ascites. The main risks are rupture and strangula- tion, complications that require emergency surgery. Hypercatabolic state Many patients with ascites present in a hypercatabolic state, which may be secondary to chronic systemic inflammation probably re- lated to translocation of bacterial products from the intestinal lumen to the systemic circulation, together with their general state of malnutrition. Other issues Drug prescribing When prescribing a drug for any patient with liver disease it is al- ways sensible for the physician to check the product literature or some source such as the British National Formulary, but in patients with ascites, the following are worthy of particular comment: • Nonsteroidal anti-​inflammatory drugs are contraindicated in cir- rhosis because of the high risk of developing renal failure. • Drugs that can cause a reduction in arterial pressure or decrease renal blood flow (e.g. angiotensin-​converting enzyme inhibitors, and angiotensin II and α1-​adrenergic receptor blockers) should be avoided in patients with cirrhosis and ascites because of an in- creased risk of renal impairment. • Aminoglycosides are associated with an increased risk of nephro- toxicity and renal failure, hence their use should be reserved for patients with bacterial infections that cannot be treated with less toxic antibiotics. • Contrast media for radiological investigations should be used with care, particularly if the patient has significant renal impairment (beware the patient whose serum creatinine is ‘not too bad’ as a consequence of low muscle mass or body mass index). However, the only study assessing renal function after the administration of contrast media showed a very low incidence of nephrotoxicity. • Nonselective β-​blockers should be used with caution in the setting of refractory ascites and in any patient with a systolic blood pres- sure less than 90 mmHg, hyponatraemia (<130 mEq/​L), or acute kidney injury. Fertility Women with cirrhosis and ascites rarely, if ever, become pregnant, since ovulation has usually ceased before the onset of ascites. Areas of controversy and for further research The roles of inflammation, oxidative stress, and immune paralysis in the development of decompensation and acute-​on-​chronic liver failure in cirrhosis should be clarified in the near future. The mech- anisms of organ failure also require investigation. New indications for albumin administration should be inves- tigated (i.e. non-​SBP infections and advanced cirrhosis, and long-​ term albumin administration in patients with ascites). Current areas of controversy are mainly focused on safety issues of two treatments: nonselective β-​blockers in patients with as- cites (there are contradictory data regarding their impact on mortality) and automated low-​flow pumps in refractory ascites (preliminary re- ports suggest an increased morbidity associated with this device). Regarding SBP and antibiotic therapy, in the near future we will probably face a spread in antibiotic resistance in the cirrhotic popu- lation. Research on new antibiotics, early markers of bacterial trans- location and infection, and microbiological techniques is required. FURTHER READING Arroyo V, Ginés P (1992). Arteriolar vasodilatation and the pathogen- esis of the hyperdynamic circulation and renal sodium and water retention in cirrhosis. Gastroenterology, 102, 1077–​8. Bernard B, et al. (1995). Prognostic significance of bacterial infection in bleeding cirrhotic patients a prospective study. Gastroenterology, 108, 1828–​34. Bernardi M, et al. (2015). Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol, 63, 1272–​84. Caraceni P, et al. (2018). Long-term albumin administration in de- compensated cirrhosis (ANSWER): an open-label randomised trial. Lancet, 391, 2417–29. Chavez-​Tapia NC, et al. (2011). Meta-​analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding—​an up- dated Cochrane review. Aliment Pharmacol Ther, 34, 509–​18. Dolz C, et al. (1991). Ascites increases the resting energy expenditure in liver cirrhosis. Gastroenterology, 100, 738–​44.

15.22.3 Portal hypertension and variceal bleeding

15.22.3 Portal hypertension and variceal bleeding 3068

section 15  Gastroenterological disorders 3068 Fernández J, et al. (2007). Primary prophylaxis of spontaneous bac- terial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology, 133, 818–​24. Fernández J, et al. (2012). Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology, 55, 1551–​61. Ginès A, et al. (1996). Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by para- centesis. Gastroenterology, 111, 1002–​10. Ginès P, Cardenas A. (2008). The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis, 28, 435–​8. Ginès P, et al (2004). Management of cirrhosis and ascites. N Engl J Med, 350, 1646–​54. Ginès P, et al. (2008). Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial. Hepatology, 48, 2041–​3. Heuman DM, et al. (2004). Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology, 40, 802–​10. Iwakiri Y. (2007). The molecules: mechanisms of arterial vasodilata- tion observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol, 41, S288–​94. Jalan R, et al. (2014). Bacterial infections in cirrhosis: a position state- ment based on the EASL Special Conference 2013. J Hepatol, 60, 1310–​24. Luca A, et  al. (1994). Favorable effects of total paracentesis on splanchnic haemodynamics in cirrhotic patients with tense ascites. Hepatology, 20, 30–​3. Moreau R, et al. (2013). Acute-​on-​chronic liver failure is a distinct syn- drome that develops in patients with acute decompensation of cir- rhosis. Gastroenterology, 144, 1426–​37. Pare P, Talbot J, Hoefs JC (1983). Serum-​ascites albumin concentration gradient: a physiologic approach to the differential diagnosis of as- cites. Gastroenterology, 85, 245–​53. Ruiz-​del-​Arbol L, et al. (2003). Systemic, renal, and hepatic hemo- dynamic derangement in cirrhotic patients with spontaneous bac- terial peritonitis. Hepatology, 38, 1210–​18. Runyon BA (1986). Low-​protein-​concentration ascitic fluid is predis- posed to spontaneous bacterial peritonitis. Gastroenterology, 91, 1343–​6. Runyon BA, Hoefs JC (1984). Culture-​negative neutrocytic ascites a variant of spontaneous bacterial peritonitis. Hepatology, 4, 1209–​11. Runyon BA, et al. (1990). Bedside inoculation of blood culture bot- tles with ascitic fluid is superior to delayed inoculation in the de- tection of spontaneous bacterial peritonitis. J Clin Microbiol, 28, 2811–​12. Runyon BA, et al. (2009). Management of adult patients with ascites due to cirrhosis: an update. Hepatology, 49, 2087–​107. Schrier RW, et al. (1988). Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology, 8, 1151–​7. Sort P, et al. (1999). Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med, 341, 403–​9. Strauss RM, Boyer TD (1997). Hepatic hydrothorax. Semin Liver Dis, 17, 227–​32. Wiest R, Garcia-​Tsao G (2005). Bacterial translocation in cirrhosis. Hepatology, 41, 422–​33. Wiest R, et al. (2012). Spontaneous bacterial peritonitis: recent guide- lines and beyond. Gut, 61, 297–​31. 15.22.3  Portal hypertension and variceal bleeding Marcus Robertson and Peter Hayes ESSENTIALS Portal hypertension refers to a pathological elevation of pressure in the veins that carry blood from the splanchnic organs to the liver which, in developed countries, most commonly results from in- creased intrahepatic resistance to portal flow as a result of liver cirrhosis. Portal hypertension is associated with development of many of the complications of cirrhosis and confers a poor prognosis. Acute variceal bleeding is a life-​threatening medical emergency which re- mains a leading cause of death in patients with cirrhosis. Endoscopic variceal ligation and endoscopic variceal obturation remain the treatments of choice for bleeding oesophageal and gastric varices respectively. Advances in care including prophylactic antibiotics, vasoactive drugs, and transjugular intrahepatic portosystemic shunt in patients with bleeding refractory to early endoscopic management has improved the mortality rate, which is now estimated at 15 to 20%. Secondary prophylaxis of variceal bleeding with nonselective β-​blockers and/​or endoscopic variceal ligation reduces recurrent bleeding and has been demonstrated to improve survival. Portal hypertension Cirrhosis is an advanced stage of progressive hepatic fibrosis re- sulting from any chronic insult to the liver. It is characterized ana- tomically by distortion of hepatic architecture and the formation of regenerative nodules, and adversely affects both quality of life and life expectancy. The presence and severity of portal hyperten- sion correlates with the development of many of the complications associated with cirrhosis and has a profound impact on a patient’s prognosis. Definition and aetiology Portal hypertension refers to a pathological elevation of pressure in the veins that carry blood from the splanchnic organs (including the spleen) to the liver. This results in increased resistance to blood flow through the portal venous system and ultimately the devel- opment of a collateral circulation to carry portal blood into the systemic veins. Clinically, portal hypertension can be defined as an elevation of the hepatic venous pressure gradient to greater than 5  mmHg. In developed countries, portal hypertension most commonly results from increased intrahepatic resistance to portal flow as a result of liver cirrhosis. Portal blood flow in humans is approxi- mately 1000 to 1200 ml/​min, and in healthy subjects, 100% of portal blood flow is recovered from the hepatic veins that drain the liver. In cirrhosis, increased intrahepatic resistance means that significantly less portal blood flow reaches the hepatic veins, with the remainder entering portosystemic collateral channels,

15.22.3  Portal hypertension and variceal bleeding 3069 of which the most clinically significant are those from gastro-​ oesophageal varices (Fig. 15.22.3.1). Portal hypertension is fur- ther exacerbated in cirrhosis by the development of circulatory changes including splanchnic vasodilatation, which leads to plasma volume expansion resulting in a hyperdynamic circula- tion and increased cardiac output with increased portal flow and raised portal pressures. Noncirrhotic portal hypertension due to prehepatic (portal vein thrombosis, schistosomiasis) or posthepatic (Budd–​Chiari syn- drome, right heart dysfunction, constrictive pericarditis) conditions are also well described. Schistosomiasis infection is a particularly common and important cause of portal hypertension in developing countries. The hepatic venous pressure gradient is a useful clinical marker of portal pressure that has been shown to correlate well with portal pressure in both alcoholic cirrhosis and hepatitis C. It is defined as the gradient between the wedged hepatic venous pressure and the free hepatic venous pressure (the normal hepatic venous pressure gradient is <5 mmHg). A portal pressure greater than 10 mmHg is the baseline elevated pressure above which variceal formation and bleeding may occur, and the hepatic venous pressure gradient is predictive of both the risk of variceal bleeding and hepatic decom- pensation; it is also prognostic for survival. In all cases, higher hep- atic venous pressure gradient readings confer a poorer prognosis, although it is rarely measured in practice because of the invasiveness of the test. Clinical features Clinical manifestations of portal hypertension may include spleno- megaly, ascites, a venous hum over the xiphoid process or umbil- icus, and the development of abdominal wall veins such as caput medusae. Portal hypertension is associated with many of the known complications of cirrhosis (Box 15.22.31). The most common of these will be discussed in the following subsections. Ascites and hepatic encephalopathy Ascites is defined as the accumulation of free fluid in the peri- toneal cavity and is the most common complication of cirrhosis. (a) (b) Fig. 15.22.3.1  Gastro-​oesophageal varices. (a) Corrosion cast showing gastro-​oesophageal varices. (b) Postmortem radiograph study of the venous anatomy at the gastro-​oesophageal junction in a normal subject. Used with permission of Vianna and colleagues. Box 15.22.3.1  Complications of cirrhosis associated with portal hypertension • Gastro-​oesophageal varices • Portal hypertensive gastropathy • Ascites • Spontaneous bacterial peritonitis • Hepatic hydrothorax • Hepatorenal syndrome • Hepatic encephalopathy • Hepatopulmonary syndrome • Portopulmonary hypertension • Cirrhotic cardiomyopathy

section 15  Gastroenterological disorders 3070 Hepatic encephalopathy is defined as a reversible impairment in neuropsychiatric function occurring in a patient with ad- vanced liver disease. It is the second most common complication occurring in cirrhotic patients after ascites. Both conditions are associated with significantly reduced quality of life and reduced survival. Ascites and hepatic encephalopathy are discussed in Chapters 15.22.2 and 15.22.4. Hepatorenal syndrome Hepatorenal syndrome is a life-​threatening but potentially re- versible cause of renal dysfunction occurring in patients with advanced cirrhosis, ascites, and liver failure. It is characterized by functional renal impairment due to decreased renal perfu- sion in the setting of portal hypertension and splanchnic arterial vasodilatation. Two forms of hepatorenal syndrome are recognized:  type 1 is characterized by an acute progressive decrease in kidney function with a median survival time of 2 weeks without treatment, whereas type 2 features more chronic and less severe kidney failure and longer survival compared with type 1. Liver transplantation is the only effective long-​term therapy for hepatorenal syndrome. Management of hepatorenal syndrome involves identification and aggressive treatment of any precipitating factors such as infection. Pharmacological treatment with terlipressin (1–​2 mg/​4–​6-​hourly IV), a vasoconstrictor aiming to reverse splanchnic vasodilation, to- gether with albumin, is the first-​line treatment for patients with type 1 hepatorenal syndrome. This combination is effective in reversing renal dysfunction in 40 to 50% of patients and improves survival in this group. Hepatopulmonary syndrome Hepatopulmonary syndrome is characterized by pathological vaso- dilatation of the pulmonary vasculature. It is defined by a clinical triad—​occurring in the absence of coexisting cardiopulmonary disease—​of (1) an arterial oxygenation deficit (Pao2 <80 mmHg), (2) intrapulmonary vasodilation, and (3) the presence of liver dis- ease with portal hypertension. The presence of hepatopulmonary syndrome should be con- sidered in all patients with liver disease who complain of dyspnoea, which is common in cirrhosis and present in at least 50% of pa- tients with this syndrome. Finger clubbing is very common in hepatopulmonary syndrome, and one should always suspect hepatopulmonary syndrome in patients with chronic liver dis- ease and clubbing. Dyspnoea may be accompanied by pulmonary findings that are more specific for hepatopulmonary syndrome, including the following: • Platypnoea—​dyspnoea that is induced by moving into an upright position and relieved by being supine. • Orthodeoxia—​hypoxia that is worse when erect. Specifically, orthodeoxia refers to a decrease in arterial oxygen tension (by

4  mmHg) or arterial oxyhaemoglobin desaturation (by >5%) when the patient moves from a supine to an upright position, which is improved by returning to the recumbent position. The diagnosis of hepatopulmonary syndrome is made by esta­ blishing that impaired gas exchange in a patient with liver disease is due to pulmonary vascular dilatation. This is usually achieved by demonstrating the following: • Impaired oxygenation—​arterial blood gases taken with the pa- tient sitting upright at rest show hypoxia (Pao2 <80 mmHg) and/​ or an elevated alveolar–​arterial (A–​a) oxygen gradient, defined as ≥15 mmHg when breathing room air. • The presence of intrapulmonary shunting—​most commonly shown with contrast-​enhanced echocardiography, in which agitated saline microbubbles are used to differentiate between the normal situation (the bubbles opacify only the right heart chambers), a right-​to-​left intracardiac shunt (microbubbles ap- pear in the left heart within three heart beats after injection), and an intrapulmonary shunt (microbubbles appear in the left heart three to six heart beats after injection). Technetium-​labelled macroaggregated albumin scanning is an alternative method of identifying pulmonary shunting and can determine the shunt fraction. There are no proven medical therapies for hepatopulmonary syn- drome and liver transplantation remains the primary treatment option. Long-​term supplemental oxygen is the most frequently re- commended therapy for symptoms such as dyspnoea. Portopulmonary hypertension Portopulmonary hypertension refers to a rare pulmonary vascular disorder of pulmonary arterial hypertension coexisting with portal hypertension in a patient where alternative causes of pulmonary ar- terial hypertension have been excluded. It is a well-​recognized com- plication of chronic liver disease and cirrhosis, but far less common than hepatopulmonary syndrome, although patients can rarely have features of both disorders. In portopulmonary hypertension, the pulmonary circulatory ab- normality is vasoconstriction with fibro-​obliteration of the vascular bed, the opposite of the changes that occur in hepatopulmonary syn- drome. Patients may present with fatigue, dyspnoea, signs of right heart failure, chest pain, and syncope. The diagnosis may be sug- gested by echocardiography but is confirmed by right heart cath- eterization. Treatment tends to be as for other causes of pulmonary arterial hypertension. Patients with moderate to severe disease can be difficult to treat with medical therapy and perioperative mortality with liver transplantation is high. Cirrhotic cardiomyopathy Cirrhotic cardiomyopathy refers to cardiac dysfunction (including impaired cardiac contractility with systolic and diastolic dysfunc- tion, as well as electromechanical abnormalities such as prolonged QT syndrome) which occurs in patients with cirrhosis and portal hypertension in the absence of other known causes of cardiac dis- ease. Patients with cirrhotic cardiomyopathy usually have normal to increased cardiac output and contractility at rest but demonstrate a blunted response to pharmacological, physiological, or patho- logical stress, with unmasking of systolic incompetence. Cirrhotic cardiomyopathy has been associated with the development of heart failure following invasive procedures such as shunt insertion and liver transplantation. Current pharmacological treatment is nonspecific and directed towards left ventricular failure.

15.22.3  Portal hypertension and variceal bleeding 3071 Variceal bleeding In patients with portal hypertension, a combination of increased splanchnic blood flow and intrahepatic resistance to portal blood flow can lead to the development of portosystemic collaterals, of which the most clinically significant are those from gastro-​ oesophageal varices. Acute variceal bleeding is a common and life-​threatening com- plication occurring in patients with portal hypertension and a leading cause of death in patients with cirrhosis. Variceal haem- orrhage continues to be associated with substantial mortality. Advances in care have seen the mortality rate associated with an episode of acute variceal bleeding significantly improve from 30 to 50% to 11 to 20% in more recent studies. This improvement in outcomes can be attributed to multiple factors, including recogni- tion of the importance of adequate resuscitation, early endoscopy, and accurate diagnosis. The therapeutic armamentarium has been significantly expanded and now includes endoscopic, adjunctive pharmacological and radiological therapies which have high efficacy at obtaining haemostasis. In addition, practice guidelines that outline optimal care for patients presenting with acute variceal bleeding have been developed. Definition Variceal haemorrhage is defined as bleeding from an oesophageal or gastric varix at the time of endoscopy or the presence of large oesophageal varices with blood in the stomach and no other recog- nizable cause of bleeding. Risk factors Gastro-​oesophageal varices (Fig. 15.22.3.2) are present in approxi- mately 50% of patients with cirrhosis at the time of diagnosis. In patients with established varices, 12% will have a first variceal haem- orrhage within 1  year and approximately one-​third will bleed at some point. Following an episode of acute variceal bleeding, 60% of patients will rebleed within 1 year. Many factors have been implicated in precipitating haemorrhage. The most significant risk factors for variceal bleeding include: (a) (c) (b) Fig. 15.22.3.2  (a) Grade 3 oesophageal varices. (b) Oesophageal varices with high-​risk stigmata (fibrin plugs at
7 o’clock and 11 o’clock). (c) Endoscopic variceal ligation of oesophageal varices. Pictures courtesy of Dr Ian Penman.

section 15  Gastroenterological disorders 3072 • large varices—​for patients with nearly identical portal hyper- tension, the likelihood of acute variceal bleeding is markedly in- creased in patients with large varices • the presence of high-​risk variceal stigmata collectively known as ‘red signs’—​red wale, markings, cherry red spots, nipple sign, haematocystic spots • other endoscopic findings—​blue varices, giant coiled varices, and panoesophageal varices • a portal venous pressure higher than 12 mmHg above inferior vena cava pressure Patients with severe liver disease (Child–​Pugh score C) are also sig- nificantly more likely to experience acute variceal bleeding. Prognosis Several factors have been validated for the prediction of complica- tions such as early rebleeding and mortality following an episode of variceal bleeding. Overwhelmingly, mortality is dictated by the severity of the underlying liver disease and hence scores such as the Model for End-​Stage Liver Disease (MELD) score and the Child–​ Pugh (Child–​Pugh–​Turcotte) score, along with the presence of hep- atic encephalopathy, are predictive of outcome. Other risk factors which confer a poor prognosis are listed in Table 15.22.3.1. Reducing the portal pressure by at least 20% or to less than 12 mmHg following an acute variceal bleeding is associated with significant protection against further bleeding. Management of acute variceal bleeding Management of a patient with acute variceal bleeding incorporates both treatment and control of the active bleeding and the prevention of complications such as rebleeding, infections, and renal failure. Primary management goals include haemodynamic resuscitation, early endoscopic intervention aiming to control bleeding, and pre- vention and treatment of complications. A summary of acute vari- ceal bleeding management is shown in Fig. 15.22.3.3. Resuscitation Acute variceal bleeding is a life-​threatening event and patients are often haemodynamically unstable or in haemorrhagic shock on presentation. Airway protection is paramount in order to prevent pulmonary aspiration, with endotracheal intubation mandatory if there is any concern about the safety of the airway. This should be considered at an early stage in encephalopathic patients, those with altered conscious state or a low Glasgow Coma Scale score, or those with severe uncontrolled bleeding. After attention (if required) to the airway, initial resuscitation is aimed at restoring haemodynamic stability and appropriate blood pressure. All patients with suspected acute variceal bleeding should receive immediate large-​bore intravenous access, and blood volume replacement with plasma expanders should be initiated as soon as possible, aiming to maintain a systolic blood pressure of about 90 to 100 mmHg. It is imperative to avoid prolonged periods of hypoten- sion to prevent complications such as infection and renal failure, both of which are associated with increased risks of rebleeding and death. A restrictive blood transfusion strategy is now accepted as standard of care and is associated with significantly improved outcomes in patients with acute upper gastrointestinal bleeding. Patients should be transfused to maintain a target haemoglobin level between 70 and 80 g/​L. Patients with rapid ongoing bleeding and those with underlying heart disease may benefit from a more liberal transfusion policy, which can be assessed on a case-​by-​case basis. Correction of coagulopathy and thrombocytopenia is widely practised with the use of both fresh frozen plasma and platelets, but there is no evidence to support this practice and endoscopy should not be delayed for this to occur. Recombinant activated factor VII has not shown any benefit in patients with acute variceal bleeding and is not recommended. Nutrition Malnutrition is prevalent among patients with chronic liver dis- ease and is associated with increased morbidity and mortality. Patients presenting with acute variceal bleeding are fasted to facili- tate treatment, but feeding should be resumed as soon as possible after haemostasis is achieved (practically this tends to be at least 24 h following control of bleeding). Enteral nutrition is preferable to parenteral nutrition due to lower cost and complications; if a naso- gastric tube is required, current guidelines recommend delaying in- sertion until at least 72 h after haemostasis and use of a fine bore tube. Administration of thiamine should also be given to alcoholic or malnourished patients to prevent Wernicke syndrome. Pharmacological management Prophylaxis and treatment of infection Infection is a strong prognostic indicator in acute variceal bleeding, associated with both early rebleeding and increased mortality. Gram-​negative bacilli are the pathogens most commonly associated with upper gastrointestinal bleeding in cirrhotic patients. Empiric prophylactic antibiotics significantly reduce the incidence of infec- tion, resulting in a decreased risk of rebleeding, all-​cause mortality, and hospital length of stay. All patients presenting with an episode of acute variceal bleeding should therefore receive prophylactic anti- biotic therapy on admission. Survival benefits are observed independently of the antibiotic agent used and hence the choice of antibiotic should take into consideration local factors such as bacterial resistance profile and treatment cost. Oral quinolones (norfloxacin 400 mg twice daily or ciprofloxacin 500 mg twice daily for 7 days) have frequently been used due to their low cost and ease of administration, and these agents can also be given intravenously. Intravenous third-​generation Table 15.22.3.1  Factors that confer a poor prognosis in patients presenting with acute variceal bleeding Advanced liver disease Child–​Pugh C liver disease High MELD score Presence of hepatic encephalopathy Factors at presentation Shock Renal impairment Bacterial infection Characteristics and severity of the
variceal bleed Active bleeding at time of endoscopy High-​risk stigmata on varices Red cell transfusion requirement Other Hepatocellular carcinoma Portal vein thrombosis Hepatic venous pressure gradient >20 mmHg

15.22.3  Portal hypertension and variceal bleeding 3073 cephalosporins such as ceftriaxone (1 g daily for 3–​5 days) are also well studied and may be more efficacious in patients with advanced cirrhosis presenting with acute variceal bleeding. Other agents with broad Gram-​negative cover such as piperacillin–​tazobactam (Tazocin) are also used in many centres. Pre-​endoscopic vasoactive therapy Vasoactive medications are commonly used in the management of acute variceal bleeding to acutely decrease splanchnic blood flow and portal pressures. Meta-​analyses and treatment guidelines advocate that the combination of vasoactive drugs and endoscopic therapy is superior to either intervention alone. Medications include vasopressin and its analogue terlipressin, and somatostatin and its analogue octreotide. The use of vasoactive medications is associated with im- proved haemostasis, decreased 7-​day mortality, decreased transfusion requirements, and shorter hospital length of stay, with terlipressin the only agent individually demonstrated to reduce mortality. Vasoactive therapy should be considered at the time of presenta- tion in all patients presenting with haematemesis who have known varices or are at risk for varices; it should not be delayed until the diagnosis is confirmed. Vasoactive therapy should be commenced prior to endoscopy if any delay is anticipated with endoscopic therapy. In situations where endoscopy is unavailable, vasoactive therapy should be considered as first-​line therapy. Treatment is gen- erally continued for 3 to 5 days. • Vasopressin:  administered by continuous intravenous infusion, but no longer recommended as a monotherapy in acute variceal bleeding due to the high risk of significant side effects including myocardial infarction and mesenteric ischaemia. Vasopressin ad- ministered in combination with nitrates (potent vasodilators) re- duces the side-​effect profile and may lower portal pressures more effectively. • Terlipressin: a synthetic vasopressin analogue with a longer half-​life and less adverse effects, and the vasoactive agent of choice in many • Endotracheal intubation mandatory to prevent pulmonary aspiration if there is any concern about airway safety (e.g. decreased GCS, encephalopathy) Airway protection • Large-bore central line or intravenous access • Fluid resuscitation aiming to maintain systolic blood pressure of
90 mmHg • Conservative blood transfusion policy (target haemoglobin level 7–8 g/dl) Haemodynamic resuscitation • Antibiotics: improve survival and prevent infection. All patients receive 3–5 days of a broad-spectrum antibiotic (IV ceftriaxone, piperacillin–tazobactam or oral fluoroquinolone) • Vasoactive medications: commonly commenced prior to endoscopy in patients with suspected acute variceal bleeding and continued for 3–5 days. Agents include terlipressin or octreotide. Pharmacological therapy • Urgent endoscopic treatment is the cornerstone of management • Endoscopic variceal ligation (EVL, ‘banding’) is the gold standard technique to control bleeding oesophageal varices • Gastric varices are treated with endoscopic injection of tissue adhesives or thrombin Endoscopic therapy • If refractory ongoing bleeding despite endoscopic and pharmacological therapy, salvage treatment options include: • Balloon tamponade with a Sengstaken–Blakemore or Minnesota tube • Deployment of a self-expanding oesophageal stent • Transjugular intrahepatic portosystemic shunt (TIPS) Salvage therapy Fig. 15.22.3.3  Management algorithm for acute variceal bleeding. GCS, Glasgow Coma Score.

section 15  Gastroenterological disorders 3074 countries outside of the United States of America. It is administered as a 1-​ to 2-​mg intravenous bolus every 4 to 6 h. Use of terlipressin in patients with acute variceal bleeding can achieve early haemostasis rates of 75 to 80% and a 34% relative risk reduction in mortality. Adverse events are uncommon, although terlipressin should not be used in patients with a history of ischaemic heart disease or periph- eral vascular disease due to a risk of inducing ischaemia. • Somatostatin: administered as an initial bolus of 250 μg followed by a 250-​ to 500-​μg continuous infusion until a bleed-​free period of 24 h is achieved. Somatostatin has shown superior haemostasis to vasopressin in studies and also has a superior safety profile with fewer side effects. Both somatostatin and octreotide have a good safety profile; side effects include hyperglycaemia and abdominal cramping. • Octreotide: a synthetic somatostatin analogue with a longer half-​ life and the most common agent used in the United States. It is ad- ministered as a 50-​μg intravenous bolus, followed by a continuous infusion at a rate of 25 to 50 μg/​h. Octreotide has been shown to be more effective than vasopressin and equivalent to other vasoactive treatments. Terlipressin and octreotide appear to be equivalent as an adjuvant therapy for control of acute variceal bleeding in con- junction with endoscopic variceal band ligation (EVL). Endoscopic management Urgent upper gastrointestinal endoscopy remains the gold standard for diagnosis and treatment of variceal haemorrhage; 80 to 90% of acute variceal bleeding episodes are successfully controlled by endo- scopic therapy. Emergency endoscopy should be performed as soon as safely possible after admission to confirm a variceal origin of the haemorrhage (which represents the leading cause of upper gastro- intestinal bleeding in cirrhotic patients) and to perform definitive haemostatic therapy. Delayed endoscopy (endoscopy >12–​15 h after admission) is associated with increased rebleeding and mortality. The two principal methods for management of oesophageal varices are endoscopic injection sclerotherapy (EIS) and EVL. Both have been shown to be effective in the control of acute variceal bleeding. Endoscopic injection sclerotherapy EIS is a technique whereby a flexible catheter with a needle tip is passed through the accessory channel of the endoscope and used to inject a sclerosing agent either into the variceal lumen or adjacent to the varix. Sclerosing agents are oily or aqueous chemicals which in- duce thrombosis of the vessel and inflammation of the surrounding tissues. EIS achieves haemostasis by variceal thrombosis and/​or ex- ternal compression of the varix by tissue oedema. EIS has a number of advantages: it is a low-​cost and (relatively) easy-​to-​use technique, it can be quickly assembled, treatment of bleeding varices does not require a second oral intubation, and the sclerosants induce rapid thrombosis. The major disadvantage of EIS is the high rate of local and systemic complications associated with the procedure. Minor complications are extremely common and include fever, retrosternal chest discomfort, dysphagia, asymptom- atic pleural effusions, and nonspecific transient chest radiographic changes. These complications do not generally require treatment and resolve spontaneously. More significant complications are listed in Table 15.22.3.2. Bacteraemia, post-​EIS oesophageal ulcer bleeding, and oesophageal strictures are the most frequent and significant ad- verse events encountered. These hazardous complications can be a consequence of incorrect injection technique, with either a large volume or a high concentration of sclerosant being injected and re- sulting in extensive wall necrosis. Mortality directly resulting from post-​EIS complications is around 2% and usually the result of re- current bleeding, perforation, sepsis, or severe respiratory disorders. EIS has been used to treat acute variceal bleeding for over 50 years. The technique was widely adopted in the 1970s which corresponded with the time of a significant improvement in survival of patients presenting with acute variceal bleeding. EIS is successful in control- ling active bleeding in at least 90% of patients and can reduce the frequency and severity of recurrent variceal bleeding. However, due to its high adverse event rate, EIS has now been superseded by EVL and should be used only in the circumstances or cases when band ligation is not available. Endoscopic variceal ligation Ligation of oesophageal varices was introduced in the 1980s and evolved from the established treatment of banding haemorrhoids. EVL involves the sucking of a variceal column into a hollow plastic cylinder attached to the tip of the endoscope, followed by the place- ment of a rubber ring onto the column which ligates and ultimately strangulates the varix (Fig. 15.22.3.2). Following variceal banding, the tissue ligated by the rubber band undergoes ischaemic necrosis accompanied by variceal thrombosis. The ligated tissue, along with the band itself, generally falls off within a few days, leaving shallow oesophageal ulcers which are shallower, have a greater surface area, and heal more rapidly than those caused by EIS. Commercial multiband devices are available for EVL which are disposable and have between 4 and 10 preloaded bands, enabling multiple varices to be ligated in a single banding session. Table 15.22.3.2  Complications of endoscopic injection sclerotherapy Category Complication Minor postprocedure Low-​grade fever Retrosternal chest pain Transient dysphagia Nonspecific chest X-​ray changes Local Injection-​induced bleeding Oesophageal ulcers/​mucosal ulceration Post-​EIS ulcer bleeding Oesophageal strictures Perforation Cardiorespiratory Pleural effusions Adult respiratory distress syndrome Pericarditis Mediastinitis Broncho-​oesophageal fistula Systemic/​infectious Fever Bacteraemia Spontaneous bacterial peritonitis Distant embolism Distant abscess

15.22.3  Portal hypertension and variceal bleeding 3075 The most common side effects associated with EVL include chest discomfort and postbanding ulceration; rarer side effects in- clude oesophageal strictures and bleeding resulting from a band falling off. To minimize chest pain and band removal, patients are generally commenced on a liquid-​only or soft diet for the first 12 h. The incidence of bacteraemia and infectious complications are significantly reduced with EVL compared to EIS. The incidence of bleeding from band-​induced ulcers following EVL varies widely between studies, but is significantly more frequent in patients undergoing EVL for acute bleeding, as compared with elective EVL for primary or secondary prevention of variceal bleeding. Patients with more severe liver disease, as evidenced by a higher Child–​ Pugh score or impaired synthetic function (hypoalbuminaemia and/​or coagulopathy) may be more likely to experience post-​EVL bleeding. The incidence of bacterial infection is also higher in pa- tients experiencing post-​EVL bleeding. Comparison of EIS and EVL Both EVL and EIS have been shown to be effective in the control of acute variceal bleeding. Multiple randomized control trials and meta-​analyses have compared EVL and EIS. These studies demon- strate that EVL is superior to EIS for eradicating varices more rapidly, with significantly less recurrent bleeding, and is also associated with significantly fewer adverse events compared to EIS. Some (but not all) studies have also demonstrated a survival advantage in patients treated with EVL. Thus, EVL should be considered the gold standard endoscopic treatment for controlling an acute variceal haemorrhage, with EIS considered only in situations where EVL is not available. Rescue therapies in cases of refractory oesophageal
variceal bleeding Despite best practice management, 10 to 20% of patients with acute variceal bleeding will experience treatment failure or early rebleeding. Any bleeding that occurs more than 48 h after the ini- tial admission for variceal haemorrhage, provided there has been at least a 24-​h period without bleeding, is considered to represent rebleeding. Approximately 40% of rebleeding episodes will occur within 5 days of the original variceal bleed. Mortality of patients in this group remains high (30–​50%) and rebleeding remains a strong predictor of death from variceal bleeding. Treatment options in the setting of rebleeding include a second endoscopy, balloon tamponade, oesophageal stenting, and transjugular intrahepatic portosystemic shunting (TIPS) or surgical portosystemic shunting. Second endoscopy In the setting of failure of initial combined treatment (endoscopy and vasoactive therapy), it is reasonable to consider a second at- tempt at endoscopic therapy to obtain haemostasis. Second endos- copy can occur either before or after a period of balloon tamponade. Balloon tamponade Balloon tamponade with a Sengstaken–​Blakemore or Minnesota tube (Fig. 15.22.3.4) is a temporizing measure that pneumatically compresses the gastric fundus and lower oesophagus to achieve haemostasis. It successfully achieves haemostasis in 60 to 90% of re- fractory variceal bleeds, and it may be life-​saving in cases of massive bleeding where endoscopic treatment is unavailable. Generally, only the gastric balloon needs to be inflated with 250 to 300 ml of air. It is important that traction on the tube is maintained, usually using wooden spatulas attached around the tube at the mouth to prevent the traction slipping. Patients should remain intubated and the tube should be deflated within 24 h. Patients require further endoscopy (or other procedures such as TIPS) immediately after deflation as at least 50% will rebleed. Use of balloon tamponade is also associated with serious complications in 6 to 20% of patients, including aspiration, oesophageal ulceration, and oesophageal perforation, the latter being associated with extremely high mortality. Ideally, insertion of the bal- loon tamponade should be performed by someone experienced with the technique as this is associated with fewer complications. Self-​expandable covered metal stents Case reports have documented the successful use of self-​expandable covered metal stents in controlling refractory oesophageal vari- ceal bleeding. Stent insertion appears to be efficacious at stopping ongoing bleeding, although there is a high rebleeding rate with con- servative management following stent removal, hence it is likely to represent a temporizing measure to enable a definitive interven- tional or surgical procedure to lower portal pressures. Transjugular intrahepatic portosystemic shunt TIPS is a radiologically placed portosystemic shunt that achieves haemostasis in approximately 95% of patients with refractory vari- ceal bleeding. The procedure is only available in specialized centres and involves creation of a low-​resistance channel between the hep- atic vein and the intrahepatic portion of the portal vein using angio- graphic techniques. TIPS does not require general anaesthesia or major surgery for placement. TIPS is a highly effective therapy in carefully selected patients. A good prognosis relies on the general condition of the patient, the value of the liver function reserve, associated comorbidities, and the timing of the procedure. The survival benefit of TIPS in patients with severe liver failure (defined as: Child–​Pugh class C cirrhosis, MELD score >22, serum bilirubin >3 mg/​dL) remains unclear. In patients with a Child–​Pugh score greater than 13, early mortality after TIPS is almost inevitable. Chronic portal vein thrombosis does not absolutely preclude TIPS insertion but makes the pro- cedure technically challenging. Contraindications to TIPS are listed in Table 15.22.3.3. Treatment guidelines for acute variceal bleeding currently cat- egorize TIPS as a second-​line treatment, applicable for patients in whom combined pharmacological and endoscopic therapy has failed to control bleeding. Its role as a salvage therapy stems from the fact that although TIPS is extremely effective in controlling variceal bleeding, two early meta-​analyses demonstrated equivalent patient Fig. 15.22.3.4  A Sengstaken–​Blakemore tube used to pneumatically tamponade varices.

section 15  Gastroenterological disorders 3076 survival to endoscopic therapy but with an increased risk of hepatic encephalopathy. More recently, the role of TIPS in acute variceal bleeding is being re-​evaluated in the setting of technical advances and new studies. The introduction of extended polytetrafluoroethylene (PTFE) covered stents has significantly improved TIPS stent patency and reduced the incidence of encephalopathy when compared with bare stents. Carefully selected patients at high risk of bleeding-​related mortality and/​or rebleeding (hepatic venous pressure gradient ≥20  mmHg, Child–​Pugh B patients with active bleeding at endoscopy or Child–​ Pugh C patients with a score <14) may benefit from early TIPS (within 3 days of admission) placement, with reduced treatment failure, hos- pital and intensive care unit length of stay, and in-​hospital and 1-​year mortality. In addition, a recent meta-​analysis concluded that early TIPS in high-​risk patients with acute variceal bleeding may improve survival with no significantly increased incidence of post-​treatment hepatic en- cephalopathy Further studies are currently underway evaluating the benefits of early TIPS in high-​risk patients with acute variceal bleeding. Surgical shunting procedures Following the introduction of TIPS, surgical shunting procedures are now rarely performed and they are no longer a first-​line rescue therapy. Procedures included shunt operations (portacaval shunts, distal splenorenal shunts) and nonshunt operations (oesophageal transections or devascularization of the gastroesophageal junction). Portal decompressive surgery and oesophageal transection were highly effective in achieving haemostasis, although they are asso- ciated with significant mortality (approximately 45–​75%). Similar to TIPS, shunt surgery also significantly increases the incidence of hepatic encephalopathy. Prophylaxis against variceal bleeding Primary prophylaxis All patients with a new diagnosis of cirrhosis are recommended to undergo endoscopic screening for the presence and size of varices so that prophylactic therapy can be given to those with varices that are at high risk of bleeding. Patients with compensated cirrhosis and no varices at index endoscopy should have endoscopy repeated every 2–3 years, with the timing influenced by whether the liver injury is ongoing. Patients with compensated cirrhosis and small varices with no high-risk stigmata may be considered for endoscopic vari- ceal surveillance annually to evaluate progression. There is emerging evidence that some patients with cirrhosis may be able to avoid screening endoscopy, with the risk of variceal bleeding assessed using noninvasive methods. The probability of high-risk varices being present appears to be very low (<5%) in pa- tients with compensated cirrhosis with a platelet count ≥150 000 and a liver stiffness of <20 kPa on transient elastography (TE), although currently this is only well validated in patients with hepatitis C. In this patient cohort, one approach may be to perform annual platelet count and TE scans, and perform endoscopic screening for varices if the platelet count drops to <150 000 and/or the LS increases to ≥20 kPa. More studies are required to validate this method. Primary prophylaxis of acute variceal bleeding, using either a nonselective β-blocker or EVL, is recommended in all patients with a high-risk of bleeding. These include: a) Patients with medium or large varices; b) Patients with small varices with high-risk stigmata (‘red signs’); c) Patients with decompensated cirrhosis (Child Pugh B or C) regardless of variceal size Both β-​blockers and EVL display equivalent efficacy and survival and the choice of modality depends on factors such as comorbidities, compliance, and access to endoscopy. Propranolol has traditionally been the β-​blocker most commonly prescribed for prophylaxis of variceal bleeding in cirrhotic patients. More recent studies have shown carvedilol, a nonselective β-​blocker with intrinsic α1-​adrenergic activity, to produce a greater decrease in portal pressure. Carvedilol (6.25 mg increasing to 12.5 mg oral daily) should be considered a first-​line agent and may reduce the incidence of acute variceal bleeding more effectively than EVL. If propranolol is selected, the dose of β-​blocker is titrated to either the maximum dose, a reduction in resting heart rate of 25% from baseline, or the develop- ment of side effects. With carvedilol, patients are commenced on 6.25 mg daily and the dose increased 1 week later to 12.5 mg if tolerated. Once treatment is initiated, it is generally continued lifelong as bleeding risk returns to baseline if the treatment is ceased. If β-​blockers are contraindicated due to comorbidities such as reactive airway disease, congestive heart failure, bradycardia, or heart block, EVL should be in- stituted. EVL involves serial episodes of variceal banding until oesopha- geal varices are eradicated; this typically takes four to six procedures. Secondary prophylaxis Following a variceal bleed, all patients should receive secondary prophylaxis with nonselective β-​blockers and EVL, or TIPS. Non­ selective β-​blockers and EVL both significantly decrease the risk of rebleeding and improve mortality; combination treatment is now re- commended as standard of care. β-blockers are an essential part of combination therapy, since their benefit extends to other complica- tions of portal hypertension. TIPS is associated with a lower rebleeding rate compared to endoscopic or pharmacological therapy, but at the expense of an increased risk of hepatic encephalopathy. TIPS is mainly considered in patients with recurrent acute variceal bleeding. Gastric varices Gastric variceal bleeding is significantly less common than oe- sophageal variceal bleeding but is another serious complication of portal hypertension. Gastric varices develop in approximately 20% Table 15.22.3.3  Absolute and relative contraindications to TIPS insertion Absolute contraindications Congestive cardiac failure Severe pulmonary hypertension Severe systemic sepsis Severe tricuspid regurgitation Unresolved biliary obstruction Relative contraindications Portal vein thrombosis Hepatocellular carcinoma Hepatic encephalopathy Severe coagulopathy Obstruction of all hepatic veins Polycystic liver disease (technically challenging with high risk of haemorrhagic complications) Adapted from Loffroy R, Estivalet L, Cherblanc V, et al. (2013). Transjugular intrahepatic portosystemic shunt for the management of acute variceal hemorrhage. World J Gastroenterol, 19, 6131–​43.

15.22.3  Portal hypertension and variceal bleeding 3077 of patients with portal hypertension and represent 5 to 10% of all upper gastrointestinal bleeding episodes in cirrhotic patients. They are also commonly seen in patients with noncirrhotic portal hyper- tension and especially in patients with splenic vein thrombosis. The risk of first bleeding from gastric varices is lower than that for oe- sophageal varices, but bleeding is typically more severe and associ- ated with higher morbidity, transfusion requirements, and mortality than oesophageal varices. Gastric varices can be found alone or in combination with oesophageal varices (Fig. 15.22.3.5). Risk factors for gastric variceal bleeding appear in Table 15.22.3.4. Gastric varices are most commonly subtyped according to Sarin’s classification based on their location in the stomach and their relation- ship to oesophageal varices (Fig. 15.22.3.6). Type 1 gastro-​oesophageal varices (GOV) represents the most common of all gastric varices (74%) and are also known as cardial varices. GOV2 and type 1 isolated gas- tric varices (IGV), at 21% and 7% of gastric varices respectively, are together referred to as fundal varices. Although less common than GOV1, fundal varices are much more likely to bleed and account for 80% of patients presenting with bleeding gastric varices. Diagnosis of gastric varices is made by endoscopy. Endoscopic ultrasonography can be used to clarify or further differentiate gastric varices if required (Fig. 15.22.3.5). If only IGV are present, exclusion (a) (b) (c) Fig. 15.22.3.5  Endoscopic image of gastric varices. (a) Large gastric varices in the fundus of the stomach. (b) Endoscopic injection of thrombin into gastric varices. (c) Endoscopic ultrasonography with Doppler flow showing multiple collaterals extending into the gastric wall in a 56-​year-​old male with known segmental portal hypertension and gastric varices as a result of splenic vein thrombosis. Images courtesy of Dr Ian Penman. Table 15.22.3.4  Risk factors for gastric variceal bleeding Risk factor Explanation Location of gastric varices IGV1 >GOV2 >GOV1 (Fig. 15.22.3.5) Size of gastric varices Large (>10 mm) >medium (5–​10 mm)

small (<5 mm) Severity of liver disease Child–​Pugh class C >B >A MELD score ≥17 Concomitant hepatocellular carcinoma Presence of portal hypertensive gastropathy Presence of high-​risk stigmata Red colour signs/​red spots Adapted from Clinics in Liver Disease, Vol. 18, Sarin SK, Kumar A, Endoscopic treatment of gastric varices, Pages 809–​27, Copyright © 2014, with permission from Elsevier.

section 15  Gastroenterological disorders 3078 of portal or splenic vein thrombosis as the underlying cause with Doppler ultrasonography is imperative. Management of acute gastric variceal bleeding The preliminary management of gastric variceal bleeding is identical to that for oesophageal bleeding: airway protection, fluid resuscita- tion, empiric antibiotic prophylaxis, and use of vasoactive agents. Evidence for the use of vasoactive drugs in acute gastric variceal bleeding is limited and efficacy is inferred from their effectiveness in controlling oesophageal variceal bleeding. Therapeutic options for acute gastric variceal bleeding include balloon tamponade, endo- scopic therapies, radiological therapies, or surgical procedures. Evidence in this area is scarce, with few randomized controlled trials and little consensus as to the gold standard treatment. Balloon tamponade Balloon tamponade with pneumatic compression of gastric varices is a temporizing measure or bridge to further definitive therapies. It can achieve haemostasis in up to 80% of patients with gastric vari- ceal bleeding, but rebleeding occurs frequently. Endoscopic management Endoscopic therapy remains the treatment of choice and all cir- rhotic patients presenting with upper gastrointestinal bleeding should be scoped as soon as possible. The endoscopic therapies util- ized for bleeding gastric varices often depend on availability and local expertise: • EIS: prior to the introduction of newer techniques, EIS with con- ventional sclerosants was used to control acute gastric variceal bleeding. EIS was less efficacious than when utilized for oesopha- geal varices, with larger volumes of sclerosant required and more side effects described. Overall, the success of EIS is questionable in the management of gastric variceal bleeding and it is not a pre- ferred haemostatic method. • EVL: EVL is also less effective for gastric varices. This is due to the fact that gastric varices are larger and located deep in the sub- mucosa, making ligation difficult. • Endoscopic variceal obturation (EVO):  EVO is the endoscopic treatment of choice to gain haemostasis of gastric varices, su- perior to both EIS and EVL. Obturation is the term used for gas- tric varices treated by glue injection, because the varix can be visible after it has been effectively treated. EVO involves injecting tissue adhesives such as N-​butyl-​2-​cyanoacrylate into the varix lumen. This rapidly undergoes exothermic polymerization on contact with water or blood, changing from a liquid to a hard brittle acrylic plastic and stemming the flow of blood from the varix. EVO can achieve haemostasis rates of over 90% in the man- agement of gastric variceal bleeding, and rebleeding rates vary from 15 to 30%. The most significant complication associated with cyanoacrylate injection relates to postprocedure thrombo- embolic phenomena including cerebral stroke, portal vein embol- ization, splenic infarction, renal, coronary, or spinal embolus, and pulmonary embolus, with rare deaths documented. Embolic and thrombotic phenomena are associated with larger volumes of glue injection. Other complications include the needle becoming stuck in the varix, gastric ulceration, retrogastric abscess, visceral fistula formation, and bacteraemia or sepsis. • Endoscopic thrombin injection: thrombin is a haemostatic agent first used for the management of gastric varices in 1947. Bovine thrombin was used originally, but due to the increased risks of prion transmission has been superseded by human thrombin. Thrombin induces haemostasis by converting fibrinogen to a fibrin clot and also influences platelet aggregation. A 5-​ml so- lution of thrombin containing 1000 units/​ml of thrombin will clot a litre of blood in under 60 s. A standard gastroscope is Gastro-oesophageal varices (GOV) are associated with oesophageal varices which extend along the lesser curve of the stomach (GOV1), or along the fundus (GOV2) Isolated gastric varices (IGV) are gastric varices without any associated oesophageal varices; these can be localised to the fundus (IGV1) or at ectopic sites in the stomach or the first part of the duodenum (IGV2) GOV-1 GOV-2 IGV-1 IGV-2 Fig. 15.22.3.6  Sarin’s classification of gastric varices. Adapted from Gastrointestinal Endoscopy, Vol. 46, Sarin SK, Long-​term follow-​up of gastric variceal sclerotherapy: an eleven-​year experience, Pages 8–​14, Copyright © 1997 American Society for Gastrointestinal Endoscopy, with permission from Elsevier.

15.22.3  Portal hypertension and variceal bleeding 3079 used for the procedure and no specific preparation is required. Thrombin injection is associated with high rates of haemostasis, low rebleeding rates, and minimal adverse effects. Rescue therapies in cases of refractory gastric
variceal bleeding When patients with gastric variceal bleeding experience treatment failure with early rebleeding, a second endoscopic therapy should be attempted if possible. If endoscopic treatments fail to control bleeding, rescue therapy options include the following: • TIPS: as gastric variceal haemorrhage is uncommon, few studies (and no randomized trials) have investigated its efficacy in the setting of bleeding gastric varices. Despite this, TIPS with a PTFE-​covered stent remains the treatment of choice for patients with acute gastric variceal bleeding who fail first-​line medical and endoscopic therapy. • Balloon-​occluded retrograde transvenous obliteration (BRTO): cardiofundal gastric varices usually have unique vascular anatomy, with spontaneous splenorenal or gastrorenal shunts that flow into the systemic circulation. BRTO is an advanced radiological pro- cedure that utilizes these shunts to access and obliterate gastric varices. With BRTO, venography is performed to identify gastric varices, gastrorenal shunts, and collateral veins; the veins draining gastric varices are subsequently embolized with microcoils and a sclerosant agent injected until all varices are obliterated. BRTO ap- pears to be highly efficacious in treating gastric varices however it is not a decompressive procedure and portal pressures may increase due to the diversion of blood flow into the portal circulation. Thus, while it is not associated with hepatic encephalopathy, it may in- crease the risk of developing oesophageal and ectopic varices. Ectopic varices Ectopic varices are defined as dilated portosystemic collateral veins occurring anywhere in the gastrointestinal tract other than the oesophagogastric region. They account for 2 to 5% of all variceal bleeds, but are the cause of bleeding in 20 to 30% of patients with extrahepatic portal hypertension. The most common sites for ec- topic varices include the duodenum, jejunum, ileum, colon, rectum, and enterostomy stoma. Bleeding from ectopic varices, while rare, can be massive and life-​threatening. Ectopic varices should be considered in patients with portal hypertension who present with acute bleeding and have negative findings on upper endoscopy. Colonoscopy is the principal method for the diagnosis of colonic varices, although the diagnostic yield may be increased with endoscopic ultrasonography. Double-​balloon enteroscopy or capsule endoscopy may be required to diagnose je- junal or ileal varices. Radiographic imaging is another common method of diagnosing ectopic varices. Management Bleeding ectopic varices are a difficult management problem and may require a multidisciplinary team of endoscopists, hepatologists, surgeons, and interventional radiologists. The diversity of their lo- cation, presentation, and complications increases the challenges of successful treatment and precludes development of standardized guidelines. The optimal therapeutic modality depends on a number of factors, including the location of varices, the patient’s clinical condition, locally available expertise and facilities, and the cause of portal hypertension. Management incorporates urgent resuscitation, immediate workup to localize the site/​source of bleeding, followed by application of a suitable treatment modality or transfer to a ter- tiary referral centre. As with other forms of variceal bleeding, vaso- active therapy and antibiotics are used, although there are no data specifically relating to ectopic variceal bleeding. Management options include the following: • Endoscopic therapy: EIS or EVO has the greatest body of evidence in the management of ectopic varices and is usually considered first-​line therapy. Most ectopic varices are within the reach of a standard gastroscope or colonoscope, and injections using cyano- acrylate, thrombin, and other combination of sclerosants have successfully controlled bleeding from duodenal, jejunal, colonic, and rectal varices in case reports. • TIPS: TIPS has successfully been used to control bleeding ectopic varices, although there are multiple reports of ectopic varices rebleeding despite a reduction of the portosystemic pressure gra- dient to less than 12 mmHg and hence other treatment modal- ities such as embolization or endoscopic therapies may also be required. • Radiological embolization: a number of case reports have demon- strated successful haemostasis of ectopic varices with percutan- eous transhepatic obliteration, the goal of which is to occlude the feeding veins supplying the varix rather than occluding the varix itself. As embolization does not decompress the portal venous system, high rebleeding rates are noted with monotherapy, and thus combination therapy with TIPS is usually recommended. • Surgery: if endoscopic and/​or interventional radiological proced- ures fail to control bleeding or are not feasible, surgery is a re- commended option if surgeons with appropriate expertise are available. Careful patient selection is important, based on an as- sessment of underlying liver function. FURTHER READING Al-​Busafi SA, et al. (2012). Clinical manifestations of portal hyperten- sion. Int J Hepatol, 2012, 203794. Biecker E (2013). Portal hypertension and gastrointestinal bleeding: diagnosis, prevention and management. World J Gastroenterol, 19, 5035–​50. Bureau C, et  al. (2004). Improved clinical outcome using polytetrafluoroethylene-​coated stents for TIPS: results of a random- ized study. Gastroenterology, 126, 469–​75. Cello JP (2005). Endoscopic treatment for bleeding esophageal varices. In: Sanyal AJ, Shah VH (eds) Clinical gastroenterology: portal hyper- tension, pp. 221–​34. Humana Press, Totowa, NJ. Chavez-​Tapia NC, et al. (2010). Antibiotic prophylaxis for cirrhotic pa- tients with upper gastrointestinal bleeding. Cochrane Database Syst Rev, 9, CD002907. Dai C, et al. (2015). Endoscopic variceal ligation compared with endo- scopic injection sclerotherapy for treatment of esophageal variceal hemorrhage: a meta-​analysis. World J Gastroenterol, 21, 2534–​41. D’Amico M, Berzigotti A, Garcia-​Pagan JC (2010). Refractory acute variceal bleeding: what to do next? Clin Liver Dis, 14, 297–​305. Dechêne A, et al. (2012). Acute management of refractory variceal bleeding in liver cirrhosis by self-​expanding metal stents. Digestion, 85, 185–​91. De Franchis R (2015). Expanding consensus in portal hypertension: re- port of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol, 63, 743–​52.

15.22.4 Hepatic encephalopathy 3080

15.22.4 Hepatic encephalopathy 3080

section 15  Gastroenterological disorders 3080 Fagundes C, Ginès P (2012). Hepatorenal syndrome: a severe, but treatable, cause of kidney failure in cirrhosis. Am J Kidney Dis, 59, 874–​85. Ferguson JW, Tripathi D, Hayes PC (2003). Review article: the man- agement of acute variceal bleeding. Aliment Pharmacol Ther, 18, 253–​62. García-​Pagán JC, et al. (2010). Early use of TIPS in patients with cir- rhosis and variceal bleeding. N Engl J Med, 362, 2370–​9. Garcia-Tsau G, Albrades JG, Berzigotti A, Bosch J (2017). Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 Practice guidance by the American Association for the Study of Liver Diseases. Hepatology, 65(1), 310–35. Garcia-​Tsao G, Bosch J (2010). Management of varices and variceal haemorrhage in cirrhosis. N Engl J Med, 362, 823–​32. Garcia-​Tsao G, et  al. (2007). Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology, 46, 922–​38. Ginès P, Schrier RW (2009). Renal failure in cirrhosis. N Engl J Med, 361, 1279–​90. Gluud LL, Krag A (2012). Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. In: Gluud LL (ed.) Cochrane Database of Systematic Reviews. John Wiley & Sons, Chichester, UK. Grace JA, Angus PW (2013). Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment. J Gastroenterol Hepatol, 28, 213–​19. Ha Hwang J, Shergill A, et al. (2014). ASGE guideline: The role of en- doscopy in the management of variceal hemorrhage. Gastrointestinal endoscopy, 80, 221–7. Helmy A, Al Kahtani K, Al Fadda M (2008). Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int, 2, 322–​34. Hwang JH, et al. (2014). The role of endoscopy in the management of variceal hemorrhage. Gastrointest Endosc, 80, 221–​7. Lebrec D, Benhamou JP (1985). Ectopic varices in portal hypertension. Clin Gastroenterol, 14, 105–​21. McAvoy NC, Plevris JN, Hayes PC (2012). Human thrombin for the treatment of gastric and ectopic varices. World J Gastroenterol, 18, 5912–​17. Norton ID, Andrews JC, Kamath PS (1998). Management of ectopic varices. Hepatology, 28, 1154–​8. Qi X, et al. (2015). Transjugular intrahepatic portosystemic shunt for acute variceal bleeding:  a meta-​analysis. J Clin Gastroenterol, 49, 495–​505. Sarin SK, Kumar A (2014). Endoscopic treatment of gastric varices. Clin Liver Dis, 18, 809–​27. Tripathi D, Hayes PC (2008). Endoscopic therapy for bleeding gastric varices: to clot or glue? Gastrointest Endosc, 68, 883–​6. Tripathi D, et al. (2006). Review article: recent advances in the manage- ment of bleeding gastric varices. Aliment Pharmacol Ther, 24, 1–​17. Tripathi D, et  al. (2009). Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology, 50, 825–​33. Turon F, et al. (2013). Variceal and other portal hypertension related bleeding. Best Pract Res Clin Gastroenterol, 27, 649–​64. Villanueva C, et  al. (2013). Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med, 368, 11–​21. Wells M, et al. (2012). Meta-​analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther, 35, 1267–​78. Wiese S, et al. (2014). Cirrhotic cardiomyopathy: pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol, 11, 177–​86. 15.22.4  Hepatic encephalopathy Paul K. Middleton and Debbie L. Shawcross ESSENTIALS Hepatic encephalopathy (HE) is a significant complication of both acute and chronic liver disease, causing much morbidity and mor- tality. It is a complex neuropsychiatric syndrome which displays a wide range of symptoms and is associated with hyperammonaemia and systemic inflammation. The West Haven criteria describe grades of severity from 0 (subclin- ical) and I (changes in awareness, mood, attention, cognition, and sleep pattern) through to IV (coma). It is further classified by the underlying aetiology: type A, due to acute liver failure; type B, secondary to portosystemic shunting; and type C, occurring in chronic liver disease in association with precipitating factors including infections, gastrointes- tinal bleeding, and electrolyte disorders, particularly hyponatraemia. There is no definitive test or set of diagnostic criteria to establish a diagnosis of HE, which remains primarily a clinical diagnosis of ex- clusion in patients with a history or clinical evidence of liver disease. Management depends on the type of HE, but for type C (the com- monest type) typically includes lactulose and rifaximin as well as the identification and management of precipitating factors. Patients with cirrhosis with ongoing overt HE despite optimal medical manage- ment have a poor outlook and should be considered promptly for liver transplantation. Introduction The syndrome of hepatic encephalopathy (HE) was first described in the late 19th century when physiology experiments conducted by Nencki and Pavlov characterized neurobehavioural changes in dogs in which portocaval shunts had been created. The dogs developed symptoms of aggression, irritability, and ataxia postoperatively, pro- gressing to convulsion and eventually coma. These symptoms wors- ened with the ingestion of meat and resulting rise in blood and brain ammonia concentration. HE is a significant complication of both acute and chronic liver disease. Patients who develop HE have significant morbidity, with symptoms affecting their quality of life, ability to work, and ability to live independently. It is also associated with significant mortality, with 3-​year survival less than 25% in those with chronic liver disease. HE continues to prove challenging in both diagnosis and man- agement, and further research is required to fully address this clin- ical need. Aetiology The 2014 joint American Association for the Study of Liver Diseases (AASLD)/​European Association for the Study of the Liver (EASL) guidelines recommend that HE is characterized by the underlying aetiology. This reflects the significant difference in pathophysiology, management, and prognosis between these groups (Table 15.22.4.1).

15.22.4  Hepatic encephalopathy 3081 Type A hepatic encephalopathy This is secondary to acute liver failure (ALF), which is defined by the time from onset of jaundice to HE. Type B hepatic encephalopathy This is secondary to portosystemic shunting or bypass and not re- lated to underlying chronic liver disease. Most cases are related to the insertion of a transjugular intrahepatic portosystemic shunt (TIPS), which is an important intervention in the management of portal hypertension but limited by the development of HE. Studies estimate the 1-​year incidence of HE as between 10 and 50%, with severely disabling encephalopathy affecting 1 to 3% of patients. Encephalopathy risk is considered during assessment for TIPS. Age over 65, history of HE, and Child–​Pugh score greater than 10 have all been shown to be associated with a higher risk of post-​TIPS HE. Type B HE has also been reported in patients, without liver dis- ease, who develop spontaneous portosystemic shunts, including congenital intra-​ or extrahepatic shunts. Type C hepatic encephalopathy This comprises most cases. The development of type C HE is com- monly associated with a precipitating factor. Precipitating factors include infections, gastrointestinal bleeding, and electrolyte dis- orders particularly hyponatraemia (Box 15.22.4.1). Epidemiology Studies suggest 30 to 40% of patients with cirrhosis will experience an episode of overt HE within their lifetime and between 20 and 80% of patients will develop minimal HE. HE is more likely to occur in those with more severe liver disease, advanced age, and with a history of previous episodes of HE and decompensation (variceal bleeding, ascites, infections). Studies have also shown the presence of diabetes to be an inde- pendent risk factor for developing the first episode of overt HE as well as being associated with more severe episodes. HE is also more commonly seen in malnourished patients. The presence of HE is associated with poorer socioeconomic status, worse unemployment, increased hospitalizations, and higher caregiver burden in comparison to other complications of cirrhosis. Pathogenesis Type A hepatic encephalopathy One of the hallmarks of ALF is the development of HE and cerebral oedema. This is thought to be secondary to hyperammonaemia, oxi- dative stress, and systemic inflammation (Fig. 15.22.4.1). Ammonia ALF reduces hepatic metabolism of bowel-​derived ammonia, re- sulting in hyperammonaemia. The ammonia concentration directly correlates with HE severity, the development of cerebral oedema, and progression to intracranial hypertension. Ammonia is also me- tabolized outside the liver in skeletal muscle and in the brain, pri- marily in astrocytes. Numerous studies have associated ammonia exposure to astrocyte swelling in cell culture and animal models. Astrocyte swelling is also a characteristic finding on autopsy in pa- tients who have died of ALF. Two hypotheses are presented to explain this association. Within the brain, ammonia undergoes conversion to glutamine via glu- tamine synthetase within astrocytes. The ‘osmolyte hypothesis’ sug- gests this increase in glutamine causes osmosis of water into the cell resulting in astrocyte swelling. This is supported by studies showing inhibition of glutamine synthetase prevents ammonia-​induced astrocyte swelling. However, glutamine levels and astrocyte swelling correlate poorly temporally, and swelling may be absent during peak glutamine levels. Moreover, peak astrocyte swelling is asso- ciated with low levels of glutamine. This led to the ‘Trojan horse’ hypothesis, which suggests glutamine is transported into the mito- chondria where it reverts back to ammonia via phosphate-​activated glutaminase. Mitochondrial ammonia accumulation then leads to oxidative stress, mitochondrial dysfunction and astrocyte swelling. Table 15.22.4.1  Categorization of hepatic encephalopathy by aetiology and common associated conditions Type Aetiology Associated conditions Type A Acute liver failure Paracetamol overdose, acute viral hepatitis, drug-​induced liver injury, pregnancy related Type B Portosystemic bypass or shunt Post TIPS, spontaneous portosystemic shunt, congenital portosystemic shunt Type C Chronic liver disease Alcohol-​related cirrhosis, nonalcoholic fatty liver disease, chronic viral hepatitis, autoimmune hepatitis, metabolic liver disease Box 15.22.4.1  Common causes of precipitating events in type C hepatic encephalopathy in order of frequency • Infections: — Respiratory tract — Gastrointestinal — Spontaneous bacterial peritonitis — Urinary tract • Gastrointestinal bleeding: — Acute — Chronic • Electrolyte derangement: — Hyponatraemia — Hypokalaemia • Dehydration • Constipation • Medication: — Opioid analgesics — Diuretics — Sedatives

section 15  Gastroenterological disorders 3082 Oxidative stress Ammonia induces oxidative stress through the production of free radicals secondary to N-​methyl-​d-​aspartate receptor activation and through calcium-​dependent processes. Within the mitochondria, it interferes with oxidative phosphorylation leading to mitochondrial dysfunction and further oxidative stress. This may result in opening of the mitochondrial permeability transition pore, destroying the energy potential of the mitochondria and further damaging en- ergy production. This energy failure may result in astrocyte swelling by impairing energy-​dependent ion channels, upregulation of aquaporins, and via activation of mitogen-​activated protein kin- ases. Oxidative stress and its associated protein phosphorylation/​ nitrosylation lead to cellular dysfunction through changes to gene expression, intracellular signalling, and synaptic plasticity. Inflammation/​infection There is growing recognition of the synergistic role of systemic in- flammation in the pathogenesis of HE. Patients with systemic in- flammatory response syndrome (SIRS) have been found to have a more rapid progression to more advanced HE with higher mortality. ALF animal models have shown increased cerebral oedema in ani- mals administered with lipopolysaccharide versus control, despite similar levels of ammonia between the groups. In ALF, plasma tu- mour necrosis factor (TNF)-​α, interleukin 8, and neutrophil Toll-​ like receptor-​9 expression correlate with severity of HE. SIRS can result from superimposed sepsis or the release of inflammatory me- diators from the necrotic liver. Patients with ALF have neutrophil and monocyte dysfunction contributing to oxidative stress and im- paired immune function, increasing the risk of developing bacterial and fungal infection. SIRS leads to activation of brain endothelium resulting in microglial activation and cerebral production of inflam- matory cytokines. Cerebral and systemic inflammation is associated with increased cerebral blood flow and ammonia delivery which may further contribute to cerebral oedema. Type B hepatic encephalopathy Nitrogen-​rich portal blood bypasses the liver either through a TIPS shunt or via spontaneous portosystemic shunts directly into the sys- temic circulation. Symptomatically and pathophysiologically it is similar to type C HE, with absence of cerebral oedema and respon- siveness to ammonia-​lowering therapies. Type C hepatic encephalopathy In type C HE, ammonia plays a pivotal role, but there is a growing recognition of the contribution of gut dysbiosis, bacterial transloca- tion, endotoxaemia, systemic inflammation, and immune dysfunc- tion in the pathogenesis (Fig. 15.22.4.2). Ammonia Ammonia has long been associated with the pathogenesis of type C HE since the seminal study examining the role of cation exchange resins for the management of peripheral oedema in patients with cirrhosis. These resins released ammonium ions and led to neuro- logical dysfunction that we now recognize as HE. However, unlike ALF, ammonia levels do not correlate well with symptoms. In type C HE, ammonia is also metabolized within astrocytes, resulting in astrocyte swelling and increased brain water, although significant cerebral oedema is not a feature of the disease. MRI studies have shown evidence of low-​grade brain oedema which is reversed with liver transplantation. Ammonia challenge in patients with cirrhosis Fig. 15.22.4.1  Pathophysiology of type A hepatic encephalopathy. H2O, water; LPS, lipopolysaccharide; NH3, ammonia.

15.22.4  Hepatic encephalopathy 3083 leads to decreased neuropsychological function with MRI changes suggestive of increased brain water. The classic neuropathological feature of type C HE is Alzheimer type II astrocystosis characterized by enlarged nuclei with mar- ginated chromatin. Alzheimer type II astrocytosis develops with exposure to ammonia both in cell culture, animal models, and in patients with congenital abnormalities of the urea cycle resulting in hyperammonaemia. Inflammation/​infection SIRS strongly correlates with the presence and severity of HE, in- dependent of ammonia concentration. In one study, an ammonia challenge resulted in altered cognition in patients while infection was present, but not once the infection had resolved. In ammonia-​ fed animal models, lipopolysaccharide administration increased brain water compared to controls, implicating synergism between ammonia and inflammation. Positron emission tomography studies have found reduced whole-​brain oxygen consumption during episodes of acute HE suggesting reduced brain metabolism or an increase in inhibitory γ-​aminobutyric acid tone. Studies have found induction of cerebral inflammation via injection of lipopolysaccharide caused decreased excitatory transmission with deficits in learning and memory, re- versible with glutamatergic antagonists and cyclooxygenase 2 inhibitors. Gut microbiota and endotoxaemia Patients with cirrhosis have increased gut permeability to bacteria and bacterial degradation products, resulting in bacterial transloca- tion and endotoxaemia. This results in hepatic macrophage produc- tion of proinflammatory cytokines such as interleukin 8 and TNFα, which induces systemic inflammation. Additionally, gut dysbiosis has become a well-​recognized feature of cirrhosis that has been found to be independently associated with severity of liver disease and development of complications. Manipulation of the microbiome with nonabsorbable antibiotics or probiotics has been shown to re- duce hyperammonaemia, endotoxaemia, and have beneficial effects on cognition. Immune dysfunction Immune dysregulation is an increasingly recognized feature in HE and contributes significantly to systemic inflammation as well as predisposing to the development of infection. Ammonia induces neutrophil dysfunction which contributes to systemic inflammation and the susceptibility to developing infection, and has been shown to be predictive of infection, organ dysfunction, and survival at 90 days and 1 year. Clinical features HE is a complex neuropsychiatric syndrome that encompasses a wide spectrum of symptoms. The West Haven criteria describe four grades of HE increasing in severity from I to IV (Table 15.22.4.2). Grade I  encompasses changes in awareness, mood, attention, cognition, and sleep pattern without disorientation or clear clin- ical findings such as asterixis. Changes to sleep pattern include in- creased daytime somnolence and reversal of the sleep–​wake cycle. Obtaining collateral history from family members or regular care- givers is vital to identify subtle changes in behaviour or orientation. With grade II, the patient becomes disorientated in time and develops symptoms of lethargy and apathy. There are more obvious personality changes with episodes of inappropriate behaviour. On examination, asterixis is present. This is most clearly identified Hepatic inflammation ↑ IL-8; TNFα Bacterial translocation NH3 Portosystemic shunting Endotoxin TLR4 Systemic inflammation endotoxaemin Bacterial overgrowth Increased gut permeability Fig. 15.22.4.2  Pathophysiology of type C hepatic encephalopathy. TLR, Toll-​like receptor.

section 15  Gastroenterological disorders 3084 with the patient positioned with their arms out straight with their wrists fully extended and fingers spread. Asterixis is a flapping tremor due to negative myoclonus with arrhythmic loss of posture. Subtle asterixis can be better detected through palpation. Grade III HE is associated with worsening confusion and dis- orientation to place, with reduction in consciousness from somno- lence to semistupor. The patient remains responsive to stimuli but may no longer be able to maintain their own airway. As the condi- tion deteriorates to grade IV encephalopathy, the patient becomes unresponsive to stimuli and falls into coma. There can be a rapid progression through stages of encephalop- athy, especially in patients suffering ALF. The Glasgow Coma Score (GCS) is valuable to use alongside the West Haven criteria in order to identify when intervention to manage conscious level is appro- priate, and for its ease in interdisciplinary communication. A grade of subclinical HE is also described, termed minimal HE. This condition has no clinical features of encephalopathy, but im- paired cognitive function can be elicited with neuropsychometric function testing. These tests should be conducted by experienced examiners on patients who are most likely to benefit from diagnosis, such as those with impaired quality of life or those in whom impair- ment may affect their work or public safety such as driving. These tests examine different components of cognitive functioning and it is advised that at least two are performed. Minimal and grade I HE both lack clear and reliable clinical fea- tures and have poor interobserver reliability. As a result, these grades can also be described as covert HE. Conversely, West Haven cri- teria grade II and above have more reliable clinical features and are termed overt HE. Clinical presentations of HE can fluctuate in their time course and can be further characterized as episodic, recurrent, or per- sistent (Fig. 15.22.4.3). Recurrent HE is defined as episodes of HE that occur within 6 months or less. Persistent HE describes the continuous presence of HE symptoms. There can often be milder persistent symptoms interspersed with episodes of more severe overt HE. Some clinical syndromes often associated with extensive port­ osystemic shunting have been described relating to HE. These in- clude HE-​related parkinsonism and hepatic myelopathy. About 25% of patients with HE have extrapyramidal symptoms including tremor, cog-​wheel rigidity, bradykinesia, shuffling gait, and loss of facial expression. Hepatic myelopathy is characterized by slowly progressive spastic paresis with hyper-​reflexia most commonly af- fecting the lower limbs and extensor plantar responses. Upper limb and sensory/​sphincter involvement have been rarely reported. Improvement of these syndromes has been reported with closure of portosystemic shunts and liver transplantation. Differential diagnosis Due to the wide spectrum of presentation of HE, there are many possible differential diagnoses to consider. In patients presenting with features of overt HE, the differential diagnosis should include causes of delirium or altered conscious- ness (Table 15.22.4.3). Conditions that occur commonly in patients with cirrhosis include sepsis and severe hyponatraemia. Other con- siderations unrelated to underlying liver disease include central nervous system infections, uraemia, lactic acidosis, and intracra- nial bleed or stroke. Alcohol-​related liver disease remains the most prevalent cause of cirrhosis in the United Kingdom. Alcohol intoxication, withdrawal, or Wernicke’s encephalopathy may present with symptoms of altered consciousness, personality change, or abnormal behaviour that may be consistent with HE. Neuroactive drugs such as opiates, benzodi- azepines, and neuroleptics should be considered. Several case reports also describe patients suffering nonconvulsive epilepsy who were initially misdiagnosed with HE, highlighting the important role of electroencephalography (EEG) in the investigation of encephalopathy. Table 15.22.4.2  Explanation of West Haven criteria for hepatic encephalopathy with comparable Glasgow Coma Scores Grade using West Haven criteria Clinical features Glasgow Coma Score 0 No abnormality apparent on clinical examination 15 I Short-​term memory loss, difficulty in concentrating, and reverse of sleep–​wake cycle 15 II Lethargy, apathy, drowsiness, flapping tremor (asterixis), disorientation, confusion, inappropriate behaviour 12–​15 (Verbal response or obeying command typically impaired) III Stuporose but easily rousable, marked confusion, incoherent speech 6–​12 IV Coma, unresponsive 3–​6 (May respond to painful stimuli) IV III II I MHE 0 0 2 4 6 Time (months) Hepatic encephalopathy Grade of HE 8 10 12 Episodic Recurrent Persistant Fig. 15.22.4.3  Representation of the fluctuant clinical course over time for patients with episodic, recurrent, and persistent hepatic encephalopathy (HE). Minimal HE and grade I represent covert HE. Grades II to IV represent overt HE.

15.22.4  Hepatic encephalopathy 3085 In patients presenting with symptoms of covert HE, other causes of impaired cognition should be considered (Table 15.22.4.4). In the elderly, primary dementias are possible differentials. Chronic alcohol excess is associated with several possible causes of cognitive impair- ment such as secondary dementia due to vitamin B12 deficiency, Korsakoff’s syndrome, or directly related to alcohol excess. These patients are also at greater risk of chronic subdural haematomas and a history of trauma should be elicited. Hypothyroidism should be considered as an important revers- ible cause of cognitive impairment. Depression is common in pa- tients with chronic disease and severe depression can present as a pseudodementia, especially in the elderly. Obstructive sleep apnoea should be considered in those presenting with increased daytime somnolence that have risk factors such as obesity and diabetes. Clinical investigation There is no definitive test or set of diagnostic criteria to establish a diagnosis of HE, which remains primarily a clinical diagnosis of ex- clusion in patients with a history or clinical evidence of liver disease. History and examination Symptoms of changes to short-​term memory, mood, cognition, sleep pattern, and personality should be elicited. In overt HE, these should be forthcoming, but may require direct questioning in covert HE. Collateral history from family members or long-​term carers is recommended. A past medical history of liver disease or risk factors for liver disease should be obtained, along with a full drug history. In the acute scenario, initial examination should take an ‘ABCDE’ approach with prompt management of the airway if compromised. An assessment of the patient’s conscious level should be performed using the GCS. On examination, stigmata of chronic liver disease may be found. The development of asterixis or hyper-​reflexia would suggest overt HE. Patients with grade II-IV HE may exhibit clonus. The presence of focal neurological deficits would suggest an alterna- tive diagnosis. Laboratory tests A full set of blood tests including full blood count, renal function, liver biochemistry, lactate, and coagulation screen should be per- formed to assess underlying liver function and screen for precipi- tants such as infection or gastrointestinal bleeding. Blood and urine cultures should be taken as part of a septic screen. In patients with ascites, an ascitic tap should be performed to assess for the presence of spontaneous bacterial peritonitis. Elevated blood ammonia has a strong association with HE in ALF, but has not been found to correlate well with symptoms in type C HE, hence although an elevated blood ammonia supports the diag- nosis of HE, a normal ammonia concentration does not exclude it. Imaging A plain chest X-​ray should be performed as part of the septic screen. A CT head should be performed in patients presenting with acute HE, especially if there is evidence of focal neurology or the GCS is reduced to rule out intracranial bleeds, stroke, and space-​ occupying lesions. A contrast abdominal CT may be able to identify portosystemic shunts. In the outpatient setting, a magnetic resonance brain scan is re- commended when patients present with chronic neurocognitive dysfunction. This helps to rules out other neurodegenerative path- ology such as Alzheimer’s, where hippocampal atrophy may be ob- served, and small vessel ischaemia. The finding of bilateral increased signal intensity in the lentiform nucleus and substantia nigra on MRI T1-​weighted imaging is suggestive of chronic portosystemic shunting. This was previously referred to as hepatocerebral degener- ation and is believed to result from chronic manganese deposition. Although this can be seen in welders and following hyperalimenta- tion therapy, it is often considered pathognomonic of HE. Neuropsychological tests Clinical tests such as the abbreviated mental test score can be used to quickly assess cognitive function. For the diagnosis of minimal HE, Table 15.22.4.3  Differential diagnosis for overt hepatic encephalopathy Infective Sepsis Meningitis Encephalitis Metabolic Hyponatraemia Hypothyroidism Lactic acidosis Alcohol related Alcohol intoxication Alcohol withdrawal Wernicke’s encephalopathy Medication Opiates Benzodiazepines Neuroleptics Diabetes related Hypoglycaemia Diabetic ketoacidosis Hyperglycaemic hyperosmolar state Neurological Intracranial bleed/​stroke Nonconvulsive epilepsy Space-​occupying lesion Table 15.22.4.4  Examples of differential diagnosis for covert hepatic encephalopathy Primary dementia Alzheimer’s disease Meningitis Encephalitis Secondary dementia Alcohol related Vitamin B12 deficiency Korsakoff’s syndrome Metabolic Hypothyroidism Hyponatraemia Other Chronic subdural haematoma Obstructive sleep apnoea Pseudodementia Space-​occupying lesion

section 15  Gastroenterological disorders 3086 guidelines recommend the use of two psychometric or neurophysio- logical tests (Table 15.22.4.5). There is no consensus on which tests are best. They require trained staff and specialist equipment that limit their use and availability, especially in resource-​poor settings. The Psychometric Hepatic Encephalopathy Score (PHES) likely represents the most accessible test in view of the lack of specialist equipment required. Electroencephalography EEG may be useful to support a diagnosis of metabolic encephalop- athy as well as to rule out alternative diagnoses such as nonconvulsive epilepsy. In overt HE, the characteristic finding is of triphasic waves on a background of generalized slowed activity. Its role in covert HE is less clear, and studies so far recommend its use alongside other neuropsychological tests. EEG requires trained and experienced staff and may not be available in all centres. Management Acute liver failure Patients presenting with HE in ALF are critically unwell and have the potential to deteriorate rapidly. Early discussion with a trans- plant centre is recommended, with prompt transfer of the patient if appropriate. Airway management Close monitoring of the GCS and airway is vital as patients may not be able to protect their airway and are at risk of aspiration. In patients presenting with grade III and IV HE, their airway is un- safe and they should undergo prompt endotracheal intubation and transfer to intensive care. HE and cerebral oedema The likelihood of progression to cerebral oedema and intracranial hypertension increases with grade of HE; patients with grade III have a 25 to 35% risk and patients with grade IV a 65 to 75% risk. In the intensive care environment, several neuroprotective strategies are undertaken, as detailed in Table 15.22.4.6. Management of hyperammonaemia High-​volume haemofiltration is the mainstay therapy in re- ducing hyperammonaemia in ALF. There is no evidence that lactulose, rifaximin, or l-​ornithine l-​arginine (LOLA) has any role in ALF. Management of infection Patients should be closely monitored for signs of infection and treated promptly with empirical broad-​spectrum antibiotics and antifungals to avoid development of intracranial hypertension. Management of hyponatraemia Hyponatraemia may promote the progression of HE and should be corrected. A randomized controlled clinical trial investigating the role of hypertonic saline in patients with ALF and advanced HE showed a reduction in the incidence and severity of intracra- nial hypertension. AASLD guidelines recommend maintaining a serum sodium concentration of 145 to 155 mmol/​L in patients at high risk of cerebral oedema, such as those with hyperammonaemia and grade III/​IV HE. Liver transplantation The definitive management of cerebral oedema with intracranial hypertension in ALF is with emergency liver transplantation, when HE resolves rapidly after transplantation. Table 15.22.4.5  Examples of psychometric or neurophysiological tests used in the diagnosis of minimal hepatic encephalopathy Test Explanation of procedure Psychometric Hepatic Encephalopathy
Score (PHES) This is a paper and pencil-​based test comprising the sum score of five subtests assessing attention, motor speed and accuracy, visual orientation, and visuospatial construction Critical flicker frequency (CFF) The patient is presented with a pulsing light that decreases in frequency (60 Hz downwards). The patient must press a button once they perceive the light pulses to have fused. The frequency when the lights fuse is measured Continuous reaction time test (CRT) The patient is presented with a series of 500-​Hz tones played at random intervals of 2–​6 s via headphones. The patient must press a button when they are heard. Reaction time is measured Inhibitory control test (ICT) Computer-​based test where the patient is shown a series of letters and must press a button when an X is followed by a Y. Pairs of XX and YY occur to lure the patient to hit the button. The rate of response to XY pairs and lure pairs is measured Stroop test Patients are shown words describing a colour printed in a different colour. The test measures the interference between recognition reaction time to a coloured field and a written colour name SCAN test Computerized test measuring speed and accuracy of performing increasingly complex digit recognition memory tasks Table 15.22.4.6  Neuroprotective measures that can be applied in an intensive care setting. Oxygen concentration and partial pressure of carbon dioxide is titrated through manipulation of mechanical respiration. Mean arterial pressure is achieved through titration of inotropes and fluid management. Temperature can be controlled using external heating devices Position Positioned 20–​30° with minimal movement Temperature ~36°C Oxygen saturations

95% Mean arterial pressure 75 mmHg Pco2 4–​4.5 kPa

15.22.4  Hepatic encephalopathy 3087 Type B hepatic encephalopathy Management of type B HE follows the same considerations as type C HE, detailed in the following ‘Type C hepatic encephalopathy’ subsection. Post-​TIPS HE In patients with post-​TIPS HE who do not respond to standard med- ical management, resizing or occlusion of the TIPS stent is a possible management option. This intervention, however, may worsen portal hypertension and increase their risk of variceal bleeding. The deci- sion to proceed with TIPS resizing should be made in cases with a clear diagnosis of type B HE because HE secondary to worsening liver function will not benefit from manipulation of the shunt. Spontaneous portosystemic shunt In cases of type B HE secondary to spontaneous portosystemic shunting, there are several studies describing resolution of symp- toms with embolization or endovascular closure of shunts. Type C hepatic encephalopathy General aspects Current AASLD/​EASL guidelines only recommend routine inter- vention for patients with overt HE. These guidelines outline a four-​ pronged management approach (Box 15.22.4.2). As in ALF, patients with type C overt HE have the potential to deteriorate to coma, hence regular monitoring of their GCS and airway is required. Patients who are unable to maintain their airway should be intubated and managed in an intensive care environment. Consideration should be made to possible alternative diagnoses explaining the patient’s symptoms. Reversible causes such as hypo- glycaemia should be investigated for and managed urgently. Identification and management of precipitating factors re- mains one of the most valuable interventions in the management of overt HE. In particular, patients should be investigated for signs of underlying infection. A full septic screen is appropriate, with a low threshold for initiating empirical broad-​spectrum antibiotics. Electrolyte abnormalities, particularly hyponatraemia, should be corrected. Gastrointestinal bleeding should be ruled out. Patients with a history of constipation should be initiated on laxatives. The use of enemas is valuable in patients with faecal loading and in those with grade III/​IV HE. Specific treatments Lactulose Lactulose is a nonabsorbable disaccharide which has historically formed the mainstay of HE management. It is metabolized by gut flora to produce lactic and acetic acid, resulting in acidification of the bowel. This promotes the conversion of absorbable gut-​produced ammonia to inabsorbable ammonium and is thought to change the gut flora to nonurease bacteria, further reducing ammonia produc- tion. Its effect as an osmotic laxative is thought to be independently beneficial and has an important role in managing or preventing constipation, a recognized precipitant of HE. Lactitol is another nonabsorbable disaccharide used as an alternative in some centres. A Cochrane meta-​analysis of randomized controlled trials found insufficient evidence to support the use of nonabsorbable disaccharides in acute HE. This was due to the lack of high-​quality trials. With the inclusion of lower-​quality trials, nonabsorbable di- saccharides were found to reduce the risk of no improvement com- pared to placebo or no intervention. No large multicentre trials of lactulose versus placebo have been conducted, but the use of lactulose is supported by decades of clinical experience and AASLD/​EASL guidelines recommend lactulose as the first-​choice treatment for episodic overt HE. Rifaximin Rifaximin is a semisynthetic antibiotic based on rifamycin that is poorly absorbed by the gastrointestinal tract. A few studies have examined its use as monotherapy compared to lactulose. Although showing similar benefit, there is currently not enough evidence to recommend it for use alone. A randomized controlled trial showed significant benefits to resolution of HE and hospital stay with rifaximin and lactulose compared to rifaximin alone. Alternative treatments Oral branched-​chain amino acids (BCAAs) are thought to have a beneficial effect on HE by improving skeletal muscle metabolism of ammonia by providing a source of glutamate. A Cochrane re- view showed a beneficial effect of BCAAs, but highlighted the lack of evidence compared with established treatments. Another thera- peutic option is L-ornithine L-aspartate, (LOLA): supplied by Hepa Merz, this is available in Europe but not the United States. Given intravenously, it stimulates the urea cycle and glutamine synthesis, which are key metabolic pathways in ammonia detoxification. A meta-​analysis found LOLA to be associated with improvement in HE with reduction in ammonia levels. AASLD/​EASL guidelines recommend the use of these treatments as alternative or additional agents in patients nonresponsive to conventional therapy. Secondary prevention After a first episode of overt HE, initiation of treatment to maintain remission should be considered, especially in those who are at high risk of recurrence such as those who have poor liver function, are malnourished, or have uncontrolled precipitants. Lactulose AASLD/​EASL guidelines recommend lactulose for the prevention of recurrent episodes of overt HE. A randomized controlled trial showed a significant benefit with lactulose versus placebo for pre- vention of recurrence of HE in patients with cirrhosis who had re- covered from an episode of overt HE. There is some evidence that lactulose has a role in primary prophylaxis in HE, but guidelines currently only recommend considering primary prophylaxis in pa- tients who are high risk of developing the condition. Box 15.22.4.2  The AASLD/​EASL recommended a
four-​pronged approach to the management of type C overt hepatic encephalopathy • Management of altered consciousness • Investigate and manage alternate diagnoses • Identification and management of precipitating factors • Commencement of empirical hepatic encephalopathy treatment

section 15  Gastroenterological disorders 3088 Rifaximin The use of rifaximin to prevent HE has been well examined. A ran- domized controlled trial showed in a large number of patients over a 6-​month period that rifaximin maintained remission and reduced the risk of hospitalization from HE better than placebo. A systemic review and meta-​analysis confirmed rifaximin to have a benefi- cial effect on HE with a possible associated reduction in mortality. AASLD/​EASL recommends rifaximin as an add-​on to lactulose for prevention of recurrent episodes of HE after the second episode. The National Institute for Health and Care Excellence (Guideline TA337) has authorized the use of rifaximin for reducing the recur- rence of episodes of overt HE in patients over 18 years old. Liver transplantation Patients with cirrhosis with ongoing overt HE despite optimal med- ical management have a poor prognosis and should be considered promptly for liver transplantation. Management of covert HE Several trials have examined the role of lactulose, rifaximin, and probiotics on the management of covert HE, but these studies are limited by the variations in methods to diagnose and assess im- provement in the condition. However, covert HE has been found to adversely impact patients’ quality of life and driving ability. In pa- tients who have found their work compromised by covert HE symp- toms, or when there is a concern for public safety, treatment may be indicated on a case-​by-​case basis. Guidelines do not recommend the routine treatment of minimal HE and covert HE. Other management considerations Nutrition Traditionally, patients suffering from HE were managed with low-​ protein diets on the premise that this would reduce gut-​derived ammonia. However, a randomized controlled trial comparing low-​ protein diet with increasing increments of protein to a diet normal in protein in patients presenting with overt HE found no significant difference in HE outcome between the groups, but found higher rates of protein breakdown in the low-​protein group. Patients with HE are more likely to be malnourished and have reduced muscle mass. Skeletal muscle is a site of extrahepatic am- monia metabolism and hence sarcopenia is a risk factor for HE. It has also been shown to be a poor prognostic factor in patients with cirrhosis. In view of this AASLD/​EASL guidelines recommend strict energy and protein intake goals for patients with HE (Box 15.22.4.3) contained within small frequent meals throughout the day. Driving Both overt HE and covert HE have a significant impact on the patient’s cognitive abilities and safety to drive. Studies have shown patients with covert HE have reduced performance in driving simulators compared to controls. There are no published guidelines, but doctors have a duty to discuss the risks of driving with any patient with HE and should ad- vise them to stop driving until they can be assessed by the Driver and Vehicle Licensing Agency in the United Kingdom. Prognosis Acute liver failure In ALF, HE is a strong independent predictor of poor outcome, with a reported odds ratio for mortality between 12 and 20. HE grade also has a significant impact on prognosis, with one study showing that patients presenting with grade I/​II HE had a 52% 3-​week transplant-​free survival rate in comparison with only a 33% rate in patients with grade III/​IV HE. Indeed, despite similar trans- plant rates, overall survival was higher in the grade I/​II group, 77%, compared with the grade III/​IV group, 56%. Type B hepatic encephalopathy Prognosis in patients with type B HE is primarily related to the severity of underlying liver disease. Higher mortality is associated with higher-​ grade HE (III/​IV), which may indicate worse underlying liver function. Type C hepatic encephalopathy In patients with cirrhosis, HE is a cardinal sign of decompensa- tion and is associated with poor outcome. One follow-​up study from the first episode of HE reported 42% survival after 1 year and only 23% survival at 3 years. Patients who develop episodic overt HE have an estimated 50% risk of recurrence within the first year. Factors associated with recurrence include poor liver function, the presence of minimal HE, and renal dysfunction. Grade of HE at the time of listing for liver transplant is an independent risk factor for waiting list mortality. Patients with grade III/​IV HE have significantly increased 90-​day mortality in comparison to patients with grade I/​II HE or in the absence of HE (24.4%, 6.8%, and 3.5% respectively). Detection of covert HE is independently associated with in- creased mortality and risk of hospitalization and is associated with an increased risk of developing future overt HE. Historically, HE was thought to fully resolve following liver trans- plantation, but more recent studies have disputed this and have shown evidence of persistent cognitive impairment and demyelin- ation despite resolution of extracellular brain oedema. However, studies are difficult to interpret as many patients will have com- peting risk factors for persistent cognitive impairment such as cere- brovascular disease or chronic alcohol excess. Future developments HE remains a clinical diagnosis based on exclusion of alternative diagnoses and a holistic appreciation of the clinical features and in- vestigations suggestive of the condition. Diagnosis of minimal HE is even more complex due to the lack of solid clinical features and the variety of neurophysiological and psychometric tests available and the uncertainty associated with their interpretation. This diagnostic uncertainty hinders clinical management and research, and in the case of covert HE precludes routine intervention. To address this, fu- ture research should aim to develop highly sensitive screening tests, Box 15.22.4.3  Recommended dietary intake per kg of ideal body weight in patients with hepatic encephalopathy • Energy intake 35 to 40 kcal/​kg/​day • Protein intake 1.2 to 1.5 g/​kg/​day

15.22.5 Liver failure 3089

15.22.5 Liver failure 3089

15.22.5  Liver failure 3089 investigate novel sensitive and specific biomarkers, further validate existing investigative tools, and develop clear diagnostic algorithms. With the growing recognition of the importance of systemic in- flammation and immune dysfunction, novel therapeutic interven- tions are required to target this pathophysiological mechanism. Areas currently under investigation to target systemic inflammation in- clude plasmapheresis, albumin-​based endotoxin removal systems, al- bumin infusion, and antioxidants. Interventions under investigation to target immune dysfunction include Toll-​like receptor antagonists and the use of T-​regulatory cells. Manipulation of the gut microbiome may have benefits for both systemic inflammation and immune dys­ function. Fecal Microbiota Transplant (FMT) therefore represents a promising area for development in the management of HE. A recent small randomized controlled trial of FMT versus standard of care found reduced hospitalization and improved cognitive testing in cir- rhotic patients with two previous documented episodes of overt HE. This trial however was designed with the primary outcome of proving safety of FMT. Further larger placebo controlled trials are required. FURTHER READING Als-​Nielsen B, Gluud LL, Gluud C (2004). Non-​absorbable disac- charides for hepatic encephalopathy:  systematic review of ran- domised trials. BMJ, 328, 7447. Bajaj JA, et al. (2017). Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology, 66, 1727–38. Bajaj JS, et al. (2013). Cognitive dysfunction is associated with poor socio-​economic status in patients with cirrhosis: an international Multicentre Study. Clin Gastroenterol Hepatol, 11, 1511–​16. Bass NM, et al. (2010). Rifaximin treatment in hepatic encephalopathy. NEJM, 362, 1071–​81. Bustamante J, et al. (1999). Prognostic significance of hepatic enceph- alopathy in patients with cirrhosis. J Hepatol, 30, 890–​5. Coltart I, Tranah T, Shawcross D (2013). Inflammation and hepatic encephalopathy. Arch Biochem Biophys, 536, 189–​96. Ferenci P, et al. (2002). Hepatic encephalopathy—​definition, nomen- clature, diagnosis and quantification final report of the working party at the 11th World Congresses of Gastroenterology Vienna 1998. Hepatology, 35, 716–​21. Lee WM, Larsen AM, Stravitz RT (2011). American Association for the Study of Liver Diseases, position paper: the management of acute liver failure: update 2011. https://​www.aasld.org/​sites/​default/​files/​guide- line_​documents/​alfenhanced.pdf National Institute for Health and Care Excellence (NICE) (2015). Rifaximin for preventing episodes of over hepatic encephalopathy. Technology appraisal guidance. NICE, London. Shawcross D, Jalan R (2005). Dispelling myths in the treatment of hep- atic encephalopathy. Lancet, 365, 431–​3. Shawcross DL, Wendon JA (2012). The neurological manifestations of acute liver failure. Neurochem Int, 60, 662–​71. Sturgeon JP, Shawcross DL (2014). Recent insights into the patho- genesis of hepatic encephalopathy and treatments. Expert Rev Gastroenterol Hepatol, 8, 83–​100. Vilstrup H, et al. (2014). Hepatic encephalopathy in chronic liver dis- ease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60, 715–​35. Weissenborn K (2015). Challenges in diagnosing hepatic encephalop- athy. Neurochem Res, 40, 265–​73. 15.22.5  Liver failure Jane Macnaughtan and Rajiv Jalan ESSENTIALS Liver failure occurs when loss of hepatic parenchymal function exceeds the capacity of hepatocytes to regenerate or repair liver injury. Acute liver failure is characterized by jaundice and pro- longation of the prothrombin time in the context of recent acute liver injury, with hepatic encephalopathy occurring within 8 weeks of the first onset of liver disease. Acute-​on-​chronic liver failure is characterized by hepatic and/​or extrahepatic organ failure in pa- tients with cirrhosis associated with an identified or unidentified precipitating event. The commonest causes of acute liver failure are acute viral hepa- titis and drugs. Acute-​on-​chronic liver failure is most commonly precipitated by infection, alcohol abuse, and superimposed viral infection. The main clinical manifestations are hepatic encephalop- athy, coagulopathy, jaundice, renal dysfunction, and haemodynamic instability. Infection and systemic inflammation contribute to patho- genesis and critically contribute to prognosis. Management Specific therapy for the underlying liver disease is administered when available, but this is not possible for most causes of liver failure. Treatment is predominantly supportive, with particular em- phasis on (1) correction or removal of precipitating factors; (2) if en- cephalopathy is present, using phosphate enemata, nonhydrolysed disaccharide laxatives, and/​or rifaximin; (3)  early detection and prompt treatment of complications such as hypoglycaemia, hypo- kalaemia, cerebral oedema, infection, and bleeding. The onset of organ failure should prompt discussion with a liver transplantation centre. Course and prognosis The mortality of acute liver failure (without liver transplantation) is about 40%. Patients with acute liver failure who do not develop en- cephalopathy can be expected to recover completely. Those who recover from an episode of acute-​on-​chronic liver failure should be considered for liver transplantation because otherwise their subse- quent mortality remains high. Introduction Liver failure is a catastrophic event culminating in multiorgan failure, requirement for organ support in intensive care, and high mortality rates. Depending upon whether the liver failure occurs on the background of a previously healthy liver or in patients with underlying cirrhosis, the conditions are referred to as acute liver failure (ALF) or acute-​on-​chronic liver failure respectively. ALF is defined by the occurrence of hepatic encephalopathy in patients with severe acute liver injury within 6 months of the onset of symptoms. Acute-​on-​chronic liver failure is much more common than ALF. The condition is characterized by acute deterioration of a cirrhotic patient, with or without a recognized precipitating event,

section 15  Gastroenterological disorders 3090 associated with organ failures and high mortality rates. These condi- tions must be distinguished from decompensated cirrhosis, which is pathophysiologically different and typically represents patients that have end-​stage cirrhosis with varying degrees of end-​organ dysfunc- tion (Table 15.22.5.1). The following sections describe the two main types of liver failure: ALF and ACLF. The syndromes Acute-​on-​chronic liver failure Historically, major complications in patients with cirrhosis were thought to represent a stepwise progression, when a patient over years progressed from compensated to a decompensated state manifest clinically by the main complications of cirrhosis, namely, jaundice, variceal bleeding, ascites, hepatic encephalopathy, and infection. Over the last few years, large, prospective clinical studies have suggested that patients can progress from any stage of liver disease to ACLF (Fig. 15.22.5.1). The current working definition of ACLF is: ‘Acute-​on-​chronic liver failure is defined as acute de- terioration of pre-​existing, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multisystem organ failure’. Diagnosis The diagnosis of ACLF is made in the context of a patient with cir- rhosis who is hospitalized with a liver-​related complication such as variceal bleeding, ascites, hepatic encephalopathy, jaundice, or infection. The studies leading up to the establishment of criteria for the diagnosis of ACLF were predicated on finding a group with a 28-​day mortality of 15% or higher. They identified that a scoring system based on a modification of the Sepsis Organ Failure Table 15.22.5.1  Types of liver failure Acute Subacute ACLF underlying cirrhosis Decompensated cirrhosis Time from symptoms to failure Weeks Months Weeks Years Common aetiology Toxic Viral Variable Variable Precipitating event Liver injury Liver injury Sepsis Alcohol Infection (others) Mortality 50% 50% 30–​40% Variable Prognostic score King’s College criteria King’s College criteria CLIF-​C ACLFs MELD score Liver histology Massive necrosis Submassive necrosis Apoptosis Necrosis Cholestasis Variable Benefit from liver transplantation Yes Yes Yes Yes Adapted from Jalan R, et al. (2014). Toward an improved definition of acute-​on-​chronic liver failure. Gastroenterology, 147, 4–​10. Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Type A ACLF TypeB ACLF Type C ACLF Hepatic and extrahepatic organ failures Precipitants • Virus • Drug • Surgery • Sepsis • Idiopathic • Jaundice • Hepatic encephalopathy • Variceal bleeding • Ascites • Ischemic • Alcohol Fig. 15.22.5.1  Clinical course of ACLF syndrome and effects on prognosis. Reprinted from Gastroenterology, Vol. 147, Jalan R, et al., Toward an improved definition of acute-​on-​chronic liver failure, Pages 4–​10, Copyright © 2014 AGA Institute, with permission from Elsevier.

15.22.5  Liver failure 3091 Assessment (SOFA) score developed for patients with sepsis was appropriate for this purpose. This scoring system is referred to as the Chronic Liver Failure (CLIF) Consortium Organ Failure score (CLIF-​OFs) and is illustrated in Table 15.22.5.2. Using this scoring system, patients can be classified into those with and those without ACLF and with a definition of severity. Patients with ACLF have high rates of short-​ and medium-​term mortality compared with those without ACLF, and mortality rates are higher in those with more advanced grades (Fig. 15.22.5.2). ACLF is, however, a dy- namic syndrome with resolution to a non-​ACLF state observed in approximately 50% of ACLF-​1, 30% of ACLF-​2, and 20% of ACLF-​3 patients with supportive care within 2 to 5 days. Conversely, pa- tients with earlier stages of ACLF may deteriorate rapidly to the more advanced stages, emphasizing the key importance of expe- dient management at diagnosis. The common causes of cirrhosis and precipitating factors of ACLF are listed in Table 15.22.5.3. Prognosis Many scoring systems have been developed to define the prog- nosis of patients with cirrhosis. The most widely used of these are the Child–​Pugh and Model for End-​Stage Liver Disease (MELD) scores. The MELD score includes bilirubin, INR, and creatinine in the model, whereas the Child–​Pugh score (Table 15.22.5.4) cap- tures the clinical features of encephalopathy and ascites in add- ition to the conventional hepatic synthetic markers of bilirubin, albumin, and INR. Neither incorporate markers of inflammation, a key prognostic determinant in ACLF, hence a scoring system spe- cific for patients with ACLF was developed, the CLIF Consortium ACLF score (CLIF-​C ACLFs), composed of the CLIF-​OFs, age, and white cell count (Table 15.22.5.5). The CLIF-​C ACLFs has been shown to have superior prognostic accuracy compared to conven- tional measures such as the MELD and Child–​Pugh scores. A fur- ther advantage is that the prognosis of the patient can be updated daily to determine prognosis as it relates to the effect of a given intervention. ACLF is an exceptionally dynamic disease with variable out- comes. Resolution occurs in approximately one-​half of patients, with deterioration in approximately one-​fifth. The clinical course of the ACLF syndrome during hospitalization is the chief determinant of short-​term mortality. The 28-​day survival in patients developing resolution of ACLF was similar to that in patients without ACLF. In particular, it is the early course of ACLF over the time intervals of the first 1 to 2 days and subsequent 3 to 7 days which are of particular prognostic relevance. Table 15.22.5.2  Diagnostic criteria of acute-​on-​chronic liver failure Diagnosis Criteria No ACLF • Patients with no organ failure • Patients with single hepatic, coagulation, circulation, or respiratory failure, serum creatinine <1.5 mg/​dl, and no hepatic encephalopathy • Patient with cerebral failure and serum creatinine <1.5 mg/​dl ACLF-​1 • Patients with renal failure • Patients with other single organ failure with serum creatinine ≥1.5 and <2 mg/​dl and/​or hepatic encephalopathy grade III ACLF-​2 • Patients with 2 organ failures ACLF-​3 • Patients with 3 or more organ failures Data reproduced from Jalan R, et al. (2014). Development and validation of a prognostic score to predict mortality in patients with acute-​on-​chronic liver failure. J Hepatol, 61, 1038–​47. 1.0 0.8 0.6 0.4 42.9% 12.8% 5.1% 26.2% 58.4% 76% No d3-7 ACLF (n = 135) d3-7 ACLF-1 (n = 61) d3-7 ACLF-2 (n = 42) d3-7 ACLF-3 (n = 78) 3.8% 21.4% 53% 62% 78.7% 89.6% 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 0 28 60 90 Time (Days) Probability of transplant-free survival Probability of Survival 120 150 180 0 28 60 23.3% (95%CI: 15.8–30.8) 12.5% (95%CI:6.3–18.7) p<,0001 10% (95%CI:4.6–15.4) 80.9% (95%CI:64.2–97.7) 90.5% (95%CI: 77.9–100) 95.2% (95%CI: 86.1–100) Early transplanted d3-7 ACLF-2 or 3 patients (n = 21) Non-transplanted d3-7 ACLF-2 or 3 patients (n = 120) 90 Time (Days) 120 150 180 (a) (b) Fig. 15.22.5.2  Transplant-​free survival curves with differing grades of ACLF determined at days 3 to 7. (a) Kaplan–​Meier 180-​day transplant-​free survival curve. (b) Probability of survival in patients with ACLF-​2/​3 (at day 3–​7) with and without early (28-​day) liver transplantation. Reproduced with permission Gustot T, et al. (2015). Clinical course of acute-​on-​chronic liver failure syndrome and effects on prognosis. Hepatology, 62, 243–​52, Copyright © 2015, John Wiley and Sons.

section 15  Gastroenterological disorders 3092 Pathophysiology The pathogenesis of ACLF is unknown. There are two underlying factors in cirrhosis which render patients susceptible to the dele- terious effect of a superimposed insult. The first is the underlying cirrhosis and the structural disturbances, portacaval shunting, portal hypertension, and metabolic disturbance this entails. The second, perhaps equally important, is a ‘leaky gut’ with translocation of bac- terial and bacterial ligands to the liver and systemic circulation. This combination of factors ‘primes’ the patient’s organs to the effect of a superimposed secondary insult. The patient therefore responds ab- normally to the superimposed insult and this results in multiorgan failure. As is clear from this description, the pathogenesis of ACLF is complex as the condition occurs on the background of existing liver disease (Predisposition), is usually precipitated by some factor (Injury), is associated with an inflammatory response (Response), and characterized by organ failure (Organ), hence the pathophysio- logical basis of the syndrome can be considered under the ‘PIRO’ framework. Role of predisposing factors (P) A number of host factors appear to predispose to the development of ACLF, in particular the severity and aetiology of underlying liver disease. The severity of underlying cirrhosis as determined by MELD and Child–​Pugh scores does not accurately predict the se- verity and prognosis of ACLF, highlighting the pathophysiological differences between ACLF and decompensated cirrhosis. Male sex and younger age have also been associated with higher risk of ACLF, although neither of these variables has been associated with an in- crease in mortality. In prospective, observational European studies of patients with ACLF and acute decompensation, alcohol was more frequently represented and hepatitis C less frequently represented as the underlying aetiology of cirrhosis in ACLF patients compared to those with acute decompensation. Conversely, hepatitis B is more frequently observed in Asian countries as a cause of cirrhosis. The outcome of ACLF even in this group of patients is dependent on the severity of organ dysfunction. Role of precipitating factors (I) Identifiable precipitating events have been described in approxi- mately 60% of ACLF patients. These insults may either be directly hepatotoxic, such as alcoholic hepatitis, viral hepatitis, drug-​induced liver injury, or vascular disorders, or an extrahepatic insult such as variceal haemorrhage or sepsis (Table 15.22.5.3), which is a common precipitating event in ACLF. Patients with cirrhosis frequently have a state of functional immune paresis with anti-​inflammatory humoral and cellular immune phenotype. Patients with advanced cirrhosis are known to have reduced neutrophil phagocytosis, diminished HLA DR monocyte expression (diminishing capacity for antigen presentation to T cells), and high circulating interleukin-​10 levels predisposing them to sepsis. Alcohol abuse in the prodromal period of ACLF is more frequently observed in Western countries and hepatitis B flares or superimposed viral hepatitis is more common in Asian populations. Cases of ACLF precipitated by extrahepatic insults, in contrast to direct hepatotoxic insults, were found to be associated with a higher 90-​day and 1-​year mortality in a cohort of 405 ACLF patients. Aetiology of the underlying cirrhosis has also been found to be asso- ciated with the development of ACLF. Demographic differences in prevalence of chronic disease are likely to result in a heterogeneity in the clinical picture but further elucidation of the mechanisms is required. Role of inflammatory response (R) Host response, in particular the nature and magnitude of the innate immune response, is a significant determinant of clinical course in ACLF. Higher leucocyte counts are associated with more severe grades of ACLF and are predictive of poor outcome. The presence of a dysregulated systemic inflammatory response syndrome (SIRS) is a cardinal feature of ACLF and appears to be a key driver pro- moting the transition from stable cirrhosis to ACLF associated with increased mortality (Fig. 15.22.5.3). Many lines of evidence implicate gut-​derived endotoxin in pro- motion of a dysregulated immune response in ACLF. This may Table 15.22.5.3  Aetiologies of underlying cirrhosis and precipitating event in acute-​on-​chronic liver failure Causes of cirrhosis (chronic insult) Alcohol Viral hepatitis (hepatitis B, C, delta) Autoimmune liver disease (primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis) Metabolic liver disease (nonalcoholic steatohepatitis, Wilson’s disease, haemochromatosis, α1-​antitrypsin deficiency) Precipitating factors (acute insult) Sepsis: bacterial/​viral/​fungal—​de novo or reactivation Alcoholic hepatitis Variceal haemorrhage Viral hepatitis Drug/​toxin-​induced liver injury Vascular (Budd–​Chiari syndrome, ischaemic hepatitis, portal vein thrombosis) Surgery None identified Table 15.22.5.4  Child–​Pugh score Parameter Points assigned 1 2 3 Ascites Absent Slight Moderate Bilirubin, mg/​dL ≤2 2–​3

3 Albumin, g/​dL 3.5 2.8–​3.5 <2.8 Prothrombin time
(s over control) 1–​3 4–​6 6 INR <1.8 1.8–​2.3 2.3 Encephalopathy None Grade 1–​2 Grade 3–​4 Grade Points 1-​year patient survival (%) 2-​year patient survival (%) A: well-​compensated disease 5–​6 100 85 B: significant functional compromise 7–​9   80 60 C: decompensated disease 10–​15   45 35

15.22.5  Liver failure 3093 account for the generation of a SIRS response in the 40% of patients without an identifiable precipitating factor. The presence of SIRS is associated with more severe encephalopathy, renal failure, and an increased incidence of bacterial infection. SIRS is associated with a hyperdynamic circulation with low systemic vascular resistance and a low mean arterial pressure resulting in low organ perfusion com- pounding organ injury. Features of a compensated anti-​inflammatory response syndrome may predominate over SIRS in subgroups of patients with ACLF in particular during later stages of the syndrome. Such patients are immune deficient and prone to nosocomial infection. This state of immunological dissonance in ACLF is evident at the level of both cell-​mediated and humoral innate immunity. Organ dysfunction (O) Development and degree of organ failure is the most important de- terminant of outcome in ACLF patients and is the defining feature. In contrast to end-​stage decompensated disease, recoverability of organ function is potentially achievable and should be managed accordingly. Hepatic failure  Hyperbilirubinaemia is almost invariably present, manifest as jaundice, and in the context of coagulopathy is considered a key criterion of ACLF. Ongoing liver injury promotes an inflammatory response, which further exacerbates liver failure. Current data suggest that apoptosis is the predominant mechanism of cell death in ACLF in patients with alcoholic cirrhosis in contrast to patients with hepatitis B in which necrosis appears to be the pre- dominant mechanism. The exact molecular mechanisms involved remain unclear, but it is likely that hepatic inflammation causes cell death and release of damage-​associated molecular patterns (DAMPs) which further exacerbate inflammation and cell death. The net result is a vicious cycle that is associated in a self-​amplifying cycle with worsening hepatic perfusion and more severe portal hypertension consequent on increased intrahepatic resistance. Kidney dysfunction  Acute kidney injury is common in patients with ACLF. From the pathophysiological standpoint, this may be due to hypovolaemia, acute tubular injury, or hepatorenal syndrome. Distinction between these entities is important. Hypovolaemic renal failure resolves quickly with volume resuscitation. Hepatorenal syn- drome has classically been considered as a functional disorder in which there is splanchnic vasodilatation and reduction in mean arterial pressure occurs with consequent activation of the sympa- thetic and renin–​angiotensin systems, resulting in intense renal Table 15.22.5.5  The CLIF Organ Failure scoring system Organ system Score = 1 Score = 2 Score = 3 Liver Bilirubin <6 mg/​dl
(<100 µmol/​litre) 6 ≤ Bilirubin ≤ 12 mg/​dl (100–​200 µmol/​litre) Bilirubin >12 (>200 µmol/​litre) Kidney (mg/​dl) Creatinine <2 mg/​dl (<175 µmol/​litre) 2 <Creatinine <3.5 mg/​dl (175–​310 µmol/​litre) Creatinine ≥3.5 mg/​dl (>310 µmol/​litre) or renal replacement Brain (West Haven) Grade 0 Grade 1–​2 Grade 3–​4 Coagulation INR <2.0 2.0 ≤INR <2.5 INR ≥2.5 Circulation MAP ≥70 mm/​Hg MAP <70 mm/​Hg Vasopressors Respiratory: Pao2/​Fio2 or Spo2/​Fio2

300 357 ≤300–​>200 214–​ ≤357 ≤200 ≤214 The bold entries represent organ failure. Fio2, Fractional inspired oxygen; INR, international normalized ratio; MAP, mean arterial pressure; Pao2, Partial pressure of oxygen; Spo2, oxygen saturation. Reprinted from J Hepatol, Vol. 62, Jalan R, et al., The CLIF Consortium Acute Decompensation score (CLIF-​C ADs) for prognosis of hospitalised cirrhotic patients without acute-​on-​chronic liver failure, Pages 831–​40, Copyright © 2015 European Association for the Study of the Liver, with permission from Elsevier. Liver failure/bacterial translocation Immune paralysis • Endotoxaemia • Reduced protein/complement synthesis • Reduced immune surveillance • Reduced albumin function Innate immunity • Neutrophils: phagocytic defect • Monocytes: DR loss • NK cells • T-cell exhaustion • Inability to profilerate • lncreased apoptosis CARS: compensatory anti-inflammatory response SIRS: systemic inflammatory response Normal ACLF: survivor ACLF: nonsurvivor Immune response Adaptive immunity Fig. 15.22.5.3  Immunopathology of ACLF.

section 15  Gastroenterological disorders 3094 vasoconstriction (Box 15.22.5.1). A significantly higher proportion of patients have evidence of acute tubular injury. Although distinct, all three entities overlap to some extent in individual patients, and all are reversible with improvement in liver function, although a few patients require prolonged renal replacement therapy despite re- covery of liver function. Brain dysfunction  The demographics and prognosis of hepatic encephalopathy (HE) in ACLF and acute decompensation appear to be different. Hepatic encephalopathy associated with ACLF is associated with a higher mortality, occurring more frequently in young alcoholic cirrhotic patients with severe liver failure and a pronounced SIRS response. In contrast, hepatic enceph- alopathy not associated with ACLF occurred in older abstinent cirrhotic patients with features of SIRS or severe liver failure. A proinflammatory response and hyperammonaemia operate syn- ergistically to result in astrocyte swelling, clinically manifest as hepatic encephalopathy in the ACLF patient. Unlike in ALF, hep- atic encephalopathy is rarely complicated by raised intracranial pressure. Cardiac and circulatory dysfunction  Circulatory support re- quirements with inotropes and/​or vasopressor agents are often significant. High circulating nitric oxide levels coupled with endo- thelial dysfunction result in a low peripheral vascular resistance. Unlike in decompensated cirrhosis in which a high cardiac output is typically observed, cardiac output is frequently reduced in ACLF. This cardiovascular abnormality is associated with an increased risk of death, particularly in those patients who present with renal dysfunction. Adrenal insufficiency  Adrenal insufficiency is reported in 51 to 68% of patients with cirrhosis and severe sepsis, and the incidence may be higher in ACLF patients. The mechanisms underlying this are not clear, but its presence is associated with increased mortality compared to patients without adrenal insufficiency. Acute liver failure ALF is a rare but rapidly progressive clinical entity associated with a high mortality without treatment. It is defined as ‘a rapid decline in hepatic function characterized by jaundice, coagulopathy (INR

1.5), and hepatic encephalopathy in patients with no evidence of prior liver disease’. Patients with ALF are classified according to the interval between the onset of jaundice to the development of encephalopathy as this carries prognostic significance: hyperacute liver failure (<7 days); ALF (7–​28 days); or subacute liver failure (28 days–​24 weeks). Drug-​induced liver injury, in particular paracetamol, is a fre- quent cause of ALF in Europe and the United States of America, accounting for more than 50% of cases. In contrast, viral hepatitis as a cause of ALF is commoner in the East, with high rates of hepa- titis B and E responsible. Causes of ALF are listed in Box 15.22.5.2. Pathophysiologically, ALF is characterized by massive hepatocyte necrosis and a pronounced SIRS. Clinical features of SIRS are com- monly observed together with a heightened susceptibility to sepsis. Significant progress has been made over the last 30 years with re- gard to management of this disorder. An improvement in critical care management (in particular with regard to raised intracranial pressure) and a well-​defined emergency liver transplantation pro- gramme are chiefly responsible for the observed significant im- provement in mortality. Clinical features Many of the clinical features of ALF may be attributed to an acute SIRS with multiorgan failure and a hyperdynamic circulation. Hepatic encephalopathy is a much feared complication of ALF and occurs as a consequence of cerebral oedema with raised intracra- nial pressure. Clinically this may be graded using the West Haven criteria. Progression of encephalopathy may be rapid and so early identification is key. ALF follows a very dynamic clinical course, the nature of which has prognostic significance. Patients with hyperacute ALF have rapid onset of hepatocellular injury evidenced biochemically by very high transaminase but often low bilirubin levels. Typical causes include paracetamol and ischaemic hepatitis. Recovery may be as rapid as onset. In contrast, subacute liver failure develops over sev- eral weeks and a biochemical picture of hyperbilirubinaemia with lower transaminases is commonly observed. Patients with subacute liver failure may manifest with clinical features of portal hyperten- sion. Such patients may be mistakenly diagnosed as ACLF or acute decompensation, hence care must be taken to clearly determine chronicity of disease. Typical causes include indeterminate hepa- titis, drug-​induced liver injury, hepatitis B, and autoimmune hepa- titis. Prognosis is poor. Establishing the underlying aetiology is an important goal of clinical assessment and may frequently be achieved from a detailed Box 15.22.5.1  Criteria for diagnosis of hepatorenal syndrome in cirrhosis • Cirrhosis with ascites • Serum creatinine greater than 1.5 mg/​dl (133 μmol/​litre) • Absence of shock • Absence of hypovolaemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/​litre) following at least 2 days of diuretic withdrawal (if on diuretics), and volume expansion with albumin at 1 g/​kg/​day up to a maximum of 100 g/​day • No current or recent treatment with nephrotoxic drugs • Absence of parenchymal renal disease as defined by proteinuria less than 0.5 g/​day, no microhaematuria (<50 red cells/​high powered field), and normal renal ultrasonography Box 15.22.5.2  Causes of acute liver failure • Dose-​dependent drug-​induced liver injury: paracetamol (acetamino- phen), ecstasy, herbal toxicity, Amanita phalloides mushroom ingestion • Idiosyncratic drug-​induced liver injury:  rifampicin, isoniazid, non­ steroidal anti-​inflammatory drugs, sodium valproate, halothane • Recreational drug use (MDMA, cocaine, khat) • Viral hepatitis: (hepatitis A, B, C, D, and E, herpes simplex virus, cyto- megalovirus, Epstein–​Barr virus, varicella zoster virus, parvovirus, adenovirus) • Vascular: right heart failure, Budd–​Chiari syndrome, veno-​occlusive disease, ischaemic hepatitis, heat stroke • Metabolic: acute fatty liver of pregnancy, Wilson’s disease, Reye’s syn- drome, galactosaemia, hereditary fructose intolerance, tyrosinaemia • Autoimmune hepatitis • Other: sepsis, malignant infiltration, primary nonfunction of a trans- planted liver

15.22.5  Liver failure 3095 history and serological investigations. Prognostic scoring systems based on aetiology and clinical measures of organ injury iden- tify high-​risk groups in which spontaneous recovery and survival without transplantation is poor. Prognosis ALF has a poor prognosis with an overall mortality of 40 to 62%, transplant-​free survival of 25 to 43%, and overall survival of 67%. The principal causes of death are cerebral oedema, sepsis, and multiorgan failure. Prognosis is heavily influenced by aetiology. Spontaneous survival is higher in paracetamol-​induced liver injury, hepatitis A virus infection, ischaemic hepatitis, and pregnancy-​related ALF. In contrast, short-​term transplant-​free survival is lower in patients with indeterminate causes, nonparacetamol drug-​induced liver injury, hepatitis B, autoimmune hepatitis, Wilson’s disease, and Budd–​Chiari syndrome. Criteria for transplantation are based on adverse prognostic de- terminants. As a consequence of better supportive care of patients with ALF, improvements in survival over the last 40 years have been observed (Fig. 15.22.5.4). Pathophysiology Liver failure occurs when hepatocellular death (either via necrosis and/​or apoptosis) exceeds regeneration. While apoptosis results in minimal inflammation, cell lysis from necrosis results in secondary inflammation. Apoptosis appears to be the principal mechanism of cell death in toxicity and viral-​induced ALF. Clinically, however, neither apoptotic nor necrotic cell death markers accurately predict survival following paracetamol-​induced ALF. The M30 antigen, a marker of apoptotic hepatocyte cell death was found to be 10-​fold elevated in ALF patients compared with normal or hepatitis C-​ infected controls. Inhibition of apoptosis with caspase inhibitors has shown early promise in preclinical studies. The development of a SIRS is a cardinal clinical feature of patho- genesis in ALF (Fig. 15.22.5.5). An expansion of tissue-​resident macrophages and infiltration of monocytes occurs in response to hepatocellular apoptosis and necrosis. While monocyte/​macro- phage populations play a key role in resolution of disease, heightened M1 proinflammatory activity further contributes to oxidative injury and exacerbation of hepatic and extrahepatic organ failure and de- velopment of a hyperdynamic circulation. Heightened neutrophil oxidative stress in concert with hyperammonaemia due to impaired urea cycle metabolism have been shown to play an important role in the development of hepatic encephalopathy with the development of cerebral oedema. The nature of the signalling pathways utilized in the innate in- flammatory response in ALF is aetiology specific. Hepatotropic viruses signal directly via pathogen-​associated molecular pat- terns (PAMPs), whereas DAMP signalling pathways have a more central role in drug toxicity. The situation is in fact more compli- cated, and convergence of PAMP and DAMP signalling potentiates organ injury. While in ALF the predominant drivers of this pathway are en- dogenous ligands such as apoptotic markers, there is increasing interest in the role of endotoxin signalling in augmenting this process. ALF has been shown to be associated with the development of sys- temic endotoxaemia and a proinflammatory response responsible for many of the deadly clinical features in ALF as previously discussed. Removal of endotoxin in a porcine model of paracetamol-​induced ALF has been shown to be associated with a significant improvement in mortality. Several lines of evidence from murine studies also con- firm the importance of the endotoxin receptor (TLR4) pathways in the pathogenesis of paracetamol-​induced ALF. The TLR4 antagonist STM28 significantly reduced liver injury, renal function, and time to encephalopathy in a murine model of paracetamol toxicity. A compensatory anti-​inflammatory response subsequently de- velops, conferring a propensity to sepsis commonly observed in ALF patients. Indeed, elements of both SIRS and compensated anti-​ inflammatory response syndrome responses frequently coexist. Previous studies have demonstrated monocyte hyporesponsiveness in ALF but coincident with elevated anti-​inflammatory cytokines. Investigation of liver failure Broad assessment of all organ systems is required in patients with ALF or ACLF to determine precipitants, identify reversible precipitating factors, and determine prognosis. Blood tests Conventional laboratory blood assays are required to provide measures of organ injury and failure (Table 15.22.5.6). These in- clude determination of coagulation status, liver and renal bio- chemistry, arterial blood gas measurements, lactate, and full blood count. Dynamic assessment of organ injury and inflammatory in- dices provides a more accurate assessment of clinical status and is used with recognized scoring systems such as the CLIF-​OFs and Kings College criteria. Comprehensive screening for sepsis is an essential element of in- vestigation of patients with ACLF and ALF given the state of func- tional immune compromise. Cultures from blood, ascites, urine, and sputum should be collected on admission, and prompt ascitic fluid microscopy performed. Urinary dipstick analysis and (if posi- tive for protein) urinary albumin-​to-​creatinine ratio should be de- termined to identify coincident intrinsic renal disease. Initial investigations should also include a screen for aetiology of liver disease and to risk stratify patients (Table 15.22.5.6). If Wilson’s disease is suspected, slit lamp examination for Kayser–​ Fleischer rings should be performed. 90 80 70 60 50 40 30 20 10 Years Hospital survival (%) 0 1973–78 1979–83 1984–88 1989–93 1994–98 1999–2003 2004–08 Fig. 15.22.5.4  Hospital survival in admissions with ALF. Reproduced from Bernal W, et al. (2013). Clinical management of acute liver failure: results of an international multi-​center survey. J Hepatol, 59, 74–​80.

section 15  Gastroenterological disorders 3096 Radiological Abdominal ultrasonography with hepatic and portal vein Dopplers is often the first-​line radiological investigation performed in ALF and ACLF. Establishing features of chronicity such as parenchymal changes in the liver and kidneys and features of portal hypertension is important in achieving the correct diagnosis. It must be noted, however, that ultrasonography is a relatively insensitive tool for the identification of cirrhosis. It is also worth noting that portal hyper- tension may be a feature of subacute liver failure and should be in- terpreted in context. A CT head scan is indicated in patients with severe encephalopathy to exclude other intracranial pathology such as haemorrhage. In ALF, quantification of liver volumes with cross-​sectional imaging modalities using CT or MRI has been used as an adjunct to provide information regarding hepatocellular mass. While this does not provide a measure of functionality, some clinical studies have suggested that low liver volumes (<1000 ml) in ALF constitute an adverse prognostic determinant, with a predicted mortality of 97%. This must be interpreted in the context of the entire clinical picture. Interval imaging (on admission and day 5) may provide further in- formation regarding the time course of disease. circulation SIRS monocyte activation TNF IL-6 monocytes “pro-inflammatory” monocytes “pro-inflammatory” macrophage macrophage activation AIAT hepatocyte death DAMPs (HMGB I, DNA, histones) TNF phagocytosis efferocytosis recruitment of monocyte-derived macro phages Kupffer cell portal vein steroids IL-10 SLPI IL-10 SLPI DR CD163 phagocytosis hepatocyte regeneration IL-6 “'anti-inflammatory” -immune-paresed- monocytes “'anti-inflammatory” macrophage hepatic vein DR CD163 phagocytosis TNF IL-6 risk of sepsis “spill-over” of inflammatory mediators CARS liver initiation propagation resolution Fig. 15.22.5.5  Pathological role of the immune response in ALF. CARS, compensatory anti-​inflammatory response syndrome. Reprinted by permission from Springer Nature: Bernsmeier C, Antoniades CG, Wendon J (2014). What’s new in acute liver failure? Intensive Care Medicine, 40, 1545–​8, copyright © 2014. Table 15.22.5.6  Investigations for acute liver failure Haematology Full blood count, coagulation screen including INR ABO blood group Biochemistry Liver function tests (bilirubin, ALT, AST, γGT, ALP, albumin) Urea, creatinine, electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate) Glucose Arterial blood analysis pH, lactate, ammonia, Po2, Pco2 Toxicology screen Paracetamol level, toxicology screen Viral screen HAV/​HEV IgM/​G, HBc IgM/​G, HBsAg, HCVIg EBV/​CMV/​HSV/​parvovirus IgM/​G HIV1/​2 Metabolic screen Serum and urinary copper, caeruloplasmin Autoantibodies ANA, SMA, LKM, immunoglobulins ALT, alanine aminotransferase; ALP, alkaline phosphatase; ANA, antinuclear antibody; AST, aspartate aminotransferase; CMV, cytomegalovirus; EBV, Epstein–​Barr virus; γGT, γ-​glutamyl transferase; HAV, hepatitis A virus; HBc, hepatitis B virus core antigen; HBsAg, hepatitis B virus surface antigen; HCVIg, hepatitis C immunoglobulin; HEV, hepatitis E virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LKM, liver–​kidney microsomal antibody; SMA, anti-​smooth muscle

15.22.5  Liver failure 3097 Endoscopic Prompt endoscopic assessment of the upper gastrointestinal tract should be performed in all patients in whom variceal haemorrhage is suspected. Anaesthetic support with airway management should be provided in the presence of large volume gastrointestinal bleeding or an encephalopathic state. Histological Transjugular liver biopsy may contribute to the assessment of ACLF patients in terms of both establishing the aetiology of pre- cipitant (such as alcoholic hepatitis) or underlying disease, and establishing the hepatocellular regenerative potential. Other fea- tures such as ductular bilirubinostasis have been associated with high risk of sepsis and an adverse prognosis. Transjugular liver biopsy is recommended in ALF if the aetiology is unclear after ex- tensive initial investigation, or if there is suspicion of underlying chronic disease. Management General Prompt institution of high-​level supportive and aetiology-​specific therapy is required to optimize the opportunity for reversibility of organ failure, a key determinant of outcome in ACLF and ALF. Early identification of adverse prognostic features to inform decisions to list for transplantation is important as the subsequent clinical de- terioration may be rapid. Management may be considered broadly under two categories: organ system support and aetiology-​specific therapy. Organ system support ACLF and ALF should be managed in a high-​level clinical care envir- onment. An algorithm for supportive care is shown in Fig. 15.22.5.6. Individual organ systems will be considered. Fig. 15.22.5.6  Management approaches for patients with cirrhosis who are admitted to the intensive care unit. ABG, arterial blood gases; BP, blood pressure; CPAP, continuous positive airway pressure; CT, computed tomography; CXR, chest X-​ray; ECG, echocardiogram; FiO2, fraction of inspired oxygen; GCS, Glasgow Coma scale; Hb, haemoglobin; HPS, hepatopulmonary syndrome; IAP, intra-​abdominal pressure; IJ, internal jugular;
PA, pulmonary artery; PaO2, arterial partial pressure of oxygen; PCWP, pulmonary capillary wedge pressure; PPH, portopulmonary hypertension; RAP, right atrial pressure; RRT, renal replacement therapy; ScvO2, central venous oxygen saturation; SVV, stroke volume variation. Reproduced with permission from Olson JC, Wendon JA, Kramer DJ, Arroyo V, Jalan R, Carcia-​Tsao G, Kamath PS (2011). Intensive care of the patient with cirrhosis. Hepatology, 54, 1864–​72, Copyright © 2011, John Wiley and Sons.

section 15  Gastroenterological disorders 3098 Brain Hepatic encephalopathy is an important prognostic determinant in both ACLF and ALF. Identification and management of patients with or at high risk of developing hepatic encephalopathy is of cen- tral importance in the management of patients. Intubation is re- quired in patients with severe hepatic encephalopathy (grade III or IV) for airway protection. Appropriate nutritional support to ensure normoglycaemia, repletion of micronutrients and electrolytes and appropriate nitrogen balance will minimize superimposed meta- bolic encephalopathy. In ACLF, the mainstay of therapy of a hospitalized patient with cirrhosis is lactulose with administration of enemas to clear the bowel as a useful adjunct. The nonabsorbable antibiotic rifaximin has been shown to improve recurrence of hepatic encephalopathy in decompensated cirrhotic patients but is frequently used in an acute context. Cerebral oedema complicated by intracranial hypertension is a potentially life-​threatening feature of severe hepatic encephalop- athy secondary to ALF but does not appear to be a predominant feature of ACLF. Reduction in ammonia and cerebral oedema is the therapeutic goal of management in this context. Reduction in cerebral ammonia uptake and metabolism may be achieved by use of sedation with intubation and moderate hypothermia. Renal re- placement therapy may also be instituted to remove high systemic ammonia. Reduction in cerebral oedema may be achieved by use of osmotherapy with boluses of hypertonic saline and/​or man- nitol and limited periods of hyperventilation-​induced hypocapnia. Invasive intracranial monitoring with direct intracranial pressure monitoring, reverse jugular oxygen saturations, and transcranial ultrasonography is indicated in patients in whom intracranial hypertension is suspected clinically. This should be performed only in tertiary units with appropriate expertise. Circulation Circulatory dysfunction is frequently observed in ACLF and ALF and is typically a composite function of hypovolaemia and circula- tory dysfunction in the presence of a pronounced systemic inflam- matory response potentially compounded by sepsis. Hypotension refractory to volume repletion warrants circulatory support to ensure adequate mean arterial and cerebral perfusion pressures, in which instance noradrenaline would be the first vasopressor of choice. The nature of circulatory support must take into account potential coexistence of cirrhotic cardiomyopathy or pulmonary hypertension. Terlipressin by means of splanchnic vasoconstriction coupled with weak peripheral vasoconstrictor properties may be used to improve renal perfusion in the hepatorenal syndrome of ACLF. Terlipressin, however, is contraindicated in the hepatorenal syn- drome of ALF as it has been shown to cause cerebral hyperaemia in severe hepatic encephalopathy, exacerbating cerebral oedema and intracranial hypertension. Kidneys The development of renal impairment in either ALF or ACLF confers a poor prognosis and hence treatment should be insti- tuted promptly to optimize organ reversibility. The mechanisms which underlie renal impairment in ALF and ACLF are frequently multiple. Circulatory dysfunction and intrinsic renal pathology fre- quently coexist and so care must be taken to thoroughly investigate to ascertain the underlying aetiologies. Renal failure is commonly observed in ALF, particularly in paracetamol-​induced ALF and the elderly, and is an adverse prognostic determinant. Management of intrinsic renal pathology should be supervised by a nephrologist. Intravenous terlipressin in combination with albumin support is first-​line therapy for management of the hepatorenal syndrome in ACLF. Caution must be used in patients at risk of ischaemic heart disease and peripheral vascular disease due to known possible extrasplanchnic vasoconstrictor effects. The role of renal replacement therapy with haemofiltration must be determined on a case-​by-​case basis, informed by the likely contribution of recoverable intrinsic renal disease versus nonrecoverable circulatory failure. Continuous rather than inter- mittent renal replacement therapy is recommended in this setting. Specific Common identifiable precipitants of ACLF include bacterial in- fection, alcoholic hepatitis, and variceal haemorrhage. As previ- ously discussed, many patients presenting with ACLF do not have a clear precipitant, and some have more than one precipitant. Drug-​ induced liver injury and viral hepatitis are common causes of ALF. Antibiotics Sepsis is a common precipitant in ACLF and complicating factor of ACLF and ALF due to the anti-​inflammatory phenotype of the innate immune response, which develops as an attempt to resolve disease. Prompt administration of empirical antibiotics is clearly im- portant in the management of sepsis. Spontaneous bacterial peritonitis is a common cause of sepsis in patients with advanced cirrhosis and occurs in approxi- mately 30% of patients managed with antibiotics alone. Prompt coadministration of albumin (1.5 g/​kg at diagnosis and 1 g/​kg on day 3) has been associated with an improvement in hepatorenal syndrome and survival and is therefore recommended in national and international guidelines. Bacterial infections other than SBP are less frequently associated with renal failure. The role of empir- ical coadministration of albumin in non-​SBP sepsis without renal failure remains the subject of ongoing studies. Prophylactic antibiotic and antifungal agents are often prescribed in ALF although there is not a strong evidence base to support this strategy. Other treatments Prognostic tools such as the Maddrey and Lille scoring systems identify patients with a high risk of mortality and for whom therapy for alcoholic hepatitis should be considered. Steroids are first-​line therapy but have no long-​term mortality benefit and the risk of sepsis must be taken into consideration. Appropriate nutritional support should be instigated. The management of variceal haemorrhage is outside the scope of this chapter but is outlined in national and international guide- lines. Specific therapies include prophylactic antibiotic and vaso- active drug administration in conjunction with endoscopic therapy. Transjugular portosystemic shunt insertion may be relatively contraindicated by the degree of organ failure.

15.22.5  Liver failure 3099 Intravenous N-​acetylcysteine should be commenced promptly in suspected paracetamol-​induced ALF and may be beneficial in nonparacetamol drug-​induced liver injury. Institution of antiviral therapy has been shown to significantly reduce mortality in ACLF secondary to hepatitis B reactivation. In contrast, no specific antiviral therapy has been proven efficacious in ALF, but nucleos(t)ide analogues should be considered for hepa- titis B-​associated ALF to minimize the risk of post-​transplantation recurrence. ALF patients with known or suspected varicella zoster or herpes simplex hepatitis should be treated with intravenous aciclovir. Oral prednisolone may be considered for ALF with mild hepatic encephalopathy due to autoimmune hepatitis but should not delay listing for transplantation. Obstetric delivery is the first line of management of ALF secondary to acute fatty liver of pregnancy/​HELLP syndrome (haemolysis, ele- vated liver enzyme levels, and low platelet levels). Synthetic function may indeed further decline within the first week postpartum and consideration of liver transplantation may be required. Extracorporeal liver assist Given the potential for recoverability of liver failure in ALF and ACLF in contrast to end-​stage decompensated cirrhosis, liver sup- port devices to bridge to recovery or transplantation are an im- portant therapeutic goal. Currently available liver support systems are not recommended outside of clinical trials, although several sys- tems (biological and nonbiological) have been evaluated. Nonbiological devices such as fractionated plasma separation and adsorption (Prometheus) and molecular adsorbent recircu- lating system (MARS) have been shown to be effective in improving cholestasis and severe hepatic encephalopathy in ACLF. This is attrib- utable to removal of protein-​bound toxins via albumin. The devices have acceptable safety and tolerability profiles in ACLF and ALF, but randomized controlled trial data have failed to show an improve- ment in survival. Interestingly, one study found that downgrading the MELD score (to <30) in ACLF using an artificial liver support system as bridging therapy improved outcomes in the responders to levels similar to those who underwent primary liver transplantation. Biological devices that incorporate hepatic cells in bioreactors are also under development. Recent data from pilot studies suggested improvement in survival rates in some groups of patients with ACLF, but their effects on patient survival in randomized controlled trials are still unknown. The HepatAssist device which utilizes porcine hepatocytes has been studied in ALF but is yet to show a survival advantage in clinical trials. Liver transplantation Liver transplantation remains the only curative treatment for ACLF in patients with failed medical treatment. Good 5-​year transplant survival data have been observed in patients with prior ACLF (74–​90%), even with a high MELD score. Outcomes with deceased circulatory death organs and live-​donor organs were found to be equivalent in this context. The Asian Pacific Association for the Study of the Liver guidelines state that ACLF patients with a MELD score higher than 30 should be considered for urgent transplant- ation. Noncardiorespiratory organ failure is not a contraindication to transplantation. While much progress has been made defining patient outcome with ACLF using the CLIF-​C ACLFs, this system has not been specif- ically applied or validated in a post-​transplantation cohort to inform listing criteria for ACLF. There is no validated criteria and scoring system for early and correct identification of patients with ACLF who would benefit from early liver transplantation. While there are many predictors of mortality, there are no reliable predictors of re- versibility of ACLF, hence there is an urgent need to identify such variables to facilitate early liver transplantation in patients likely to benefit from it. The King’s College criteria for transplant listing of ALF were first described in 1989, incorporating adverse prognostic determinants identified from a retrospective analysis of a single-​centre cohort of 588 patients over 22 years (Table 15.22.5.7). Separate criteria were described for paracetamol and nonparacetamol-​induced ALF due to the different performance characteristics of parameters correlating with prognosis in the two aetiologies. Current criteria include factors influencing hepatic regeneration (age, poor prognostic aetiologies such as drug-​induced or seronega- tive ALF) together with conventional markers of hepatocellular function such as INR and bilirubin. The criteria are weighted to- wards encephalopathy, reflective of their key influence on prog- nosis. The inclusion of pH reflects not only hepatocellular but also multiorgan failure and, more recently, lactate has been incorporated into the criteria and is of particular prognostic use in paracetamol-​ induced ALF. A particular emphasis is laid on the course of enceph- alopathy and multiorgan failure. In nonparacetamol-​induced ALF, prognostic criteria reflect a greater contribution of hepatic regener- ation on outcome. Subsequent studies have identified that while King’s College criteria have good positive predictive values, negative predictive values are poorer (particularly in the nonparacetamol group), sug- gesting that patients who do not meet them may still have a signifi- cant chance of dying. While they continue to be widely used, other scoring systems have been evaluated (including MELD, SOFA, and APACHE II scores) and in some studies have been shown to be su- perior to the King’s College criteria. In practice, the best method of assessment is a dynamic one, with daily monitoring of prognostic- ally important parameters. Table 15.22.5.7  King’s College criteria Paracetamol-​ induced ALF Arterial pH <7.3 (regardless of presence of hepatic encephalopathy) Or all 3 of the following: INR >6.5 Creatinine >300μmol/​L Hepatic encephalopathy grade III–​IV Lactate >3.5 (4 h after resuscitation) or >3
(12 h after resuscitation) Nonparacetamol-​ induced ALF INR >6.5 (regardless of presence of hepatic encephalopathy) Or 3 of 5 the following (regardless of presence of hepatic encephalopathy): Age <10 or >40 years Bilirubin >300μmol/​L Coagulation: INR >3.5 Duration of jaundice to encephalopathy >7 days Aetiology: indeterminate, drug-​induced

15.22.6 Liver transplantation 3100

15.22.6 Liver transplantation 3100

section 15  Gastroenterological disorders 3100 Other approaches to further improve prognostic criteria include sequential assessment of liver volumes by CT. This is a new tool to assess liver collapse and thus infer hepatocellular reserve, although it does not provide a measure of functionality. One study found that a liver volume of less than 1000 ml was associated with a pre- dicted mortality of 97%. Other attempts to improve on conventional scoring systems include the ALFSG (US Acute Liver Failure Study Group) index, utilizing a combination of clinical end-​points and the biomarker of apoptosis M30. This was found to better predict outcomes of patients with ALF than the King’s College criteria or MELD, but requires further validation. Future directions While much progress has been made in the last few years in char- acterizing the clinical phenotype and prognosis of ACLF, the underlying pathological mechanisms remain incompletely under- stood. It is evident from clinical studies that a dysregulated SIRS is a central driver of pathogenesis. Precipitating events may be initiators of ACLF but do not determine outcome. It is therefore likely that individual host susceptibility to injury (via PAMP/​ DAMP signalling pathways in particular) and regenerative poten- tial accounts for the observed heterogeneity in clinical outcome. A  clearer understanding of these underlying mechanisms will inform targeted immunotherapy. The goal of therapy in ACLF and ALF is to prevent or at least reverse organ failure and thus improve outcome. Organ failure occurs when organ injury overwhelms regenerative re- sponse. Unlike chronic decompensated disease in which regen- erative capacity has been exhausted, there may be potential for reversibility of organ dysfunction in patients with ACLF and ALF. Therapeutic interventions are likely to focus on abroga- tion of SIRS to diminish organ injury and either promotion of hepatocellular regeneration or bridging therapies with liver sup- port devices. Biomarkers to inform hepatocellular regenerative potential, extracorporeal support systems, and the use of growth factors to promote hepatocellular regeneration remain unmet clin- ical needs. Finally, further work is required to determine optimal criteria for early identification of patients requiring transplant- ation for ACLF. FURTHER READING Acute-​on-​chronic liver failure Arroyo V, et  al. (2015). Acute-​on-​chronic liver failure:  a new syn- drome that will re-​classify cirrhosis. J Hepatol, 62 Suppl 1, S131–​43. Gustot T, et al. (2015). Clinical course of acute-​on-​chronic liver failure syndrome and effects on prognosis. Hepatology, 62, 243–​52. Jalan R, et al. (2014). Development and validation of a prognostic score to predict mortality in patients with acute-​on-​chronic liver failure. J Hepatol, 61, 1038–​47. Jalan R, et al. (2015). The CLIF Consortium Acute Decompensa­ tion score (CLIF-​C ADs) for prognosis of hospitalised cirrhotic patients without acute-​on-​chronic liver failure. J Hepatol, 62, 831–​40. Moreau R, Jalan R, Arroyo V (2015). Acute-​on-​chronic liver failure: recent concepts. J Clin Exp Hepatol, 5, 81–​5. Moreau R, et al. (2013). Acute-​on-​chronic liver failure is a distinct syn- drome that develops in patients with acute decompensation of cir- rhosis. Gastroenterology, 144, 1426–​37.e1–​9. Acute liver failure Bernal W, et al. (2015). Acute liver failure: a curable disease by 2024? J Hepatol, 62 Suppl 1, S112–​20. Bernsmeier C, Antoniades CG, Wendon J (2014). What’s new in acute liver failure? Intensive Care Med, 40, 1545–​8. Hillman L, et al. (2016). Clinical Features and Outcomes of Comple­ mentary and Alternative Medicine Induced Acute Liver Failure and Injury. Am J Gastroenterol, 111, 958–65. Polson J, Lee WM, American Association for the Study of Liver Disease (2005). AASLD position paper: the management of acute liver failure. Hepatology, 41, 1179–​97. 15.22.6  Liver transplantation John G. O’Grady ESSENTIALS Liver transplantation is an established treatment for liver conditions that broadly fall into the categories of acute liver failure, end-​stage chronic liver disease, primary hepatic malignancy, and metabolic dis- ease. The expected 1-​year survival rate is over 90% and some patients are alive more than 40 years after transplantation. Organs retrieved from deceased donors account for most transplant activity in the West, while living donation dominates in the East. Disease severity scores for cirrhosis heavily influence selection of patients with cirrhosis for transplantation. The prototype is the MELD (Model for End-​Stage Liver Disease) score, based on serum bilirubin, serum creatinine, and INR: a score of 16 is considered the threshold that confers benefit from liver transplantation. Hepatocellular carcinoma accounts for most of the malignancy group and selection is largely determined by tumour bulk assessed by the number and size of lesions. Immunosuppression strategies based on tacrolimus, with or without other drugs including mTOR (mechanistic target of rapamycin) in- hibitors, antiproliferative agents, or prednisolone, are highly effective in preventing loss of the graft through classical rejection processes. Recurrence of original disease is the main cause of loss of graft function, with recurrence of hepatitis C a particularly challenging problem, al- though new direct-​acting antiviral agents are likely to radically improve outcomes. Technical problems can also result in graft loss due to hep- atic artery thrombosis or diffuse ischaemic cholangiopathy, especially in livers harvested from donors after cardiac death. Anastomotic biliary strictures are the commonest technical complication, with 15 to 20% of patients requiring some form of endoscopic or surgical intervention. There is a considerably increased risk of myeloproliferative disease and skin cancers in transplant recipients, as well as aetiology-​specific risk, for example, colorectal malignancies with primary sclerosing chol- angitis. Many patients die having achieved a normal life expectancy, and death with a functioning graft is the commonest terminal scenario.

15.22.6  Liver transplantation 3101 Introduction Liver replacement has been an option for the management of a broad range of liver diseases in adults for about three decades. Improved immunosuppression strategies are credited with the tran- sition from a 20-​year period of experimentation to a clinically based service with acceptable outcomes. The number of liver transplants performed globally on an annual basis is around 30 000, with early success rates well over 90%. Liver transplantation in the West is largely based on cadaveric donation with the constraints imposed by the limited availability of organs. By contrast, in the East most liver transplantation activity is by means of living donation and continues to increase. Indications The indications for liver transplantation are usually categorized under acute liver failure, end-​stage chronic liver disease, malignancy (mostly hepatocellular carcinoma), and metabolic disease. There is overlap between the latter three categories, exemplified by patients with cirrhosis complicated by hepatocellular carcinoma, and by end-​stage liver disease caused by a metabolic condition that is also cured by liver transplantation, e.g. Wilson’s disease. Acute liver failure Acute liver failure accounts for 4 to 6% of transplantation activity. These patients are given the highest level of priority in most alloca- tion systems and typically receive grafts within days of being placed on a waiting list. A range of prognostic models are in use that at- tempt to identify patients who would benefit from a transplant early in the course of the disease. These are generally considered to be accurate in predicting death, but perform less well in identifying all patients at risk of death. The most influential determinants of out- come are aetiology, age, rate of progression from onset of jaundice to encephalopathy, coagulation parameters, serum bilirubin, and serum creatinine. Young patients with a defined aetiology and rapidly progressive disease (hyperacute liver failure) often survive without emergency liver transplantation. By contrast, older patients with subacute liver failure have a very high mortality without trans- plantation. As the disease progresses, adverse clinical events, such as cerebral oedema or cardiovascular instability, may indicate the poor prognosis and determine the need for transplantation, albeit with a narrower window of opportunity. Cirrhosis All aetiologies of cirrhosis are potentially suitable for liver trans- plantation, but alcohol, nonalcohol-​related fatty liver disease, and hepatitis C account for most cases. The indications for liver trans- plantation in end-​stage liver disease were initially developed on an aetiology-​specific basis that reflected advanced disease or severe impairment of quality of life, albeit with some common themes. However, the need for liver transplantation is increasingly being informed by generic prognostic formulae that predict short-​term survival, with the Model for End-​Stage Liver Disease (MELD) being the prototype. MELD is calculated using serum bilirubin, serum creatinine, and INR, although another version includes serum so- dium (MELD-​Na), which is similar to the United Kingdom Model for End-​Stage Liver Disease (UKELD). A MELD score of 16 or a UKELD score of 49 are considered to be the thresholds above which patients would benefit from a liver transplant. Some patients with cirrhosis but with scores below these thresholds have specific clin- ical complications that may also be effectively managed by liver transplantation (Table 15.22.6.1). Hepatocellular carcinoma Hepatocellular carcinoma arising in a cirrhotic liver accounts for most patients undergoing liver transplantation. The tumour may be the specific indication for liver transplantation in patients with compensated cirrhosis or a secondary indication in patients with Table 15.22.6.1  Variant syndromes that may indicate a need for liver transplantation Cirrhosis present Diuretic resistant ascites Not suitable for transjugular intrahepatic portosystemic shunt Chronic hepatic encephalopathy Failure of all therapy including rifaximin Hepatopulmonary syndrome Arterial Po2 <7.8, A–​a gradient >20 mmHg Intractable pruritus Failure of all other therapies Recurrent cholangitis Failure of medical, surgical, and endoscopic options No cirrhosis Familial amyloidosis Transthyretin gene mutation in absence of debilitating cardiac disease Primary hyperlipidaemia Familial hypercholesterolaemia or low-​density lipoprotein receptor abnormalities Primary hyperoxaluria Simultaneous or sequential renal transplant Crigler–​Najjar syndrome Auxiliary graft an option Polycystic liver disease Alone or in combination with kidney transplant Tumours Neuroendocrine metastases Primary resected and bulk <50% liver volume Epithelioid haemangioendothelioma Absence of extrahepatic disease Adenomatosis or haemangiomas Extensive disease with hepatomegaly

section 15  Gastroenterological disorders 3102 end-​stage disease. An important difference between these two groups is the inability of the latter group to tolerate strategies aimed at controlling disease progression, essentially bridging patients through to transplantation. The selection is based on patterns of tumour bulk, as determined by size and number of lesions, α-​fetoprotein levels, evidence of tu- mour biology, and absence of alternative treatments with curative potential. The Milan criteria are the most widely used but also the most restrictive of the selection models, setting upper limits of 5 cm in diameter for a single nodule or 3 cm if two or three nodules are present. There is some evidence indicating that more extensive tumour bulk that responds well to therapy, such as transarterial chemoembolization, may be suitable for liver transplantation, a con- cept described as ‘downstaging’. A quarter of patients listed for liver transplantation have disease progression that results in deselection. Small, solitary tumours that are suitable for resection or ablative therapy are no longer being prioritized for liver transplantation. Hepatocellular carcinoma arising in noncirrhotic livers is rarely suitable for liver transplantation, unless it is of the fibrolamellar variant that is seen in young adults. Epithelioid haemangioendothelioma is another tumour seen in young adults that may benefit from transplant- ation. Cholangiocarcinoma is, in general, a contraindication to liver transplantation, although acceptable outcomes have been achieved in highly selected patients receiving aggressive pretransplantation therapies. Metastatic disease from neuroendocrine tumours may be suitable for transplantation, as may some patients with benign disease (Table 15.22.6.1). Patient selection and organ allocation Patients with indications for liver transplantation are assessed for suitability based on the absence of contraindications and likelihood of surviving the operation. The number of specific contraindications to transplantation is now relatively small (Box 15.22.6.1). Potential candidates are more likely to be declined on the basis of a pattern of coexisting comorbidities, particularly frailty, limited cardiopul- monary reserve under stress, and pre-​existing conditions such as malignant disease with unfavourable prognoses. The decision with respect to the suitability of an individual patient is usually made by an extensive multidisciplinary team. Alcohol consumption A commitment to abstaining from alcohol is consistently expected in patients being considered for transplantation with alcohol-​related liver disease, but there are inconsistencies between transplanting centres with respect to the detail of that commitment. Risk factors associated with a return to harmful alcohol consumption are out- lined in Box 15.22.6.2 and these broadly influence selection policy in individual programmes. The need for a significant duration of so- briety prior to listing for transplantation is the most contentious. Recent favourable reports relating to liver transplantation in the context of acute alcoholic hepatitis argues against the universal re- quirement for established sobriety. Policy is also variable with re- spect to the use of recreational drugs and range from zero tolerance to exclusion of patients actively injecting the drugs. Other factors Blood group compatibility and size are the main logistical param- eters considered in matching donors and recipients. The quality of the graft is also a consideration as so-​called extended criteria donors may not be considered suitable for all potential recipients. Donation after cardiac death is one example, but other characteris- tics have been described to quantify the donor-​associated risk. HLA matching is not normally required. The allocation of organs to specific patients is now usually deter- mined by systems that assess need or benefit. MELD and its iterations are the most widely used. Some allocation systems direct allocation to a specific patient based strictly on the MELD score, but others direct the organ to a specific transplant programme with some flexi- bility as to who receives the graft. Patients with hepatocellular car- cinoma or exceptional indications have their MELD score adjusted with time in order to get access to an organ. Transplantation options and operations Most liver transplantations using cadaveric organs implant the en- tire liver. Organs harvested after brain death are associated with the best outcomes, but organs from donors with controlled car- diac death are being increasingly used as an alternative when need outstrips supply or waiting times are protracted. Living donation results in one lobe of the liver being available for implantation. Cadaveric organs may be split into right and left lobes, typically Box 15.22.6.1  Specific conditions that usually contraindicate liver transplantation • Complete occlusion of portomesenteric venous system • Severe pulmonary hypertension unresponsive to therapy • AIDS-​defining illness not responding to therapy • Hepatocellular carcinoma with vascular invasion or extrahepatic disease • Current alcohol abuse in absence of commitment to positive care plan • Current intravenous drug use Box 15.22.6.2  Risk factors associated with return to alcohol consumption • Abstinence from alcohol for less than 6 monthsa,b • Family history of alcoholisma • Poor social supporta • Absence of spouse or partner in lifeb • Personality disorder • Anxiety or depressionb • Age under 40 years • Age over 50 yearsb • Females • Failed rehabilitation • Return to alcohol consumption after related illness • Cigarette smoking • Other substance abuse a Factors identified in a meta-​analysis. b Coexisting factors associated with escalation of risk.

15.22.6  Liver transplantation 3103 for transplantation into an adult and a child, respectively. Auxiliary transplantation involves replacing one lobe of the liver, leaving the other in situ, and is performed in acute liver failure and some meta- bolic abnormalities. Domino transplantation occurs when a liver with a metabolic defect is transplanted into another patient (e.g. familial amyloid polyneuropathy). Surgical procedure The transplantation operation has three phases—​hepatectomy, anhepatic, and reperfusion. Vascularized adhesions in the context of portal hypertension are a risk for haemorrhage during the dis- section phase. The severity of the portal hypertension can be miti- gated by the use of venovenous bypass. The anhepatic phase may be associated with deterioration in coagulation capabilities or lac- tate accumulation, but in acute liver failure can lead to stabilization of neurological and cardiovascular complications. Reperfusion of the implanted liver may be associated with severe haemodynamic compromise. Reperfusion syndrome is defined as a fall in mean ar- terial pressure of more than 30% from baseline, occurring within 5 min of reperfusion and lasting for at least 60 s. This may lead to life-​threatening ventricular hypokinesia or refractory arrhythmias. The transplant involves four sets of anastomoses that are relevant to the management of the transplant recipients because each is po- tentially a site of technical complications. The arterial anastomosis is typically end to end, but arterial conduits to the aorta can be used if the anatomy is not favourable. The portal vein anastomosis is also end to end but requires some patency in the portomesenteric venous system. The intrahepatic cava may be removed with the liver and the cava replaced with two anastomoses. The alternative approach dis- sects the liver away from the cava and anastomoses the hepatic veins individually, the so-​called piggy-​back technique. In most patients undergoing primary liver transplantation, the donor and recipient bile ducts are anastomosed directly. However, when the bile duct is diseased, as in patients with primary sclerosing cholangitis, the donor duct is directly linked to a loop of bowel or Roux loop. Multiorgan transplantation Liver transplantation can be performed in combination with a range of other organs in the initial transplant intervention. The commonest scenario is the combination of liver and kidney, either because of in- trinsic renal disease or failing renal function consequent to the liver disease. The allocation systems that favour the sickest patients have seen the greatest increase in the use of liver–​kidney combinations, as exemplified by the introduction of MELD in the United States of America in 2002. Up to 10% of liver transplants for end-​stage liver disease undergo simultaneous renal grafting. Renal transplantation is indicated if patients have been receiving dialysis for 6 to 8 weeks prior to transplantation, or if a kidney biopsy shows more than 30% glomerulosclerosis or interstitial fibrosis. Nevertheless, some of these patients recover native renal function after successful liver transplantation. Heart, lung, and pancreas transplantations have been performed with liver transplantations. The indications may be interlinked, for example, pulmonary hypertension in patients with end-​stage liver disease. Alternatively, one of the organs may facilitate the transplantation of a second organ, for example, lung and liver grafting in patients with cystic fibrosis. The liver may be included in a combination of intestinal organs transplanted en bloc including stomach, small intestine, and pancreas. Transplant rejection and immunosuppression Graft rejection Prevention of rejection of a transplanted organ is essential. Modern immunosuppressive strategies have dramatically reduced the con- tribution of rejection to graft failure. Acute cellular rejection during the first few weeks occurs in as few as 10 to 25% of patients and presents a limited threat to graft survival as steroid-​resistant rejec- tion rates are in the order of 5% of patients requiring treatment, and many of these respond to antibody therapy. Later episodes of acute cellular rejection occurring spontaneously or in the context of nonadherence with immunosuppression can be more resistant to therapy including the range of antibodies available. Chronic rejection of the graft now occurs in less than 2% of pa- tients, having previously caused graft failure in about one in six pa- tients within a year of transplantation. By contrast, the liver used to be considered almost immune to antibody-​mediated rejection but this is now recognized as a cause of graft failure in about 2% of pa- tients. The presence of class II donor-​specific antibodies points to the diagnosis of antibody-​mediated rejection if the other diagnostic requirements are fulfilled. Plasma cell hepatitis, previously known as de novo autoimmune hepatitis, is increasingly being considered to be within the spectrum of graft rejection. The histological features of these entities are outlined in Table 15.22.6.2. Immunosuppression Immunological stability is typically achieved with a regimen based on a calcineurin inhibitor combined with other agents determined by the need for potency or avoidance of toxicity. Tacrolimus is the most commonly used calcineurin inhibitor. Prednisolone is used exten- sively during the first 3 months after liver transplantation but often withdrawn thereafter unless the indication for transplantation was Table 15.22.6.2  Histological features suggestive of immune-​ mediated liver injury Acute cellular rejection Portal tract infiltration rich in lymphocytes and often containing eosinophils Bile duct injury Endothelialitis Chronic rejection Ductopenia in >50% of portal tracts Foamy cell arteriopathy (if appropriate-​sized artery captured in biopsy) Antibody-​mediated rejection Centrilobular hepatocyte swelling Microvascular injury Bile duct proliferation Single cell necrosis Hepatic canalicular cholestasis Positive C4d staining at sites of injury Plasma cell hepatitis Portal tract infiltrate containing plasma cells Interface hepatitis

section 15  Gastroenterological disorders 3104 an autoimmune disease. A third agent (e.g. azathioprine, everolimus, or mycophenolate) can be used from the outset or introduced when the need for another drug is demonstrated by problematic patterns of rejection or the need to reduce dosing of the calcineurin inhibitor because of related toxicity. A range of antibodies are used as part of the induction immunosuppression regimen or in the treatment of steroid-​resistant rejection. Antibodies directed against interleukin-​ 2 receptors are most frequently used in the former role, and against lymphocytes or thymocytes in the latter. Complications of the transplantation episode Primary nonfunction of the transplanted liver is the earliest com- plication encountered, with an incidence up to around 5%. Risk factors may be identifiable, as with donation after cardiac death, but it can occur unexpectedly. The management is emergency retransplantation. Early graft dysfunction is a less discrete entity with evidence of suboptimal function from the outset (Box 15.22.6.3). This occurs in up to 23% of patients and has serious implications with a 7-​fold increase in graft failure and an 11-​fold increase in the risk of death during the immediate post-​transplantation period. Chronologically, the earliest threats to grafts that have established function are hepatic artery thrombosis and acute cellular rejection. Hepatic artery thrombosis occurs in 3% of patients, is poorly tol- erated, and is another indication for emergency retransplantation unless very prompt detection and revascularization is feasible. Ultrasonic assessment of vascular patency is an integral part of the investigation of any deterioration of graft function during the first 2 weeks. The development of acute cellular rejection is suggested by an increase in liver enzymes 5 to 10 days postoperatively, but the diagnosis should be confirmed and severity staged by liver biopsy. Milder episodes are either not treated or managed by an increase in the dose of tacrolimus, but more severe patterns are initially treated with high-​dose steroids. Renal dysfunction is one of the most significant complications during this period. This may be impaired prior to transplantation or deteriorate afterwards for a range of reasons, including preventable factors such as hypovolaemia, drug toxicity, and interactions. Renal replacement therapy is required in 10 to 15% of patients. Impaired glycaemic control is the other frequently occurring metabolic abnormality in the early phase, both as a new diagnosis and in the sizeable cohort of patients with diabetes prior to trans- plantation. Tight glycaemic control is recommended to prevent de- hydration and bacterial infections. Significant volumes of fluid may also be lost from the abdominal cavity, particularly in patients with severe ascites prior to the transplantation, and these should be ap- propriate replaced. Bacterial infections are common with the usual sites being wound, abdominal cavity, lungs, and urinary tract. Management is directed by local antibiotic policy. Systemic fungal infection is more fre- quently encountered in patients transplanted for acute liver failure and in sicker patients with combinations of prolonged need for in- tensive care, renal failure, and cholestasis. Herpes simplex infection of the lips and mouth is common during the first week but is easily diagnosed and treated. The risk of developing cytomegalovirus (CMV) infection is determined by donor and recipient serological status and prophylaxis is instituted when a seronegative patients receives an organ from a donor with past exposure to CMV. Regular surveillance for CMV viremia is widely practised in patients with lower risk profiles. Technical complications Biliary complications Biliary complications occur in up to 20% of patients. The earliest risk relates to a leak at the site of the anastomosis with an incidence of 8%. This may be due to a technical issue or related to ischaemia. Initial management is with placement of a biliary stent endoscopic- ally when the anastomosis is duct to duct, or percutaneously when a Roux loop has been fashioned. Surgical correction is required in a few patients. The commonest of the complications (13%) is a stric- ture at the anastomotic site, when stent placement is again the initial intervention after balloon dilatation. Surgical revision of the biliary anastomosis is considered if a number of cycles of dilatation and stenting fail to establish satisfactory bile drainage. Nonanastomotic strictures of the biliary tract are more challenging to manage. This pattern of diffuse changes may be a sequel to hepatic artery throm- bosis but is also seen in organs donated after cardiac death. It is re- ferred to as ischaemic cholangiopathy, and retransplantation of the liver may be indicated when the symptoms of cholestasis and recur- rent infection cannot be managed medically. Vascular complications Late hepatic artery thrombosis occurs in 6% of patients but may be less devastating than the pattern of graft injury seen in the first weeks after transplantation. Biliary strictures and intrahepatic ab- scesses are the main presentations, but occlusion of the artery can be associated with good graft function in the long term if effective revascularization has occurred through the development of collat- eral vessels. The need for retransplantation is determined by the pattern of complications that develop rather than the diagnosis of arterial thrombosis per se. Hepatic artery stenosis may be detected on ultrasonography and can be amenable to balloon dilatation when considered to be haemodynamically significant. Portal vein stenosis is less likely to require intervention unless it is considered to be the cause of portal hypertension. Thrombosis of the portal vein is present in 8% of patients with cirrhosis under- going liver transplantation and recurs in 13%. Pre-​existing complete thrombosis of the portal vein increases 30-​day mortality to 11%. New thrombotic occlusion of the portal vein may be associated with identifiable and modifiable risk factors such as an underlying pro- coagulant disorders as well as diseases associated with thrombophilia (e.g. primary sclerosing cholangitis and HIV/​AIDS). Box 15.22.6.3  Parameters indicative of early graft dysfunction Any one of the following: • Bilirubin greater than 180 µmol/​litre or 10 mg/​dl at 7  days after transplantation • INR greater than 1.5 at 7 days after transplantation • Aspartate aminotransferase or alanine aminotransferase greater than 2000 IU/​litre within 7 days of transplantation

15.22.6  Liver transplantation 3105 Venous outflow obstruction occurs more frequently when the cava is spared and the hepatic veins are anastomosed individu- ally. This may be transient if swelling of the graft leads to torsion of the hepatic veins. Dilatation of stenosis or stent insertion may be required if venous outflow obstruction is confirmed by venous pressure measurements and histology demonstrating features of congestion. Long-​term management Immunosuppression Immunosuppression requirements decrease 6 months and longer after liver transplantation and this allows a cautious and progres- sive reduction in the number of drugs used and in drug doses. Most patients are on monotherapy with tacrolimus or dual therapy using tacrolimus and a second agent at 2 years after transplantation. The target blood level of tacrolimus is also reduced by about 50% at this time. The reduction in immunosuppression requires stable graft function and the specifics of the changes often reflect the pattern of side effects or complications encountered in individual patients. A few patients will develop operational tolerance and retain good graft function despite withdrawal of immunosuppression, but these patients cannot be confidently identified in advance of the with- drawal of immunosuppression. Investigation and management of late graft dysfunction Liver function tests are monitored at regular but increasing inter- vals after liver transplantation. The development of an abnormal profile requires immediate investigation that reflects the likely balance of immune-​mediated injury, technical complications, and possibility of recurrent disease. Patient characteristics and the interval since the transplant will influence the direction of the investigations. Acute cellular rejection is the most pressing diagnosis to estab- lish and a more likely explanation of abnormal liver function tests in younger patients within a few years of transplantation. This re- flects the higher rate of nonadherence to the immunosuppression regimen in these patients. Autoimmune hepatitis typically recurs in the second or third year and may be precipitated by a programmed reduction in steroid therapy. The related entity of plasma cell hepa- titis in patients without a pre-​existing diagnosis of autoimmune hepatitis is suggested by the detection of appropriate autoantibodies and elevated IgG levels. The possibility of recurrent disease should be considered in patients with hepatitis B and C. Hepatitis E is being increasingly recognized as a cause of chronic hepatitis in recipients of organ transplants, and 70% of patients respond to treatment with ribavirin. A pattern of cholestatic liver function tests should start with con- sideration of biliary strictures. Unlike the native liver, ultrasound examination is not a reliable screen for duct dilatation and mag- netic resonance cholangiography is required when the ultrasound examination does not identify an abnormality. When duct dilata- tion extends down to the ampulla, the possibility of intraluminal material should be excluded before considering a diagnosis of sphincter of Oddi dysfunction, which is relatively common after liver transplantation. Mild increases in cholestatic enzymes some years after liver transplantation for primary biliary cholangitis can reasonably be ascribed to recurrence of the disease and trigger treat- ment with ursodeoxycholic acid. Fertility Reproductive capability improves rapidly after liver transplantation. Nonterminated pregnancies resulted in spontaneous abortion in 17%, stillbirth in 1%, and live births in 82% of episodes. The risk of pre-​eclampsia is significantly higher than in the general popula- tion at around 20%. Preterm birth rates are in the order of 40% and caesarean section more likely than in the general population. With the exception of avoiding mTOR (mechanistic target of rapamycin) inhibitors and mycophenolate, routine alterations in immunosup- pression therapy are not required during pregnancy. Long-​term complications of liver transplantation Renal and cardiovascular disease The impetus to reduce immunosuppression is, in part, due to the contribution of the immunosuppressive drugs to the high incidence of renal and cardiovascular disease in liver transplant recipients. The incidence of end-​stage renal disease has been as high as 25% 10 years after transplantation. Calcineurin inhibitor dosing is ad- justed when there is evidence of deteriorating renal function until the glomerular filtration rate stabilizes on a lower dose or the drug is discontinued in the most severe cases. Aggressive management of hypertension and diabetes mellitus are also important in preserving renal function. The metabolic syndrome develops in up to 50% of patients and there is a high prevalence of systemic hypertension, diabetes mellitus, dyslipidaemia, and obesity. New-​onset diabetes mellitus develops in up to 25% and new-​onset obesity in around 20% of patients within the first 2 years after transplantation. The presence of the metabolic syndrome is associated with a fourfold higher risk of having a car- diovascular event. Withdrawal of corticosteroid therapy is generally indicated in these patients. The targets and strategies for the man- agement of these morbidities are similar to the general population. Disease recurrence Recurrence of the original disease is possible for many diseases managed by liver transplantation and is a major determinant of outcome (Table 15.22.6.3). Reinfection with hepatitis B or hepa- titis C was associated with significant mortality and need for retransplantation. In the case of hepatitis B, prevention of reinfec- tion using long-​term immunoglobulin coupled with oral antiviral agents has almost eliminated graft injury as a consequence of recur- rence of this virus. Recurrent infection is still seen in a few patients who are nonadherent with therapy or who develop drug resistance and in patients developing recurrence of related hepatocellular carcinoma. Recurrence of hepatitis C was universal and more problem- atic, with approximately one-​third of patients developing acceler- ated graft injury with cirrhosis or graft failure within 1 to 5 years of transplantation. Early indications are that the direct-​acting antiviral drugs will have a dramatic impact on this pattern of

section 15  Gastroenterological disorders 3106 disease recurrence. Firstly, more patients have cleared the virus before transplantation and seem to have little risk for recurrence. Secondly, the antiviral drugs seem to be as effective in the post-​ transplantation setting as in the general population. Tolerability also seems to be comparable unless there is potential for drug–​ drug interactions. It is anticipated that the direct antiviral agents will have a significant impact on long-​term survival and reduce the requirement for retransplantation. The spectrum of fatty liver disease recurs both in the presence and absence of alcohol. Steatosis can be severe and established within a year of transplantation. The history of resumption of alcohol con- sumption may be suppressed. A resumption of alcohol consumption occurs in up to 50% of patients and about 15% do so in a hazardous manner with the implication of reduced survival 10 years after trans- plantation. The implications of recurrence of nonalcohol-​related disease on graft function and survival are less clear cut as a consider- able proportion of mortality is attributable to the associated diseases rather than graft failure. All of the autoimmune diseases have the potential to recur, but with a range of consequences. The most benign pattern is seen in primary biliary cholangitis, where although the diagnosis is fre- quently confirmed by liver biopsy, few cases progress to liver failure during the first two decades after transplantation. The consequences of recurrence of primary sclerosing cholangitis are potentially more serious, with some patients progressing to graft failure as quickly as 5 years after transplantation. The diagnosis requires a combin- ation of compatible liver histology and classical changes of random strictures on cholangiography with exclusion of alternative explan- ations relating to ischaemic injuries acquired during harvesting of the organ or complications with the hepatic artery. The risk of developing primary sclerosing cholangitis recurrence is increased twofold in patients with ulcerative colitis who have an intact colon. Autoimmune hepatitis recurrence is usually detected when in- creased serum transaminases are detected on routine follow-​up. The diagnosis requires a liver biopsy and most cases respond well to an increase in the corticosteroid component of the immunosuppres- sion regimen. Hepatocellular carcinoma recurs in 15% of patients selected using the most conservative approach known as the Milan cri- teria. No effective strategies have been identified to reduce the incidence of disease with adjuvant therapy in patients identified as high risk, or to modify the progression of tumour once it has recurred. Post-​transplantation lymphoproliferative disease Post-​transplantation lymphoproliferative disease is an important consideration in liver transplant recipients who are unwell because it can occur any time after transplantation and has many modes of presentation. The link to Epstein–​Barr virus has become less sig- nificant, with the exception of younger patients. Screening with lactate dehydrogenase levels and positron emission tomography scans in suspicious cases has simplified the diagnostic pathway. Reducing the intensity of immunosuppression remains an initial response, but most cases now require additional therapy. Anti-​ CD20 monoclonal antibodies and conventional chemotherapy are the strategies most commonly used. The mortality rate is in the order of 40%. Outcomes Mortality The overall survival rates after liver transplantation are now very good, with 1-​year survival rates over 95% for elective liver trans- plantation and around 85% for emergency transplantation being reported by individual centres. MELD scores at the time of trans- plantation correlate poorly with outcome and a clear relationship with mortality is only apparent at scores of 35 or above. Patients with chronic liver disease who are in intensive care environments at the time of transplantation have inferior 1-​year survival rates of around 60%. Hospitalized patients who are older and have associ- ated comorbidities or renal dysfunction also have increased post-​ transplantation mortality. Registry data from Europe and the United States of America indicate 5-​year graft survival rates in the order of 75 to 80%. The survival rates differ significantly by aetiology of the original liver disease, reflecting a combination of impact of recurrence and the pattern of comorbidities linked to each disease. Among pa- tients with chronic liver disease, the best 5-​year survival rates are seen with primary biliary cholangitis, primary sclerosing cholan- gitis, and nonalcohol-​related disease; intermediate outcomes in alcohol-​related disease; and the highest mortality is associated Table 15.22.6.3  Disease recurrence after liver transplantation Cause of liver disease Incidence of disease recurrence (%) Diagnosis Management Consequence Alcohol 15–​50 Compatible histology in context of alcohol consumption Abstain from alcohol Increased mortality at 5–​10 years Nonalcoholic fatty liver disease (NAFLD) Compatible histology Tight control of weight, elements of metabolic syndrome Hepatitis B 5 Hepatitis B virus DNA positive Antiviral drugs Limited impact Hepatitis C 100 Liver histology Antiviral drugs Increased mortality at 5 years Primary biliary cholangitis 40 Liver histology Ursodeoxycholic acid Limited impact but occasional retransplant Primary sclerosing cholangitis 15–​40 Cholangiography and liver histology No specific therapy May require retransplantation Autoimmune hepatitis 40% Liver histology Corticosteroids Limited impact

15.22.6  Liver transplantation 3107 with hepatitis C virus and hepatocellular carcinoma. The survival rates are poorer for retransplants and decrease progressively with the number of transplantations performed in individual patients. The 5-​year survival rates for the third or subsequent transplant- ation falls to less than the 50% threshold commonly used as an indicator of utility. Extended survival is being increasingly documented in popula- tions of liver transplant recipients. Patients who were 55 years of age or older at the time of transplantation have been shown to have the potential of a normal life expectancy measured over a 20-​year period. Younger patients continue to lose life years when compared to the general population. Premature mortality is mainly associ- ated with malignant disease, infection, and renal or cardiovascular disease. Late deaths from infection are caused by pneumonia or sepsis-​ related multiorgan failure as opposed to opportunistic infections. Renal and cardiovascular diseases contribute to about 40% of pre- mature death, particularly beyond the first decade after transplant- ation. Data at 20 to 25  years after transplantation indicate that mortality increases when the glomerular filtration rate falls to less than 60 ml/​min but increases exponentially below a threshold of 30 ml/​min. The fourfold risk of cardiovascular disease identified in pa- tients with the metabolic syndrome also reflects in higher mortality at this time, especially in men. Morbidity Lymphoproliferative disease (20-​fold increase), skin malignancy (30-​fold increase), and selected tumours with pre-​existing as- sociated risk profiles dominate the malignant category. Patients with alcohol-​related disease have a marked increase in malig- nancies of the lung and upper gastrointestinal tract. Patients with primary sclerosing cholangitis and ulcerative colitis are at increased risk of colon cancer and should have enhanced sur- veillance at yearly intervals. However, there is no evidence of a generalized increased risk of common cancers such as breast, prostate, and colon. Quality of life studies before and after liver transplantation docu- ment a dramatic improvement in quality of life in patients with chronic liver disease, but they also demonstrate a shortfall in some domains relating to physical and emotional well-​being. There is also evidence of underperformance of those still in education and those of working age, with only 40 to 45% returning to work after the transplant. FURTHER READING Ashwani S, et al. (2013). Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation, 95, 755–​80. Deshpande NA, et al. (2012). Pregnancy outcomes of liver transplant recipients: a systematic review and meta-​analysis. Liver Transplant, 18, 621–​9. Kim WR, et al. (2019). OPTN/​SRTR 2103 annual data report: liver. Am J Transplant, 19 Suppl 2, S184–​283. Lucey MR, et al. (2013). Long-​term management of the successful liver transplant:  2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl, 19, 3–​26. Madhwal S, et al. (2012). Is liver transplantation a risk factor for car- diovascular disease? A meta-​analysis of observational studies. Liver Transplant, 18, 1140–​6. McCaughan GW, Vajdic CM (2013). De novo malignant disease after liver transplantation? Risk and surveillance strategies. Liver Transplant, 19, S62–​7. Nadim MK, et al. (2012). Simultaneous liver-​kidney transplantation summit: current state and future directions. Am J Transplant, 12, 2901–​8. Neuberger J, et al. (2008). Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut, 57, 252–​7. O’Grady JG (2014). Timing and benefit of liver transplantation in acute liver failure. J Hepatol, 60, 663–​70. Ojo AO, et al. (2003). Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med, 349, 931–​40. Rodriguez-​Castro K, et  al. (2012). Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a sys- tematic review. Transplantation, 94, 1145–​53. Schoening WN, et al. (2013). Twenty-​year longitudinal follow-​up after orthotopic liver transplantation: a single-​center experience of 313 consecutive cases. Am J Transpl, 13, 2384–​94. Seehofer D, et al. (2013). Biliary complications after liver transplant- ation: old problems and new challenges. Am J Transplant, 13, 253–​65. Singal AK, et al. (2019). Simultaneous liver kidney transplantation. Transpl Int, 32, 343–52. Siniscalchi A, et al. (2016). Post reperfusion syndrome during liver transplantation:  from pathophysiology to therapy and preventive strategies. World J Gastroenterol, 22, 1551–​69. Website European Liver Transplant Registry: http://​www.eltr.org

15.23 Hepatitis and autoimmune liver disease 3108

15.23 Hepatitis and autoimmune liver disease 3108

15.23.1 Hepatitis A to E 3108

15.23.1 Hepatitis A to E 3108

CONTENTS 15.23.1 Hepatitis A to E  3108 Graeme J.M. Alexander and Kate Nash 15.23.2 Autoimmune hepatitis  3119 G.J. Webb and Gideon M. Hirschfield 15.23.3 Primary biliary cholangitis  3127 Jessica K. Dyson and David E.J. Jones 15.23.4 Primary sclerosing cholangitis  3135 Kate D. Lynch and Roger W. Chapman 15.23.1  Hepatitis A to E Graeme J.M. Alexander and Kate Nash ESSENTIALS The clinical picture with each of the five major hepatitis viruses A, B, C, D, and E depends firstly upon whether infection is acute, with resolution, or evolves into chronic infection; secondly, on the grade of hepatic inflammation; and thirdly, the stage of fibrosis. Acute icteric hepatitis is the most easily recognized conse- quence of infection and is generally a self-​limited condition. In otherwise healthy individuals, only hepatitis B and C cause chronic viral hepatitis. In immunosuppressed individuals, hepatitis A can follow a protracted course, while hepatitis E can evolve to chronic infection. A  specific diagnosis is made by the combination of serology and polymerase chain reaction. Uncomplicated cases recover spontaneously; there is no proven therapy to enhance re- covery. Acute liver failure caused by viral hepatitis now has a good outcome, with liver transplantation available for those with poor parameters at onset. Protection against hepatitis A and B is available, both by active vac- cination and (less often now) by passive administration of hepatitis B immunoglobulin preparations. Vaccines for hepatitis C are some distance away, but for hepatitis E are under investigation. Vaccination against hepatitis B also protects against hepatitis D. Features of particular hepatitis viruses Hepatitis A virus (HAV): faecal–​oral transmission; incubation 2 to 6 weeks; acute self-​limited hepatitis; no specific treatment. Hepatitis B virus (HBV): parenteral transmission; incubation 4 to 24 weeks; may present with acute hepatitis, with prodrome some- times including prominent arthritis, fever, and urticarial rash, but anicteric infection is common; most (>90%) patients clear HBV after acute infection, but failure to clear hepatitis B surface antigen within 6 months defines ‘chronic carriage’, which is associated with a spec- trum of histological damage and clinical manifestations ranging from clinically silent to cirrhosis and hepatocellular cancer. Most patients with chronic infection benefit from antiviral therapy (interferon-​α or nucleotide and nucleoside analogues). Hepatitis C virus (HCV): parenteral transmission; incubation 2 to 26 weeks; acute episode most often subclinical; more than 85% of patients fail to clear the virus and become chronic carriers, which leads to cirrhosis in 5 to 10% after 15 to 25 years, which then predis- poses to hepatocellular cancer; astonishing progress with a range of tailored antiviral agents targeting key viral enzymes has led to viral elimination in over 95% of patients across the spectrum of disease and viral genotype, with little risk of side effects. Hepatitis D virus (HDV): an RNA virus that acts like a cuckoo by replacing the hepatitis B viral core with the hepatitis D viral core and tends to produce more severe liver disease; treatment is as for hepatitis B. Hepatitis E virus (HEV):  faecal–​oral transmission; incubation about 6 weeks; higher risk of acute liver failure if acquired during midtrimester pregnancy; no specific treatment, although some re- ports suggest ribavirin may be helpful. Introduction Viral infection is the most common cause of hepatitis and remains a clinical problem worldwide, particularly in developing countries. The five major hepatitis viruses (A, B, C, D, and E) account for most cases of viral hepatitis in clinical practice (Table 15.23.1.1). Although these viruses are unrelated, they share tropism for the liver (Table 15.23.1.2). Other viruses that produce systemic infection can also infect the liver and cause hepatitis that is usually asymptom- atic, but occasionally hepatitis can be the dominant manifestation of infection (e.g. cytomegalovirus, Epstein–​Barr virus, and herpes 15.23 Hepatitis and autoimmune liver disease

15.23.1  Hepatitis A to E 3109 simplex virus). Many other viruses are known to infect the liver but do not appear to cause clinical disease (e.g. hepatitis G, transfusion-​ transmitted, and Sen viruses). This chapter describes the clinical and pathological aspects of viral hepatitis including investigation, man- agement, and prophylaxis. Specific virology of hepatitis viruses is covered in Chapters 8.5.21 and 8.5.22. Clinical outcome of hepatitis virus infection The clinical manifestation of viral hepatitis varies according to the severity of inflammation induced in the liver and whether the virus is cleared from the liver or persists in the long term. This variation in clinical picture is influenced by both viral and host factors including lifestyle and the immune response to the virus. In most cases, it is the host immune response to the virus that is responsible for lysis of infected hepatocytes and liver inflammation. Patients who de- velop a strong immune response to the virus may therefore have more severe inflammation and a more symptomatic acute illness, but a greater likelihood of achieving viral clearance. Conversely, those who mount a weaker virus-​specific immune response may have a milder or subclinical illness but then develop persistent in- fection, which over many years can lead to cirrhosis predisposing to hepatocellular carcinoma. Acute viral hepatitis is generally a self-​limiting illness with low mortality. The preicteric or prodromal phase lasts up to 2 weeks. The patient is viraemic and feels generally unwell with anor- exia, nausea, vomiting, diarrhoea, headaches, myalgia, and arth- ralgia. Fever is usually mild and there may be upper abdominal discomfort. Symptoms usually improve at this point, while jaun- dice may worsen and last several days to several weeks. Ascites and oedema occur rarely in more severe cases. Most cases recover com- pletely, although it may take several weeks or months and residual fatigue is common. The severity of acute hepatitis is best measured by the bilirubin and prothrombin time, with less reliance placed on the alanine aminotransferase (ALT) concentration. Identification of those at risk of liver failure using these parameters is discussed elsewhere, but the onset of hepatic encephalopathy indicates a poor prognosis. There are several variations on the clinical course of acute hepatitis: • Anicteric hepatitis: infection is asymptomatic or characterized by mild flu-​like symptoms that resolve within 2 to 3 weeks. Jaundice does not occur, or is not noticed, and the ‘illness’ is often not rec- ognized as viral hepatitis. • Cholestatic hepatitis:  jaundice develops accompanied by dark urine and pale stools after an initial viral prodrome character- ized by malaise, anorexia, fever, and upper abdominal pain. The jaundice may be accompanied or followed by pruritus. The ic- teric period last for a few days to a few weeks and subsides slowly. Residual fatigue may last several months. • Relapsing hepatitis: jaundice worsens transiently after an initial improvement, before eventual recovery. • Acute liver failure: massive hepatocyte necrosis occurs, with liver failure characterized by jaundice and coagulopathy followed by encephalopathy. Fulminant disease is defined by the development of encephalopathy within 2 weeks of the onset of jaundice. • Subacute liver failure: liver failure develops at a slower rate, with encephalopathy appearing more than 2 weeks after the onset of jaundice. Hepatitis A, B, C, and E can all cause an acute self-​limiting hepa- titis. Fulminant hepatitis can occur with hepatitis A, B, and E but is very rare with hepatitis C. Hepatitis B and C are the main causes of chronic viral hepatitis, when the virus persists in the liver over years to decades causing varying degrees of inflammation and fibrosis. Hepatitis D infection, which only occurs in patients in- fected with hepatitis B, can contribute to either acute or chronic inflammation. Table 15.23.1.1  Viruses affecting the liver Major hepatotropic viruses Hepatitis A, B, C, D, and E Systemic viruses capable of causing hepatitis Epstein–​Barr virus, cytomegalovirus, herpes simplex virus, adenovirus Minor hepatotropic viruses Hepatitis G virus, Sen virus, transfusion-​transmitted virus Tropical viruses Yellow fever, dengue fever, haemorrhagic viruses Table 15.23.1.2  Features of hepatitis viruses Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Virus Picornavirus (RNA) Hepadnavirus (DNA) Flavivirus (RNA) Subviral particle (RNA) Hepeviridae (RNA) Spread:   Faecal–​oral   Blood   Vertical   Sexual Yes Rare No Rare

No Yes Yes Yes

No Yes Occasional Occasional

No Yes Rare Occasional

Yes No No No Incubation Short 2–​4 weeks Long 2–​6 months Intermediate 2–​16 weeks Long Short 4–​6 weeks Chronic liver disease Rare case reports only Yes Yes Yes Rare, with immune compromise Liver cancer No Yes Rare Yes No Immunization:   Passive   Active

Immunoglobulin Vaccine

Immunoglobulin Vaccine

HBV vaccine

section 15  Gastroenterological disorders 3110 Acute viral hepatitis Particular viruses Hepatitis A virus Hepatitis A virus (HAV) is the most common type of viral hepa- titis worldwide and causes 20 to 40% of clinically apparent hepa- titis; older patients are more likely to be symptomatic. It is an RNA virus, acquired in almost all cases by the faecal–​oral route, usually from ingestion of food or water contaminated with human faeces, although transmission via transfusion of blood or blood products or transplantation of organs from viraemic patients has been reported. The virus is endemic and infection is reported worldwide, but occurs primarily in Third World countries with overcrowding and poor sanitation, particularly since the introduction of highly ef- fective vaccination programmes in wealthier countries. In some developing countries, serological evidence of past infection is pre- sent in up to 100% of children, with lifelong immunity. In Western countries, prior infection varies between 5 and 40% depending on age, social class, and other factors. Infection may also be spread through close contact with an infectious person. Promiscuous men who have sex with men have a higher incidence of infection. Infection with HAV may result in subclinical infection, symp- tomatic clinical infection with or without jaundice, or acute liver failure. It does not cause chronic infection or chronic hepatitis, although prolonged acute infection is reported rarely in immuno- suppressed individuals. Frequently the disease is mild or asymp- tomatic, particularly in the young. The incubation period between infection and symptoms, if they develop, is between 2 and 4 weeks. Viral shedding in the faeces ceases in most people as symptoms de- velop. Symptoms of acute hepatitis, if present, typically last less than 2 months. Severe hepatitis or acute liver failure may occur but is rare and the mortality rate is low (0.4%). Deaths occur more com- monly in the elderly or in people with pre-​existing chronic liver disease. During convalescence, 10 to 15% of patients may have a relapse of the hepatitis, but this settles spontaneously. Extrahepatic complications are rare but may include arthritis, vasculitis, myocar- ditis, and renal failure. Hepatitis B virus Hepatitis B virus (HBV) infection is a DNA virus that is common worldwide, with over 1 billion people infected at some point in their lives. Around 300 million people are chronic carriers with the main burden of disease being in South East Asia and sub-​Saharan Africa, where prevalence rates reach 10 to 15%. The dominant mode of transmission worldwide is vertical transmission from a mother with chronic infection to an infant, during pregnancy, at birth, or during close family contact in early childhood. Other modes of transmis- sion include transfusion of blood and blood products, reuse of con- taminated needles medically or by drug addicts, exposure in dialysis units, tattooing, and sexual contact (both homosexual and hetero- sexual). The virus is highly infectious (50–​100 times more infectious than HIV). Transmission can occur between household contacts by uncertain means, possibly including contact with broken skin or mucous membranes. The incubation period of HBV is 6 to 26 weeks. Those who are infected around the time of birth develop symptoms rarely, but most (90–​95%) develop chronic infection. In contrast, 90 to 95% of adults infected with the virus develop a self-​limiting acute illness resulting in viral clearance. The acute illness is often not recognized and may be asymptomatic, but if symptoms do occur, there is usually a viral prodrome with nausea, myalgia, arthralgia, and fever, which may then be followed by jaundice. Anicteric infection may occur, in which case the infection may not be recognized as hepatitis. The illness usually lasts a few weeks and then gradually improves in most cases, although acute liver failure may develop and has significant mortality (0.3%). In most cases, HBV is cleared after acute infection and hepatitis B surface antigen (HBsAg) disappears from the blood within weeks. The time to produce a protective hepatitis B surface antibody (anti-​ HBs) varies greatly and sometimes does not occur, although such patients are not at risk of a further infection. If the patient fails to clear HBsAg within 6 months they are considered chronic carriers. A failure to eradicate hepatitis B e antigen (HBeAg) within 12 weeks is often associated with progression to the carrier state. Extrahepatic symptoms occur in up to 10% of cases and include serum sickness-​like immunological syndrome with fever, urticarial rash, membranous glomerulonephritis, and polyarteritis due to immune complex deposition. Other immune-​mediated haem- atological disorders such as aplastic anaemia and essential mixed cryoglobulinaemia occur rarely. Hepatitis C virus Hepatitis C virus (HCV) was discovered in 1989 as the dominant cause of non-​A, non-​B hepatitis. It is an RNA virus spread primarily by blood-​to-​blood contact associated with intravenous drug use, poorly sterilized medical equipment, and transfusion of blood or blood products. Vertical transmission is well described, while sexual transmission is uncommon but not unknown. The incubation period of the virus typically ranges from 2 to 16 weeks. HCV infection causes acute symptoms in only 15% of cases and thus is often unrecognized. Symptoms, if they develop, are generally mild and nonspecific including fatigue, nausea arthralgia, and myalgia. Jaundice is unusual and fulminant hepatitis is very rare. About 80% of infected individuals fail to clear the virus and develop chronic hepatitis. HCV infection is therefore usually not recognized until late in the chronic phase. At least six different geno- types are recognized with different epidemiological associations and treatment responsiveness. Hepatitis D virus Hepatitis D virus (HDV), also referred to as hepatitis delta virus, is a small RNA subviral particle enveloped in HBsAg. It is unable to replicate on its own and can only propagate in the presence of HBV. Active HBV protein synthesis, including HBsAg, is reduced by delta infection, while HBV replication is reduced substantially such that patients often become HBV DNA negative. Transmission of HDV can occur simultaneously with HBV (coinfection) or superimposed on chronic hepatitis B (superinfec- tion). Coinfection may result in an otherwise unremarkable acute hepatitis but there is a higher incidence of liver failure than with HBV infection alone. If HBV infection resolves with viral clearance then HDV will also be cleared. Superinfection of a chronic HBV carrier with HDV may result in worsening of liver function. The superinfection may be transient or chronic HDV carriage may de- velop. Chronic infection with HBV and HDV results in more rapid

15.23.1  Hepatitis A to E 3111 progression to liver cirrhosis and an increased risk of developing hepatocellular carcinoma. HDV is transmitted by all parenteral routes demonstrated for hepatitis B, including sexual transmission, but appears to be more common in intravenous drug abusers. Eastern Asia, sub-​Saharan Africa, and South America are areas of moderate to high incidence. The infection is rare in many developed countries, being most common in Mediterranean regions with a high incidence of intra- venous drug use. Hepatitis E virus Like HAV, hepatitis E virus (HEV) is an RNA virus transmitted via the faecal–​oral route. HEV is prevalent in most developing countries where spread is usually due to faecal contamination of food or water; person-​to-​person transmission is uncommon. In Western countries, HEV cases may be imported or be a zoonosis from infected animals, particularly pigs. The virus has been detected in over 50% of do- mestic pigs in some areas and meat products on sale in developed countries have been found to contain the virus. Some research sug- gests that food must reach 70°C for 20 min to eliminate the risk of infection, a standard not always achieved with barbeques. There are three serotypes with distinct species and geographic distributions. HEV typically causes an acute self-​limiting infection but chronic infection is well described in immunocompromised patients (e.g. organ transplant recipients who receive immunosuppressive medi- cation to prevent rejection). The incubation period is about 6 weeks. Viral RNA becomes detectable in the stool and blood during the in- cubation period. Recovery leads to viral clearance from the blood, while faecal excretion may persist for several weeks after the onset of clinical symptoms. The disease is usually mild, but severe liver dis- ease can occur and the overall mortality rate of approximately 2% is higher than that with HAV. Pregnant women, especially those in the third trimester, are particularly susceptible to developing fulminant hepatitis and mortality rates of 20% are seen in this group. Ribavirin has been used with clinical success in patients with prolonged acute infection on a background of immunocompromise. Other viruses Some viruses (e.g. cytomegalovirus, Epstein–​Barr virus, and herpes simplex virus) can cause hepatitis as part of a multisystem illness. Hepatitis may be a minor, unrecognized component of the viral illness or the dominant clinical manifestation; the latter is especially true of those with immune compromise or on long-​term immune suppression. Hepatitis G virus, Sen virus, and transfusion-​transmitted virus are well characterized as viral infections within the liver but they do not cause significant disease, even in those with immune compromise. Cases of unexplained non-​A/​B/​C/​D/​E hepatitis and fulminant liver failure occur and may be caused by hepatotropic viruses that have not yet been described. Clinical features Symptoms of acute hepatitis are often nonspecific including nausea, fatigue, arthralgia, and myalgia. Clinical examination may dem- onstrate jaundice, right upper quadrant tenderness, and mild hep- atomegaly. Palpable splenomegaly, as opposed to that detected by liver ultrasonography, is uncommon in classical viral hepatitis and more typical of systemic viral infection with cytomegalovirus or Epstein–​Barr virus. Skin manifestations may include urticarial or vasculitic rash, spider naevi, and scratch marks as a result of pruritus. Persistent vomiting in cases of severe hepatitis may result in elec- trolyte disturbance, renal impairment, and hypoglycaemia. Rapid shrinkage of the liver may occur and ascites and peripheral oedema may develop. The onset of encephalopathy indicates hepatic failure and deterioration to coma can be very rapid. Investigation In the prodrome, the serum bilirubin is usually normal, but hepatocellular enzymes (aspartate transferase and ALT) are usually raised and levels may exceed 10 times normal. The serum alkaline phosphatase elevations are more modest, generally two to three times normal. Urine analysis reveals increased urobilinogen. As an episode evolves into the cholestatic phase, the serum transaminase levels fall, alkaline phosphatase and bilirubin levels may rise, and urine analysis demonstrates excess bilirubin. In severe cases, there may be evidence of liver failure, reflected in impairment of synthetic liver function with prolongation of the prothrombin time and a fall in serum albumin. Virological tests that may be used in the investigation of acute hepatitis are outlined in Table 15.23.1.3. An initial virological screen for suspected viral hepatitis includes anti-​HAV IgM antibodies, IgM anti-​HBc, HBsAg, anti-​HCV antibodies, anti-​cytomegalovirus IgM antibody, and anti-​Epstein–​Barr virus IgM antibody. Anti-​HEV antibody testing is not available universally, but testing for anti-​ HEV IgM antibody should be undertaken in any case of suspected acute viral hepatitis or unexplained abnormality of liver blood tests due to the increased prevalence in this infection. Fulminant hep- atic failure secondary to hepatitis B can present occasionally after HBsAg has been cleared from the serum; a positive IgM hepatitis B core antibody (anti-​HBc) confirms the diagnosis. Figures 15.23.1.1 to 15.23.1.4 indicate the typical serological evolution of acute viral hepatitis A, B, C, and E. All patients with HBV infection should be tested for HDV infec- tion. The presence of serum IgM anti-​δ with IgM anti-​HBc suggests acute coinfection with both viruses. Superinfection with HDV is characterized by detection of IgM anti-​δ in a patient who is already negative for IgM anti-​HBc, but positive for IgG anti-​HBc. Hepatic imaging is utilized primarily to exclude other causes of acute hepatic illness, especially biliary obstruction. Liver biopsy is required infrequently unless there is doubt regarding the diagnosis or, more often, if underlying chronic liver disease is suspected. In such cases, biopsy may require correction of clotting factors and a transjugular approach. Differential diagnosis The differential diagnosis is from other causes of acute hepatitis: • Drug-​induced jaundice: this is the most common alternative diag- nosis and the clinical course can be very similar. A thorough drug history should be undertaken, including those prescribed as well as those acquired over the counter and herbal medicines. • Autoimmune hepatitis:  about one-​third of patients with auto- immune hepatitis present with a clinical picture of acute hepatitis, most often middle-​aged females. High levels of liver-​specific auto- antibodies and elevated IgG levels are found frequently or may develop in the early stages, but the distinction can be difficult since

section 15  Gastroenterological disorders 3112 low titres of autoantibodies and moderate elevations in IgG also occur in some cases of viral hepatitis. • Alcohol-​related hepatitis: this may present acutely with jaundice, but elevations of serum transaminases are generally much less marked and these enzymes are often normal; there may be an as- sociated high leucocyte count and inflammatory response. • Obstructive jaundice:  this classically causes less marked rises in transaminases but higher levels of alkaline phosphatase, al- though the clinical picture may not always be clear cut, especially in the early stages. Obstruction is usually confirmed by abdom- inal imaging with ultrasound examination demonstrating dilated biliary ducts. • Hepatic ischaemia: this can follow episodes of hypotension and present with an acute hepatitis that may cause transient jaundice and coagulopathy. • Wilson’s disease: very rare but important to consider as there is a high incidence of acute liver failure with a substantial risk of mortality. • Malignant infiltration of the liver: may mimic acute viral hepatitis. • Pregnancy-​associated syndromes: HELLP (haemolysis, elevated liver function tests, low platelets) and acute fatty liver may present with a picture of acute hepatitis, but are rare and less common in pregnancy than acute viral hepatitis. Management Most cases of hepatitis recover spontaneously and management is supportive. There is no proven therapy that enhances recovery. Many cases can be managed at home, but more severe cases may benefit from hospital admission for symptomatic management and to observe for early signs of liver failure. Clinicians should be alert to electrolyte disturbance, renal dysfunction, and hypo- glycaemia that may require intravenous replacement. Alcohol and potentially hepatotoxic drugs should be withdrawn. Pruritus can be difficult to manage but resolves when the cholestatic phase of the illness has passed. Ursodeoxycholic acid, cholestyramine and antihistamines, cool baths, and moisturizing lotion may help. Management of patients with fulminant hepatic failure is covered in Chapter 15.22.5. Hepatitis C infection is recognized occasionally during the acute stage and viral elimination is accelerated with interferon (IFN)-​α. Newer agents have not yet been studied in this context. Patients with acute infection who have not cleared the virus within 12 weeks should be considered for a more conventional antiviral approach. The use of antiviral therapy for moderate or severe acute HBV infection has no evidence base but is an approach that has been adopted by some in the field, particularly when there is an elevated prothrombin time, in order to reduce the duration and severity of infection. Table 15.23.1.3  Serological tests used in the assessment of acute hepatitis Test Timing Interpretation IgM anti-​HAV Appears around onset of jaundice; persists for around 4 months Acute or recent infection IgG anti-​HAV Persists lifelong Indicates acute, recent, or past infection. Also produced following active vaccination HBsAg Appears from about 6–​12 weeks after acute infection and then disappears Viral protein in the blood, indicates the patient is infected
with HBV Anti-​HBs Develops a few weeks after jaundice and persists lifelong Protective antibody, indicates that viral infection has cleared Also produced after active vaccination HBeAg Rises early and usually declines rapidly by 1 month Infectious phase of HBV infection, high titre of HBV DNA Anti-​HBe Appears as HBeAg is cleared, persists Immune response to infectious virus IgM anti-​HBc First antibody to appear and persists about 4 months. May be the only marker of recent infection in the window between clearing HBsAg and developing HBsAb Acute HBV infection IgG anti-​HBc Persists long term Acute, recent, or past infection HBV DNA Cleared in 2 months in most cases Infectious virus in the blood Anti-​HCV Appears several weeks after infection, persists lifelong Acute, recent, or past infection HCV RNA Present at onset of symptoms Active viral replication HDVAg Present at onset of symptoms Presence of viral protein in blood IgM anti-​HDV Appears at week 1 and disappears at week 5–​6 Acute or chronic infection IgG anti-​HDV Appears at onset, persists in chronic carriage Acute, chronic or past infection IgM anti-​HEV From onset of symptoms, persists for 4–​6 weeks Acute or recent infection IgG anti-​HEV From onset of symptoms, persists for several years Acute, recent or past infection Exposure 0 1 2 3 4 Months 1gM anti-HAV Transaminase (ALT) Onset of clinical illness 1gG anti-HAV 5 6 Fig. 15.23.1.1  Typical serology of hepatitis A infection.

15.23.1  Hepatitis A to E 3113 Onset of clinical illness Exposure HCV RNA Transaminase (ALT) Anti-HCV Months 0 1 2 3 4 5 6 7 8 12 Fig. 15.23.1.3  Serological changes during acute hepatitis C with viral clearance. Exposure 0 1 2 3 4 Months 5 6 Transaminases (ALT) HEV RNA in faeces IgG anti-HEV IgM anti-HEV Fig. 15.23.1.4  Typical serological changes of hepatitis E infection. Exposure 0 1 2 3 4 5 6 7 8 Transaminases (ALT) HBV DNA HBs Ag 1gM-anti-HBc anti-HBs 1gG-anti-HBc Onset of clinical illness Fig. 15.23.1.2  Serological changes during acute hepatitis B with viral clearance.

section 15  Gastroenterological disorders 3114 Prevention The frequency of enteric infections with HAV or HEV can be re- duced by improved sanitation, better hygiene, and decreasing overcrowding. Active immunization against HAV with formalin-​ inactivated viral preparations is a safe, rapid, and effective means of protection and is advisable for Western individuals prior to travel to highly endemic areas. Early postexposure vaccination may also be of benefit. Patients with established chronic liver dis- ease should also be offered the vaccine to prevent HAV-​related decompensation of underlying liver disease. Vaccines are being developed for HEV. Passive protection against hepatitis B is available soon after ex- posure (sexual contact or needlestick injury) using specific high-​ titre immunoglobulins against HBV (HBIg). Active immunization to HBV initially involved a vaccine derived from viral proteins in infected blood, but now uses recombinant viral envelope (HBsAg) proteins. The vaccine is safe and the conventional programme of three doses over a 6-​month period leads to protective immunity in 90% of individuals. Early postexposure vaccination may also be of benefit. Nonresponders may responder to further vaccine boosting or may be candidates for newer vaccines containing additional viral antigens. Vaccination strategies vary from country to country, from universal vaccination in infancy to vaccination restricted to high-​risk individuals. Universal vaccine practice has been shown in Taiwan to reduce the incidence of chronic viral carriage, chronic liver disease, and hepatocellular carcinoma within a few years of initiation. Active immunization is recommended immediately after birth for children born to infected mothers. Those born to highly infectious mothers, as judged by the presence of HBeAg and high circulating HBV DNA levels, should also be offered passive HBIg within hours of birth. In some infants in some parts of the world, vaccination may fail with evolution to chronic in- fection with a mutated HBsAg ‘escape’ virus selected by the vac- cine programme, especially with viraemic mothers who also receive HBIg. There is no vaccine currently available for HCV, although clin- ical trials are underway. The major difficulty is the rapid evolu- tion of changes in the composition of HCV structural proteins as the virus mutates rapidly, producing many quasispecies. Passive immunization with gammaglobulin containing antibodies to HCV is not protective. For similar reasons, patients treated suc- cessfully with effective antiviral agents may remain susceptible to reinfection Chronic viral hepatitis Chronic hepatitis B Chronic HBV infection is defined as the persistence of HBsAg in blood for more than 6 months. After infection up to 10% of adults and more than 90% of infected infants become chronic HBV car- riers. Failure to clear the virus is associated with infection as a neo- nate or infant, those infected late in life, male sex, and those with a weaker immune response, either naturally or as a result of disease or medication. Around 1% of chronic carriers clear the virus spon- taneously each year. There is geographical variation in the carriage rates with notably high levels in East Asia and sub-​Saharan Africa (10–​20%) and lower prevalence in Northern Europe and North America (<1%). Phases of chronic hepatitis B virus infection The clinical outcome of chronic HBV carriage is varied and influ- enced by the strength of the immune response mounted by the host, the duration of infection, and alterations in viral replication with time. The natural history of chronic infection is characterized by dif- ferent phases (Table 15.23.1.4). In the early phase of infection (‘tol- erant’ or ‘replicative’ phase) the virus replicates avidly, expressing HBeAg and producing high levels of infectious viral particles (HBV DNA levels usually >106 IU/​ml). ALT levels are usually normal and, if undertaken, liver biopsy often shows little inflammation or scar- ring. This stage is variable in length but may be prolonged over many decades, especially if infection is acquired as an infant. Later in infection the host immune response increases associ- ated with hepatic inflammation. During this ‘inflammatory phase’, HBeAg seroconversion may occur, with loss of HBeAg and devel- opment of antibody to HBeAg (anti-​HBe). The amount of inflam- mation and necrosis, measured biochemically or with histology, influences the prognosis of chronic HBV infection. Some patients pass through this phase easily and sustain little in the way of liver disease. In others, viral replication persists, often without symptoms, and repeated cycles of inflammation and repair lead to progressive scarring of the liver. Following HBeAg seroconversion, many patients retain con- trol of the virus and have undetectable levels of HBV DNA in the blood (‘nonreplicative’ phase). The virus remains quiescent in the liver without causing further inflammation. Viral sequences may be- come integrated into the host genome and HBsAg production may continue. A significant number, however, develop mutants in the precore and basal core promoter regions of the viral genome leading Table 15.23.1.4  Serological tests in chronic HBV infection Phase HBsAg Anti-​HBs IgM anti-​HBc IgG anti-​HBc HBeAg Anti-​HBe HBV DNA Early months + − + + + − +++ Tolerant + − − + + − +++ Inflammatory + − −a + +/​− +/​− ++ Nonreplicative + − − + − + Or minimal Reactivation (precore mutant) + − − + − + ++ a IgM anti-​HBc persists at low titre in the long term but is usually not detected by commercial tests that have been set to be positive only at high titre and thus detect acute infection. During acute flares, levels may rise and be detected as weak positive results.

15.23.1  Hepatitis A to E 3115 to continued viral replication with rising HBV DNA levels in the presence of anti-​HBe antibody. Chronic HBeAg-​negative HBV can follow an aggressive course, may lead to the rapid development of cirrhosis and hepatocellular carcinoma, and requires long-​term or even indefinite treatment. Investigation After establishing the diagnosis of chronic HBV infection, it is ne- cessary to define the virological status of the patient with respect to infectivity and viral replication, and the hepatic status with respect to the presence of inflammation and liver damage. Interpretation of viral status may be complicated by the emergence of viral mutants, particularly the precore mutant that results in absent HBeAg expres- sion, but which nonetheless is associated with active inflammation and circulating HBV DNA. Serological markers of chronic HBV in- fection and their relevance to the phases of chronic HBV infection are outlined in Fig. 15.23.1.5. Chronic hepatitis B causes a spectrum of histological patterns and liver biopsy may be useful in assessing the severity of liver disease. During the tolerant phase, the inflammatory response to the virus may be minimal such that the histological appearances are virtually normal. Virally infected hepatocytes can be seen as ‘ground-​glass’ cells on routine staining or by immunohistochemical staining for viral antigens. Biopsies undertaken during the replicative phase demonstrate chronic lymphocytic infiltration of portal tracts with varying extent of periportal and/​or lobular inflammation. Fibrosis spreads from the portal tracts and in some cases spurs of fibrosis de- velop and progress into cirrhosis. These histological appearances can be categorized in terms of inflammatory activity and stage of fibrosis. In general, the replicative phase of HBV infection with HBeAg posi- tivity, particularly in its later phase, is associated with more marked inflammation than the subsequent anti-​HBe-​positive stage. Noninvasive methods of assessing liver fibrosis have been intro- duced and are supplementing (and, in some clinical practices, replacing) liver biopsy. Direct biomarkers of fibrosis, such as hya- luronic acid and procollagen III N-​peptide, have been measured in serum and combined in various algorithms. These have validated accuracy against liver biopsy in assessing fibrosis in patients with chronic hepatitis B.  Readily available indirect markers of altered hepatic function such as platelet count, coagulation studies, and the levels of ALT and aspartate transferase, have also been utilized. Such tests have some utility in clinical practice but are not liver specific and can be influenced by comorbid conditions. Transient elastography is a rapid and objective technique for staging liver fi- brosis by measuring the stiffness of the liver, expressed in units of kilopascals. It has proven utility in defining minimal and advanced hepatic fibrosis, particularly when the disease is stable. Caution should be observed, however, during suspected inflammatory phases of chronic HBV infection when these tests may be less re- liable since none of these parameters is an accurate measure of in- flammation and inflammatory activity precedes fibrosis. Clinical features Chronic HBV infection is frequently asymptomatic and often clinic- ally silent for many years. There may be nonspecific symptoms such as fatigue or upper abdominal discomfort. Progression to cirrhosis is not inevitable and, where it does occur, it usually takes many years, although the rate varies. The condition may be detected coinci- dentally through investigation of abnormal liver function tests or hepatomegaly, or recognized on screening (e.g. during pregnancy or via contact tracing of family members or other at-​risk individ- uals). Some patients present at a late stage with established cirrhosis. Episodes of enhanced inflammation (‘flares’) may give rise to tran- sient worsening of liver function tests, particularly elevations of transaminases and occasionally jaundice at any stage of the disease. Physical examination is frequently normal, or there may be stigmata of chronic liver disease (e.g. jaundice, splenomegaly, ascites, oedema, and encephalopathy). Chronic HBV infection may also give rise to a number of extrahepatic manifestations. These include glomerulonephritis, polyarteritis nodosa, and cryoglobulinaemia. The incidence of hepatocellular carcinoma in chronic HBV is high, probably increased over 100-​fold over noninfected controls. In those with HBV cirrhosis, repeated cycles of damage followed by repair can lead to errors during DNA repair, which in turn Replicative phase IgG anti-HBc HBs Ag HBe Ag+ HBV DNA ALT levels Up to 20–40 years Non-replicative phase Reactivation Pre-core mutant HBeAb+ eAg to eAb conversion Inflammatory phase Fig. 15.23.1.5  Serological markers during chronic hepatitis B.

section 15  Gastroenterological disorders 3116 lead to hepatocarcinogenesis. The virus is also capable of causing hepatocellular carcinoma in the absence of cirrhosis by integrating viral genomic sequences into infected cells. Management The ultimate goals of treatment in chronic HBV infection are to prevent progression to cirrhosis and development of hepatocellular carcinoma. The prospects of an individual patient clearing the virus spontaneously or with therapy are relatively low, but suppression of HBV replication (clearance of HBeAg and undetectable HBV DNA) can induce remission of liver disease (normalization of ALT and reduced intensity of hepatic inflammation). The two current approaches are the use of IFN-​α or inhibitors of viral replication, nucleotide and nucleoside analogues. Patient selection is important. For IFN therapy, those with active inflammation have the greatest potential for benefit. Most such patients have circulating HBeAg, an elevated ALT (two to five times normal) and lower levels of serum HBV DNA (<1000 IU/​ml). In the absence of elevated transaminases, the response to treatment is very poor. Interferons IFNs have antiviral, antiproliferative, and immunomodulatory effects. They increase host T-​cell-​mediated viral clearance by processes including enhancement of hepatocyte class I HLA ex- pression. The main theoretical advantage of IFN-​α treatment is the absence of induction of viral mutations to drive resistance and the potential that the host develops immune-​mediated control of HBV infection when therapy ceases. Treatment involves subcutaneous injections of IFN-​α administered weekly in pegylated form (long acting, conjugated to polyethylene glycol) for 6 to 12  months. Side effects include fever, malaise (particularly in the first few weeks of treatment), anaemia, alopecia, and depression. HBeAg to anti-​HBe seroconversion or loss of HBV DNA occurs in 30 to 40% of cases and may be associated with an inflammatory flare during the second or third month. HBsAg clearance occurs in less than 10% of cases. Women, those with a shorter duration of carriage, Westerners, and those without an additional immuno- suppressed background (such as HIV infection) respond more favourably. Most responders have a sustained response although 10 to 20% of patients who clear HBeAg experience reactivation of HBV replication, usually within the first year after completing therapy. Successful treatment with sustained suppression of HBV replication is associated with improved histological progression and reduced liver-​related mortality due to decompensation or hepatocellular carcinoma. Antiviral drugs Nucleoside and nucleotide analogues inhibit both viral reverse transcriptase and DNA polymerase resulting in inhibition of viral replication. Agents used in the treatment of HBV are shown in Table 15.23.1.5. These drugs have the advantage of oral bioavail- ability and minimal side effects but the disadvantage that their ef- fects are suppressive rather than curative, hence treatment has to be given long term. Discontinuation of therapy has to be undertaken with caution and careful monitoring as it may be followed by re- lapse with flares of inflammatory activity. Table 15.23.1.5  Nucleoside and nucleotide analogues used for treating chronic HBV Drug Dose Notes Lamivudine 100 mg daily Inexpensive Potent, rapid decline in HBV DNA HBeAg seroconversion <20% after 12 months Rapid emergence of resistant strains (YMDD mutants) 20% after 1 year, 80% after 4 years In developed countries, use now replaced by newer agents Adefovir dipivoxil 10 mg daily Weak activity, slow decline in HBV DNA HBeAg seroconversion <15% after 12 months Capable of suppressing wild type and YMDD mutant Effective in combination with lamivudine Nephrotoxicity limits clinical usefulness Telbivudine 600 mg daily Weakly acting agent High tendency for resistant virus (YMDD mutant) Not recommended in international guidelines Tenofovir disoproxil fumarate 245 mg daily Potent nucleotide analogue Structurally similar to adefovir but less nephrotoxic Requires monitoring of renal function, can cause proximal renal tubulopathy with hypophosphataemia and osteomalacia High barrier to resistance Active against YMDD mutant 76% virological response after 12 months 74% histological response after 12 months 21% HBeAg seroconversion after 12 months Entecavir 0.5–​1 mg daily Potent nucleoside analogue High barrier to resistance 70% histological response after 12 months 70% virological response after 12 months HBeAg seroconversion = 20% after 12 months Weak activity against YMDD mutant Emtricitabine 200mg daily Potent inhibitor of HBV and HIV Selects for YMDD mutant virus Used in combination with tenofovir for HIV/​HBV coinfection

15.23.1  Hepatitis A to E 3117 Antiviral use can induce viral mutations and development of resistant viruses able to cause hepatic flares. This was a particular problem with earlier drugs such as lamivudine, but the newer potent HBV inhibitors tenofovir and entecavir have a higher barrier to re- sistance and viral mutations are seen rarely, even after several years of therapy. Monitoring of HBV DNA levels is a key part of effective management of antiviral therapy and suppression of levels to un- detectable or minimal levels is regarded as the aim of therapy. Antiviral agents are used in additional specific situations. Reactivation of HBV replication in chronic HBV carriers under- going immunosuppressive or cancer chemotherapy can have serious consequences, including icteric flares and even decompensation and death. The use of prophylactic lamivudine during immunosup- pressive therapy in HBV DNA-​negative patients and for 6 months afterwards can reduce the rate of HBV reactivation, the severity of hepatic flares, and mortality. Highly viraemic HBeAg mothers carry approximately a 10% risk of vertical HBV transmission des- pite a combination of active and passive vaccination of the neonate. Lamivudine and more recently tenofovir therapy in the last tri- mester of pregnancy have been shown to be safe (although the num- bers studied are much smaller for the latter) and to reduce the risk of intrauterine and perinatal transmission of HBV and thus may be considered for this indication. If used only for this indication it may be discontinued within 3 months after delivery with close moni- toring. This approach is not an alternative to vaccination and does carry the risk of an inflammatory flare after treatment withdrawal, and not all physicians are convinced that this is the correct approach. Chronic hepatitis C Approximately 200 million people worldwide are infected with hepa- titis C. Prevalence rates vary geographically from around 0.5% in the United Kingdom to greater than 20% in some parts of Africa and Asia. Within developed countries, there are marked variations in preva- lence from 0.04% in healthy blood donors, 1% in patients attending genitourinary clinics, to up to 50% in people who inject drugs. In developed countries, recreational drug use is the dominant mode of HCV transmission from sharing needles as well as the paraphernalia used to prepare drugs, hence participants of needle-​ exchange programmes are still at risk. Prior to the 1990s, blood transfusion and treatment of clotting disorders with plasma concen- trates were important modes of transmission. This has been reduced almost to zero with the advent of effective screening of blood prod- ucts. In developing countries, poorly sterilized medical and dental equipment, including vaccination programmes, tattooing, dentistry, and communal shaving practices, as well as infected blood products, are the primary sources of infection. Sexual transmission of HCV is infrequent and those in long-​term monogamous relationships are generally at very low risk of trans- mitting the virus. Those with multiple partners are at higher risk and outbreaks of HCV have been reported in HIV-​positive and HIV-​ negative homosexual men in several cities in Europe. Perinatal transmission occurs in approximately 5% of infants born to HCV infected women. Breastfeeding and close household contact do not appear to transmit the virus. Clinical features Acute HCV infection is usually asymptomatic and thus unrecog- nized. Most patients (60–​85%) who become infected with HCV fail to clear the virus and become chronic carriers. Chronic infection induces a persistent necroinflammatory response in the liver and 20 to 30% of patients develop cirrhosis over a 20-​year period. Once cirrhosis has developed, the risk of developing liver failure is 2 to 5% per year, while that for hepatocellular carcinoma is 1 to 4% per year. Factors associated with disease progression include excessive alcohol consumption, obesity, diabetes, male sex, older age at infec- tion, and coinfection with HIV or HBV. In addition to its effects on the liver, HCV is associated with extrahepatic manifestations. These are thought to reflect either antigen–​antibody complex formation or the induction of cross-​reacting autoimmunity and can themselves carry significant morbidity and risks of mortality (Table 15.23.1.6). Patients may be diagnosed incidentally during investigation of fatigue or abnormal liver function tests, with manifestations of chronic liver disease, or when investigated for symptoms or signs of an associated extrahepatic manifestation of HCV. In addition, screening programmes are being developed for high-​risk individ- uals including prisoners and intravenous drug users. Investigation As in HBV, assessment of a patient with HCV involves both the viro- logical and the hepatic status. The initial screening test for HCV is detection of circulating anti-​HCV antibodies. Screening is recom- mended in those with risk factors for disease and patients found to have abnormal liver biochemistry. Anti-​HCV antibodies stay posi- tive for life, regardless of therapy. False-​negative results may be seen in acute infection, immunocompromised patients, or those with end-​stage renal disease. Active infection is diagnosed by detection of HCV RNA in the blood by polymerase chain reaction assays. Highly sensitive quantitative commercial assays are available for detecting virus and for monitoring responses during and after treatment. Viral genotyping (types 1–​6) and subtyping (a and b) is important as re- sponse to treatment varies between genotypes. Unless reinfected, genotypes do not change during the course of infection and repeat testing is not required. The severity of inflammation in the liver correlates poorly with serum ALT and viral load. Histological assessment may reveal both significant inflammation and progressive fibrosis despite normal serum ALT. The histological changes in the liver are similar to those in HBV, with portal inflammation of varying degrees, periportal hepatocyte necrosis, and progressive fibrosis leading to cirrhosis. The presence of lymphoid follicles in portal tracts and parenchymal Table 15.23.1.6  Extrahepatic manifestations of HCV infection Autoimmune Thyroid disease Sialadenitis Immune thrombocytopenic purpura Haematological Cryoglobulinaemia Monoclonal gammopathy Lymphoma Ocular Dry eyes Pulmonary Fibrosis Renal Membranoproliferative glomerulonephritis Skin Porphyria cutanea tarda Lichen planus Leucocytoclastic vasculitis Bone Osteosclerosis

section 15  Gastroenterological disorders 3118 steatosis are more characteristic of HCV. As with chronic HBV in- fection, noninvasive methods of assessing liver fibrosis and moni- toring progression in patients with HCV are increasingly being used in clinical practice. Management The main goal of treatment of chronic HCV infection is to clear the virus. Sustained loss of viral RNA is associated with a 70% reduc- tion in the risk of liver cancer, a 90% reduced risk of mortality re- lated to liver disease, as well as resolution of symptoms and reduced risk of transmission to the wider community. All patients should be considered for treatment, but the cost of therapy means that some healthcare providers prioritize those with more advanced liver dis- ease for newer, expensive treatment regimens. Those with mild dis- ease may have to choose whether to have treatments with greater side effects and lower success rates or to wait until better therapies are available for them. Interferon and ribavirin Until 2011, the standard of care was combination therapy with pegylated IFN-​α-​2a or IFN-​α-​2b (weekly injection) plus oral ribavirin. The mode of action of IFN-​α has been discussed previ- ously under HBV treatment. Ribavirin is a guanosine analogue that inhibits viral RNA synthesis. It has no direct action against HCV but augments the response to IFN by unknown mechanism(s). Genotypes 2 and 3 respond well to 6 months of treatment with IFN-​ α plus ribavirin, with clearance rates of up to 80%. For genotypes 1 and 4, treatment for 12 months produced sustained loss of viral RNA in 40 to 50% of patients, though prolonged therapy (up to 72 months) increased viral clearance rates further. Older patients respond less well. Polymorphisms in IFN-​λ-​3 determine both spon- taneous elimination of HCV as well as the efficacy of IFN-​based treatments. Use of serial and quantitative RNA analysis can define nonresponders in whom therapy can be abandoned after 3 months as well as rapid responders who may have sustained remission and substantially shorten duration therapy. Therapy is associated with side effects that affect treatment up- take, compliance, and accessibility. Thrombocytopenia, leucopenia, and anaemia may limit the ability to sustain IFN therapy, though the use of growth factors may help. Psychiatric side effects or pre-​ existing diagnoses may contraindicate or limit IFN use, and it is contraindicated in decompensated cirrhosis, reflecting both a lack of efficacy and a high incidence of side effects. Ribavirin induces cough, rash, dyspnoea, and insomnia in about 25% of patients and there is predictably a dose-​dependent haemolytic anaemia. The drug is contraindicated in renal failure as it accumulates and then causes severe haemolysis. Both pregnancy and fathering children need to be avoided while taking ribavirin. Newer agents A major breakthrough in the management of HCV came with the development of cell culture systems that support complete HCV replication. This improved the basic understanding and led to the identification of specific viral targets and antiviral compounds. In 2011, first-​generation protease inhibitors telaprevir and boceprevir were approved as add-​on therapy to IFN and ribavirin in treatment-​ naïve and treatment-​experienced genotype 1 patients. Addition of these directly acting antiviral agents boosted response rates to 70 to 80%. These agents have significant limitations however, including a low barrier to resistance, limited genotypic activity, clinically signifi- cant side effects, worsening liver function in patients with cirrhosis, significant drug interactions, and multiple daily dosing. The development of new directly acting antiviral agents with different modes of action has broadened treatment options con- siderably. These all-​oral, IFN-​free regimens are a radical change to clinical practice and provide the opportunity for cure in patients who previously could not be treated. Combinations of these agents can eradiate viral infection with treatment durations of 12 weeks or less in many patients, and with few or no side effects. Treatment ap- pears to be well tolerated even in those with liver decompensation, a group who were previously ineligible for treatment with IFN-​based regimens. The HCV RNA polymerase inhibitor sofosbuvir has been shown to be extremely effective in most genotypes in combination with ribavirin, often without IFN. These new drugs are expensive, however, and current accessibility is under tight control by regulatory bodies in many countries. In the United Kingdom in 2015, those with the most severe disease were pri- oritized for treatment with the NS5B polymerase inhibitor sofosbuvir with or without ribavirin in combination with NS5A inhibitors daclatasvir and ledipasvir. Many other IFN-​free regimens are now available and many more are in development, hence this field is al- tering rapidly. Guidelines are being updated regularly at http://​www. hcvguidelines.org/​. Choice of agents should take into account drug–​ drug interactions, which are regularly updated on the University of Liverpool’s website (http://​www.hep-​druginteractions.org). Coinfection with HIV Treatment of HIV–​HCV coinfected patients is a growing practice. HIV–​HCV coinfected patients suffer more liver-​related morbidity and mortality, and overall mortality, than HCV monoinfected pa- tients, and they benefit greatly from eradication of HCV. Uptake of HCV therapy was lower in coinfected patients due to historically lower response rates, patient comorbidity, and adverse effects of IFN-​based therapy. With the advent of HCV directly acting antiviral agents, more coinfected patients can be treated, but this requires close monitoring and awareness of complex drug interactions be- tween antihepatitis and antiretroviral medication. Other patients, previously identified as difficult to treat, including those with post-​ transplant HCV and those with renal impairment, may now be con- sidered for treatment with directly acting antiviral agents, but such patients require meticulous monitoring. Chronic hepatitis D Chronic HDV generally follows superinfection of a chronic HBV carrier. HBV–​HDV chronic infection tends to cause more severe liver disease, and 10–​15% of chronic HDV carriers progress rapidly (within 1–​2 years) to cirrhosis. In most patients, HDV acts to sup- press HBV replication so that markers of HBV activity, such as HBV DNA, in the serum may be low and occasionally undetectable. Liver damage in these patients is essentially due to HDV alone. High-​titre anti-​HDV IgG is present and correlates with HDV replication. Anti-​ HDV IgM may also persist in chronic infection and HDV RNA is usually positive on polymerase chain reaction assays. The main goal of treatment is to eradicate both HBV and HDV. IFN-​α is the only approved treatment for chronic HDV. Treatment frequently suppresses HDV replication with normalization of ALT

15.23.2 Autoimmune hepatitis 3119

15.23.2 Autoimmune hepatitis 3119

15.23.2  Autoimmune hepatitis 3119 level and decreased necroinflammation on liver biopsy. Some pa- tients may clear HDV transiently, although HBsAg often persists and most patients experience virological relapse of HDV when therapy is discontinued. Histological response, however, can be maintained for many years. In general, HBsAg clearance is required to cause sus- tained HDV clearance. Chronic hepatitis E HEV infection usually produces an acute, self-​limiting illness with clearance of the virus within a few weeks. It is now recognized, how- ever, that HEV infection can induce chronic hepatitis and even cirrhosis in immunosuppressed patients, for example, solid organ transplant patients, those with HIV infection, and those with haem- atological disease. Chronic HEV infection is often asymptomatic and may be de- tected during the investigation of abnormal liver function tests. Alternatively, patients may have symptoms such as fatigue, abdom- inal pain, fever, or jaundice. Chronic infection in the immunosup- pressed is best identified by looking for HEV RNA in plasma since antibody responses may be impaired. In transplant recipients, redu- cing the dose of immune suppression may allow viral clearance in some cases. In the remaining patients, as well as HIV-​positive and haematological patients, antiviral therapies such as IFN–​ribavirin or ribavirin alone have been found to be efficient in eradicating chronic infection. Liver transplantation for viral hepatitis Liver transplantation is indicated both in fulminant hepatic failure due to acute hepatitis and in advanced chronic hepatitis with cir- rhosis. Recurrence of viral hepatitis after transplantation for chronic viral infection has been a major concern for two decades. The use of HBIg and nucleoside analogues allows control in HBV, but severe recurrence has been a significant problem after transplantation for HCV until recently. IFN-​based treatments have been used cautiously in well-​selected patients with limited success. The new oral IFN-​free regimens offer substantial promise for this high-​risk group. FURTHER READING AASLD-IDSA HCV guidance panel (2018). Hepatitis C guidance 2018 update: AASLD-IDSA recommendation for testing, managing, and treating hepatitis C virus infection. Clin Infect Dis, 67, 1477–92. American Association for the Study of Liver Diseases/​Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://​www.hcvguidelines.org Balagopal A, Thomas DL, Thio CL (2010). IL28B and the control of hepatitis C virus infection. Gastroenterology, 139, 1865–​76. Brown RS Jr, et al. (2015). Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-​analysis. Hepatology, 63, 319–​33. Coiffer B (2006). Hepatitis B virus reactivation in patients receiving chemotherapy for cancer treatment role of lamivudine prophylaxis. Cancer Invest, 24, 548–​52. European Association for the Study of the Liver (2017). EASL 2017 clinical practice guidelines on the management of chronic hepatitis B infection. J Hepatol, 67, 370–98. European Association for the Study of the Liver (2018). EASL re- commendations on treatment of hepatitis C 2018. J Hepatol, 69, 461–​511. Gutierrez JA, Lawitz EJ, Poordad F (2015). Interferon-​free, direct-​acting antiviral therapy for chronic hepatitis C. J Viral Hepat, 22, 861–​70. Kamar N, et al. (2014). Hepatitis E virus infection. Clin Microbiol Rev, 27, 116–​38. Koh C, Heller T, Glenn JS (2019). Pathogenesis of and new therapies for hepatitis D. Gastroenterology, 156, 461–76. Lavanchy D (2012). Viral hepatitis: global goals for vaccination. J Clin Virol, 55, 292–​302. Lim TR, Tan BH, Mutimer DJ (2014). Evolution and emergence of a new era of antiviral treatment for chronic hepatitis C infection. Int J Antimicrob Agents, 43, 17–​25. Locarnini S, et al. (2015). Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. J Hepatol, 62 Suppl 1, S76–​86. Martin A, Lemon SM (2006). Hepatitis A virus: from discovery to vac- cines. Hepatology, 43 Suppl 1, S164–​72. McQuaid T, Savini C, Seyedkazemi S (2015). Sofosbuvir, a significant paradigm change in HCV treatment. J Clin Transl Hepatol, 3, 27–​35. Peters van Ton AM, Gevers TK, Drenth JP (2015). Antiviral therapy in chronic hepatitis E: a systematic review. J Viral Hepat, 22, 965–​73. Rehermann B, Nascimbeni M (2005). Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol, 5, 215–​29. Rizzetto M (2018). Targeting hepatitis D. Seminar Liver Dis, 38, 66–72. Terrault NA, et al. (2018). Update on prevention, diagnosis, and treat- ment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology, 67, 1560–99. Verna EC (2014). Hepatitis viruses and liver transplantation: evolving trends in antiviral management. Clin Liver Dis, 18, 575–​601. Webster DP, Klenerman P, Dusheiko GM (2015). Hepatitis C. Lancet, 385, 1124–​35. 15.23.2  Autoimmune hepatitis G.J. Webb and Gideon M. Hirschfield ESSENTIALS Autoimmune hepatitis is an idiopathic inflammation of the liver at- tributed to immune responses against self-​antigens presumed to be of hepatocyte origin. It is typically a relapsing and remitting cor- ticosteroid responsive condition associated with hepatitic serum liver tests, elevated gammaglobulins, and positive immune serology. Histological features are not specific but often include expanded portal tracts with a lymphoplasmacytic infiltrate. Epidemiology: predominantly affects women (female:male, 8:1), may occur throughout life, has some heritable component, and 40% of patients have other autoimmune diseases (e.g. thyroiditis, type 1 diabetes, or coeliac disease). Clinical features: many patients are asymptomatic and identified through investigation of abnormal serum liver tests. Presentation may be with anorexia, nausea, hepatic discomfort, and jaundice, but others may have nonspecific malaise or extrahepatic manifestations

section 15  Gastroenterological disorders 3120 such as arthralgia, arthritis, or fever. Clinical signs vary greatly, ranging from none to jaundice and tender hepatomegaly to fulminant hep- atic failure. One-​third of patients present as cirrhotic. Diagnosis:  characteristic laboratory findings include elevated serum transaminase activities, hypergammaglobulinaemia (as IgG), and circulating autoantibodies (e.g. antismooth muscle antibodies, anti-​liver–​kidney microsomal antibodies, and antinuclear anti- bodies). Diagnosis depends on the combination of clinical features and biochemical, immunological, and liver biopsy abnormalities, with exclusion of viral and other aetiologies. There may be overlap features with other autoimmune liver diseases (primary sclerosing cholangitis or primary biliary cholangitis). Treatment and prognosis:  the condition tends to progress to hepatic fibrosis and cirrhosis. Most cases should be treated with an immunosuppressive regimen, typically prednisolone with azathioprine in the first instance, and most require long-​term im- munosuppression. Crude 10-​year survival rate is 65% for those presenting with cirrhosis and greater than 95% for those pre- senting without. End-​stage decompensated cirrhosis and acute nonresponsive autoimmune hepatitis with liver failure can be indi- cations for liver transplantation. Introduction Autoimmune hepatitis is an uncommon but treatable immune-​ mediated liver disease. It is characterized by a destructive immune response to hepatocytes in the absence of an identified causative agent. Disease severity ranges from mild hepatitis to fulminant liver failure. The disease may occur at any age, is female predominant, and is associated with other autoimmune conditions. Active hepa- titis is usually indicated by elevation in serum activity of aspartate aminotransferase and alanine aminotransferase. Characteristically, patients also have elevated immunoglobulin G values. Most patients exhibit autoantibodies which are used to aid diagnosis, subclassify disease, and predict treatment outcome. In the absence of definable aetiological agents, diagnosis re- quires both exclusion of other possible causes of liver injury and identification of sufficient supportive biochemical, serological, and histological features. Many patients have fibrosis or cirrhosis at pres- entation. Fibrosis may progress despite therapy. The mainstay of medical management is immunosuppression in the form of cortico- steroids, followed by later addition of corticosteroid-​sparing agents, most commonly azathioprine. Most patients respond to corticoster- oids and require long-​term immunosuppression to prevent relapse. A few patients require liver transplantation, and post-​transplant re- currence is recognized. Aetiology and pathogenesis The aetiology of autoimmune hepatitis is incompletely understood, but there is evidence for both genetic and environmental influences. Genetic factors In common with many other autoimmune diseases, autoimmune hepatitis has associations with HLA alleles. Certain haplotypes confer increased disease susceptibility and also influence severity. For example, in Caucasian European populations, disease risk is increased by carriage of DRB103:01 and DRB104:01. The former predicts more aggressive disease, while the latter predicts later onset. HLA associations, however, vary between populations. Genome-​ wide association work has associated autoimmune hepatitis risk in Europeans with the gene locus SH2B3, which is shared by several autoimmune diseases. Environmental factors Evidence for a specific environmental trigger is lacking in most cases of autoimmune hepatitis, but a well-​established link between cer- tain drugs and development of drug-​induced autoimmune hepatitis has led to the proposal of molecular mimicry or alteration of self-​ antigens as potential mechanisms. Similarly, the industrial agent trichloroethylene may trigger autoimmune hepatitis, although its experimental induction requires the use of autoimmunity-​ predisposed mice. Several viral infections induce transient expres- sion of the same autoantibodies seen in autoimmune hepatitis, which has led to the hypothesis that antigens introduced or exposed by viral infection may also trigger an autoimmune response. Indeed, classical autoimmune hepatitis following confirmed viral hepatitis is described clinically. Immunological factors Disturbances in regulatory T-​cell regulatory function have been proposed as important in autoimmune hepatitis. Animal models with thymic deficiency or with deficiencies in regulatory signalling molecules may develop an analogous hepatitis with autoantibodies. Similarly, humans with the familial disorder auto- immune polyendocrine type 1 syndrome have deficits in thymic self-​antigen presentation. This impairs the generation of self-​ specific regulatory T cells and 20% develop autoimmune hepa- titis alongside other autoimmune phenomena. Immune-​mediated hepatitis is also recognized in the context of functional CTLA-​4 mutations and GATA-​2 deficiency, both of which are genes with immunoregulatory roles. The pathogenesis of autoimmune hepatitis involves the loss of immune tolerance to antigens on hepatocytes. There is the gen- eration of an adaptive immune response and the generation of high-​titre autoantibodies. Antibodies typically appear at the same time as inflammation and it is unclear whether they are important to pathogenesis. Antigen-​specific T cells reactive to hepatocyte antigens are described. These develop effector phenotypes and se- crete proinflammatory cytokines, resulting in progressive inflam- mation of the liver of variable severity. When hepatitis is severe and necrosis widespread, there may be acute liver failure. More typically, there is a progressive fibrosis leading to cirrhosis, which may subsequently cause liver failure and/​or complications of portal hypertension. Epidemiology Autoimmune hepatitis is relatively uncommon, with an incidence of approximately 1 in 100 000 per year and a prevalence of around 1 in 10 000, but the frequently subclinical nature of autoimmune hepa- titis means that its prevalence may be underestimated. Alongside

15.23.2  Autoimmune hepatitis 3121 nonalcoholic fatty liver disease, ‘burnt-​out’ autoimmune hepatitis is a likely cause of those presenting with cryptogenic cirrhosis. Autoimmune hepatitis is the primary indication for approximately 5% of liver transplant activity in the United Kingdom and United States of America. In common with other major autoimmune diseases, auto- immune hepatitis has a marked female predilection. The disease course is similar in men and women. Subclassification into type 1 and type 2 diseases may be made according to autoantibody pro- file (Table 15.23.2.1). Overall, presentation peaks in the fourth to fifth decade, but the disease may occur at any age, with paediatric presentation of type 2 autoimmune hepatitis common. There is geographic variation in the incidence of autoimmune hepatitis with the highest rates in northern Europe, where there is also a higher frequency of the type 2 subtype. In addition, native North American populations have higher incidences than their geographical neighbours of Caucasian background. Patients from non-​Caucasian, non-​Japanese backgrounds may develop more ag- gressive disease, and African American patients more frequently present with cirrhosis. Pathology Liver biopsy is a cornerstone of diagnosis despite no single feature being pathognomonic. The histology of autoimmune hepatitis is characterized by lymphoplasmacytic infiltrate (Fig. 15.23.2.1). This is most marked around the portal areas but may breach the interface between portal tract and liver parenchyma, so-​called interface hepatitis. The infiltrate is rich in both cytotoxic and helper T cells, and also in B cells and mature antibody-​producing plasma cells. Of these, the presence of plasma cells is most sug- gestive of the diagnosis and is less typical of viral aetiologies. Emperipolesis, where there is penetration by one cell into and through a larger cell (e.g. lymphocyte through hepatocyte), may be visible. Periportal hepatocytes may exhibit necrosis. In more severe cases, necrosis becomes confluent and may bridge between central hepatic veins. Rosettes of regenerating hepatocytes may be identifiable as well as the full spectrum of mild fibrosis through to established cirrhosis. Fibrosis typically starts in the periportal region. The presence of bridging necrosis or worse is predictive of later development of cirrhosis and associated with poor outcomes when untreated. Steatosis is not a feature of autoimmune hepatitis but may be co- incident. Evidence of cholestasis, iron or copper deposition, or (par- ticularly) marked steatosis, suggests alternative aetiologies. Around 10% of cases demonstrate biliary inflammation without bile duct destruction. There is also recognition that autoimmune hepatitis can ‘cross-​over’ with other autoimmune liver conditions, and that in some patients coincident ‘overlap’ of two disease processes can be found. Clinical features The presentation of autoimmune hepatitis spans asymptomatic dis- ease through to fulminant liver failure, with around 25% of patients being asymptomatic at presentation. Where symptoms are present, they are typically nonspecific and include right upper quadrant pain, nausea, arthralgia, pruritus, amenorrhoea, and those of as- sociated autoimmune phenomena such as sicca (Table 15.23.2.2). Symptoms may not remit even when immunosuppression is suc- cessful in controlling inflammation. Patients may describe a per- sonal or family history of autoimmunity. Although having relations with autoimmune hepatitis increases individual risk, the disease is sufficiently uncommon that most will not have an affected relation. Table 15.23.2.1  Type 1 and type 2 autoimmune hepatitis Type 1 Type 2 Proportion of cases 90% 10% Geography Worldwide More frequent in northern Europe Sex ratio 3:1 9:1 Median age of presentation Fourth to fifth decade First to second decade Presentation Variable Often acute, established cirrhosis common at presentation Autoantibodies ANA, anti-​SMA LKM HLA HLA-​DRB103:01, DRB104:01 HLA-​DRB103:01, DRB107:01 Prognosis Good Disease more aggressive with cirrhosis more common Relapse after drug withdrawal 70% Near universal Fig. 15.23.2.1  Representative histology of active autoimmune hepatitis. Liver biopsy specimen with haematoxylin and eosin stain. There is dense lymphoplasmacytic infiltration focused on a portal tract but breaching into the lobule portal, representing interface hepatitis. Several foci of hepatocytes demonstrating ballooning and rosette formation are present.

section 15  Gastroenterological disorders 3122 Attention should be paid to drug exposure, and to symptoms or personal histories suggestive of alternative causes of liver diseases (Table 15.23.2.3). Approximately one-​third of cases of autoimmune hepatitis are identified as a result of symptoms, but in current practice most pa- tients are diagnosed following abnormal liver biochemistry without symptoms. Half will have some fibrosis at presentation, and up to a third are cirrhotic. There are no specific features on physical examination. Where there is acute hepatitis, there may be fever, hepatomegaly, upper abdominal tenderness, and jaundice. There may be physical evi- dence of chronic liver disease and/​or hepatic decompensation. Severe autoimmune hepatitis may lead to liver failure: either acute fulminant disease or decompensated chronic disease with ascites and encephalopathy. Similarly, there may be evidence of coincident autoimmune phenomena such as hypothyroidism, coeliac disease, inflammatory arthritis, or psoriasis. Differential diagnosis The differential diagnosis of autoimmune hepatitis includes all po- tential causes of hepatic inflammation (Table 15.23.2.3). Both new and long-​established drug treatments should be considered as po- tential causes (Box 15.23.2.1). The International Autoimmune Hepatitis Group has produced simplified criteria for the diagnosis of autoimmune hepatitis (Table 15.23.2.4). Investigation Autoimmune hepatitis typically causes elevations in serum alanine aminotransferase and aspartate aminotransferase (together termed transaminases). Serum alkaline phosphatase and γ-​glutamyl trans- ferase are typically proportionally less elevated or normal. Other basic laboratory measures may reveal jaundice, evidence of hep- atic synthetic dysfunction, portal hypertension, anaemia, or renal impairment. Elevated serum IgG is characteristic of autoimmune hepatitis and occurs in over 90% of cases. The increase is polyclonal and may be ac- companied by lesser increases in IgA and IgM. An elevated globulin fraction on routine biochemical testing may be a clue to diagnosis. Autoantibodies are present in around 90% of cases (Table 15.23.2.5 and Fig. 15.23.2.2). Specific testing is required to exclude other aeti- ologies, even in the presence of autoantibodies. Tests include viral serology and assessment for metabolic diseases such as Wilson’s and α1-​antitrypsin deficiency according to the differential diagnosis. Table 15.23.2.2  Disease associations with autoimmune hepatitis Disease Approximate frequency (%) Thyroiditis 10–​20 Diabetes 10 Inflammatory bowel disease 5–​10 Rheumatoid arthritis 5–​10 Psoriasis 3 Sjögren’s syndrome 3 Systemic lupus erythematosus 1 Coeliac disease 1 Multiple sclerosis 1 One or more extra-​hepatic autoimmune conditions 40 Table 15.23.2.3  Differential diagnosis of autoimmune hepatitis Condition Notes Drug-​induced liver injury May be indistinguishable from autoimmune hepatitis, but potential offending agents should be stopped Viral hepatitis: • Hepatitis A • Hepatitis B (± hepatitis D) • Hepatitis C • Hepatitis E • Epstein–​Barr virus • Cytomegalovirus Viral hepatitis may induce autoantibodies including low-​titre ANA, SMA, and LKM. These are most frequent with hepatitis C Metabolic conditions: • Nonalcoholic steatohepatitis • Wilson’s disease • α1-​antitrypsin deficiency • Haemochromatosis Other autoimmune conditions: • Primary biliary cholangitis • Primary sclerosing cholangitis The presence of antimitochondrial antibodies suggests primary biliary cholangitis particularly when cholestatic liver tests are present; abnormalities on biliary imaging may suggest primary sclerosing cholangitis. Both typically cause marked elevations in alkaline phosphatase Toxic liver injury: • Alcohol • Paracetamol Hepatic complications of pregnancy: • Cholestasis of pregnancy • Acute fatty liver of pregnancy • Haemolysis, elevated liver enzymes, and
low platelets (HELLP syndrome) The development of these conditions is more common than autoimmune hepatitis developing during pregnancy

15.23.2  Autoimmune hepatitis 3123 Imaging, typically ultrasonography, is used to look for evidence of bil- iary pathology and to indirectly assess the degree of fibrosis. In chil- dren, it is recommended to actively seek overlap features of sclerosing cholangitis by magnetic resonance cholangiography; in adults, the po- tential for overlap should also be recognized, especially in treatment-​ unresponsive disease. Liver biopsy is usually required to reach a confident diagnosis of autoimmune hepatitis and to provide the clinician and the patient with reassurance that long-​term immunosuppression is appropriate. Management Pharmacological There are few controlled trials in the treatment of autoimmune hepa- titis and much is based on case series and data from when diagnostic methods were less accurate. However, the American Association for the Study of Liver Disease, the European Association for the Study of the Liver, and the British Society of Gastroenterology have all pro- duced guidelines. See Fig. 15.23.2.3 for a summary treatment algo- rithm for autoimmune hepatitis. Corticosteroids There is consensus that first-​line treatment requires corticosteroids. Prednisolone—​or its dose-​equivalent precursor prednisone—​is usually recommended. Initial regimens vary from 20 mg per day to 1 mg/​kg per day of prednisolone. Typically, the dosage of prednis- olone is then slowly reduced to the minimum required to maintain normal liver biochemistry and serum immunoglobulin levels. It is then continued at this level for an extended period, with patients typ- ically requiring 12 to 18 months of corticosteroids. Individualized approaches to treatment are important, as is recognition of the need for slow and prolonged therapy. Adherence to therapy is essential for good outcomes, and nonadherence is commonly recognized in patients with treatment-​unresponsive disease. In autoimmune hepatitis patients without cirrhosis, an alternative to prednisolone is the synthetic corticosteroid budesonide. This has fewer side effects than prednisolone due to its extensive first-​pass hepatic metabolism, and it has been demonstrated to have equal ef- ficacy in noncirrhotic patients. Treatment with budesonide is typic- ally started at 9 mg/​day and titrated downwards. Other immunosuppressants The need for long-​term immunosuppression in autoimmune hepa- titis requires the use of agents other than corticosteroids to reduce side effects, which are near universal by 2 years. Most commonly, the purine antimetabolite azathioprine is prescribed at, or shortly after, the commencement of prednisolone or budesonide. A delay in commencing azathioprine is advised when liver disease is unstable. Recommended azathioprine dosages vary and are typically 1 to 2 mg/​kg per day. Dosing may be titrated to serum thiopurine metab- olite levels. In some, the related antimetabolite mercaptopurine is better tolerated than azathioprine. Follow-​up studies have reported improved outcomes of azathioprine combination therapy as compared with corticoster- oids alone. Patients typically require 2 to 5 years of azathioprine treatment and lifelong treatment is increasingly offered, particu- larly in those with significant liver fibrosis. Studies identify the failure to use azathioprine (or equivalent) as one factor associated with poor long-​term outcomes. Transplantation Transplantation should always be considered if patients have de- compensated liver disease or a fulminant presentation. Care of such patients needs to include discussion with a transplant unit so that individualized assessment can be made as to the risk:benefit ratio of immunosuppression versus transplantation. Elective transplantation in the context of autoimmune hepatitis is most commonly indicated in those with decompensated end-​ stage/​portal hypertensive disease. However, first-​presentation de- compensated chronic disease with active hepatitis may respond to immunosuppression. Acute severe hepatitis may also respond to im- munosuppression, but a lack of biochemical improvement within a week of corticosteroids is ominous. Fulminant disease with enceph- alopathy necessitates superurgent transplantation. Corticosteroids in this setting are frequently harmful and not beneficial. Box 15.23.2.1  Drugs particularly associated with the induction of autoimmune hepatitis • Minocycline • Nitrofurantoin • Hydralazine • Methyldopa • α-​ and β-​interferons • Infliximab, adalimumab, and etanercept • Ipilimumab • Nonsteroidal anti-​inflammatory drugs • Khat and black cohosh Note: many other drugs and herbal remedies may cause variable liver injury distinct from autoimmune hepatitis under the general term ‘drug-​induced liver injury’. Table 15.23.2.4  Simplified diagnostic criteria for autoimmune hepatitis Variable Criterion Points ANA or SMA Titre ≥1:40 1 One or more of: 2 ANA or SMA ≥1:80 LKM ≥1:40 SLA Positive Serum immunoglobulin G

Upper limit of normal 1 ≥1.1 × upper limit of normal 2 Liver histology Compatible 1 Typical 2 Evidence of viral infection Absent 2 Total Probable autoimmune hepatitis ≥6 Definite autoimmune hepatitis ≥7 A maximum of two points is awarded for the presence of autoantibodies. Produced by the International Autoimmune Hepatitis Group.

section 15  Gastroenterological disorders 3124 Other treatment considerations Prolonged treatment with corticosteroids mandates careful at- tention to their potential side effects. Bone health, glucose tol- erance, the development of cataracts, weight gain, hypertension, opportunistic infection, and adrenal suppression must all be considered. Specific side effects of other immunosuppressants must also be considered, for example, bone marrow suppression with azathioprine and increased long-​term cancer risk. Patients should not smoke. For those on azathioprine, sun block is recom- mended, and women should adhere to screening guidelines for cervical malignancy in particular. Superinfection with hepatitis A or B may worsen precarious liver function and immunization Table 15.23.2.5  Major autoantibodies associated with autoimmune hepatitis Antibody Target Notes ANA Variable nuclear antigens including histones, centromeres, DNA, and chromatin Supports diagnosis of type 1 autoimmune hepatitis, especially at higher titres. Primary biliary cholangitis-​associated ANA demonstrates a different and distinct staining pattern. SMA Components of smooth muscle including actin Supports diagnosis of type 1 autoimmune hepatitis F-​actin Filamentous actin component of smooth muscle and cytoskeleton Supports diagnosis of type 1 autoimmune hepatitis; more specific than SMA. LKM-​1 Cytochrome P450 2D6 Supports diagnosis of type 2 autoimmune hepatitis SLA/​LP Soluble antigens of liver and pancreas cytoplasm Predicts poorer outcome; specific to autoimmune hepatitis LC-​1 Forminino-​transferase cyclodeaminase Predicts poorer outcome AMA Pyruvate dehydrogenase complex More consistent with primary biliary cholangitis, present in a small minority of autoimmune hepatitis cases ANA, antinuclear antibodies; AMA, antimitochondrial antibodies; F-​actin, filamentous actin antibodies; LC-​1, liver cytosol antibody type 1; LKM-​1, liver–​ kidney microsomal antibody 1; SLA/​LP, soluble liver antigen/​liver pancreas; SMA, smooth muscle antibodies. These antibodies are detected by indirect immunofluorescence and require expert interpretation; the soluble antigen SLA/​LP requires an enzyme-​linked immunoabsorbance assay based technique;
F-​actin and LKM-​1 may also be detected by ELISA. (a) (b) (c) (d) Fig. 15.23.2.2  Autoantibodies associated with autoimmune hepatitis. (a) Antinuclear antibody—​there is homogeneous staining of the nuclei of this human epithelial cell line. (b) Antismooth muscle antibody—​the muscular walls of arterioles and the muscularis propria are stained in a section of rodent stomach. (c) Anti-​liver–​kidney microsomal 1 antibody shows homogeneous staining of the cytoplasm of hepatocytes in a section of rodent liver. (d) Anti-​liver–​kidney microsomal 1 antibody stains the cytoplasm of large proximal tubules but not smaller distal tubules in a section of rodent kidney. These images are of indirect immunofluorescence of patient sera with anti-​immunoglobulin G fluorescent secondary antibody.

Working diagnosis of autoimmune hepatitis Commence corticosteroids (prednisolone or, if not cirrhotic, consider budesonide) Addition of azathioprine (usual target dose 1–2 mg/kg). In jaundiced patients, azathioprine is not usually initiated until the bilirubin is < 100 µmol /litre Patients with inactive, ‘burnt-out’ disease on histology may not require immunosuppression Patients with decompensated liver disease or fulminant acute presentations should be managed in conjunction with a liver transplant unit. The risks and benefits of immunosuppression in patients with severe disease need careful consideration Taper corticosteroid dose while attempting to normalize liver biochemistry and immunoglobulin G levels. Corticosteroid taper must be individualized to the patient Mercaptopurine and mycophenolic acid can be considered in patients intolerant of azathioprine. Failure of normalization of transaminases and IgG by 6 months Normalization of liver biochemistry and IgG by 6 months Usually 12–18 months of low- dose corticosteroids and 2–5 years of azathioprine Consider nonadherence and alternative diagnoses. Intensify or alter immunosuppression Monitor for side effects of therapy and survey for complications of cirrhosis. Withdrawal of azathioprine can be considered in noncirrhotic patients with normal liver biochemistry and immunoglobulins. Long-term immunosuppression is often favoured. SLA-positive and LKM-1 positive patients should be considered for lifelong therapy. Response? 3–4 weeks Yes No Fig. 15.23.2.3  Summary treatment algorithm for autoimmune hepatitis. This represents the authors’ approach to treatment, although care of patients with autoimmune hepatitis should always be individualized. Typical starting doses of prednisolone are 20 mg/​day to 1 mg/​kg/​day depending on disease severity. Budesonide is started at 9 mg/​ day. Azathioprine is titrated to 1 to 2 mg/​kg/​day. In presentations with jaundice, azathioprine should be delayed until bilirubin is clearly settling and below 100 µmol/​L. Typical long-​term maintenance doses of prednisolone are usually less than 10 mg/​day. Options for patients unresponsive to treatment after 6 months include increasing corticosteroid and azathioprine doses or the use of tacrolimus, ciclosporin, or rituximab. At all points consideration should be given to referral for transplant assessment or tertiary centre opinion. In responders without cirrhosis or other unstable systemic disease, a single attempt at treatment withdrawal may be attempted after at least a year (usually longer) of normalized laboratory indices.

section 15  Gastroenterological disorders 3126 is recommended. In patients with hepatitis despite apparent ad- equate immunosuppression, consideration of superimposed Epstein–​Barr virus, cytomegalovirus, or hepatitis E is sensible. Varicella zoster, influenza, and pneumococcal immunizations are also suggested for immunosuppressed patients. Where cirrhosis is present, consideration should be given to surveillance for hepatocellular carcinoma, which eventually af- fects around 1% of cirrhotic autoimmune hepatitis patients. Surveillance for the presence or development of oesophageal varices is standard. Nutritional support may be necessary with advanced cirrhosis. Prognosis Most patients respond to therapy. Overall, 90% achieve remission of laboratory indices with resolution of histological inflammation. Importantly, histological remission typically occurs months after normalization of transaminases and immunoglobulins. Poorer prognosis is associated with onset in those aged less than 18 years, cirrhosis at presentation, and the presence of soluble liver antigen/​ liver pancreas (SLA/​LP), liver–​kidney microsomal antibody 1 (LKM-​1), or liver cytosol antibody type 1 (LC-​1) antibodies. Some patients, however, do not respond to corticosteroid and azathioprine therapy. Incomplete adherence to the treatment regimen is the most likely explanation, but alternative diagnoses should also be reconsidered. However, liver biochemistry and serum immunoglobu- lins do not respond without explanation in some patients. In these cases, increased doses of corticosteroids and azathioprine have been used with variable success. There are reports of the use of tacrolimus, mycophenolic acid, ciclosporin, rituximab, and infliximab. However, there is considerable heterogeneity in approach between centres and typically subspecialist input is required in these cases. Both patients and physicians may consider ceasing immunosup- pression after a period, usually of at least 2 years, of normal serum biochemistry and immunoglobulins. However, even when repeat biopsy shows no evidence of inflammatory activity, autoimmune hepatitis relapses in over 70% of patients, leading many to manage pa- tients on long-​term monotherapy with azathioprine. One approach is a single trial without immunosuppression for those with resolved inflammation on repeat biopsy, in the absence of cirrhosis, and after a prolonged period of normal biochemistry and immunoglobulins. The high risk of relapse means that cessation of immunosuppression is not recommended for those with cirrhosis or those in poor overall health. Relapse usually commits patients to lifelong therapy. Transplantation In autoimmune hepatitis, the prognosis after liver transplantation is good, with 5-​year survival rates in excess of 80%. Rates of infection appear higher in the first year after transplantation requiring careful monitoring. Patients awaiting liver transplantation should have their immunosuppression burden reduced. Notably, the require- ment for post-​transplantation immunosuppression may be higher than in other conditions, although there is a similar rate of acute episodes of graft rejection. Autoimmune hepatitis may recur in a patient transplanted for the condition. Reported rates of recurrence vary widely and are up to 50%. Disease recurrence is more frequent when active inflammation is found in the recipient explant, and when pretransplantation im- munoglobulins are elevated. The diagnosis requires histological examination in the context of compatible biochemistry and/​or im- munoglobulins:  autoantibodies typically persist after transplant- ation and are therefore less useful for diagnosis of recurrence. A syndrome resembling autoimmune hepatitis may be seen in liver transplants performed for other indications and is termed de novo autoimmune hepatitis. The process is an alloimmune hepatitis and is considered by many to reflect a variant of rejection. Special circumstances Cross-​over syndromes Autoimmune hepatitis may share features with primary biliary cholangitis (previously known as primary biliary cirrhosis) or pri- mary sclerosing cholangitis. Such conditions may be referred to as ‘cross-​over’ or ‘overlap syndromes’, but precise definitions are lacking. Typically these presentations are less responsive to im- munosuppression and may evolve over time. In children, autoimmune sclerosing cholangitis is frequent (up to 50%) when sought in those with autoimmune hepatitis. In adult patients, 10% will likely have some cholangiopathy if cholangiog- raphy is performed. Antimitochondrial antibody-​negative primary biliary cholangitis may be mistaken for autoimmune hepatitis, and treatment resistant primary biliary cholangitis may also have prom- inent features of hepatitis that lead to consideration of the presence of ‘overlap’. Only a few patients have sufficient evidence of both hepatitis and biliary disease to represent true ‘overlap’. Some patients present years after a typical diagnosis of primary biliary cholangitis with classical corticosteroid-​responsive autoimmune hepatitis and represent clear ‘cross-​over’. Inactive disease Some patients may present with ‘burnt out’ disease. Here there is variable fibrosis with no or minimal inflammation but with sero- logical evidence of autoimmune disease. Cohort studies have shown that those with little inflammatory activity on biopsy may not benefit from immunosuppression. Most manage these patients, who are typically elderly, by observation alone. Pregnancy Autoimmune hepatitis may complicate pregnancy, or more com- monly a patient with autoimmune hepatitis may become preg- nant. This situation presents particular management challenges. Typically, therapy with prednisolone and azathioprine is maintained during conception, pregnancy, and breastfeeding with the goal of maintaining stable disease. Particular attention is paid to the pres- ence of portal hypertension including oesophageal varices, altered glucose tolerance in the context of corticosteroid use, the risk of opportunistic infection, and the possibility for fluctuations in dis- ease activity and immunosuppression requirements, particularly postpartum. Classically, disease remits in the second and third tri- mester but over 20% of patients flare within the first few months after delivery. Ideally pregnancy is planned so that the risks and benefits of continuing immunosuppression may be discussed and so that exposure to potentially teratogenic medications, such as mycophenolate, is avoided.

15.23.3 Primary biliary cholangitis 3127

15.23.3 Primary biliary cholangitis 3127

15.23.3  Primary biliary cholangitis 3127 Acknowledgements Prof Stefan Hübscher, Pathology, University Hospitals Birmingham, and Dr Abid Karim, Clinical Immunology, University Hospitals Birmingham, United Kingdom. FURTHER READING de Boer YS, et al. (2014). Genome-​wide association study identifies vari- ants associated with autoimmune hepatitis type 1. Gastroenterology, 147, 443–​52.e5. Hennes EM, et al. (2008). Simplified criteria for the diagnosis of auto- immune hepatitis. Hepatology, 48, 169–​76. Kirstein MM, et al. (2015). Prediction of short-​ and long-​term outcome in patients with autoimmune hepatitis. Hepatology, 62, 1524–​35. Manns MP, et al. (2010). Budesonide induces remission more effect- ively than prednisone in a controlled trial of patients with auto- immune hepatitis. Gastroenterology, 139, 1198–​206. Obermayer-​Straub P, et al. (2001). Hepatic autoantigens in patients with autoimmune polyendocrinopathy-​candidiasis-​ectodermal dystrophy. Gastroenterology, 121, 668–​77. Trivedi PJ, et al. (2018). Grand round: Autoimmune hepatitis. J Hepatol, doi: 10.1016/j.jhep.2018.11.006. van Gerven NM, et al. (2015). HLA-​DRB103:01 and HLA-​DRB1 04:01 modify the presentation and outcome in autoimmune hepa- titis type-​1. Genes Immun, 16, 247–​52. Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME (2018). Cellular and molecular mechanisms of autoimmune hepatitis. Annual Review of Pathology: Mechanisms of Disease, 13(1), 247–92. 15.23.3  Primary biliary cholangitis Jessica K. Dyson and David E.J. Jones ESSENTIALS Primary biliary cholangitis (PBC), previously known as primary bil- iary cirrhosis, is a chronic, cholestatic liver disease in which the biliary epithelial cells lining the small intrahepatic bile ducts are the target for immune-​mediated damage, leading to progressive ductopenia and cholestasis. The cause is unknown but presumed to be autoimmune. The disorder affects women (>90% of cases) and usually has an in- sidious onset in middle age. Younger patients are less common but have a more aggressive disease course. Fatigue and pruritus are the most common presenting symptoms. Findings on examination vary widely, ranging from no abnormality to jaundice with hyperpigmen- tation, scratch marks, and rarely the features of advanced liver disease. Diagnosis of PBC is based on three criteria: (1) cholestatic liver function tests, with increases in serum alkaline phosphatase and
γ-​glutamyl transferase, (2)  presence of serum antimitochondrial antibodies (found in more than 95% of cases), and (3) compatible liver histology. Many asymptomatic patients are recognized fol- lowing the incidental discovery of antimitochondrial antibodies or elevated levels of serum alkaline phosphatase. First-​line treatment is with ursodeoxycholic acid which can lead to significant improvement in liver biochemical values. Second-​line treatment is with obeticholic acid. No immunosuppressive drug regimen has been proven effective. Progression may be slow, but eventually patients can develop cirrhosis. Cholestyramine is used as first line to treat pruritus. There is no recognized treatment for fatigue. Liver transplantation is indicated in some cases. Introduction The term primary biliary cirrhosis was first used in the 1940s before the advent of serological testing and when the disease was recognized in end stage. With current diagnostic approaches, the vast majority of patients are identified early in the disease and are noncirrhotic. This, together with the use of the term cirrhosis with its erroneous implication of an alcohol aetiology among nonexperts, has led a pa- tient-​driven move to change the name of the condition to primary biliary cholangitis (PBC), and it has been known as such since 2015. PBC is a chronic inflammatory liver disease characterized by damage to the small intrahepatic bile ducts. There is an autoimmune component to the disease with high titres of characteristic auto- antibodies, portal tract T-​cell infiltrates, genetic associations with immunoregulatory gene polymorphisms, and clinical associations with other autoimmune conditions. Bile duct injury is progressive, with a cycle of cholestatic cell damage. The combination of immune and cholestatic injury results in progressive liver injury, fibrosis, and, ultimately, cirrhosis. PBC impact patients through the development of advanced liver disease, and through systemic symptoms that can occur at any point in the disease course. First line therapy is with the hydro- philic bile acid ursodeoxycholic acid (UDCA) which has individual trial and meta-analysis evidence suggesting improvement in prog- nosis. Second line treatment is with the Farnesoid X Receptor agonist Obeticholic Acid (OCA) which has trial evidence to suggest a signifi- cant improvement in surrogate markers of disease severity in patients showing an inadequate response to UDCA. Symptomatic treatment approaches are effective for pruritus. Recent advances in disease patho- genesis are now translating into novel, second-​line therapies. Aetiology Genetic basis PBC appears to be typical of autoimmune disease in having a complex aetiology. A genetic component is suggested by familial predisposition (the sibling relative risk is 10.5) and an increased concordance rate in monozygotic twins. Genome-​wide association studies have shown remarkably consistent findings internationally, with the strongest as- sociations being within the HLA region (Table 15.23.3.1). Other as- sociations are with pathways regulating antigen presentation, the phenotype of the cellular immune response, and the trafficking of im- mune cells into the liver. No associations at a genome-​wide level of sig- nificance have been reported with nonimmune loci. The genetic basis of disease phenotype remains to be explored and genetic approaches currently have no role to play in disease management. Although there is an increased incidence of PBC in family members, absolute risk re- mains low, hence screening of family members is not recommended in the absence of other findings leading to clinical suspicion.

section 15  Gastroenterological disorders 3128 Environmental factors There is both epidemiological and mechanistic evidence sug- gesting that environmental triggers may be responsible for break- down of immune tolerance in genetically susceptible individuals, but studies looking for the specific trigger are lacking. There is spatial variation in PBC both in terms of worldwide prevalence and within smaller geographical areas, with disease clusters in urban areas. An excess of cases over a limited time-​period within limited geographical areas (space-​time clustering) also points to a role for transient environmental agents in disease aetiology. Large case–​control studies have suggested other factors within the environment and disease associations that may relate to dis- ease risk: history of urinary infections, history of smoking, use of hair dye, eczema, psoriasis, and shingles. However, study results are conflicting and need further exploration (Table 15.23.3.2). Challenges in identifying environmental risk factors include the time between exposure and onset and the latent period between disease onset and diagnosis. Epidemiology PBC predominantly affects women (90% of patients) with a me- dian age at onset of approximately 60 years. The strong association between female sex and PBC suggests that female sex hormone ef- fects may be important in pathogenesis. Using accepted epidemio- logical criteria, PBC is confirmed as ‘definite’ by the presence of all three of:

  1. elevation of serum alkaline phosphatase of liver origin for at least 6 months
  2. presence of antimitochondrial antibodies or PBC-​specific anti­ nuclear antibodies (titre>1:40) in serum
  3. diagnostic or compatible liver biopsy (showing characteristic florid bile duct lesions) Table 15.23.3.1  Genetic associations in PBC identified in high-​ quality studies Chromosome Position (MB) Probable gene association 1 2.5 67.7 197.5 MMEL1, TNFRSF14 IL12RB2 DENND1B 2 191.8 228.7 STAT1, STAT4 CCL20 3 17.0 119.2 159.7 PLCL2 CD80 IL12A, SCHIP1 4 103.4 NFKB1 5 35.9 158.7 IL7R IL12B 6 26.21–​33.74 137.5 MHC (multiple) IL22RA2 7 36.9 128.6 ELMO1 IRF5, TNPO3 9 117.5 TNFSF15 11 64.1 111.2 118.8 RPS6KA4 POU2AF1 CXCR5, DDX6 12 6.4 111.8 TNFRSF1A SH2B3, ATXN2 13 43.1 TNFSF11 (RANKL) 14 68.2 103.6 RAD51L1 TNFAIP2 16 11.3 85.9 CLEC16A, SOCS1 IRF8 17 38.1 44 IKZF3, ZPBP2, GSDMB, ORMDL3 MAPT 19 10.5 50.9 TYK2 SPIB 21 45.6 ICOSLG 22 39.8 MAP3K71P1, SYNGR1 Table 15.23.3.2  Environmental and related associations in PBC identified in high-​quality case–​control studies Risk factor Howel 2000 (UK) Gershwin 2005 (multivariate analysis) (USA) Prince 2010 (OR compared to epidemiological cases) (UK) OR 95% CI AOR 95% CI OR 95% CI Medical/​family history Family history of PBC 4 0.4–​44 10.7 4.2–​27.2 2.26 1.05–​5.21 Psoriasis 4.6 1.2–​17.3 1.90 1.21–​2.91 Eczema 0.13 0.02–​1.0 0.96 0.63–​1.46 Urinary infections 1.7 0.96–​3.0 1.5 1.19–​1.91 2.06 1.56–​2.73 Lifestyle Ever smoked 2.4 1.4–​4.1 1.57 1.29–​1.91 1.63 1.27–​2.09 Alcohol consumption 0.7 0.3–​1.8 0.57 0.39–​0.83 Hair dye 1.29 1.00–​1.80 Hair perm 1.13 0.78–​1.65 Nail varnish 1.002 1.0–​1.003 AOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio.

15.23.3  Primary biliary cholangitis 3129 The presence of two features is defined as ‘probable’ PBC. The com- bination of antimitochondrial antibodies at diagnostic titres and ele- vated alkaline phosphatase is over 95% accurate for diagnosing PBC, an observation which has led to a dramatic reduction in the need for liver biopsy for diagnosis (it is now mainly reserved for prognostic and treatment assessment). Although these criteria were developed to standardize diagnosis in the context of epidemiological studies, they have entered widespread clinical use. PBC is a rare disease (prevalence <50/​100 000 population), with higher prevalence in Northern Europe and much lower prevalence in Asia and Africa, although there is a paucity of good epidemio- logical studies from these areas (Table 15.23.3.3). Some studies have suggested that the prevalence of PBC is increasing over time, but this may be due to improved case finding, increased dis- ease awareness, differences in study populations, and methods of identifying cases. There are an increasing number of patients being identified with antimitochondrial antibodies (or other PBC-​specific auto- antibodies) but normal liver function tests, and they are at risk of developing overt clinical PBC during follow-​up. Current advice is that these patients undergo regular monitoring, but not be treated until a serum liver biochemical abnormality is seen. Large-​scale patient cohorts such as the 6000-​patient UK-​PBC cohort have allowed identification of male sex and younger age at diagnosis as risk factors for inadequate response to therapy. Young age of disease onset is also strongly associated with high symptom burden, particularly fatigue. Pathogenesis/​pathology The pathogenetic process in PBC is one of sequential immune and cholestatic cytopathic injury to biliary epithelial cells lining small intrahepatic bile ducts, followed by ductopenia, progressive biliary fibrosis, and ultimately cirrhosis (Fig. 15.23.3.1). Autoimmune phenomena are almost universal with high-​titre autoantibodies and liver infiltrating autoreactive T-​cell responses directed most Table 15.23.3.3  Prevalence of PBC in well-​designed epidemiology studies Study Country Prevalence Kim, 2000 USA 65.4 per 100 000 (95% CI 43.0–​87.9) for women 12.1 per 100 000 (95% CI 1.1–​23.1) for men 40.2 per 100 000 (95% CI 27.2–​53.1) overall Witt-​Sullivan, 1990 Canada 23 per 100 000 Metcalf, 1997 England 24 per 100 000 overall 90 per 100 000 women ≥40 years Kingham, 1998 England 20 per 100 000 James, 1999 England 25 per 100 000 Rautiainen, 2007 Finland 18 per 100 000 overall 29 per 100 000 women Lofgren, 1985 Sweden 13 per 100 000 Danielsson, 1990 Sweden 15 per 100 000 Inoue, 1995 Japan 3 per 100 000 Mori, 1997 Japan 5 per 100 000 Liu, 2010 China 49 per 100 000 Watson, 1995 Australia 1.9 per 100 000 overall 5.1 per 100 000 women >24 years CI, confidence interval. Cholestasis Immune injury Ductopaenia Fibrosis Immunotherapy Bile acid therapy Antifibrotic therapy Transplantation Fig. 15.23.3.1  Pathogenetic pathway for PBC and implications for potential approaches to therapy: proposed model for the pathogenesis of PBC. An initial autoimmune response leads to injury to small intrahepatic bile ducts and retention of toxic hydrophobic bile acids. These cause a secondary cycle of bile duct injury and, cumulatively with immune injury, progressive ductopenia and secondary hepatocyte injury, fibrosis, and cirrhosis. In an alternative proposed model, the ‘upstream’ immune injury is itself a consequence of primary cholestasis leading to altered self-​antigen processing. The concept of a cumulative impact of immune and cholestatic injury remains valid in both models. Potential approaches to therapy are to target the initial immune response, the cholestatic cycle, the downstream fibrotic reaction, and, in the context of advanced disease, organ replacement through transplantation.

section 15  Gastroenterological disorders 3130 typically at highly conserved mitochondrial self-​antigens (2-​oxoacid dehydrogenase enzymes, in particular the E2 component of pyru- vate dehydrogenase complex (PDC-​E2)). Autoreactive T-​cell re- sponses are most marked in early disease leading to the view that cytotoxic T-​cell responses directed at biliary epithelial cells might be an early aspect of the disease process. There is no evidence to suggest that autoantibody responses are pathogenetic. In addition to biliary epithelial cell apoptosis, senescence is also seen, sug- gesting that the pathway to injury is more complex than a simple immune ‘hit’. The bile acid pool is abnormal in PBC, with increased levels of toxic hydrophobic secondary bile acids that can also cause bil- iary epithelial cell apoptosis and give rise to a secondary cycle of cholestasis following initial immune injury. This interplay of processes has implications for the sequencing of therapy, in particular the applicability and timing of immunotherapeutics. A component of bile acid-​driven biliary epithelial cell injury may be a defect in a normal protective process of active transport of bicarbonate into the bile duct. Normalization of this ‘bicarbonate umbrella’ represents a novel potential approach to treatment (Fig. 15.23.3.2). Interface hepatitis can accompany the characteristic granu- lomatous portal tract inflammation and duct injury, and has been associated with more severe, and less treatment-​responsive forms of the disease (Fig. 15.23.3.3). One area of controversy has been the extent to which interface hepatitis represents an overlap process with autoimmune hepatitis. Whereas true overlap pa- tients do exist, patients meeting diagnostic criteria for both PBC and autoimmune hepatitis are uncommon, and most patients exhibiting interface hepatitis probably have a more aggressive form of PBC. Conventional disease staging uses four-​stage scores such as the Scheuer score (Table 15.23.3.4) that focus on ductopenia, portal tract change, and fibrosis, but underplay interface hepatitis. Appreciation of the importance of interface hepatitis followed the development of the scores and all underplay its significance. Newer scoring systems are needed to more accurately reflect cur- rent understanding of disease pathogenesis. Liver biopsy is likely to play an increasing role in treatment stratification as molecular pathology markers associated with higher-​risk disease are recog- nized, but the patchy nature of the disease in the liver must be borne in mind when considering liver biopsy findings. A few patients have an aggressively ductopenic form of disease characterized by profound cholestasis. Prognosis is poor, pruritus is prominent, and treatment resistance is the norm. These patients typically come to transplantation. Apoptosis Apoptosis Senescence (1) (2) (3) Cytotoxic T-cell Natural killer (NK) cell Pyruvate dehydrogenase (PDH) component/epitope Anti-PDH antibody Bicarbonate transporter (AE2 etc) Bicarbonate ‘umbrella’ Hydrophobic bile acid Reactive oxygen species (ROS) Latent TGF-β Active TGF-β Fig. 15.23.3.2  Proposed mechanisms for biliary epithelial cell injury in PBC. Three mechanisms, which are not mutually exclusive, have been postulated for biliary epithelial cell (BEC) injury: (1) direct and indirect immune injury related to B-​cell and T-​cell autoreactivity; (2) apoptotic injury to BEC through the actions of retained hydrophobic bile acids. Susceptibility to such injury is increased by loss of a protective ‘bicarbonate umbrella’; (3) BEC senescence driven by oxidative stress and the activation of latent transforming growth factor (TGF)-​β.

15.23.3  Primary biliary cholangitis 3131 Clinical features Hepatological PBC is characterized by cholestatic liver biochemistry (elevated al- kaline phosphatase and γ-​glutamyl transferase) and PBC-​specific autoantibodies. Serum autoantibodies specific for mitochon- drial, nuclear, and centromere antigens are present in approxi- mately 95% and 30% of patients, respectively (Table 15.23.3.5). A titre of 1/​80 or greater for any autoantibody linked to PBC is regarded as positive, and an elevated IgM level is characteristic. Screening ultrasonography should be performed to exclude alter- native diagnoses. Magnetic resonance cholangiopancreatography should be considered in patients with negative autoantibodies and cholestatic liver biochemistry to exclude primary sclerosing chol- angitis. Gallstones are common in PBC patients but often asymp- tomatic. Periportal lymphadenopathy is frequent and related to the underlying disease process. Elevated bilirubin and decreasing serum albumin levels are features of advanced disease and suggest poor prognosis. Risk scores, each including serum bilirubin, have been designed to predict prognosis in patients with PBC. The Mayo risk score (age, serum bilirubin and albumin, coagulation time, and the pres- ence of fluid retention and/​or use of diuretics) predicts outcome in advanced disease but does not identify high-​risk patients in early disease. More recently, simple assessments of the biochemical re- sponse to treatment have been shown to accurately identify high-​ risk patients who may have reduced survival or increased need for liver transplantation (Table 15.23.3.6). It is unclear which risk/​response criteria are optimal for use in clinical practice. (a) (b) (c) Fig. 15.23.3.3  The histology of PBC. (a) Interface hepatitis in PBC. A feature which can lead to suspicion of overlap with AIH, this is increasingly recognized as a manifestation of aggressive PBC. (b) Bile duct lesion in PBV. There is granulomatous destruction of a medium-​ sized bile duct radicle in which the epithelium appears hyperplastic. Epithelioid macrophages are surrounded by a chronic inflammatory cell infiltrate. Haematoxylin and eosin. (c) Stage 4 PBC: an established micronodular cirrhosis; the halo effect seen around the nodules is a characteristic feature of primary biliary cholangitis. Haematoxylin and eosin. Images (b) and (c) courtesy of A.D. Burt. Table 15.23.3.4  Scheuer score for staging PBC Stage Histological features 1 Florid duct lesions and portal inflammation without interface activity 2 Interface hepatitis, ductular proliferation, and periportal fibrosis 3 Bridging necrosis or bridging fibrosis 4 Cirrhosis

section 15  Gastroenterological disorders 3132 Symptomatic Cirrhotic PBC patients experience the typical problems of ad- vanced liver disease, including encephalopathy, ascites, and weight loss, albeit typically in a less marked form than in cirrhosis of other aetiologies. In addition, patients frequently experience character- istic symptoms that can occur at any point in the disease course, in particular pruritus and fatigue (Table 15.23.3.7). Up to 80% of patients experience pruritus at some point in the disease course. In its severest form it can be life-​altering, with scratching leading to deep excoriations. PBC pruritus shares characteristics with other forms of cholestatic pruritus, including typical scalp, hands, and feet involvement. Conventionally thought of as being caused by irritant, retained bile acids, recent studies have highlighted the role played by the autotoxin pathway in cholestatic itch, which can improve in end-​stage disease. Fatigue in PBC is complex and affects over 50% of patients (20% severely). Large cohort studies using a disease-​specific quality of life measure (the PBC-​40) have suggested that fatigue is the major con- tributor to poor life quality and can be exacerbated by social isola- tion. The aetiology of PBC fatigue remains unclear. Table 15.23.3.5  Autoantibody associations of PBC: the archetypal antimitochondrial antibodies are diagnostic for PBC but their presence or titre has no prognostic significance. Where present, the characteristic antinuclear antibodies (which need to be distinguished from the diffusely staining antinuclear antibody seen in autoimmune hepatitis) are both diagnostic and associated with worse prognosis. Detection can be either by immunofluorescence or enzyme-​ linked immunosorbent assay for specific antigens Cellular location Antigen Frequency (%) Clinical significance Mitochondrial Pyruvate dehydrogenase (PDH) E2 component PDH-​E1α PDH-​E1β 2-​Oxoglutarate dehydrogenase complex-​E2 Branch-​chain 2-​oxo acid dehydrogenase complex-​E2 95+ 40–​66 2–​10 39–​88 53–​89 Diagnosis Diagnosis Diagnosis Diagnosis Diagnosis Nuclear Gp210 Nucleoporin p62 Sp100 10–​47 32 20 Diagnosis and prognosis Diagnosis Diagnosis and prognosis Table 15.23.3.6  Criteria for assessing treatment response in PBC Criteria Treatment response criteria Sample size Results Barcelona criteria Response to treatment defined by ALP decrease >40% of baseline values or normal levels after 1 year of treatment 192 patients (181 women) 8.9% died or fulfilled criteria for liver transplantation Observed survival higher than that predicted by Mayo model and lower than control population (p <0.001) 61% responded to treatment Survival of responders was significantly higher than that predicted by Mayo model and similar to that estimated for control population (p = 0.15) Paris I criteria Treatment response defined as:

  1. ALP <3× ULN and
  2. AST <2× ULN and
  3. Bilirubin <1× ULN 292 patients 10-​year transplant-​free survival rate of 90% (95% CI, 81–​95%), compared to 51% (95% CI, 38–​64%) for those who did not (p <0.001) Paris II criteria Early-​stage PBC defined by normal bilirubin and albumin at baseline Response treatment criteria: ALP and AST ≤1.5× ULN with normal bilirubin level 165 patients Average follow-​up 7 years All adverse events observed in nonresponders (p <0.001) Toronto criteria ALP <1.67× ULN at 2 years of treatment
    with UDCA 69 patients with follow-​up liver biopsy performed approximately 10 years after initial histological diagnosis Histological progression in stage of fibrosis observed in paired liver biopsies was associated with absence of biochemical response at 2 years: ALP >1.67× ULN, p = 0.001; OR 12.14;
    95% CI 2.69–​54.74 when defined as an increase in one stage ALP >1.76× ULN, p = 0.03; OR 5.07; 95% CI 1.17–​21.95 when defined as an increase in two stages Ductopenia (>50% loss) predicted histological progression (p = 0.012) and biochemical response to UDCA (p = 0.002) Rotterdam criteria PBC classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal) Biochemical response defined by normalization of abnormal bilirubin and/​or albumin levels 375 patients Median follow-​up time 9.7 years Prognosis for early PBC comparable to Dutch population and better than predicted by Mayo risk score Survival of responders better than that of nonresponders (according to Paris and Rotterdam criteria (p <0.001)). Prognosis of early PBC comparable for responders and nonresponders Prognosis of responders significantly better in those with (moderately) advanced disease ALP, alkaline phosphatase; AST, aspartate aminotransferase; CI, confidence interval; OR, odds ratio; ULN, upper limit of normal.

15.23.3  Primary biliary cholangitis 3133 Associated conditions The strongest disease associations are with other autoimmune con- ditions, reflecting shared immunogenetic risk (Table 15.23.3.8). The presence of associated autoimmune disease should be con- sidered in fatigued patients as a number of these associated condi- tions are themselves potentially treatable causes of fatigue. Cholestatic disease associations include fat-​soluble vitamin deficiency and associated osteoporosis. The specific impact of osteoporosis in PBC has been overstated with the relatively high rates seen reflecting more disease demographics than specific risk. Increased falls risk is also seen in PBC due to an association with autonomic dysfunction contributing to the osteoporotic fracture risk. Atherosclerotic cardiac risk does not appear to be increased in PBC despite cholesterol elevation and an increased smoking rate identified in epidemiological studies. This reflects the fact that the cholesterol elevation is typically of high-​density lipoprotein/​ lipoprotein X. Anecdotal reports suggested an association with breast cancer but there is no increase in cancer risk in PBC in well-​designed studies, with the exception of hepatocellular carcinoma in ad- vanced disease. Differential diagnosis The specificity and sensitivity of the PBC-​associated autoantibodies usually prevents diagnostic uncertainty. Approximately 5% of PBC patients are negative for antimitochondrial antibodies, but most of these will be positive for the PBC-​specific nuclear antibodies and do not require liver biopsy for diagnosis. However, liver biopsy is required for the diagnosis of true autoantibody-​negative PBC. This ensures that the main differential diagnoses of small-​duct PSC, sarcoidosis, graft-​versus-​host disease (in the appropriate context), idiopathic ductopenia, and genetic cholestasis syndromes are not overlooked. Management Prognostic therapy The licensed first line therapy for PBC is the hydrophilic bile acid UDCA (13–​15 mg/​kg), which has been demonstrated in phase III trials subjected to meta-​analysis to reduce the risk of death or need for liver transplantation (Table 15.23.3.9). UDCA is well tolerated and recommended for use in all patients. Its mode of action remains unclear, although effects include choleresis (increase in volume of bile secretion), antiapoptotic actions, and a diluting effect, with UDCA displacing toxic hydrophobic bile acids in the bile pool. Patients who are under-​responsive to UDCA should be considered for second-​line treatment with obeticholic acid, which has shown benefit in terms of liver biochemistry in a phase III trial. This is a semisynthetic bile acid analogue and agonist for the farnesoid X re- ceptor, which suppresses bile acid production and alters excretion. It can be used in combination with UDCA when the response to UDCA has been inadequate, or as monotherapy in patients intolerant of UDCA. Bezafibrate, a Peroxisome Proliferator-Activated Receptor Alpha (PPARa) agonist, also significantly improves liver biochemistry in UDCA-under-responsive patients but, in contrast to Obeticholic Acid, is not currently licensed for this indication. There is no evidence to support the nonselective use of immuno- suppressive drugs. Stratified approaches to therapy utilizing second-​ line therapeutics in the subgroup of patients who show an inadequate response to UDCA are now being developed. There are also ongoing studies exploring the impact on bile acid biology and cholestasis of fibrates (acting through the PPARα pathway). Although the stratified approach has been explored for novel immunotherapeutic agents, re- sults have been disappointing. This may reflect the challenge of therapy sequencing (Fig. 15.23.3.1). Studies to identify molecular markers of stratification for enhanced risk in PBC are now being undertaken with the aim of allowing earlier targeted use of second-​line therapy. Symptomatic therapy Effective treatment is available for pruritus (Table 15.23.3.10). First-​ line treatment is with the bile acid sequestrant cholestyramine. Tolerability can be an issue and the drug can be made more accept- able by the addition of fruit juice. Second-​line agents include rifam- picin (a good evidence base with meta-​analysis confirming efficacy), which probably works through pregnane X receptor agonism, and oral opiate antagonists including naltrexone, which probably target opiate neurotransmission in the pruritus pathway. Other therapy approaches such as gabapentin, apical sodium-​dependent bile acid transporter inhibitors, and physical methods such as nasobiliary Table 15.23.3.7  Symptom associations of PBC: data are from the UK-​PBC cohort of over 2000 patients. Features of severe/​advanced disease are uncommon in the patient population as a whole. Systemic symptoms such as fatigue are common and, with the exception of the small subgroup of patients with very advanced disease, unrelated to disease severity. PBC-​40 is a validated PBC-​ specific quality of life tool widely used in clinical and trials practice Symptom Prevalence (%) Disease severity association? Fatigue (PBC-​40 domain) 55 No (other than end stage) Vasomotor autonomic (OGS) 40 No (other than end stage) Emotional (PBC-​40 domain) 45 No Social (PBC-​40 domain) 33 No Cognitive (PBC-​40 domain) 33 No (other than end stage) Sleep disturbance 30 No Pruritus (PBC-​40) 28 Cholestasis not severity Depression (HADS) 10 No Jaundice <5 Yes Ascites <5 Yes HADS, Hospital Anxiety and Depression Scale; OGS, Orthostatic Grading Scale. Table 15.23.3.8  Autoimmune associations of PBC Condition Reported prevalence (%) Sjögren’s syndrome 3.5–​47 Raynaud’s syndrome 12–​24 Autoimmune thyroid disease 9–​23 Scleroderma 8–​17 Rheumatoid arthritis 1.8–​17 Type 1 diabetes mellitus <1 Coeliac disease 3 Systemic lupus erythematosus 1.8–​3

section 15  Gastroenterological disorders 3134 drainage and albumin dialysis are experimental. Patients failing first-​ and second-​line therapy should be referred to specialist centres. There are no specific therapies for fatigue. The possibility of as- sociated conditions that are contributing should be considered. Pruritus, particularly if prominent at night, can be associated with significant fatigue and should be treated. Reducing autonomic dys- function, addressing daytime somnolence, and treating depression (all associated features) can also reduce the impact of fatigue. Coping strategies are critical, as are addressing issues such as social isolation. UDCA is not effective at treating PBC symptoms. Liver transplantation Liver transplantation is an effective treatment for end-​stage PBC, increasing life expectancy. In the United Kingdom, patients must Table 15.23.3.9  Therapy in primary biliary cirrhosis Agent All patients or stratified use Notes Licensed therapy Obeticholic acid (5–10 mg/day) Stratified Second-line bile acid therapy licensed for use in patients showing an inadequate response to UDCA or who are intolerant of UDCA UDCA (13–​15 mg/​kg) All Second-line bile acid therapy licensed for use in patients showing an inadequate response to UDCA or who are intolerant of UDCA Emerging therapy with an evidence base Fibrate (various) Stratified Addition in UDCA nonresponders improves biochemistry. Phase III trial evidence. Potential safety concerns and label precludes use in some jurisdictions Budesonide (6 mg/day) Stratified Some evidence that addition to UDCA improves efficacy. Trial base weak. Contraindicated in patients with perihepatic shunting Therapy with unclear utility Prednisolone ± azathioprine/​ mycophenolate mofetil Both Ineffective in broad-​based use with substantial side effects. Wide experience of use in patients deemed to have overlap but no structured evidence. Unclear role in new paradigms of second-​line therapy in UDCA nonresponders Ineffective therapies Ciclosporin 2.5–​4 mg/​kg/​day All Limited efficacy. Renal toxicity and hypertension May be value in exploring again in the setting of stratified therapeutics Methotrexate 15 mg/​week All Some benefit but outweighed by toxicity (in particular pulmonary). May be value in exploring again in the setting of stratified therapeutics Chlorambucil 0.5–​4 mg/​day All Potentially toxic Colchicine 0.6–​1.2 mg/​day All Minor benefits but insufficient evidence to support use d-​Penicillamine 250–​100 mg/​day All No convincing benefit. Excessive toxicity Azathioprine 1–​2 mg/​kg per day All Limited efficacy. May be value in exploring again in the setting of stratified therapeutics Mycophenolate mofetil 1 g/​day All Some efficacy in pilot study. May be value in exploring again in the setting of stratified therapeutics Table 15.23.3.10  Stepwise approach to the management of pruritus in PBC Agent Dose Additional notes

  1. Cholestyramine 4 g/​day to a maximum of 16 g/​day as tolerated Must be given 2–​4 h before or after UDCA (usually give UDCA at night) Pharmacy advice to avoid interactions with concomitant medications Suggest give at breakfast time (1 h before or after eating) if gallbladder in situ Mixing with orange squash and leaving in fridge overnight improves palatability
  2. Rifampicin 300–​600 mg/​day Risk of hepatotoxicity—​need regular monitoring of liver function tests (LFT)s; start at 150 mg daily then titrate upwards if LFT not elevated, repeating LFTs 2 weeks after dose increment
  3. Naltrexone 50 mg/​day (normal maximum dose, although higher doses have been used in the specialist clinic setting) Start at 12.5 mg/​day to avoid withdrawal symptoms
  4. Sertraline 100 mg/​day Titrate dose to symptoms and as tolerated Needs interaction at the primary/​secondary care interface—​change over if on alternative antidepressant. Note: in widespread use
  5. Physical approaches Albumin dialysis (and related approaches) Nasobiliary drainage Salvage procedures which should be considered in specialist centres only Limited trial evidence Significant morbidity and cost
  6. Transplantation Highly effective High cost Limited organ availability raises questions of prioritization for a symptomatic indication

15.23.4 Primary sclerosing cholangitis 3135

15.23.4 Primary sclerosing cholangitis 3135

15.23.4  Primary sclerosing cholangitis 3135 meet the minimal listing criteria (United Kingdom Model for End-​ Stage Liver Disease score of 49 or greater) based on a combination of markers of disease severity including bilirubin, INR, creatinine, and sodium. Pruritus that is unresponsive to all conventional therapies (a so-​called variant syndrome) is also an indication for transplant- ation in PBC, with very good outcomes. Fatigue is not an appro- priate sole indication for transplantation as there is no symptomatic improvement after transplantation. Rising serum bilirubin correlates very well with poor survival and patients with PBC should be considered for transplantation when their bilirubin exceeds 50 μmol/​litre. Once jaundice is present, clin- ical deterioration can be rapid, so early referral to a transplant centre is paramount. Recurrent PBC after transplantation occurs in approximately 20% of patients but rarely causes clinical problems. Liver biopsy is required for diagnosis given the frequency of raised alkaline phos- phatase following transplantation and the persistence of character- istic autoantibodies. The role of UDCA after transplantation is yet to be defined. Prognosis following transplantation is very good in PBC. Prognosis/​outcome Prognosis in PBC is variable. In most patients, typically presenting at older ages and showing a biochemical response to UDCA, the dis- ease has a low impact with a small risk of progression to cirrhosis and only limited symptom impacts. Clinical assessment tools are currently being developed to aid the identification of such low-​risk patients to facilitate their safe management in primary care. In up to 30% of patients, however, the disease is more aggressive and associated with a significant risk of progression. Risk is increased in patients presenting below the age of 50 and in those expressing PBC-​ specific ANA. Additional risk markers include inadequate biochem- ical response to UDCA, the presence of biochemical (low albumin and elevated bilirubin), haematological (low platelet count) features sug- gestive of pre-​existing cirrhosis, and the presence of interface hepatitis on liver biopsy. Failure to meet UDCA response criteria should be an indication for stratified second-​line therapeutic approaches, either as at present in the context of clinical trials, or in due course prescribed second-​line therapeutics. In the uncommon patients with true auto- immune hepatitis overlap, both conditions should be treated. The ductopenic form of the condition has a poor prognosis due to aggres- sive cholestasis and typically needs transplantation. Complications Patients with PBC are at risk of the same complications of cirrhosis as seen in disease of other aetiologies. Well-​compensated cirrhotic patients can be difficult to recognize, but clinicians should be vigilant for synthetic liver dysfunction (rising bilirubin and falling albumin), evidence of portal hypertension (thrombocytopenia, splenomegaly, and/​or varices), and radiological evidence of cirrhosis (including splenomegaly). Screening for hepatocellular carcinoma should be undertaken in cir- rhotic patients in accordance with international guidelines (European Association for the Study of the Liver/​European Organisation for Research and Treatment of Cancer and American Association for the Study of Liver Diseases): abdominal ultrasonography at 6-​monthly intervals. α-​Fetoprotein has recently been removed from international guidelines but is still widely used in clinical practice. All cirrhotic PBC patients require endoscopic screening for oesophagogastric varices. An initial screening endoscopy should be performed when the diagnosis of cirrhosis is made. If negative, pa- tients with compensated cirrhosis should have further endoscopy every 2 to 3 years. If small varices are present, endoscopy should be repeated in 1 to 2 years. Patients with decompensated cirrhosis should have yearly endoscopy. Hepatic encephalopathy is unusual in PBC but if present should be treated using standard approaches. Uncertainties/​controversies/​future developments There are two areas of significant challenge in PBC at present. The first is how to recognize in a timely fashion and treat using stratified therapeutic approaches the typically younger patients with high-​risk PBC, and then deliver those stratified approaches in normal prac- tice in a disease where physician awareness is often limited. The second is how to treat the pervasive fatigue which is the predom- inant symptom of the condition and which is currently untreatable. FURTHER READING Dyson JK, et al. (2015). Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastroenterol Hepatol, 12, 147–​58. Dyson JK, et al. (2015). Unmet clinical need in autoimmune liver dis- eases. J Hepatol, 62, 208–​18. European Association for the Study of the Liver (2009). EASL clin- ical practice guidelines: management of cholestatic liver diseases.
J Hepatol, 51, 237–​67. Gulamhusein AF, Hirschfield GM (2018). Best Pract Res Clin Gastroenterol, 34–35, 17–25. Harms MH, et  al. (2018). Improving prognosis in primary biliary cholangitis—Therapeutic options and strategy. Best Pract Res Clin Gastroenterol, 34–35, 85–94. Lindor KD, et al. (2009). Primary biliary cirrhosis. Hepatology, 50, 291–​308. Webb GJ, Siminovitch KA, Hirschfield GM (2015). The immunogenetics of primary biliary cirrhosis: a comprehensive review. J Autoimmun, 64, 42–​52. 15.23.4  Primary sclerosing cholangitis Kate D. Lynch and Roger W. Chapman ESSENTIALS Primary sclerosing cholangitis is a chronic cholestatic liver disease caused by diffuse inflammation and fibrosis that can involve the entire biliary tree. The cause is unknown, but it is presumed to be

section 15  Gastroenterological disorders 3136 immune mediated, and there is a close association with inflamma- tory bowel disease, particularly ulcerative colitis. The disorder tends to affect men (male:female, 2:1), some pre- senting with fatigue, intermittent jaundice, weight loss, right upper quadrant pain, and pruritus, but many are asymptomatic at diag- nosis, which is made incidentally when a persistently raised serum alkaline phosphatase is discovered, usually in the clinical setting of ulcerative colitis. Serum biochemical tests usually indicate cholestasis, but diag- nosis is based on three criteria: (1) generalized beading and sten- osis of the biliary system on cholangiography; (2)  absence of choledocholithiasis or a history of bile duct surgery; and (3) exclu- sion of bile duct cancer, usually by prolonged follow-​up. There is no curative medical treatment. Pruritus is initially man- aged with cholestyramine, with second-​line treatments including ri- fampicin and naltrexone. Orthotopic liver transplantation is the only option available for young patients with advanced liver disease. Introduction Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by diffuse inflammation and fibrosis that can in- volve the entire biliary tree. The progressive pathological process obliterates intrahepatic and extrahepatic bile ducts, ultimately leading to biliary cirrhosis, portal hypertension, and hepatic failure. Cholangiocarcinoma develops in approximately 10% of patients. PSC was initially considered to be a rare disease, but the advent of endoscopic retrograde cholangiopancreatography (ERCP) in the early 1970s established the diagnosis in a progressively larger number of patients. This led to the realization that PSC has a much wider clinical and pathological spectrum than was previously recognized. Serum biochemical tests usually indicate cholestasis, but diag- nosis is based on three criteria: (1) generalized beading and sten- osis of the biliary system on cholangiography; (2)  absence of choledocholithiasis or a history of bile duct surgery; and (3) exclu- sion of bile duct cancer, usually by prolonged follow-​up. Aetiopathogenesis The cause of PSC remains unknown. There is a very close associ- ation, however, between PSC and inflammatory bowel disease (IBD), particularly ulcerative colitis. Approximately two-​thirds of northern European patients with PSC have coexisting ulcerative colitis, and PSC is the most common form of chronic liver disease found in ulcerative colitis. In southern Europeans, about one-​half of patients with PSC will have ulcerative colitis. However, in Japan only 20% of patients will also have IBD. This difference in popula- tions may be real or may represent differences in case finding as not all the patients studied had had colonoscopy and colonic biopsies performed. Approximately 3 to 10% of patients with ulcerative col- itis will develop PSC, with greater risk associated with pancolitis as compared with only distal disease. Any proposed aetiopathogenic factor must explain the close association with IBD. Current evidence suggests that PSC is an immunologically mediated disease, probably triggered in genet- ically susceptible subjects by acquired toxic or infectious agents arising from the biome, which may then gain access through the ‘leaky’ diseased colon. Immunogenetic factors Case reports of families in whom members developed ulcerative col- itis and PSC led to the search for a human leucocyte antigen (HLA) association. A close link with the HLA A1-​B8-​DR3 haplotype has been found, in common with other organ-​specific autoimmune dis- eases such as autoimmune chronic active hepatitis. Independent associations with HLA DR2 and DR6 have also been documented. HLA A1-​B8-​DR3, DR2, and DR6 are equally distributed in patients with PSC, with or without ulcerative colitis. It has been suggested that DR3, DR6, and DR2 encode for amino acids in the HLA β-​chain that may enhance antigen presentation by the HLA molecule to the T-​cell receptor. Further evidence of an immune-​mediated basis for this condition has been provided by recent, large genome-​wide association studies and Immunochip studies. These have both confirmed the HLA asso- ciations found in initial candidate gene studies and also a further 22 non-​HLA risk loci have been identified, including FUT2 involved in regulating bacteria in the intestine and interleukin-​2 loci and other genes found in other autoimmune diseases. These emphasize the im- portance of the acquired and innate immune responses and inter- action with the biome in the pathogenesis of PSC. Cellular immune abnormalities Elevated circulating immune complexes associated with activation of complement via the classic pathway have been found in the serum and bile of patients with PSC. In common with other autoimmune diseases there are reduced levels of T-​regulatory cells circulating in the serum of these patients, leading to an increased ratio of T-​helper to T-​regulatory cells. Infiltration of portal tracts by increased num- bers of mononuclear cells is seen in liver biopsies from patients with PSC, and most of these cells are activated T lymphocytes. Current evidence suggests that PSC is an immunologically me- diated disease, perhaps triggered in genetically susceptible subjects by acquired toxic or infectious agents which are presented through antigen-​presenting cells to activated T lymphocytes. Unlike normal biliary cells, the biliary epithelial cells in PSC express HLA class II molecules and also intercellular adhesion molecules (ICAM) such as ICAM-​1. It has been suggested that the biliary disease is mediated by long-​lived memory T cells derived from the inflamed gut which enter the enterohepatic circulation, hence gaining access to the liver. Aberrant expression of gut homing chemokines (such as CCL25) and adhesion molecules (such as MAdCAM-​1) on biliary cells cause recruitment of these gut-​derived T cells to the liver, which in turn leads to biliary inflammation and damage. However, the reason (‘trigger factor’) for the aberrant bile duct expression is unknown. Alternative hypothesis—​exposure to
bacterial components An alternative hypothesis has been proposed in which the ini- tial event is the reaction of an immunologically susceptible host to bacterial cell wall products, resulting in hepatic macrophages producing tumour necrosis factor-​α and endotoxin. The ex- posure to bacterial components and increased gut permeability

15.23.4  Primary sclerosing cholangitis 3137 would be increased by the presence of IBD, but could also, in theory, occur during episodes of gut infection. The resulting in- crease in peribiliary cytokine and chemokine secretion would attract activated neutrophils, monocyte/​macrophages, T cells, and fibroblasts. The deposition of concentric fibrosis could result in atrophy of the biliary epithelial cells secondary to ischaemia. The resulting bile duct loss would lead to progressive cholestasis, fibrosis, and secondary biliary cirrhosis. This hypothesis does not, however, explain the relative scarcity of patients with Crohn’s colitis and PSC, and does not take into account the strong cir- cumstantial evidence of immune mediation and autoimmunity, previously described. Epidemiology The incidence and prevalence of PSC varies depending on geo- graphic location. For unknown reasons, the prevalence appears to be higher in Europe the further north one lives, with some of the highest figures reported from cohorts in Scandinavia. In a Swedish study, the prevalence of ulcerative colitis was 171 per 100 000 population and that of PSC 6.3 per 100 000 population. A recent population study from New Zealand demonstrated a preva- lence of PSC of 11.7 per 100 000, while studies from North America and South Wales have demonstrated a prevalence of 20 per 100 000 population in men. The incidence of PSC appears to be increasing, though whether this represents a true increase in incidence or a higher awareness/​ detection rate is unclear. There is a clear male predominance, with a male:female ratio of 2:1. Most patients present between the ages of 25 and 40 years, al- though PSC may be diagnosed at any age. Indeed, it is recognized as an important cause of chronic liver disease in children. Clinical features The clinical presentation is variable:  some patients may present with fatigue, intermittent jaundice, weight loss, right upper quad- rant pain, and pruritus. Attacks of acute cholangitis are surprisingly rare and usually follow instrumental biliary intervention, such as ERCP. Physical examination is abnormal in approximately one-​half of symptomatic patients; the most common findings are jaundice and hepatosplenomegaly. Most patients with PSC are asymptomatic at diagnosis, which is made incidentally when a persistently raised serum alkaline phos- phatase is discovered, usually in the clinical setting of ulcerative colitis. Later, as the disease progresses, portal hypertension is a prom- inent feature of liver decompensation, with the presence of ascites and oesophageal varices usually preceding the onset of liver syn- thetic dysfunction (such as hypoalbuminaemia and coagulopathy). Hyperbilirubinaemia/​jaundice occurs with progression of liver disease, due to both cholestasis from strictures and liver synthetic dysfunction. Intermittent ascending cholangitis and development of cancer are features which can occur (see ‘Malignancy’), and the sudden deterioration with jaundice, itching, and worsening liver en- zymes should prompt investigation for complications. Differential diagnosis The term ‘secondary sclerosing cholangitis’ is used to describe the typical bile duct changes when a clear predisposing factor to duct fibrosis, such as previous bile duct surgery, can be identified, and these must be considered and excluded before a diagnosis of PSC is made. The causes of secondary sclerosing cholangitis are shown in Box 15.23.4.1. IgG4-​related sclerosing cholangitis An important differential diagnosis to recognize and rule out is IgG4-​related sclerosing cholangitis (IgG4-​SC), which tends to in- duce a longer stenosis on cholangiography in contrast to the short stenosis of patients with PSC. At the time of diagnosis, it is therefore important to test for the subtypes of IgG, and in particular IgG4. IgG4-​SC is a disorder characterized often (but not always) by raised serum IgG4 levels, involvement of other organs with IgG4-​related disease (such as type 1 autoimmune pancreatitis), and characteristic findings on liver biopsy (fibroinflammatory involvement is observed mainly in the stroma of the bile duct wall, whereas the bile duct epi- thelium is intact). Raised serum IgG4 levels (>1.4 g/​litre) are found in 7 to 22% of patients with PSC, as opposed to only 0 to 1% with other liver diseases/​healthy controls. By itself, however, a raised serum IgG4 level is not sufficient to make the diagnosis of IgG4-​SC. A recent study found that a serum IgG4 level of greater than four times the upper limit of normal had an excellent positive predictive value for differentiating IgG4-​SC from PSC, but this only occurs in 42% of patients with IgG4-​SC. Additionally, in the setting of a margin- ally raised IgG4 level (one to two times the upper limit of normal), an IgG4:IgG1 ratio of greater than 0.24 supports a diagnosis of IgG4-​SC. It is important to diagnose IgG4-​SC where present, as this has an excellent response to systemic corticosteroid therapy, un- like PSC. Interestingly, if the criteria are not met for a diagnosis of IgG4-​SC, elevated serum IgG4 levels (>1.4 g/​litre) confers a poorer prognosis in patients with PSC, the explanation for which is unknown. Box 15.23.4.1  Causes of secondary sclerosing cholangitis • Previous bile duct surgery with stricturing and cholangitis • Bile duct stones causing cholangitis • Intrahepatic infusion of 5-​fluorodeoxyuridine • Formalin insertion into hepatic hydatid cysts • Alcohol insertion into hepatic tumours • AIDS/​immunodeficiency states—​probably infective (chronic cyto- megalovirus or cryptosporidial infection) • IgG4-​associated cholangitis • Cholangiocarcinoma • Diffuse intrahepatic metastasis • Eosinophilic cholangitis • Histiocytosis C • Mast cell cholangiopathy • Portal hypertensive biliopathy • Recurrent pancreatitis Adapted from American Association for Study of the Liver (AASLD) guidelines.

section 15  Gastroenterological disorders 3138 Clinical investigation A summary of investigations performed in the work up of PSC is shown in Box 15.23.4.2. Blood tests Serum biochemical tests usually indicate cholestasis, but PSC may cause no abnormalities of serum biochemistry. The serum alkaline phosphatase is often raised to more than three times normal, and mild elevations in liver transaminases are seen in most patients. Serum bilirubin is not usually elevated until later stages of the dis- ease. Levels of bilirubin and alkaline phosphatase may fluctuate widely in an individual patient during the course of the disease. Hypoalbuminaemia is unusual until the disease becomes advanced. Like primary biliary cirrhosis, a disease with which it shares many features, symptomatic PSC is characterized by hyper­ gammaglobulinaemia; high concentrations of serum IgM are found in patients with advanced disease, and high levels of IgG are found in all children with PSC. Smooth muscle antibody and antinuclear factor are also found in approximately one-​third of patients with PSC, usually in low titres. Serum mitochondrial antibodies are absent. A cytoplasmic antineutrophil antibody is found in the serum of 80% of patients with PSC and approximately 30 to 40% of patients with ulcerative colitis. However, the antibody is not specific for PSC and is found in 50% of patients with autoimmune chronic active hepatitis (type 1). The antigen(s) are distinct from those found in granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) and microscopic polyangiitis, which have been shown to be proteinase 3 and myeloperoxidase. Current evidence suggests that the antigen may be a nuclear envelope protein. The pathogenetic significance of the circulating antibody is not clear, and it is not clinically useful as a diagnostic test. Titres of the antibody do not change after hepatic transplantation. Radiological features Magnetic resonance cholangiopancreatography (MRCP) provides a noninvasive method of imaging the biliary tree, and has become established as the standard technique for the diagnosis of PSC as there is a significant risk of cholangitis or acute pancreatitis after diagnostic ERCP. MRCP has a high sensitivity (86%) and very high specificity (94%) for diagnosing PSC. ERCP is reserved for the few patients in whom there is diagnostic uncertainly after MRCP. The cholangiographic appearances on MRCP and/​or ERCP are usually diagnostic and consist of multiple, irregular stricturing and dilatation (beading of the intrahepatic and extrahepatic bil- iary ducts) (Figs. 15.23.4.1 and 15.23.4.2). In some patients, the in- volvement is localized to the intrahepatic system, and rarely only the extrahepatic bile ducts may be involved. Small diverticula are found along the common bile duct in about 20% of patients and are pathognomonic. Transabdominal ultrasonography should also be informed in the initial investigations to rule out choledocholithiasis. Box 15.23.4.2  Investigations to perform at diagnosis of PSC • Liver enzymes—​γ-​glutamyl transferase, alkaline phosphatase, alkaline transaminase • Bilirubin • Complete blood count • IgG and IgM levels • Antineutrophil cytoplasmic antibody • Antinuclear antibody • Smooth muscle antibody • IgG1 and IgG4 levels • Ultrasonography • MRCP (with or without ERCP) • Liver biopsya a Liver biopsy is only indicated when MRCP/​ERCP is normal and/​or suspicion of overlap syndrome. Fig. 15.23.4.1  Endoscopic retrograde ERCP demonstrating diffuse stricturing and dilatation of the biliary tree. Fig. 15.23.4.2  MRCP with diffuse intrahepatic strictures indicating sclerosing cholangitis.

15.23.4  Primary sclerosing cholangitis 3139 Liver biopsy Liver biopsy is reserved for cases where there is a question of overlap with autoimmune hepatitis or the MRCP is normal (in which case the variant small duct PSC is considered—​see ‘Prognosis’). It is im- portant to note that PSC, pathologically, is a patchy, focal disease, and there is a risk that sampling at percutaneous liver biopsy may miss the diagnosis. The histological appearances on liver biopsy are only diagnostic for PSC in one-​third of patients, although some form of biliary disease can usually be identified. The characteristic early features of PSC are periductular ‘onion skin’ fibrosis and inflammation, portal oedema, and bile duct- ular proliferation resulting in the expansion of the portal tracts (Fig. 15.23.4.3). Later, fibrosis spreads into the liver parenchyma to form fibrous septa, leading inevitably to biliary cirrhosis. As in primary biliary cirrhosis, with disease progression an oblit- erative cholangitis occurs, leading to complete replacement of the intralobular bile ducts by connective tissue—​the so-​called vanishing bile duct syndrome. In addition, piecemeal necrosis, copper-​binding protein, cholestasis, and occasional portal phle- bitis may be present. Association with other diseases Many diseases have been associated with PSC (Box 15.23.4.3). The most important association is with IBD, occurring in approxi- mately 70% of patients. 70% of the IBD in PSC is due to ulcerative colitis, 15% due to Crohn’s disease, and 5% due to IBD-unspecified. Regardless of subtype, the IBD is usually a pancolitis, often with rectal sparing and mild involvement of the ileum, and is usually fairly mild to quiescent in nature with minimal to no symptoms. Given the fairly specific IBD phenotype in PSC, it is often postu- lated that the colitis associated with PSC may represent a distinct form of colitis, namely PSC/IBD with a distinct genetic back- ground. This hypothesis has been strengthened by recent studies which have shown distinct genetic differences between ulcerative colitis and Crohn’s disease and PSC/IBD. Although the symptoms of ulcerative colitis usually develop before those of PSC, the onset of the latter may precede the symptoms of colitis by some years. The outcome of PSC is completely unrelated to the activity, se- verity, or clinical course of the colitis, and colectomy has no effect on the progression of the cholangitis. Management There is no curative medical treatment for PSC. This is indicated by the plethora of medical, endoscopic, and surgical approaches that have been advocated. Treatment of cholestasis, complications, and specific disease processes may all be required in the management of an individual patient. Symptomatic measures Management of cholestasis A few PSC patients may be troubled by pruritus. This is best man- aged initially by the bile acid sequestrant, cholestyramine, admin- istered orally. The dose should be increased until relief is obtained. Second-​line treatments include rifampicin and the opioid antag- onist naltrexone. Replacement of fat-​soluble vitamins is necessary when patients become jaundiced. Metabolic bone disease (usually osteoporosis) is a common complication of advanced PSC. Calcium supple- mentation with vitamin D3 should be given prophylactically in jaundiced patients, and bisphosphonates considered in those with osteoporosis. Management of complications Broad-​spectrum antibiotics such as ciprofloxacin should be given for acute attacks of cholangitis. If cholangiography shows a well-​ defined obstruction to the main extrahepatic bile ducts, then mechanical relief must be considered. Balloon dilatation of the strictures performed at ERCP may prove useful in symptomatic patients with well-​defined localized particularly ‘main duct’ stric- tures, and can lead to a striking improvement in symptoms and serum biochemistry. In a few patients, the best approach is to intro- duce a temporary prosthesis (stent) through the obstruction. This may be placed nonoperatively by the percutaneous transhepatic route or at ERCP. Another common complication is the development of small bil- iary stones (brown pigment) and biliary sludge, which can lead to a rapid clinical or biochemical deterioration. In these patients, Fig. 15.23.4.3  The hepatic histological changes of early PSC showing a concentric (onion skin) fibrosis around the bile ducts. Long arrow, bile duct; short arrow, hepatic artery. Box 15.23.4.3  Diseases associated with primary sclerosing cholangitis • Ulcerative colitis • Crohn’s colitis • Chronic pancreatitis • Retroperitoneal fibrosis • Riedel’s struma • Autoimmune pancreatitis • Retro-​orbital tumours • Sjögren’s syndrome • Angioimmunoblastic lymphadenopathy • Histiocytosis X • Autoimmune haemolytic anaemia

section 15  Gastroenterological disorders 3140 endoscopic sphincterotomy with extraction of the biliary debris can be beneficial. Specific treatment Medical The medical treatment of PSC has included trials of corticosteroids, immunosuppressive drugs, synthetic bile acids, and antibiotics, either alone or in combination. The results have been universally disappointing, although assessment of treatment of this uncommon disease is difficult because the clinical course fluctuates, survival is variable, and some patients may remain asymptomatic for long periods of time. In general, corticosteroids are not indicated in PSC because clinical trials have not demonstrated efficacy. Moreover, there is evidence that, even in male patients, metabolic bone disease may be accelerated by corticosteroids. They should be reserved for the few patients who also exhibit features of autoimmune hepatitis (PSC/​autoimmune overlap) confirmed on liver biopsy, or in those patients with IgG4-​associated cholangitis. Ursodeoxycholic acid (UDCA) is a nonhepatotoxic hydro- philic bile acid which has been used widely for the treatment of cholestasis—​it reduces levels of cholestatic liver enzymes. Doses of 15 to 20 mg/​kg daily have been shown to improve liver blood tests and have shown a trend towards increased survival, though not to statistical significance. Unfortunately, in a large random- ized controlled trial, while improvements were seen biochemically, high-​dose UDCA (28–​30 mg/​kg) was shown to be associated with a worse clinical outcome (composite endpoint of death, liver trans- plantation, cirrhosis, oesophageal varices, or cholangiocarcinoma) compared with those on placebo. There is limited data which sug- gest that UDCA may lower the prevalence of colonic dysplasia and possibly cholangiocarcinoma, although this has not been shown in all studies. Current international guidelines differ in their recommenda- tions as to the use of ursodeoxycholic acid in PSC. While high-​dose UDCA should never be prescribed, lower doses of 15 to 20 mg/​kg appear to be safe in clinical trials, and are associated with a greater proportion of patients having normalization of alkaline phosphatase compared with placebo. A firm recommendation regarding UDCA use in PSC cannot be made, and practice varies among different centres and countries. Transplantation Liver transplantation is the only management option available in pa- tients with end-​stage PSC and decompensated liver disease, and PSC is in the top five most common indications for this procedure in the United Kingdom and United States of America. Recent results have been very encouraging, with 5-​year survival rates of 75 to 90% being obtained in most centres, comparing favourably with those for other forms of chronic liver disease. PSC recurs in the transplanted liver in 30% of patients at 5 years after transplantation, and in a few patients recurrence has led to problems with liver decompensation, requiring retransplantation. It has been shown recently that graft survival is optimized if patients have previously had a colectomy with end ileostomy. Furthermore, in patients with a colectomy and ileal pouch anal anastamosis, graft survival was reduced, indicating a potential role for the microbiota in the setting of graft survival in PSC. Proven cholangiocarcinoma is a contradiction to transplantation because the tumour recurs rapidly after transplantation with im- munosuppression, although there are a few centres in the United States of America and Europe who transplant highly selected cases after neoadjuvant chemotherapy with reasonable outcomes. Prognosis and complications The course of PSC is highly variable and unpredictable. The me- dian survival from presentation to death or liver transplantation in symptomatic patients was previously quoted as approximately 10 to 12 years; however, these data were from transplant-​centre cohorts of patients with PSC and subsequent epidemiological observational studies incorporating non-liver transplant centres suggest a longer median survival of 22 years. In the past, most patients died of hepatic failure following deepening cholestatic jaundice, but with the advent of successful liver transplantation the majority of patients die of ma- lignancy, either hepatobiliary or colonic. Large epidemiological studies, predominantly retrospective, have identified various features which convey a poorer clinical outcome. These include a persistently raised alkaline phosphatase above 1.5 times the upper limit of normal; raised bilirubin; the presence of a dominant stricture; older age at diagnosis; and the presence of ulcerative colitis (as opposed to Crohn’s disease). Gender and the presence or not of IBD have not been associated with transplant- free survival. Several prognostic risk scores encompassing some of these fac- tors have been put forward, including the Mayo Risk Score, the Amsterdam-Oxford Model for PSC, and the UK-PSC Risk Score. Whilst these are mainly used in the clinical trial setting, they may be useful in risk stratifying patients in clinical practice, and identifying patients who should be put forward for clinical trials of new thera- peutic agents in PSC. Malignancy About 7 to 13% of patients with long-​standing PSC develop cholangiocarcinoma, which usually follows a very aggressive course, with mean survival after the diagnosis of cholangiocarcinoma of only 9 months. Unfortunately, there are no factors that will predict which patients will develop this cancer. Tumour markers such as carcinoembryonic antigen and carbohydrate antigen 19-​9 have not proven to be useful as potential early serum markers of the develop- ment of bile duct cancer in PSC. Annual MRCP examinations have been advocated as surveillance in PSC, but clinical evidence of ef- fectiveness is lacking. Patients are also at increased risk of developing gallbladder cancer and hepatocellular carcinoma, and annual transabdominal ultra- sound surveillance is recommended, with cholecystectomy should gallbladder polyps be present, particularly those greater than 0.8 cm in size. Patients with PSC and IBD are at greater risk of developing colo- rectal dysplasia and colonic cancer than those with ulcerative colitis alone. In a Swedish study, the absolute accumulative risk of developing colorectal dysplasia/​cancer in the PSC/​ulcerative colitis group was 9%, 31%, and 50%, respectively, after 10, 20, and 25 years of disease duration. In the group with ulcerative colitis alone, the corresponding

15.23.4  Primary sclerosing cholangitis 3141 risk was 2%, 5%, and 10%, respectively. Several studies suggest the in- creased risk of colorectal cancer is only in those PSC patients with ul- cerative colitis, and not those with Crohn’s diease. Colorectal cancer in patients with PSC predominates in the right colon. Liver transplant- ation does not reduce the risk of colorectal neoplasia and may increase it because of the need for long-​term immunosuppression. Guidelines recommend that patients with PSC and concomitant colitis (regard- less of subtype) should have annual surveillance colonoscopies for early detection and prevention of colorectal dysplasia and carcinoma. Special circumstances—​small duct PSC A variant of the disease called ‘small duct PSC’ is applied to the ap- proximately 10% of patients with characteristic clinical and histo- logical findings but who have normal cholangiography. These patients usually present with abnormal cholestatic biochemical tests in the context of IBD. The absence of macroscopic cholangiographic abnor- malities necessitates liver biopsy for the diagnosis of small duct PSC. Their prognosis is very good, with no reports of malignancy in this group, and progression to advanced liver disease is rare. Median survival is 29.5 years compared to 10 to 22 years for classical PSC. However, 20 to 25% of patients with small duct PSC may progress to classical PSC over time, which then confers the usual prognosis out- lined earlier. Patients with small duct PSC should be monitored for any deterioration (such as a sudden rise in alkaline phosphatase or bilirubin concentration, or new symptoms), which should prompt repeat imaging of bile ducts. Areas of uncertainty, controversy and future developments There are a range of new medical therapies being trialled in PSC with some preliminary beneficial results in Phase II trials. These include the novel bile acid nor-UDCA as well as the FXR agonist, obeticholic acid. Further phase III trials are awaited Anti-fibrotic therapies are in development for PSC, although the recent trial of an anti-lysyl oxidase like 2 agent failed to reach its pri- mary endpoint. There is some evidence, particularly in children, that antibiotics may be beneficial in PSC, and trials are ongoing, mostly with vancomycin. Distinct intestinal microbiome signatures have been identified in PSC compared with controls, though with differing findings among several studies. This has led to the hypothesis that faecal micro- biota transplantation would be beneficial in PSC, and a case report demonstrating this has been published. Prospective clinical trials are awaited. Whilst not currently in routine clinical practice, there is increasing evidence for the use of noninvasive markers of fibrosis as a predictor of clinical outcome. With regards to transient elastography (TE), a cut-off value of >9.9kPa has been associated with worse survival in PSC, and there is a current ongoing prospective clinical trial further evaluating TE as a meaningful prognostic tool. Meanwhile, there is also evidence for the serum biomarker panel, European Liver Fibrosis (ELF) test, for predicting clinical outcomes in PSC. Further validation trials are awaited. However, there is some evidence that if a patient with PSC has normalization of their serum alkaline phosphatase, or reduction to less than 1.5 times the upper limit of normal, they will have a better outcome than if it remains persistently elevated, as measured by clinical endpoints of development of cholangiocarcinoma, liver transplantation, and/​or death. There is an urgent need for surrogate markers in PSC which will accurately reflect long-​term prognosis in assessing clinical trials of therapy. FURTHER READING Al Mamari S, et  al. (2013). Improvement of serum alkaline phos- phatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholan- gitis. J Hepatol, 58, 329–​34. Björnsson E, et al. (2002). Patients with small duct primary scler- osing cholangitis have a favourable long term prognosis. Gut, 51, 731–​5. Chapman RW, Williamson KD (2017). Are dominant strictures in pri- mary sclerosing cholangitis a risk factor for cholangiocarcinoma? Current Hepatology Reports, 16(2), 124–9. Dyson JK, et al. (2018). Primary sclerosing cholangitis. The Lancet, 391(10139), 2547–59. doi:10.1016/S0140-6736(18)30300-3. European Association for the Study of the Liver (2009). EASL clin- ical practice guidelines: management of cholestatic liver diseases. J Hepatol, 51, 237–​67. Goode EC, et al. (2019). Factors associated with outcomes of patients with primary sclerosing cholangitis and development and validation of a risk scoring system. Hepatology, doi:10.1002/hep.30479. Hirschfield GM, et al. (2013). Primary sclerosing cholangitis. Lancet, 382, 1587–​99. Sedki M, Levy C (2018). Update in the Care and Management of Patients with Primary Sclerosing Cholangitis. Current gastroenter- ology reports, 20(7), 29. doi:10.1007/s11894-018-0635-8. Tabibian JH, O’Hara SP, Lindor KD (2014). Primary sclerosing chol- angitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol, 49, 901–​8. de Vries EM, et al. (2018). A novel prognostic model for transplant- free survival in primary sclerosing cholangitis. Gut, 67(10), 1864–9. doi:10.1136/gutjnl-2016-313681. Weismüller TJ, et al. (2017). Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology, 152(8), 1975–84.e8. doi:10.1053/j.gas tro.2017.02.038.

15.24 Other liver diseases 3142

15.24 Other liver diseases 3142

15.24.1 Alcoholic liver disease 3142

15.24.1 Alcoholic liver disease 3142

CONTENTS 15.24.1 Alcoholic liver disease  3142 Ewan Forrest 15.24.2 Nonalcoholic fatty liver disease  3147 Quentin M. Anstee and Christopher P. Day 15.24.3 Drug-​induced liver disease  3155 Guruprasad P. Aithal 15.24.4 Vascular disorders of the liver  3166 Alexander Gimson 15.24.5 The liver in systemic disease  3169 James Neuberger 15.24.6 Primary and secondary liver tumours  3178 Graeme J.M. Alexander, David J. Lomas, William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison 15.24.7 Liver and biliary diseases in infancy and childhood  3191 Richard J. Thompson 15.24.1  Alcoholic liver disease Ewan Forrest ESSENTIALS The incidence of alcoholic liver disease (ALD) follows the trend of per capita alcohol consumption, with hepatic injury which extends from fatty liver to alcoholic hepatitis and cirrhosis. It is unclear how alcohol causes liver disease, but postulated mechanisms include (1) oxidative stress and acetaldehyde generated by the metabolism of ethanol, and (2) innate and adaptive immune responses. Factors determining the susceptibility to liver disease in heavy drinkers are believed to include a variety of host and environmental factors, with genetic factors increasingly recognized. Clinical manifestations are extremely variable, and some patients remain relatively well while others suffer the effects of severe hepatic failure. Although patients can come to light with a life-​threatening complication, most often they develop symptoms which are not immediately related to the liver, such as nonspecific digestive symptoms or psychiatric complaints. The key to the early recog- nition of alcohol-​related disease is having a high index of suspi- cion, with confirmation by (1) direct questioning for alcohol history and alcohol-​related symptoms; (2) clinical examination for signs of chronic liver disease; (3) supportive investigations, including aspar- tate aminotransferase, which is less than 500 IU/​litre and greater than the alanine aminotransferase level; and (4) liver biopsy, which may be required in some cases of diagnostic uncertainty and to confirm the stage of the disease, revealing alcoholic fatty liver, alco- holic hepatitis, or cirrhosis. Management is governed by the stage and severity of the liver disease, but always includes abstinence and adequate nutritional support. In selected patients with severe acute alcoholic hepatitis, corticosteroids can reduce short-​term mortality. Transplantation re- mains the only effective treatment for advanced alcoholic cirrhosis, although this remains controversial, mainly because of concerns about post-​transplant recidivism. Introduction Alcohol consumption has been a part of human society since an- cient times. The archaeological record has found evidence of the production of fermented drinks from 7000 bce. In ancient Greece, alcohol consumption and intoxication were integral parts of male-​ dominated evening symposia. The Greeks believed in the medicinal properties of alcohol but were also aware of its association with liver damage. In the United Kingdom, the distillation of spirits and subsequent drunkenness became an increasing problem in the 18th century, leading to government measures to curb consumption. More recent measures taken in the 20th century such as limitation of drinking hours during the First World War and Prohibition in the United States of America (1919–​1933) may not have been popular but were associated with a reduction in deaths from cirrhosis. Epidemiology The World Health Organization reports that the average annual al- cohol per capita consumption worldwide is 6.2 litres of pure alcohol. In Europe, this increases to 10.9 litres, which equates to 16.8 litres 15.24 Other liver diseases

15.24.1  Alcoholic liver disease 3143 per drinker of whom 22.9% engage in heavy episodic drinking (>60 g alcohol on a single occasion at least monthly). Worldwide, 5.9% of all deaths every year result from harmful use of alcohol. Overall, 5.1% of the global burden of disease and injury is attribut- able to alcohol, as measured in disability-​adjusted life years. There is a strong correlation between the death rate from cirrhosis and the per capita alcohol consumption. Increases in alcohol-​related deaths are closely related to the affordability and availability of al- cohol, with the fall in alcohol price relative to income paralleling the increase in mortality. This association is the rationale behind the campaign for control of alcohol pricing which is supported by the World Health Organization. In the United Kingdom, the death rate from liver disease has been increasing in contrast to many other Western European coun- tries. The major cause of these liver deaths is alcoholic liver disease (ALD), and ALD is the commonest cause of alcohol related death. The peak age age-​range for death from ALD is 50 to 59 years old, and in England one in eight hospital admissions for ALD resulted in death in 2012. Risk factors While it is clear that the risk of ALD is closely related to the amount of alcohol consumed, the exact threshold for damage is unclear. Drinking more than 60 g of alcohol per day is associated with a 60% risk of alcoholic liver injury, and the highest risk of cirrhosis occurs at more than 120 g per day. However, even drinking more than 25 g per day is associated with an overall increased risk of cirrhosis (in the United Kingdom, 1 unit of alcohol equals 8 g alcohol). The pat- tern of drinking is also relevant, with daily drinking and drinking outside mealtimes identified as risk factors for cirrhosis. In addition to the direct role of alcohol, individual factors also play a part in ALD development (Box 15.24.1.1). Sex is relevant, with women being more susceptible to the hepatotoxic effects of al- cohol and developing ALD more quickly when compared to men drinking equal amounts of alcohol. This may be due to differences in the metabolism and volume of distribution of alcohol between men and women, but may also reflect the effect of oestrogens on oxidative stress. Genetic susceptibility also influences the development of ALD, with monozygotic twins having a higher concordance of alcohol-​ related cirrhosis than dizygotic twins. Extensive genetic studies have identified some polymorphisms related to alcohol metabolism and cytokine production which appear to be associated with increased risk of ALD. A variation in the prevalence of ALD between different racial groups is also noted, although it is unclear whether this is largely environmental or genetic. Obesity is a major risk factor for the development of cirrhosis among those drinking excessively. This is probably due the overlapping pathophysiologies of both ALD and nonalcoholic fatty liver disease, with both disease processes fuelled by oxidative stress. Obesity also creates a proinflammatory and profibrogenic environment. The coexistence of chronic hepatitis C infection and alcohol misuse can rapidly accelerate liver damage and is estimated to in- crease the risk of cirrhosis by 30-​fold. Pathology and pathophysiology The term ALD encompasses a spectrum of histological features and conditions. The main histological groupings of ALD are alco- holic steatosis, with or without significant fibrosis (in up to 100% of drinkers with a daily alcohol intake of greater than 60 g/​day), al- coholic steatohepatitis (in 10–​35%), and established cirrhosis (in approximately 15%) (Fig. 15.24.1.1). The natural history of ALD appears to progress from a normal liver through steatosis to fibrosis and cirrhosis with some, but not all, patients also passing through a phase of clinical alcoholic hepatitis. The steatosis is macrovesicular and predominantly in perivenular hepatocytes. Although sometimes perceived as a benign manifest- ation of ALD, the presence of steatosis alone is a risk factor for sub- sequent progressive fibrosis and cirrhosis. The features of alcoholic hepatitis are a perivenular steatohepatitis, often with Mallory bodies, hepatocyte ballooning, megamitochondria, canalicular cholestasis, and a neutrophil infiltrate. The presence of an alcoholic steatohepatitis again accelerates the rate of fibrosis and risk of cirrhosis. The presence of bilirubinostasis has been recognized as an important feature of alcoholic hepatitis which may have prognostic significance. With persistent injury, progressive perivenular and perisinusoidal fibrosis develops, leading to bridging fibrosis. Over time, the fibrosis progresses with the occurrence of regenerative nodules resulting in development of a predominantly micronodular cirrhosis. Alcohol metabolism and the pathophysiology of ALD The predominant mechanism of alcohol metabolism in normal circumstances is its oxidation to acetaldehyde and then to acetate, Box 15.24.1.1  Risk factors for alcoholic liver disease in addition to amount of alcohol ingested • Female sex • Chronic hepatitis C • Obesity • Genetic polymorphisms — Alcohol dehydrogenase and acetaldehyde dehydrogenase — TNF-​α and IL-​10 promoters — Patatin-​like phospholipase domain-​containing protein 3 (PNPLA3) • Daily drinking/​drinking outside mealtimes Cirrhosis (10–15%) Normal Liver (0–30%) Steatosis (60–100%) Steatohepatitis (10–35%) Fig. 15.24.1.1  Pathological patterns of alcoholic liver disease in harmful drinkers.

section 15  Gastroenterological disorders 3144 catalysed by their respective dehydrogenases (Fig. 15.24.1.2). This leads to the production of the reduced form of nicotinamide ad- enine dinucleotide (NADH). With excessive alcohol exposure, two other oxidative pathways become increasingly important: the microsomal ethanol oxidizing system involving the alcohol-​ inducible enzyme cytochrome P450 2E1, and the peroxisomal en- zyme catalase. These alternative pathways lead to the production of reactive oxygen species. Nonoxidative metabolism of alcohol is relatively minor but does account for the production of fatty acid ethyl esters. Hepatic steatosis develops largely on account of the altered NADH/​NAD ratio which promotes triglyceride synthesis and in- hibits β-​oxidation of fatty acids. Export of triglycerides form the liver is reduced due to alcohol-​mediated downregulation of transfer proteins. Steatosis is also promoted by nonoxidative fatty acid esterification. The production of reactive oxygen species by oxidative metab- olism leads to oxidative stress and lipid peroxidation (Fig. 15.24.1.3). This is augmented by further reactive oxygen species produc- tion by Kupffer cells, which are activated by low-​grade portal endotoxaemia as a consequence of alcohol-​induced increased intestinal permeability. The oxidative stress is amplified by the relative lack of innate antioxidants such as glutathione, which is often depleted by alcohol excess. Oxidative stress induces redox-​ sensitive transcription factors which lead to increased production of tumour necrosis factor-​α (TNFα) and the neutrophil activating interleukin 8 (IL-​8). TNFα along with lipid peroxidation leads to inflammation, necrosis, mitochondrial disruption, and apoptosis. In addition, acetaldehyde may form protein adducts which can act as neoantigens, triggering immune-​mediated damage. This com- bination of immune activation, cytokines, and oxidative stress causes alcoholic hepatitis. Fibrosis in ALD is a result of increased collagen production by hepatic stellate cells, which are directly activated by acetaldehyde it- self as well as by TNFα, IL-​8, growth factors derived from damaged hepatocytes, and reactive oxygen species. Diagnosis A detailed clinical history documenting the type, pattern, and amount of alcohol consumed should be taken. Screening tools for alcohol use disorders such as the AUDIT questionnaire or its abbre- viated forms, such as the FAST or AUDIT-​C questionnaires, should be carried out, but it is important to recognize that not all patients with ALD have alcohol dependency. A diagnosis of ALD can be considered in patients with a com- bination of a history of alcohol excess (>30 g/​day), clinical evi- dence of liver disease, and compatible laboratory investigations. However, as only a minority of alcohol misusers develop advanced ALD, other forms of liver disease should be excluded. A screen for chronic viral, autoimmune, and hereditary liver disease should be carried out. Up to 20% of people with alcoholic liver disease will have another coexistent liver disease such as viral hepatitis. Imaging should be performed to identify obstructive, structural, or neoplastic disease, with an abdominal ultrasound examination with Doppler of the portal and hepatic veins. Further imaging can be undertaken with either CT or MRI if other pathology is suspected. In cases of doubt, a liver biopsy can be a useful tool to exclude other causes of liver disease. However, percutaneous liver biopsy may be contraindicated in the clinical setting by the presence of as- cites and/​or a coagulopathy. Risks can be minimized by performing a transjugular liver biopsy, although the quality of the sample may be less satisfactory. Clinical features and investigation Many patients, even those with advanced ALD, may be asymptom- atic until hepatic decompensation occurs. Presentation may vary from an incidental discovery of abnormal liver blood tests through to acute-​on-​chronic liver failure or decompensated cirrhosis. In ALD, serum aspartate aminotransferase (AST) is rarely more ALCOHOL ACETALDEHYDE ACETATE CYP2E1 NAD NADH ALDH NAD NADH ADH Catalase NADP NADPH Reactive Oxygen Species (ROS) ACETA T TE A ALDH NAD NADH Catalase CYP2E1 NADP NADPH Reactive Oxygen Species (ROS) ALCOHOL NAD NADH ADH Mitochondria Peroxisomes Cytosol MEOS: Microsomal Ethanol Oxidizing System Reactive Oxygen Species (ROS) Fig. 15.24.1.2  Oxidative metabolism of alcohol. The primary pathway is oxidation by alcohol dehydrogenase (ADH) and then acetaldehyde dehydrogenase (ALDH). CYP2E1, cytochrome P450 2E1. ALCOHOL Kupffer Cell Neutrophil Cytotoxic Lymphocyte Hepatocyte ROS TNFα IL-8 ROS ROS Acetaldehyde Protein Adducts NECROSIS and APOPTOSIS GUT Endotoxin NADH STEATOSIS Fig. 15.24.1.3  The pathophysiology of alcoholic steatohepatitis. Metabolism of alcohol produces NADH which leads to steatosis. Reactive oxygen species (ROS) from Kupffer cell activation, neutrophils, and alcohol metabolism lead to necrosis and apoptosis.

15.24.1  Alcoholic liver disease 3145 than 500 IU/​litre, serum alanine aminotransferase (ALT) rarely over 300 IU/​litre, and the AST:ALT ratio usually more than 1.5. The degree of elevation of the transaminase enzymes is a clue as to the presence of liver injury but not the severity of ALD. Commonly used indicators of alcohol excess such as γ-​glutamyl transferase and mean cell volume are not specific for either al- cohol abuse or ALD. Patients presenting only with abnormal liver blood tests may have simple steatosis, but may have ‘silent’ cirrhosis. Clues to the presence of chronic liver disease, such as stigmata of chronic liver disease (spider naevi, palmer erythema, gynaeco- mastia) or portal hypertension (splenomegaly, caput medusae, otherwise unexplained thrombocytopenia) should be sought. Transient elastography to assess liver stiffness can be useful to assess the stage of ALD, but the presence of ascites or acute inflammation with an alcoholic hepatitis may interfere with this assessment and render it uninterpretable. Alcoholic hepatitis Acute alcoholic hepatitis is characterized by new-​onset jaundice (serum bilirubin >80 μmol/​litre) which has developed over the pre- vious 3 months with a history of alcohol excess (>80 g/​day males,

60 g/​day females) within 2 months. Alcoholic hepatitis is often, but not invariably, associated with other features such as pyrexia, a peripheral leucocytosis, hepatomegaly, or a hepatic bruit. There may be other features of decompensated liver disease such as encephal- opathy and ascites. Most patients with alcoholic hepatitis will have coexistent cirrhosis. The clinical presentation of alcoholic hepatitis can be similar to sepsis and it is therefore vital that potential sources of infection are investigated with blood and urine cultures, chest radiography, and (when relevant) ascitic fluid analysis. Sepsis should be excluded or satisfactorily treated before assessment or specific treatment of alcoholic hepatitis is initiated. The need for a biopsy to diagnose alcoholic hepatitis before starting specific treatment is controversial. Histological con- firmation in cases of clinical uncertainty is clearly necessary, but routine liver biopsies are probably not required where the clinical and investigational features are consistent with alcoholic hepatitis. Cirrhosis Patients may present with decompensated chronic liver disease in a less acute fashion. They may have peripheral oedema, ascites, and encephalopathy, but are not necessarily jaundiced. Precipitants of hepatic decompensation such as sepsis, gastrointestinal bleeding, electrolyte imbalance, or the development of hepatocellular car- cinoma should be sought. Management Abstinence The cornerstone to the management of ALD is long-​term abstin- ence. Brief interventions (5–​20-​min motivational consultations) carried out opportunistically in the hospital setting can have an effect for up to 1 year (see Chapter 26.6.1 for further discus- sion). As many as 50% of patients can significantly reduce or ab- stain from alcohol absolutely after simple advice from a physician. Ideally, alcohol dependency should be managed in concert with addiction services to ensure appropriate intervention and com- munity follow-​up. Several medical therapies are available for the treatment of al- cohol abuse including disulfiram, naltrexone, nalmefene, and acamprosate. However, the evidence base for these approaches in patients with advanced ALD is sparse. There have been studies using the γ-​aminobutyric acid type B receptor inhibitor baclofen in patients with cirrhosis, with some promising results. Patients admitted acutely with ALD are at risk of alcohol with- drawal syndrome. The oxidative metabolism of benzodiazepines may be impaired in those with advanced disease leading to an accumulation of active drug. This may precipitate or exacerbate hepatic encephalopathy. For patients with evidence of liver dys- function, shorter-​acting agents such as lorazepam should be con- sidered. See Chapter 26.5.4 for further discussion. Nutrition Patients with ALD are typically in a hypercatabolic state with protein-​energy malnutrition. This is of prognostic significance and increases the likelihood of the development of complications such as infection, encephalopathy, and ascites. Patients with alcoholic hepatitis are almost invariably malnourished to some degree. In these patients, more than 50% of energy prior to hospital admission may have come from alcohol inges- tion. Malnutrition may be self-​evident on global assessment with clinical evidence of muscle wasting, but anthropometry with mid-​upper arm circumference, hand grip strength and triceps skinfold thickness measurements may provide early indications of undernutrition and allow prompt nutritional support. Protein and calorie nutritional support should be provided ei- ther as dietary supplements or via enteral feeding regimens, aiming for protein consumption of up to 1.2 to 1.5 g/​kg and calorie intake up to 35 to 40 kcal/​kg. Thiamine replacement should be prescribed to prevent the development of Wernicke’s encephalopathy, in ac- cordance with published guidelines. Studies have not shown that combinations of antioxidants are beneficial in alcoholic hepatitis. One study has shown a long-​term survival benefit in alcoholic hepatitis with a liver-​specific nu- tritional formulation administered by nasogastric feeding tube, but tolerance of such feeding routes is often poor in patients with decompensated ALD and severe alcoholic hepatitis. Acute alcoholic hepatitis Assessment of severity A clinical diagnosis of alcoholic hepatitis encompasses a wide spectrum of disease, with severe acute alcoholic hepatitis having a 28-​day mortality of up to 60%. Assessment of the severity of alco- holic hepatitis is vital not only to identify those patients with a poor prognosis, but also to target treatment effectively. The discriminant function has been used for this purpose, with a value more than 32 being associated with a poor prognosis, although it suffers from a lack

section 15  Gastroenterological disorders 3146 of specificity and overall accuracy. It relies upon the measurement of prothrombin time, which can vary significantly between dif- ferent laboratories (Table 15.24.1.1). The Glasgow Alcoholic Hepatitis Score is a more accurate score, validated throughout the United Kingdom. A value of 9 or more is associated with a poor prognosis. Both the discriminant function and the Glasgow Alcoholic Hepatitis Score have been used to identify patients who will benefit from specific treatment of alcoholic hepatitis. The Model for End-​Stage Liver Disease (MELD) score has been used to assess prognosis in alcoholic hepatitis, but the threshold for identifying a poor outcome remains unclear and it has yet to be shown to able to identify patients likely to benefit from additional treatment. Steroids and other pharmacological treatments Use of corticosteroids in alcoholic hepatitis has been contro- versial, with concerns about the risk of precipitating sepsis with such treatment. The STOPAH trial addressed this question with the largest study of alcoholic hepatitis ever performed. Over 1000 patients with a discriminant function greater than 32 were randomized to corticosteroids (prednisolone 40 mg/​day for 4 weeks), pentoxifylline (400 mg three times a day for 4 weeks), or placebo in a factorial design. Overall mortality was not sig- nificantly different between the four groups, but despite serious infections being more likely in corticosteroid-​treated patients, on multivariate logistic regression corticosteroid use was asso- ciated with an improved 28-​day survival, although this survival benefit was lost by 90  days. This 28-​day survival advantage with corticosteroids has been observed in a subsequent meta-​ analysis. In STOPAH, pentoxifylline was not seen to improve survival at any time point despite a previous study suggesting benefit. Other studies have confirmed that the combination of pentoxifylline and corticosteroids offers no additional benefit to corticosteroids alone. One study has suggested that the addition of N-​acetylcysteine to corticosteroids may be of use by reducing episodes of sepsis, but confirmatory studies are required. The anti-​TNFα drugs infliximab and etanercept have been studied in alcoholic hepatitis without evidence of improved outcome and a concerning increase in sepsis. Overall, corticosteroid is the only pharmacological treatment shown to be of any benefit in alcoholic hepatitis. It is possible to identify patients who are responding to such treatment as a fall in bilirubin after 1 week of corticosteroid treatment is associated with a survival benefit. From this observation, the Lille score has been de- veloped to identify responders and nonresponders to corticosteroid treatment. It is possible that the measured corticosteroid benefit is limited on account of the poor specificity of the discriminant function in identifying those who might benefit from corticosteroids. The Glasgow alcoholic hepatitis score may better guide corticosteroid treatment as those patients with a score of less than 9 do not appear to benefit from it, whereas those with a score of 9 or more have im- proved 28-​ and 84-​day survival with corticosteroid treatment com- pared with untreated controls. Survival from alcoholic hepatitis in the short-​term may be modi- fied by corticosteroid treatment, but longer-​term outcome is closely related to the achievement of abstinence. Cirrhosis The complications of alcohol-​related cirrhosis, such as ascites, variceal haemorrhage, and encephalopathy, should be managed in the same way as for other forms of chronic liver disease. Patients with cirrhosis should have 6-​monthly liver ultrasonography and α-​fetoprotein for hepatocellular carcinoma screening, and screening endoscopy for oesophageal varices. There are no specific treatments available for alcoholic cirrhosis other than liver transplantation. Long-​term prognosis is closely Table 15.24.1.1  Prognostic scores used in the assessment of alcoholic hepatitis Discriminant function Discriminant function = 4.6 (prothrombin time − control prothrombin time) + total bilirubin (mg/​dl)     Poor prognosis ≥32 MELD MELD = 3.8 × log(bilirubin [mg/​dl]) + 11.2 × log(INR) + 9.6 × log(creatinine [mg/​dl]) + 6.4 Glasgow Alcoholic Hepatitis Score 1 2 3 Age <50

50 White cell count <15 15 Urea <5 5 Bilirubin <125 125–​250 250 INR <1.5 1.5–​2.0 2.0     Poor prognosis >8 Lille Score R = 3.19 – (0.101 x age in years) + (0.147 x albumin day 0 in g/L) + (0.0165 x ECBL in mM) – (0.206 x renal insufficiency)# – (0.0065 x bilirubin day 0 in mM) – (0.0096 x INR day 0)                         # creatinine >115μM Score = EXP(–​R)/​[1 + EXP(–​R)]     Poor Prognosis ≥ 0.45

15.24.2 Nonalcoholic fatty liver disease 3147

15.24.2 Nonalcoholic fatty liver disease 3147

15.24.2  Nonalcoholic fatty liver disease 3147 related to the stage of disease, as assessed by standard chronic liver disease scores such as the MELD score or the Child–​Pugh score. The prognosis is improved by sustained abstinence. Liver transplantation Liver transplantation should be considered for those patients whose clinical condition remains poor despite sustained abstin- ence. Although there is no requirement for a set period of abstin- ence before considering liver transplantation, many patients will improve clinically up to 6  months after stopping drinking, and such improvement might render referral for transplant unneces- sary. Those patients who are assessed for transplant require a rigorous psychiatric evaluation. Despite this, around 10% of pa- tients transplanted for ALD will return to problem drinking. In the long term, recidivism is associated with an increased mortality and may also adversely affect the attitude of the public to this form of treatment in ALD. Liver transplantation for alcoholic hepatitis has been suggested for a highly selected group of patients who have not responded to corticosteroids (‘Lille nonresponders’). This is a controversial area, with concerns raised about the appropriate use of donor organs and reservations about the specificity of Lille nonresponse to predict mortality. Such nonresponders may still have a 50% survival without transplantation. FURTHER READING European Association for the Study of Liver (2012). EASL clinical prac- tical guidelines: management of alcoholic liver disease. J Hepatol,
57, 399–​420. Forrest EH, et al. (2005). Analysis of factors related to mortality in al- coholic hepatitis and the derivation and validation of the Glasgow alcoholic hepatitis score. Gut, 54, 1174–​9. Hodgson R, et al. (2002). The FAST alcohol screening test. Alcohol Alcohol, 37, 61–​6. Lafferty H, Stanley AJ, Forrest EH (2013). The management of al- coholic hepatitis:  a prospective comparison of scoring systems. Aliment Pharmacol Ther, 38, 603–​10. Louvet A, et al. (2007). The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with ster- oids. Hepatology, 45, 1348–​54. Lucey MR, Mathurin P, Morgan TR (2009). Alcoholic hepatitis.
N Engl J Med, 360, 2758–​69. Mathurin P, et al. (2011). Early liver transplantation for severe alco- holic hepatitis. N Engl J Med, 365, 1790–​800. Mathurin P, et al. (2013). Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a random- ized clinical trial. JAMA, 310, 1033–​41. National Institute for Health and Care Excellence (NICE) (2010). Alcohol-​use disorders: diagnosis and clinical management of alcohol-​ related physical complications. Clinical guideline. NICE, London. Nguyen-​Khac E, et al. (2011). Glucocorticoids plus N-​acetylcysteine in severe alcoholic hepatitis. N Engl J Med, 365, 1781–​9. Seth D, et  al. (2011). Pathogenesis of alcohol-​induced liver dis- ease: classical concepts and recent advances. J Gastroenterol Hepatol, 26, 1089–​105. Thursz MR, et  al. (2015). Steroids or pentoxifylline for alcoholic hepatitis. N Engl J Med, 372, 1619–​28. 15.24.2  Nonalcoholic fatty
liver disease Quentin M. Anstee and Christopher P. Day ESSENTIALS Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the developed world, affecting 20 to 30% of Western adults. NAFLD occurs with a range of severity from simple steatosis (nonalcoholic fatty liver, NAFL) through nonalcoholic steatohepatitis (NASH) to fibrosis and, ultimately, cirrhosis. The condition is a mani- festation of the metabolic syndrome and so is strongly associated with obesity, insulin resistance, and dyslipidaemia. Dietary and gen- etic factors appear to determine susceptibility to the disease and its progression. In most patients, the condition is discovered incidentally when ab- normal values of serum liver-​related liver tests are reported. The diag- nosis is usually one of exclusion. Liver biopsy is not always required but, in the absence of well-​validated noninvasive biomarkers, remains the only way to detect steatohepatitis and accurately stage fibrosis of intermediate severity. However, biopsy is not practical in all cases and so a staged approach to patient assessment and risk stratification is ad- vised. Treatment is directed at components of the metabolic syndrome to reduce cardiovascular disease and liver disease progression: weight loss through diet and exercise has been shown to ameliorate NAFLD. A range of novel pharmacological drug treatments are under evaluation. Introduction Excessive hepatic fat accumulation is a common radiological and histological finding. In the absence of excessive alcohol consump- tion this is termed nonalcoholic fatty liver disease (NAFLD), which describes a broad spectrum of histologically defined progressive liver disease (Fig. 15.24.2.1). NAFLD ranges from hepatic stea- tosis (nonalcoholic fatty liver, NAFL) where hepatocellular trigly- ceride accumulation is >5%, through inflammatory nonalcoholic steatohepatitis (NASH), to fibrosis or cirrhosis, and in some cases hepatocellular carcinoma. Critically, most patients with NAFLD do not progress beyond steatosis, but a substantial minority do progress to cirrhosis and end-​stage liver disease and so experience associated morbidity and mortality. The presence of NAFLD is also an inde- pendent risk factor for development of cardiovascular disease and stroke. The key challenge in the management of NAFLD is to iden- tify the patients at greatest risk of disease progression so that treat- ment may be targeted at those that will benefit most. Aetiology Hepatic steatosis and steatohepatitis may be attributable to a di- verse range of acquired exposures as well as numerous rare mono- genic inherited disorders (summarized in Table 15.24.2.1). The

section 15  Gastroenterological disorders 3148 Steatohepatitis (NASH) Cirrhosis Steatosis (NAFL) NAFLD Fat infiltration >5% with or without mild inflammation Steatosis + necroinflammation (ballooning, Mallory bodies, megamitochondria) Increasing fibrosis, eventually leading to cirrhosis Fig. 15.24.2.1  NAFLD—​a spectrum of liver disease. Table 15.24.2.1  Aetiology of steatosis and steatohepatitis Aetiological factor Predominant pattern of histological steatosis Acquired metabolic and/​or nutritional disorders Metabolic syndrome (obesity, insulin resistance/​ type 2 diabetes mellitus) Macrovesicular Starvation and cachexia Macrovesicular Protein malnutrition (Kwashiorkor, anorexia nervosa) Macrovesicular Dietary choline deficiency Macrovesicular Total parenteral nutrition Macrovesicular Drugs Amiodarone Macrovesicular Aspirin Microvesicular Chloroquine Macrovesicular Corticosteroids Macrovesicular Methotrexate Macrovesicular NSAIDs (naproxen, ibuprofen, ketoprofen) Microvesicular Nucleoside analogues used in HAART (zidovudine, didanosine, zalcitabine, fialuridine, etc.) Microvesicular Oestrogens Macrovesicular Tamoxifen Macrovesicular Tetracycline Microvesicular Valproic acid Microvesicular Toxins Amanita phalloides mushroom poisoning Bacillus cereus emetic toxin Microvesicular Carbon tetrachloride Ethanol Macrovesicular Petrochemicals Toxic shock syndrome Microvesicular Aetiological factor Predominant pattern of histological steatosis Genetic factors Abetalipoproteinaemia Macrovesicular Alpers’ disease Microvesicular Cholesterol ester storage disease Microvesicular Familial combined hyperlipidaemia Familial hypobetalipoproteinaemia Glycogen storage disease Inherited defects in fatty acid β-​oxidation Microvesicular Lecithin–​cholesterol acyltransferase deficiency Microvesicular Lipodystrophy Macrovesicular Lysosomal acid lipase deficiency (Wolman’s disease) Microvesicular Ornithine transcarbamylase deficiency Microvesicular Wilson’s disease Macrovesicular Infections Chronic hepatitis C (genotype 3) Macrovesicular Bacterial overgrowth following jejunoileal bypass Macrovesicular Others Acute fatty liver of pregnancy Microvesicular Coeliac disease HELLP syndrome Microvesicular Reye’s syndrome Microvesicular Metals HAART, highly active antiretroviral therapy; NSAIDs, nonsteroidal anti-​inflammatory drugs.

15.24.2  Nonalcoholic fatty liver disease 3149 most common aetiological factors underlying the development of NAFLD are central obesity, insulin resistance/​type 2 diabetes mellitus, hypertension, and dyslipidaemia, a group of chronic condi- tions indicative of increased cardiovascular risk that together com- prise the ‘metabolic syndrome’. NAFLD is also associated with conditions including polycystic ovary syndrome, obstructive sleep apnoea, and small-​bowel bac- terial overgrowth. Due to sedentary lifestyles and the increasing consumption of diets enriched in fats and carbohydrates, the meta- bolic syndrome is now endemic in many developed countries and so the incidence of NAFLD has risen rapidly to become the leading cause of chronic liver disease worldwide. Epidemiology The true worldwide prevalence of NAFLD is not known as estimates vary between the populations studied due to different ethnicities, dietary patterns, and the sensitivity of the modality used to detect disease. Overall, however, NAFLD is estimated to affect approxi- mately 20 to 30% of the population in Western countries and 5 to 18% in Asia, with about 1 in 10 NAFLD cases exhibiting features of NASH. Studies from the United States of America indicate that the frequency of steatosis varies significantly with ethnicity (45% in Hispanics, 33% in white people, and 24% in black people) and sex (42% white males vs 24% white females). Prevalence increases dramatically when populations with known metabolic syndrome risk factors are selected. Illustrating this, 91% of obese patients (body mass index (BMI) ≥30 kg/​m2), 67% of overweight (BMI 25–​30 kg/​m2), and 25% in normal weight individuals in an un- selected European population sample had NAFLD, and 40 to 70% of patients with type 2 diabetes mellitus also have NAFLD. Of concern, while the prevalence of most liver diseases is stable, the prevalence of NAFLD is increasing, placing a greater burden on healthcare resources. There is an important paradox: most individuals with features of the metabolic syndrome develop steatosis and so NAFLD is highly prevalent in the general population, but only a subgroup progress to advanced liver disease and experience liver-​related morbidity (Fig. 15.24.2.2). During a median 12.6-​year follow-​up period in a cohort of 619 NAFLD patients, an overall 33.2% risk of death or liver transplantation was observed, with liver-​related mortality being the third most common cause of death, after cardiovascular disease and extrahepatic malignancy. Challenging the dogma that ‘simple’ steatosis is a benign con- dition with no clinical sequelae, serial biopsy studies indicate that patients with either steatosis or NASH may exhibit progres- sive fibrosis, with approximately 40% showing increased fibrosis, 40% stable disease, and 20% disease regression over a 6-​ to 7-​year period. The presence and severity of hepatic fibrosis on liver bi- opsy (or as assessed by noninvasive testing) appears to be the single most important determinant of long-​term prognosis, with advanced fibrosis/​cirrhosis (fibrosis stages F3–​4) being predictive of liver-​related events, transplantation, and death in patients with NAFLD. Compared with cases without histological evidence of fi- brosis, the presence of early [F1–​2] fibrosis conferred an 11.2-​fold risk. This increased to an 85.8-​fold risk in patients with advanced [F3–​4] fibrosis/​cirrhosis. The average age of NASH patients is 40 to 50 years and for NASH cirrhosis is 50 to 60 years, but the emerging epidemic of childhood obesity means that NAFLD is present in increasing numbers of younger patients and so the age that patients develop significant liver disease is likely to fall. Pathogenesis/​pathology It is generally accepted that the initiating events in NAFLD are dependent on the development of obesity and insulin resistance. Together these lead to increased fatty acid content in the liver due to the combination of de novo lipogenesis and fatty acid import from Early fibrosis F1 F2 F3 F4 Advanced fibrosis & Cirrhosis Steatosis Steatosis + Lobular Inflammation NASH +/–Portal Inflammation Steatotic/Steatohepatitic phase Fibrotic phase Rates of Fibrosis Progression vary between individuals Environmental Factors Diet, Microbiome, Xenobiotics Genetic & Epigenetic Factors Genetic variants in PNPLA3, TM6SF2, MBOAT7, HSD17B13 DNA methylation Risk of Death or Transplantation Fig. 15.24.2.2  Natural history of NAFLD.

section 15  Gastroenterological disorders 3150 dietary sources and adipose tissue stores. This places hepatocytes under considerable metabolic pressure, promotes lipotoxicity, in- creases oxidative stress secondary to free radical production during β-​ and ω-​fatty acid oxidation, and induces endoplasmic reticulum stress. Hepatocellular triglyceride accumulation (i.e. steatosis) is the histologically visible evidence of these metabolic stressors but is it- self unlikely to be directly harmful to the liver, being an adaptive response through which potentially lipotoxic fatty acids are parti- tioned into relatively inert intracellular stores. Ultimately, these in- sults combine with the additive effects of endotoxin-​initiated Kupffer cell cytokine release and immune-​mediated hepatocellular injury to induce cellular damage and activate cell death pathways, marking the transition to steatohepatitis. If these processes persist, stellate cell activation, collagen deposition, and hepatic fibrosis occur. Interpatient variation in disease progression and prognosis is thought to be determined by the combined effects of environ- mental (dietary and intestinal flora) exposures acting on a suscep- tible polygenic background. Studies implicate single nucleotide polymorphisms in a number of genes including PNPLA3, TM6SF2, MBOAT7 and HSD17B13 as factors that modify development of NAFLD and subsequent progression of fibrosis. Clinical features NAFLD is frequently asymptomatic although may be associated with nonspecific symptoms such as fatigue and mild right upper quadrant abdominal discomfort due to steatotic hepatomegaly distending the liver capsule. It is most commonly identified as an incidental radiological finding or a mild biochemical abnormality noted during routine blood tests taken for another indication. Alternatively, patients with progressive NAFLD may present late in the course of disease with complications of cirrhosis and portal hypertension such as variceal haemorrhage, or hepatocellular car- cinoma (HCC). HCC is a frequent complication of NAFLD (cu- mulative incidence 2.4–​12.8%) that may occur in both precirrhotic and postcirrhotic patients. Recognized independent risk factors for NAFLD progres- sion and advanced fibrosis include age greater than 45  years, presence of diabetes (or severity of insulin resistance), obesity (BMI >30  kg/​m2), and hypertension (Table 15.24.2.2). These factors are clinically useful as they assist with identification of ‘high-​risk’ patient groups. There are no specific physical signs to establish a diagnosis of NAFLD. Hepatomegally may be noted, but abdominal adiposity may hamper effective examination. In the absence of advanced disease, where the classical stigmata associated with the presence of chronic liver disease such as jaundice, spider naevi, and ascites may be apparent, clinical examination is frequently unremarkable. In light of the strong association between NAFLD and the meta- bolic syndrome, height and weight should be recorded, hip/​waist circumference measured, and evidence of end-​organ damage due to insulin resistance and hypertension sought. Differential diagnosis Key to the diagnosis of NAFLD is recognition that an individual possesses features of metabolic syndrome (central obesity, insulin resistance/​type 2 diabetes mellitus, dyslipidaemia, and hyperten- sion) and therefore is at risk of NAFLD. The more features of the metabolic syndrome that are present, the higher the probability that a patient has underlying NAFLD and the more likely they are to ex- hibit steatohepatitis and progressive liver disease. There are many causes for steatosis and steatohepatitis and hence a potentially wide differential diagnosis (Table 15.24.2.1). In practice, the principal differential is between metabolic syndrome-​ related NAFLD and alcoholic liver disease. Discriminating these is reliant upon a detailed history and seeking corroboration from family members (where available) to ensure that any history of concealed excessive alcohol consumption is excluded. An arbi- trary threshold for ethanol consumption of less than 20 g/​day for women and less than 30 g/​day for men is adopted to sustain a diag- nosis of NAFLD. Metabolic syndrome-​related NAFLD sensitizes the liver to the effects of other injurious processes such as alcohol consump- tion. As obesity and the wider metabolic syndrome become en- demic within the population, the distinction between NAFLD and alcohol-​related liver disease can easily become blurred with these apparently mutually exclusive conditions coexisting in some indi- viduals. To avoid this diagnostic oxymoron, the condition may be described as ‘dual-​aetiology fatty liver disease’. Table 15.24.2.2  Common risk factors for NAFLD Risk factor Effect Age Higher risk of NAFLD and advanced fibrosis aged >45 Metabolic syndrome (obesity, insulin resistance/​type 2 diabetes mellitus, dyslipidaemia, and hypertension) 70–​90% of metabolic syndrome patients have NAFLD. The more features an individual possesses, the greater the likelihood of NASH and severity of fibrosis Sex Males >females Ethnicity High risk in Hispanics, white individuals intermediate, lower risk in black individuals Dietary factors Diets high in cholesterol, saturated fats, and fructose but low in carbohydrate increase risk Caffeine may be protective Obstructive sleep apnoea Increased risk of hepatic fibrosis Genetic factors Variants in Patatin-​like phospholipase domain-​containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes are associated with greater steatosis, NASH, and more advanced liver fibrosis. PNPLA3 mutations also increase the risk of NAFLD-​associated hepatocellular carcinoma

15.24.2  Nonalcoholic fatty liver disease 3151 A detailed drug history including prescribed medication, over-​ the-​counter medication, and traditional/​herbal remedies should be taken. Clinical investigation Once excessive alcohol consumption has been excluded and other confounding environmental factors discounted, investi- gation of suspected NAFLD should be directed first towards ex- clusion of other liver diseases and then confirming the presence of NAFLD: • Exclusion of other liver diseases:  laboratory testing should confirm absence of chronic viral hepatitis (hepatitis B virus sur- face antigen and hepatitis C virus serology), autoimmune liver disease (antinuclear antibodies, antimitochondrial antibodies, smooth muscle antibodies, liver–​kidney microsomal type 1 anti- bodies, immunoglobulins) and other treatable metabolic dis- eases (haemochromatosis, Wilson’s disease, coeliac disease, α1 antitrypsin deficiency). • Confirmation of the presence of NAFLD:  may be obtained radiologically or histologically. • Assessment of underlying liver damage: discriminating steatosis from NASH and determining the extent of hepatic fibrosis pre- sent (i.e. grade and stage of disease) is important to assist with individual risk stratification and prognostication. This has trad- itionally necessitated liver biopsy for histological assessment, but techniques for noninvasive testing to detect significant liver fi- brosis are becoming more robust. Biochemical tests The diagnosis, staging, and long-​term follow-​up of NAFLD is made more complicated as there is no single blood test that is diagnostic for NAFLD or which can be used to accurately determine disease severity and treatment response. Aminotransferases Elevations of serum alanine transaminase (ALT) and aspartate transaminase (AST) are modest and usually less than twice the upper limit of normal. Although many NAFLD cases are first de- tected due to the incidental finding of a mild transaminitis, these routine biochemical tests are insensitive with approximately 80% of patients having normal-​range ALT levels. Indeed, ALT levels fall as hepatic fibrosis progresses and so the characteristic AST/ALT ratio of less than 1 commonly seen in NAFLD reverses (AST/ALT

  1. as fibrosis progresses toward cirrhosis, meaning that fibrosing steatohepatitis and/​or advanced liver disease may be present even in those with normal-​range ALT levels. Other biochemical markers Other laboratory abnormalities that may be present include non­ specific elevations of γ-​glutamyl transferase, low-​titre antinuclear antibodies, and/​or antismooth muscle antibody in 20 to 30% of patients, and elevated ferritin levels despite normal transferrin sat- uration. These can lead to diagnostic uncertainty as they may be incorrectly ascribed to high alcohol consumption, autoimmune hepatitis, and haemochromatosis respectively. Raised ferritin levels and the presence of increased IgA levels are indicative but not diag- nostic of more advanced fibrosis. Radiological studies Steatosis can readily be detected by various imaging modalities. Ultrasonography is widely available and cost-​effective and is there- fore most often used. A steatotic liver appears ‘bright’ due to in- creased echogenicity, but this finding is subjective and provides only a qualitative assessment of hepatic fat content. Sensitivity of ultrasonography is poor when less than 33% of hepatocytes are steatotic and so significant steatosis can be missed. Alternatives in- clude CT, MRI-derived Proton Density Fat Fraction (MRI-PDFF), or magnetic resonance spectroscopy, which offer greater sensitivity for detecting lesser degrees of steatosis but are resource inten- sive and not widely used in routine practice. Currently no widely available clinical imaging modality can distinguish steatosis from steatohepatitis or accurately quantify intermediate stages of fibrosis short of cirrhosis. Assessing the severity of the underlying liver disease In the absence of routinely available ‘standard’ tests to con- firm the diagnosis, assess the degree of inflammation, and accurately determine the extent of liver fibrosis to assist prog- nostication, liver biopsy is commonly used and remains the ‘gold standard’ investigation. However, it is invasive, carries a modest but appreciable risk of complications, and is unsuitable for widespread use outside the secondary care setting. Several noninvasive techniques, both commercial and noncommercial, have been proposed that may be used to predict the presence of NAFLD or the stage of fibrosis. The performance of selected tests that are commonly used are summarized in Table 15.24.2.3. Of these, simple scores like the NAFLD Fibrosis Score and FIB-​4 Score, or specialist panels such as the Enhanced Liver Fibrosis (ELF) Test, offer the ability to rule out significant underlying liver disease (fibrosis stages F3–​4) with a high degree of confi- dence and so are widely used to assist risk stratification, enabling invasive testing to be reserved for those where it may offer clin- ically relevant additional information. All three tests have also been shown to be predictive of long-​term disease outcome and mortality. Techniques that measure liver stiffness as a surrogate for fi- brosis severity, such as ultrasonography-​based transient elasto­ graphy (Fibroscan), are also widely adopted, although adiposity can interfere with accuracy in some patients. Promising alter- natives that are emerging include acoustic radiation force im- pulse imaging and magnetic resonance elastography. In general, noninvasive techniques have good negative predictive values for advanced fibrosis but more modest specificity and so lower positive predictive values. A suggested algorithm for the assess- ment and risk stratification of patients with NAFLD is provided in Fig. 15.24.2.3. Histology NAFLD ranges from hepatic steatosis, through inflammatory steatohepatitis, to fibrosis or cirrhosis (Fig. 15.24.2.1). The histo- logical classification of NAFLD, which allows grading of disease

section 15  Gastroenterological disorders 3152 activity and staging of fibrosis progression, is based on the assess- ment of three domains: • Degree of steatosis: this usually has a mainly centrilobular, acinar zone 3, distribution. Steatosis levels fall as cirrhosis develops and so NAFLD is underdiagnosed in the setting of advanced liver disease. It is thought to be the underlying cause of 30 to 75% of cases of ‘cryptogenic cirrhosis’ where no clear aetiology is apparent. • Grade of steatohepatitis (i.e. hepatocellular injury and inflam- mation): specific features of hepatocellular injury and inflamma- tion include hepatocyte ballooning degeneration with or without acidophil bodies or spotty necrosis and a mild, mixed inflam- matory infiltrate. These may be accompanied by Mallory–​Denk bodies. • Stage of fibrosis, scored from F0 (none) to F4 (cirrhosis): perisinusoidal fibrosis is a characteristic feature of NASH. To improve consistency between histopathologists, either of two well-​validated and widely used semiquantitative histological scoring systems may be used. These are the NIDDK NAFLD Activity Score (NAS) and the FLIP Steatosis/​Activity/​Fibrosis Score (SAF) (Table 15.24.2.4). Both are robust, but the SAF score may have some advantages as it specifically reports degree of steatosis and grade of activity separately, while these are combined as a single value in the NAS. Management Management of patients with NAFLD depends largely on the stage of disease and is reliant on careful risk stratification. There are at pre- sent no licensed prescription medications that are of proven efficacy for the treatment of NAFLD. Despite this, there are well-​defined evidenced-​based therapeutic interventions that reduce morbidity and mortality. Weight reduction and lifestyle modification All patients with NAFLD require advice about lifestyle modification aimed at weight loss and increased physical activity. A sustained loss of 7 to 9% of body weight reduces steatosis, hepatocellular in- jury, and inflammation. Weight loss of >10% may lead to regres- sion of fibrosis, if sustained. To achieve this, a calorie-​restricted diet (600 kcal/​day less than required to maintain body weight) should be recommended, targeting a weight loss of 0.5 kg per week, and patients should be advised to increase physical activity, performing at least 30 min of moderate exercise five times per week. Selected patients may benefit from pharmacological weight-​reduction treat- ments (e.g. orlistat) or bariatric surgery. Management of cardiovascular risk and the metabolic syndrome The presence of constituents of the metabolic syndrome should be sought and aggressively treated to reduce cardiovascular risk. The use of statins is not contraindicated in patients with NAFLD. Liver-​directed pharmacotherapy for high-​risk patients Although no pharmacological therapies are licensed for the treat- ment of NAFLD, there is evidence to support the use of specific classes of drugs to treat diabetes and hypertension that may offer some additional liver specific benefits. There are some preliminary evidence that angiotensin-​converting-​ enzyme inhibitors and angiotensin II receptor blockers may slow progression of liver fibrosis. Metformin does not appear to be an effective treatment for NAFLD but may reduce development of NAFLD-​associated hepatocellular carcinoma, with a 7% per annum reduction in hepatocellular car- cinoma risk reported in one retrospective study. Pioglitazone im- proves histological NASH, with a recent meta-​analysis suggesting that it may have some additional antifibrotic effects. Weight gain is a well-​recognized adverse effect of this treatment and long-​term use Table 15.24.2.3  Noninvasive tests for NAFLD and NAFLD fibrosis Test Formula Sensitivity and specificity Fatty Liver Index (FLI) predicts NAFLD FLI = (e 0.953 × loge (triglycerides) + 0.139 × BMI + 0.718 × loge (γGT) + 0.053 × waist circumference − 15.745)/​(1 + e 0.953 × loge (triglycerides) + 0.139 × BMI + 0.718 × loge (γGT) + 0.053 × waist circumference − 15.745) × 100 High risk (FLI >60) Intermediate (FLI 30–​60) Low risk (FLI <30) Se 0.87, Sp 0.86 NAFLD Fibrosis Score (NFS) predicts advanced fibrosis [F3–​4] NFS = −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/​m2) + 1.13 × IFG or diabetes (yes = 1, no = 0) + 0.99 × AST/​ALT ratio − 0.013 × platelet (× 109/​L) − 0.66 × albumin (g/​dL) High risk (NFS >0.676): Se 0.51, Sp 0.98, PPV 0.90, NPV 0.85 Indeterminate (NFS −1.455 to 0.676). Low risk (NFS <−1.455): Se 0.82, Sp 0.77, PPV 0.56, NPV 0.93 FIB-​4 score predicts advanced fibrosis [F3–​4] FIB-​4 = age (years) × AST (IU/​L)/​platelet count (×109/​L) × √
ALT (IU/​L) High risk (FIB-​4 >2.67): Se 0.33, Sp 0.98, PPV 0.80, NPV 0.83 Indeterminate (1.30–​2.67) Low risk (FIB-​4 <1.30): Se 0.74, Sp 0.71, PPV 0.43, NPV 0.90 Enhanced Liver Fibrosis (ELF) test predicts advanced fibrosis [F3–​4] ELF = −7.412 + (ln(HA) × 0.681) + (ln(PIIINP) × 0.775) + (ln(TIMP1) × 0.494) High risk (ELF > 0.3576): Se 0.80, Sp 0.90, PPV 0.71, NPV 0.94 Low risk (ELF < 0.3576) Fibroscan predicts advanced fibrosis [F3–​4] Ultrasonography-​based transient elastography measures the velocity of an elastic shear wave propagating through the liver to assess liver stiffness. Three probes S, M, and XL are used according to body habitus. Greater adiposity may limit test accuracy High risk (M >9.6 kPa; XL >9.3 kPa): M/​XL Se 0.75/​0.57,
Sp 0.92/​0.90, PPV 0.72/​0.71, NPV 0.93/​0.84 Indeterminate (M 7.9–​9.6; XL 7.2–​9.3) Low risk (M <7.9 kPa; XL <7.2 kPa): M/​XL Se 0.91/​0.78,
Sp 0.75/​0.78, PPV 0.52/​0.60, NPV 0.97/​0.89 γGT, γ-​glutamyl transferase; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity. Simple scores such as NFS and FIB-​4 are based on the results of routinely available blood tests and anthropometrics. In contrast, commercial tests such as the ELF Test rely on measurement of nonstandard indices (hyaluronic acid (HA), amino-​ terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-​1)) and Fibroscan requires specialist equipment.

Calculate FIB-4 Score Age <65: FIB-4 <1.3 Age >65: FIB-4 <2.0 1.3/2.0 to 2.67 More than 2.67 Low risk High risk Transient elastography (fibroscan)
M probe <7.9k Pa M probe 7.9–9.6 kPa XL probe 7.2–9.3 kPa XL probe <7.2k Pa

M probe >9.6 kPa
XL probe >9.3 kPa
Advanced [F3–4] Fibrosis Unlikely Advanced [F3–4] Fibrosis Likely Indeterminate Manage in primary care, lifestyle advice, address CVD risks, Recalculate NFS 3–5 years. Refer to secondary care Fibrosis F0–1 Fibrosis F2–3 Cirrhosis F4 Lifestyle advice, address CVD risks, NAFLD directed therapy Lifestyle advice, address CVD risks, NAFLD-directed therapy, HCC & variceal surveillance Suspected NAFLD Features of the metabolic syndrome, radiological evidence of steatosis and/or abnormal liver biochemistry, raised FLI, alternative diagnoses including high alcohol consumption excluded Recalculate NAFLD fibrosis score in 3–5 years or if patient develops type 2 diabetes Indeterminate Liver Biopsy Fig. 15.24.2.3  NAFLD risk stratification and management algorithm. Several different risk stratification algorithms have been proposed. This example represents a pragmatic approach to risk stratification that sequentially applies tests with high negative predictive value so that liver biopsy is reserved for a highly selected group of patients at high risk of advanced fibrosis/​cirrhosis. The NAFLD Fibrosis Score may be substituted for the FIB-4 Score, or a validated commercial fibrosis panel such as the ELF Test may replace Fibroscan as the second-​stage screen for fibrosis. Age adjusted thresholds for FIB-4 Score are shown. These maintain the high NPV of the test, which otherwise falls in patients aged >65 years. CVD, cardiovascular disease; FLI, Fatty Liver Index; HCC, hepatocellular carcinoma; NFS, NAFLD Fibrosis Score; NPV/​PPV, negative/​positive predictive value. F0–​4 refer to histological stage of fibrosis.

section 15  Gastroenterological disorders 3154 of thiazolidinediones in patients with diabetes has been associated with congestive heart failure, bladder cancer, and bone fractures. Preliminary data suggests that the glucagon-​like peptide-​1 agonist Liraglutide may be beneficial in slowing NAFLD progression, which effect may be largely through weight loss. Vitamin E (800 IU/​day) has been shown to lower ALT levels and to ameliorate histological steatohepatitis in pre-cirrhotic, nondiabetic patients in the PIVENS and TONIC trials, but a clear benefit on liver fibrosis was not demonstrated. Concern regarding an association with increased all-​cause mortality and prostate cancer mean that its use remains controversial, but it is considered by many to be a first-​ line therapy for selected patients with histologically confirmed NASH without cirrhosis or type 2 diabetes. A Cochrane analysis in 2017 of pharmacological interventions for NAFLD found most of the evidence to be of very low quality and concluded that there was no proven benefit for the majority of agents tested up to that point. However, there is substantial drug develop- ment activity in this field with a number of pharmacological agents currently in clinical trials such as FXR agonists, PPARa/d/g agonists and CCR2/5 antagonists. It is therefore likely that additional, liver-​ directed therapies will become available within the next few years. Prognosis The presence of NAFLD appears to be associated with greater all-​cause mortality, estimated to be 34 to 69% higher than the age and sex-​ matched general population. In most cases it has an indolent course, with patients ultimately succumbing to nonhepatic causes of death (principally cardiovascular disease), but some patients exhibit a more aggressive and rapidly progressive form of disease that leads to cirrhosis. FURTHER READING Natural history Angulo P, et al. (2015). Liver fibrosis, but no other histologic features, is associated with long-​term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology, 149, 389–​97.e10. Anstee QM, Targher G, Day CP (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol, 10, 330–​44. Ekstedt M, et al. (2015). Fibrosis stage is the strongest predictor for disease-​specific mortality in NAFLD after up to 33 years of follow-​ up. Hepatology, 61, 1547–​54. McPherson S, et al. (2015). Evidence of NAFLD progression from stea- tosis to fibrosing-​steatohepatitis using paired biopsies: Implications for prognosis and clinical management. J Hepatol, 62, 1148–​55. Musso G, et al. (2011). Meta-​analysis: natural history of non-​alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-​invasive tests for liver disease severity. Ann Med, 43, 617–​49. Diagnosis and risk-​stratification Angulo P, et al. (2007). The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology, 45, 846–​54. Anstee Q, Day C (2015). The genetics of non-​alcoholic fatty liver
disease:  spotlight on PNPLA3  & TM6SF2. Semin Liver Dis, 35, 270–​90. Burt AD, Lackner C, Tiniakos DG (2015). Diagnosis and assessment of NAFLD: definitions and histopathological classification. Semin Liver Dis, 35, 207–​20. Dyson JK, McPherson S, Anstee QM (2013). Non-​alcoholic fatty liver disease:  non-​invasive investigation and risk stratification. J Clin Pathol, 66, 1033–​45. Table 15.24.2.4  Validated histological scores commonly used for reporting NAFLD liver biopsies The FLIP Steatosis/​Activity/​Fibrosis Score (SAF) NIDDK NAFLD Activity Score (NAS) Histological feature Category Definition Histological feature Category Definition Steatosis 0 1 2 3 <5% 5–​33% 34–​66%

66% Steatosis 0 1 2 3 <5% 5–​33% 34–​66% 66% (S) Steatosis score 0–​3 PLUS Hepatocyte ballooning 0 1 2 None Clusters of hepatocytes with rounded shape and pale cytoplasm Same as grade 1 with enlarged hepatocytes (>2× normal size) Hepatocyte ballooning 0 1 2 None Few Many PLUS PLUS Inflammation 0 1 2 None < 2 foci per 20× field 2 foci per 20× field Inflammation 0 1 2 3 None 1–​2 foci per ×20 field 2–​4 foci per ×20 field 4 foci per ×20 field (A) Total = activity score 0–​4 (NAS) Total = NAFLD activity score 0–​8 Fibrosis 0 1a 1b 1c 2 3 4 No fibrosis Zone 3 mild perisinusoidal Fibrosis Zone 3 moderate Perisinusoidal fibrosis Periportal/​portal fibrosis only Zone 3 plus portal/​periportal fibrosis Bridging fibrosis Cirrhosis Fibrosis 0 1a 1b 1c 2 3 4 No fibrosis Zone 3 mild perisinusoidal Fibrosis Zone 3 moderate Perisinusoidal fibrosis Periportal/​portal fibrosis only Zone 3 plus portal/​periportal fibrosis Bridging fibrosis Cirrhosis (F) Fibrosis score 0–​4 Fibrosis score 0–​4

15.24.3 Drug- induced liver disease 3155

15.24.3 Drug- induced liver disease 3155

15.24.3  Drug-induced liver disease 3155 Therapy Gawrieh S, Chalasani N (2015). Pharmacotherapy for non-​alcoholic fatty liver disease. Semin Liver Dis, 35, 338–​48. Lombardi R, et  al. (2017). Pharmacological interventions for non-​ alcohol related fatty liver disease (NAFLD): an attempted network meta-​analysis. Cochrane Database Syst Rev, 3, CD011640. Nguyen V, George J (2015). Non-​alcoholic fatty liver disease manage- ment: dietary & lifestyle modifications. Semin Liver Dis, 35, 318–​37. 15.24.3  Drug-​induced liver disease Guruprasad P. Aithal ESSENTIALS Drug-​induced liver disease encompasses a wide range of pathology including idiosyncratic drug-​induced liver injury (DILI), acute fatty liver, autoimmune hepatitis, sclerosing cholangitis, granulomatous hepatitis, and nodular regenerative hyperplasia, as well as drug-​ associated fatty liver disease, cirrhosis, and liver tumours. The vast majority of commonly used drugs are reported to be as- sociated with DILI, including over-​the-​counter preparations, herbal remedies, and dietary supplements. It is important to consider drug therapy as an aetiology when assessing patients presenting with hepatocellular or cholestatic patterns of liver injury. Systematic evaluation and prompt diagnosis followed by discontinuation of the particular medication is crucial to prevent the development of acute liver failure and to avoid inappropriate investigations. Both candidate gene and genome-​wide association studies have identified the critical role of the adaptive immune system in the pathogenesis of idiosyncratic DILI. Human leucocyte antigen alleles that are strongly associated with DILI have the potential to assist in the clinical investigation of patients suspected to have DILI in par- ticular circumstances. Introduction The term hepatotoxicity has been used nonspecifically in the litera- ture to describe the pathological process leading to hepatocyte death and liver injury from medications, alcohol, illicit drugs, and envir- onmental toxins as well as overdoses. Drug-​induced liver disease encompasses a wide range of pathologies where drug therapy has been implicated as an underlying aetiology. Over 350 medications have been associated with adverse effects on the liver, which is prob- ably due to the central role of the liver in the metabolism and clear- ance of most drugs. Idiosyncratic drug-​induced liver injury (DILI) is defined as an adverse hepatic reaction that is unexpected on the basis of the pharmacological action of the drug administered; this includes acute liver injury, the most common form, and should be distinguished from the consequences of drug overdose. Case definitions and phenotypes Liver biochemical tests are most commonly used in clinical prac- tice to detect liver injury. These generally include serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin. Case definitions for DILI include one of the following thresh- olds: (1) fivefold or higher elevation above the upper limit of normal (ULN) for ALT, (2) twofold or higher elevation above the ULN for ALP (particularly with accompanying elevations in concentrations of γ-​glutamyl transferase in the absence of known bone pathology driving the rise in ALP level), or (3) threefold or higher elevation in ALT concentration and simultaneous elevation of bilirubin con- centration exceeding twice the ULN. Liver injury is designated ‘hepatocellular’ when there is a fivefold or higher rise in ALT alone, or when the ratio of serum activity (activity is expressed as a mul- tiple of ULN) of ALT to ALP is 5 or more. Liver injury is designated ‘cholestatic’ when there is a twofold or higher rise in ALP alone, or when the ratio of serum activity of ALT to ALP is 2 or less. When the ratio of the serum activity of ALT to ALP is between 2 and 5, liver injury is termed ‘mixed’. Several other distinct phenotypes of drug-​induced liver diseases are discussed in this chapter. Each of these forms is identified using the same characteristic features as used to define the primary condi- tion such as autoimmune hepatitis, primary sclerosing cholangitis, and others. Epidemiology Standard toxicological studies during the preclinical phase of drug development do not reliably detect potential hepatotoxicity of a novel agent; the concordance between liver toxicity in animals and humans is poor. Hepatic adverse reactions are therefore one of the top three organ toxicities identified in phase I to III trials, and are responsible for 22% of 79 drug candidates being dropped from clin- ical development. As hepatic adverse reactions are too low in inci- dence to be detected in clinical trials, the hepatotoxic potential of new medications may only be recognized when a large number of people have been exposed to the drug; therefore, hepatotoxicity has been the second most common reason for withdrawal of approved drugs from the market worldwide, accounting for 32% of 47 such drug withdrawals between 1975 and 2007. Incidence and prevalence of DILI Idiosyncratic DILI due to commonly used medications continues to be encountered in clinical practice. A prospective population-​based study from Iceland estimated the crude incidence of DILI to be 19 per 100 000 inhabitants per year. The incidence of DILI was similar in women and men, but increased from 9 per 100 000 among 15-​ to 29-​year-​olds to 41 per 100 000 among those over 70 years of age. The increase in DILI incidence with age has been attributed to increasing use of medications with age. The incidence of acute serious liver in- jury requiring hospitalization has been estimated to be 0.7 to 1 per 100 000 population per year. In a recent audit from the United Kingdom, involving 881 con- secutive patients presenting with jaundice in whom biliary ob- struction had been ruled out by imaging, DILI was the underlying

section 15  Gastroenterological disorders 3156 aetiology in 15% of cases and the second most common cause of hepatocellular jaundice after alcoholic liver disease, which ac- counted for 25% of cases. Idiosyncratic DILI contributes to 7 to 22% of cases of acute liver failure worldwide, highlighting the potentially serious consequences of this adverse reaction. Drugs implicated Spontaneous reporting, case reports or series, and more recently hepatotoxicity registries have been the main source of information regarding hepatic adverse reaction due to specific drugs or a class of drugs. In addition to variability of reporting, lack of an accurate denominator (number of people taking the particular medica- tion) means that neither the incidence of DILI due to a particular medication nor its relative contribution to the burden of DILI can be reliably estimated. This issue has been exemplified by the find- ings of a recent prospective study which estimated that 1 in 2350 taking co-​amoxiclav and 1 in 133 on azathioprine developed DILI when compared to previous estimates of 1 in 10000 and 3.4 in 100, respectively. A systematic evaluation of reports of hepatotoxicity due to drugs compiled at the website LiverTox (established by the National Institutes of Health, Bethesda, Maryland, United States of America) has resulted in the categorization of drugs based on the number of convincing reports in the published literature. This process concluded that 353 drugs (excluding herbal remedies, dietary supplements, and illicit substances) were linked to DILI, of which 48 were implicated in more than 50 cases each and included in the highest category of causes of DILI (the vast majority are listed in Table 15.24.3.1). Over 80% of the drugs included in this category were associated with more than 100 reports of DILI, positive rechallenge (recurrence of DILI on re-​exposure) were described with over 90% of these agents, and all of these drugs were linked to death. Table 15.24.3.1 includes a list of common agents associated with particular forms of drug-​induced liver disease. Prognosis In the population-​based cohort, 1% of patients presenting with DILI die, while large registries of idiosyncratic DILI (consisting mainly of cases from secondary care) report that 5 to 10% of patients die or receive liver transplantation in a period of 6 months after DILI onset. Those who present with jaundice are more likely to reach these outcomes compared to those who present with less severe manifestations (13 vs 4%), and a hepatocellular pattern of DILI has a worse prognosis than a cholestatic or mixed pattern. The prognosis of those who develop acute liver failure as a consequence of idiosyn- cratic DILI is worse than that due to other aetiologies. Once acute liver failure develops in patients with DILI, 50 to 80% either die or require transplantation in contrast to 15 to 40% of those secondary to paracetamol overdose. Acute liver injury due to drugs resolves in those who survive the initial episode, but evidence of persistent liver injury (‘chronicity’) 12 months after the onset of DILI has been observed in a small, yet significant proportion of patients on long-​term follow-​up. Several longitudinal cohorts have reported that 6 to 14% of patients have persistent elevation of liver enzymes. In those who were investigated with liver biopsy, chronic hepatitis, fibrosis, ductopenia (vanishing bile duct syndrome), and cirrhosis have been detected histologically. Among 685 survivors of DILI with jaundice at presentation from one cohort, 3.4% were hospitalized over 10 years of follow-​up for reasons related to their liver disease. Diagnoses of autoimmune Table 15.24.3.1  Common drugs associated with specific forms of drug-​induced liver diseases Phenotype of liver disease Drug group Medications Idiosyncratic DILI Antimicrobials Co-​amoxiclav, erythromycin, flucloxacillin, interferon alpha/​peginterferon, isoniazid, ketoconazole, minocycline, nevirapine, nitrofurantoin, pyrazinamide, rifampicin, co-​trimoxazole, and sulphonamides Central nervous system Carbamazepine, chlorpromazine, dantrolene, halothane, phenytoin, and valproate Cardiovascular Amiodarone, hydralazine, methyldopa, quinidine, statins (atorvastatin and simvastatin) Immunomodulatory Azathioprine/​6-​mercaptopurine, infliximab, interferon beta, methotrexate, and thioguanine Antineoplastic Busulfan, floxuridine, and flutamide Rheumatological Allopurinol, auranofin/​gold products, diclofenac, ibuprofen, nimesulide, and sulindac Endocrine Anabolic androgenic steroids, oestrogens/​progestins, and propylthiouracil Others Disulfiram and ticlopidine Autoimmune hepatitis Diclofenac, halothane, indomethacin, infliximab, methyldopa, minocycline, nitrofurantoin, and statins Secondary sclerosing cholangitis Amiodarone, atorvastatin, co-​amoxiclav, gabapentin, infliximab, 6-​mercaptopurine, sevoflurane, and venlafaxine Granulomatous hepatitis Allopurinol, carbamazepine, methyldopa, phenytoin, quinidine, and sulphonamides Acute fatty liver Amiodarone, didanosine, stavudine, valproate, and zalcitabine Drug-​associated fatty liver disease Methotrexate, 5-​fluorouracil, irinotecan, and tamoxifen Nodular regenerative hyperplasia Azathioprine, busulphan, bleomycin, cyclophosphamide, chlorambucil, cysteine arabinoside, carmustine, doxorubicin, 6-​ thioguanine, and oxaliplatin Ductopenic (vanishing bile duct) syndrome Azathioprine, androgens, co-​amoxiclav, carbamazepine, chlorpromazine, erythromycin, oestradiol, flucloxacillin, phenytoin, terbinafine, co-​trimoxazole Liver tumours Anabolic androgenic steroids and oral contraceptives

15.24.3  Drug-induced liver disease 3157 hepatitis as well as cirrhosis leading to decompensation and death were observed as long-​term outcomes. Risk factors Pathogenesis of DILI involves interaction of a number of drug and host-​related factors which determine the occurrence of these rare events during entirely appropriate therapeutic use of medications (Fig. 15.24.3.1). There are indications that certain risk factors may also influence the phenotype of the adverse reaction, its severity, or duration. Nongenetic factors Idiosyncratic DILI is clearly distinct from overdose, but the thera- peutic dose of a drug could influence the amount of reactive metab- olite formed and hence make further downstream events leading to clinical DILI more likely. Drugs with a daily dose of up to 10 mg are less likely to be associated with DILI than those with a dose of at least 50 mg/​day dose. The latter group of drugs is also associated with severe consequences of DILI, such as acute liver failure, transplant- ation, and death. Similarly, medications with greater than 50% hep- atic metabolism and biliary excretion are more frequently associated with severe DILI. Although there is no clear association between age and sex and susceptibility to DILI, these host factors may influence the phenotype of DILI; while hepatocellular pattern of DILI is more common in women less than 50 years of age, men over 60 years of age develop a predominantly cholestatic pattern of DILI. Genetic susceptibility Absorption, distribution, metabolism, and excretion genes Since drug absorption, distribution, metabolism, and excretion are the key determinants of variability in drug responses in humans, genes that encode proteins involved in regulating these aspects of drug disposition have been investigated as risk factors for DILI. Cytochrome P450 Genes from the cytochrome P450 family have potentially a key role in determining susceptibility to DILI due to the involvement of these enzymes in oxidative metabolism of drugs, including the formation of reactive intermediates. One such example is that of bosentan (the endothelin receptor antagonist)-​related DILI with the CYP2C92 variant which is associated with decreased enzyme activity. Isoform CYP2B6 has been linked to DILI secondary to ticlopidine and efavirenz; oxidative metabolism of both of these drugs is mediated by CYP2B6 enzyme activity. The alleles CYP2B61H and 1J associ- ated with increased CYP2B6 activity have been found to increase the risk of ticlopidine DILI, while the CYP2B66 allele, associated with decreased CYP2B6 activity and higher levels of plasma efavirenz, is a risk factor for DILI from this drug. UDP glucuronosyltransferases Conjugation with glucuronic acid is a major pathway of drug me- tabolism. Drugs which include carboxylic acid groups form acyl glucuronides, and these conjugates may form covalent adducts with cellular proteins leading ultimately to DILI. Other glucuronides such as phenol glucuronides have also been implicated in DILI. Slow metabolism of tolcapone may be associated with hepatotox- icity as polymorphisms in the gene encoding the main tolcapone metabolizing enzyme UGT1A6 are significantly associated with ele- vated transaminase levels. Another UDP-​glucuronosyltransferase gene UGT2B7 has been linked to liver injury from diclofenac. Possession of UGT2B72 is associated with higher glucuronidation and increased hepatic levels of diclofenac acyl glucuronide, hence an increased risk of hepatic adverse reaction. In addition, a recent genome wide association study (GWAS) demonstrated that two intronic single nucleotide polymorphisms (SNPs) in UGT2B7 and another in the adjacent UGT2B4 gene were associated with DILI due to diclofenac. N-​acetyltransferases The N-​acetyltransferases conjugate xenobiotics with acetyl groups; NAT1 and NAT2 are two isoforms. Isoniazid, an essential compo- nent of most antituberculosis regimens, is metabolized by genetic- ally polymorphic N-​acetyltransferase 2 (NAT2). NAT2 metabolic activity depends on the number of active alleles (NAT24 and *12). A meta-​analysis of 38 studies involving 2225 patients and 4906 controls concluded that slow acetylators (without any active alleles) develop hepatotoxicity more often than rapid acetylators (with two active alleles); the risk ratio of the association between NAT2 genotype and adverse hepatic reaction varied among dif- ferent ethnic groups. ATP-​binding cassette transporters ATP-​binding cassette (ABC) transporter family gene products transport both bile acids and drugs. ABCC2 has a major role in the biliary excretion of many glucuronide conjugates. Carriage of an up- stream SNP in ABCC2 (C-​24T) has been associated with the risk of DILI among diclofenac users; this SNP lowers the expression of the ABCC2 protein and leads to cellular accumulation of the reactive diclofenac acyl glucuronide. In a study based in Korea, one SNP in linkage disequilibrium with C-​24T and another in the promoter region of ABCC2 were risk Daily dose, hepatic metabolism, biliary excretion HLA genotypes Cytochrome P450, UDP-glucuronosyl transferase, N- acetyltransferases, pregnane X receptor, ABC transporters Fig. 15.24.3.1  Genetic and nongenetic risk factors that contribute to the development of DILI.

section 15  Gastroenterological disorders 3158 factors for DILI caused by a range of drugs. Genotypes of ABCB1 which codes for another transporter have been associated with DILI due to nevirapine. Pregnane xenosensing receptor The nuclear receptor pregnane xenosensing receptor (PXR) is a transcriptional regulator for several genes responsible for metab- olism and disposition of both drugs and endogenous factors such as bile acids. Numerous drugs act as PXR agonists. SNPs in the PXR gene (NR1I2) have been associated with an increased risk of DILI due to flucloxacillin and diclofenac. Antioxidant genes It is plausible that an individual’s ability to deal with oxidative stress generated by reactive metabolites is one of the determinants of sus- ceptibility to DILI. Accordingly, genotypes of isoforms of gluta- thione S-​transferases (GSTM1 and -​T1), glutathione peroxidase I  (GPX1), and mitochondrial manganese-​dependent superoxide dismutase (SOD2) have been investigated as risk factors for DILI. Perspective Overall, it is difficult to draw firm conclusions from the studies dis- cussed previously due to heterogeneity between the cohorts and lack of replication. It is also important to note that most of the evidence related to the role of absorption, distribution, metabolism, and ex- cretion genes in DILI has come from candidate gene case–​control studies with small sample sizes, variable case definitions, and the modest relative risks associated with particular alleles or genotypes. Human leucocyte antigen genetic risk factors Several candidate gene studies and GWAS have found consistent as- sociations between both human leucocyte antigen (HLA) class I as well as class II alleles and DILI. Strongest of such associations is that between HLA‐B5701 and flucloxacillin-​induced liver injury, where 84% of patients carried the risk allele (compared to 5% of the population-​based controls) with an 81-​fold increased risk of DILI. HLA class II haplotype DRB11501-​DQB10602 has been found to be a risk factor for co-​amoxiclav DILI consistently across different ethnic groups; the haplotype is found in 53 to 70% of patients com- pared to 12 to 33% of controls. Association between DILI due to lapatinib (a kinase inhibitor) and DRB107:01-​DQA102:01 has also been confirmed in two different cohorts. However, as there is extensive linkage disequilibrium in the major histocompatibility complex (MHC) region, it is difficult to conclude that HLA alleles which have the strongest associations are causally related to par- ticular forms of DILI. In addition to influencing the susceptibility to DILI, specific HLA genotypes have also shown protective associations; an 80% reduc- tion in co-​amoxiclav DILI was seen in those carrying the DRB107 allele. In contrast, DRB107 is associated with an increased risk of flucloxacillin DILI, while DRB115 is associated with a reduced risk. Recently, a GWAS demonstrated an association between the HLA class I allele A*33:01 and DILI in general, and the cholestatic or mixed form of DILI in particular. DILI secondary to a number of struc- turally dissimilar compounds including terbinafine, fenofibrate, ticlopidine, sertraline, enalapril, and erythromycin contributed to this association, highlighting a crucial role for adaptive immune re- sponse in the pathogenesis of DILI. Pathogenesis It is increasingly clear that the grouping of DILI as metabolic or immunological idiosyncrasy is too simplistic. The rarity of idio- syncratic DILI among those exposed to a drug indicates that com- binations of a number of drug-​specific and host-​related factors are involved in its pathogenesis. Formation of protein reactive molecules (haptens) Drugs (prohaptens) in general are low molecular weight organic chemicals and therefore too small to be antigenic. The liver is central to the biotransformation of most drugs, a process which generally leads to the formation of stable metabolites and their safe excretion. Genetic and environmental factors that influence the expression and activities of the drug metabolizing enzymes (phases I and II), transporters involved in the excretion (phase III) of drug metabolites, and PXRs that regulate a number of these pro- cesses, together determine the rate of formation and accumulation of reactive metabolites. Overwhelming oxidative stress induced by reactive metabolites can lead to hepatocellular injury, particularly when cellular defence is impaired or these reactive metabolites covalently bind to cellular proteins interfering with vital cellular function. However, unlike in the case of hepatotoxicity as a result of paracetamol overdose, for- mation of reactive metabolites alone is insufficient to cause clinically significant idiosyncratic DILI. Instead, development of subclinical hepatocyte injury may underlie asymptomatic elevations of liver enzymes seen more frequently in association with exposure to medications. These initial steps are probably necessary precursors of downstream events in pathogenesis (Fig. 15.24.3.2), hence drug-​ specific factors such as daily dose, lipophilicity, hepatic metabolism, and biliary excretion influence the hepatotoxic potential of a par- ticular compound. Role of drug-​specific antigens and antibodies The importance of further downstream events in the development of DILI is highlighted by the fact that an increasing number and range of medications such as diclofenac, antibiotics, and antitubercular agents taken in their standard therapeutic doses have been asso- ciated with drug metabolite–​protein adducts. Antibodies to drug-​ related adducts have also been found in those taking diclofenac in the absence of DILI, although these adducts have been detected more frequently in patients with DILI. A wide range of anti-​isoniazid, anticytochrome P450, and autoantibodies have been demonstrated in most of a group of patients with antituberculosis therapy-​induced acute liver failure, although the role of these antibodies in the devel- opment of organ damage remains unclear. Adaptive immune response The observations that there is a period of latency between the ex- posure to the drug and manifestation of DILI, as well as its re- currence with the re-​exposure to the drug (consistent with the formation of memory T cells) following its initial resolution on drug withdrawal, suggest that the adaptive immune response contributes to underlying mechanisms. Emerging evidence from recent GWASs further establishes a central role of components of the adaptive im- mune system, especially drug-​specific T cells, in mediating the im- mune responses in the pathogenesis of DILI.

15.24.3  Drug-induced liver disease 3159 HLA molecules are central to the activation of T cells responsible for initiating the inappropriate immune response that underlies DILI. Both branches of the highly specific adaptive immune re- sponse rely on the selective presentation of antigens to T cells by HLAs, highly polymorphic proteins also known as MHC proteins. MHC class I molecules are expressed by almost all nucleated cells, including hepatocytes as well as biliary epithelial cells, and these are encoded by the HLA-​A, HLA-​B, and HLA-​C loci. MHC class I pro- teins usually associate with peptide antigens consisting of 9 to 11 amino acids generated by the partial degradation of self-​proteins which could include drug metabolite–​cellular protein adducts. The MHC I–​antigen complex is then expressed on the cell surface and elicits an immune response if a non-​self antigen is recognized, causing the activation of CD8+ T cells, which leads to the cell-​ mediated killing of the original cell. The first GWAS involving DILI demonstrated that possession of the HLA-​B5701 allele was associated with an 81-​fold increased risk of DILI on exposure to flucloxacillin when compared with ancestry-​matched controls. Another GWAS involving co-​amoxiclav DILI described a novel association involving HLA-​A02:01. Both flucloxacillin and co-​amoxiclav DILI cohorts include a predom- inantly cholestatic/​mixed pattern of DILI cases. Most recently, a GWAS demonstrated an association between DILI, treated as a single phenotype, and HLA-​A*33:01; this association was stronger with cholestatic/​mixed pattern of cases and strongest with terbinafine DILI. HEPATOCYTE BILE CANALICULUS DRUG DRUG DRUG DRUG endogenous protein no presentation so no response metabolite Covalent adduct damage ‘danger’ signals proliferation Antibodies processing + HLA processing + HLA Hapten pathway self protein gives no response MHC I presentation activated T cell destroys hepatocyte MHC II presentation TCR activates cytotoxic immune response activates immune responses if costimulation by cytokines/danger signals Hapten pathway pathways altered peptide repertoire pi pathways pi pathway non-covalent direct binding no APC required APC Covalent adduct Covalent adduct Covalent adduct other endogenous proteins MEMORY B CELL B CELL Y Y Y Y Y CD4+ T CELL CD8+ T CELL metabolite metabolite endocytosis endogenous protein Covalent adduct Fig. 15.24.3.2  Putative mechanisms underlying the pathogenesis of idiosyncratic DILI. pi, pharmacological interaction.

section 15  Gastroenterological disorders 3160 MHC class II proteins are only expressed by specialized antigen-​ presenting cells and are encoded by the HLA-​DP, HLA-​DQ, and HLA-​DR loci within the MHC genetic region. MHC class II proteins have a larger binding cleft that can accommodate 12 to 25 residues of an antigenic peptide often derived from an extracellular, non-​ self protein (processed in the endosome following endocytosis). These MHC class II–​antigen complexes are recognized by CD4+ T cells, which subsequently elicit an immune response. The asso- ciation of a single HLA allele with DILI due to several chemically unrelated compounds has been observed in relation to the associ- ation of DRB115:01 with co-​amoxiclav and lumiracoxib, as well as DRB107:01 with DILI from lapatinib and ximelagatran. The associations of A33:01 with DILI in general and DILI sec- ondary to a number of structurally dissimilar compounds including terbinafine, fenofibrate, ticlopidine, sertraline, enalapril, and erythromycin, together with recent findings from in vitro studies on T-​cell responses to flucloxacillin and amoxicillin–​clavulanate, sup- port the hypothesis that either the parent drug or metabolites bind covalently to cellular or circulating protein to form adducts. The drug metabolite–​protein complex then binds to the peptide binding groove of HLA molecules leading to activation and differentiation of T cells with a consequent adaptive immune response-​mediated liver injury (Fig. 15.24.3.2). Evidence that most drugs showing the A33:01 association undergo hepatic metabolism and biliary excre- tion may explain the association of A33:01 with a cholestatic pat- tern of DILI and could indicate that metabolites contribute to the mechanism leading to hepatotoxicity. In the case of co-​amoxiclav, neither the amoxicillin nor the clavulanic acid components are subject to P450-​mediated metab- olism, and in the case of flucloxacillin, the extent of metabolism is very limited. However, activation of T cells by flucloxacillin requires covalent binding to protein and presentation of the drug by antigen-​ presenting cells expressing HLA-​B57:01; broadly similar findings have been reported for co-​amoxiclav-​induced T-​cell proliferation. Pharmacological interaction concept The pharmacological interaction concept hypothesizes that drugs act directly via noncovalent interactions with MHC proteins or T-​ cell receptors without the presence of an antigenic peptide. Drugs could also interact with peptides that are already associated with an MHC molecule to activate T cells. In the case of ximelagatran, neither the drug nor its metabolites bind covalently to proteins specifically, hence neoantigen formation required for the hapten pathway does not occur. However, in vitro studies have demon- strated that ximelagatran as well as its intermediate metabolite melagatran-​ethyl can directly bind to an HLA-​DRB10701 mol- ecule, indicating that pharmacological interaction may be the underlying mechanism leading to the activation of immune re- sponse (Fig. 15.24.3.2). Altered peptide repertoire model According to this model, drugs can noncovalently occupy sites within the peptide binding groove of MHC proteins, hence altering the specificities of the MHC peptide binding. This leads to the pres- entation of self-​peptide antigens that are different to those normally bound. This has been proposed as the central mechanism mediating the cutaneous hypersensitivity reaction secondary to abacavir. In the experiments that described this mechanism, flucloxacillin did not modify the affinity of HLA-​B5701-​binding peptides for HLA, indicating that the particular mechanism may not be involved in DILI. Danger signal This ‘costimulation or danger hypothesis’ proposes that immune ac- tivation requires two signals, first an engagement of the T-​cell re- ceptor with an MHC–​peptide complex presenting the antigen, then a second costimulatory ‘alarm or damage signal’ from injured or dis- tressed cells. Danger signals are released by cells following damage caused by infection, toxins, and sterile inflammation. Immune rec- ognition of danger signals occurs through pattern recognition re- ceptors including Toll-​like receptors expressed by most cells found in the liver. In this context, it is interesting to note that antibiotics—​ even with their short duration of exposure (as prescribed in courses of days to weeks)—​are a group of drugs commonly associated with DILI; it plausible that ongoing sepsis could act as a costimulatory signal. In addition to pathogen-​associated molecular patterns (rep- resenting exogenous danger), damage-​associated molecular pat- terns (representing endogenous damage) can also be recognized by Toll-​like receptors. Drugs or their reactive metabolites may cause subtle hepatocyte injury or bind to cellular components disrupting their function. Damage-​associated molecular patterns released as a result of subclinical injury may act as the neces- sary costimulatory signal leading to the activation of antigen-​ presenting cells to trigger an immune-​mediated hepatocyte and/​ or cholangiocyte damage. Diagnosis Hepatotoxicity shares its manifestations with liver diseases from other aetiologies and therefore has to be considered in the differ- ential diagnosis of all acute presentations of liver disease, including those presenting with what appears to be hepatic manifestations of systemic diseases. Specific drugs could also be risk factors for certain forms of chronic liver diseases. Both misinterpretation of liver biochemistry results and failure to recognize the possibility of specific drug therapy as an underlying reason behind a particular pattern of liver biochemical abnormalities continue to occur. One hospital-​based study found that a proactive system identified a 12-​fold higher incidence of acute drug-​induced liver enzyme elevations compared to that identified in routine clinical practice, hence raising suspicion is the first step in the process of diagnosis of DILI (Fig. 15.24.3.3). Diagnosis of DILI is incorrectly made in half of cases; failure to identify a drug as the cause of clinical manifestation, as well as missing a correct alternative diagnosis, both occur in routine practice. Accuracy of clinical diagnosis of DILI (about 45%) is a problem both in primary care and in hospital settings. Delay in diagnosis can mean continued exposure to the offending medi- cation, with consequent worsening of DILI leading to acute liver failure in some cases. Prolonged exposure to drugs has also been associated with delayed resolution of DILI, even after withdrawal of the drug, and with chronicity in a few cases. Missed diagnoses such as biliary obstruction from gallstones and autoimmune hepa- titis due to incorrect attribution of the clinical problem to DILI can

15.24.3  Drug-induced liver disease 3161 have serious consequences, hence systematic assessment is the key to an accurate diagnosis. Causality assessment methods These involve structured evaluation of several factors in relation to the clinical presentation that support or refute the link between the drug and the manifestations. The temporal relationship be- tween intake and discontinuation of the suspected drug and onset and disappearance of the manifestation is one of the important factors to consider in the diagnosis. This requires precise informa- tion regarding all the drugs, their doses, and durations, including nonprescription (over-​the-​counter), herbal, and complementary medications which patients may not consider as relevant. Most DILI occurs between day 4 and 3 months of initial therapy, although some occur later during the first year of treatment. By contrast, DILI due to some drugs (e.g. nitrofurantoin) typically appears more than a year after initial exposure. Ischaemic hepatitis with its characteristic rapid ALT elevation peaking within the first 72 h following circula- tory shock, cardiorespiratory arrest, or exacerbation of heart failure is an important differential diagnosis to consider, especially in sec- ondary care. Similarly, perioperative hypotension manifests with liver injury earlier during the postoperative period than DILI from anaesthetic agents. Different components that form causality assessment have been incorporated into tools that assist in a structured evaluation of cases suspected to have DILI. Two such tools are the Roussel Uclaf Causality Assessment Method, developed by Council for International Organizations of Medical Sciences, and the Clinical Diagnostic Scale. These tools attribute scores (numerical weighting) with regards to specific domains that include the temporal relationship between drug exposure and clinical features, the course of these manifestation once the drug is discontinued, the recur- rence of liver injury on re-​exposure to the drug, rigour of exclu- sion of alternative diagnoses, the presence or absence of risk factors and extrahepatic features of an adverse liver reaction, as well as the strength of previous reports of a particular type of DILI. These val- idated tools were developed to facilitate pharmacovigilance of hep- atic adverse reactions and have been effectively used to harmonize phenotyping of DILI between international groups of researchers. Although it is unrealistic to apply causality assessment tools rou- tinely in clinical practice, these provide a template on which a reli- able process of diagnosis and decision-​making can be based. Acute biliary obstruction (e.g. from gallstones within the common bile duct) accounts for more than half the cases of jaundice, and one-​ quarter of cases presenting with an acute hepatocellular pattern of liver enzyme increase (AST >400 IU/​litre) and 5% of those with ALT greater than 1000 IU/​litre. It is therefore imperative to perform hepatobiliary imaging first to exclude this aetiology. Autoimmune hepatitis has an acute presentation in about 40% of people, and it can have a remitting and relapsing course. Early diagnosis and intervention is crucial to improve outcomes in both DILI and autoimmune hepatitis, hence in-​depth investigations are of paramount importance. Ischaemic hepatitis is associated with greater than 50% in-​hospital mortality and should be distinguished from DILI as comorbidity associated with ischaemic hepatitis precludes the consideration of liver transplantation, even when fulminant liver failure ensues. In about 80% of patients with ischaemic injury, lactate dehydrogenase reaches very high concentrations with an ALT/​lactate dehydro- genase ratio less than 1, a pointer that can be used in the diagnostic Acute rise in liver biochemistry New-onset manifestations Consider DILl Drug history Causality assessment Consider specific tests for DILl • HLA genotyping • Lymphocyte transformation test New systemic manifestations • Skin rash • Eosinophilia • Generalized itching • Jaundice • Acute liver failure • New medication introduced (with in the past 3 months in particular) • Course of antibiotics in the past 6 weeks • Over-the-counter medications • Herbal remedies or complementary medications • Temporal relationship with the drug and the manifestation • Exclusion of biliary obstruction • Evidence to support or refute alternative explanation for the manifestation • Tests that support or refute alternative diagnosis

section 15  Gastroenterological disorders 3162 process. Recently, hepatitis E infection has become a more common cause of acute viral hepatitis than hepatitis A, B, and C infections; cytomegalovirus, Epstein–​Barr virus, and herpes zoster virus also contribute a few cases, all of which resemble DILI in their clinical features. The list of other exclusions to secure a confident diagnosis of DILI is exhaustive: investigations should be tailored to suit the particular clinical context. Role of liver biopsy DILI can cause any known pattern of liver pathology, but certain histological features are particularly suggestive of drug-​induced aetiology although there are no specific diagnostic histological fea- tures. The benefits of performing a liver biopsy should be weighed against the disadvantages and its limitations. Liver biopsy is worth- while when (1) autoimmune hepatitis is one of the differential diag- noses under consideration (Fig. 15.24.3.4), (2) the event does not resolve as expected on drug discontinuation, and (3)  in circum- stances where the clinical/​laboratory features are atypical, or (4) the patient appears to suffer an as yet unrecognized form of DILI. Genetic tests A strong and consistent association between HLA genotypes and DILI has raised the prospect of the potential use of genetic testing in the risk stratification of patients prior to therapy, but the incidence of DILI is too low to use such testing routinely. However, most HLA alleles associated with DILI have a very high negative predictive value of greater than 0.95; hence, they can be used to rule out ad- verse hepatic reactions due to particular drugs when the certainty of diagnosis is of paramount importance. Key examples of associ- ations of specific HLA alleles with DILI from particular medications include HLA-​B5701 with flucloxacillin, HLA-​DRB11501 with co-​amoxiclav, and HLA-​A33:01 with terbinafine and other drugs (fenofibrate, ticlopidine sertraline, enalapril, and erythromycin). A high negative predictive value of a genetic test can also be used to identify the correct agent underlying DILI when the patient has been exposed to two concomitant medications, both with the pro- pensity to cause DILI. HLA genotyping is being carried out regularly in centres with transplantation programmes and these services are readily access- ible to other secondary care hospitals. In particular, HLA B5701 genotyping is routinely performed prior to prescription of abacavir (effectively reducing cutaneous hypersensitivity due to the drug), hence protocols and processes are well established with an ability to perform genotyping within 1 day of receipt of a sample. Lymphocyte transformation test This investigation, also called the lymphocyte proliferation or stimu- lation test, measures the proliferation of T cells from the blood sam- ples of a patient suspected to have suffered DILI in response to that particular drug. Principles underlying this test have been supported by the generation of drug-​specific T-​cell clones from individuals who have had a positive response, and also by the pharmacological interaction concept which states that drugs can directly interact with the T-​cell receptor, without previous metabolism or need to bind to proteins. When applied to a cohort of well-​characterized patients with DILI, results of lymphocyte transformation tests have been variable, ranging from occasional positive cases based on reports from Europe to about a 45% positive rate in cohorts from Japan. In addition, when evaluated in the context of cutaneous hypersensi- tivity, the test has an estimated 15% false-​positive rate. The lympho- cyte transformation test is cumbersome, technically demanding, and hence not widely available. Other forms of drug-​induced liver disease Drug-​induced autoimmune hepatitis Many drugs have been reported to have induced the syndrome that shares many features of idiopathic autoimmune hepatitis. In a cohort of cases with the diagnosis of autoimmune hepatitis, 9% were con- sidered to be induced by drugs, and conversely drug-​induced auto- immune hepatitis accounts for 9% of all DILI. Most of these drugs have appeared in case reports or small case series and include nitro- furantoin, minocycline, diclofenac, statins, and antitumour necrosis factor-​α agents (Table 15.24.3.1). Drug-​induced autoimmune hepa- titis is difficult to distinguish from the idiopathic form as both have very similar biochemical, clinical, and liver histological features, hence the causal relationship between the drug and autoimmune hepatitis can be best established only when the manifestations re- solve completely on drug withdrawal and do not recur on prolonged follow-​up (over 2 years). Secondary sclerosing cholangitis Previously, sclerosing cholangitis had been described following transarterial infusion of chemotherapeutic agents, but these are re- sults of ischaemic injury to the biliary tract rather than toxicity from chemotherapeutic agents themselves. However, secondary scler- osing cholangitis with diffuse inflammatory stricturing of the biliary tree on magnetic resonance cholangiopancreatography has more re- cently been described in a small proportion of patients presenting with acute cholestatic DILI (Fig. 15.24.3.5), over 90% of whom were women, with two-​thirds presenting with jaundice. Drugs impli- cated were co-​amoxiclav, sevoflurane, amiodarone, infliximab, 6-​ mercaptopurine, gabapentin, venlafaxine, and atorvastatin. Fig. 15.24.3.4  Liver biopsy showing portal inflammation and interphase hepatitis secondary to diclofenac-​induced autoimmune hepatitis.

15.24.3  Drug-induced liver disease 3163 Granulomatous hepatitis Granulomata are circumscribed accumulations of macrophages, some of which may fuse to form multinucleated giant cells, with a surrounding rim consisting of lymphocytes that have developed with stimulation of mononuclear cells from a variety of cytokines. Considering the long list of infectious and immunological conditions associated with hepatic granulomata, the diagnosis of drug-​related granulomatous hepatitis depends upon a temporal relationship be- tween exposure to the drug and the clinical manifestation, ruling out an alternative explanation for histological changes, and previous reports in the literature. Allopurinol, carbamazepine, phenytoin, quinidine, methyldopa, and sulphonamides are some of the medi- cations which have been associated with this form of hepatotoxicity. Acute fatty liver This is a distinct form of acute hepatotoxicity associated with drugs that affect mitochondrial function. Microvesicular steatosis and the absence of glycogen in the hepatocytes are characteristic histological features as the liver uses glycolysis to compensate for the lack of ATP produced by mitochondria. Impaired mitochon- drial function leads to apoptosis and liver failure manifesting with hypoglycaemia, lactic acidosis, hyperammonaemia, and cerebral oedema. Dramatically rapid development of organ failure precedes the clinical syndrome, with an acute rise in liver enzymes and jaun- dice that follow, hence having a high index of suspicion is crucial in identifying the drug aetiology when approaching a patient with ‘anicteric hepatic encephalopathy’. Described initially as ‘Reye’s syndrome’ in children treated with salicylate, the incidence of this condition has been reduced markedly by restricting the use of aspirin in those under the age of 16 years and the use of parenteral preparations of tetracycline. Sodium valproate is one of the drugs currently used that has been linked to the de- velopment of acute fatty liver; idiosyncratic hepatotoxicity occurs 1 in 37 000 people taking the drug, and the risk increases to 1 in 500 in children on combination of multiple drugs. A case–​control study demonstrated an association between variation in the polymerase γ gene, POLG, which codes for the mitochondrial DNA polymerase γ, and valproate-​induced hepatotoxicity. Nucleoside analogue reverse transcriptase inhibitors are one class of drugs which are liable to cause hepatotoxicity by interfering with mitochondrial function. Symptomatic adverse hepatic reac- tions occur with an incidence of 1.2 times per 1000 person/​year. Stavudine, zalcitabine, and didanosine have higher affinities for mitochondrial DNA polymerase γ, leading to the depletion of mito- chondrial DNA, and hence have a higher rate of hepatotoxicity than abacavir, zidovudine, lamivudine, and tenofovir. Early recognition and withdrawal of the drug is the critical step in the management of these potentially life-​threatening adverse events. Fatty liver disease Nonalcoholic fatty liver disease (NAFLD) is an entity associated with accumulation of fat in more than 5% of hepatocytes, with or without inflammation and fibrosis, in those who do not consume alcohol over the amount considered moderate (14 units in men and women per week). When the condition is associated with metabolic syndrome or idiopathic it is considered primary NAFLD; drugs are the aetiology behind some secondary NAFLD cases. This entity is different from acute fatty liver described previously. Methotrexate After more than five decades of clinical use, methotrexate is  the  most  frequently  used  nonsteroidal  immunosuppres- sant  therapy  worldwide, with rheumatoid arthritis and psoriasis being common indications for its use. Reports that long-​term methotrexate therapy is associated with fatty infiltration and fi- brosis with a potential to progress to cirrhosis have resulted in a plethora of guidelines recommending intense monitoring regi- mens, including liver biopsies at regular intervals. The proportion of patients estimated to have any degree of liver fibrosis varies from 6 to 72%; with advanced fibrosis ranges from 0 to 33%, and cirrhosis from 0 to 26%. Such wide ranges of reported pathology are due largely to heterogeneity of cohorts, study designs, methods of evaluating histological changes, and case mix. A recent study highlighted the rarity of decompensated cirrhosis associated with methotrexate therapy; of over 150 000 adults who had been listed for or received liver transplantation during a 24-​year period, only 117 (0.07%) had methotrexate-​associated cirrhosis. Methotrexate polyglutamate within the cell interferes with pyrimidine and purine synthesis, through which it exerts its therapeutic effect. In addition, methotrexate indirectly affects methylenetetrahydrofolate reductase and hence the generation of methionine from homocysteine. Excess homocysteine induces endoplasmic reticulum stress, which, when unresolved, leads to fatty infiltration of the liver. Homocysteine, in addition, can also ac- tivate proinflammatory cytokines and activate hepatic stellate cells, leading to liver fibrosis. The development and progression of chronic drug-​associated liver disease is determined by interaction between a number of fac- tors related to the drug (such as cumulative dose), the host (such as SNPs in the methylenetetrahydrofolate reductase gene), and/​or the environment (such as alcohol consumption, obesity, and type 2 diabetes). Caucasian ethnicity and female sex are associated with Fig. 15.24.3.5  Magnetic resonance cholangiopancreatography showing diffuse structuring of intra-​ and extrahepatic bile ducts due to drug-​induced sclerosing cholangitis.

section 15  Gastroenterological disorders 3164 decompensated cirrhosis although it is unclear whether this merely reflects the predominance of women and Caucasians among pa- tients with rheumatoid arthritis and psoriasis respectively. Assessment of the risk:benefit ratio of long-​term methotrexate therapy depends upon the efficacy of the drug in an individual weighed against the rate of progression of hepatic fibrosis. The pri- mary objective of monitoring is to detect hepatic fibrosis that is of clinical significance, yet reversible on withdrawal of the drug. Several clinical algorithms that incorporate noninvasive markers of liver fibrosis such as ‘enhanced liver fibrosis’ panel and transient elastography are currently being evaluated as tools to monitor pa- tients on methotrexate therapy. Tamoxifen Treatment with tamoxifen, an oestrogen-​receptor antagonist, has been associated with accumulation of fat within the liver. In a multicentre trial involving more than 5000 women, tamoxifen therapy was associated with a twofold risk of developing fatty liver over a 5-​year period, with an incidence of 0.4% per year in the treated group compared with 0.2% in the placebo group. This as- sociation was restricted to overweight and obese women, and the increased risk manifested within the first 2 years of treatment. Other factors associated with the development of nonalcoholic fatty liver disease included hypercholesterolaemia and arterial hypertension. Among those who had a liver biopsy, most had mild to moderate nonalcoholic steatohepatitis histologically (Fig. 15.24.3.6), but none progressed to cirrhosis after a median follow-​up of 8.7 years. In a large registry of 810 patients with breast cancer treated with tamoxifen, 16 (2%) developed fatty liver on treatment. Tamoxifen was associated with an eightfold risk of developing fatty liver; age and body mass index were other risk factors. The median time from the start of tamoxifen to the diagnosis of drug-​associated fatty liver disease was 22 months; when tamoxifen was discontinued, liver en- zymes improved. Only two patients had biopsy-​documented cir- rhosis in this registry, although a few more have been described in case reports. Chemotherapy-​associated steatohepatitis Reactive oxygen species generated by chemotherapy and intended to induce tumour cell apoptosis can also lead to the development of steatohepatitis, especially in those with pre-​existent hepatic steatosis; obesity is associated with an increased risk. Drugs com- monly associated with steatohepatitis include 5-​fluorouracil and irinotecan. Chemotherapy-​associated steatohepatitis increases the risk of infections, liver failure, and overall mortality following major liver resections (for hepatic metastasis). Nodular regenerative hyperplasia Some drugs can injure endothelial cells of sinusoids and portal venules with consequent occlusion or dropout of smaller radicles. Widespread vascular changes lead to diffuse nodularity within the hepatic parenchyma. The hepatocytes within the nodule are arranged in plates that are more than one cell in thickness, while hepatocytes are compressed and atrophic into thin, parallel plates between nodules (Fig. 15.24.3.7). Characteristically, the nodules are not separated by fibrosis, although there can be perisinusoidal fibrosis and incomplete fibrous septa. In patients on azathioprine therapy, the cumulative rate of development of nodular regenerative hyperplasia has been estimated to be 0.5% over 5 years and 1.5% in 10 years. Other drugs associated with this form of liver disease are 6-​thioguanine, busulphan, bleomycin, cyclophosphamide, chlor- ambucil, cysteine arabinoside, carmustine, and doxorubicin. In re- cent literature, oxaliplatin is the most common drug associated with this pathology. In a large group of patients treated with oxaliplatin, nodular regenerative hyperplasia was found on histology in 25% and features consistent with sinusoidal obstruction syndrome in over 50% of patients. Liver tumours Liver cell adenoma is a benign neoplasm of the liver with an esti- mated incidence of 3 per million per year. Among regular users of oral contraceptives, its annual incidence is at 3 to 4 per 100 000 al- though it may be lower with newer pills. The hormonal dose and duration of medication have been associated with the risk of ad- enoma development, which is highest in women over 30 years of age after using oral contraceptives for more than 24 months. The morphology of hepatic adenomas, with their extensive prolif- eration of blood-​filled sinusoids supplied by high-​pressure arterial Fig. 15.24.3.6  Liver biopsy showing evidence of fat-​laden hepatocytes and fibrosis due to tamoxifen-​associated fatty liver disease. Fig. 15.24.3.7  Liver biopsy with reticulin stain demonstrating hypertrophic cell plates surrounded by atrophic cell plates typical of nodular regenerative hyperplasia attributed to azathioprine therapy.

15.24.3  Drug-induced liver disease 3165 flow, makes 20 to 40% of them bleed spontaneously causing right upper quadrant pain; intraperitoneal bleeds and ruptures leading to deaths have been reported. Progression to hepatocellular carcinoma occurs in about 10% of adenomas. Ultrasonographic features of hepatic adenomas are nonspecific, but triple-​phase CT scanning or MRI are able to distinguish them from haemangiomas, fibronodular hyperplasia, and hepatocellular carcinomas in the vast majority of patients. A causal association between oral contraceptives and hepatic tumours has been accepted as there have been several reports of regression or resolution of adenomas after cessation of the drugs, although such regression may be less likely when the exposure to oral contraceptives is prolonged. Hormone receptors have also been found in many hepatic adenomas. However, there have also been reports of progression to hepatocellular carcinoma 3 to 5 years after stopping oral contraceptives; hence, surgical resection should be considered based on the site, size, and number of hepatic tumours, as well as certainty regarding their nature on imaging. An association of liver tumours with androgens was first de- scribed in patients with Fanconi’s anaemia on anabolic androgenic steroids. Hepatic adenomas, hepatocellular carcinomas, and others (cholangiocarcinoma and angiosarcoma) occur in those who take androgens for Fanconi’s anaemia and other forms of aplastic an- aemia as well as for other reasons (such as body builders, hereditary angio-​oedema, and immune thrombocytopenia). In a large series including 133 cases, hepatocellular carcinomas were associated with oxymetholone and methyltestosterone, while adenomas were as- sociated with danazol. Both oral and parenteral therapies were as- sociated with the development of tumours, which appeared after a median period of 4 to 6 years of exposure to the medications. Male predominance among cases may be related to exposure of males to this medication. The causal association between anabolic andro- genic steroids and hepatic tumours has been inferred from obser- vations of regression of hepatic lesions upon discontinuation of the medications, but the occurrence of tumours many years after dis- continuation of therapy has been reported. Management The importance of drug-​induced liver disease and DILI in particular lies not in the overall number of cases alone, but in the severity of some reactions and their potential reversibility on prompt discon- tinuation of the offending medication. The role of corticosteroids in the treatment of DILI has not been systematically evaluated, but corticosteroid therapy does not improve clinical outcomes in drug-​induced acute liver failure. However, it is difficult to distinguish drug-​induced autoimmune hepatitis from the idiopathic form; hence, in practice, some pa- tients are treated with corticosteroids at the time of acute presen- tation. Under such circumstances, one should consider withdrawal of all immunosuppressant drugs when clinically appropriate, and then monitor closely. Patients who do not relapse within a period of 24 months of complete withdrawal of immunosuppressive therapy can be considered to have suffered drug-​induced autoimmune hepa- titis. There is no clear evidence that ursodeoxycholic acid therapy changes outcome in the cholestatic form of DILI, although the drug has been widely used for all forms of cholestasis. In 11 to 30% of patients with DILI, re-​exposure to the particular agent will result in the recurrence of the adverse reaction. Recurrent DILI develops more rapidly (generally after days or weeks) than following initial exposure, manifests with jaundice in two-​thirds, requires hospitalization in half of cases, and in 13% leads to death. Inadvertent re-​exposure to the particular drug must there- fore be avoided. The only exception to this could be the first line antituberculosis regimen that is highly effective, relatively inexpen- sive, and yet associated with the well-​recognized risk of DILI. If second-​line antituberculosis medications are entirely unaffordable, then the benefits of reintroduction of the same drugs following resolution of the initial event with careful monitoring should be weighed against the risks of recurrent DILI. Prevention Recent advances in the understanding of the molecular basis of DILI have highlighted the role of adaptive immunity and the contribution of host susceptibility in the pathogenesis of these adverse reactions. Incorporating these factors into the in vitro models used during pre- clinical evaluation of new compounds would improve the detection of the hepatotoxic potential of these molecules early during drug devel- opment. However, it is unrealistic to expect each and every effective drug to be entirely free from adverse effects. Although preprescription pharmacogenetics testing is currently not cost-​effective, it is foresee- able that both genetic and nongenetic factors are incorporated into refined algorithms which will allow minimizing the risk of a particular medication in an individual under specific circumstance. FURTHER READING Aithal GP (2011). Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol, 7, 139–​50. Aithal GP (2015). Pharmacogenetic testing in idiosyncratic drug-​ induced liver injury (DILI): current role in clinical practice. Liver Int, 35, 1801–​8. Aithal GP, et al. (2011). Case definition and phenotype standardiza- tion in drug-​induced liver injury (DILI). Clin Pharmacol Ther, 89, 806–​15. Bjornsson ES, Aithal GP (2014). Immune-​mediated drug-​induced liver injury. In Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice, 2nd edition, pp. 401–​12. Springer, New York. Björnsson ES, et al. (2013). Incidence, presentation, and outcomes in patients with drug-​induced liver injury in the general population of Iceland. Gastroenterology, 144, 1419–​25. Björnsson ES, Hoofnagle JH (2015). Categorization of drugs impli- cated in causing liver injury: critical assessment based upon pub- lished case reports. Hepatology, 63, 590–​603. Dawwas MF, Aithal GP (2014). End-​stage methotrexate-​related liver disease is rare and associated with features of metabolic syndrome. Aliment Pharmacol Ther, 40, 938–​48. Grove JI, Aithal GP (2015). Human leukocyte antigen genetic risk factors of drug-​induced liver toxicology. Expert Opin Drug Metab Toxicol, 11, 395–​409. Hunt CM (2010). Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-​induced liver injury: a systematic review. Hepatology, 52, 2216–​22.

15.24.4 Vascular disorders of the liver 3166

15.24.4 Vascular disorders of the liver 3166

section 15  Gastroenterological disorders 3166 Padda MS, et  al. (2011). Drug-​induced cholestasis. Hepatology, 53, 1377–​87. Ramappa V, Aithal GP (2013). Hepatotoxicity related to anti-​ tuberculosis drugs:  mechanisms and management. J Clin Exp Hepatol, 3, 37–​49. Urban, Daly AK, Aithal GP (2014). Genetic basis of drug-​induced liver injury: present and future. Semin Liver Dis, 34, 123–​33. 15.24.4  Vascular disorders of
the liver Alexander Gimson ESSENTIALS The liver’s complex blood supply and high metabolic activity may be affected in a number of clinical situations when there is reduced splanchnic inflow and impaired hepatic venous outflow. Budd–​Chiari syndrome is caused by obstruction to hepatic venous outflow, usually by thrombosis within the hepatic veins. Causes in- clude myeloproliferative disease, malignancy, and hypercoagulable states. Presentation may be acute, subacute, or chronic, and the diag- nosis requires consideration in any patient presenting with acute liver failure, acute hepatitis, or chronic liver disease. Diagnosis is made by Doppler ultrasonography of the hepatic veins and confirmed with CT or MRI scanning. Management depends on the presentation, but involves anticoagulation in all cases, and thrombolysis, measures to decompress the liver, and liver transplantation in some. Survival is about 75% at 5 years. Other conditions discussed include congestive hepatopathy, ischaemic hepatopathy, hepatic artery aneurysm, and portal vein thrombosis. Budd–​Chiari syndrome Budd–​Chiari syndrome is caused by obstruction to hepatic venous outflow. It is described as primary when the obstruction is caused by a process arising within the veins (e.g. thrombosis), and secondary when due to another process (e.g. compression or invasion by ma- lignancy). It is a rare condition (incidence about 2 per million in both men and women) that can present at any age (median 50 years). Most cases develop insidiously over months, but about 20% present acutely. An underlying predisposing cause can be found in most pa- tients, often in combination (Table 15.24.4.1). Clinical features Acute Budd–​Chiari syndrome, which develops over a few weeks, typically presents with fever, right upper quadrant pain, and tender hepatomegaly, which may be associated with hepatic encephalop- athy if there is fulminant liver failure (5% of cases). Jaundice and ascites develop rapidly but may not be evident at presentation. Liver blood tests show elevation of bilirubin, aminotransferases (typically 100–​500 IU/​L), and alkaline phosphatase (typically 300–​400 IU/​L). Subacute Budd–​Chiari syndrome usually presents with vague epigastric or right upper quadrant pain. Ascites and pedal oedema may be present but are not invariable. The latter is thought to be due to hypertrophy of the caudate lobe of the liver causing com- pression of the inferior vena cava, into which it drains directly, ra- ther than through the hepatic veins. Abnormal venous collaterals may be seen on the abdominal wall. Variceal bleeding can occur. Patients with chronic Budd–​Chiari syndrome develop symptoms as a consequence of cirrhosis. In both subacute and chronic cases, Table 15.24.4.1  Causes of the Budd–​Chiari syndrome Cause Example Notes Myeloproliferative disease (50% cases of Budd–​Chiari syndrome) Polycythaemia rubra vera Essential thrombocythaemia Malignancy (10% cases) Hepatocellular carcinoma Benign liver lesions (5–​10% cases) Hepatic cysts and abscesses Hypercoagulable states Oral contraceptive use Clotting factor mutations, e.g. factor V Leiden, factor II (G20210A) deficiency, antithrombin III, protein C and S deficiency, antiphospholipid syndrome Paroxysmal nocturnal haemoglobinuria Nearly 20% of cases occur in women who are taking the oral contraceptive, are pregnant, or have recently given birth Anatomical abnormality Membranous webs of inferior vena cava and/​or hepatic veins Miscellaneous conditions Behçet’s disease Inflammatory bowel disease Coeliac disease Other autoimmune conditions Idiopathic Some may have undiagnosed myeloproliferative disorder; always check for JAK2 mutations Note: multiple risk factors may contribute in an individual case, for example, a combination of factor V Leiden mutation with a myeloproliferative disorder or use of the oral contraceptive.

15.24.4  Vascular disorders of the liver 3167 serum bilirubin, aminotransferases, and alkaline phosphatase may be normal or mildly/​moderately elevated, but clinically obvious jaundice is rare. Diagnosis The very variable presentations of Budd–​Chiari syndrome mean that it should be considered in the differential diagnosis of patients pre- senting with acute liver failure, acute hepatitis, or chronic liver dis- ease. The diagnosis can usually be made by Doppler ultrasonography of the hepatic veins (Fig. 15.24.4.1) and confirmed with CT or MRI scanning (Fig. 15.24.4.2), which provide additional information re- quired for treatment planning. Venography may be required if uncer- tainty remains after these tests, looking for the characteristic ‘spider’s web’ pattern in occluded hepatic veins. Liver biopsy is not generally required. Causes listed in Table 15.24.4.1 should be sought. Management and prognosis Treatment, when possible, should be given for any underlying cause. With regards to the thrombosis within the hepatic veins, the initial priorities are to initiate anticoagulation (usually commencing with low molecular weight heparin), unless there are very strong contra- indications, and to deal with any complications of portal hyperten- sion that are present. Thrombolysis may be given, depending on balance of benefits and risks in each case, if imaging reveals an acute (usually regarded as <4 weeks) and well-​defined clot, but thrombolysis should not be administered to patients with chronic Budd–​Chiari syndrome. Angioplasty and stenting may be used in symptomatic patients with suitable anatomy, but stenting should only be performed after dis- cussion with a liver transplant centre because it may compromise the prospects for subsequent liver transplantation. Apart from patients with subacute or chronic presentation and well-​compensated liver disease, measures to decompress the liver should be considered in most cases with the aim of preventing progression of liver disease. This can be done in many cases by placement of a transjugular intrahepatic portosystemic shunt. Less commonly, it may be possible to surgically create a shunt between the mesenteric or portal venous system and the inferior vena cava, thereby reducing blood flow and pressure within the liver. Liver transplantation may be the only option for those in whom these treatments are not possible or fail, or who have decompensated cirrhosis. Long-​term anticoagulation will be necessary, even after transplantation. Before treatments were available, mortality at 3 years was 90%. Recent series report 5-​year survival rates of about 75%. Features associated with poor prognosis include old age, severe liver failure, refractory ascites, chronic disease at presentation, and occlusion of the portal vein (which limits treatment options). Congestive hepatopathy Congestive hepatopathy may occur in the context of reduced car- diac output and high right-​sided venous pressure, due to con- strictive pericarditis, mitral stenosis, tricuspid regurgitation, or cardiomyopathy. The hepatic congestion and reduced liver sinus- oidal perfusion is usually asymptomatic as the heart failure dom- inates the clinical scenario. There is an elevated jugular venous pressure, with ‘v’ waves in the presence of tricuspid regurgitation, hepatomegaly, and a positive hepatojugular reflex. The liver may be pulsatile when tricuspid regurgitation is severe. The consequent reduced sinusoidal blood flow can lead to ischaemia in zone 3 of the hepatic lobule and histological changes are characterized by centrilobular congestion with surrounding fatty change, initially described as the ‘nutmeg liver’. If the disorder is long-​standing, there may be progressive fibrosis extending peripherally from the centrilobular to the periportal areas although regenerative nodules are usually not present. (a) (b) Fig. 15.24.4.1  Colour Doppler ultrasonographic images in a patient with acute Budd–​Chiari syndrome showing (a) absent flow in the middle hepatic vein (MHV), and (b) biphasic flow in the right hepatic vein (RHV). The inferior vena cava is patent (arrows). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 3168 A modestly elevated serum bilirubin level may be the only ab- normality, with a normal serum alkaline phosphatase and elevated aminotransferases. Although minor changes in liver biochemistry are observed in cases with chronic biventricular heart failure, true cases of cardiac cirrhosis are very uncommon, as are major com- plications from portal hypertension. Occasionally, this situation is complicated by the presence together of an alcohol-​induced liver injury and an alcoholic cardiomyopathy. In these circumstances, it may be necessary to undertake histological examination of the liver as well as measuring right-​sided cardiac pressures and free and wedged hepatic venous pressure gradients. The treatment for congestive hepatopathy centres on improving cardiac function with standard therapies. Ischaemic hepatopathy This refers to the diffuse hepatic injury that follows an acute re- duction in hepatic blood flow. It may be due to any of the causes of sudden shock (haemorrhage, cardiac arrest, severe septic shock) but a similar syndrome has also been described in hepatic sickle cell crisis, following liver transplantation with hepatic artery throm- bosis, and in severe respiratory failure and hypoxaemia. Histology shows a centrizonal necrosis and blood tests demonstrate marked elevation of transaminases, prolonged prothrombin time, and jaundice. The differential diagnosis includes other cause of sudden hep- atocyte necrosis, including drug hepatotoxicity and viral hepatitis. Rarely, acute liver failure with encephalopathy may develop in the most severe cases of ischaemic hepatopathy, with mortality up to 50% in pooled series. There is no specific treatment for the liver dys- function in this context, management being directed at the cause of the impaired hepatic perfusion. Hepatic artery aneurysm Hepatic artery aneurysms have been found in a number of con- ditions but are most common after surgery. They may also be found in the Osler–​Weber–​Rendu syndrome, Behçet’s syndrome, polyarteritis nodosa, and as part of systemic sepsis with fungal in- fection. It may be an incidental finding on an angiogram or present (a) (b) (c) (d) Fig. 15.24.4.2  Acute Budd–​Chiari syndrome. CT images acquired before contrast administration (a) and afterwards—​arterial phase (b), portal venous phase (c), and 3-​min delayed (d) images. These show diffuse peripheral oedema and hypoattenuation due to congestion (asterisks in (a)), early enhancement of the central portion of the liver ((b) and (c)) with delayed enhancement of the congested periphery (d). The hepatic veins are occluded (arrows in (c) and (d)). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.24.5 The liver in systemic disease 3169

15.24.5 The liver in systemic disease 3169

15.24.5  The liver in systemic disease 3169 with pain, sometimes in the back and rarely after cholecystectomy with jaundice and biliary obstruction. Spontaneous rupture has been associated with haemobilia and is a major medical emergency presenting with severe abdominal pain and shock followed by jaun- dice. Treatment is with either hepatic artery embolization or surgery. Portal vein thrombosis Spontaneous thrombosis of the portal vein, although often asymp- tomatic, may cause a range of serious medical complications. A thrombosis may develop in one or more of the intrahepatic portal vein branches, or within the main portal vein itself, and may involve the superior mesenteric or splenic veins which join to form the main trunk of the portal vein. Thrombosis may result from infection after birth arising in the umbilical vein, following acute pancreatitis (occasionally isolated to the splenic vein alone), surgery or abdominal trauma, as a com- plication of cirrhosis with or without an additional hepatocellular carcinoma, pancreatic and other intrabdominal malignancy, retro- peritoneal fibrosis, and a number of thrombophilic states. These include polycythaemia rubra vera, any cause of thrombocytosis, factor V Leiden and factor II (G20210A) deficiency, antithrombin III, protein C and S deficiency, paroxysmal nocturnal haemoglobin- uria, and the lupus anticoagulant. Septic thrombosis of the portal vein may also occur associated with another infective focus within the abdomen, such as acute appendicitis or diverticular disease. Often asymptomatic, portal vein thrombosis may present as haemorrhage from oesophageal or gastric varices, and rarely with biliary obstruction from choledochal varices. The diagnosis can be made at Doppler ultrasound examination of the liver, CT, or mag- netic resonance angiography. Endoscopic therapy with variceal band ligation or injection sclerotherapy is required when portal vein thrombosis presents with variceal haemorrhage. Occasionally, surgical shunts can decompress the portal venous system, but this is often not possible due to the extensive nature of the thrombosis. Clot lysis is not possible as the thrombosis is usually long-​standing. Anticoagulation, when given early after identification of an acute portal vein thrombosis, may im- prove long-​term portal vein patency. In chronic portal vein throm- bosis, it has been shown to reduce the risk of further thrombotic events in the splanchnic circulation and does not increase the risk of variceal haemorrhage. FURTHER READING Das CJ, et al. (2018). Role of radiological imaging and interventions in management of Budd-Chiari syndrome. Clin Radiol, 73, 610–24. Giallourakis CC, Rosenberg PM, Friedman LS (2002). The liver in heart failure. Clin Liver Dis, 6, 947–​67. Valla DC (2018). Budd-​Chiari syndrome/​hepatic venous outflow ob- struction. Hepatol Int, 12 Suppl 1, 168–​80. Webster G, Buroughs A, Riordan S (2005). Portal vein thrombosis—​ new insights into aetiology and management. Aliment Pharmacol Ther, 21, 1–​9. Zanetto A, Pellone M, Senzolo M (2019). Milestones in the discovery of Budd-Chiari syndrome. Liver Int, 39, 1180–5. 15.24.5  The liver in systemic disease James Neuberger ESSENTIALS The liver is affected in many systemic diseases, with important examples being: Cardiovascular diseases—​raised venous pressure (e.g. cardiac failure and constrictive pericarditis) can lead to hepatic congestion, which sometimes causes nausea, vomiting, right upper quadrant pain, and (rarely) jaundice. Hepatomegaly is frequent in moderately severe heart failure. Cardiac cirrhosis is a rare complication. Pulmonary diseases—​conditions that involve the liver as well as the lungs include cystic fibrosis, sarcoidosis, and α1-​antitrypsin deficiency. Gastrointestinal diseases—​inflammatory bowel disease is asso- ciated with a range of hepatic pathology including fatty change, pericholangitis, sclerosing cholangitis, autoimmune hepatitis, cir- rhosis, and (rarely) amyloidosis. Hepatobiliary disease associated with total parenteral nutrition varies from a mild, asymptomatic dis- ease to jaundice, cirrhosis, and liver failure. Coeliac disease may rarely present with abnormal liver tests. Obesity, especially in association with the metabolic syndrome, may be associated with nonalcoholic hepatitis and steatohepatitis. Endocrine diseases—​autoimmune hepatitis and primary biliary cholangitis may be associated with autoimmune endocrine dis- orders. Both hypothyroidism and hyperthyroidism can cause abnor- malities of liver function, which are usually mild. Haematological diseases—​conditions associated with abnormal blood clotting, such as protein C or S deficiency and paroxysmal nocturnal haemoglobinuria, may lead to Budd–​Chiari syndrome (hepatic vein thrombosis). The liver may be involved in both non-​ Hodgkin’s lymphoma and leukaemia. Infectious diseases—​agents that particularly affect the liver (e.g. viral hepatitis) are discussed in other chapters although many systemic infections also infect the liver. Abnormal liver function may occur during many systemic infections, but it is rare for patients with sepsis to present primarily with liver symptoms, although jaundice, ab- normal liver function tests, or (very rarely) fulminant hepatic failure may be the principal presenting feature. Rheumatological diseases—​hepatic disease may either be a conse- quence of treatment or occur in association with other autoimmune diseases. Introduction The liver may be affected in many systemic diseases. It may be dam- aged by toxic, infectious, immunological, vascular, or hormonal fac- tors, with the damage affecting hepatocytes, cholangiocytes, and/​or vascular (often microvascular) structures. In most instances, dis- turbance of liver structure and/​or function is a minor component of the disease, but in some cases, systemic disease may present as liver disease or disturbance of liver tests (although the so-​called liver function tests are neither tests of liver function nor liver specific).

section 15  Gastroenterological disorders 3170 In this chapter, some of the abnormalities of liver function seen in systemic disease are discussed. Liver disease may also impact other organs, so distinguishing the prime lesion may be difficult: for example, cirrhosis may be asso- ciated with cirrhotic cardiomyopathy and, conversely, heart failure may lead to cirrhosis, Budd–​Chiari-​like syndrome or even acute liver failure. Both acute hepatitis and acute liver failure may be a presentation or major feature of such diverse conditions as heat stroke, acute heart failure, and chronic inflammatory conditions. Many infections can affect the liver: for example, jaundice may be a feature of systemic sepsis, pneumonia, or lymphoma, and many infections, for example, Q fever or influenza, may have an associated hepatitis. Drug-​induced liver injury The possibility that drugs used to treat systemic disease may cause liver injury must always be borne in mind. The diagnosis of drug-​ induced liver injury is usually one of exclusion and one agent may be associated with multiple patterns of liver damage. See Chapter 15.24.3 for further discussion. Cardiovascular disease Congestive cardiac failure Most patients with chronic congestive cardiac failure have few symp- toms related to hepatic congestion, although nausea, vomiting, and right upper quadrant pain may occur occasionally. Hepatomegaly is present in most patients with moderately severe heart failure. Rarely, cardiac cirrhosis develops and may be associated with splenomegaly and ascites. With progressive failure, jaundice occurs in about one-​ quarter of patients. The standard liver tests may show a rise in serum bilirubin, which rarely exceeds 50 µmol/​litre and is usually predominantly unconjugated. The serum aminotransferases may also be elevated but rarely exceed twice the upper limit of normal although con- centrations in excess of 1000 IU/​litre may be found in severe acute heart failure. Serum alkaline phosphatase is rarely elevated. The pro- thrombin time is often prolonged by a few seconds. Ultrasonography may show widened hepatic veins. The liver is usually enlarged and a cut section shows the classical nutmeg appearance, with the pale periportal zones alternating with darker centrilobular zones. Microscopically there is congestion, with dilatation of the terminal hepatic venules and adjacent sinusoids, and areas of centrilobular necrosis. With chronic heart failure, there may be features of centrilobular necrosis and fibrosis. Jaundice and transaminitis may be present in acute heart failure, and in rare cases the patient may present with signs and symptoms of acute liver failure. Constrictive pericarditis Hepatic complications of constrictive pericarditis occur late in the course of the illness. Cardiovascular features of constrictive peri- carditis are described elsewhere (see Chapter  16.8). The liver is enlarged and there may be associated splenomegaly. Jaundice and ascites may develop. Ultrasonography of the liver will show en- largement with dilated hepatic veins. Tricuspid incompetence Tricuspid incompetence most commonly occurs as a result of right heart failure but may also result from congenital or acquired disease of the tricuspid valve. The liver is enlarged and pulsatile. Tumours of the heart Tumours of the right atrium, including myxoma and myosarcoma, may infiltrate the hepatic veins resulting in a Budd–​Chiari syn- drome (a syndrome of hepatic venous thrombosis, characterized by abdominal pain, progressive ascites, and diarrhoea). Cardiac myxoma may be associated with abnormalities of liver function tests, including increased serum bilirubin and alkaline phos- phatase, and a reduction in serum albumin and total protein. Hypoxia Hypoxic episodes, especially during surgery, may lead to an acute liver injury resulting from an ischaemic hepatitis. The clinical severity ranges from an asymptomatic elevation of serum amino­ transferases to fulminant hepatic failure. The syndrome may be followed by a period of cholestasis. The aminotransferases may be- come greatly elevated (in excess of 10 000 IU/​litre). Histologically there is hepatocellular necrosis in the absence of inflammation, most marked in acinar zone 3 (the perivenular area). Similar changes may be seen in patients with heat stroke. Syndromes affecting both heart and liver Several conditions affect both heart and liver, including Alagille’s syndrome (a multisystemic disorder, associated with JAG1 mutations and characterized by a paucity of intrahepatic bile ducts, leading to a biliary cirrhosis, and cardiac syndromes such as pulmonary sten- osis and other cardiac abnormalities), biliary atresia (where up to 10% may have congenital heart disease), and cardiomyopathy, and may be associated with a variety of inherited and acquired diseases affecting both organs including alcohol excess, haemochromatosis, tyrosinaemia, and mitochondrial cytopathy. Drugs such as the im- munosuppressive agent tacrolimus may also cause cardiomyopathy. Pulmonary disease Cirrhosis Lung disease is not uncommon in patients with cirrhosis; the hepatopulmonary syndrome and portopulmonary hypertension may resolve after treatment of the underlying liver disease or after liver transplantation. In contrast, abnormalities of liver function in patients with pulmonary disease may arise either as a consequence of that disease or of diseases affecting both lung and liver. In most patients with chronic lung disease, abnormalities of liver function are mild and may be manifest only by more functional tests of liver function such as abnormalities of bromosulphophthalein clear- ance. In more advanced disease, associated with hypoxia, there may be more widespread disturbances of liver function, with ele- vation of serum aminotransferase, bilirubin, alkaline phosphatase, and γ-​glutamyl transferase. However, abnormality of liver function

15.24.5  The liver in systemic disease 3171 in patients with pulmonary disease is associated mainly with pul- monary hypertension rather than lung disease or hypoxia per se. Pneumonia Some patients with pneumococcal pneumonia may have jaundice. It usually manifests on the fourth or fifth day of the illness and is seen particularly in patients with consolidation of the right lower lobe. The serum bilirubin rarely exceeds 100 mol/​litre, and abnormal- ities of other liver tests are unusual. The cause of the jaundice is not known: factors that have been implicated are glucose-​6-​phosphatase deficiency, associated acute haemolysis, hypoxia, fever, and direct toxicity. The increased amounts of inflammatory cytokines seen in such patients may also contribute to the jaundice. Abnormal liver function tests are also seen in patients with le- gionnaires’ disease and are characterized by elevation of aspartate aminotransferase and alkaline phosphatase. Jaundice is less common and tends to occur only in patients who are severely ill. Diseases that involve both lung and liver α1-​Antitrypsin deficiency The syndrome of α1-​antitrypsin deficiency arises as a consequence of a point mutation that leads to misfolding of the protein that renders it unable to follow the normal secretory pathway and leads to its ac- cumulation in the endoplasmic reticulum of the hepatocyte, which may result in hepatitis, fibrosis, and cirrhosis. The clinical spectrum varies widely: it was initially described in relation to pulmonary em- physema but it subsequently became clear that the liver, kidney, and pancreas can also be involved. In children, liver disease often pre- sents as neonatal hepatitis or jaundice, usually in the first 2 months of life: in one-​third it resolves, one-​third develop fibrosis, and the remainder develop progressive cirrhosis often requiring transplant- ation. In adults, the disease often presents with signs or symptoms of portal hypertension or cirrhosis or their complications; some adults will have had unexplained hepatitis as a neonate. The liver shows the characteristic histological features of periodic acid–​Schiff-​positive, diastase-​resistant globules in the liver, but these globules are not diagnostic of the disease. Patients usually have the Pi ZZ phenotype. Whether the Pi MZ or other phenotypes are associated with liver disease is less clear. Liver disease is more severe in those with add- itional causes such as alcohol excess, diabetes mellitus, or obesity. The prognosis is unpredictable but many patients develop pro- gressive disease, often requiring liver transplantation. There is no proven effective treatment. The onset of cholestasis often heralds liver failure. In cases where lung and liver disease coexist, the only effective therapy is with a triple transplant (heart, lung, and liver), but this is rarely done. Cystic fibrosis The increasing success in treating respiratory complications in chil- dren with cystic fibrosis has resulted in a greater number surviving to develop liver disease. Abnormal liver tests are found in up to half of the children, and in adults up to a quarter of patients with cystic fibrosis develop a biliary cirrhosis. Clinically, patients present with cholestasis and jaundice. The pathogenesis and aetiology of this cholestasis are poorly understood. In most cases, liver disease is characterized by the development of a focal biliary cirrhosis that in- creases with time. Early involvement of the liver is characterized by the presence of eosinophilic granular material in the portal ducts. There is proliferation of bile ducts and portal fibrosis. This progresses to a focal biliary cirrhosis, which then develops into a multilobular cirrhosis with onset of symptoms of cholestasis and jaundice. However, many patients have evidence of biliary obstruction shown by imaging the biliary tree by magnetic resonance or endoscopic retrograde cholangiopancreatography. There is some evidence that infusion of N-​acetylcysteine into the biliary tree may relieve the obstruction in the extrahepatic biliary tree. The onset of jaundice and ascites is associated with a poor prognosis. Standard liver tests may underestimate the severity of the liver disease. Treatment with ursodeoxycholic acid will improve the liver tests and may improve liver function. Other causes of cholestasis in patients with cystic fibrosis include gallstones and pancreatic insufficiency associated with increased loss of faecal bile salts, a consequent decrease in the size of the bile-​ salt pool, and the development of lithogenic bile. Treatment is uncertain. Open-​label studies have suggested that ursodeoxycholic acid, 10 to 15 mg/​kg per day, may result in bio- chemical improvement, weight gain, and improved nutrition. However, whether this agent has any long-​term effect remains to be established. The effects (if any) of cystic fibrosis transmem- brane conductance regulator modulators and potentiators on cystic fibrosis-​related liver disease are not yet clear. Liver transplantation, sometimes with lung transplantation, may be required. Sarcoidosis Sarcoidosis, a systemic granulomatous disease of unknown aeti- ology, involves the liver in up to 70% of cases, but symptoms and signs are relatively uncommon. Hepatomegaly and splenomegaly occur in about one-​quarter of patients. While jaundice is rare, eleva- tion of the serum alkaline phosphatase is not uncommon; abnormal- ities of liver tests occur in up to one-​third of patients. Complications of granulomatous infiltration of the liver are unusual. There are cases where liver failure develops. More commonly, portal hypertension may occur, with bleeding varices or ascites and may be present in up to one in five patients; portal hypertension may occur in the absence of cirrhosis, usually as a consequence of presinusoidal or sinusoidal obstruction associated with the granulomas or biliary fibrosis. As with sarcoid elsewhere, the diagnosis is supported by an ele- vated concentration of serum angiotensin-​converting enzyme but this lacks both sensitivity and specificity. Imaging using ultrason- ography, especially if contrast-​enhanced ultrasonography, CT, or MR may show multiple hypointense or hypoattenuated nodules within the liver. The diagnosis is usually made by the finding of noncaseating granulomas which, in the liver, are concentrated around the portal tracts. These granulomas are usually large and consist of multinuclear giant cells with lymphocytes and areas of epithelioid cells. Many patients respond to corticosteroids, although the portal hypertension may persist, possibly due to established presinusoidal fibrosis. Overlap with primary biliary cholangitis (formerly known as primary biliary cirrhosis) is well recognized, and cases have been described with typical sarcoid involvement of both lungs and liver in the presence of bile duct damage consistent with primary biliary cholangitis. These patients are antimitochondrial antibody posi- tive. Other causes of granulomatous hepatitis are discussed later in this chapter.

section 15  Gastroenterological disorders 3172 Gastrointestinal tract disorders Inflammatory bowel disease The spectrum of liver abnormality associated with inflammatory bowel disease ranges from fatty change to pericholangitis, sclerosing cholangitis, autoimmune hepatitis. cirrhosis, and amyloidosis. The reported incidence of liver abnormalities in inflammatory bowel disease varies from 3 to 10%. In general, abnormalities of liver func- tion tests correlate poorly with severity of liver disease determined histologically. Ulcerative colitis is more commonly associated with abnormality of liver function tests than is Crohn’s disease. There is no clear-​cut relation between the onset of symptoms of inflammatory bowel disease and of the liver abnormalities. In gen- eral, symptoms of ulcerative colitis precede changes in liver func- tion tests by about 8 years but liver disease may precede by many years the onset of clinically apparent inflammatory bowel disease. Conversely, liver disease may become manifest several years after colectomy. Furthermore, there is no clear-​cut correlation between the severity of inflammatory bowel disease and the incidence or se- verity of liver disease. Indeed, in many patients with primary scler- osing cholangitis, the colitis tends to be a pancolitis but is often quiescent (Table 15.24.5.1). Fatty change is relatively common on histological examination of liver in patients with inflammatory bowel disease and probably multifactorial in origin, relating to the degree of ill health, poor nutrition, and use of corticosteroids. As a patient’s condition improves, the fatty infiltration resolves. Primary sclerosing cholangitis is associated with inflammatory bowel disease in about 10% cases whereas nearly 90% of patients with primary sclerosing cholangitis have inflammatory bowel disease. Primary sclerosing cholangitis is a premalignant condition, associated with bile duct carcinoma in 5 to 20%. In patients with primary sclerosing cholangitis and ulcerative colitis, there is an increased risk of colon cancer. Cirrhosis occurs in up to 10% of patients dying with colitis. The cause of the cirrhosis is not known, but it may, in some cases, relate to alcohol, to chronic hepatitis C infection from drug transfusions, or to drug toxicity, rather than primary sclerosing cholangitis. Although autoimmune hepatitis in association with inflamma- tory bowel disease is rare, it is important to diagnose it because many cases have features similar to autoimmune hepatitis and respond well to corticosteroids. Other hepatic complications of inflammatory bowel disease in- clude granulomatous hepatitis, amyloid infiltration of the liver, bile duct carcinoma, gallbladder cancer, and gallstones. Coeliac disease In patients with coeliac disease, there may be minor abnormal- ities of liver function tests, characterized by elevation of serum aminotransferases; they usually resolve with treatment. Coeliac dis- ease may also be associated with autoimmune diseases affecting the liver, including primary biliary cholangitis, cryptogenic cirrhosis, sclerosing cholangitis, and autoimmune hepatitis. Up to 4% of pa- tients with primary biliary cholangitis may have coeliac disease and up to 3% of patients with coeliac disease may have primary biliary cholangitis. Gastrointestinal bypass surgery Jejunoileal bypass surgery may be associated with a significant de- gree of liver impairment; the changes in the liver range from simple fatty infiltration to cirrhosis. In a few cases, there may be features identical to those of alcoholic hepatitis. In those in whom liver func- tion tests are deranged, there is a likelihood of progression, and although treatment with metronidazole has been advocated, restor- ation of normal anatomy appears to be the only effective treatment. Total parenteral nutrition The association of hepatobiliary disorders with total parenteral nutrition (TPN) has been recognized over the last two decades. Although the pathogenesis remains obscure, most studies suggest that the incidence is failing to less than 5% of patients. Clinically, TPN-​associated hepatobiliary disease varies from a mild, asymp- tomatic disease with acalculous cholecystitis, biliary sludge, or hep- atomegaly, to jaundice, cirrhosis, and liver failure. Biochemically, the severity of abnormalities will reflect the severity of the disease but elevations of liver enzymes, such as aspartate and alanine trans- ferases, lactate dehydrogenase, and alkaline phosphatase, and serum bilirubin are common. The histological features vary from a mild fatty infiltrate or cholestasis to a more severe picture resembling alcoholic fatty liver. In chronic cases, cirrhosis will develop. The mechanism is uncertain. Suggestions include hypoxic enterocytes, nutritional depletion, sepsis, toxicity of certain unidentified amino acids, and carnitine deficiency (Table 15.24.5.2). Once a patient develops abnormal liver function, and provided that other causes have been excluded, there is little alternative other than to reduce or stop parenteral nutrition and find other ways of providing adequate nutrition. Obesity and malnutrition Obesity is occasionally associated with abnormalities of liver tests, es- pecially of the serum aminotransferases. Cutaneous manifestations of chronic liver disease may develop. The liver ultrasound exam- ination will show a fatty liver, and liver histology a macrovesicular fatty infiltration. Rarely, a nonalcoholic steatohepatitis syndrome will develop. Nonalcoholic fatty liver disease is described in detail in Chapter 15.24.2. The liver is also affected in malnutrition. In those with severe protein-​calorie malnutrition (Kwashiorkor), fatty liver may be seen, possibly as a consequence of loss of peroxisomes and reduced β-​oxidation of long-​chain fatty acids. Table 15.24.5.1  Liver and biliary disorders associated with inflammatory bowel disease Parenchymal Granuloma Pericholangitis Autoimmune hepatitis Primary biliary cholangitis Liver abscess Amyloid Biliary Gallstones Primary sclerosing cholangitis IgG4 cholangitis/​autoimmune cholangitis Cholangiocarcinoma

15.24.5  The liver in systemic disease 3173 The liver in autoimmune and endocrine disease Autoimmune hepatitis may be associated with autoimmune endo- crine disorders, such as thyroid disease and vitiligo. In addition to those conditions, such as haemochromatosis, where both liver and pancreas are affected, diabetes mellitus itself is associated with liver abnormalities. The liver may be enlarged due to excess stores of fat and glycogen. In severe cases, there may be a nonalcoholic steatohepatitis syndrome which can lead to hepatic fibrosis and cirrhosis. Liver abnormalities are seen much more com- monly in type 2 diabetes (20–​75%) compared with well-​controlled type 1 diabetes (<1%). Hypothyroidism may be associated with a mild hyperbilirubinaemia and elevations of serum transaminases (which may be of muscle origin). Ascites occurs very rarely. Hyperthyroidism is also associated with mild abnormalities of liver function which resolve on treatment of the thyroid disorder. Henoch–​Schönlein purpura is associated with jaundice and cholestasis. The liver in haematological diseases Procoagulant disorders Procoagulant disorders such as protein C or S deficiency and parox- ysmal nocturnal haemoglobinuria may lead to a Budd–​Chiari syn- drome (thrombosis of the hepatic vein) or portal vein thrombosis. Haemolysis Jaundice may accompany haemolysis, usually through an increase in unconjugated bilirubin. In patients with underlying liver disease, there may be an elevation of both conjugated and unconjugated bili- rubin out of proportion to the degree of haemolysis. Patients with chronic haemolytic anaemia are at risk of developing haemosiderosis. Iron is deposited initially in the Kupffer cells but spread to the par- enchyma will subsequently occur. The identification of the genes for hereditary haemochromatosis (HFE) has greatly helped in the dis- tinction between primary and secondary iron overload. The haemo- lytic anaemias are associated with an increased risk of pigment gallstones, which may lead to liver and biliary tract disease. Sickle cell disease Most of the abnormalities of liver function in sickle cell disease are due to haemolysis or infections transmitted by blood transfusion. Kupffer cell hyperplasia, haemosiderosis, fibrosis, or cirrhosis may be due to iron overload following multiple transfusions. Patients sometimes present with fever, severe right upper quadrant pain, and jaundice, with rapid enlargement of the liver as part of the hepatic sequestration syndrome (so-​called sickle cell intrahepatic cholestasis). The liver histology may show clumps of sickled red cells in the sinusoids, erythrophagocytosis, sinusoidal dilatation, and bilirubinostasis. There is an increased risk of gallstones and their complications may result in jaundice. High serum ferritin and conjugated serum bilirubin levels are good predictors of poor prognosis. Thalassaemia As with sickle cell disease, there is an increase in haemolysis and the complications of blood transfusions. Gallstones are common Multiple transfusions Patients who are maintained with regular transfusion of blood or blood products (e.g. those with thalassaemia or haemophilia) are at risk of developing viral hepatitis B or C, or much less commonly hepatitis A  and E.  Although transfusion-​associated transmission of blood-​borne viruses is greatly reduced by current screening tests, because of the window period, such cases do still very occasionally occur. Haemophagocytic syndrome Features of the haemophagocytic syndrome include hepato- megaly. In addition to the coagulopathy, hypofibrinogenaemia, hyponatraemia, and hyperferritinaemia (which is often in excess of 10 000 μg/​L), there may be jaundice and elevated levels of serum aminotransferases. Liver histology shows haemophagocytosis, si- nusoidal dilatation, and Kupffer cell hyperplasia. Lymphoreticular disease In patients with Hodgkin’s disease, liver tests are of limited value in predicting liver involvement. Jaundice is a recognized feature, but may be due to several different causes. For example, haemolysis may complicate Hodgkin’s disease, and occasionally there is a bland cholestasis in the absence of infiltration, which usually resolves when the disease is treated. In some cases, there is a vanishing bile duct syndrome. The clinical manifestations of liver involvement in Hodgkin’s disease relate to the degree of infiltration. In rare cases, patients present with fulminant hepatic failure: the clue to infiltra- tion is a large liver as most cases of viral or drug-​related fulminant hepatic failure are associated with small livers. Liver biopsy may be diagnostic. Primary lymphoma of the liver has been described but is rare. The liver may be involved in both non-​Hodgkin’s lymphoma and leukaemia. The diagnosis is usually made by biopsy. Some patients with non-​Hodgkin’s lymphoma have a chronic hepatitis preceding diagnosis or treatment. A casual effect cannot be excluded. Both Hodgkin’s disease and non-​Hodgkin’s lymphoma may be associated with obstructive jaundice due to hilar obstruction by nodes; this is more common in the latter and resolves with treatment. Table 15.24.5.2  Factors contributing to liver dysfunction in patients receiving TPN Underlying sepsis Systemic Local Small-​bowel colonization Underlying disease Duration of TPN Pre-​existing liver disease Underlying condition Nutritional factors Excess nonprotein calories Essential fatty acid deficiency Amino acid toxicity Carnitine deficiency Bile acid abnormalities Drug toxicity

section 15  Gastroenterological disorders 3174 The liver and infections Abnormal liver function may occur during systemic infections, both Gram positive and Gram negative, although it is unusual for patients with sepsis to present primarily with liver symptoms (Table 15.24.5.3). However, jaundice, abnormal liver tests, or even, occasionally, fulminant hepatic failure may be major presenting features of sepsis. The liver tests usually show a significant eleva- tion of serum bilirubin (mainly conjugated); serum alkaline phos- phatase and aminotransferase activity are usually less increased. The pathophysiology is becoming clearer; endotoxins induce sinusoidal endothelial cells and hepatocytes to produce inflamma- tory cytokines such as interleukins 2, 6, and 12 and tumour ne- crosis factor-​α, which are thought to have a post-​transcriptional effect on bile uptake and transporter receptors. There may also be haemolysis, drug-​induced liver injury, and hepatic ischaemia. The treatment is of the underlying infection. Bacterial infections Pneumococcal infections are discussed in ‘Pneumonia’. Mening­ ococcal infections are occasionally associated with features sug- gestive of viral hepatitis. Jaundice may be associated with the toxic shock syndrome associated with Staphylococcus aureus. Gonococcal infection is a well-​recognized cause of liver disease. The clas- sical Fitzhugh–​Curtis syndrome, perihepatitis, is characterized by sudden onset of severe pain in the right upper quadrant, occurring classically in a woman with a previous history of pelvic inflamma- tory disease. On examination there may be little to find, although tender hepatomegaly and a hepatic rub may be present. Where laparotomy has been performed in the mistaken diagnosis of chole- cystitis, perihepatitis with adhesions and pus around the liver may give the clue to the diagnosis. In chronic infection, adhesions de- velop between the surface of the liver and the anterior abdominal wall. The condition usually resolves without treatment, although the use of penicillin causes a more rapid resolution. Abnormalities of liver function may occur in gonococcal bacteraemia, peritonitis, and endocarditis. Perihepatitis is also reported in association with syph- ilis and chlamydial infections. In childhood, some infections with Escherichia coli may be asso- ciated with hepatitis and jaundice. Jaundice is rare in older patients, although pregnant women seem more susceptible. Abnormalities of liver function occur in systemic streptococcal and staphylococcal infection and in enteric fevers, paratyphoid, and typhoid. In typhoid infection, hepatomegaly is common and jaun- dice occurs in about 10% of patients, although up to a third have ab- normal liver function tests, with increased levels of aminotransferase and normal values for alkaline phosphatase. The hepatomegaly rap- idly responds with treatment. There may be an associated cholecyst- itis. In gas gangrene, deep jaundice may occur may occur in up to a fifth of patients. The liver may be infected and a plain radiograph of the abdomen may show gas within the liver. Liver damage and jaundice are associated with Listeria monocytogenes and Legionella pneumophilia infections. Brucellosis may also be associated with jaundice and abnormal liver function tests. All three forms of brucella have been associated with abnormal liver function. Characteristically, the liver biopsy shows a marked inflammatory infiltrate and fibrosis with multiple large or small granulomas scattered throughout the parenchyma. Although some reports have suggested granulomatous hepatitis due to brucella may progress to cirrhosis, the data are not convincing. The common causes of liver granulomas, including infections, are listed in Table 15.24.5.4. Actinomycosis israelii and bovis are commensals that rarely cause disease. Actinomycotic infection of the liver may occur, the patient presenting with abdominal pain, anorexia, and fever. In one case re- port, the liver was found to have small, multilocular abscesses. Tuberculosis may present with granulomatous hepatitis, biliary tuberculosis, a solitary tuberculoma, or tuberculosis of the biliary tract. The liver is involved in up to 85% of patients with tuberculosis, Table 15.24.5.3  Systemic infections affecting the liver Bacterial Actinomycosis Brucellosis Chlamydia Clostridium welchii Escherichia coli Gonorrhoea Granuloma inguinale Listeriosis Legionella pneumophilia Melioidosis Meningococcus Nocardia Shigella Streptococcus Staphylococcus Typhoid and paratyphoid Tularaemia Yersinia Mycobacterial Tuberculosis Leprosy Others Protozoal Giardiasis Kala-​azar Malaria Toxoplasmosis Fungal Aspergillosis Blastomycosis Candidosis Cryptococcus Coccidiomycosis Histoplasmosis Rickettsial Q fever Rocky Mountain spotted fever Spirochaetes Leptospirosis Lyme disease Relapsing fever Syphilis

15.24.5  The liver in systemic disease 3175 particularly those with miliary disease. The presence of multiple granulomas in the liver should raise the possibility of tuberculosis, although—​as seen in Table 15.24.5.4—​the differential diagnosis of granulomatous hepatitis is long. With the increasing incidence of atypical mycobacterial infections, lesions similar to tuberculosis can be found. In those infected with Mycobacterium avium intracellulare there are numerous acid-​fast bacilli, often in the absence of granu- lomas. Rarely, tuberculosis may cause jaundice because of lymph node obstruction of the biliary tree. Acute leptospirosis is frequently accompanied by jaundice, al- though frank liver failure is uncommon. The jaundice is mainly cholestatic, although there may be liver cell damage. Syphilis may rarely be associated with hepatitis or jaundice. Rickettsial infection Liver involvement in Q fever (Coxiella burnetii) is recognized, al- though symptoms of liver disease are uncommon. Hepatomegaly is frequent and liver function tests may show an elevation of serum alkaline phosphatase and, rarely, a picture resembling viral hepa- titis. Histologically, the liver has areas of focal necrosis, Kupffer cell proliferation, lipogranuloma formation, and mononuclear cell in- filtration in the portal tracts. The characteristic histological feature of Q fever is eosinophilic fibrinoid necrosis but this is not specific. Treatment is with chloramphenicol or tetracycline. Liver involve- ment has a much greater incidence in Rocky Mountain spotted fever (Rickettsia rickettsia). Fungal infections The liver may be involved in fungal infection, often in patients with immunodeficiency such as with AIDS, following chemotherapy, and after organ transplantation. Histoplasmosis, cryptococcosis, aspergillosis, blastomycosis, and candidiasis are all causes of liver damage. The liver is usually involved in disseminated fungal infec- tions. Cryptococcal infection has also been associated with a pri- mary biliary cholangitis-​like condition. Protozoal infections Many protozoal infections involve the liver. In toxoplasmosis, while most patients are asymptomatic and liver involvement is mild, hepatitis may occur and on biopsy Toxoplasma gondii may be found in the liver. In malaria, due to either Plasmodium fal- ciparum or vivax, abnormality of liver function may be observed. Hepatomegaly is common and often associated with jaundice. The jaundice is in part due to haemolysis but liver tests may show a pic- ture suggestive of viral hepatitis. Histological examination may show characteristic features of Kupffer cell proliferation with black malarial pigment and mononuclear cell infiltrate. Frank hepatic failure is extremely rare. Schistosomiasis is one of the most common causes of liver dis- ease worldwide. A  heavy infection of fertile schistosomes in the portal system results in deposition of eggs that induce an immune response, leading to portal fibrosis and granuloma formation, portal hypertension with consequent splenomegaly, ascites, and variceal haemorrhage. Hepatocyte function is well preserved. There is a com- plex interaction between schistosomal eggs and the immune system; the degree of fibrosis is directly related to the number of eggs and the duration of infection. The diagnosis is made on stool examination or finding schistosomes in the liver. Successful treatment is associated with a significant but variable improvement in the degree of portal hypertension. Treatment of the portal hypertension is dependent on the medical facilities available. As parenchymal function is well preserved, these patients usually tolerate a portosystemic shunt. Coinfection of patients with schistosomiasis and hepatitis B or C virus is associated with aggressive progression. Viral infections Hepatitis may be a significant feature of viral infection other than the classical hepatitis viruses. Thus, infection with cytomegalovirus, Epstein–​Barr virus, herpes viruses, measles, rubella, Coxsackie virus, adenoviruses, and ECHO viruses may all cause a significant hepatitis. Such viral infections (especially cytomegalovirus) are more common in immunosuppressed patients. Cytomegalovirus infection in the context of HIV or immunosuppression may cause a sclerosing cholangitis. The diagnosis is made serologically but in some cases, such as with cytomegalovirus, herpes, and adenoviral infections, the liver histology may show characteristic features. In the immunosuppressed, hepatitis viruses B and E are more likely to run a chronic course, resulting in chronic hepatitis, fibrosis, and cirrhosis. In many Western countries, there is an increase in in- fection with hepatitis E virus genotype 3; treatment is with ribavirin. Treatment of hepatitis B virus is discussed elsewhere. Some viruses, such as respiratory syncytial virus and influenza virus, may induce a hepatitis associated with cytokine-​associated immune activation. Table 15.24.5.4  Common causes of hepatic granulomas Infective Bacterial: Mycobacteria Brucellosis Rickettsial Spirochaetal Parasitic: Amoebiasis Ascariasis Giardiasis Schistosomiasis Toxocariasis Viral: Cytomegalovirus Epstein–​Barr virus Fungal Drugs Allopurinol Sulphonamides Phenylbutazone Parenchymal disease Primary biliary cholangitis Primary sclerosing cholangitis Malignancy Hodgkin’s disease Other Sarcoid Systemic lupus erythematosus Whipple’s disease Collagen disease Erythema nodosum Crohn’s disease Toxins: beryllium and silicon

section 15  Gastroenterological disorders 3176 Other particular infective conditions Pyogenic liver abscess Pyogenic liver abscesses may occur as part of a systemic illness as a consequence of portal phlebitis, often associated with bowel sepsis, biliary tract disease, direct trauma, septicaemia, and in association with carcinoma of the colon or bacterial endocarditis. Most com- monly they arise out of portal phlebitis, with the primary focus being the appendix, colon, diverticular disease, or in the pelvis (Table 15.24.5.5). Although abscesses may occur in patients with in- flammatory bowel disease, this is relatively rare. The patient presents with abdominal pain, pyrexia, nausea, and weight loss, although fever is less common in children. Hepatomegaly may be present and the liver is sometimes tender. The serum albumin is often reduced and alkaline phosphatase elevated. There is usually a marked neu- trophil leucocytosis, but this is not invariable. The diagnosis is made on imaging of the liver. A chest radiograph may show elevation of the right hemidiaphragm with an associated pleural effusion or even lung consolidation. Ultrasonography, CT scanning, and MRI may define an hepatic abscess. Treatment of a solitary abscess is usually by percutaneous drainage in the first instance. Under ultrasonographic or CT guidance, a percutaneous drain should be established for single abscesses, and even in some cases of multiple abscesses. The ab- scesses should be drained to dryness and antibiotics given ac- cording to the sensitivities of the organisms isolated. Pathogens are usually anaerobic or aerobic gut coliforms, especially Streptococcus milleri, although S. aureus is common in children. The success rate of treatment with drainage and systemic antibiotics is 80 to 90%. Fatality is high in children and the elderly, in those with coexisting disease such as diabetes mellitus, and those with delayed diagnosis. Once the abscess has been drained, the primary source of infection must be sought and appropriate management instituted. Surgery may be required for patients with multiple abscesses or for those with abscesses that do not respond to simple drainage and anti- biotic therapy. Liver abscess due to hydatid and amoeba are dis- cussed elsewhere. HIV as a cause of liver disease Liver disease in patients with HIV infection may be due to pre-​ existing hepatitis virus, opportunistic infections, or neoplasms, but in some cases the abnormality of liver function may be due to the virus itself. Such patients have nontender hepatomegaly with anorexia, weight loss, and low-​grade fever. Liver function tests show a slight derangement with cholestasis. The liver biopsy shows nonspecific features including Kupffer cell hyperplasia, fat infiltra- tion, noncaseating granulomas, and portal tract inflammation; oc- casionally, Mallory bodies may be present. Other causes of hepatobiliary abnormality in patients with HIV include primary hepatic infection due to viral hepatitis. Other causes of liver damage in AIDS Many patients with AIDS are also at risk from hepatitis B, C, and D. As discussed elsewhere, these patients respond less well to inter- feron than those who are HIV negative. Other infections that are more common in these patients include cytomegalovirus, herpes virus, cryptosporidiosis, and mycobacteria including tuberculosis and M. avium intracellurare. Drug-​induced liver damage must always be considered in HIV patients with abnormal liver tests, and it has been suggested that such patients are more susceptible to drug hepatotoxicity. Thus, many of the anticonvulsants, analgesics, and antimicrobials are as- sociated with hepatocellular damage, and antibiotics may also be associated with cholestasis. Other abnormalities that may be of less significance clinically include peliosis hepatis and fatty infiltration. The biliary tree may also be affected in HIV infection inducing a syndrome superficially resembling primary sclerosing cholangitis. This is characterized by a rapid elevation of the serum alkaline phos- phatase, which may be associated with pain in the right upper quad- rant and, later, jaundice. Ultrasonography may be unhelpful, although dilated and thickened walls of the bile duct may be seen. Otherwise, endoscopic retrograde cholangiopancreatography will show the char- acteristic changes of sclerosing cholangitis with bleeding, dilatation, and stricture. Both cryptosporidial and cytomegaloviral infections have been associated with this form of sclerosing cholangitis. The liver may be involved in a number of other ways. There is an association between AIDS and lymphomas, be they Burkitt’s, large cell, or immunoblastic. The liver and/​or spleen may be the site of these tumours and hepatic involvement may be present in up to a third of those with gastrointestinal lymphomas. Tumours may be microscopic or macroscopic. The hepatic masses are often asymp- tomatic but if large may cause pain in the right upper quadrant, fever, jaundice, and abnormalities of liver function tests, especially of the serum alkaline phosphatase. Kaposi’s sarcoma may affect the liver and biliary tree but is often asymptomatic. Autoimmune and rheumatic conditions Liver abnormalities are not uncommon in patients with rheum- atological disorders, although rarely prove a significant problem. Liver test abnormalities occur in around 50% of those with Sjögren’s syndrome and 30% with systemic lupus erythematosus, and liver histology abnormalities are found in around 20% in both. More sig- nificant involvement may either be a consequence of treatment or occur in association with other autoimmune diseases. For example, those diseases assumed to have an autoimmune basis, such as auto- immune hepatitis or primary biliary cholangitis, may be associated with extrahepatic rheumatological diseases such as sicca syndrome. Rheumatoid arthritis Abnormalities of liver structure and function are uncommon in patients with rheumatoid arthritis, although minor abnormalities of liver function tests occur in 20 to 50%. Nodular regenerative hyperplasia may cause complications of portal hypertension. Felty’s syndrome Felty’s syndrome is characterized by the triad of splenomegaly, hypersplenism, and seropositive rheumatoid arthritis. Liver Table 15.24.5.5  Sources of a pyogenic abscess Source Percentage of cases Obstructive biliary tree 30–​40 Intra-​abdominal infection 15–​25 Systemic infection 15–​20

15.24.5  The liver in systemic disease 3177 function tests tend to be more commonly deranged than in uncom- plicated rheumatoid arthritis. Anti-​inflammatory therapy may con- tribute to the abnormal liver tests. Histological examination of the liver shows lymphocytic infiltration and, rarely, an established cir- rhosis. Nodular regenerative hyperplasia has been described, as it has in rheumatoid arthritis. Although portal hypertension and vari- ceal haemorrhage may occur, jaundice is unusual. Systemic lupus erythematosus Abnormalities of liver function in patients with systemic lupus erythematosus are usually minor, although spontaneous rupture of the liver has been described. The pattern of liver disease in patients with systemic lupus erythematosus varies from minimal change to chronic persistent hepatitis, chronic active hepatitis, and cirrhosis. In others, a granulomatous hepatitis has been described. Polyarteritis nodosa In contrast to rheumatoid arthritis, liver involvement in polyarteritis nodosa is relatively uncommon, although hepatic arteritis may occur, leading to aneurysm. Rupture of an aneurysm is rare and is characterized by fever, pain in the right upper quadrant, and jaun- dice. In most cases, abnormalities of liver function are due to an as- sociated hepatitis C virus infection. Polymyalgia rheumatica Abnormalities of liver function are well recognized in patients with polymyalgia rheumatica. These abnormalities (elevation of serum alkaline phosphatase and aminotransferase activity) usually resolve with effective treatment. Histologically, the liver shows mild portal inflammation with occasional liver cell necrosis. Granulomas and steatosis may also be seen. Sjögren’s syndrome Symptoms of sicca syndrome are common in patients with liver dis- ease, particularly primary biliary cholangitis, and abnormalities of salivary gland function have been described in all patients in some series. Sicca syndrome is also found in patients with cryptogenic cirrhosis and autoimmune hepatitis. In patients with Sjögren’s syn- drome, there is often hepatomegaly and minor derangement of liver tests, particularly serum alkaline phosphatase, in 25%. The liver may show nonspecific inflammatory infiltration. Amyloid The liver may be involved in both primary and secondary amyloid- osis; liver involvement is found in over 80% of patients with either form. In general, however, liver involvement has few significant clin- ical consequences, although jaundice, hepatitis, portal hyperten- sion, and spontaneous rupture have been described. Clinically, the liver is enlarged. The serum alkaline phosphatase is usually greatly elevated; jaundice is uncommon. It is believed that liver biopsy may be particularly hazardous in patients with amyloid because there may be an increased risk of bleeding after biopsy. The liver histology is similar in both primary and secondary amyloid with protein deposition in the portal tracts, vessel walls, and space of Disse. Cryoglobulinaemia The reported incidence of liver disease in essential, mixed cryoglobulinaemia varies greatly. In 20 to 50% of patients there is an association with hepatitis C viral infection. Up to half of patients have evidence of infection with hepatitis B virus, and up to 10% have chronic active hepatitis or cirrhosis with jaundice. Antiphospholipid syndrome Patients with antiphospholipid syndrome may develop liver abnor- malities. Mostly this is reflected by vascular disease such as arterial, venous, or portal venous thrombosis, veno-​occlusive disease, or, rarely, hepatic infarction. Some patients develop nodular regenera- tive hyperplasia. Other conditions Malignancy Although the liver may become infiltrated by metastatic cancer, ab- normalities of liver tests can be seen in the absence of infiltration. This may be due to a systemic effect of tumour-​derived cytokines, to the hepatotoxic effects of drugs, or the effects of irradiation, or the effects of malnutrition. Paraneoplastic syndromes occur, for ex- ample, cholestasis may be seen with lymphoma, ovarian cancers, and renal cell carcinoma. In other cases, such as with nonseminomatous testicular tumours, ‘liver’ enzymes may be synthesized by the tu- mour cells so abnormal ‘liver tests’ may not indicate any form of liver damage. Stauffer syndrome (abnormal liver tests, sometimes with hepatomegaly) is a rare complication of renal cell carcinoma which resolves after resection of the primary; it is believed to be caused by tumour production of interleukin 6. The liver in the sick patient Abnormalities of liver tests are commonly seen in patients who are critically sick and are associated with a poor prognosis. There are many causes of abnormal liver tests in this situation (Box 15.24.5.1). ‘Intensive therapy unit jaundice’ occurs in up to 10% of intensive therapy unit patients, usually in the context of sepsis or abdominal trauma. Hepatomegaly is often present but the cutaneous features of chronic liver disease are absent. Encephalopathy is uncommon. The liver tests show a rise in serum bilirubin with a smaller and less consistent rise in serum alkaline phosphatase and aminotransferase levels. The clotting is only mildly deranged and blood sugar levels tend to be high rather than low. The cause of intensive therapy unit jaundice is unclear but factors such as ischaemia, hypoxia, and hep- atocyte necrosis may occur. Treatment is of the underlying cause. Box 15.24.5.1  Abnormal liver tests in the critically ill patient • Sepsis • Underlying, pre-​existing liver disease • Drug-​induced liver injury • Trauma • Ischaemia • Haemolysis • Parenteral nutrition • Acalculous cholecystitis

15.24.6 Primary and secondary liver tumours 3178

15.24.6 Primary and secondary liver tumours 3178

section 15  Gastroenterological disorders 3178 Graft-​versus-​host disease The liver is often affected by graft-​versus-​host disease that may follow allogeneic and solid organ transplantation, especially when large numbers of donor T cells are transplanted (intentionally or in- advertently) which react with major or minor HLA antigens (such as in bowel or liver transplantation). Graft-​versus-​host disease may present as asymptomatic elevation of liver tests, cholestasis, or an acute hepatitis. Liver involvement usually follows skin and bowel involvement. The liver histology shows lymphocytic infiltration of small bile ducts and apoptosis of epithelial cells. Liver disease in pregnancy This is discussed in Chapter 14.9. Abnormalities of liver function may occur in hyperemesis gravidarum and pre-​eclampsia, as well as the liver diseases unique to pregnancy, which include cholestasis of pregnancy, acute fatty liver of pregnancy, and HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome. FURTHER READING Babkhanian Z, Donovan JA (2013). Biliary manifestations of systemic disease. Gastrointest Endosc Clin N Amer, 23, 333–​46. DeLemos AS, Friedman LS (2013). Systemic causes of cholestasis. Clin Liver Dis, 17, 301–​17. Flamm SL (2012). Granulomatous liver disease. Clin Liver Dis, 16, 387–​96. Gizard E, et al. (2014). Systematic review: the epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease. Aliment Pharmacol Ther, 40, 3–​15. Kelly T, Buxbaum J (2015). Gastrointestinal manifestations of cystic fibrosis. Dig Dis Sci, 60, 1903–​13. Kosters A, Karpen SJ (2010). The role of inflammation in cholestasis—​ clinical and basic aspects. Semin Liver Dis, 30, 186–​94. Leffler DA, Green PH, Fasano A (2015). Extraintestinal manifestation of celiac disease. Nat Rev Gastroenterol Hepatol, 12, 561–​71. Maheshwari A, Thuluvath PJ (2011). Endocrine diseases and the liver. Clin Liver Dis, 15, 55–​67. Neuberger J (ed) (2013). The liver in systemic disease. Best Pract Res Clin Gastroenterol, 27, 469–​629. 15.24.6  Primary and secondary
liver tumours Graeme J.M. Alexander, David J. Lomas,
William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison ESSENTIALS Benign, as well as malignant tumours arise in the liver. The most important include the following: Hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, but with marked geographical variation in incidence; it usually arises on a background of cirrhosis. It is usually asymp- tomatic unless the cancer is advanced. Cross-​sectional imaging with contrast with either CT or MRI is sufficient to make a firm diagnosis. Serum α-​fetoprotein is elevated in most cases. Historically, tumour biopsy was reserved for indeterminate cases, but molecular analysis may soon guide management of HCC and tumour biopsy to aid this could become the norm. Early diagnosis, perhaps through surveil- lance, increases the proportion of patients that can be considered for curative treatment, including surgical resection, radiofrequency ablation, or liver transplantation. The presence of symptoms denotes a poor prognosis, with less than 10% of patients surviving 3 years. Cholangiocarcinoma Cholangiocarcinoma accounts for 7 to 10% of primary liver malig- nancies. Jaundice is an early feature in those with hilar or extrahepatic tumours, whereas patients with early peripheral intrahepatic tumours are often asymptomatic. The diagnosis of cholangiocarcinoma can be very difficult to make. Tissue from peripheral tumours can be obtained directly by percutaneous biopsy with ultrasonographic or CT guidance, and at endoscopic retrograde cholangiopancreato­ graphy as brushings or biopsy for tumours of larger-​order ducts. Resection results in cure for only a few patients. Palliative approaches include photodynamic therapy, conventional radiotherapy, and high-​dose local irradiation. Biliary stents relieve jaundice and may reduce the frequency of episodes of cholangitis. Benign liver tumours Haemangioma, usually an incidental finding, has a prevalence of
2 to 5% in the population. Focal nodular hyperplasia (prevalence 0.4–​0.8%) is found predominantly in fertile women and is typically an incidental finding during abdominal imaging. Biopsy is required if there is diagnostic uncertainty and in particular to differentiate from hepatic adenomas, which are also typically incidental findings but may present with abdominal pain and carry risks of spontaneous haemorrhage and malignant transformation. Interventions include surgery, radiofrequency ablation, transarterial embolization, or a combination of each according to location and patient fitness. Secondary liver tumours Secondary tumours may be a presenting feature but more often are found during staging for primary malignancy or during follow-​ up. Symptoms include abdominal pain and hepatomegaly and later jaundice and ascites. If the primary is not apparent, targeted
liver biopsy usually confirms malignancy; immunohistochemical assessment is helpful in determining the source. For most patients with multiple metastases to the liver, the prognosis is poor and treatment palliative. Introduction Several diverse benign and malignant tumours arise in the liver. Benign tumours are relatively common and often incidental; dis- tinction is occasionally challenging and some harbour malignant

15.24.6  Primary and secondary liver tumours 3179 potential. Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy, almost always arising on a background of liver damage, most often manifest as cirrhosis. Early diagnosis and careful patient selection can lead to cure with surgical approaches including liver transplantation. Advances in understanding the molecular mechanisms in- volved in hepatocarcinogenesis are likely to yield novel thera- peutic agents. The prognosis of cholangiocarcinoma remains poor although prospects for earlier diagnosis and curative treatment are improving; intrahepatic cholangiocarcinoma and intermediate hepatocellular–​cholangiocarcinoma are increasingly recognized subtypes. Other primary liver malignancies are rare and thus op- timal management, including the role of transplantation, is not well defined. Secondary liver tumours are common. Treatment is palliative except for colorectal metastases, when surgical resection may extend life expectancy, and neuroendocrine tumours where liver-​directed therapy and surgical options may provide effective palliation. Hepatocellular carcinoma HCC is the fifth most common cancer worldwide as well as the third most common cause of cancer-​related death. Most tumours arise on the background of cirrhosis and typically grow slowly with late spread to extrahepatic sites including adrenals, lymph nodes, lung, and bone. Symptoms may not be apparent until the cancer is already advanced and because of late presentations most deaths occur within 1 year of diagnosis. Selected at-​risk patients benefit from enrolment into surveillance programmes where early detection permits a more expansive range of therapeutic options including cure with surgery or radiofrequency ablation. Epidemiology The geographical distribution of HCC worldwide is uneven. More than 80% of cases occur in sub-​Saharan and West Africa, China, and Asia. The incidence has always been lower in Western Europe and North and South America. In Taiwan, the introduction of universal vaccination against hepatitis B virus (HBV) has been followed by a substantial reduction in the incidence of HCC. However, the inci- dence of HCC following chronic hepatitis C virus infection is rising in most parts of the world, a rise that will be arrested eventually with the introduction of effective antiviral therapies. HCC is now the fastest-​growing cause of cancer-​related death in men in Europe, the United Kingdom, and the United States of America; much of this increase is a consequence of nonalcoholic fatty liver disease as a single risk factor or as a cofactor alongside alcohol-​related liver disease or chronic viral hepatitis. There is no doubt that many cases labelled as metastatic disease in the past are now attributed more accurately to HCC with the widespread avail- ability of cross-​sectional imaging. The main risk for HCC is cirrhosis. Men are at a threefold in- creased risk compared to women. Other risk factors include viral hepatitis, obesity, type 2 diabetes mellitus, the presence and dur- ation of chronic viral hepatitis, excessive alcohol consumption, and smoking. Age is an important risk factor and the incidence rises with each decade. For the minority with HCC arising in the absence of liver injury, males and females are affected equally and the pres- entation is more often in the third and fourth decades. Some cases arise in those with liver disease short of cirrhosis; most of these are a consequence of hepatitis B virus infection acquired in early life; a small number have genetic haemochromatosis; HCC is seen in- creasingly in older men with nonalcoholic fatty liver disease with fibrosis short of cirrhosis. Aetiology and prevention HCC usually occurs in the context of chronic liver injury: 80% of patients worldwide with HCC have cirrhosis, which in most can be attributed to chronic viral hepatitis, alcohol-​related or nonalcoholic fatty liver disease. Global prevention of HCC needs to address these risk factors in particular. HCC is the commonest cause of death in haemochromatosis but is uncommon with cirrhosis due to α1-​antitrypsin deficiency, Wilson’s disease, autoimmune hepa- titis, or primary biliary cholangitis. Glycogen storage disease type 1a (GSD1a), tyrosinaemia, and acute intermittent porphyria are rare metabolic disorders that predispose to HCC. Many patients with HCC have more than one aetiological risk factor. Hepatitis B virus HBV is the most common cause of HCC worldwide; an estimated 380 million infected individuals harbour a 100-​fold increased rela- tive risk of developing HCC. HCC can arise in the absence of cir- rhosis almost certainly because of the combination of chronic liver inflammation in combination with integration of viral DNA into the hepatocyte genome. In areas where HBV is endemic, vertical trans- mission to the fetus or baby results in high rates of chronicity; in low-​risk areas, the virus is more likely to be acquired horizontally later in life, when 90% clear infection. Risk factors for HCC among HBV carriers include male sex, cirrhosis, older age, family history of HCC, Asian or African eth- nicity, and coinfection with hepatitis C or D.  Aflatoxin B1, a hepatocarcinogen produced by the aspergillus fungus and pre- sent in stored foods in HBV-​endemic areas, has been implicated in susceptibility to HCC via direct disruption of the TP53 tumour-​ suppressor gene. Higher circulating viral DNA levels are associated with a greater risk of HCC. Conversely, sustained effective antiviral therapy is associated with a reduced risk of HCC. In Taiwan, the introduction of universal vaccination has now been associated with a substantial fall in the incidence of HCC. Hepatitis C virus Hepatitis C virus (HCV) is a leading cause for cirrhosis and HCC development in most countries and plays a particularly important role in Western countries and in Japan where HBV is less common. HCV-​infected individuals have a 17-​fold increased relative risk of developing HCC. For those who develop HCV-​related cirrhosis the annual incidence of HCC thereafter is 1 to 4%. HCC in relation to HCV in the absence of cirrhosis is rare and in most a second risk factor is present. In the West, the peak incidence of HCC related to HCV infection may not yet have been reached, and many infected individuals remain undetected. No vaccine is currently available. However, effective antiviral therapy reduces the risk of HCC and highly effective therapy for most HCV genotypes is now available (although expensive).

section 15  Gastroenterological disorders 3180 Alcohol Alcohol is a well-​established risk factor for HCC and acts synergis- tically with chronic viral hepatitis and the many manifestations of insulin resistance. Attempts to reduce per capita alcohol consump- tion would impact favourably on HCC prevalence. Nonalcoholic fatty liver disease Insulin resistance manifest as hypertension, type 2 diabetes mellitus, and a high body mass index are associated with an increased risk of HCC, most likely through evolution to cirrhosis due to nonalcoholic fatty liver disease. Haemochromatosis Patients with haemochromatosis and cirrhosis have up to a 200-​fold increased relative risk of HCC, which persists despite iron removal. Iron has a direct mitogenic effect through stimulation of hepatocyte proliferation. Early recognition through screening of those at risk and venesection before the onset of significant fibrosis should re- duce deaths from HCC. Pathogenetic mechanisms Important strides have been made in understanding the molecular biology of HCC development and progression. Alterations of many proteins involved in cell cycle regulation, such as p53 and cyclin/​ CDK complex and several intracellular signalling pathways under- going oncogenic activation (specifically Ras/​Raf/​Mek/​Erk, Wnt/​ β-​catenin and PI3k/​Akt/​mammalian target of rapamycin (mTOR)) appear key. The role of several growth factors and angiogenic factors in the tissue microenvironment, such as epidermal growth factor (EGF) and vascular EGF, has been confirmed. These pathways may present therapeutic options in the future. Cirrhosis is characterized by decreasing hepatocyte prolifer- ation as regenerative capacity becomes exhausted. A  hypothesis for HCC development in the context of hepatocyte senescence in- volves critical telomere shortening which then triggers DNA re- pair mechanisms and chromosomal instability as the first step. Some tumours may originate from a particular subpopulation of stem cells, which persist in the adult liver and are found in portal triads. These ‘oval’ cells retain the potential to proliferate and differ- entiate into either hepatocytes or biliary epithelial cells; they have been implicated in the development of HCC as well as intermediate hepatocellular–​cholangiocarcinoma. Clinical features Increasingly, HCC is first identified at imaging, either through screening or liver ultrasonography requested because of a change in clinical circumstance. When symptomatic, HCC may present with the triad of pain in the right upper quadrant, hepatomegaly, and weight loss. Patients presenting with these symptoms usually have large tumours, which are often palpable. Decompensation in any patient with cirrhosis (manifest as worsening ascites, variceal haemorrhage, jaundice, encephalopathy, or a combination of these) should always be considered a possible manifestation of evolution from cirrhosis to HCC. Very rarely the first manifestation is sudden abdominal pain and swelling associated with haemoperitoneum due to tumour rupture, where imaging and analysis of ascitic fluid confirm the diagnosis; angiography is helpful and offers a treatment option through em- bolization. Other liver structures may be involved including, in order of frequency, the portal vein, hepatic veins, and the bile duct. Other rare presentations include haemobilia, pyrexia of unknown origin, and infrequently paraneoplastic manifestations such as poly- cythaemia, hyperthyroidism, hypercalcaemia, and hypoglycaemia. Investigation The diagnosis of HCC is confirmed with a combination of blood tests, various imaging techniques, and histology. Serum markers The α-​fetoprotein concentration is the only laboratory test used in routine practice for the diagnosis of HCC. It is a glycoprotein synthesized by fetal liver and maternal plasma concentrations reach a maximum at the end of the first trimester, declining rapidly after birth to adult levels (0–​10 ng/​ml). Elevated levels are found in about 80% of patients with HCC and tend to be higher in African and East Asian populations (median 10 000 ng/​ml) than in those from low-​ incidence areas (median 1000 ng/​ml). This difference may reflect the different stage of disease at diagnosis. Specificity of α-​fetoprotein varies according to aetiology and the presence of cirrhosis, but is elevated in most cases. Concentrations of α-​fetoprotein above 200 ng/​ml in patients with a liver mass are con- sidered diagnostic; the differential diagnosis includes nonseminoma germ cell tumours and hepatoblastoma (in infants). A few cases with elevated levels are reported in families in the absence of disease and attributed to single nucleotide polymorphisms. Serum α-​fetoprotein increases with tumour growth and serial measurements showing a steady rise are strongly indicative of HCC, but most patients with HCC without cirrhosis have a normal α-​fetoprotein level. A mod- estly raised and fluctuating α-​fetoprotein level is common in patients with chronic HCV infection without HCC. The plasma α-​fetoprotein level also rises during recovery from severe liver injury and falls with recovery. Other plasma markers, including α-​fetoprotein vari- ants, have been considered but have not been adopted into clinical practice. Liver imaging Ultrasonography is inexpensive, safe, can detect HCC as small as 1 cm in diameter, and is the mainstay of screening programmes. HCC is typically hypoechoic (Fig. 15.24.6.1). Further imaging is always required for a definite diagnosis. Sensitivity is operator and patient dependent and is reduced in those with heterogeneous and nodular texture livers or with a high body mass index. In these, screening may best be performed alternating between liver ultrason- ography and MRI of the liver. Liver ultrasonography sensitivity can be improved with microbubble contrast. Doppler ultrasonography can detect tumour vascularity and portal vein flow patency prior to therapeutic intervention. The visibility of a mass during liver ultra- sonography will inform subsequent attempts at biopsy or ablation. Multislice CT is an established imaging modality for the diagnosis and staging of HCC and for planning surgical resection, providing clear definition of critical structures and liver volume measure- ment. The use of intravenous contrast medium allows more detailed characterization: a combination of arterial phase enhancement and portal venous ‘washout’ is almost diagnostic for HCC in lesions over

15.24.6  Primary and secondary liver tumours 3181 2 cm in size in a cirrhotic liver (Fig. 15.24.6.2). Smaller lesions and those with a less typical vascular profile require additional imaging with MRI, which may improve diagnostic certainty. The sensitivity of CT is imperfect; 30% of tumours less than 2 cm in size remain undetected when compared with subsequent explant histology. CT is helpful in demonstrating hepatic features consistent with cirrhosis or portal hypertension and provides important staging information regarding tumour involvement in chest, lymph nodes, peritoneum, adrenals, and macrovascular invasion The sensitivity and specificity of MRI for the detection of HCC is better than CT, especially for indeterminate lesions at CT and those smaller than 2 cm, but is less informative for extrahepatic staging purposes. A particular advantage is the range of contrast mechan- isms that can detect focal steatosis and restricted water diffusion. Excellent visualization of the hepatic arterial supply can be obtained by selective catheterization at angiography; as the vascular supply for HCC is predominantly arterial, a diagnostic ‘tumour blush’ is seen in most cases. However, angiography is now mainly used for therapy rather than diagnosis. A few HCCs (5–​10%) have atypical features as a result of fat or glycogen accumulation or infarction that can alter the imaging char- acteristics. Remaining uncertainty is usually resolved by biopsy of the focal lesion. Without a firm diagnosis, continued surveillance is mandatory. Liver biopsy Histology remains the gold standard for diagnosis, although inter- pretation may be challenging, for example, distinguishing between well-​differentiated HCC and severe dysplasia. On microscopic examination, HCC is typically composed of large eosinophilic or clear cells, arranged in trabeculae; intercellular bile is diagnostic when present (Fig. 15.24.6.3). Specific immunohistochemical staining is needed occasionally to distinguish poorly differenti- ated HCC from metastatic disease. Immunohistochemical markers for hepatocytes, such as hepatocyte paraffin 1 and α-​fetoprotein, may help where morphology is not characteristic. Biopsy of the Fig. 15.24.6.1  Ultrasonography showing a small (1.4-​cm) hypoechoic nodule in the liver (arrow). This finding is suggestive but not diagnostic for HCC and further evaluation with contrast-​enhanced CT or MRI is warranted. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. (a) (b) Fig. 15.24.6.2  Hepatocellular carcinoma (arrow) in a cirrhotic liver demonstrating typical arterial enhancement (a) and portal phase washout (b) on CT.

section 15  Gastroenterological disorders 3182 background liver should always be considered as the presence of cir- rhosis both increases the probability of a focal lesion being HCC and has implications for management. Percutaneous biopsy carries a small risk (<2%) of tumour seeding along the tract (relating to needle gauge) and has been avoided by some practitioners prior to curative treatments. Coagulopathy and ascites are additional hazards. For inaccessible lesions of sufficient concern, and where imaging is not diagnostic, laparoscopic biopsy or wedge resection is an alternative. Notwithstanding these issues, histological examination and sta- ging of surgical specimens are important for prognosis in HCC; poor differentiation grade and vascular invasion are strongly associ- ated with tumour recurrence following resection or transplantation. Determining prognosis based on needle-​derived specimens is more challenging due to variation of differentiation and vessel involve- ment across the tumour. Dissection of mutations in HCC has highlighted three groups of mutated genes related to aetiological risk factors including CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Further analyses have identi- fied more mutations associated with progression, including TERT, FGF3, FGF4, FGF19, CCND1, TP53, and CDKN2A. Molecular ana- lysis may therefore soon guide management of HCC, and tumour biopsy to aid this could become the norm. Surveillance The value of liver ultrasonographic surveillance for HCC remains contentious, but nevertheless is advised in all or most cirrhotic pa- tients by national and international guidelines. It has been shown to be cost-​effective in cirrhosis where the annual risk of HCC exceeds 1.5%. Cirrhosis due to chronic viral hepatitis, alcohol-​related and nonalcoholic fatty liver disease, haemochromatosis, and stage 4 pri- mary biliary cirrhosis fulfil that criterion. Incidence data for HCC in cirrhosis due to autoimmune hepatitis and α1-​antitrypsin deficiency are less robust. According to international guidelines, HBV carriers considered at increased risk include Asians (men >40 years, women >50 years), Africans (from adulthood), those with a family history of HCC, and older white men with active disease. With HCV infection, surveil- lance can be limited to those with advanced fibrosis or cirrhosis. For surveillance of HCC, liver ultrasonography repeated every 6 months has a sensitivity of 65–​80% with a specificity exceeding 90%; the standard 6-​month interval is based on average tumour doubling times. α-​Fetoprotein alone is inadequate as a screening test as it lacks sensitivity, though is typically used in conjunction with ultrasonography. Management Cure is the goal, but extended survival is now reported with many approaches. Several treatment options are available; increasingly, therapeutic approaches are used in combination or sequentially. HCC is distinguished from almost all cancers by the absolute need to consider underlying liver function. Many patients with HCC will die from liver failure as part of the natural course of cirrhosis or ex- acerbated by treatment focused on HCC. Liver transplantation, sur- gical resection, and radiofrequency ablation all have the potential for cure and should be considered as first-​line therapies. In general, transarterial chemoembolization (TACE)/​embolization (TAE) is considered palliative with survival benefit, but for small lesions may occasionally be curative. A role for systemic internal radiotherapy has not yet been established. Sorafenib is targeted specifically at those with more advanced HCC; other tyrosine kinase inhibitors have proved disappointing. Cytotoxic drugs are considered ineffective. Sirolimus and analogues undoubtedly affect HCC beneficially, but a precise role for mTOR inhibitors has yet to be established. Surgical resection There are two important factors: patient fitness for surgery and tech- nical feasibility. Operative mortality is low with careful patient se- lection and laparoscopic approaches reduce risk further. Assuming cardiovascular fitness, the best candidates are those without cir- rhosis with a single tumour, or those with cirrhosis with minimal portal hypertension and well-​preserved liver function. Selection of patients with cirrhosis should be restricted to those in Child–​Pugh class A and a hepatic venous pressure gradient less than 12 mmHg. Survival in such cases reaches 70% at 5 years. The risk of hepatic de- compensation rises in those falling outside those criteria, with 50% survival in the presence of portal hypertension and 30% with jaun- dice. Increasingly, the estimated residual volume is another factor in selecting those most likely to survive surgery. Microscopic analysis of the whole tumour provides a clear indication of the likelihood of recurrence. Even after successful surgery there remains a significant risk that a new primary might develop. It can be difficult to distinguish recurrent disease from a new pri- mary. Early recurrence is usually due to dissemination prior to sur- gery, whereas later recurrence is more likely to be the result of de novo tumour development. Recurrence is associated with microvascular invasion, the maximal rate of proliferation, and the presence of satel- lite nodules, rather than the size of the lesion per se, although larger lesions are more likely to have adverse features. Surgical resection after spontaneous rupture of HCC is often essential if haemorrhage is not arrested by TAE. Liver transplantation Transplantation confers a significant long-​term survival benefit for patients with cirrhosis, curing both the tumour and the underlying liver disease, but is not without risk. Donor shortage has restricted selection to those with predicted survival comparable to non-​HCC indications. The Milan criteria (single tumour ≤5 cm or up to three tumours ≤3 cm) predict a 70% 5-​year survival and 10% recurrence rate. Patients awaiting transplantation usually undergo palliative Fig. 15.24.6.3  Biopsy specimen from a well-​differentiated HCC showing eosinophilic cells arranged in a trabecular pattern with pseudoglandular formation and bile plugs.

15.24.6  Primary and secondary liver tumours 3183 therapy with TACE/​TAE or radiofrequency ablation on the waiting list, but current waiting times result in a 25% dropout rate due to tumour growth after 12 months. Local management decisions will differ regarding priority for HCC on the liver transplant waiting lists. Extension of the Milan (or similar) criteria is considered fre- quently, which reflects observations that not all larger tumours ex- hibit ‘bad biology’ while some very small tumours recur soon after liver transplantation. In some transplant centres, patients with larger tumours that respond well to local therapy are considered for liver transplantation. Better methods to predict tumour behaviour, inde- pendent of size, are still required. It is not unusual for HCC recurrence after liver transplantation to be extrahepatic, reflecting preoperative seeding. For these, treat- ment decisions are specific to the circumstance. Recent observations support the early observations that post-​transplantation immuno- suppression with the mTOR inhibitor sirolimus reduces or delays tumour recurrence. Explant histology can be used to identify those at greater risk of recurrence and a need for increased surveillance. Ablative therapy Ablation is undertaken for tumours usually less than 3 cm in size. Several approaches are used, including radiofrequency, microwave, laser, high-​intensity focused ultrasonography, or freezing, aiming to destroy the tumour and the local penumbra. For small lesions these treatments can be curative, but the reassurance of seeing the excised tumour under the microscope is absent. Whether a small lesion is ablated or resected will depend on lo- cation and patient fitness. Tumours in contiguity with vascular structures or the liver capsule may be less suited to ablation. Liver ultrasonography or CT is needed to guide placement for therapy and ablation cannot be undertaken unless the mass is seen clearly with these modalities. The procedure can be undertaken laparoscopic- ally or as an adjunct to surgery when there is a second less access- ible lesion. The procedure is followed very occasionally by abscess formation at the site of the tumour. Tumour tracking up the needle used for therapy has been reported. Post-​treatment images reveal an avascular region following successful therapy. Survival after radiofrequency ablation is 75% at 3 years, similar to that for surgical resection of small tumours; for larger tumours mor- tality and recurrence rates increase exponentially with size. Embolization therapies: TACE and selective internal
radiation therapy TACE is considered for more extensive disease where surgical ap- proaches or ablation are not applicable. It often needs to be repeated and this is safe provided it remains effective and liver function is ad- equate. TACE involves injection of a chemotherapeutic agent (typ- ically doxorubicin bound to beads) into hepatic arterial branches supplying the tumour, followed by embolic occlusion. Infarction and necrosis ensue since tumours derive 95% of their blood supply from the hepatic artery. To avoid extensive infarction of neighbouring liver tissue, portal vein patency is essential. Although cure is very rare, up to 60% of patients respond and tumour progression is delayed with a 20 to 60% improvement in 2-​year survival. A postembolization syndrome of abdominal pain and fever is common, indicating tu- mour necrosis. There is a real risk of abscess formation so antibiotic prophylaxis is recommended. The most worrisome complication is the development of liver decompensation in those with borderline liver function prior to the procedure, hence careful assessment is es- sential; patients with jaundice or ascites rarely do well. The best can- didates have preserved liver function without vascular involvement or extrahepatic spread. Although TAE, which is used by many, achieves similar objective responses, only TACE has shown survival benefit in recent meta-​ analysis. Selective internal radiation therapy is similar in concept except that radioactive yttrium bound to beads designed to lodge in tumour capillaries is injected. The role for this approach in relation to other modalities has not yet been established. Chemotherapy HCC is considered resistant to chemotherapy and there is no benefit from systemic therapy. Responses to cytotoxic drugs, typically doxorubicin, are limited and hampered by side effects. Tamoxifen, octreotide, pravastatin, and gemcitabine have not shown any impact on survival. Agents targeting particular molecular pathways have not ful- filled early or theoretical promise with the exception of sorafenib, a multikinase inhibitor that reduces proliferation and angiogenesis. Randomized controlled trials in patients with cirrhosis without liver decompensation show a small survival benefit, but many are in- tolerant of the associated side effects. Radiotherapy HCC is also considered resistant to radiotherapy, but some tumours respond well and it has proved useful for local and bone metastases. Prognosis Symptomatic presentation carries a poor prognosis; less than 10% of patients survive 3  years. Surveillance programmes, however, identify one-​third of patients at an early stage when curative treat- ment is possible. Estimating prognosis depends on tumour stage, liver function, and overall health. Several staging systems have been proposed and are in clinical use, although none has been adopted universally. The Barcelona Clinic Liver Cancer system links tumour stage and Child–​Pugh status with treatment strategy to optimize prognosis. Fibrolamellar hepatocellular carcinoma This rare variant presents in individuals in or around the third decade. Risk factors are not apparent, cirrhosis is not found, and the α-​fetoprotein level is not elevated. The tumour tends to grow slowly; regional lymph node metastases are common. Histology is charac- teristic and reveals dense fibrotic bands surrounding eosinophilic tumour cells. The prognosis is much better than for HCC, probably because of slow growth in a young patient in the absence of liver injury, so regeneration is prompt. Although recurrence is common after resection, patients often do well with repeated surgery for liver masses and/​or affected nodes. Hepatoblastoma This primary hepatic malignancy occurs in children, mostly under 3 years of age. The optimal treatment approach of resection combined

section 15  Gastroenterological disorders 3184 with chemotherapy achieves 5-​year survival of 80%. Transplantation is an effective rescue therapy. Cholangiocarcinoma This is an epithelial malignancy of the biliary tree, which on anatomical grounds is separated into intrahepatic or extrahepatic and the latter then divided into hilar and lower duct tumours. Cholangiocarcinoma is less common than HCC and comprises around 7 to 10% of primary liver malignancies. The prognosis is poor unless detected very early, usually fortuitously. Epidemiology and aetiology Cholangiocarcinoma occurs most commonly in the sixth and sev- enth decades, is much more common in men, and twice as common in Asians. The incidence of intrahepatic cholangiocarcinoma ap- pears to be increasing worldwide. The highest reported incidence is in northern Thailand, due to endemic biliary infection with the trematode Opisthorchis viverrini. A high incidence is also seen in Korea where a similar infection with the fluke Clonorchis sinensis is prevalent. Other risk factors for the intrahepatic variant include oriental fibrocholestatic hepatitis, primary sclerosing cholangitis, Epstein–​Barr virus, HCV infection, and exposure to Thorotrast (thorium dioxide which was used as contrast for angiographic pro- cedures between 1930 and the 1950s). The developmental abnormal- ities Caroli’s disease, congenital hepatic fibrosis, and von Meyenburg complexes are also associated with an increased risk of intrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinoma is associated with primary scler- osing cholangitis, abnormal anatomy at the choledochopancreatic junction, choledochal cysts, and infection by either C. sinensis or O. viverrini. Pathogenesis Most of the aetiological factors associated with cholangiocarcinoma induce chronic inflammation within the biliary tree, for example, age, cholelithiasis, smoking, alcohol consumption, developmental abnormalities of the biliary tree, parasitic biliary infection, and primary sclerosing cholangitis. Chronic inflammation stimulates inducible nitric oxide and free radical production in bile duct epi- thelial cells. These processes in turn induce oxidative DNA damage and telomere shortening with resultant loss or gain of critical genes involved in cellular control. Methylation of tumour suppressor pro- moters and cholangiocyte resistance to apoptosis are thought to be relevant to oncogenesis. Pathology Cholangiocarcinoma is an adenocarcinoma with a prominent stromal reaction. Histological variants include adenosquamous, signet cell, sarcomatous, clear cell, and lymphoepithelial. Three contrasting growth patterns have been applied to both intrahepatic and extrahepatic cholangiocarcinoma:  mass-​forming, periductal-​ infiltrative, and intraductal. Mass-​forming is the commonest mode of presentation of intrahepatic cholangiocarcinoma; tumours are often large, up to 15 cm in diameter. The margin is typically well circumscribed and lobulated and central necrosis may be present. Multicentricity is common, probably because of the propensity of the tumour to in- vade adjacent peripheral branches of the portal vein. Mass-​forming tumours arising from extrahepatic ducts tend to be smaller, typically less than 2 cm. Periductal-​infiltrative cholangiocarcinoma is most common at the hilum (Fig. 15.24.6.4), growing along the bile ducts and there- fore elongated, spiculated, or branchlike. These tumours are difficult to detect radiologically. Most intraductal cholangiocarcinomas are papillary adeno- carcinomas comprising innumerable frond-​like proliferative columnar epithelial cells with slender fibrovascular cores. The tumours are usually small, sessile, or polypoid, often spreading superficially along the mucosal surface, often resulting in multiple tumours (papillomatosis) along the biliary tree. Occasionally, a large mass occludes the bile duct; some tumours produce profuse amounts of mucin akin to pancreatic intraductal papillary mu- cinous tumours. Clinical features With peripheral intrahepatic masses, patients present with upper abdominal pain, anorexia, malaise, and weight loss. Jaundice is an early feature of hilar tumours. Hepatomegaly is usual and spleno- megaly may occur in the context of a secondary biliary cirrhosis due to prolonged obstruction. Investigation A confident diagnosis of cholangiocarcinoma can be very difficult to make. Liver function tests are typically cholestatic with eleva- tion of plasma bilirubin and alkaline phosphatase concentrations. α-​Fetoprotein concentrations are usually normal or only slightly raised. Carbohydrate antigen (CA)-​19-​9, a glycoprotein secreted by bile duct cells, is used as a tumour marker but has poor sensitivity and specificity. In patients with primary sclerosing cholangitis, a CA19-​9 level over 100 U/​mL is 80% specific for the presence of a superimposed cholangiocarcinoma. Depending on location, cross-​sectional imaging or magnetic res- onance cholangiopancreatography (MRCP) may be helpful but not diagnostic. Mass-​forming intrahepatic cholangiocarcinoma often reveals persistent peripheral enhancement on contrast-​enhanced Fig. 15.24.6.4  Histological slide of resection margin following surgical resection of hilar cholangiocarcinoma showing neurovascular invasion, predictive of a poor outcome. Reproduced from Kerr DJ, Haller DG, van de Velde CJH, Baumann M (2016). Oxford Textbook of Oncology, 3rd edition with permission from Oxford University Press.

15.24.6  Primary and secondary liver tumours 3185 CT imaging (Fig. 15.24.6.5). For extrahepatic hilar tumours, MRCP demonstrates first-​ and second-​order duct involvement; a mass may be evident which is hypointense on T1-​weighted imaging, but hyperintense on T2-​weighted imaging. The differential diagnosis of hilar lesions includes inflammatory pseudotumour and metastasis. A periductal-​infiltrative tumour appears on MRCP as a concentric irregular thickening of the bile duct with an abrupt calibre change (Fig. 15.24.6.6). An intraductal neoplasm may be visualized as an enhancing mass confined to the lumen of the bile duct. In all three, the ducts peripheral to the tumour may appear dilated with associ- ated atrophy of the liver. Percutaneous transhepatic cholangiography may help if prox- imal involvement of the biliary tree cannot be determined at MRCP and then used to drain segments prior to surgery. Endoscopic retrograde cholangiopancreatography with brush cytology and biopsy, or choledochoscopy, may assist in the diagnosis of a ma- lignant biliary stricture. Cytological analyses of specimens for an- euploidy by digital image analysis or for chromosomal alterations using fluorescence in situ hybridization improves diagnostic ac- curacy considerably but are not available routinely. Endoscopic ultrasonography-​guided fine needle aspiration of hilar masses can achieve a sensitivity and specificity for malignancy of 89% and 100%, respectively. This technique can also be used to identify ma- lignant lymph nodes. Positron emission tomography imaging may be a useful adjunct for diagnosis; laparoscopy can detect occult peritoneal spread. Management and prognosis For peripheral tumours, the main treatment approach is resection with prospect of cure, although results are generally disappointing. Poor prognostic factors include a preoperative CA19-​9 concen- tration greater than 1000 U/​mL, multifocal disease, liver capsule invasion, regional lymph node metastases, and mass-​forming or periductal infiltrative histology. Extrahepatic tumours of the distal duct should be considered for a Whipple’s procedure. Hilar tumours may be suitable for curative resection with an extended hemihepatectomy with anastomosis of a jejunal Roux loop to a hilar bile duct. Contraindications to surgery include bilateral involvement of second-​order radicles and portal vein or hepatic artery encasement contralateral to the resection side. Despite surgical advances, the median 5-​year survival for hilar tu- mours following resection is around 20% and controlled trials of ad- juvant chemotherapy are needed. More commonly, curative excision is not possible, and the aim is to establish biliary drainage. A stent (a) (b) Fig. 15.24.6.5  Parenchymal cholangiocarcinoma on CT: (a) unenhanced, (b) portal phase. Note the delayed central enhancement (arrow) and overlying capsular retraction typical of a fibrotic lesion. Fig. 15.24.6.6  Maximum intensity projection of three-​dimensional MRCP demonstrates intrahepatic biliary dilatation and a stricture of the common hepatic duct due to a hilar cholangiocarcinoma (arrows).

section 15  Gastroenterological disorders 3186 can be placed through the growth endoscopically or via a percutan- eous transhepatic route to relieve jaundice and possibly reduce the frequency of episodes of cholangitis. Unilateral self-​expanding metal stent placement has been shown to be effective and cost-​effective if survival is expected to exceed 6 months. MRCP may assist optimal stent positioning. Photodynamic therapy may prolong survival. Conventional radiotherapy and high-​dose local irradiation within the biliary tree with an iridium-​192 wire may produce symptomatic relief. If bil- iary drainage can be achieved by these procedures, survival for 1 to 2 years is not unusual. In most countries, liver transplantation is not considered for cholangiocarcinoma as historical data indicate a high level of re- currence and related mortality. However, long-​term survival has been reported in highly selected cases with unresectable hilar cholangiocarcinoma, based on high-​dose neoadjuvant radiotherapy (external and internal) with chemosensitization and operative sta- ging to exclude patients with regional lymph node metastases, with 5-​year post-​transplantation survival of greater than 80%. Vascular complications were more common than expected and such findings need to be replicated before adoption. Malignant vascular tumours Angiosarcoma Angiosarcoma of the liver is a rare, aggressive primary tumour, often multifocal, which may arise in a cirrhotic liver. About 200 new cases are reported worldwide annually. Peak incidence is in the sixth and seventh decades and men are affected more commonly than women. In 75% of cases there is no recognized cause. There are associations with arsenic, vinyl chloride, and Thorotrast. Angiosarcoma is re- ported in workers in the vinyl chloride industry; strict safety regu- lations have been introduced but new cases still present because of the long latent period. Long-​term androgen use, haemochroma- tosis, and von Recklinghausen disease (neurofibromatosis type 1) are other associations. Vinyl chloride-​associated tumours are asso- ciated with TP53 mutations, while KRAS2 mutations are associated with Thorotrast-​related and sporadic angiosarcoma. Patients may present with symptoms of hepatic venous outflow obstruction (abdominal pain and ascites) akin to the Budd–​Chiari syndrome; 15% present with an acute abdominal crisis following tu- mour rupture and 15% present with splenomegaly and pancytopenia. A few present with metastases to lung, spleen, or bone marrow. Signs of high-​output cardiac failure may be present; ascites may be blood stained after spontaneous haemoperitoneum. Disseminated intravas- cular coagulation may be associated (Kasabach–​Merritt syndrome). On CT and MRI these tumours demonstrate a variety of appear- ances, although most have focal hypodense areas, often haemor- rhagic, which demonstrate arterial enhancement with intravenous contrast (Fig. 15.24.6.7). A typical reticular pattern due to previous Thorotrast accumulation may be evident on CT, and vascular lakes may be observed on angiography. Diffuse infiltration may give rise to a nonspecific heterogeneous appearance of the liver. Liver biopsy is diagnostic in 25% of percutaneous and 65% of open procedures, the latter is preferred due to the risk of bleeding. Histology shows typical spindle or pleomorphic tumour cells with eosinophilic cytoplasm growing along the vascular lumen. The growth and blockage of sinusoids is associated with sinusoidal con- gestion and then liver cell atrophy. These cells are derived from vas- cular structures so express CD34 (Fig. 15.24.6.8). If Thorotrast or vinyl chlorides are the cause there may be considerable periportal and subcapsular fibrosis. Curative resection is rarely possible and chemotherapy is unproven. Hepatic epithelioid haemangioendothelioma This rare malignant tumour of vascular endothelial origin runs a clinical course resembling low-​grade angiosarcoma. It is usually multifocal and slow growing. Patients are more often female and pre- sent in the fifth decade with right upper quadrant pain. Histological appearances are characteristic, with a spindle lesion infiltrating hepatocyte plates and hepatic veins. Immunohistochemistry using the vascular marker CD34 helps confirm the diagnosis. Resection is associated with a 5-​year survival of 75% but may be unfeasible technically and recurrence is common. Transplantation is under- taken in a few, highly selected cases, but with an unpredictable out- come since recurrence is hard to predict. There is no proven role for chemotherapy. Benign liver tumours Haemangioma This is the most common benign tumour of the liver found in 2 to 5% of the general population with female preponderance; le- sions are often multiple. Histology, which is needed rarely, reveals multiple, large blood-​filled spaces, lined by endothelial cells, with varying degrees of hyalinization and fibrosis. Cavernous haem- angioma refers to lesions larger than 4 cm which are fed by hepatic arterial branches and have a slow internal circulation. Haemangiomas are usually discovered incidentally during abdominal imaging. Larger tumours can cause abdominal symp- toms from mass affect and have been reported to cause portal hypertension, haemobilia, caval thrombosis, and a consumptive coagulopathy (Kasabach–​Merritt syndrome). Spontaneous or traumatic ruptures have also been reported. Fig. 15.24.6.7  Portal phase CT examination demonstrating multiple focal hepatic and splenic lesions with vascular elements in an aggressive angiosarcoma.

15.24.6  Primary and secondary liver tumours 3187 The typical appearance on ultrasonography is a well-​circumscribed, uniform hyperechoic mass. MRI is a more sensitive and specific mo- dality, demonstrating a lesion that is hypointense on T1-​weighted imaging and hyperintense on T2-​weighted views. Dynamic imaging shows nodular peripheral enhancement with progressive centripetal ‘fill-​in’ and retention of contrast in the portal phase (Fig. 15.24.6.9). Occasionally biopsy is required to confirm diagnosis in larger lesions where typical features are not present. Usually no treatment is required and patients can be given re- assurance. Large symptomatic haemangiomas can be managed by surgical resection or embolization. Avastin has been reported to shrink such masses. Liver transplantation has been performed on rare occasions when resection is impossible and symptoms are intractable. Focal nodular hyperplasia Focal nodular hyperplasia (FNH) is the second most common benign tumour of the liver, with a prevalence of 0.4 to 0.8%. It is nine times more prevalent in women than men and usually pre- sents in the third or fourth decades. Tumours are often multiple and occasionally reach a considerable diameter, but most often are under 5 cm in size. The oral contraceptive pill does not in- duce FNH formation, but oestrogens promote FNH growth and vascularity. Histology shows a central large fibrous septum containing a branch of the hepatic artery, which divides in a star-​shaped manner and is not accompanied by either the portal vein or bile duct. Within the central ‘stellate scar’ there is bile ductular pro- liferation surrounded by polyclonal nodular hyperplasia of the hepatic parenchyma giving a pseudobiliary cirrhotic pattern. The hyperplastic response of the hepatic parenchyma may be driven by angiopoietins released from the hepatic artery branch, or in response to a hyperperfusion injury. The less common, recently recognized ‘telangiectatic’ variant is now classified as an adenoma. FNH is usually detected on ultrasonography but requires further characterization. On MRI the lesion demonstrates (a) (b) (c) (d) Fig. 15.24.6.9  Typical hepatic haemangioma on MRI with high signal on (a) heavily T2-​weighted imaging; (b) low signal on T1-​weighted imaging; (c) peripheral nodular arterial enhancement; and (d) progressive infilling and persisting enhancement on delayed imaging. (a) (b) Fig. 15.24.6.8  Biopsy specimen from an angiosarcoma showing irregular cells with pleomorphic and hyperchromatic nuclei infiltrating the sinusoids and terminal hepatic vein branches ((a) haematoxylin and eosin; (b) stained for CD34).

section 15  Gastroenterological disorders 3188 homogeneous signal intensity with the central scar hypointense on T1-​weighted imaging and hyperintense on T2-​weighted imaging (Fig. 15.24.6.10a). In 80% of lesions less than 3 cm in size, a cen- tral scar may not be visible. With administration of contrast medium, avid arterial enhancement occurs around the scar (if present) and the lesion then becomes isointense in the portal phase. With delayed imaging, the central scar may become hyperintense. Hepatobiliary contrast media such as gadoxetic acid (Primovist) typically accumu- late in FNH lesions on delayed imaging, which may help discrimin- ation from adenomas that do not retain the agent (Fig. 15.24.6.10b). If the imaging techniques are not diagnostic, targeted biopsy usually confirms the diagnosis. The prognosis is excellent and malignant change has not been recorded. For women on the oral contraceptive pill where FNH appears likely, but biopsy is not straightforward, a surveillance ap- proach with cessation of oestrogen use may provide reassurance. Hepatic adenoma Hepatic adenoma is 10 times less common than FNH and rare in men, with a female-​to-​male ratio of 4:1, and they share CT and MRI features of hepatic arterial enhancement and isointensity in the venous phase. Hepatic adenoma may be multiple, and it is not un- usual to find both FNH and adenoma in the same liver. The presence of more than 10 adenomas defines hepatic adenomatosis. The incidence of adenomas among long-​term users of the oral contraceptive pill is approximately 4 per 100 000 and increases with length of contraceptive use. In women who do not use oral contra- ceptives, or have used them for less than 2 years, the incidence is 1 per million. Adenomas may increase in size in pregnancy and shrink with suspension of oestrogen use, and often become undetectable following the menopause. A few cases arise due to genetic predisposition. Patients with GSD1a may develop inflammatory hepatic adenoma, especially men and those aged over 25 years. Adenoma expressing HNF-​1α may be associated with a family history of maturity-​onset diabetes mellitus of the young type 3 (MODY 3). Most are associated with somatic variants including inflammatory/​telangiectatic with muta- tions in gp-​130, previously classified as telangiectatic FNH, HNF-​1α positive, and β-​catenin positive. The incidence of adenoma is also increased in patients with type 2 diabetes mellitus, haemochroma- tosis, acromegaly and in men using anabolic steroids. On microscopic examination, adenomas consist of trabeculae of mature-​appearing hepatocytes with absent portal tracts and Kupffer cells, though arterial branches are present. Genetic mutations have been identified which correlate with distinct biological phenotypes. Biallelic HNF1A mutations define adenomas with marked steatosis, a lack of both cytological abnormalities and inflammatory infil- trates, and a very low risk of malignant transformation. Mutations resulting in β-​catenin (CTNNB1) activation are present in 15% of cases and are associated with a higher risk of transformation into HCC. A third group of adenomas has been defined by the absence of known mutations but the presence of inflammatory infiltrates and features such as sinusoidal dilatation, ductular reaction, and cytological abnormalities. Such ‘telangiectatic’ adenomas, origin- ally called telangiectatic FNH, are thought to have a higher risk of bleeding and may harbour malignant potential. Mutations in the IL6ST gene encoding gp130, activating the interleukin-​6 pathway, have been associated with most of these lesions. A fourth group comprises adenomas without known mutations or inflammatory infiltrates. Hepatic adenoma is typically an incidental finding but may present with abdominal pain, which may be severe and associ- ated with cardiovascular compromise, in which case spontaneous rupture and haemorrhage should be considered (Fig. 15.24.6.11). The main risks, which make the distinction between adenoma and FNH important clinically, are spontaneous haemorrhage and malignant transformation, and for both complications the risk is linked to size, such that tumours with a diameter greater than 5 cm should be considered for intervention. The risk of haemorrhage is greater with telangiectatic tumours, while malignant transform- ation is seen more often with GSD1a or with β-​catenin-​expressing adenomas. CT imaging of complex adenomas may demonstrate an area of haemorrhage and occasionally internal fat or calcification, making the appearances relatively nonspecific. More typical le- sions demonstrate homogeneous enhancement in the hepatic arterial phase with lesions becoming isoattenuating in the portal venous phase. With MRI, adenomas are hyperintense or isointense (a) (b) Fig. 15.24.6.10  Delayed ‘hepatobiliary’ phase imaging on MRI following gadoxetic acid administration demonstrates typical accumulation in (a) focal nodular hyperplasia (arrow) but nonspecific low signal in other lesions such as (b) adenoma (arrow).

15.24.6  Primary and secondary liver tumours 3189 on T1-​weighted imaging and often slightly hyperintense on T2-​ weighted imaging (Fig. 15.24.6.12). These appearances can be indistinguishable from FNH when no central scar is present. The MRI demonstration of fat within the lesion may help identify the HNF1A variant. It is suggested that lesions larger than 5  cm should be con- sidered for resection because of the risk of bleeding or malignant transformation. A conservative approach involves discontinuation of the oral contraceptive pill or androgens, which may reduce tu- mour size, weight loss with attention to insulin resistance, and sur- veillance imaging. Interventions include surgery, radiofrequency ablation, TAE, or a combination of each according to location and patient fitness. Smaller lesions may grow after resection of a large lesion. Spontaneous haemorrhage can often be controlled with TAE. Inhibitors of β-​catenin are being sought for targeted therapy. Lymphangioma Lymphangiomas consist of dilated lymphatic channels that compress normal liver parenchyma. Often these occur as part of multisystem disease affecting bone, brain, soft tissues, and lung. Typically, using MRI, multiple cystic areas in the liver are seen that do not enhance with contrast. Angiomyolipoma While common in the adrenals and kidneys, these lesions can be found in the liver and are associated in 6 to 10% of cases with tu- berous sclerosis. Mesenchymal hamartoma This lesion is more common in males and usually manifests within the first 2  years of life. Patients usually present with progressive (a) (b) Fig. 15.24.6.11  CT image of an acutely presenting spontaneous adenoma rupture. Unenhanced imaging demonstrates hyperdense blood clot ((a) and (b), star) with low-​attenuation fluid anteriorly. This fails to enhance following contrast administration (b) whereas the focal arterial enhancement posteriorly ((b), arrow) indicates the underlying adenoma. (a) (b) (c) (d) Fig. 15.24.6.12  Multiple adenomas (arrows) demonstrating subtle signal variation on (a) T2-​weighted MRI;
(b) T1-​weighted imaging; (c) homogeneous arterial enhancement (arrows); and (d) isointensity on portal phase imaging.

section 15  Gastroenterological disorders 3190 abdominal swelling. Structurally, the tumour is composed of mixed endodermal and mesodermal components in a connective tissue stroma. Surgical resection is the treatment of choice. Biliary cystadenoma This cystic lesion usually occurs in middle-​aged women. Papillary infolding is characteristic on ultrasonography or CT. Malignant po- tential is recognized and distinction from cystadenocarcinoma on radiology alone is difficult. Cystic aspiration for diagnosis is un- helpful and complete excision is required to avoid recurrence. Secondary liver tumours The liver is a common site for metastases, which thrive on the rich blood supply and favourable milieu for tumour growth. Secondaries are often discovered as part of the staging process for primary malig- nancy (synchronous) or during follow-​up (metachronous) or indeed may be the initial presentation. Liver function tests may be normal, but the alkaline phosphatase level usually rises with increased tu- mour mass. Symptoms include abdominal pain; with extensive infil- tration, jaundice and ascites may occur and presentation with acute liver failure is reported. If a primary tumour is not apparent, tar- geted liver biopsy under ultrasonography usually confirms malig- nancy and an immunohistochemical panel for antigens may point to the origin. For most primary cancers with liver involvement, the prognosis is poor and treatment palliative. However, there are notable excep- tions such as colorectal and neuroendocrine tumours. A quarter of patients with colorectal cancer have liver metastases at presenta- tion with a median survival untreated of between 6 and 9 months. Hepatic resection in appropriate candidates where the primary has been resected achieves 30 to 40% 5-​year survival, with cure in some patients. The liver remnant must be adequate and disease should be preferably unilobar. The role of adjuvant chemotherapy is un- clear, nor is it clear if there is benefit from synchronous resection of primary and secondary disease. Portal vein embolization of the tumour-​affected lobe has become a standard method for increasing the size of the liver remnant to reduce the risk of decompensation. Innovative approaches include downstaging the tumour using sys- temic chemotherapy to within criteria for resection, the same no- tion applies with systemic internal radiotherapy, hepatic arterial infusion of chemotherapy, targeted therapies against EGF recep- tors, and combining radiofrequency ablation with surgery to pre- serve liver volume. None of these modalities has been subject to randomized study. Neuroendocrine tumours typically grow slowly and are therefore more amenable to therapy even when multifocal within the liver. Directed therapies such as surgical debulking, embolization, TACE, and ablation have been shown to improve symptoms and slow pro- gression although survival benefit is unproven. Sirolimus, somato- statin analogues, and targeted agents against vascular EGF activity also appear efficacious. For carcinoid tumour, where the primary has been removed and there is no evidence of extrahepatic disease, survival after liver transplantation approaches 70% at 5 years with recurrence-​free survival nearer 50%. Gastrointestinal stromal tumours are also slow growing and metastasize to the liver and good control can be achieved using a combination of surgical resection and tyrosine kinase inhibitors. FURTHER READING Bioulac-​Sage P, et al. (2008). Benign and malignant vascular tumors of the liver in adults. Semin Liver Dis, 28, 302–​14. Bioulac-Sage P, et  al. (2019). Snapshot summary of diagnosis and management of hepatocellular adenoma subtypes. Clin Res Hepatol Gastroenterol, 43, 12–9. Bruix J, Reig M, Sherman M (2016). Evidence-​based diagnosis, sta- ging, and treatment of patients with hepatocellular carcinoma. Gastroenterology, 150, 835–​53. Chow FC, Chok KS (2019). Colorectal liver metastases: an update on multidisciplinary approach. World J Hepatol, 11, 150–72. Garrot C, Stuart K (2007). Liver-​directed therapies for metastatic neuroendocrine tumours. Hematol Oncol Clin North Am, 21, 545–​60. Habib A, et al. (2015). Transarterial approaches to primary and sec- ondary hepatic malignancies. Nat Rev Clin Oncol, 12, 481–​9. Ito F, et al. (2009). Hilar cholangiocarcinoma: current management. Ann Surg, 250, 210–​18. Khan AS, Dageforde LA (2019). Cholangiocarcinoma. Surg Clin North Am, 99, 315–35. Kulke MH, et al. (2019). Real-world treatment patterns and clinical outcomes in advanced gastrointestinal neuroendocrine tumors
(GI NET): a multicenter retrospective chart review study. Oncologist, pii, doi: 10.1634/theoncologist.2018-0519. Lazar DC, et al. (2019). Malignant hepatic vascular tumors in adults: characteristics, diagnostic difficulties and current management. World J Clin Oncol, 10, 11–35. Llovet JM, Bruix J (2003). Systematic review of randomized trials for unresectable hepatocellular carcinoma:  chemoembolization im- proves survival. Hepatology, 37, 429–​42. Llovet JM, et al. (1999). Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis, 19, 329–​38. Maluf D, et al. (2005). Hepatic angiosarcoma and liver transplant- ation:  case report and literature review. Transplant Proc, 37, 2195–​9. Mazzaferro V, et al. (1996). Liver transplantation for treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med, 334, 693–​9. Nault JC, et  al. (2013). High frequency of telomerase reverse-​ transcriptase promoter somatic mutations in hepatocellular car- cinoma and preneoplastic lesions. Nat Commun, 4, 2218. Pilati C, et al. (2014). Genomic profiling of hepatocellular adenomas reveals recurrent FRK-​activating mutations and the mechanisms of malignant transformation. Cancer Cell, 25, 428–​41. Rebouissou S, et al. (2009). Frequent in-​frame somatic deletions ac- tivate gp130 in inflammatory hepatocellular tumours. Nature, 457, 200–​4. Woodall CE, et al. (2008). Hepatic malignant epithelioid hemangio­ endothelioma: a case report and review of the literature. Am Surg, 74, 64–​8. Zucman-​Rossi J, et al. (2015). Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology, 149, 1226–​39.

15.24.7 Liver and biliary diseases in infancy and

15.24.7 Liver and biliary diseases in infancy and childhood 3191

15.24.7  Liver and biliary diseases in infancy and childhood 3191 15.24.7  Liver and biliary diseases in infancy and childhood Richard J. Thompson ESSENTIALS Most liver diseases that occur in adults also occur in children, but some present almost exclusively in early childhood. Neonatal jaun- dice is common and usually short-​lived. Onset before 24 h, or con- tinuation beyond 2 weeks, strongly suggests an underlying pathology. Biliary atresia is an important cause, with surgery and liver transplant- ation allowing many patients to survive to adolescence and adult- hood. Some genetic causes of cholestasis (e.g. MDR3 deficiency) can present in adults. A long list of metabolic disorders present with evidence of liver involvement, with later manifesting diseases including those with ac- cumulation of material in the liver. Liver transplantation is an excel- lent treatment for many of these disorders, and a growing number of metabolic disorders that do not cause liver disease per se are now being successfully managed through liver replacement, with patients surviving into adult life. Introduction Nearly every liver disease that occurs in adults also occurs in chil- dren. However, there are important liver diseases that present almost exclusively in early childhood and others where the presentation and treatments are notably different from those seen later in life. The year of life with the highest likelihood of presentation with liver disease is the first. In most cases, the connection to the mother, via the placenta, prevents liver disease causing problems before birth, although antenatal-​onset liver failure and even cirrhosis have been documented. The diseases with the greatest differences from those seen in adult life are discussed here. Neonatal cholestasis Neonatal jaundice is common. The overwhelming majority is unconjugated and short-​lived. Onset before 24 h, or continuation beyond 2 weeks, strongly suggests an underlying pathology. However, if more than 20% of the bilirubin is conjugated at any stage, underlying liver disease is sufficiently likely to require investigation. Pigment in neonatal stool is derived almost exclusively from bile, and newborn urine is colourless. Pale stools and dark urine are therefore the clinical features most suggestive of neonatal cholestatic liver disease. Biliary atresia Biliary atresia is the most common diagnosis underlying neonatal cholestasis and it is the exclusion of this diagnosis that drives much of the investigation of these babies. The cause is unknown, but sev- eral different underlying aetiologies may result in a very similar clin- ical phenotype. Several common viruses, including cytomegalovirus, have been implicated, although their exact contribution is still unclear. The car- dinal feature is an inflammatory sclerosis, usually involving the en- tire biliary tree. Complete occlusion is usually limited to the hepatic bile ducts, but this does cause acholic stools. Intraoperative cholangiography comes closest to being a diag- nostic test. A decision in favour of surgery is usually arrived at using a combination of investigations, which do vary depending on local facilities. Ultrasonography, in highly skilled hands, can be strongly suggestive. Although invasive, percutaneous liver biopsy is per- formed in most cases and usually reveals highly suggestive features (Fig. 15.24.7.1). The adoption of the Kasai portoenterostomy dramatically changed the outlook for babies with biliary atresia, and when combined with the availability of liver transplantation has improved 2-​year survival from less than 5% to greater than 90%. In addition to surgery, several anti-​inflammatory agents have been tested in this condition, though none have yet been shown to improve disease outcome. α1-​Antitrypsin deficiency The PiZ allele for the SERPINA1 gene is widely distributed, but the frequency is greatest in northern Europe such that homozy- gotes are as common as 1 in 3000 individuals in several countries. Only approximately 10% of such individuals present with neonatal cholestasis. Within that group, the outcome of the disease is also highly variable, with a quarter progressing rapidly and needing early liver transplantation. It remains quite unclear why there is such variable presentation and outcome among individuals who are all homozygous for the same allele. Truly effective treatment for patients presenting in infancy will require inhibition of the polymerization of the mutant protein and a significant increase in serum levels. While such targeted therapy is awaited, the severe group require liver replacement, with a much larger cohort going on to develop chronic liver disease. At presentation, α1-antitrypsin deficiency can appear very similar to biliary atresia and needs to be excluded before surgery in Fig. 15.24.7.1  Histological appearances of biliary atresia, showing marked portal tract expansion, bile duct proliferation, and bile plugs (haematoxylin and eosin, original magnification ×100). Image courtesy of Dr Maesha Deheragoda.

section 15  Gastroenterological disorders 3192 high-​prevalence areas. Serum levels of α1-​antitrypsin are unreliable in excluding the diagnosis, which should be based on isoelectric fo- cusing or genetic testing. Genetic cholestasis Several multisystem syndromes associated with neonatal-​onset cholestatic liver disease have been described. In addition, a rapidly growing number of defective genes have been found to underlie cholestatic disorders with onset in all age groups (Table 15.24.7.1). Syndromic cholestasis Alagille syndrome was defined clinically with a phenotype including intrahepatic cholestasis with a variable spectrum of other features, notably involving the facies, heart, eyes, and bones. The defect lies in the Notch signalling pathway, with most patients having heterozygous mutations in Jagged 1, a Notch ligand. A few patients instead have mu- tations in NOTCH2. The mutations are not fully penetrant, with family members having partial, sometimes trivial, phenotype. Mutations in NOTCH2 are probably less penetrant than those in JAG1. The com- bination of cardiac disease, notably peripheral pulmonary stenosis, with end-​stage liver disease can make these patients particularly diffi- cult to manage and may preclude liver transplantation. Nonsyndromic cholestasis Progressive familial intrahepatic cholestasis is a useful clinical de- scription which has been steadily unravelled into distinct pheno- types following the discovery of different genetic defects. However, in each case it has also become clear that there are later-​onset vari- ants, and that even presentation in adulthood does not preclude progression to end-​stage liver disease. For most diseases there is a reasonable genotype/​phenotype correlation, with severe early-​onset disease being associated with severely damaging mutations on both alleles. Milder disease results from more subtle variants, or in some cases mutations only on one allele. The bile salt export pump (BSEP) is the main transporter of bile salts from the hepatocyte into bile. Complete failure of bile acid transport leads to severe, unremitting liver disease, with extreme pruritus. Presentation is in the first few months of life, with giant cell hepatitis (Fig. 15.24.7.2) and normal serum levels of γ glutamyl transferase. Severe BSEP deficiency has a 15% risk of hepatocellular carcinoma formation, most occurring in the first 5  years of life. Individuals with no BSEP protein are at three times greater risk than other BSEP-​deficient patients. The same group are also at risk of post-​liver transplantation graft dysfunction due to alloantibodies blocking the function of BSEP in the donor organ. Table 15.24.7.1  Major genetic causes of cholestasis Disease Genes Inheritance Protein Characteristic liver features Extrahepatic features Notes Alagille syndrome JAG1 or NOTCH2 AD Jagged 1 or Notch 2 Paucity of bile ducts Cardiac, ophthalmic, renal, intestinal, pancreatic Cardiac diseases may determine prognosis. Subtle immune dysfunction ARC syndrome VPS33B or VIPAS39 AR VPS33B or VIPAR Failure of polarization of hepatocytes Arthrogryposis, renal dysfunction, and ichthyosis NISCH CLDN1 AR Claudin 1 Sclerosing cholangitis Ichthyosis TJP2 deficiency TJP2 AR TJP2 (ZO2) Abnormal tights junctions on TEM Possibly gastrointestinal and neurological Hypercholanaemia through to PFIC Neonatal sclerosing cholangitis DCDC2 AR DCDC2 Hypoplastic sclerotic biliary tree, bile duct proliferation on biopsy Minimal renal involvement BSEP deficiency ABCB11 AR BSEP Giant cell hepatitis None HCC, post-​transplant alloantibodies MDR3 deficiency ABCB4 AR or AD MDR3 Small duct cholangiopathy, ICP None Clinical presentation can be late. HCC and cholangiocarcinoma FIC1 deficiency ATP8B1 AR FIC1 Bland cholestasis Gastrointestinal, pancreas, renal Variable phenotype complicates liver transplant AR, autosomal dominant; AD, autosomal recessive; HCC, hepatocellular carcinoma; ICP, intrahepatic cholestasis of pregnancy; PFIC, progressive familial intrahepatic cholestasis; TEM, transmission electron microscopy. Fig. 15.24.7.2  Histological appearances of BSEP deficiency, showing multinucleated giant cell transformation, a nonspecific feature of severe cholestasis is young children (haematoxylin and eosin, original magnification ×200). Image courtesy of Dr Maesha Deheragoda.

15.24.7  Liver and biliary diseases in infancy and childhood 3193 Multidrug resistance protein 3 (MDR3) is a transporter, similar to BSEP, but essential for the entry of phospholipids into bile. A re- duction in MDR3 function leads to reduced lipids and increased free bile acid concentrations in bile. This results a cholangiopathy, which may be microscopic and not radiological. Mild cases show signifi- cant improvement with ursodeoxycholic acid. Individuals with biallelic mutations generally present in childhood. Those with re- duced function from both alleles, or even just complete loss of func- tion from one allele, can present with progressive liver disease in adulthood. Both hepatocellular carcinoma and cholangiocarcinoma complicate late disease. Familial intrahepatic cholestasis 1 (FIC1) is a protein that con- tributes to the maintenance of plasma membrane lipid asymmetry. Deficiency of this transporter leads to cholestasis and abnormal- ities in other epithelia, including diarrhoea, pancreatic and renal tubular dysfunction, and deafness; all to a very variable degree. The multisystem nature of the disease means that liver transplantation is much less satisfactory than in the previous two conditions. The liver parenchyma is a polarized epithelium with some of the transport processes described previously contributing to the vectorial transport from blood to bile. The canalicular space is the apical domain of the epithelium. This space is separated from the basolateral space by an array of cell–​cell junctional com- plexes. The most apical component of these structures are the tight junctions, themselves largely composed of claudins. Mutations in claudin 1 result in the syndrome of neonatal ichthyosis and scler- osing cholangitis. Mutations in tight junction protein 2, which is a cytoplasmic component of these structures, underlies a spectrum of diseases spanning isolated hypercholanaemia and severe early-​onset liver disease. Numerous defects in cilia formation or function have been shown to underlie a range of diseases usually manifesting as renal and hep- atic phenotypes. Fibrocystic disease of the liver is strongly associ- ated with autosomal recessive polycystic kidney disease. Mutations in DCDC2 have recently been associated with neonatal sclerosing cholangitis, along with minimal renal involvement. Management of cholestasis Much of the management of cholestatic liver disease revolves around minimizing the impact of the disease on the rest of the child. Treatment is therefore centred on vitamin supplementation and nu- trition. Liver transplantation has always been the fallback option, especially in the conditions where the disease is isolated to the liver. Depletion of bile acids has, however, been attempted by various means to alleviate pruritus, but also in the hope of changing the natural history of the disease. The most common option is partial external biliary diversion through creation of a fistula between the anterior abdominal wall and the gall bladder. The proportion of pa- tients in which this works varies between diseases, but might be as high as two-​thirds. Pharmacological alternatives to this surgery may become available. Neonatal liver failure Neonatal liver failure is probably significantly underdiagnosed. In very sick newborns with multiorgan failure, it is often unclear where the primary problem lies. Equally, some of the causes of neonatal liver failure are in fact part of a multisystem disease. Many cases still do not have a diagnosis and may well reflect undiagnosed meta- bolic disorders or are the consequence of infection, viral or other- wise. Liver biopsy is rarely a diagnostic option and other modalities are relied upon. Other than support of the multisystem failure, the key questions are whether a diagnosis with a specific treatment can be made, and equally if there is a contraindication to liver transplantation. Gestational alloimmune liver disease This condition was called neonatal haemochromatosis for many years, its diagnostic features being iron deposition in multiple or- gans with severe liver damage of antenatal onset. Although the exact disease mechanisms have not been established, there is good evi- dence that transplacental maternal alloantibodies are implicated. Exogenous immunoglobulin during subsequent pregnancies dra- matically reduces the severity of the disease, which otherwise re- curs in greater than 70% of cases. Iron may be an epiphenomenon. Liver transplantation is an excellent, though extremely challenging, treatment. Haemophagocytic lymphohistiocytosis Isolated bone marrow failure may be the only manifestation of haemophagocytic lymphohistiocytosis, but multisystem disease often presents with liver failure. Haemophagocytosis may be seen in the bone marrow of acutely sick patients of any age. However, in the newborn period this is usually due to a recessive genetic defect. Mutations in the perforin gene (PRF1) are the most common causes and highlight the fact that the underlying defect is in T lymphocytes, although it is macrophages that are seen to be causing the damage. Treatment requires immunosuppression and bone marrow trans- plantation. Liver transplantation is not indicated. In addition to gestational alloimmune liver disease and haemophagocytic lymphohistiocytosis, which are particular to new- born infants, neonatal liver failure can be the result of any number of infectious agents, and several of the metabolic diseases discussed in the following sections. The most noteworthy infectious cause is herpes simplex infection which is very often multisystem in nature and associated with very poor survival. Metabolic liver disease A long list of metabolic disorders present with evidence of liver in- volvement, particularly in the first few months of life. Clinical pres- entation can be through failure of energy supply, hepatocellular synthetic failure, or failure of clearance of toxic metabolites, the most evident being jaundice. Later manifesting diseases include those with accumulation of material in the liver. Liver transplant is an excellent treatment for many of these disorders; indeed, a growing number of metabolic disorders that do not cause liver disease per se are now being successfully managed through liver replacement. Galactosaemia Galactosaemia results from a deficiency of galactose-​1-​phosphate uridyltransferase. Clinical presentation varies between jaundice or hypoglycaemia, and multiorgan failure. In many countries, the disease is included in neonatal screening programmes, though not

section 15  Gastroenterological disorders 3194 in the United Kingdom. The diagnosis should be made through measurement of galactose-​1-​phosphate uridyltransferase activity in peripheral red blood cells. Management of the presenting illness should probably be followed by lifelong exclusion of lactose from the diet, though the degree to which this is necessary in adults is not completely clear. Tyrosinaemia type 1 Tyrosinaemia type 1 results from deficiency of fumarylacetoacetate hydrolase, the final step in the tyrosine degradation pathway. Presentation is with a variable degree of liver dysfunction, often with relatively mild jaundice. The disease is caused by toxic intermediate metabolites, notably fumarylacetoacetate and succinylacetone. Detection of the latter in the urine is the most utilized diagnostic test. Untreated, severe liver and renal disease is often complicated by early hepatocellular carcinoma. Treatment has been revolutionized by the introduction of nitisinone, which inhibits 4-​hydroxyphenylpyruvate dioxygenase upstream in the metabolic pathway, effectively changing the dis- ease to the much milder tyrosinaemia type 3. Dietary restriction of tyrosine is still required, and hepatocellular carcinoma is not com- pletely prevented, but outcomes have been markedly improved. Early treatment has been shown to be beneficial; hence, a strong case for neonatal screening for this condition has been made. Glycogen storage diseases Glycogen storage diseases are a heterogeneous group of conditions. In the majority of hepatic manifesting forms, the intracellular re- tention of glycogen and the consequent inability to release glycogen during hypoglycaemia are the cardinal features. Types I, III, VI, and IX manifest the classical phenotype, though with different degrees of severity. In most cases, the management focuses on prevention of hypoglycaemia. The avoidance of hepatic adenomas is a major driver to improve control. Of these four types only type III is associ- ated with significant muscle involvement. Glycogen storage disease type IV results from a lack of the glycogen branching enzyme, and results in both cirrhosis and myocardial disease. Mitochondrial disease Although mitochondria contain their own genome, most of the genes required for mitochondrial assembly and function are en- coded by nuclear DNA. Most mitochondrial cytopathies presenting in early life are due to recessive mutations in nuclear genes. Enzymes involved in the respiratory chain are themselves encoded by mul- tiple genes, some nuclear and some mitochondrial. Other defects are in proteins required for mitochondrial DNA replication and result in mitochondrial DNA depletion; these, however, are still usually nuclear. The management of mitochondrial cytopathies is particu- larly difficult because of their multisystem involvement. Liver disease in older children Autoimmune liver disease Autoimmune disease can present at any age but most frequently presents early in the second decade. Subclassification is possible on clinical and serological grounds, and is important in terms of outcome and complications. Autoimmune hepatitis may be diag- nosed in the absence of cholangiopathy and is associated with other autoimmune disorders and inflammatory bowel disease, each in approximately one-​fifth of cases. Autoimmune hepatitis type 1 may be diagnosed in the presence of antinuclear and smooth muscle antibodies, but in the absence of liver–​kidney microsomal antibodies. Autoimmune hepatitis type 2 more frequently presents with acute liver failure and is diagnosed by the presence of liver–​kidney microsomal antibodies. Autoimmune sclerosing cholangitis has an antibody profile similar to autoimmune hepatitis type 1, but includes a cholangiopathy. The typical histology is shown in Fig. 15.24.7.3. The latter disease is associated with other autoimmune disorders and inflammatory bowel disease in approxi- mately half of cases. That the three conditions are distinct entities is reinforced by different HLA associations. Autoimmune liver disease in children is treated with immunosup- pression, usually consisting of oral prednisone, though the addition of steroid-​sparing agents such as azathioprine or mycophenolate mofetil is common. Ursodeoxycholic acid is added in the case of autoimmune sclerosing cholangitis. Biochemical and serological remission can be achieved in most cases of autoimmune hepatitis. Immunosuppression can be withdrawn in a substantial minority of type 1 individuals, but rarely in type 2. In autoimmune sclerosing cholangitis, the inflammatory component may be brought under control but ultimately liver transplantation is still required if the underlying damage is severe. Cystic fibrosis Cystic fibrosis is a multisystem disorder characterized by abnor- malities of anion distribution at multiple epithelia. Presentation in infancy is usually with gastrointestinal or respiratory symptoms, though very small numbers present with neonatal jaundice. Patients with hepatic involvement more frequently present later in the first decade with signs of chronic liver disease, notably with portal hypertension and splenomegaly. In most cases, endoscopic manage- ment of portal hypertension is the mainstay of treatment. Splenic Fig. 15.24.7.3  Histological appearances of autoimmune hepatitis, showing interface hepatitis with lymphoplasmacytic infiltration (haematoxylin and eosin, original magnification ×100). Image courtesy of Dr Maesha Deheragoda.

15.24.7  Liver and biliary diseases in infancy and childhood 3195 embolization has been advocated but is not widely employed. A few patients with cystic fibrosis have now been successfully treated using multiorgan transplantation. For most, their liver disease along with pancreatic insufficiency is largely managed through nutritional supplementation. Wilson disease Wilson disease results from the accumulation of copper in the liver and other organs, notably the central nervous system, as a conse- quence of a functional lack of the Wilson disease protein encoded by ATP7B. Most paediatric patients with Wilson disease present with liver disease, half with chronic liver disease and half with acute liver failure (although the latter is acute on chronic). Numerous diagnostic strategies have been used, reflecting the fact that none are perfect. Caeruloplasmin levels are typically low, but are normal in 20% of cases. Urinary copper excretion, before and after exposure to penicillamine, has been widely used, but is relatively compli- cated and not completely specific. Similarly, liver copper content measurement can be extremely useful, but patients with chronic cholangiopathy can be indistinguishable by this method. Genetic testing is now widely used, and is highly sensitive and specific. The cost and time taken for testing have both fallen significantly. Medical treatment for Wilson disease is very effective, using penicillamine or trientine. Zinc has been used in combination with chelators, separating the oral dosing, but its use as monotherapy is controversial. In the context of acute liver failure, medical therapy may be insufficient to reverse the damage and liver transplantation is required. A scoring system has been widely used to predict the need for transplantation in this context. Transition to adulthood Adolescence is a difficult enough period without the addition of chronic disease. Diseases which require daily medication for main- tenance relapse significantly more often in adolescents. Those with autoimmune disease and transplant recipients cause the greatest concern, but for all patients a planned approach, not only to see them through this period but also to prepare them for adult life, has been shown to make a difference. Transition is not a point in time but rather a period of life through which some can pass much more quickly than others. FURTHER READING Liberal R, et al. (2016). Cutting edge issues in autoimmune hepatitis. J Autoimmun, 75, 6–​19. Taylor SA, Whitington PF (2016). Neonatal acute liver failure. Liver Transpl, 22, 677–​85. Verkade HJ, et al. (2016). Biliary atresia and other cholestatic child- hood diseases: advances and future challenges. J Hepatol, 65, 631–​42.

15.25 Diseases of the gallbladder and biliary tree

15.25 Diseases of the gallbladder and biliary tree 3196

ESSENTIALS Diseases of the gallbladder and bile ducts are common, with gall- stones and their complications being most frequent. Less common are biliary strictures, usually malignant, which are caused by adeno- carcinomas of the pancreas, bile ducts, ampulla of Vater, and gallbladder. Rarely encountered are sclerosing cholangitis and a var- iety of congenital disorders. Disorders of the biliary system include gallstones, which cause biliary colic (severe right hypochondrial pain, often with nausea and vomiting) and cholecystitis by obstruction of the cystic duct, and bile duct obstruction (cholestasis), with jaun- dice, dark urine, and pale stools, itching, and sometimes constant right hypochondrial pain. Fevers and rigors may indicate bac- terial infection of the biliary tract (cholangitis), which frequently accompanies partial obstruction. Weight loss may be due to fat malabsorption but can also be caused by malignancy. Prolonged biliary obstruction leads to skin changes of increased pigmenta- tion (due to melanin) and cholesterol deposition (xanthelasma and xanthoma). Biliary cirrhosis can cause portal venous hyper- tension and liver cell failure. Disorders of the biliary system generally give rise to the bio- chemical picture of cholestasis: the serum (conjugated) bilirubin concentration may be normal or raised; serum alkaline phos- phatase, γ-​glutamyl transferase, and bile acids are elevated; serum transaminases show only modest elevation. Bilirubinuria is present, with the disappearance of urobilinogen from the urine indicating complete biliary obstruction. Imaging is critical in the diagnosis of biliary disease, initially by ultrasonography, with CT and MRI in more complicated cases. However, these investigations sometimes provide insufficient anatomical detail for diagnosis or planning of treatment, and fur- ther imaging with the cholangiographic techniques of magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) are required. ERCP and PTC can be used to place biliary stents. Introduction Diseases of the gallbladder and the biliary tree are common. Symptomatic gallstones are the most frequently encountered problem and are found in the bile duct as well as in the gallbladder. Bile duct strictures are also common and have multiple causes, both benign and malignant, posing a diagnostic and therapeutic challenge. Cholangiocarcinoma encompasses malignancy at sites throughout the biliary tree. Choledochal cysts and other congenital abnormalities are rare but important disorders. Investigation of biliary disease comprises distinct phases. First, the pathology causing the symptoms should be located. This will be either primarily in the gallbladder (usually due to gallstones) or bile ducts (often obstructive, causing cholestasis and jaundice), or both. It is important to differentiate biliary tract problems causing jaundice from parenchymal liver disease and haemolytic and other ‘prehepatic’ hyperbilirubinaemias; to locate the site of the problem or level of obstruction; and then to define the type of pathology. Treatment of biliary tract disease comprises treatment of the primary pathology. This may mean removal of gallstones and the gallbladder, or relief of cholestasis/​obstruction by surgical, endo- scopic, or interventional radiology techniques. Cholestatic disease with normal bile ducts will often indicate the need for a liver biopsy to identify a hepatic parenchymal cause. Anatomy The biliary system comprises all structures between the biliary canaliculus and the ampulla of Vater, including the gallbladder (Fig. 15.25.1). Bile collects in the biliary canaliculi, which co- alesce into ever larger bile ducts to create the ‘biliary tree’. The common hepatic duct forms at the junction of left and right hep- atic ducts that drain the two halves of the liver. The common bile duct forms below the junction of the common hepatic duct and the cystic duct and runs in the posterior aspect of the head of the pancreas, usually joining the pancreatic duct before passing out through the sphincter of Oddi at the ampulla of Vater. Anatomical variants are common and of surgical importance, particularly in 15.25 Diseases of the gallbladder and biliary tree Colin Johnson and Mark Wright

15.25  Diseases of the gallbladder and biliary tree 3197 regard to the arrangements of the ducts draining the right liver and the insertion of the cystic duct. Failure to recognize these variants can lead to duct injury and subsequent bile leak during cholecystectomy. Biliary physiology Bile is made by hepatocytes and excreted into the biliary canaliculi as they coalesce to form the biliary tree. Bile has digestive and excretory functions and its components are extensively re- cycled during enterohepatic recirculation. The principal compo- nents of bile are shown in Box 15.25.1. Bilirubin is formed from haemoglobin breakdown. Bile salts are products of cholesterol metabolism, and 95% of bile salts secreted are reabsorbed at the terminal ileum and undergo enterohepatic circulation. Those primary bile salts entering the large intestine are converted to secondary bile salts by the large intestinal microbiota. Some sec- ondary bile acids are reabsorbed in the colon, but most are ex- creted in the stool. The normal bile acid pool is about 3 to 5 g and recirculates throughout the day. Synthesis is controlled by negative feedback from bile acids reabsorbed into the portal vein. Normally bile acids are coalesced with phospholipids into micelles which contain chol- esterol in their interior and thus solubilize it. Drugs and drug metabolites are also excreted in bile. Fluid and electrolyte composition is controlled by cholangiocyte absorption during passage down the bile ducts. Bile sterility is maintained by free flow of bile, with some innate immunity. Between meals, some bile is stored in the gallbladder where it is concentrated. The gallbladder contracts and empties in response to cholecystokinin released by the presence of food (mainly fat and protein digestion products) in the duodenum. Clinical features of biliary disease Irrespective of pathology, certain features are consistent throughout the range of bile duct disorders and include the features of cholestasis (jaundice, pale stools, dark urine, pruritus), nausea and vomiting, weight loss and malabsorption, sepsis and pain (which may range from dyspepsia-​type discomfort to acute biliary colic). Complications include secondary biliary cirrhosis, portal hyper- tension, progressive liver failure, and development of malignancy (Table 15.25.1). Physical signs specific to the biliary tree include jaundice, ex- coriations of the skin, tenderness in the right upper quadrant, and palpable organomegally. The presence of a palpable gallbladder implies obstruction below the origin of the cystic duct and also indicates the absence of chronic inflammation of the gallbladder, which most commonly arises due to gallstones (Courvoisier de- scribed that in a patient with jaundice and a palpable nontender gallbladder, the diagnosis is not likely to be gallstones). Investigation of biliary disease Laboratory investigation The typical features of cholestasis include elevated conjugated hyperbilirubinaemia (with bilirubinuria), alkaline phosphatase, and γ-​glutamyl transferase. Transaminases are more typically ele- vated in hepatitic conditions but may be raised in biliary sepsis. Malabsorption of vitamin K may lead to a prolonged prothrombin time. Levels of other fat-​soluble vitamins will also be low. Associated sepsis will result in a raised peripheral white cell count and elevated C-​reactive protein. Gallstones in the gallbladder frequently do not affect liver biochemistry. Stone CBD Cystic duct Gallbladder Pancreatic duct Common hepatic duct Intrahepatic ducts Fig. 15.25.1  MRCP revealing stones in the distal common bile duct (CBD) (white arrow). Biliary anatomy is also shown (blue arrows). Box 15.25.1  Bile composition • Water (97%) • Electrolytes • Primary bile acids: cholic and chenodeoxycholic acid • Secondary bile acids • Phospholipid (e.g. lecithin) • Cholesterol • Bilirubin • Drugs and drug metabolites • IgA Table 15.25.1  Complications of biliary disease Complication Manifestation Cholestasis Cholangitis Malabsorption: • weight loss • vitamin deficiencies Osteoporosis Chronic obstruction Secondary biliary cirrhosis: • portal hypertension • liver failure Chronic inflammation Cholangiocarcinoma

section 15  Gastroenterological disorders 3198 Tumour markers Carbohydrate antigen 19-​9 (CA19-​9) is widely used as a diagnostic test in biliary malignancy but is severely limited by low sensitivity and specificity. The latter is especially affected by its elevation in ob- structive jaundice from other causes. CA125 is not useful. New bio- markers are needed. Imaging Cross-​sectional imaging techniques (ultrasonography (including endoscopic ultrasonography (EUS)), CT, MRI) are used to identify obstructed bile ducts and to determine the level of obstruction and likely cause, as well as associated features such as metastases, local invasion of tumours, and complications such as portal vein throm- bosis and the development of portal hypertension. Cholangiography (magnetic resonance cholangiopancreato­ graphy (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC)) and cholangioscopy either via the Spyglass System or ultraslim biliary endoscopes give further information including direct visualization and biopsy of biliary epithelium (Fig. 15.25.2). EUS is used in the visualization of the extrahepatic bile ducts, hilar masses including perihilar lymph nodes, and gallbladder. EUS can also be used for tissue acquisition via fine needle aspiration as well as staging of tumours. Intraductal ultrasonography, though not widely available, is good for assessing periductal tumour extension and portal vein invasion. Endoscopic retrograde cholangiopancreatography ERCP is useful as both a diagnostic and therapeutic tool. Because of the potential complications, ideally the technique should only be used where there are therapeutic or tissue acquisition procedures to be performed. The main therapeutic indications are to decom- press obstructed biliary systems and to remove gallstones from the common bile duct. The technique is also a useful platform for direct cholangioscopy and electrohydraulic and laser lithotripsy. Brushings obtained via ERCP have variable sensitivity and spe- cificity depending on the disease present. Sensitivity is generally low for cancers, although specificity is high if detected. Modalities to improve sensitivity in cholangiocarcinoma include looking for chromosomal aneuploidy with fluorescent in situ hybridization (FISH) or digital image analysis (DIA), although at the time of writing these techniques are not widely available even in advanced healthcare settings (see Chapter 15.24.6). Gallstones Epidemiology Gallstones are common, with incidence varying across different populations. They are found in 8% of the United Kingdom popu- lation aged over 40. The incidence increases with age, and women are more often affected than men, particularly before menopause. Obesity is an independent factor leading to an increased incidence of gallstones in younger individuals: between 19 and 45% of mor- bidly obese patients have gallstones. Although gallstones are common, most affected individuals have no symptoms. In population studies, as few as 10% of people with gallstones have current or previously reported symptoms. In people in whom gallstones are discovered incidentally, only 2 to 4% will develop symptoms over the course of a year and the removal of the gallbladder in asymptomatic people is not recommended, especially in the elderly. Pathophysiology Bile is a complex mix of cholesterol and phospholipids, which in equilibrium maintain a saturated solution of cholesterol. If choles- terol content rises (or bile salt or lecithin concentrations fall), then cholesterol will crystallize (Fig. 15.25.3). Cholesterol gallstones con- tain over 70% cholesterol and are the most common type of stone seen in Western populations. Mixed stones contain cholesterol and calcium bilirubinate, and tend to be hard, multiple, and multifa- ceted, often radiopaque. (a) (b) Fig. 15.25.2  Spyglass cholangioscopy showing the change in mucosa between an indeterminate stricture (a) and normal bile duct (b). Biopsies can be obtained under direct vision. 50 100 0 50 100 0 50 Vesicles and liquid crystals (multilamellar vesicles) Micellar phase Percentage of bile acids Solid crystals (cholesterol monohydrate) Percentage of cholesterol Percentage of phosphatidycholines 100 0 Fig. 15.25.3  Triangular solubility plot of cholesterol. Crystals will form outside of the micellar phase.

15.25  Diseases of the gallbladder and biliary tree 3199 Primary pigment stones are composed of calcium bilirubinate and are hard, black, and associated with haemolytic anaemias (including anaemia due to mechanical heart valves) and cirrhosis. The mechanism of their formation is less well understood, but probably represents a high relative concentration, allowing crystal- lization. Pigment stones in the bile duct are associated with para- sitic infestation (in Asia) and with duct obstruction. These duct stones are soft and friable. Bacterial β-​glucuronidase deconjugates bilirubin, which then combines with calcium and forms calcium bilirubinate stones. Biliary sludge can also accumulate in the bile ducts and is commonly found on stents which have been in place for prolonged periods of time and also on other foreign bodies, pro- viding evidence for nucleation as a step in the pathophysiology. Consumption of a ‘Western diet’ results in cholesterol super- saturation of bile, which favours precipitation and crystal growth (Fig. 15.25.4). Oestrogen exposure (pregnancy, hormone replace- ment therapy) or other conditions with increased steroid hormone turnover increases cholesterol content in bile and therefore favours gallstone formation. Bile also contains crystal growth inhibitors which slow the increase in size of cholesterol crystals. This allows the evacuation of crystals from the gallbladder during normal emptying before progression to gallstones. In some individuals (or families), these growth inhibitors may be deficient, leading to a predisposition to gallstones. Most stones start in the gallbladder; some migrate into the common bile duct. Impaired gallbladder motility (reduced emptying) is an important component of gallstone formation. It explains the increase in gallstones after vagotomy, in diabetics (autonomic neuropathy), after prolonged treatment in an intensive therapy unit, and in people treated with somatostatin. Reduced bile salt reabsorption in terminal ileal Crohn’s disease or after re- section of the terminal ileum is the reason for the high incidence of gallstones seen in those conditions. Clinical features The clinical features of gallstones include acute presentation with biliary colic or acute cholecystitis, and less severe upper gastrointes- tinal symptoms, sometimes nonspecific. Gallstones may also first present with complications such as obstructive jaundice or acute pancreatitis. In addition, there are many patients with chronic upper abdominal symptoms which may be attributed to the presence of gallstones. Symptoms occur when gallstones start to move from the gallbladder, either obstructing the cystic duct causing biliary colic or cholecystitis (acute or chronic), or entering the common bile duct where they cause obstructive jaundice, cholangitis, colic, or pan- creatitis (Table 15.25.2). Laparoscopic cholecystectomy should be offered to symptomatic patients. About 10 to 20% of patients with symptomatic gallbladder stones have stones in the bile ducts as well. Gallstones in the common bile duct carry a risk of severe complications and therefore should be removed wherever possible. The method of choice is ERCP, although if the patient requires cholecystectomy, some centres will offer laparoscopic bile duct clearance at the same procedure. Intraoperative cholangiography is recommended for patients with a high pretest probability of stones, such as those with dilated bile ducts on imaging. Acute presentations Biliary colic Biliary colic arises when a gallstone impacts in the neck of the gallbladder and obstructs the cystic duct. Sustained gallbladder contraction raises pressure within the gallbladder and generates the pain perceived as biliary colic. This is usually centred in the right upper quadrant or epigastrium. The pain may radiate around the lower ribs to the right lower chest at the back, or it may seem to Pathogenesis of stone formation is different for cholesterol stones, soft brown stones, and pigment stones Cholesterol stones Excess cholesterol in bile Western diet Obesity Pregnancy Oral contraceptive Reduced bile salt excretion Terminal ileal Crohn’s Ileal resection Reduced gallbladder motility Vagotomy Octreotide Prolonged fasting Reduced antinucleating factors in bile Cholesterol crystals or other debris Bacterial colonization Bilirubin deconjugation Pigment precipitation Excess bile pigment production Haemolytic anaemias Spherocytosis Growth into stones Crystal formation Pigment stones Mixed or soft stones Fig. 15.25.4  Pathogenesis of the three types of gallstones—​cholesterol, mixed/​soft stones, and pigment stones.

section 15  Gastroenterological disorders 3200 pass directly through from the front to back. Occasionally, the pos- terior radiation is to the lower pole of the scapula and rarely, the pain may be felt on the left. These radiations are explained by the origin of the gallbladder from lower thoracic segments and the transmis- sion of visceral sensation through the splanchnic nerves to the lower thoracic spinal cord. The pain may be severe enough to require par- enteral opioids, and it resolves when the gallbladder contraction re- solves and the stone disimpacts. Biliary colic has a slower periodicity than colic from other organs. Biliary colic usually rises and falls over a period of 30 min to 2 h and may last up to 6 h, in contrast to small-​bowel colic, ureteric colic, or colonic colic which peaks every 20 or 30 s to a few minutes. Biliary colic often arises after a large meal. There is little evidence to sup- port the commonly held belief that the consumption of fatty food is particularly likely to stimulate an attack. Patients often describe retching or vomiting with the pain, and a substantial minority report being woken by the pain. Acute cholecystitis Acute cholecystitis arises when a stone remains impacted in the neck of the gallbladder (Fig. 15.25.5). Increased pressure in the gallbladder leads to mucosal injury by sequential ischaemia, chem- ical irritation by bile salts, and eventually bacterial infection. The symptoms may initially resemble biliary colic, but the pain persists for more than 12 h.  The ensuing inflammation leads to tender- ness over the gallbladder (which is often minimal in biliary colic). Inflammation affecting the diaphragm may cause referred pain over the acromion, and an inflammatory mass may be palpable in the right upper quadrant. The patient will have systemic signs of infec- tion (fever, leucocytosis) and will be anorexic. Complications in- clude the following: • Perforation—​in severe cases the inflammatory process may lead to necrosis of the gallbladder wall, allowing perforation and biliary peritonitis. As a result of transmural inflammation, the omentum may be adherent around the gallbladder and the resulting perfor- ation can be localized into a pericholecystic abscess. If the perfor- ation occurs on the hepatic aspect of the gallbladder, the abscess may penetrate into the liver. • Empyema—​in the absence of a perforation, cholecystitis may resolve by drainage of bile through the cystic duct, but often the impacted stone prevents this. The gallbladder remains in- flamed, perhaps encased in a protective fold of omentum. The gallbladder content becomes purulent, due to bacterial proliferation and by the exudation of neutrophils. This is effect- ively an abscess contained within the lumen of the gallbladder and is termed an empyema. • Mucocele—​occasionally, an impacted stone will isolate the gallbladder content from the rest of the biliary tree in the ab- sence of bacterial infection. The mucosa, although inflamed, continues to absorb water from bile, and secrete mucus: this scenario leaves the gallbladder containing clear or bile-​stained mucus. The patient with a mucocele will often recall a severe episode of biliary pain, consistent with cholecystitis. Symptoms may partly resolve, but there is usually ongoing right upper quadrant pain and tenderness, with symptoms of sufficient se- verity to cause repeated admissions to hospital until cholecyst- ectomy is performed. • Mirizzi’s syndrome—​occasionally, a patient will become jaun- diced as a result of stones in the gallbladder in the absence of common duct stones. This situation arises when a stone im- pacted in the neck of the gallbladder causes sufficient inflamma- tion around the gallbladder and adjacent bile duct to compress the duct (Fig. 15.25.6). Chronic presentation Biliary dyspepsia and chronic cholecystitis Patients with vague, mild, and nonspecific upper abdominal symp- toms who are found to have gallstones are a diagnostic challenge. As noted previously, approximately 90% of gallstones are asymptom- atic, but huge numbers of patients suffer dyspeptic symptoms. One survey in the United Kingdom found that 40% of people suffered upper abdominal dyspepsia, and that 25% of these had consulted their general practitioner for these symptoms in the preceding 6 months. There was no difference in symptoms between patients Table 15.25.2  Complications of gallstones Gallbladder stones Biliary colic Acute cholecystitis leading to: • abscess formation • gallbladder necrosis • perforation Chronic cholecystitis Common bile duct stones Acute cholangitis Acute pancreatitis Obstructive jaundice Other Fistulation to other hollow organs Gallstone ileus Perforation Stone impacted in cystic duct Bile duct Bile injures ischaemic mucosa, leading to inflammation of wall Mucosa suffers ischaemic injury Stones in gallbladder Tension in wall impairs blood flow Fig. 15.25.5  Pathogenesis of acute cholecystitis.

15.25  Diseases of the gallbladder and biliary tree 3201 with gallstones and those that were gallstone free, so it is difficult to attribute these ‘vague’ symptoms to the presence of stones. There is little evidence that so-​called biliary dyspepsia is associated with the presence of stones. Many surveys of patients in the United Kingdom who have had cholecystectomy find that 20 to 30% of patients con- tinue to suffer dyspeptic symptoms postoperatively. Symptoms other than typical biliary colic are often not related to gallstones, and there is no evidence to link gallstones with epigas- tric discomfort, belching, nausea, or idiosyncratic food intolerance. Heartburn and reflux symptoms may be more common in patients with gallstones but are not directly related to the presence of gall- stones and may be exacerbated by cholecystectomy. If cholecystec- tomy is done in patients with these symptoms (whether or not they have typical biliary colic or acute cholecystitis), then these symp- toms will still be present after operation. The differential diagnosis of a patient with gallstones and upper abdominal symptoms includes peptic ulcer, nonulcer dyspepsia, antroduodenal dysmotility, and irritable bowel syndrome. Complications Acute cholangitis Symptoms and signs include pain, fever, and jaundice. The right upper quadrant is tender. The patient may be jaundiced with a tachycardia and hypotension. Investigation reflects these findings. Ultrasonography may show dilated bile ducts. Acute cholangitis not rapidly responding to antibiotics or with signs of shock requires urgent biliary decompression with sphincterotomy, and stenting with or without stone extraction. If ERCP is not possible or available, then PTC or cholecystostomy are options. Acute open surgery should be avoided in critically ill patients. Gallstone pancreatitis Gallstone pancreatitis occurs when a gallstone lodges in the common channel or compresses the septum between the distal biliary and pancreatic ducts. This causes increased pressure in the pancreatic duct and reflux of digestive enzymes into the gland. Acute gallstone pancreatitis associated with biliary obstruction or cholangitis war- rants urgent ERCP, sphincterotomy, and stone extraction. Optimal timing is unclear. Studies have shown benefit with reduced mortality and complications if ERCP is performed within 72 h where there is concurrent cholangitis or biliary obstruction but have not been designed to answer whether earlier (within 24 h) ERCP would be better. Most clinicians experienced in this situation will aim for ERCP as soon as logistically possible and once the patient is stable enough to undergo the procedure safely. After complications have settled, cholecystectomy should be con- sidered, although the sphincterotomy will have prevented further episodes of pancreatitis and removal of the gallbladder is only re- quired if the gallstones are symptomatic. Cholecystoduodenal fistula This is a rare and potentially serious complication of gallstone dis- ease, which can be recognized as pneumobilia on a plain abdom- inal X-​ray or ultrasonography. This is thought to result from erosion (usually) into the duodenum by a gallstone in the gallbladder. Rarely such fistulas may involve the colon or the stomach. The stone will either be passed naturally or may cause small bowel obstruction. With improved laparoscopic techniques, laparoscopic stapling of the cholecystoduodenal fistula and cholecystectomy is sometimes possible. Gallstone ileus This more commonly affects elderly women and may be the first presentation of gallstone disease. It accounts for 1 to 4% of all cases of mechanical intestinal obstruction, but up to 25% of cases in pa- tients over 65 years of age. The bowel obstruction can be managed relatively easily with an open or laparoscopic ileotomy. Because there is usually dense fibrosis around the gallbladder and the fistula, cholecystectomy may be difficult and it is best to defer surgery on the gallbladder until the patient has recovered from the emergency presentation and treatment. Diagnosis Ultrasonography is commonly the first investigation for biliary symptoms because of its wide availability and ease of use, and it is highly sensitive and specific for diagnosis of gallbladder stones (>95% in good hands). The presence of dilated ducts gives evidence of obstruction, and ultrasonography is around 30 to 70% sensitive and 90% specific for common bile duct stones depending on symp- toms and blood tests (pretest probability). A normal examination does not, therefore, rule them out, and where suspicion is high, other tests should be used. MRCP or EUS are the usual next steps depending on avail- ability, with sensitivities of around 95% when pretest probability is moderate to high. Each has its advantages and disadvantages. MRCP has no endoscopic or sedation risks, is useful where there is altered anatomy, and allows later independent review of images (Fig. 15.25.7). EUS can often be used where MRCP is not possible due to the presence of a pacemaker/​implanted cardiac defibril- lator, mechanical heart valves, intracranial metal clips, morbid obesity, or severe claustrophobia. CT also has a role as it is often used when the cause of pain or sepsis is uncertain and is useful for differential diagnosis. Obstructing disease of the bile ducts is most commonly due to gallstones (Fig. 15.25.8), but a wide range of stricturing disorders both benign and malignant must also be considered. Large stone in cystic duct causes inflammation and fibrosis around the bile duct, compressing it Bile duct Cystic duct Stone Fig. 15.25.6  Mechanism of biliary obstruction in Mirizzi’s syndrome: there are no stones in the bile duct.

section 15  Gastroenterological disorders 3202 Management Laparoscopic cholecystectomy With the introduction of laparoscopic cholecystectomy, a shift oc- curred in the balance between benefit of operation and the asso- ciated risks and discomfort. Very few patients are now treated by alternative techniques. Laparoscopic surgery allows most patients to be treated as a day case, with return to normal activities within 2 weeks. Complication rates are low, the most serious being injury to the bowel or a bile duct, which occur in less than 1% of cases. About half of those with persistent bile leak after surgery arise from injury to a duct within the gallbladder bed, which usually closes with simple drainage or drainage combined with duct decompression by sphincterotomy and stent. Cholecystectomy relieves symptoms of biliary colic and acute cholecystitis, but other nonspecific symptoms often persist after operation. Common bile duct stones Optimal elective management of common bile duct stones is by ERCP. If the gallbladder is in situ this may be either before or soon after laparoscopic cholecystectomy. ERCP during cholecyst- ectomy may be cost-​effective and convenient for patients but is rarely practical. Laparoscopic bile duct exploration with a flexible choledocoscope is another option and is preferred to open duct ex- ploration because of a lower rate of trauma to the duct, increased chance of primary duct closure, and less use of T tubes with a lower risk of biliary strictures in the future. Preoperative imaging or intraoperative cholangiography is recommended for patients with a high pretest probability of stones (principally those with dilated ducts on ultrasound). Endoscopic removal of gallstones ERCP is an evolving technique for the removal of stones and em- ploys increasingly complex therapeutic options. The basic principles of treating stone disease are as follows: (1) gain and then increase access to the common bile duct by cutting (sphincterotomy) (Fig. 15.25.9) with or without stretching (sphincteroplasty) the Fig. 15.25.7  MRCP revealing stones in the distal common bile
duct (arrow). CBD stones Fig. 15.25.8  ERCP cholangiogram demonstrating stones (seen as filling defects) in the common bile duct (CBD). Fig. 15.25.9  Balloon sphincteroplasty to facilitate removal of large common bile duct stones. Variable sizes of balloon are available, but in general it is wise not to exceed the diameter of the common bile duct above in order to reduce the risk of perforation.

15.25  Diseases of the gallbladder and biliary tree 3203 sphincter of Oddi; (2)  obtain a cholangiogram to identify the number and size of the stones; (3) where necessary, reduce the size of stones in order to facilitate their removal, either by crushing (Fig. 15.25.10) or applying direct energy to them; (4) remove the stones by dragging or grasping them from the duct (Fig. 15.25.11); (5) where removal is not possible, ensure biliary drainage is secured with appropriate stenting. Other methods of treating gallstones Extracorporeal shock wave lithotripsy, oral bile acid therapy, and contact dissolution of gallstones are seldom used in the era of lap- aroscopic surgery and ERCP. These treatments lost their appeal when laparoscopic surgery became available because they are slow, requiring many months, and cumbersome, with repeated imaging needed to monitor progress. They also leave the gallbladder in situ and the patient is thus at risk of recurrence of gallstones. By contrast, laparoscopic cholecystectomy and ERCP are day-​case treatments that remove the gallbladder, permanently relieve symptoms in most patients, and have a very low complication rate in skilled hands. Direct cholangioscopy-​facilitated electrohydraulic lithotripsy (EHL) or laser lithotripsy Under direct vision at cholangioscopy, energy can be delivered directly to large troublesome stones to cause fragmentation. EHL uses a high-​voltage spark to create rapid thermal expansion of fluid and a subsequent hydraulic pressure wave. Laser litho- tripsy (Fig. 15.25.12) uses pulsed energy to create the same effect. Following fragmentation, stones can be removed by traditional methods including balloons and baskets. Open surgery Despite all of these techniques, endoscopic therapy occasionally fails and a surgical solution may be sought. Where the gallbladder is still present, this may involve laparoscopic bile duct explor- ation at the time of cholecystectomy. Where the gallbladder has Fig. 15.25.10  Clearance of common bile duct stones with a balloon trawl (black arrow). Note previous cholecystectomy clips (white arrows). Fig. 15.25.11  Crushing lithotripter for stone removal. (a) (b) (c) (d) Fig. 15.25.12  Laser lithotripsy of difficult common bile duct stones. Gallstones are targeted and fragmented with high-​energy lasers under direct vision using cholangioscopy, thereby allowing extraction with baskets and balloons. Panels (a) and (b), before lithotripsy; panels (c) and (d), after lithotripsy.

section 15  Gastroenterological disorders 3204 previously been removed, open duct exploration may be required. In rare cases where stones cannot be removed (usually after mul- tiple attempts), hepaticojejunostomy may be required because of the long-​term risk of secondary biliary cirrhosis and recurrent cholangitis. Laparoscopic-​assisted ERCP in altered surgical anatomy Increasing use of bariatric surgery means that it may not be possible to access the bile duct from the duodenum via the mouth. Nevertheless, gallstone disease is very common after bariatric sur- gery and stones in both the gallbladder and common bile duct represent a difficult problem. This may be overcome by a com- bined approach of the surgical team using laparoscopic techniques to access the stomach remnant and hence duodenum via the transperitoneal route. The ERCP can then be carried out as normal. Alternatives to cholecystectomy In some very frail, elderly persons, those with significant comorbidi­ ties, and those with advanced cirrhosis, cholecystectomy presents too great a risk. In these situations, ERCP is often undertaken as definitive treatment of bile duct stones, or to prevent recurrence of pancreatitis, with biliary sphincterotomy and ductal clearance. Where stone extraction is not possible, biliary stenting is often used, usually with placement of double-​pigtail stents to ensure that drainage is maintained, although cholangitis is still a common com- plication. With this approach, regular stent changes every 3 months are associated with much lower rates of cholangitis and mortality than with an ‘on-​demand’ stent change practice. Complications of management of gallstones Complications of ERCP ERCP is an invasive surgical procedure and must not be under- taken lightly. The most common complication is pancreatitis, which overall occurs in 2 to 3% of cases, even in expert hands. Risk factors for pancreatitis include multiple cannulation attempts, multiple cannulations, and injection of contrast into the pancre- atic duct. Perforation may occur in any part of the upper gastro- intestinal tract in relation to passage of the endoscope but is most commonly related to sphincterotomy and/​or precut papillotomy. Guide-​wire perforation also occurs. When recognized and treated by keeping the patient nil by mouth and administering antibiotics, most cases of guide-wire perforation settle without the need for surgery. Sepsis and bleeding also occur. Rectal indomethacin (100 mg) has been shown to halve the rate of post-​ERCP pancreatitis. In difficult cases where access to the pan- creatic duct inadvertently occurs, the placement of a pancreatic duct stent can further reduce incidence of pancreatitis. Postcholecystectomy syndromes This is a poorly defined group of symptoms which includes some specific conditions (e.g. bile salt-​related diarrhoea and gastro-​ oesophageal reflux) that result from cholecystectomy. However, many patients given this label in fact have some other condition which has not been affected by the removal of the gallbladder. It is self-​evident that, if cholecystectomy has been performed in patients with symptoms unrelated to the gallbladder (whether or not they have typical biliary colic or acute cholecystitis), then these symp- toms will still be present after operation. Most patients with symptoms after cholecystectomy have nonulcer dyspepsia. If the symptoms are troublesome, investigations should aim to exclude other pathology. Liver function and liver ultrason- ography will exclude parenchymal disease; upper gastrointestinal endoscopy may be helpful to look for peptic ulceration and gastro-​ oesophageal reflux, and colonoscopy or CT colonography may be considered if there are lower gastrointestinal symptoms. Serology for Helicobacter pylori and for endomysial antibody to exclude coeliac disease may be helpful. Any treatable condition should be managed appropriately. Gastro-​oesophageal reflux Reflux symptoms occur or are increased after cholecystectomy in at least 10% of patients as a result of disruption of the feedback mech- anism that controls release of cholecystokinin (CCK). After chole- cystectomy, postprandial and fasting CCK levels in the blood are raised. In addition to causing gallbladder contraction and relaxation of the sphincter of Oddi, CCK also causes relaxation of the gastric cardia and a fall in lower oesophageal sphincter pressure, which facilitates reflux. In most patients these symptoms settle within 12 months, but some will require temporary or long-​term proton pump inhibitors. Bile salt diarrhoea After cholecystectomy, between 1 and 5% of patients report in- creased bowel frequency. Stools may be softer than previously but are rarely loose. This occurs in the absence of identifiable bowel path- ology and is caused by disruption of circulation of bile salts so that more enter the colon where they are irritant to the mucosa. Normal enterohepatic circulation of bile salts requires almost complete re- absorption in the terminal ileum. The absence of the gallbladder re- duces the capacitance of the biliary system so that bile production during fasting cannot be accommodated. Some bile enters the duo- denum as a result. In addition, the raised fasting levels of CCK after cholecystectomy may reduce sphincter pressure, and also favour re- lease of bile in the absence of food. The higher concentration of bile salts reaching the colon in the absence of luminal residue which usu- ally adsorbs some of the bile salts leads to mucosal irritation in the caecum. This impairs water absorption leading to passage of softer, more frequent stools. The diagnosis can be confirmed with a SeHCAT test. Radiolabelled bile salt is ingested and 1 week later the amount of retained isotope indicates normal or impaired bile salt absorption. Mild symptoms may require no treatment other than explanation of the cause. More severe symptoms often respond to reduction of dietary fibre and/​or antidiarrhoeal medication (codeine or loperamide). Cholestyramine which binds intraluminal bile salts is effective, but many patients find it unpalatable and prefer other measures or adjust to their new bowel habit. There is often improvement in symptoms during the months after operation, but if symptoms are still present after 1 year they are likely to be permanent. Sphincter of Oddi dysfunction Sphincter of Oddi dysfunction is an increasingly recognized clinical syndrome comprising right upper quadrant pain with or without ab- normal liver biochemistry and with or without dilated bile ducts.

15.25  Diseases of the gallbladder and biliary tree 3205 The gold standard for diagnosis is biliary manometry. An alternative strategy involves injection of botulinum toxin into the sphincter and clinical assessment of symptoms. When the diagnosis is confirmed, formal sphincterotomy can be performed, often resulting in long-​ lasting relief of pain. Risk of pancreatitis is very high in this group and the patient should be counselled to this effect. This syndrome can be subclassified into types 1, 2, and 3 by the Milwaukee system (Table 15.25.3) with the best results reported in type 1 patients who have abnormal liver function associated with di- lated ducts during an attack of pain. See Chapter 15.26.1 for further discussion of sphincter of Oddi dysfunction in the context of acute pancreatitis, including the Rome III diagnostic criteria. Indeterminate biliary strictures Biliary strictures are a diagnostic challenge because of their wide differential diagnosis, common lack of unequivocal features on imaging, and the need to obtain tissue, which can be difficult to get. The wide range of possible pathologies (Table 15.25.4) have very dif- ferent outcomes and management. Pragmatic approaches which assume a cancer diagnosis run the risk of high-​morbidity surgery or inappropriate metal stenting in benign cases. Watchful waiting risks missing cancers when they are potentially curable. This is a common problem in hepatobiliary medicine and the diagnostic algorithms are con- tinuously evolving: a suggested approach to diagnosis is shown in Fig. 15.25.13. With the increasing recognition of IgG4 disease in these difficult cases, a trial of steroids for 4 to 6 weeks may be jus- tified on the grounds that major surgery can be avoided in some. The disadvantage to this approach is that time may be lost where a tumour becomes impossible to resect, and infective complications might be more common. Obstructive jaundice due to biliary tract disease Regardless of the type of obstruction, effective biliary decompres- sion (either endoscopically or percutaneously) is of benefit to pa- tients. This improves symptoms of cholestasis, improves nutrition, and, in some cases, improves survival. In gallstone-​related disease, removal of the offending stone is usually sufficient to relieve obstruc- tion. In stricturing disease, stenting is usually required. In malignant disease, drainage allows palliative chemotherapy or neoadjuvant chemotherapy to be given. For palliation, stenting has less morbidity than surgical bypass. At least a third of the liver needs to be drained for decompres- sion to be effective. The best mode of decompression therefore de- pends on the location of the obstruction. Distal disease involving the common bile duct or common hepatic duct can be treated with a single stent, which is best placed endoscopically. Between 75 and 80% of hilar strictures can be successfully decompressed with a single stent, but strictures at the hilum may require multiple stents, which can sometimes be achieved at ERCP although more often PTC is required. For malignant disease, there is increasing use of self-​expanding metal stents which give longer palliation and long-​ term patency (Fig. 15.25.14, Fig. 15.25.15). In malignant disease where strictures are present, there are sev- eral novel endoscopic approaches to therapy aimed at maintain­ing longer patency of the stent. These include photodynamic therapy, Table 15.25.3  Milwaukee Classification for sphincter of Oddi dysfunction 1 Biliary pain, abnormal liver function tests (LFTs), dilated bile ducts 2 Biliary pain, abnormal LFTs or dilated ducts 3 Biliary pain Table 15.25.4  Aetiology of biliary strictures with key clinical features Pathology Clinical features Cholangiocarcinoma Imaging, cytology/​FISH/​histology PSC with dominant stricture Imaging, negative cytology/​histology Autoimmune (IgG4) cholangitis Imaging, serology, IgG4 cytology/​histology Involvement of other organs Mirrizi’s syndrome History compatible with cholecystitis Postoperative History of gallbladder/​bile duct surgery, often with associated complications. History of liver transplant, type of anastomosis Stone-​related stricture History, stones on imaging Trauma History Post radiation History Ischaemic/​post-​transarterial chemoembolization History Vasculitis History, serology Infection, e.g. HIV, tuberculosis, worms History, serology Extraluminal compression: • Pancreatic cancer • Chronic pancreatitis • Lymph node metastases • Lymphoma • Pancreatic cysts • Retroperitoneal disease History, imaging Indeterminate stricture History, examination, CT/MRI/bloods Associated mass? Yes EUS/percutaneous biopsy No ERCP +/-Spyglass +cytology/fish/dia/biopsy Diagnosis? No Yes Definitive treatment Re-evaluate ? Trial of steroids Fig. 15.25.13  Algorithm for investigation of indeterminate biliary strictures.

section 15  Gastroenterological disorders 3206 radiofrequency ablation, and brachytherapy. All of these tech- niques need to be combined with self-​expanding metal stents for optimal results. Specific causes of biliary strictures Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is discussed in Chapter 15.23.4. Dominant strictures of the extrahepatic bile ducts are defined as a stenosis of 1.5 mm or less in the common bile duct or 1 mm or less in the hepatic duct. The presence of a dominant stricture in patients with PSC is a common clinical problem and one which carries a worse overall prognosis (especially in the setting of inflammatory bowel disease). They may be present at presentation, when evalu- ation is as for an indeterminate stricture. If a dominant stricture develops in a patient with known PSC, it is crucial to exclude a cholangiocarcinoma. Symptomatic strictures warrant endoscopic therapy with ERCP which should also include the acquisition of brush cytology with or without FISH/​DIA where available. Biliary sphincterotomy and bal- loon dilatation of stricture under antibiotic cover appears to improve survival and reduce the risk of cholangiocarcinoma developing sub- sequently. The role of placing biliary stents is unclear; there is no evidence of benefit for plastic stents, although fully covered self-​ expanding metal stents may help by slowly dilating the stricture. IgG4-​related sclerosing cholangitis IgG4-​related disease is a multisystem disorder, first described in 2003 as autoimmune pancreatitis. It is now recognized to affect many organs with several clinical phenotypes. IgG4 disease of the bile duct is increasingly recognized as an important cause of inde- terminate strictures. Its diagnosis is important as it has a specific treatment, and diagnosis avoids major surgery or problems related to ‘pragmatic’ metal stent placement. Tissue acquisition with direct cholangioscopy and immunostaining of biopsies for IgG4 facilitates diagnosis. The HISORt criteria (histology, imaging, serology, other organ involvement, and response to therapy) (Table 15.25.5) en- compass a number of clinical features to assist with diagnosis. There is a male preponderance and it mainly occurs in the fifth and sixth decades of life. The natural history is not yet established and the differential diagnosis includes cholangiocarcinoma, pancre- atic carcinoma, and primary and secondary sclerosing cholangitis depending on the location of the strictures. Pathogenesis is poorly understood but differs from many other autoimmune diseases in that there appears to be T helper (Th)-​2 and regulatory T-​cell drivers as opposed to the more normal Th1/​Th17 phenotype. Treatment is typically with steroids, although there are no high-​ quality trials at the time of writing: 30 to 40mg of prednisolone is typ- ically given for 4 weeks, then tapering 5 mg every 2 weeks. Response to steroids helps make the diagnosis, with CT/​ERCP changes seen within 4 to 6 weeks. A nonresponse may indicate the wrong diag- nosis but may also result from burnt-​out disease or a more fibrotic phenotype. Relapse is common and, if it occurs, can be retreated with steroids followed by azathioprine. (a) (b) Fig. 15.25.14  (a) Hilar stricture with almost complete occlusion of the hepatic duct going into the right hepatic duct and with no filling of left ducts. (b) Placement of an uncovered self-​expanding metal stent with decompression of right-​sided biliary ducts. (a) (b) Fig. 15.25.15  Biliary stricture just below the hilum before (a) and after (b) placement of an uncovered self-​expanding metal stent. The stent is traversing the ampulla and extends up into the intrahepatic ducts. Bile in the side branches will drain through the mesh of the stent. Table 15.25.5  HISORt diagnostic criteria for IgG4-​related sclerosing cholangitis Histology of
the bile duct Lymphoplasmacytic sclerosing cholangitis Lymphoplasmacytic infiltrate with >104 IgG4 positive cells/​high powered field Storiform fibrosis Obliterative phlebitis Imaging of the bile duct Axial imaging reveals 1 or more strictures (intrahepatic, proximal extrahepatic, or pancreatic bile duct with thickening and inflammation) Fleeting or migratory strictures Serology IgG4 in serum (can be normal in up to 20%, can be elevated in other conditions, e.g. 9% of PSC) Other organ involvement Pancreas, kidney, salivary glands (sclerosing sialadenitis), lungs, pericardium, meninges, pituitary and encompasses retroperitoneal fibrosis, Reidel’s thyroiditis and Mikulicz’s disease Response to steroid therapy Normalization of liver enzymes or resolution of stricture

15.25  Diseases of the gallbladder and biliary tree 3207 Secondary sclerosing cholangitis Secondary sclerosing cholangitis develops in response to an identifi- able process involving biliary obstruction, including chronic obstruc- tion of any cause, stones, parasites, surgical trauma of biliary tree, ischaemic cholangitis (e.g. after transarterial chemoembolization), and recurrent pancreatitis. Cholangiocarcinoma Cholangiocarcinoma is discussed in Chapter 15.24.6. Gallbladder cancer Except when discovered incidentally after laparoscopic cholecystec- tomy, when the cancer is often confined to the gallbladder wall and metastatic spread is minimal, gallbladder cancer often presents at an advanced stage with direct invasion into bile duct, liver, duodenum, or colon, and spread to local nodes, or liver metastases. It is often asymptomatic until obstructive symptoms arise. On imaging, gallbladder cancer appears as irregular thickening of the gallbladder wall or an intraluminal mass with enhancement after intravenous contrast. In patients with symptoms of biliary dis- ease, ultrasonography is often the first test used. This may show the mass and will detect dilated ducts. However, cross-​sectional imaging using CT or MRI is best, obtaining good views of masses, dilated ducts and enlarged lymph nodes. MRI allows excellent views of hepatobiliary anatomy and when combined with an MRCP shows ductal involvement, demonstrates hilar vascular involvement, and is also good for viewing liver metastases. MRI is not as good as CT for identifying distant metastases, and in clinical practice both are commonly used. Treatment is by surgical resection if possible, with extensive lymphadenectomy to clear the hepatoduodenal ligament and resec- tion of the adjacent liver segments (4 and 5). Some surgeons advocate clearance of bile duct and lymph nodes from the hepatoduodenal ligament, to leave only skeletonized hepatic arteries and portal vein. When gallbladder cancer is discovered incidentally after laparo- scopic cholecystectomy, the patient should be referred urgently to a hepatobiliary surgeon for consideration of early repeat operation to resect segments 4 and 5 of the liver with lymph node clearance. This policy greatly improves the chance of cure, and the BILCAP trial has also shown survival benefit for adjuvant capecitabine after surgical resection of gallbladder cancer Congenital disorders of the bile ducts Choledochal cysts These are rare congenital abnormalities of the bile ducts, most commonly diagnosed in children and most prevalent in east Asian populations. They may be found incidentally or as a result of their complications which include malignant transformation, cholangitis, pancreatitis, and cholelithiasis. Adult patients typically present with biliary or pancreatic symptoms such as abdominal pain or jaundice. The cysts represent increased risk for stone disease during biliary stasis, and for biliary malignancy. Anomalous pancreaticobiliary duct union outside of the duo- denal wall is present in 30 to 70%, with a long common channel TYPE 1 TYPE 3 TYPE 4 TYPE 5 TYPE 2 Fig. 15.25.16  Classification of choledochal cysts.

section 15  Gastroenterological disorders 3208 (>15 mm from the ampulla). This allows reflux of pancreatic juice into the biliary tree. It is thought that the enzymes may then con- tribute to cyst formation with inflammation of the cyst walls and hyperplasia. Intrahepatic cysts are associated with portal fibrosis and bile duct proliferation as well. Cysts are classified into five types depending on location and shape (Fig. 15.25.16, Table 15.25.6). Cholangiography is the most sensitive way to define ductal anatomy. Associations include double common bile duct, sclerosing cholangitis, hepatic cysts, and annular pancreas. Types 1 and 4 are most associated with cholangiocarcinoma (Fig. 15.25.17). Management of type 1 and 4 cysts is by excision, which depending on cyst involvement may include hepatic or Whipple’s resections. Types 2 and 3 are usually left alone. Type 5 (Caroli’s disease) may require transplantation due to recurrent sepsis and progressive liver failure. FURTHER READING Johnson CD (2003). Arris & Gale lecture. Regulation and responses of gallbladder muscle activity in health and disease. Ann R Coll Surg Engl, 85, 297–​305. National Institute for Health and Care Excellence (NICE) (2014). Gallstone disease: diagnosis and management of cholelithiasis, chole- cystitis and choledocholithiasis. NICE, London. Soares KC, et al. (2014). Choledochal cysts: presentation, clinical dif- ferentiation, and management. J Am Coll Surg, 219, 1167–​80. Table 15.25.6  Types of choledochal cyst Type Comment 1 90% of cases. Cystic lesion of the bile duct. May present as a dilated common bile duct . Lacks biliary mucosa 2 Diverticulum of common bile duct 3 Intraduodenal (lined by duodenal mucosa) 4 Intra-​ and extrahepatic duct involvement 5 Caroli’s disease. Intrahepatic saccular dilatations, communicating with bile ducts. Can be associated with extensive fibrosis Fig. 15.25.17  Type 1 choledochal cyst with anomalous pancreaticobiliary duct union (white arrow) complicated by cholangiocarcinoma (blue arrow).

15.26 Diseases of the pancreas 3209

15.26 Diseases of the pancreas 3209

15.26.1 Acute pancreatitis 3209

15.26.1 Acute pancreatitis 3209

CONTENTS 15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay 15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen 15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira 15.26.1  Acute pancreatitis R. Carter, Euan J. Dickson, and C.J. McKay ESSENTIALS Acute pancreatitis affects 300 to 600 new patients per million popu- lation per year and is most commonly caused by gallstones or al- cohol. Careful imaging reveals that most so-​called idiopathic acute pancreatitis is due to small (1–​3-​mm diameter) gallstones. Diagnosis is made by a combination of a typical presentation (upper abdominal pain and vomiting) in conjunction with raised serum amylase (more than three times the upper limit of normal) and/​or lipase (more than twice the upper limit of normal). Several other acute abdominal emergencies can mimic acute pancreatitis and may be associated with a raised serum amylase. In equivocal cases, a CT scan is indicated to exclude other causes and confirm the diagnosis. Initial management is with (1) analgesia, (2) ensuring adequate oxygenation, and (3) intravenous fluid administration. The revision of the Atlanta classification separates patients clinically into (1) mild—​ with early resolution without complications, (2)  moderate—​local complications without organ failure, and (3) severe—​complications associated with organ failure. Mild acute pancreatitis responds to analgesia and intravenous fluids. If gallstones have been identified, then cholecystectomy (or endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy where clinically appropriate) should be performed during the same admission, or at least within 2 to 4 weeks to pre- vent recurrent attacks. Severe acute pancreatitis carries a high mortality (up to 20%). Management in the early stages is centred on organ support (respiratory, circulatory, and renal failure). Later management involves surgical or radiological intervention for sepsis, usually within a specialist pancreatic unit. With regard to some specific aspects of management:  (1) there is no indication for a nasogastric tube or starvation:  en- teral feeding of patients with prolonged illness is associated with fewer risks and side effects than total parenteral nutrition. (2)  Antibiotics should not be given until and unless a specific indication arises. (3) ERCP—​occasionally cholangitis may be as- sociated with hyperamylasaemia, in which case urgent biliary decompression at ERCP is indicated. (4) There are no pharmaco- logical agents that benefit any form of acute pancreatitis. (5) The case for decompressive laparotomy for abdominal compartment syndrome remains unproven. Epidemiology Population studies from Scotland and Finland have shown the in- cidence of acute pancreatitis is about 400 patients/​million per year. Incidence would appear to be rising, with a 100% increase in the hospitalization rate in the United States of America over the last 20 years, a 75% increase in admissions in the Netherlands, and a 3.1% yearly rise in incidence in the United Kingdom. The mean age at presentation is 53 years with a roughly equal sex distribution, al- though the largest increase in incidence has been among women under 35  years, which may reflect increasing obesity within the population. The disease was most prevalent in those with poorer socioeconomic status, especially where alcohol was the cause. Overall mortality is from 2.0 to 7.5%, highest in those who are over 70 years, obese individuals, and those with comorbidity at the time of onset. Prospective and retrospective studies record 45 to 50% of deaths as occurring in the initial week of the illness secondary to fulminant multiple organ failure. 15.26 Diseases of the pancreas

section 15  Gastroenterological disorders 3210 Clinical features Sudden onset of severe upper abdominal pain focused in the epigas- trium with vomiting is the most common presentation. This tends to progressively lessen in severity over the first 48 to 72 h, and it is not usually a significant factor beyond this time. There may be upper abdominal tenderness and guarding, but these signs are often less marked than might be suspected from the severity of the pain, and bowel sounds are usually absent in the early stages. Vomiting is prevalent in the first 12 h of illness, contributing to hypovolaemia and hypotension. Clinical jaundice is rare on admission, although minor abnormalities of biochemical liver blood tests occur in 80% of patients with a biliary aetiology. Occasionally, hyperamylasaemia occurs in association with cholangitis, which if overlooked may re- sult in irreversible multiple organ failure. The presence of jaundice and pyrexia on the day of admission is therefore an indication for ur- gent endoscopic retrograde cholangiopancreatography (ERCP) and biliary decompression. Pathology The initial phase of acute pancreatitis is characterized by oedema and the development of an acute inflammatory infiltrate, rich in neutrophils, with tiny spots of fatty tissue necrosis, mainly on the surface but also in the intralobular fatty tissue. In mild cases, the changes are most marked in the peripancreatic tissue, but because the initial pancreatic histological change is within the intralobular fat, there is a relationship between extent of necrosis and the amount of fat within the pancreas. In severe disease, intravascular throm- bosis and local enzymic necrosis leads to confluent areas of fat ne- crosis, which extends beyond the pancreas into the peripancreatic fat. Within the pancreas, disseminated ductal and periductal ne- crosis may be evident. Diagnosis and assessment of severity The diagnosis is usually made from the clinical presentation of upper abdominal pain and vomiting associated with an elevation of serum amylase or lipase. A CT scan should be performed when the diagnosis is not clear. This often demonstrates pancreatic oe- dema and peripancreatic inflammatory stranding, fluid collec- tions, and poor contrast enhancement of the gland (Fig. 15.26.1.1). Occasionally, the diagnosis may first be made at laparotomy, when simple washout and closure is all that should be done. The differential diagnosis is that of an acute abdomen (Box 15.26.1.1). A raised amylase may be associated with several of these conditions, but the (near) universal availability of CT has simplified diagnosis when doubt exists. Biochemical abnormalities A multitude of biochemical phenomena are found in acute pan- creatitis. Various pancreatic enzymes are released that are useful as diagnostic markers. Acinar cell disruption leads to high serum levels of amylase, lipase, trypsin, chymotrypsin, phospholipase, elas- tase, trypsinogen activation peptide, and phospholipase activation peptide. These are also elevated in peritoneal and retroperitoneal tissues as well as lymphatic fluid. C-​reactive protein, an acute-​phase reactant, is of most use for longitudinal monitoring of progress. Very high concentrations of circulating cytokines occur in the blood at an early stage in the disease, including tumour necrosis factor-​α, platelet activating factor, and interleukin 6 with maximal levels in those with severe pancreatitis: these are of research interest rather than clinical value. Grading disease severity Many biochemical scoring systems attempting to objectively grade severity of an attack of acute pancreatitis have been developed, including the Glasgow and Ranson scoring systems. While there is value in directing less experienced clinicians to the multisystem organ dysfunction associated with a severe attack, none are suffi- ciently accurate to direct treatment, and the utility lies in assessing equipoise within clinical trials, with regard to which the APACHE II system has been shown to be useful in the stratification of severity of acute pancreatitis. CT scanning can be useful in demarcating location and ex- tent of pancreatic injury, and a CT severity index has been de- veloped, although CT is more commonly used to monitor the development of evolving complications. In practice, sequen- tial physiological scoring systems (e.g. NEWS) can assist the Fig. 15.26.1.1  CT scan 36 h from onset of pain showing reduced enhancement of neck and body, a perfused pancreatic tail, and peripancreatic stranding. Box 15.26.1.1  Differential diagnosis of acute pancreatitis • Mesenteric ischaemia/​infarction • Small-​bowel obstruction/​perforationa • Renal failure • Macroamylasaemia • Dissecting aortic aneurysm • Diabetic ketoacidosis • Perforated duodenal ulcera • Acute cholangitisa • Acute cholecystitisa • Atypical myocardial infarctiona • Ectopic pregnancya a Amylase is usually normal.

15.26.1  Acute pancreatitis 3211 identification of clinical deterioration and are in common use in most surgical units. Other factors affecting prognosis Other factors affecting prognosis include age and obesity. Many studies have shown that those aged over 70 years have a higher mor- tality. Chronic cardiorespiratory or renal impairment is common in this age group and further increases the risk of death. Acute pan- creatitis carries a significantly higher mortality and morbidity in patients with a body mass index of more than 30 kg/​m2, mainly because of an increased risk of hypoxaemia, but also from other associated factors. Aetiology Aetiological factors and rare associations of acute pancreatitis are listed in Boxes 15.26.1.2 and 15.26.1.3. Major factors Biliary disease and alcohol abuse together account for over 80% of patients with acute pancreatitis in most prospective studies. Gallstones Gallstones are the predominant cause of acute pancreatitis and all patients should have an abdominal ultrasound examination to identify these, even where there is a history of alcohol excess. Smaller stones pass through the cystic duct more easily and are at increased risk of precipitating acute pancreatitis. Endoscopic ultrasonography (EUS) is more sensitive than transabdominal ultrasonography in identifying small gallstones (microlithiasis). This may be helpful in demonstrating gallstone aetiology in those patients previously labelled ‘idiopathic’. The mechanism by which gallstones induce acute pancreatitis is not certain, but increased back pressure in the pancreatic duct fol- lowing transient impaction of a migrating gallstone at the ampulla of Vater is considered to be the likely initiating event. Subsequent intracellular events lead to activation of proteases within acinar cells, acinar cell injury, and a local inflammatory response. Alcohol The proportion of patients in whom pancreatitis is due to alcohol abuse is dependent on the population under study: rates may be as high as 70 to 80% (in New York (United States of America) and Helsinki (Finland)). The risk is highest in young males who drink in excess of 80 g of alcohol per day. Smoking is a cofactor in the devel- opment of both acute and chronic pancreatitis. Many patients with a possible alcohol history also have gallstones and the diagnosis of alcohol-​induced acute pancreatitis should be one of exclusion. Alcohol probably causes acute pancreatitis through intracellular lysosomal release modulated by elevations in cytosolic and mito- chondrial ionized Ca2+ concentration. Minor factors Drugs The drugs most commonly implicated in causing acute pancreatitis are valproic acid, azathioprine, l-​asparaginase, and corticosteroids. There is equivocal evidence regarding thiazide and other diuretics. However, unless viral titres have been determined, together with adequate biliary investigations including endoscopic examination of the ampulla of Vater, it is unwise to ascribe acute pancreatitis to a particular drug. Repeat exposure to the same drug again causing acute pancreatitis is the strongest evidence of a direct association. Viral infection Viral infection, particularly mumps, Coxsackie B, and viral hepa- titis, can cause acute pancreatitis. One clinical feature that may prove useful is prodromal diarrhoea, which is rare in all other types of acute pancreatitis. Of increasing importance are the effects of HIV infection, where acute pancreatitis may be associated with both the primary viral infection and treatment (antiretroviral drugs). Single combination agent therapy (tenofovir, lamivudine, and efavirenz) is considered the most pancreas friendly, but the evidence for favouring one agent over another is weak. Alcohol abuse is common in many HIV-​positive patients, particularly in Africa, and it may be difficult to define a specific causal agent. Box 15.26.1.2  Aetiological factors in acute pancreatitis (according to frequency) Major • Biliary disease • Alcohol abuse Minor • After ERCP • Sphincter of Oddi dysfunction • Hyperparathyroidism • Hyperlipoproteinaemia • Blunt or surgical trauma • Autoimmune pancreatitis • Drugs • HIV-​associated pancreatitis • Hereditary (trypsinogen gene defects) • Ampullary or pancreatic tumour • Cancers metastatic to pancreas: — Renal — Stomach — Breast — Ovarian — Lung Box 15.26.1.3  Rare associations with acute pancreatitis • Hypothermia • Coxsackie B virus • Mumps virus • Sclerosing cholangitis • α1-​Antitrypsin deficiency • Virus infection (non-​HIV) • Worm infestationa • Scorpion biteb • Duodenal duplication a In South-​East Asia. b In Trinidad.

section 15  Gastroenterological disorders 3212 Benign pancreatic duct stricture A focal area of pancreatic necrosis in a primary attack of acute pan- creatitis can cause secondary fibrosis with main duct stricture for- mation and segmental ‘upstream’ recurrent attacks of pancreatitis as a consequence. Stricture dilatation or occasionally surgical de- compression or distal pancreatectomy may be required. Congenital or developmental anatomical abnormalities can present with pancreatitis (choledochal cyst, duodenal duplication, anomalous pancreaticobiliary junction). Pancreas divisum (nonunion of main and accessory ducts) occurs in 3 to 5% of people and is not con- sidered to be a primary cause of pancreatitis. Periampullary or obstructive pancreatic tumours Periampullary adenoma or carcinoma resulting in upstream ob- struction of the main pancreatic duct is an important association. Ampullary tumours are best diagnosed with side-​viewing endo- scopic biopsy. With the increase in this approach to diagnosis, tu- mours at or close to the ampulla have been shown to cause 0.4% of cases of acute pancreatitis. Effective treatment of the tumour abol- ishes recurrent attacks. This usually involves surgical resection, but endoscopic laser therapy or endoscopic papillectomy can be effective in older and less fit patients. Carcinoma of pancreas can occasionally present with clinical acute pancreatitis and other primary tumours (such as neuroendocrine tumours) or tumours metastasizing to the pancreas (such as renal carcinoma) may present in this way, prob- ably by causing pancreatic duct obstruction. Pancreatitis in association with a side branch intraductal papillary mucinous neoplasm is considered a risk factor for malignant trans- formation and requires assessment for potential resection following resolution. Hyperparathyroidism Hypercalcaemia secondary to hyperparathyroidism is now recog- nized to be an uncommon cause of acute pancreatitis. Removal of a parathyroid adenoma usually prevents further acute pancreatitis since persistent hypercalcaemia appears to be the provoking factor. Hyperlipidaemia Patients with type I and type V hyperlipoproteinaemia may de- velop acute pancreatitis in the absence of alcohol ingestion when triglyceride levels exceed 11 mmol/​litre. Both subtypes are asso- ciated with chylomicrons, of which greater than 90% are trigly- cerides. Dietary restriction of lipids and various lipid-​lowering drugs are valuable in therapy. Hyperlipidaemia of any cause where triglyceride levels reach in excess of 2000 mg/​dl may cause acute pancreatitis, and acute pancreatitis may rarely complicate hyper- lipidaemia of pregnancy or diabetic ketoacidosis. High triglyceride levels may be present during an attack of acute pancreatitis and identifying high fasting lipid levels following resolution is key to confirmation. Hypothermia This is an important association. In younger patients, this may be associated with alcohol abuse, particularly if patients fall asleep out of doors, or in the elderly in an unheated house. Management is directed at gradual warming and supportive measures for organ compromise. Hereditary This condition is increasingly being studied since the discovery of genetic mutations of the cationic trypsinogen gene (PRSS1), which shed light on the mechanism of acute pancreatitis. A Europe-​wide study (EUROPAC) has tracked multiple families in the United Kingdom and Europe, and similar work in Japan and the United States of America is ongoing. The two most common mutations are R122H and N29I. An autosomal dominant pattern of inheritance is seen. Severe acute inflammatory changes are rare and diagnosis is often delayed. Patients usually have a long history of recurrent ab- dominal pain from childhood or adolescence. Changes of chronic fibrosis may be present at diagnosis. Typically, chronic pancreatitis is evident by the age of 20 to 40 years, and the risk of pancreatic car- cinoma in those aged over 60 years is significantly increased. Mutations in the cystic fibrosis transmembrane conductance regulator gene (CTFR) and the pancreatic secretory trypsinogen in- hibitor gene (SPINK1) are also linked to pancreatitis. Trauma Hyperamylasaemia may occur after blunt abdominal trauma, usu- ally from a crush injury to the body of the pancreas against the ver- tebral column. The risk of associated injuries to surrounding organs is high, and in the acute phase these are usually more significant than the pancreatic injury. The identification of a pancreatic injury during a trauma laparotomy should be managed by simple drainage in most cases. When there is transection of the main pancreatic duct, therapeutic options include endoscopic transpapillary stenting and distal pancreatectomy. Late presentation is associated with pseudo- cyst formation due to leakage from the damaged pancreatic duct. Pancreatic manipulation during surgical mobilization for colonic, gastric, or splenic surgery may result in inflammation. Iatrogenic Surgical or endoscopic procedures involving the ampulla of Vater can induce pancreatitis. In recent years, diagnostic ERCP (2% risk of acute pancreatitis) has largely been replaced by noninvasive imaging modalities (EUS and magnetic resonance cholangiopancreatography). This has reduced the overall incidence of postprocedural acute pancreatitis, but EUS fine needle aspiration of pancreatic lesions, particularly close to the main duct, can itself result in pancreatitis. The risk of acute pancreatitis increases to 4 to 6% where a therapeutic endoscopic sphincterotomy has been per- formed and may be as high as 20% in high-​risk patients (sphincter of Oddi dysfunction). Iatrogenic perforation should be considered in all patients who develop pancreatitis after therapeutic ERCP, and patients with early organ dysfunction or abdominal signs should undergo a CT without delay if any doubt exists as this will affect management (antibiotics). Autoimmune pancreatitis This is a rare condition, which is considered part of the systemic IgG4-​related autoimmune disease spectrum and is associated with other autoimmune diseases (polyarteritis nodosa, systemic lupus erythematosus, other vasculitides) and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). It may present as abdominal pain with obstructive jaundice more typical of chronic than acute pancreatitis. Other features may include (1)  an increased IgG4/​

15.26.1  Acute pancreatitis 3213 IgG ratio in serum, (2)  homogeneous gland enlargement with a well-​defined halo on CT, (3) characteristic diffuse abnormality on EUS, and (4) periductal lymphoplasmacytic infiltrate on biopsy. The latter may also be associated with abnormalities in the extrahepatic biliary tree resembling sclerosing cholangitis (IgG4-​associated cholangiopancreatopathy). Focal autoimmune pancreatitis may prove difficult to differentiate from carcinoma. A good response to steroids is diagnostic (HISORt criteria). Worm infestation Ascaris lumbricoides within the ampullary area may manifest as acute pancreatitis clinically, and other worms lodged in this area can produce the same effect. Sphincter of Oddi dyskinesia Rarely, sphincter of Oddi dyskinesia can present with acute ab- dominal pain, although the more common presentation is one of chronic relapsing abdominal discomfort. The attacks associated with hyperamylasaemia are usually mild (except where pancrea- titis follows an ERCP). With regard to functional gallbladder and sphincter of Oddi disorders (SODs), the Rome III diagnostic criteria for functional gastrointestinal disorders require episodes of pain in the epigastrium or right upper quadrant and all of the following: epi- sodes lasting 30 min or longer; recurrent symptoms occurring at different intervals (not daily); the pain builds up to a steady level and is moderate/​severe enough to interrupt the patient’s daily ac- tivities or lead to a visit to the emergency department; the pain is not relieved by bowel movements, postural change, or antacids; and exclusion of other structural disease that would explain the symp- toms. If these criteria are satisfied, then Rome III allowed further classification into functional gallbladder disorder (SOD I), where the gallbladder is present and biochemical tests are normal; func- tional biliary SOD (SOD II), where amylase and lipase are normal, but association of at least two episodes of pain with elevation of serum transaminases, alkaline phosphatase, or conjugated bilirubin is a supportive criterion; and functional pancreatic SOD (SOD III), characterized by elevation of serum amylase and/​or lipase. More re- cently, Rome IV, recognizing good evidence that sphincterotomy is no better than sham treatment in patients previously classified as having SOD III, discarded the use of this term and renamed SOD II ‘Functional Biliary Sphincter Disorder’. However, whether this exists as a clinical entity remains a matter of debate, and whether it is a potential cause of acute pancreatitis is controversial. Most clinicians would not recommend pancreatic sphincterotomy in the absence of ampullary stenosis. Classification of severity The original Atlanta classification of acute pancreatitis dichotom- ized clinical behaviour into mild or severe acute pancreatitis, and intervention for necrosis was often focused on early removal of sterile or infected necrosis, usually by open necrosectomy. This oversimplification proved inadequate in clinical practice and the Atlanta criteria were revised in 2013 to address the importance of early systemic organ dysfunction in determining disease severity and outcome (Table 15.26.1.1). The outcome following interven- tion for the management of local fluid or necrotic collections is also heavily influenced by the degree of systemic disturbance, and this is reflected in an additional category of ‘moderately severe’ pancrea- titis, where collections are present in the absence of organ dysfunc- tion. In addition to disease severity, mortality is strongly associated with age and comorbidity. The significance of infection has been recognized in an addendum adding a category of ‘critical’, recog- nizing that those patients with sepsis and organ failure have the highest mortality. This classification further separates local complications/​collec- tions on the basis of time from presentation (<4 or >4 weeks) and on the presence of necrosis, leading to definitions aimed at permit- ting comparison of case series (Table 15.26.1.2). The ‘early’ phase is characterized by the initial host response to the pancreatitis, the severity being determined by the magnitude of organ disturbance/​ failure, and a ‘late’ phase typified by the persistence of organ dys- function and the management of local or systemic complications. The vast majority of acute fluid collections without necrosis will re- solve within 4 weeks, and a persistent fluid collection with minimal or no necrotic component (‘pseudocyst’) is very rare. Collections may be sterile or infected. Most clinically significant peripancreatic complications are therefore related to either acute necrotic collec- tions (<4 weeks) or walled-​off pancreatic necrosis (>4 weeks). This temporal separation is somewhat arbitrary as the clinical manage- ment and surgical approach is determined by multifactorial indi- vidual patient factors. However, this does serve to provide a timeline beyond which, if appropriate, intervention should be delayed. Management General aspects The principles of organ support in critical illness should be followed, ensuring reversal of hypoxaemia, restoration of circulating volume, and maintenance of tissue perfusion ideally within a critical care en- vironment. Early restoration of circulating blood volume is associ- ated with an improved outcome. The combination of fluid lost from vomiting and loss of capillary integrity can be very substantial. The introduction of vasoconstrictor therapy should only be considered after establishing adequate volume resuscitation. Hypoxaemia re- flects disease severity in acute pancreatitis, and while most patients Table 15.26.1.1  Grades of severity of pancreatitis (based on the clinical parameters of the presence or absence of organ failure and/​or complications Mild acute pancreatitis • No organ failure • No local or systemic complications Moderately severe acute pancreatitis • Organ failure that resolves within 48 h (transient organ failure) and/​or • Local or systemic complications without persistent organ failure Severe acute pancreatitis • Persistent organ failure (>48 h): • Single organ failure • Multiple organ failure Critical acute pancreatitis In addition to the other three categories taken from the Atlanta revision, an additional ‘critical’ category (persistent organs failure and sepsis) was proposed by Petrov et al.

section 15  Gastroenterological disorders 3214 can be managed with supplemental humidified oxygen, assisted ven- tilation may be required in more severe cases. For initial resuscitation, Ringer’s lactate is recommended, with goal-​directed intravenous fluid (5–​10 ml/​kg per hour) to produce 0.5 ml/​kg of urine per hour. Renal replacement therapy by haemo- dialysis or haemofiltration may be required if renal failure becomes established. The more severe cases of acute pancreatitis are charac- terized by the development and persistence of a systemic inflam- matory response syndrome, one aspect being the development of a swinging pyrexia. This is often inappropriately taken as evidence of sepsis but is usually a reflection of the inflammatory cascade and the presence of devitalized tissue in the retroperitoneum rather than bacterial infection. Specific aspects ERCP There is no role for early ERCP in mild disease. High fever within the first 24 h is rare and, if associated with jaundice, is suspi- cious of ascending cholangitis where the cholangitis, rather than any pancreatic inflammation, is driving organ dysfunction. This is the only unequivocal indication for ERCP and biliary decom- pression. The role of early ERCP remains controversial in all other circumstances. Several randomized studies and cohort series have looked at the role of early ERCP with endoscopic sphincterotomy compared with conservative management in acute gallstone pan- creatitis. A number of meta-​analyses have failed to demonstrate a definite benefit, and early ERCP is difficult to justify in patients who are not jaundiced. Antibiotics The dual peak in mortality in acute pancreatitis is well recognized. The late peak is determined by complications associated with ne- crosis, including the development of pancreatic or peripancreatic infection. The consensus of the most recent systemic reviews/​meta-​ analyses is that there is no evidence supporting the use of prophy- lactic antibiotics in either mild or severe acute pancreatitis, and the recommendation is to avoid their use, using targeted antibiotic therapy for episodes of proven infection. It is, however, reasonable to commence antibiotics in the deteriorating patient with radiological and clinical evidence of sepsis while awaiting culture confirmation. Nutrition support There is no benefit from enteral feeding in mild pancreatitis, and these patients need have no dietary restrictions. Assisted feeding may be required in severe acute pancreatitis to provide long-​term nutritional support. Randomized studies have shown that enteral nutritional support is cheaper and is associated with fewer side ef- fects than total parenteral nutrition. In addition, there is no differ- ence in outcome with nasogastric compared to nasojejunal feeding. In clinical practice, therefore, the mode of nutritional support does not appear to influence the disease process, and the choice of de- livery relates to tolerance and minimizing morbidity associated with the delivery system. Probiotics may be detrimental in acute pancrea- titis and specifically supplemented nutrition should only be admin- istered in the context of clinical trials. It has been suggested that nutritional support may help to pre- serve mucosal function and limit the stimulus to the inflammatory response. The experimental evidence supporting this has not been confirmed in clinical practice and there is no evidence that the mode of feeding alters disease progression. Other approaches Previous randomized studies have failed to provide sufficient evi- dence to recommend the use of antiproteases, antisecretory, anti-​ inflammatory agents, or antioxidant therapy in patients with acute pancreatitis. There is therefore no proven pharmacological therapy for the treatment of acute pancreatitis. Intervention for postacute pancreatitis fluid
and necrotic collections The definitions surrounding acute fluid-​predominant and acute nec- rotic collections have been detailed previously in Table 15.26.1.2. Due to the complexity and diversity of an individual patient’s clinical course, it is challenging to define specific triggers for intervention. Delayed intervention where possible, along with planned minim- ally invasive sepsis control, has become key to management in most pancreatic units. There is no role for early (week 1) intervention unless vascular complications are suspected. Intervention is most commonly required for suspected or proven sepsis of acute necrotic collections or walled-​off necrosis after resolution of the initial in- flammatory phase. Optimal management may involve a number or combination of techniques and require discussion with a specialist regional pancreatic centre. The indication for early (<6 weeks) intervention is for the con- trol of proven or suspected sepsis. Secondary clinical or biochemical deterioration after the initial period of organ compromise should lead to a full bacteriological septic screen and contrast-​enhanced CT scan. Gas within an acute necrotic collection or walled-​off necrosis are indicative of bacteriological contamination but may result from spontaneous fistulation into the intestine (particularly where there is an air–​fluid level). In general, fistulation into the foregut may be associated with clinical improvement despite CT appearances, while Table 15.26.1.2  Local complications in acute pancreatitis (2012 Revised Atlanta Classification) Timescale Necrosis absent Necrosis present <4 weeks Acute peripancreatic fluid collection (peripancreatic fluid associated with interstitial oedematous pancreatitis with no associated peripancreatic necrosis) Acute necrotic collection (a collection containing variable amounts of both fluid and necrosis; the necrosis can involve the pancreatic parenchyma or the extrapancreatic tissues)

4 weeks Pancreatic pseudocyst (an encapsulated collection of fluid with a well-​defined inflammatory wall usually outside the pancreas with minimal or no necrosis) Walled-​off necrosis (a mature, encapsulated collection of pancreatic or extrapancreatic necrosis that has developed a well-​defined inflammatory wall) Infection Each collection type may be sterile or infected

15.26.1  Acute pancreatitis 3215 hindgut fistulation often results in clinical deterioration mandating intervention. Smaller gas bubbles are more commonly associated with bacterial translocation and require drainage by one of the methods described in the following subsections if clinically indi- cated (Fig. 15.26.1.2). Sepsis associated with acute necrotic collections or early walled-​off necrosis Initial walled-​off necrosis The trend in the last 20 years has been towards minimizing the mag- nitude of any intervention while achieving adequate sepsis control. Initially most methods were aimed at mirroring the open surgical debridement techniques to achieve clearance of any necrotic ma- terial as this was felt to be key to recovery, but the importance of sepsis control over removal of necrosis has increasingly been rec- ognized. This was perhaps the most significant finding within the PANTER trial from the Dutch Pancreatitis Study Group, which not only provided randomized data regarding the management of infected pancreatic necrosis, but also demonstrated that a third of patients (35% within PANTER) with pancreatic or peripancreatic necrosis may resolve completely with simple percutaneous drainage. In this trial, patients requiring surgical intervention for pancreatic necrosis were randomized to either primary open necrosectomy or a ‘step-​up’ approach based on percutaneous drainage as the initial intervention, with progression to retroperitoneal debridement with lavage if no improvement was observed. There is now a consensus advocating a principle of early organ support, nutritional optimiza- tion, followed ideally by delayed and selective minimally invasive intervention if required. More recently the role of endoscopic (EUS) transmural cysto­ gastrostomy in the management of postacute walled-​off collections has emerged as an alternative to percutaneous or surgical drainage. The choice between initial percutaneous or endoscopic drainage is determined by several factors including (1) the anatomy of the disease, for example, the position of the collection relative to the stomach, colon, liver, spleen, and kidney; (2)  patient physiology, as the ability to perform EUS-​guided puncture within an intensive therapy unit setting, without the need for patient transfer to the radiology department for CT-​guided drainage, may influence the management decision where a patient is in extremis, and unstable to transfer; and (3) institutional capabilities. Secondary intervention The ‘step-​up’ concept is based on staged sepsis control as a bridge to surgery or as definitive treatment in some patients. The require- ment for secondary intervention usually arises from blockage of the percutaneous drain, or cystogastrostomy with solid necrotic ma- terial. Simple replacement, upsizing, or insertion of multiple drains has been proposed rather than embarking on one of the secondary intervention techniques described in ‘Particular interventional techniques’. The Dutch Pancreatitis Study Group compared the success of fur- ther upsizing of percutaneous drainage versus retroperitoneal de- bridement as the initial enhanced step-​up procedure if immediate resolution did not occur and showed that more that 50% of patients in the dilatation-​alone group settled without formal necrosectomy. Drawbacks included limited ability to remove necrotic debris, pro- longed hospitalization, and the need for multiple procedures. The use of grasping forceps to extract the debris after sequential tract dilatation has been described in a small series, as has the use of as- sist devices such as stone retrieval baskets, but these techniques are seldom performed in clinical practice. Probably more important than the method of drainage, a dedicated team of surgeons/​radi- ologists prepared to proactively address any undrained sepsis is critical for successful percutaneous management of necrotizing pancreatitis. Particular interventional techniques The open lateral approach initially described in the 1980s utilized a loin/​subcostal and retrocolic approach to allow debridement of pan- creatic and peripancreatic necrosis. This open approach was associ- ated with major morbidity (enteric fistula 45%, haemorrhage 40%, and colonic necrosis 15%), and failed to gain popularity. Minimally invasive pancreatic necrosectomy For percutaneous necrosectomy, the catheter is exchanged for a radiological guidewire and then a low-​compliance balloon dilator is inserted into the collection and dilated to 34 FG. Access to the cavity is maintained by an Amplatz sheath through which is passed an operating necroscope to allow debridement under direct vision. The necroscope has an operating channel that permits standard (5-​mm) laparoscopic graspers as well as an irrigation/​suction channel. The directed, high-​flow lavage promotes rapid evacu- ation of pus and liquefied necrotic material, revealing black or grey devascularized pancreatic tissue and peripancreatic fat, which if loose is extracted in a piecemeal fashion until, after several pro- cedures, a cavity lined by viable tissue or granulating pancreas is created. At the end of each procedure an 8 FG catheter sutured to a 24 FG drain is passed into the cavity (Fig. 15.26.1.3a) to allow con- tinuous postoperative lavage of warmed fluid, initially at 250 ml/​h. Subsequent conversion of the lavage system to simple drainage may be all that is required prior to recovery, or the procedure may be repeated until sepsis control is achieved and interval CT confirms resolution. Video-​assisted retroperitoneal debridement A video-​assisted retroperitoneal debridement (VARD) procedure is performed with the patient placed in a supine position with the left side 30 to 40° elevated. A subcostal incision of 5 cm is placed in the Fig. 15.26.1.2  An acute necrotic collection after 17 days illustrating small gas bubbles, managed initially by EUS-​guided cystogastrostomy within a step-​up framework.

section 15  Gastroenterological disorders 3216 left flank at the midaxillary line, close to the exit point of the percu- taneous drain. Using the in situ percutaneous drain as a guide, the retroperitoneal collection is entered. The cavity is cleared of puru- lent material using a standard suction device. Visible necrosis is carefully removed with the use of long grasping forceps, and deeper access under direct vision is facilitated using a 0° laparoscope, and further debridement performed with laparoscopic forceps. As with a percutaneous necrosectomy, sepsis control rather than complete necrosectomy is the aim of this procedure and only loosely adherent pieces of necrosis are removed, minimizing the risk of haemorrhage. Two large-​bore single-​lumen drains are positioned in the cavity and the fascia closed to facilitate a closed continuous postoperative lavage system. Endoscopic necrosectomy Endoscopic cystogastrostomy was initially reported for the man- agement of a mature pancreatic abscess with minimal necrosis, but the technique has evolved in the last 10 years to become an estab- lished procedure, with endoscopic transmural exploration and de- bridement of the retroperitoneum. Single-​step drainage under EUS guidance may be carried out by either a transgastric or (less com- monly) a transduodenal route and is preferred to ‘blind’ drainage as EUS allows for identification of the collection where there is no ob- vious bulge seen within the stomach and helps identify a safe route for puncture, free from intervening vessels (Fig. 15.26.1.3b). The presence of significant walled-​off necrosis is no longer considered a contraindication, but concerns do remain regarding the adequacy of endoscopic drainage, particularly in solid predominant or larger collections. The major limitation of this technique is that instru- ments have yet to be developed to facilitate the adequate removal of loose solid material from the cavity when this is compromising drainage through the cystogastrostomy. Where there is extensive necrosis, delayed endoscopic necro­ sectomy may be required. It is the chapter authors’ practice to defer this for a week following the initial drainage procedure to allow the fluid component to drain and any associated sepsis to improve. A re- cent systematic review of 14 studies including 455 patients found an overall success rate of 81% and mortality of 6%, but these studies are in highly selected patients and all but one was retrospective. One small randomized trial compared endoscopic with surgical drainage and found a reduction in significant complications with the endoscopic approach. Endoscopic necrosectomy is, however, a challenging pro- cedure and not without risk. Major complications including fatal air embolism, bleeding, and perforation occurred in 26% of patients in the multicentre GEPARD study. The use of carbon dioxide insuffla- tion is therefore now recommended. A persistent problem is the lack of availability of suitable endoscopic devices to achieve necrosectomy, and although endoscopic access to the cyst cavity is now facilitated by metallic stents, piecemeal necrosectomy using standard graspers, baskets, and snares is a time-​consuming and painstaking process. One possible modification is the use of intracavity hydrogen peroxide to facilitate necrosectomy, but further experience is required before this can be recommended for routine practice. An early randomized pilot study exploring the outcome of endo- scopic transmural drainage versus minimally invasive intervention (VARD) (the PENGUIN trial) suggested at least equivalence, if not benefit, from endoscopic drainage. This study has been criticized due to very small numbers and an excessive mortality (40%), com- pared to historical results, within the VARD arm. The TENSION trial demonstrated that the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major compli- cations or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group and many now favour endo- scopic drainage as the index intervention. Open surgical necrosectomy Worldwide, open necrosectomy is still commonly employed, but increasingly is being superseded by the procedures previously de- scribed, or performed within a ‘step-​up’ format after initial percutan- eous drainage has produced sepsis control. Three general variations of open necrosectomy are currently practised; although the proced- ures are broadly similar in terms of the necrosectomy, they differ in terms of how they prevent recurrence of an infected collection within the debridement cavity: (1) open necrosectomy with open or closed packing, (2) open necrosectomy with continuous closed postoperative lavage, and (3) programmed open necrosectomy. (a) (b) Fig. 15.26.1.3  Initial ‘step-​up’ drainage using (a) minimally invasive retroperitoneal pancreatectomy percutaneous lavage drain and (b) EUS-​guided transgastric cystogastrostomy with a self-​expanding metal stent.

15.26.1  Acute pancreatitis 3217 Management of late collections A significant proportion of patients with postacute collections do not develop sepsis-​related complication in the early phase, allowing the collection to organize and mature. Failure to thrive, persistent discomfort, and nutritional failure are the common indications for late intervention for walled-​off necrosis. Nutritional intake may be limited by a combination of early satiety and postprandial pain. The extent of actual necrosis, as opposed to reduced enhancement of the parenchyma on contrast-​enhanced CT, often results in an overesti- mation of the extent of necrosis. Spontaneous resolution of even large collections is not infrequent, hence continued nonintervention is often the best approach, particularly where ongoing maturation of a collection may be anticipated and where the clinical picture is improving. In any individual case, the choice of intervention may be guided by factors including the clinical picture, the position of the collection in relation to the stomach and duodenum, and available expertise. Laparoscopic cystogastrostomy For many years, the conventional approach to the management of late walled-​off pancreatic necrosis was open pancreatic cystogastrostomy with necrosectomy. This procedure can now be safely and effectively carried out using a laparoscopic approach, which has the potential advantage of allowing a one-​stage removal of any solid component and may also be combined with a cholecystectomy if appropriate. Endoscopic ultrasonography-​guided
cystogastrostomy/​necrosectomy Many reports in the literature describe EUS-​guided drainage of ‘pseudocysts’, but it is now recognized that true pancreatic pseudocysts are rare following acute pancreatitis as some degree of necrosis is usually present where collections persist. The revised Atlanta criteria define these collections as walled-​off necrosis, but there is still a spectrum of clinical presentations. EUS-​guided drainage of these collections is now an established technique in specialist units and several different modifications to the technique have been described. The frequent requirement for repeated endo- scopic procedures, particularly in the presence of significant ne- crosis, have led to a former preference to select fluid-​predominant walled-​off necrosis collections for this approach, but this assump- tion is being currently challenged within a randomized trial in the chapter authors’ unit. (a) (c) (b) Fig. 15.26.1.4  Examples of complications following acute pancreatitis. (a) Haemorrhage from the splenic artery into a retroperitoneal collection. (b) Acute necrotic collection with fistulation into the colon. (c) Portal vein thrombosis and cavernous malformation.

15.26.2 Chronic pancreatitis 3218

15.26.2 Chronic pancreatitis 3218

section 15  Gastroenterological disorders 3218 Specific complications of acute pancreatitis Acute pancreatic pseudocyst It is rare that an acute inflammatory collection persists beyond 4 weeks and contains little or no debris (as required by the Atlanta definitions). Unfortunately, necrosis is poorly demonstrated by CT (MRI is more sensitive), and an acute fluid collection on CT may appear homogeneous. Pancreatic pseudocyst most commonly oc- curs in the lesser sac and often represents a closed pancreatic fis- tula, as a breach in the main or major pancreatic duct can frequently be demonstrated by ERCP. Transpapillary duct stenting and ERCP should be avoided if possible as these lead to the introduction of in- fection in more than 10% of patients. In the absence of sepsis, fluid-​ predominant acute fluid collections may be adequately drained as a one-​step procedure by EUS-​guided endoscopic transmural pro- cedures, although repeated tract dilatation is often required. By contrast, solid-​predominant acute fluid collections, especially in younger, fit patients, may be best dealt with by internal surgical drainage to the stomach or to a defunctioned Roux loop of jejunum. This procedure can be done either laparoscopically or during open surgery, depending on local expertise, and can also be combined with a cholecystectomy. Haemorrhage Poorly controlled sepsis within a collection can present with acute internal haemorrhage into a collection, or bleeding from a drain site (Fig. 15.26.1.4a). Venous bleeding can be controlled by tam- ponade, but arterial haemorrhage requires urgent CT angiography, proceeding to angiographic embolization where appropriate. Where this is unsuccessful and surgical intervention is required, the prog- nosis is grave as the bleed is usually associated with a combined hypovolaemic and septic deterioration and associated multiple organ dysfunction. Visceral fistulation Spontaneous discharge of a postacute collection into the gastro- intestinal tract is not uncommon and can decompress the collec- tion and result in clinical improvement. Fistulation into the lower gastrointestinal tract often results in a poorly drained collection and defunctioning ileostomy or resection of the affected segment is then required (Fig. 15.26.1.4b). Pancreatic ascites This condition rarely occurs in association with acute pancreatitis, but when it does it is due to spontaneous decompression of a pancre- atic pseudocyst, with escape of pancreatic juice into the peritoneal cavity. Amylase-​rich fistula fluid is common after percutaneous drainage, when internal control can often be successfully achieved by endoscopic transpapillary drainage. Splenic and portal vein thrombosis The use of CT to monitor progress has resulted in the increased recognition of splenic and segmental portal vein thrombosis. Splenic vein thrombosis does not usually require treatment, but thrombus in the portal or superior mesenteric vein requires anticoagulation either with low molecular weight heparin or war- farin (Fig. 15.26.1.4c). FURTHER READING Appelros S, Borgstrom A (1999). Incidence, aetiology and mortality rate of acute pancreatitis over 10 years in a defined urban popula- tion in Sweden. Br J Surg, 86, 465–​70. Banks PA, et al. (2013). Classification of acute pancreatitis –​ 2012: re- vision of the Atlanta classification and definitions by international consensus. Gut, 62, 102–​11. Cotton PB, et al. (2016). Rome IV. Gallbladder and sphincter of Oddi disorders. Gastroenterology, 150, 142–​9. Hollemans RA, et al. (2015). Predicting success of catheter drainage in infected necrotizing pancreatitis. Ann Surg, 263, 787–​92. Moretti A, et al. (2008). Is early endoscopic retrograde cholangiopan­ creatography useful in the management of acute biliary pancreatitis? A meta-​analysis of randomized controlled trials. Dig Liver Dis, 40, 379–​85. Petrov MS, et al. (2008). Early endoscopic retrograde cholangiopan­ creatography versus conservative management in acute biliary pancreatitis without cholangitis:  a meta-​analysis of randomized trials. Ann Surg, 247, 250–​7. van Brunschot S, et al. (2018). Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial. Lancet, 391(10115), 51–8. van Santvoort HC, et al. (2010). A step-​up approach or open necro­ sectomy for necrotizing pancreatitis. N Engl J Med, 362, 1491–​502. Villatoro E, Mulla M, Larvin M (2010). Antibiotic therapy for prophy- laxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev, 5, CD002941. Wilson C, Heath DI, Imrie CW (1990). Prediction of outcome in acute pancreatitis: a comparative study of APACHE II, clinical assessment and multiple factor scoring systems. Br J Surg, 77, 1260–​4. Working Group IAP/​APA Acute Pancreatitis Guidelines (2013). IAP/​APA evidence-​based guidelines for the management of acute pancreatitis. Pancreatology, 13 Suppl 2, e1–​15. 15.26.2  Chronic pancreatitis Marco J. Bruno and Djuna L. Cahen ESSENTIALS Chronic pancreatitis is a major source of morbidity, loss in quality of life, and healthcare expenditure. It is most commonly caused by chronic alcoholism in adults and cystic fibrosis in children, but there are many other causes. Patients typically present with severe abdom- inal pain, but this may vary and even be absent. Exo-​ and endocrine insufficiency usually occur late in the disease course and reflect per- manent loss of pancreatic parenchyma due to ongoing inflamma- tion and fibrosis, exocrine insufficiency, manifesting as steatorrhea and weight loss due to fat maldigestion and endocrine insufficiency as diabetes mellitus. Diagnosis is confirmed by imaging investigations such as CT, MRI, and endoscopic ultrasonography. Endoscopic retrograde cholan­ giopancreatography to diagnose chronic pancreatitis is obsolete.

15.26.2  Chronic pancreatitis 3219 Hormone stimulation tests (e.g. secretin–​cholecystokinin stimulation test) to diagnose exocrine insufficiency are largely abandoned because of their complexity and burden to patients. They are replaced by faecal elastase testing, even though this test is less sensitive. Management focuses on the treatment of pain using a stepwise approach. Initially, nonopioid analgesics are prescribed. Next, when feasible, endoscopic therapy is initiated, including pancreatic stone fragmentation by extracorporeal shock-​wave lithotripsy, endotherapy to remove stone fragments, and placement of plastic stents to dilate any concomitant pancreatic duct strictures. If that fails or when, for example, the pancreatic head is enlarged, surgical intervention is in- dicated. Medical management includes enteric-​coated pancreatic enzyme preparations and treatment of diabetes mellitus, usually by means of insulin. Abstinence from alcohol and smoking are important predictors of disease and treatment outcome. Introduction Chronic pancreatitis is an ongoing inflammatory disorder, char- acterized by irreversible structural and functional impairment of the pancreas. This is in contrast to acute pancreatitis, which is a re- versible condition. Chronic pancreatitis evolves slowly, over 10 to 20 years, and is often associated with disabling pain and loss of pancreatic function. The disease is relatively rare, but its prevalence is increasing, probably due to increased alcohol and tobacco use. Moreover, im- proved imaging techniques provide opportunities to detect the disease at an earlier stage. Treatment is challenging because of the variability in aetiology and presentation, the unpredictability of the disease course, and the lack of prospective evidence regarding treatment options. Aetiology The M-​ANNHEIM classification recognizes that chronic pancrea- titis is a complex disease in which multiple causative risk factors are likely to interact (Table 15.26.2.1). Alcohol has long been recog- nized as a risk factor and more recently, cigarette smoking has been added as an independent, dose-​related risk. Together, alcohol and smoking are responsible for over 60% of chronic pancreatitis cases and are a major determinant of disease progression. Hereditary pan- creatitis refers to the expression of a disease-​causing gene mutation. Familial pancreatitis refers to pancreatitis that occurs in a family with an incidence higher than would be expected by chance alone: it may or may not be caused by a genetic defect. Idiopathic pancreatitis is defined as pancreatitis in isolated cases in which other causes of the disease have been excluded. Epidemiology Chronic pancreatitis is a major source of morbidity, loss in quality of life, and healthcare expenditure. Its incidence is esti- mated at 4 to 14 per 100 000 per year and its prevalence as 42 to 50 per 100 000, albeit with marked geographical variation. It is ranked in the top 10 of digestive disease diagnoses in hospital registra- tions. In the United Kingdom (63 million inhabitants), it has been shown that patients with chronic pancreatitis consume a dispro- portionately high volume of resources, with costs estimated at £285.3 million per year. Over the years, the incidence of chronic pancreatitis has mark- edly increased, mainly due to an increase in the diagnosis of alcohol-​related chronic pancreatitis, although heightened clinical awareness and increased use of cross-​sectional imaging modalities (CT, MRI) and endoscopic ultrasonography (EUS) may also con- tribute. Traditionally, the disease was more common in men, but nowadays men and women are almost affected equally. Racial differences in the incidence have been reported, with African Americans affected two to three times more than Caucasians, but it remains unclear whether this is explained by differences in genetic susceptibility or by environmental and societal factors. Pathogenesis/​pathology The pathophysiological mechanisms and natural course of chronic pancreatitis are not well understood. The 1984 Cambridge system Table 15.26.2.1  The M-​ANNHEIM multiple risk factor classification of chronic pancreatitis M Pancreatitis with Multiple risk factors A Alcohol consumption:   Excessive (>80 g/​day)   Increased (20–​80 g/​day)   Moderate (<20 g/​day) N Nicotine consumption (in cigarette smokers: description by pack-​years) N Nutritional factors:   Nutrition (e.g. high caloric proportion of fat and protein)   Hyperlipidaemia H Hereditary factors:   Hereditary pancreatitis   Familial pancreatitis   Early-​onset idiopathic pancreatitis   Late-​onset idiopathic pancreatitis   Tropical pancreatitis (possible mutations in the PRSS1, CFTR,
  or SPINK1 genes) E Efferent duct factors:   Pancreas divisum   Annular pancreas and other congenital abnormalities of the
  pancreas   Pancreatic duct obstruction (e.g. tumours)   Post-​traumatic pancreatic duct scars   Sphincter of Oddi dysfunction I Immunological factors:   Autoimmune pancreatitis   Sjögren’s syndrome-​associated chronic pancreatitis   Inflammatory bowel disease-​associated chronic pancreatitis   Chronic pancreatitis with autoimmune diseases (e.g. primary
  sclerosing cholangitis, primary biliary cirrhosis) M Miscellaneous and rare metabolic factors:   Hypercalcaemia and hyperparathyroidism   Chronic renal failure   Drugs   Toxins

section 15  Gastroenterological disorders 3220 stated that acute and chronic pancreatitis were two completely separate disease entities. Later, in the proceedings of the Second International Symposium on the Classification of Pancreatitis in Marseille, it was acknowledged that acute pancreatitis can progress to chronic disease, albeit seldom. The so-​called necrosis–​fibrosis theory connects both entities by explaining that development of fi- brosis with obstruction of pancreatic ducts is triggered by ongoing acute inflammation. This finally evolved into the ‘sentinel acute pancreatitis event’ (SAPE) hypothesis, which suggests that acute and chronic pancreatitis constitute different ends of a disease con- tinuum, the latter being triggered by the former, provided that there is ongoing damage to the pancreas, for example, by repeated bouts of acute inflammation. Observational studies indicate that about 10% of patients with a first episode of pancreatitis and a third of patients with recurrent episodes develop chronic disease, the risk being higher among smokers, alcoholics, and men. When the initial pancreatitis attack is not too severe, anti-​ inflammatory mechanisms prevent further influx of macrophages and activation of stellate cells, leading to a full clinical, morpho- logical, and functional recovery. However, when the initial hit is of sufficient severity, or when recurrent acute pancreatitis attacks occur (second hit), this may act as a driving force to attract mono- cytes which become resident macrophages. Through the produc- tion of transforming growth factor-​β, such macrophages activate pancreatic stellate cells, leading to glandular fibrosis. Several life- style factors known to induce oxidative stress (e.g. smoking and al- cohol use) promote ongoing or recurrent inflammation and acinar cell injury. A genetic predisposition also plays an important role in the pathogenesis of chronic pancreatitis. The classical example is her- editary pancreatitis, in which autosomal dominant mutations in the cationic trypsinogen genes (PRSS1, -​2, and -​3) cause a severe form of chronic pancreatitis that develops in 80% of affected indi- viduals, starting in early childhood. Other known polymorphisms related to the development of chronic pancreatitis include muta- tions in genes such as CTRC (chymotrypsin C), CASR (calcium sensing receptor), CTSB (cathepsin B), SPINK1 (serine protease inhibitor kazal type 1), CFTR (cystic fibrosis transmembrane conductance regulator), and CLDN2 (claudin 2). The import- ance of genetic susceptibly is exemplified by the discovery of mu- tations in half of the patients with presumed idiopathic chronic pancreatitis. The combined effect of various risk factors, for ex- ample, moderate drinking, smoking, and having a mutation in one of the relevant genes, is poorly understood. This also is a likely explanation of why certain people develop chronic pancreatitis, while others do not, despite being exposed to the same environ- mental risk factors. Clinical features Pain Pain is the most prominent symptom in patients with chronic pancreatitis. Classically, pancreatic pain is located in the epigas- trium and radiates to the back. It may be chronic or intermittent and is frequently aggravated or provoked by food intake. It is often accompanied by nausea and vomiting. Over 90% of patients are hospitalized for debilitating pain at least once in their lifetime. Patients suffering from constant pain are admitted to a hospital more than five times as frequently as those with intermittent pain. A few patients do not have pain but may develop pancreatic insufficiency. Chronic pancreatitis may run an unpredictable course. Often there is a discrepancy between the severity of clinical symptoms and the extent of morphological changes; in other words, patients with minor morphological changes on imaging may have se- vere pain, while patients with prominent ductal dilation and large intrapancreatic stones may be completely asymptomatic. Pain in chronic pancreatitis is thought to be multifactorial, resulting from increased ductal and parenchymal pressure due to pancreatic duct obstruction caused by strictures and stones, neuropathic changes due to entrapment of pancreatic nerves by fibrotic tissue and injury due to oxidative stress, and centrally acting mechanisms related to chronic exposure to pain stimuli. Psychosocial factors and coping mechanisms (personal and social network) are deemed of great im- portance in the perception of pain and the requirement and depend- ence on (opioid) analgesics. Quality of life Chronic pancreatitis has an adverse effect on quality of life. The dis- ease burden is often such that it interferes with normal daily activ- ities and work productivity, and many patients become unemployed. Patients often suffer from severe opioid-​dependent chronic pain, chronic fatigue, and fear of future health problems. Exo-​ and endocrine function More than half of chronic pancreatitis patients develop exocrine pancreatic insufficiency at some point in their disease course. On average, it takes 5 to 8 years to develop exocrine insufficiency as more than 90% of maximal secretory capacity of pancreatic en- zymes needs to be lost before clinical symptoms develop. Symptoms include fat malabsorption with steatorrhea (fatty, pale coloured, voluminous, fool smelling stool), abdominal pain and discom- fort, weight loss, and deficiencies of fat-​soluble vitamins (A, D, E, K). Besides fat digestion due to lipase deficiency, protein (prote- ases deficiency) and carbohydrate (amylase deficiency) digestion also are affected. From a clinical perspective, however, treatment of fat maldigestion and adequate supplementation of lipase is the hallmark of treatment because there are endogenous compensa- tory mechanisms for protein and carbohydrate digestion. Lately, it has become apparent that metabolic bone disease secondary to osteopenia (45%) and osteoporosis (10%) occurs more frequently in patients with chronic pancreatitis compared to a reference popu- lation, even in exocrine-​sufficient patients. More than half of all patients with chronic pancreatitis develop diabetes mellitus, which most often occurs after exocrine pancre- atic insufficiency has developed, some 10 to 15 years after disease onset. This form of pancreatogenic diabetes is referred to as type 3c diabetes mellitus. It differs from diabetes type 1 and 2 with regard to the underlying pathophysiological mechanism as well as the clin- ical consequences. In pancreatogenic diabetes, there is a loss of com- plete islet cell mass. Therefore, not only insulin function is affected, such as in type 1 diabetes mellitus (reduced number of β cells) and type 2 diabetes mellitus (insulin resistance), but also the function of

15.26.2  Chronic pancreatitis 3221 counter-​regulatory hormones such as glucagon and pancreatic poly- peptide. This renders patients with pancreatogenic diabetes more susceptible to hypoglycaemia. Prognosis The life expectancy of patients with chronic pancreatitis is signifi- cantly lower than that of the general population. In some series, years of life lost are reported to be as high as 10 to 15. Principal causes of death are often indirectly related to chronic pancreatitis and associated with a lifestyle of self-​neglect and chronic substance abuse, for instance, lung and throat cancer (due to heavy cigarette smoking), malnutrition, complications of diabetes including cardio- vascular events, and suicide. Chronic pancreatitis also confers an in- creased risk for developing pancreatic cancer, with a relative risk of 2 to 5 and an absolute risk of 4% per 20 years. Recent studies from Denmark suggest that, according to the duration of pancreatitis, the risk of cancer may be greater. Other complications Pancreatic pseudocysts are among the most common complications and occur in about a quarter of patients. Cysts may develop in the course of an exacerbation (‘acute-​on-​chronic pancreatitis’) or as a result of ductal disruption or obstruction. Depending on the size, location, and whether the content is sterile or not, pseudocysts may be asymptomatic. Larger cysts may give rise to pain, gastric outlet obstruction, or biliary obstruction. Biliary obstruction may also be caused by a benign stricture of the intrapancreatic portion of the common bile duct. Vascular complications include portal and splenic vein thrombosis in case of recurrent or ongoing acute in- flammation and, rarely, an acute bleeding from a pseudoaneurysm, which is mostly located in the wall of a pseudocyst. Differential diagnosis The M-​ANNHEIM diagnostic criteria classification system ranks the probability of a patient having chronic pancreatitis into three categories; definite, probable, or borderline (Box 15.26.2.1). When obvious risk factors are involved and characteristic mor- phological features are present (i.e. pancreatic duct dilation and calcifications), the diagnosis of chronic pancreatitis does not pose much of a challenge. In advanced cases, however, the possibility of concurrent pancreatic cancer must always be considered, in particular when a patient with previous stable disease develops new symptoms such as weight loss, jaundice, or diabetes. The M-​ANNHEIM clinical staging system for chronic pancreatitis is shown in Table 15.26.2.2. A challenging disease entity that is increasingly being recognized is so-​called early chronic pancreatitis. These patients have symp- toms resembling pancreatic-​type pain, but without morphological or functional abnormalities of the pancreas. In such cases, EUS may be helpful to establish a diagnosis of ‘early chronic pancreatitis’ (see ‘Clinical investigations’). Autoimmune pancreatitis is a unique form of pancreatitis. Type 1 autoimmune pancreatitis is the classical form, histologically characterized as ‘lymphoplasmacytic sclerosing pancreatitis’ and part of a systemic relapsing–​remitting immune-​mediated fibroinflammatory IgG4-​related disease, which can involve mul- tiple organs (i.e. biliary tract, kidneys, and salivary glands) and re- lapses frequently. Type 2, or ‘idiopathic duct-​centric pancreatitis’, is histologically characterized by granulocyte epithelial lesions, with few or no IgG4-​positive cells. The diagnosis of autoimmune pancreatitis is challenging. In some cases, it may resemble the clin- ical presentation of pancreatic cancer. It has a dramatic response to immunosuppressive medication, with quick resolution of as- sociated symptoms. Nevertheless, many patients develop chronic pancreatitis-​like features, including pancreatic duct abnormalities and glandular atrophy. After a median follow-​up of 6 years, about half of the patient still use immunosuppressive medication to pre- vent relapses and exocrine and endocrine insufficiency are highly prevalent, 82% and 57% respectively. In patients presenting with isolated exocrine insufficiency but without abdominal pain, the Shwachman–​Diamond syn- drome must be considered, which is the second most common cause for exocrine pancreatic insufficiency in children, after cystic fibrosis. Box 15.26.2.1  M-​ANNHEIM diagnostic criteria of chronic pancreatitis The diagnosis of chronic pancreatitis requires a typical clinical history (such as recurrent pancreatitis or abdominal pain, except for primary painless pancreatitis) Based on these features, three forms are defined: Definite chronic pancreatitis Definite chronic pancreatitis is established by one or more of the fol- lowing additional criteria: 1 Pancreatic calcifications 2 Moderate or marked ductal abnormalities (according to the Cambridge classification) 3 Marked and persistent exocrine insufficiency, defined as pancreatic steatorrhea markedly reduced by enzyme supplementation 4 Typical histology of an adequate histological specimen Probable chronic pancreatitis Probable chronic pancreatitis is established by one or more of the fol- lowing additional criteria: 1 Mild ductal alterations (according to the Cambridge classification) 2 Recurrent or persistent pseudocysts 3 Pathological test of pancreatic exocrine function (such as faecal elastase-​1 test, secretin test, or secretin–​pancreozymin test) 4 Endocrine insufficiency (i.e. abnormal glucose tolerance test) Borderline chronic pancreatitis Borderline chronic pancreatitis is already established and is defined by a typical clinical history of the disease, but without any of the add- itional criteria required for a definite or probable diagnosis. This form is also established as a first episode of acute pancreatitis with or without (1) a family history of pancreatic disease (i.e. other family members with acute pancreatitis or pancreatic cancer) or (2)  the presence of M-​ANNHEIM risk factors. Pancreatitis associated with alcohol consumption Pancreatitis associated with alcohol consumption requires in addition to the above-​listed criteria, one of the following features: 1 History of excessive alcohol intake (>80 g/​day for some years in men, smaller amounts in women), or 2 History of increased alcohol intake (20–​80 g/​day for some years), or 3 History of moderate alcohol intake (<20 g/​day for some years)

section 15  Gastroenterological disorders 3222 Clinical investigation Imaging Transabdominal ultrasonography is a rapid, noninvasive, and in- expensive diagnostic tool, but not well suited to diagnose chronic pancreatitis. It lacks sensitivity and specificity, in particular in less advanced cases. CT allows for a comprehensive diagnostic evaluation of the pan- creas and surrounding organs. The diagnosis and staging of chronic pancreatitis relies on the presence and severity of dilatation of the pancreatic duct and its side branches, pancreatic calcifications, and parenchymal atrophy (Fig. 15.26.2.1). It is also helpful to screen for complications, such as pseudocysts, portosplenic venous throm- bosis, arterial pseudoaneurysms, and pancreaticopleural fistulas. It is also useful to exclude other nonpancreatic abnormalities. MRI is a sensitive and specific diagnostic tool for the diagnosis of chronic pancreatitis and its complications. There are many different MRI techniques, conventional and more experimental methods, including perfusion MRI and diffusion-​weighted MRI. The latter technique has the potential to diagnose chronic pancreatitis at an early stage as it can measure the diffusion of water molecules, which is likely to be diminished in the case of fibrosis. Parenchymal fea- tures of chronic pancreatitis on conventional MRI include abnormal (a) (c) (d) (b) Fig. 15.26.2.1  CT series in a patient with chronic pancreatitis. A large obstructing intraductal stone is visible in the main pancreatic duct within the pancreatic head ((a), arrow) with upstream dilation and an associated pancreatic pseudocyst ((b), arrow). In the pancreatic tail, multiple stones are visible both in the main pancreatic duct as well as within the pancreatic parenchyma ((c, d) arrows). Table 15.26.2.2  M-​ANNHEIM clinical staging of chronic pancreatitis Asymptomatic chronic pancreatitis 0: subclinical stage a: period without symptoms (determination by chance, e.g. autopsy) b: acute pancreatitis—​single episode (possible onset of chronic pancreatitis) c: acute pancreatitis with severe complications Symptomatic chronic pancreatitis I: stage without pancreatic insufficiency a: (recurrent) rcute pancreatitis (no pain in between episodes)* b: recurrent or chronic abdominal pain (including pain in between episodes of acute pancreatitis) c: I a/​b with severe complications II: stage of partial pancreatic insufficiency a: isolated exocrine (or endocrine) pancreatic insufficiency (without pain) b: isolated exocrine (or endocrine) pancreatic insufficiency (with pain) c: II a/​b with severe complications III: stage of painful complete pancreatic insufficiency a: exocrine and endocrine insufficiency (with pain, e.g. requiring pain medication) b: III a with severe complications IV: stage of secondary painless disease (burnout) a: exocrine and endocrine insufficiency without pain or severe complications b: exocrine and endocrine insufficiency without pain, but with severe complications

15.26.2  Chronic pancreatitis 3223 decreased signal intensity on fat-​suppressed T1-​weighted images and delayed and limited enhancement after contrast administration. Its diagnostic accuracy can be augmented by using hormonal stimu- lation of the pancreas by means of intravenous secretin to stimu- late exocrine secretion in order to search for subtle changes in the pancreatic ductal system caused by early periductal fibrosis, and by quantitatively measuring pancreatic fluid excretion into the duo- denal lumen using multislice fast T2-​weighted sequences to evaluate the exocrine pancreatic function. EUS may be particularly sensitive to detect early morphological changes in chronic pancreatitis. Ductal and glandular features that are suggestive of early fibrosis include hyperechoic foci, strands, in- creased lobularity, hyperechoic duct margins, and atrophy. In the Rosemont EUS classification for early pancreatitis, the likelihood of (early) chronic pancreatitis is based on the presence of minor criteria, including cysts, dilated ducts 3.5  mm in size or greater, irregular pancreatic duct contour, dilated side branches of at least 1 mm, hyperechoic duct wall, strands, nonshadowing hyperechoic foci, and lobularity with noncontiguous lobules, and major fea- tures, including hyperechoic foci with shadowing, main pancreatic duct calculi, and lobularity with honeycombing (Table 15.26.2.3, Fig. 15.26.2.2). Long-​term follow-​up will reveal whether this con- cept of early chronic pancreatitis, based on the presence of EUS criteria, holds. Pancreatic function tests Pancreatic function tests can be divided into direct and indirect tests, the former being dependent on direct hormonal (secretin) stimulation of the pancreas, and into noninvasive and invasive tests, the latter involving oral intubation. The oral intubation test, with collection of pancreatic secretions by means of duodenal fluid aspiration, is the most sensitive test and able to detect subtle im- pairment of pancreatic function before clinical symptoms have developed. However, the test is cumbersome and available only in selected tertiary referral centres where it is mainly used for research purposes. Generally, indirect noninvasive pancreatic function tests are used, including faecal trypsinogen, faecal elastase, 13C/​14C-​octanoate breath test, or faecal fat measurements. The latter is a test of fat (mal)digestion and not a pancreas-​specific function test. Overall, indirect pancreatic function tests are not very sensitive and usu- ally become positive when a patient has already developed clinical symptoms of maldigestion. False-​positive test results occur when, for example, faecal elastase measurements are performed in watery stools. Measuring faecal fat excretion is useful to quantity the de- gree of maldigestion. For a reliable assessment of the fecal fat ab- sorption coefficient, it is important to collect stool for 2 to 3 days after a run-​in period of 2 to 3 days while using a diet with a fixed fat intake between 80 and 100 g/​day. Management Abstinence from alcohol and smoking Alcohol and smoking are important factors in the initiation and disease progression of chronic pancreatitis. Often, physicians fail to discuss the negative impact of smoking. Both alcohol and smoking cessation should play a prominent role in chronic pan- creatitis treatment. Apart from giving information and support, patients should be encouraged to enrol in a substance abuse treat- ment programme. Pain relief Analgesics Most patients with chronic pancreatitis require analgesics. Acetaminophen and nonsteroidal anti-​inflammatory drugs are first line, but pain is often debilitating and half of the patients will require opioids. To prevent substance abuse in this susceptible patient group, tramadol, a less strong synthetic opioid derivate, may serve as an alternative. Other drug treatments Several drugs other than analgesics have been advocated for pain relief in chronic pancreatitis patients, but without solid evidence. Table 15.26.2.3  Diagnosis of (early) chronic pancreatitis based on the Rosemont criteria (EUS diagnosis of chronic pancreatitis should be made in the appropriate clinical setting) I. Consistent with chronic pancreatitis A. 1 major A feature and ≥3 minor features B. 1 major A feature and 1 major B feature C. 2 major A features II. Suggestive of
chronic pancreatitisa A. 1 major A feature and <3 minor features B. 1 major B feature and ≥3minor features C. ≥5 minor features (any) III. Indeterminate for chronic pancreatitisa A. 3 to 4 minor features, no major features B. major B feature alone or with <3 minor features IV. Normal ≤2 minorb features, no major features a Diagnosis requires confirmation by additional imaging study (ERCP, CT, MRI, or pancreatic function test). b Excludes cysts, dilated main pancreatic duct, hyperechoic nonshadowing foci, dilated side branch. Adapted from Catalano MF, et al. (2009). EUS-​based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc, 69, 1251–​61. Fig. 15.26.2.2  EUS features of ‘early’ chronic pancreatitis; hypoechoic foci without shadowing (1), hyperechoic strands (2), and lobularity with honeycombing (three or more contiguous lobules) (3).

section 15  Gastroenterological disorders 3224 Pancreatic enzyme replacement therapy to treat pancreatic-​type pain is still widely used. The presumed rationale is its capacity to decrease duodenal cholecystokinin release, resulting in a lower hor- monal drive to stimulate pancreatic enzyme secretion and hence, a lower intrapancreatic pressure. A meta-​analysis of six randomized controlled trials showed no benefit. Two trials, however, studying non-​enteric-​coated preparations, as opposed to enteric-​coated pre­ parations, demonstrated some positive effect. Therefore, if one considers a pancreatic enzyme preparation to ameliorate pancreatic-​ type pain, one should prescribe a non-​enteric-​coated preparation in combination with a proton pump inhibitor to prevent early gastric denaturation of lipase. Antioxidants, such as methionine, vitamin C, and selenium have also been advocated. The underlying theory is based on studies showing increased oxidant stress, dietary insufficiency of antioxidants, and reduced antioxidant capacity in chronic pancreatitis patients. A  recent review assessed 12 randomized trials and concluded that antioxidants reduce pancreatic pain to some extent, but that the clinical relevance of this small re- duction is uncertain and more evidence is needed. Finally, octreotide, a synthetic somatostatin analogue, has been tried in the management of chronic pancreatitis pain, with insufficient supporting data. Other medical interventions Medical treatment is often unable to offer satisfactory pain relief. Sometimes, temporary placement of a feeding tube can result in an effective pancreatic ‘rest’. EUS-​guided coeliac plexus block or neurolysis are less ef- fective in chronic pancreatitis than in pancreatic cancer. They provide a transient effect (2–​4 months) in about half of the pa- tients. Nevertheless, this may form a welcome break in a patient having debilitating pain. It appears that surgical thoracoscopic splanchnicectomy provides similar pain relief to endoscopic coeliac plexus interventions, but randomized trials are lacking. As pancreatic duct obstruction is considered to play a key role in the development of pain, ductal drainage has become standard treatment for patients with painful obstructive chronic pancreatitis. An obstruction may be caused by strictures, ductal stones, or both, and can be decompressed either surgically or endoscopically. In contrast to biliary obstruction, decompression is not considered to be indicated in the absence of symptoms. Endoscopic pancreatic duct drainage The aim of endoscopic drainage is to decompress the pancreatic duct and restore outflow of pancreatic juices into the duodenum. It involves sphincterotomy, extracorporeal shock-​wave lithotripsy of pancreatic duct stones, removal of stone fragments, and dilatation of strictures by means of temporary stent insertion (Fig. 15.26.2.3). There is sufficient data to conclude that endoscopic pancreatic duct drainage is technically feasible and safe. Morbidity is observed in 6 to 58%, but most complications are stent related and easy to treat. Prospective studies comparing different techniques are practically nonexistent. Fibrotic pancreatic duct strictures are typically resilient and re- quire rigorous dilation therapy by means of long-​term stenting. For this, the European Society of Gastrointestinal Endoscopy (ESGE) recommends use of a 10 FG plastic stent, tailored to the shape of the pancreatic duct and the length of the stricture. To prevent compli- cations, planned stent exchanges are recommended every 6 months. If possible, it is recommended to insert a cumulative number of stents to increase the dilatation force. Even more aggressive dilation may be achieved by larger-​diameter self-​expandable metal stents. Although still in an experimental phase, studies with pancreatic duct self-​expandable metal stents have shown promising results, with success rates up to 86%. Intraductal stones are found in 32 to 90% of patients presenting with chronic pancreatitis and hence, endoscopic shockwave litho- tripsy has become a cornerstone of endotherapy. Not only does it improve outcomes, it also expands the scope of endoscopic drainage as most ductal stones are impacted and too large (>7 mm) to be removed without fragmentation. Complications are rare and the reported morbidity varies between 5 and 10% (most fre- quently acute pancreatitis). Mortality seems extremely low; only two studies have reported procedure-​related deaths. However, it is notable that extracorporeal shock-​wave lithotripsy is not a simple procedure:  it requires general anaesthesia, multiple procedures, specialized equipment, and experience. Whether stone fragments need to be removed during a consecutive endoscopic retrograde cholangiopancreatography (ERCP) remains to be resolved. The only prospective study on this subject showed no advantage of stone clearance. The ESGE guidelines, however, recommend that (a) (c) (d) (b) Fig. 15.26.2.3  Patient with calcifying obstructive chronic pancreatitis and opioid-​dependent pain. (a) Pancreaticogram after extracorporeal shock wave lithotripsy showing a highly abnormal pancreatic duct with a severe stricture in the pancreatic head after removal of stone fragments. (b) Dilation of the pancreatic duct stricture with an 8-​mm dilation balloon. (c) The patient underwent progressive stenting of the pancreatic duct stricture for a period of 12 months with a maximum of three 10 FG stents. (d) Pancreaticogram after stent removal after 1 year showing adequate dilation of the stricture. The clinical response was good. The patient could stop using opioids and had mild intermittent pain responsive to the use of paracetamol.

15.26.2  Chronic pancreatitis 3225 this restrictive policy of not removing stone fragments should be reserved for expert centres only. Surgical treatments Surgery for chronic pancreatitis is well documented, with favourable perioperative morbidity and mortality when compared to equivalent procedures for neoplasms. Surgical treatment encompasses decom- pression (drainage) and various resection procedures, or a combin- ation of both. An obvious advantage of a drainage-​only procedure is the preservation of functional pancreatic tissue. In contrast, when the pancreatic head is enlarged, a combination of decompression and head resection is often advocated. As such, the ‘motor of the disease’ is removed, which may attenuate the disease course. A tail resection may be performed in the case of a segmental (obstructing) chronic pancreatitis of the pancreatic tail (Fig. 15.26.2.4). The most definitive surgical treatment is a total pancreatectomy with islet autotransplantation to prevent diabetes. In the largest series to date of 409 consecutive recipients, pain relief was accom- plished in 85%, while the endocrine pancreatic function was pre- served in 94% of those who received more than 300 000 islets. As this technique requires islet-​cell isolation facilities, it will remain limited to expert centres and is still considered a procedure of last resort. Timing and choice of pancreatic duct
drainage procedures The only two prospective randomized trials comparing endoscopic and surgical drainage concluded that surgery was superior, at least in patients with complex disease and a combination of strictures and stones. Cahen et al. reported pain relief in 32% of the patients assigned to endoscopic drainage, as compared with 75% of the group assigned to surgical treatment. However, this does not necessarily write off endoscopic pancreatic duct drainage. It may well be that chronic pan- creatitis patients with less complex pathology benefit from endoscopic treatment at an earlier disease stage, but this remains to be proven. The latest ESGE guidelines state that endoscopic drainage should be considered the first-​line intervention. Although it is acknow- ledged that surgery provides better pain control according to ran- domized trials, it is stated that based on certain prognostic factors, such as stones located in the head, absence of strictures, a short disease duration and discontinuation of alcohol and tobacco, those patients can be identified with a potentially favourable response to endoscopic therapy. This should be followed by multidisciplinary response evaluation. Pain relief must be assessed 6 to 8 weeks after endoscopic drainage and unresponsive patients should be referred for surgery. When stricture resolution is not accomplished after (a) (c) (b) Fig. 15.26.2.4  Patient with segmental chronic pancreatitis of the tail. (a) CT showing the pancreatic body (1), an intraductal stone (2), and an atrophic pancreatic tail with a dilated pancreatic duct (3). (b) Magnetic resonance cholangiopancreatography showing an irregular and dilated pancreatic duct in the tail (1) and a normal pancreatic duct in pancreatic head and body (2). In between these, a stricture is visible. (c) Surgical resection specimen showing the intraductal stone with periductal fibrosis. Courtesy of Dr. B. Groot Koerkamp, Dept. of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

section 15  Gastroenterological disorders 3226 a treatment period of 1 to 2 years, patients should be advised to undergo definite surgical treatment. The typical surgical patient has had a 5-​ to 10-​year history of chronic pancreatitis, including chronic pain, prior to their oper- ation. Rather than subjecting patients to years of pain, chronic an- algesic use, and multiple endoscopic procedures, several studies suggest that early surgery may mitigate disease progression, prevent the development of intractable and difficult-​to-​treat pain, and pre- serve pancreatic function, all leading to a substantial improvement in quality of life. Further prospective studies are required. Treatment of pancreatic insufficiency Exocrine insufficiency In exocrine insufficiency, pancreatic enzyme supplementation can prevent steatorrhea-​related symptoms and malnutrition. The individual enzyme dose varies according to the remainder pan- creatic function and the dietary fat content. Generally, dosages range from 25 000 to 75 000 units of lipase for a main meal and 10 000 to 25 000 units for snacks. Patients should be instructed to vary their dose according to their fat intake and to increase the dose in case of ongoing steatorrhea-​related symptoms and weight loss (up to a maximum of 400 000 units of lipase per day). It is important to stress that, in principle, patients should main- tain a normal diet without fat restriction. Because malnutrition is common and optimal usage of pancreatic enzyme preparations confusing, patients should be referred for dietary counselling. Every patient with chronic pancreatitis should be screened regu- larly for vitamin deficiencies and a decreased bone mass (by per- forming bone densitometry). Endocrine insufficiency Patients with chronic pancreatitis should also be monitored for pancreatogenic or type 3c diabetes. In pancreatogenic diabetes, hyperglycaemia typically manifests in the postprandial state and may be overlooked. In the latest European Pancreatic Club and International Association of Pancreatology recommendations, use of the oral glucose tolerance test is advocated apart from annual de- termination of fasting glucose and haemoglobin A1c levels. There is no consensus on the treatment of pancreatogenic dia- betes and prospective studies examining the effects of different glucose-​lowering agents are lacking. Generally, insulin regimens are considered to be most effective, despite an increased risk of hypogly- caemia, due to reduced counter-​regulation by glucagon. Management of other complications Biliary obstruction An estimated 3 to 23% of patients with chronic pancreatitis de- velop common bile duct obstruction, either because of acute in- flammatory oedema or due to a fibrotic stricture. Biliary drainage is always indicated, regardless of obstructive symptoms, to prevent secondary biliary cirrhosis. Fibrotic strictures related to chronic pancreatitis are difficult to treat. Success rates using plastic stents vary between 10 and 40%. If endoscopic therapy is chosen, an ag- gressive approach should be taken with cumulative insertion of an increasing number of stents at each 3-​monthly scheduled ERCP. When a stricture has not resolved after 1 year, the chance of endo- scopic resolution has become practically nil and the patient should be referred for surgery. Currently, fully covered self-​expandable metal stents seem a promising treatment alternative to use of (a) (e) (c) (d) (b) Fig. 15.26.2.5  EUS-​guided drainage of a pancreatic pseudocyst. (a) A large pseudocyst in the head of the pancreas punctured under EUS guidance with a 19 G EUS needle. (b) Under fluoroscopic control, a long guidewire is introduced into the pseudocyst. (c) The cystogastrostomy tract is dilated with an 8-​mm dilation balloon. (d) Endoscopic view of the first pigtail plastic stent being positioned with its distal end into the cyst and its proximal end into the stomach. (e) Fluoroscopic image of two pigtail stents internally draining the pancreatic pseudocyst.

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

15.3 Methods for investigation of gastroenterologi

15.3 Methods for investigation of gastroenterological disease 2734

15.3.1 Colonoscopy and flexible sigmoidoscopy 2734

15.3.1 Colonoscopy and flexible sigmoidoscopy 2734

CONTENTS 15.3.1 Colonoscopy and flexible sigmoidoscopy  2734 James E. East and Brian P. Saunders 15.3.2 Upper gastrointestinal endoscopy  2740 James E. East and George J. Webster 15.3.3 Radiology of the gastrointestinal tract  2748 Fiachra Moloney and Michael Maher 15.3.4 Investigation of gastrointestinal function  2757 Jervoise Andreyev 15.3.1  Colonoscopy and flexible sigmoidoscopy James E. East and Brian P. Saunders ESSENTIALS Colonoscopy involves full oral bowel preparation and planned examination of the whole large bowel, while flexible sigmoidos- copy is usually performed after a phosphate enema and visualizes only the rectum and left colon. In expert hands, after appropriate explanation to the patient (which increases the chances of the pro- cedure being well tolerated), and (usually) some form of ‘conscious sedation’, total colonoscopy is possible in 98 to 99% of cases in the absence of obstruction, a severely ulcerated colon, or other contraindication. The indications for colonoscopy are wide and constantly ex- panding, and are likely to continue to do so until alternative less invasive techniques (‘virtual colonoscopy’ or genetic tests) are per- fected. Common indications include patients with or requiring (1) bleeding, anaemia, or occult blood loss; (2) chronic diarrhoea or known inflammatory bowel disease, which is accurately and easily assessed by endoscopy and biopsy; (3) polyps that can be removed endoscopically; and (4) surveillance for cancer preven- tion. Therapeutic colonoscopy now allows resection of almost all benign colonic polyps and some very early cancers as well as dila- tation of anastomotic or Crohn’s disease strictures and stenting of malignant strictures. Introduction Colonoscopy involves full oral bowel preparation and planned examination of the whole large bowel, while flexible sigmoidos- copy is usually performed after a phosphate enema and visualizes only the rectum and left colon. In expert hands, after appropriate explanation to the patient (which increases the chances of the procedure being well tolerated), and (usually) some form of ‘con- scious sedation’, total colonoscopy is possible in 98 to 99% of cases in the absence of obstruction, a severely ulcerated colon, or other contraindication. Equipment Colonoscopes range from 60 to 70-​cm flexible sigmoidoscopes or thin, very flexible paediatric instruments also used in adults with fixation or stricturing, up to 165-​cm colonoscopes with dif- ferent flexibility characteristics and instrumentation channel sizes. Further technical improvements include higher resolution, zoom magnification, better control ergonomics, adjustable shaft flexibility, image enhancement, and magnetic imaging of shaft loops without fluoroscopy. Thin ultrasound probes for use with conventional in- struments, and other more advanced technologies are available in specialist centres. A large range of accessories can be introduced through the suc- tion/​instrumentation channel of a colonoscope, including biopsy or grasping forceps; washing, spraying, or deflation tubes; cytology brushes; and injection needles. Therapeutic accessories include bi- opsy forceps, polypectomy snares and retrieval devices, cutting wires, endoscopic knives, coagulating forceps and argon plasma co- agulating catheters, laser light guides, haemostatic clip and nylon loop applicators, dilating balloons, and metal stent introducers. CO2 15.3 Methods for investigation of gastroenterological disease

15.3.1  Colonoscopy and flexible sigmoidoscopy 2735 insufflation apparatus has become a standard of care as the gas is exhaled within 10 to 15 min and ensures that patients are not left distended and uncomfortable after the procedure. Cleaning and disinfection As for all flexible endoscopes, skilled maintenance, regular checks, and meticulous cleaning are essential. All parts, including air, water, and instrumentation channels, must be accessed during cleaning. It is not possible to sterilize a colonoscope but scrupulous mechanical cleaning and ‘high-​level disinfection’ rapidly inactivate viral agents (including HIV and hepatitis B and C) and bacteria. However, myco- bacterial spores require prolonged disinfection agents and may be present in patients with HIV/​AIDS, thus mandating invariably high standards of disinfection. Even with purpose-​built washing ma- chines, designed to perfuse the various channels of an endoscope, it can take up to an hour to clean and disinfect an instrument, so mul- tiple colonoscopes are required to provide a routine service. Almost all accessories are now ‘single-​use’ disposables but any others require equally rigorous cleaning and autoclave sterilization or high-​level disinfection. Prions are not removed by ‘high-​level disinfection’ and hence instruments must be quarantined when they have been used for ‘invasive’ endoscopy, including biopsy, in a patient known to have or to be at risk of variant Creutzfeldt–​Jacobs disease; how- ever, ‘invasive’ procedures in a patient at risk of variant Creutzfeldt–​ Jacobs disease due to receipt of pooled plasma concentrates is no longer deemed to confer a high risk of endoscope contamination and standard decontamination is acceptable. Patient preparation Psychological Psychological preparation of the patient should not be forgotten, since most of those scheduled for colonoscopy are apprehensive, whether through embarrassment, expected discomfort, or fear of colorectal cancer. Explanatory literature and a friendly telephone manner at the time of booking the exam can help a great deal. Equally, a warm and reassuring atmosphere on reception, while obtaining informed consent, and also during the procedure, can help transform colonoscopy from an ordeal into a reasonable and well-​tolerated experience. Bowel preparation Flexible sigmoidoscopy preparation is normally by disposable enema (hypertonic phosphate or similar) given or self-​administered 30 min before the procedure. Some patients prefer to avoid the in- dignity of an enema by taking full oral preparation and this is also advisable in any patient with a colon narrowed by pronounced di- verticulosis or stricturing. Full bowel preparation is usually the most unpleasant part of col- onoscopy. Oral preparation must be preceded by dietary restric- tions, which include stopping iron or constipating agents in the preceding days and a low-​fibre diet (with no nuts, mushrooms, or iron-​containing red wine) for at least 24 h. Fluid overload is the commonest approach, usually achieved by ingestion of 3 to 4 litres of isotonic polyethylene glycol–​electrolyte solution, which avoids electrolyte losses. Various commercial poly- ethylene glycol–​electrolyte combinations exist, flavoured and pack- aged for posting. However, up to 10% of patients become nauseated, vomit, or become distended and stop drinking, which can result in poor preparation, especially in the proximal colon. A new low-​ volume 2-​litre polyethylene glycol preparation with ascorbic acid has recently been shown to be better tolerated and equally effective as the traditional 4-​litre polyethylene glycol preparation. Purgative preparation is a very cheap and well-​tolerated alterna- tive, although a few individuals can suffer cramping, incontinence, or vasovagal reaction. After the dietary restrictions previously de- scribed and senna or bisacodyl tablets on the afternoon before examination, a litre of isotonic osmotic laxative (commonly magne- sium citrate) is drunk followed by other clear fluids. Drinking con- tinues up to the time of the procedure to avoid solidification in the proximal colon, which can result in adherent residue that is difficult to flush or aspirate. Recently, the use of ‘split-​dose’ bowel preparation has been ad- vocated in international guidelines whereby approximately half the dose of preparation is given on the day of the procedure, with the rest the day before. This consistently improves bowel preparation and is now the standard of care. If there is any possibility that the patient is obstructed, full oral preparation is contraindicated because of the possibility of per- foration; a smaller volume should be given, supplemented by en- emas. In the presence of massive bleeding it may be preferable to proceed directly to colonoscopy, relying on the purgative effect of blood rather than wasting time on preparation. Nasal-​tube lavage is an alternative compromise before emergency colonoscopy (with the angiography team alerted in case adequate views prove impossible). Medication There is surprisingly wide variation around the world in attitudes to colonoscopy. In certain countries with enough anaesthetists avail- able (France, Australia), propofol anaesthesia is routinely employed. In others (Japan, China) and many institutions in Scandinavia, Germany, or northern Italy, unsedated colonoscopy is the norm. Fashions and opinions change and the trend is to some form of medication. Conscious sedation ‘Conscious sedation’ is offered to most patients in the United Kingdom, unless they are likely to be easy to examine (flexible sig- moidoscopy, previously easy examination, male sex, sigmoid resec- tion, or stoma) or are motivated to manage without medication in order to leave rapidly afterwards or to drive home. To generalize, women have longer colons and are more likely to suffer without sed- ation. The unpleasant gnawing quality of ‘visceral pain’ caused by the inevitable stretching of colon or attachments during insertion is, in a tolerant patient, quite manageable for a few spells of 20 to 30 s. The 50:50 mixture of nitrous oxide and oxygen (Entonox) has been introduced into many endoscopy units as a short-​acting inhaled an- algesic to help with these short episodes of pain, especially at flexible sigmoidoscopy; however, prolonged examinations or the sensitivity of patients with irritable bowel syndrome can be much helped by a minimal dose of a sedative–​analgesic combination. Combining a low dose of benzodiazepine (typically, midazolam 2–​3 mg, intra- venously), with an opiate analgesic (e.g. fentanyl 25–​100 μg, intra- venously) reduces discomfort and anxiety and gives the patient a well-​deserved feeling of euphoria. Low-​level sedation of this kind

section 15  Gastroenterological disorders 2736 does not inhibit conversation or the ability to complain of pain or to change patient position when necessary. Smaller doses should be given in older or sick patients but incremental larger doses (espe- cially opiates) can be needed in apprehensive younger ones. Pulse oximetry monitoring and nasal oxygen is routine, and resuscitation equipment and reversal agents (flumazenil, naloxone) should be im- mediately accessible. Sedated patients should be accompanied home. General anaesthesia General anaesthesia is rarely needed and has the disadvantage that an unconscious patient cannot change position spontaneously, and also that removal of the warning given by pain may tend to more aggressive techniques. However, physician-​administered ‘propofol sedation’ is increasingly advocated in the United States of America and Germany and undoubtedly, in patients with particular reasons for anaesthesia, propofol gives excellent results with rapid recovery compared to high doses of conventional sedation. Antispasmodics Antispasmodics are decried by many on the basis that they are thought to elongate the colon and make insertion more difficult, but an atonic colon may allow more accurate steering and less need for gas distension reducing looping during insertion. Randomized trials assessing benefits of Buscopan for adenoma detection during with- drawal are conflicting but we routinely use hyoscine N-​butyl bromide to speed insertion and optimize the view during examination. Antibiotics The use of antibiotic prophylaxis prior to colonoscopy or flexible sigmoidoscopy to prevent endocarditis has been abandoned in new guidelines, even for patients previously considered at high risk, for example, those with previous endocarditis, both in the United Kingdom and in the United States of America. Specific cases may still need prophylaxis, such as those with severe neutropenia. Procedures Flexible sigmoidoscopy Although rigid sigmoidoscopy (a misnomer as it usually only exam- ines the rectum) is commonly still practised in colorectal outpatient clinics, it provides only limited views in the unprepared upper rectum. Flexible sigmoidoscopy after enema bowel cleansing is the kindest and most logical means of examining proximal to the rectosigmoid junction (15 cm), whereas the distal rectum and anal canal are well, and in skilled hands often better, seen with a rigid instrument. In the presence of severe diverticular disease, it may be impossible to reach even the mid-​sigmoid region without expertise and a thin endoscope. After hysterectomy, adhesions may make it uncomfortable to examine without sedation. For this reason, al- though flexible sigmoidoscopy is both better tolerated and more accurate and effective than aggressive, rigid proctosigmoidoscopy, depth of insertion should be limited to what is tolerable by the indi- vidual patient. Some endoscopists mistakenly attempt to reach the splenic flexure routinely. Without fluoroscopy or magnetic endo- scope imaging, even expert endoscopists can be completely mis- taken between the sigmoid-​descending junction and the splenic flexure. At 60 cm of insertion the tip of the instrument can be any- where between the mid-​sigmoid and the hepatic flexure, and there are no positive localizing landmarks. Insertion usually follows digital lubrication with jelly, the blunt tip of the instrument being inserted as the sphincters relax. Thereafter the instrument is coaxed in, as gently as possible, without haste or force, steering and corkscrewing around bends with twisting move- ments. Forceful insertion with loss of visualization, guesswork, and blind ‘push through’ are all avoided as far as possible. Any small polyps (up to 6 mm) that may be adenomas are normally snared at once, as they may be difficult to see on withdrawal (when the colon has been shortened and convoluted) or if left for subsequent col- onoscopy. Because of the remote possibility of explosive gas con- centrations after limited preparation, either repeated suction with air reinflation or use of CO2 should precede electrosurgery; alterna- tively, ‘cold snaring’ with physical removal of the polyp can be used. The use of flexible sigmoidoscopy for colorectal cancer screen­ ing has increased following three recent, very large, random- ized, population-​based studies in the United Kingdom, Italy, and the United States of America reporting that one-​off flexible sig- moidoscopy prevents left-​sided colorectal cancer and colorectal cancer-​related death. This level of evidence is not yet available for colonoscopy. Total colonoscopy In expert hands, and in the absence of obstruction, a severely ulcer- ated colon, or other contraindication, total colonoscopy is possible in 98 to 99% of cases, with little sedation or suffering and virtually no complications. In less expert hands, ‘total colonoscopy’ or ‘com- pletion’ rates as low as 75% have been reported. The principal differ- ence in technique between expert and inexpert is the ability, while keeping sufficient orientation for steering purposes, to pull back and crumple the segment of colon already traversed, and simultaneously straighten the way or bend ahead. The ideal is to keep the colono- scope as straight as possible and to pleat or ‘concertina’ the colon over it, avoiding the unnecessary loops and pain caused by pushing too hard or too long. The ideal is not always immediately achievable, so patience and determination—​tempered by humanity—​are essen- tial qualities for the colonoscopist (see Video 15.3.1.1). Paradoxically, a freely mobile colon, without the conventionally fixed segments in the descending and ascending parts, can be as dif- ficult to traverse as one with adhesions. This is principally because atypical loops may form, sometimes uncontrollable until the instru- ment tip eventually reaches a fixed point, which gives a ‘hold’ and allows the shaft to be straightened back. Happily, this type of long and mobile colon, although a nightmare for the endoscopist, typic- ally also has long attachments so that the patient experiences little discomfort. From the point of view of the patient, colonoscope stretch dis- comfort is felt as ‘wind pain’, rapidly relieved as soon as the causative loop can be straightened. True overdistension is easily removed by aspiration. Once the colonoscope has successfully passed into the descending colon and has been straightened back to remove sigmoid colon looping, it is likely that the rest of the insertion phase will be con- siderably easier. When the colonoscope shaft is straight, it feels re- sponsive and free, as do the angling controls: the more looped the colonoscope is, the less responsive the instrument becomes, and the

15.3.1  Colonoscopy and flexible sigmoidoscopy 2737 more the patient suffers. Avoiding looping and responding to pain are the basis for successful, kind, and safe insertion. Good technique also minimizes instrument repair bills and maximizes accuracy and ease of targeting lesions, since a straight instrument handles better. This practical philosophy underlies the reason for simple but effective ‘tricks of the trade’ such as position change. It is obvious that in the left lateral position there will be pooling of any fluid in the left colon; the transverse colon will also tend to sag down and so make the splenic flexure more acute. It therefore follows that, where there is a poor view or difficulty in insertion, position change may improve matters (to supine or right lateral at the splenic, but back to left lateral again for the hepatic flexure). Adding only the simple principles of pulling back as often as possible to straighten each loop before tackling the next, avoiding overdistension to keep the bowel reasonably deflated and supple, and trying hand pressure from an assistant whenever an unavoidable loop may be accessible (sigmoid and transverse colon), the art of colonoscopy is explained. Insensitivity, impatience, or aggression results in the endoscopist being too muscular and tense to handle the shaft and controls sen- sitively, and so more likely to cause needless looping, pain, failure, and complications. CT colonography and capsule colonoscopy CT colonography (‘virtual colonoscopy’) is an alternative for in- complete colonoscopy, for those with significant comorbidities, or for patients who prefer not to have colonoscopy. The diagnostic performance appears similar to colonoscopy in meta-​analysis for cancer and polyps 1 cm or larger in size, but less good for smaller polyps or flat lesions. Capsule colonoscopy, whereby a double-​ended videocapsule endoscope is swallowed after bowl preparation, is another alterna- tive (PillCam COLON 2). This provides video images as the capsule tumbles through the colon and appears to have similar diagnostic performance for larger adenomas and cancers as colonoscopy, but is less good for significant sessile serrated polyps and smaller lesions. Approximately 10% of capsule examinations are unreadable due to inadequate preparation or failure of the capsule to transit the whole colon. Colonoscopy remains the criterion standard for whole-​colon examination. Indications The indications for colonoscopy are wide and constantly expanding, and are likely to continue to do so until alternative, less invasive tech- niques (virtual colonoscopy or genetic tests) are perfected. Where there is a shortage of endoscopic personnel, skill, or facilities it is possible to reduce the load of total colonoscopy by cross-​referring for CT imaging. It is also possible to combine CT with prior flexible sigmoidoscopy on the same visit, on the basis that limited colonos- copy covers the highest yield area, which is also the most prone to missed diagnosis or overdiagnosis. Gastrointestinal bleeding High-​yield indications include patients with bleeding, anaemia, or occult blood loss. Persistent bleeding, especially if dark or mixed in with the stool, is of sinister import, although it may be due only to local mucosal traumatization in diverticular disease. Good clinicians may select out for sigmoidoscopy patients with obvi- ously fresh bleeding on defecation or with spotting on toilet paper. However, the presence of blood in a patient aged 50 years or more (so at risk for colorectal neoplasia) is increasingly used as an ex- cuse for the reassurance of a whole-​colon screening examination. Of all patients with blood loss referred for colonoscopy, around 10% will have a ‘significant’ lesion, either a neoplastic polyp of 1 cm diameter or greater or malignancy. Colonoscopy is considered the investigation of choice for major bleeding, being readily available and offering immediate therapy and a high degree of diagnostic ac- curacy. Angiodysplasia, small ectatic vascular lesions in the prox- imal colon of older people with bleeding or anaemia, is relatively rare but is an example of a condition easily diagnosed and treated by colonoscopy (Fig. 15.3.1.1). Diarrhoea and inflammatory diseases Chronic diarrhoea or known inflammatory disease is accurately and easily assessed by endoscopy and biopsy (Fig. 15.3.1.2). The terminal ileum can be accessed in more than 80% of cases by an experienced endoscopist. Endoscopic differential diagnosis be- tween the focal or aphthous ulcers with intervening normal mucosa in Crohn’s disease and the generally reddened surface of ulcerative colitis is easy and definitive in around 90% of cases. A few remain as ‘indeterminate colitis’ and differential diagnosis can be more dif- ficult in severe or chronic cases. The possibility of infective colitis, including tuberculous or amoebic, must be borne in mind and extra specimens taken for microscopy and culture if in doubt. Biopsies typically show a somewhat greater extent of inflammation than is visible to the eye, and so must be taken at intervals around the colon in any patient with bowel frequency to exclude microscopic colitis (collagenous or lymphocytic). Chronic inflammatory bowel disease affecting more than one-​half of the colon carries an increased long-​ term risk of cancer or mucosal dysplastic (precancerous) change, and so indicates intermittent surveillance from 8 to 10 years after onset of symptoms. Ischaemic colitis, typically affecting a short seg- ment around the splenic flexure, can show changes ranging from mild reddening to marked ulceration or even near gangrene. Fig. 15.3.1.1  Angiodysplasia in the right colon. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2738 Polyps Polyps of almost any size can be removed endoscopically (Fig. 15.3.1.3, Video 15.3.1.2). Removal of very large sessile polyps in the distal rectum, for which transanal proctological manage- ment has been indicated, was traditionally not attempted by endoscopists but these are now manageable by endoscopic sub- mucosal dissection, with superior view and greater safety. The place of laparoscopic removal or a combined approach for large sessile polyps in the proximal colon is in evolution. Otherwise even overtly malignant polyps or polypoid cancers with no ad- enoma present can be managed by endoscopy alone if complete removal is confirmed histologically and histological factors are favourable (well-​ or moderately well-​differentiated tumour, no lymphovascular invasion, <1 mm of invasion below the muscularis mucosae). Around 5 to 10% of polyps will contain focal, high-​grade dys- plasia or invasive carcinoma but are endoscopically removable. Placing one or more sterile carbon tattoos near a polypectomy site gives a permanent marker for endoscopic follow-​up, or localizes it if surgery or laparoscopy becomes indicated by the histology results. Lasers were previously used for ablation of postpolypectomy rem- nants, but the alternative of argon plasma coagulation is cheaper, easier, and safer. Surveillance Cancer prevention or surveillance colonoscopy gives a good guar- antee to the patient, even when negative, both because of the accuracy of colonoscopy and the generally slow time course of de- velopment of colonic neoplasms (Fig. 15.3.1.4). Follow-​up at 3-​ to 5-​year intervals after polypectomy yields further (usually small) adenomas in 30 to 50% of patients, especially those with three or more, or large, polyps on the initial examination. There is reason- able evidence to suggest that the incidence of colorectal cancer is significantly reduced by polypectomy and follow-​up, but occasional breakthrough cancers occur and any bleeding or suggestive symp- toms should be reported. Patients at genetic risk merit colonoscopic surveillance, especially those with a first-​degree relative with (a) (b) Fig. 15.3.1.2  Colonoscopic appearance of (a) normal colon and (b) inflamed colon. From Keshav SC (ed) (2008). Medical masterclass: Module 8, Gastroenterology and hepatology, 2nd edition. London: Royal College of Physicians. Fig. 15.3.1.3  Cold snaring diminutive adenoma. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press. Fig. 15.3.1.4  Colon cancer. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press.

15.3.1  Colonoscopy and flexible sigmoidoscopy 2739 colorectal cancer under 45 years of age, two or more affected first-​ degree relatives, or those assessed genetically as belonging to a Lynch syndrome (hereditary nonpolyposis colon cancer) family with autosomal dominant risk (see Chapter  15.16). Follow-​up, ablating minute or ‘flat’ adenomas, is scheduled at intervals of 1 to 5 years according to perceived individual risk. Other indications Abnormalities found on other diagnostic methods, when checked colonoscopically, frequently turn out to be spurious—​presumably faecal. Most positive occult blood tests prove to be false positive for neoplasm. Other findings, such as anastomotic strictures, typ- ically after Crohn’s resection, are usually easily and effectively di- lated by the endoscopist using a ‘through-​the-​scope’ balloon. Even patients with typical malignant ‘applecore’ strictures should ideally have preoperative total colonoscopy to exclude other synchronous neoplasms, if necessary using a small-​diameter instrument (some- times a paediatric gastroscope). If this proves impossible, colon- oscopy should be rescheduled within 6  months after resection. Colonoscopy has effectively supplanted diagnostic laparotomy and avoids the numerous resections previously performed for diver- ticular disease when the radiologist ‘could not exclude the possibility of malignancy’, which the endoscopist can achieve in a few minutes. Low-​yield indications There are low-​yield indications for colonoscopy, where alternative in- vestigations such as flexible sigmoidoscopy or ‘virtual colonoscopy’ may be justified. These include patients with simple constipation of long standing, bloating, left iliac fossa discomfort, or combinations of these symptoms suggesting ‘irritable bowel syndrome’. In many patients, the extra accuracy and therapeutic potential of one-​off col- onoscopy may be justified. In older patients, however, the greater like- lihood of diverticular disease and difficult (therefore more hazardous) colonoscopy is a disincentive compared to the rapidity and safety of scanning. Contraindications, risks, and limitations There are few contraindications to colonoscopy. It is, however, a rela- tively strong vasovagal assault with potential for arrhythmias and so is contraindicated for 2 to 3 months after myocardial infarction. The tip, shaft, and air pressure involved in insertion have potential to exacerbate any existing risk of perforation. Colonoscopy is thus contraindicated in the acute phase and 2 weeks after an episode of diverticulitis and in severe acute or deeply ulcerated colitis of any variety (ulcerative, Crohn’s, ischaemic, or infective). Patients with acute localized or rebound tenderness of the abdomen, free air, or dilated colon on radiography should not be submitted to colon- oscopy without special reason, due consultation, and by an expert endoscopist—​who may decide to abandon the procedure. The risks of diagnostic colonoscopy, as implied earlier, are to a great extent related to the training, personality, and manual skills of the endoscopist. Regrettably, large-​scale audit shows figures of around 1 perforation in 1500 to 2000 examinations, whereas in specialist centres complications are exceedingly rare. The overall figures can be justified by the avoidance of the morbidity and mortality of surgery. Therapy inevitably increases the likelihood of complications, principally bleeding but occasionally perfor- ation after polypectomy or dilatation. Perforation may be actual (perhaps needing surgery) or threatened as the ‘postpolypectomy syndrome’ (managed conservatively with rest and antibiotics). Immediate bleeding can occur in around 1% of polypectomies but is usually easily stopped by submucosal adrenaline injection or by local electrocoagulation, clipping, or nylon loop application. Delayed haemorrhage can occur up to 14 days after removal or local coagulation of even small polyps; it is usually self-​limiting, but can be substantial and require admission to hospital and trans- fusion. Aspirin is no longer considered a risk factor but antiplatelet agents such as clopidogrel should be stopped for a week before and after polypectomy. Anticoagulants should similarly be discon- tinued or special measures instituted. The greatest causes of colonoscopy-​related mortality (1 in 10 000 examinations) are patients referred (not always correctly) for sur- gery following endoscopic complications and deaths directly due to oversedation, usually in older people. There have been unnecessary deaths when a physician has persisted in conservative management without involving a surgeon in management of suspected perfor- ation. Surgical fatalities or major morbidity have resulted in other patients found at operation to have sustained only a point perfor- ation, which would clearly have sealed spontaneously. In managing suspected perforation, due consultation between endoscopist and an endoscopically aware, preferably laparoscopy-​oriented, sur- geon is essential. The endoscopist should not be too proud to abandon an examination which is proving unreasonable, rather than to oversedate the patient; it is safer and kinder to change to CT colonography (‘virtual colonoscopy’) to image the unexamined proximal colon, ideally during the same visit. The major limitations of colonoscopy relate to the fact that it is dependent on manual skills and that tortuous, angulated, and haustrated colonic anatomy results in some blind spots for the endoscopist. Areas that the endoscopist sees are extremely accur- ately evaluated, with a resolution of less than 1 mm. The percentage of mucosa unseen is uncertain but is probably around 10 to 15% overall. The likelihood of larger and ‘significant’ lesions being missed is much lower than this because colonic neoplasms are usually pro- tuberant. Paradoxically, pathology can be missed in the capacious distal rectum or the anal canal, which can be avoided by retroverting the endoscope and/​or examining with a rigid proctoscope as well. Cost-​effectiveness and relationship to
other techniques Flexible endoscopy seems superficially expensive and is demanding of professional time. However, modern colonoscopes are surpris- ingly robust and, properly handled and maintained, will perform thousands of examinations without expensive repairs. Newer teaching methods, including the use of computer simula- tion and imaging techniques that do not use X-​rays, should help to improve manual skills and instrument handling and speed up the training and assessment of doctors or nurse practitioners performing colonoscopy or flexible sigmoidoscopy. There has been shown to be considerable variation between endoscopists in detecting adenomas, which translates into increases in postcolonoscopy cancers and death from postcolonoscopy cancers for poor detectors; hence, quality

15.3.2 Upper gastrointestinal endoscopy 2740

15.3.2 Upper gastrointestinal endoscopy 2740

section 15  Gastroenterological disorders 2740 assurance is essential and international efforts to encourage audit and set key performance indicators are underway. Colonoscopists should be aware of their own adenoma detection rates. Flexible endoscopy leaves only gas (air or CO2) in the colon, and can immediately be followed by scanning if incomplete. Total colonoscopy, its accuracy increasing to near microscopic levels with newer and more agile instruments, is likely to remain the diagnostic ‘gold standard’ for the foreseeable future. However, evolving newer methods such as virtual colonoscopy by scanning will be more acceptable to some patients and so have an invalu- able role in screening and selection, in spite of their lack of tissue diagnosis or therapy. Since endoscopy can check an abnormal scan immediately, it is quite likely that colonoscopy will lose some of its present front-​line diagnostic role. Nonetheless, it is equally likely that requirements for colonoscopy will increase overall as population screening for colorectal cancer prevention becomes an accepted routine. FURTHER READING Allison MC, et al. (2009). Antibiotic prophylaxis in gastrointestinal endoscopy. Gut, 58, 869–​80. Atkin W, et al. (2010). Once-​only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised con- trolled trial. Lancet, 375, 1624–​33. Corley DA, et al. (2014). Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med, 370, 1298–​306. Johnson DA, et al. (2014). Optimizing adequacy of bowel cleansing for colonoscopy: recommendations from the US multi-​society task force on colorectal cancer. Gastroenterology, 147, 903–​24. Waye JD, et  al. (eds) (2009). Colonoscopy:  principles and practice. Wiley-​Blackwell, Oxford. 15.3.2  Upper gastrointestinal endoscopy James E. East and George J. Webster ESSENTIALS Endoscopy is the procedure of choice in patients with retrosternal or upper abdominal symptoms who require investigation, and is essential in significant gastrointestinal bleeding to identify and—​ in most cases—​treat the cause, with various therapeutic methods possible for erosions, ulcers, and oesophageal varices. More recent developments in the practice of upper gastro- intestinal endoscopy include the use of enteroscopy for direct vision of the small bowel, video capsule endoscopy for diag- nosis of obscure bleeding lesions, and an expanding range of minimally invasive therapeutic techniques. Endoscopic retro- grade cholangiopancreatography is the standard of care for the removal of gallstones from the common bile duct, and palliating obstructing pancreatobiliary tumours. Introduction Development of endoscopes Flexible fibreoptic endoscopes were developed in the mid 1960s, leading to the growth of gastrointestinal endoscopy as we now know it. The recent availability of cheaper, miniaturized charge coupled devices (video chips) has led to the development of video endo- scopes, providing an excellent clear view that does not deteriorate with age (as it does with fibreoptic devices). The external specifications and handling of the new video endo- scopes are similar to their earlier fibreoptic counterparts and thus the techniques for disinfection and endoscopy are similar for both ranges of equipment. The disadvantage of the modern equipment is that the video endoscopy system needs considerable hardware. In most instances, a video monitor, a light source, and a processor are located in an endoscopy unit and are less easily moved to a different location such as the intensive therapy unit or operating theatre for emergency endoscopy. With improvements in video processors and endoscopes, the endoscopic video image can be magnified:  modern instruments will zoom up to 100 times magnification, and mucosal detail can also be enhanced electronically so that small lesions a few milli- metres in size can be seen quite clearly. The modern video endo- scope image can be instantly printed out or archived digitally on a computer system. The latest types of high-​definition endoscope, processor, and monitor can also be used for two new techniques, narrowed spectrum endoscopy (narrow band imaging, Fujinon intelligent colour enhancement, and iScan) and autofluorescence imaging. Narrowed spectrum endoscopy enhances the visualization of mu- cosal patterns and microcapillaries in the superficial mucosa with short-​wavelength (blue light) illumination using optical or digital filters. This enhances the visualization and diagnosis of otherwise poorly identifiable lesions. Autofluorescence imaging utilizes the property of short-​wave light in the blue area of the spectrum to ex- cite green autofluorescence from normal mucosa, predominantly from collagen. Thickening of the mucosa by malignant infiltration tends to inhibit this and abnormal tissue may fluoresce less, al- lowing for endoscopic detection of a subtle abnormality in a false colour image. Endoscopy units It is now well recognized that the care of the instruments and other equipment, together with the important aspects of patient safety, are greatly improved by having a purpose-​built endoscopy unit staffed by experienced endoscopic nursing staff who are trained in handling and disinfecting endoscopes and in patient safety during and after intravenous sedation. Most endoscopy units have a purpose-​built disinfecting machine which can take single or multiple instruments. After suitable mech- anical cleaning, a disinfecting agent will be automatically pumped through the channels of the instrument for a given period of time and flushed out afterwards. The choice of disinfecting agent varies between units but the trend has been away from hazardous agents such as glutaraldehyde (Cidex) to less harmful agents, such as Nu-​ Cidex, Tristel, or Sterilox, that do not need sophisticated extraction and ventilation.

15.3.2  Upper gastrointestinal endoscopy 2741 Endoscopy procedure For routine, straightforward diagnostic upper gastrointestinal en- doscopy, many patients are now routinely endoscoped without sed- ation, after local anaesthetic spray to the pharynx only. ‘Unsedated endoscopy’ is suitable for high-​throughput diagnostic services. The development of transnasal upper gastrointestinal endoscopy with slim (4–​5-​mm diameter) endoscopes has improved tolerability. However, large numbers of endoscopies, particularly in apprehen- sive or sick inpatients and those needing more complex procedures, are still performed under intravenous sedation. There are now clear guidelines, such as those drawn up by the British Society of Gastroenterology, for the practice of adminis- tering intravenous sedation for endoscopic procedures. Patients are now monitored with pulse oximetry and oxygen is given rou- tinely to ill or elderly patients, and to other patients if oxygen sat- uration falls during the procedure. The precise choice of sedation varies between units and will depend on the patient and the type of procedure performed; however, benzodiazepines (e.g. midazolam) are the most common sedative agents used, often combined with an opiate (e.g. fentanyl) for more lengthy or invasive procedures. On rare occasions, general anaesthesia will need to be used for endos- copy, usually for children or adults with ventilatory problems. There is an increasing trend in some countries for complex procedures to be performed under propofol anaesthesia. Endoscopic retrograde cholangiopancreatography (ERCP) particularly benefits from deep sedation. Specially trained anaesthetic nurses can administer this. Specific risks of infection with endoscopy Current disinfecting agents and schedules will eradicate hepatitis B and C and HIV. All endoscopic staff wear disposable gloves and the nurse nearest the patient’s mouth will usually wear a visor to cover eyes, nose, and mouth, particularly with a patient of known infective risk. As there is no effective way of sterilizing an endoscope against prions (at present thought to be the transmissible agent in variant Creutzfeldt–​Jakob disease (vCJD)), the current United Kingdom Department of Health guidelines make it clear that all equipment used for invasive endoscopic procedures, that is, not simple visually diagnostic procedures, on patients with known or suspected vCJD should be quarantined afterwards; however, ‘invasive’ procedures in a patient at risk of vCJD due to receipt of pooled plasma concen- trates is no longer deemed to confer a high risk of endoscope con- tamination and standard decontamination is acceptable. Patients with suspected or known vCJD therefore should not be endoscoped unless no alternative way of diagnosis or treatment is available. In the past, patients with heart murmurs or prosthetic valves were routinely given antibiotics to cover endoscopic procedures related to a perceived risk of endocarditis. However, international guide- lines now do not recommend prophylaxis for diagnostic procedures, which is reserved for ERCP, endoscopic ultrasound (EUS)-​guided cyst aspiration, those with neutropenia, and those undergoing per- cutaneous endoscopic gastrostomy (PEG). Diagnostic endoscopy of the upper gastrointestinal tract In recent years, it has become routine to take gastric biopsies in pa- tients with peptic problems to detect the presence of Helicobacter pylori. The routine use of a CLO test, where mucosal biopsies are inserted into a gelatin well containing a colouring agent that turns yellow to red in the presence of helicobacter urease is cheap and accurate (Fig. 15.3.2.1). In some patients with infection resistant to multiple eradication therapies, gastric biopsies may be needed in this situation for culturing the bacteria to ascertain sensitivity. In younger patients where malignant disease is less of a concern, serum, faecal, or breath test analysis is an acceptable alternative to establishing helicobacter infection and thus such patients could be treated initially without endoscopy and gastric biopsy, the so-​called test and treat strategy, saving resources. Most oesophagogastric cancers in the United Kingdom are diagnosed when the patient is symptomatic (Fig. 15.3.2.2, Video 15.3.2.1) and thus the finding of a mucosal cancer is rare. Endoscopists in Asia, however, commonly find mucosal gastric cancers, and these may be underdiagnosed in the West. Dysplastic lesions and early cancers in Barrett’s oesophagus are increasingly common. Although most lesions are straightforward to diagnose endoscopically and biopsies are usually confirmatory, more subtle early cancers can be found with high-​quality examination, making organ-​preserving endoscopic therapy possible. Missed or interval upper gastrointestinal cancers occur at a similar rate to those in the lower gastrointestinal tract (10% of all cancers found within 3 years of a normal gastroscopy), leading to a renewed interest in quality at upper gastrointestinal endoscopy. Cancers that infiltrate the wall of the stomach below the mucosa are difficult to diagnose endoscop- ically as endoscopic biopsies are usually quite superficial. In this situation, a ‘double-​punch’ type technique is useful, where a second biopsy is taken from the deeper submucosa through the small defect of the first biopsy. Linitis plastica is difficult to assess endoscopically, particularly where anticholinergic and other agents may have been used routinely to inhibit peristalsis at the start of the endoscopy. In such patients, cross-​sectional imaging with CT can demonstrate widespread gastric thickening. Fig. 15.3.2.1  A negative (top) and positive (bottom) CLO test result, obtained within 1 h of placing gastric biopsies on the test cards. From Medical masterclass, 2nd edition, RCP London (2008) with permission.

section 15  Gastroenterological disorders 2742 Small bowel endoscopy (push and balloon-​assisted enteroscopy) For many years, routine upper gastrointestinal endoscopes were not of sufficient length to pass beyond the duodenojejunal flexure into the small bowel. Enteroscopes are now made that can be advanced under direct vision down the upper small intestine or, alternatively, a paediatric colonoscope may be used. Direct visualization of the deep small bowel can be achieved using single-​ or double-​balloon enteroscopes, where a balloon on an overtube, and on the tip of the scope in the double-​balloon technique, allows the small bowel to be concertinaed over the enteroscope. Bidirectional approaches (oral and anal) can allow direct visualization, biopsy, and therapy to the entire small bowel in skilled hands. Sonde enteroscopy where a thinner endoscope is allowed to pass down the small bowel spon- taneously with the help of an inflated balloon and then the bowel lumen is visualized on withdrawal is now obsolete. Use of a standard upper gastrointestinal endoscope up and down the small intestine through small enterotomies at the time of laparotomy, with a sur- geon concertinaing the small bowel over the shaft of the endoscope to find bleeding points, is now rarely used and carries significant morbidity. Small bowel biopsy using a Crosby capsule has been completely superseded by routine upper gastrointestinal endoscopy with biop- sies from the distal duodenum. Such biopsies have been shown to be very representative of the upper jejunal mucosa. This technique is now used as standard in the diagnosis of coeliac disease. Video capsule endoscopy of the small bowel In the last decade, a new technique of visualizing the small intestine has been developed and, although relatively expensive, is now widely available and has revolutionized small bowel imaging. A small cap- sule containing a miniature video chip and transmitter can be swal- lowed by the patient or released at the time of endoscopy. Providing the small intestine has been cleared with a colonoscopy-​type bowel preparation, the capsule transmits individual images of high quality every 0.5 s to a receiver strapped on the abdomen. The capsule takes about 4 h to pass down the small intestine. This technique is particularly useful in the detection of superfi- cial mucosal lesions, such as angiodysplasia in obscure gastrointes- tinal bleeding or early Crohn’s disease, that might otherwise be undetected by X-​ray examination using barium, or CT or magnetic resonance enterography, and to guide use of the much more invasive balloon-​assisted enteroscopy. Caution is needed as capsules may get stuck in strictured small bowel, leading to intestinal obstruction. Endoscopic ultrasound The development of endoscopes with dual capability of endoscopic and ultrasound imaging has led to a growing range of applications for diagnostic and therapeutic EUS. Either a rotating or a fixed linear-​array transducer provides an ultrasound image at a point where the endoscopist can accurately direct the probe in the lumen of the oesophagus, stomach, or duodenum. Although CT scanning will stage most larger tumours of the upper gastrointestinal tract, pancreas, and bile duct, EUS is particularly useful in staging small tumours and mucosal tumours. The use of contrast media may enhance the EUS definition of discrete lesions. Therapeutic endoscopy of the upper gastrointestinal tract Over the last 30  years, a wide range of therapeutic manoeuvres have been developed for use in various situations in the upper gastrointestinal tract. Gastrointestinal bleeding Oesophageal and gastric varices (Fig. 15.3.2.3) can cause torren- tial bleeding and are now most commonly treated by endoscopic banding (Fig. 15.3.2.4). With this technique the varix is sucked into a cap on the tip of the endoscope and a tight elastic band slipped over the varix. Multiple bands can be applied to obliterate the variceal columns. Gastric varices are better treated by the use of cyanoacrylate glue or thrombin to obliterate the larger variceal Fig. 15.3.2.3  Oesophageal varices at risk of bleeding. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press. Fig. 15.3.2.2  Exophytic oesophageal adenocarcinoma causing stenosis and dysphagia.

15.3.2  Upper gastrointestinal endoscopy 2743 lumen. Sclerotherapy with ethanolamine oleate under direct vi- sion is now generally avoided due to the risk of secondary bleeding from mucosal ulceration and sometimes later oesophageal stric- ture formation. Bleeding erosions and ulcers can be injected with dilute adren- aline (1:10 000), but international guidelines now recommend dual therapy with the addition of a second technique, either multicontact diathermy probes or heater probes to coapt the vessel walls, or endo- scopic clips to provide mechanical tamponade. Bleeding vascular abnormalities, such as angiodysplasia, can be treated with thermal probes, endoscopic clips, or more recently with argon plasma coagulation. An ionized stream of argon gas provides a safe and predictable way of coagulation without direct contact with the mucosa, and although more costly, it is more ef- fective than simple touch diathermy devices and has replaced thermal laser coagulation. The most recent addition to the thera- peutic armamentarium for gastrointestinal bleeding are haemo- static powders delivered via a catheter, which can be useful for bleeding in difficult positions, for diffuse tumour bleeding, or as a rescue therapy. Benign oesophageal strictures Commonly, a peptic stricture above a hiatus hernia secondary to reflux will produce dysphagia but benign strictures due to other causes, such the swallowing of corrosive substances and postsurgical anastomotic strictures, can be treated by the same endoscopic tech- niques. In the past, bougies of increasing size were passed over a previously endoscopically placed guide wire and the stricture slowly dilated. More recently, high-​pressure dilating balloon catheters, passed directly through the scope under direct endoscopic vision, or over a wire under radiological screening, have been used. These are useful for short strictures, but there may still be a place for over-​the-​ wire bouginage in very long or complex strictures. Recurrent benign strictures can now be stented with removable covered metal mesh stents for 6 to 8 weeks to try to prevent restricturing. Biodegradable stents are being developed. Achalasia of the cardia can be treated with balloon dilatation using a larger balloon 30 to 40 mm in diameter, where the aim is to rupture muscle fibres to weaken the circular muscle sphincter. Alternatively, botulinum toxin can be injected through the mucosa into the muscle sphincter circumferentially at the time of endoscopy. The improvement in swallowing after this procedure is limited, and it may need to be repeated every 6 months. Malignant gastro-​oesophageal strictures Most patients with nonoperable tumours of the stomach or oe- sophagus producing dysphagia are palliated by the insertion of some sort of oesophageal stent. The older silicon rubber prostheses have been replaced by self-​expanding metal mesh stents which can be very easily and safely placed through a malignant stricture, often without the need for prior dilatation, thus reducing the risk of perforation. Most of these stents now have a membrane to prevent tumour in- growth through the mesh (‘covered stents’) but this will sometimes occur at one or either end. Such tumour overgrowth can be treated with argon plasma coagulation or restenting. Brachytherapy can be given via an endoscopically sited tube through the stricture before or after stenting. Postoperative anastomotic strictures after oesophagogastric re- section, sometimes associated with a leak, can now be managed with covered self-​expanding metal stents. The newer stents are po- tentially removable a few months later when the stricture and leak have sealed. Removal of foreign objects Most solid objects such as marbles, rings, and coins should pass spontaneously. The need for removing foreign bodies is usually be- cause they are sharp and may cause damage if left in situ. Most ob- jects can be snared or trapped in a basket and removed intact. Sharp objects can be pulled into an endoscopic overtube to protect the oe- sophagus from damage during removal. Polyps and mucosal cancers Most gastric polyps are entirely benign and do not need removing, but should be biopsied to confirm their benign nature. Leiomyomas of the stomach or duodenum can be watched if small, but if more than 5 cm in size should probably be removed. Endoscopic mucosal resection and endoscopic submucosal dissection Patients with larger mucosal tumours usually used to undergo open or laparoscopic surgery but newer endoscopic mucosal resection techniques can successfully curatively treat lesions that do not infil- trate beyond the submucosa. Careful prior assessment with EUS is sometimes needed to make sure that a small tumour can be technic- ally removed in this way. Lesions can be elevated by the submucosal injection of saline and then removed en bloc or piecemeal, as for polyps in the colon. This can be done for small mucosal cancers or dysplastic lesions in Barrett’s oesophagus or similar lesions of the stomach, duodenum, or ampulla of Vater. Newer accessories with a suction cap and banding device, similar to that used with varices, allow the mucosal lesion to be trapped and removed with a snare Fig. 15.3.2.4  Variceal band ligation: a tight rubber ring has been placed around the base of the varix. Note transparent cap is part of banding device. Courtesy Dr. Sreelakshmi Kotha, Royal Free Hospital, London.

section 15  Gastroenterological disorders 2744 without damage to the muscle layer and therefore with a lower risk of perforation. The technique of endoscopic submucosal dissection has become increasingly used for gastric mucosal dysplastic lesions, especially in the Far East, where the lesion is isolated with a modified endoscopic needle knife and resected en bloc, even for large lesions, reducing recurrence rates and providing definitive pathology. Ablative therapy Although endoscopic mucosal resection and endoscopic submucosal dissection can resect focal lesions effectively, in Barrett’s oesophagus a potentially large area of at risk columnar (Barrett’s) mucosa will remain. Repeated resection can lead to strictures; however, recently radiofrequency ablation balloon devices have become available. A radiofrequency balloon that tightly conforms to the oesophageal lumen is placed to cover the Barrett’s segment after resection of any nodular dysplastic areas. Radiofrequency energy is then applied to ablate the superficial Barrett’s mucosa, which then re-​epithelializes with squamous mucosa reducing but not eliminating future cancer risk. Other techniques such as argon plasma coagulation can be used to ablate smaller Barrett’s areas. Assisted nutrition There are now many types of enteral feeding tube that can be sited in the upper gastrointestinal tract. Although most fine-​bore feeding tubes can be passed on the ward or under radiological control, the prior passage into the stomach of an endoscopic guide wire that is then rerouted through the nose can allow feeding tubes to be posi- tioned accurately, often through an oesophageal stricture or difficult anastomosis, or positioned in the duodenum in patients with gas- tric stasis. The endoscopic positioning of a nasojejunal feeding tube, beyond the duodenojejunal flexure, is now becoming a common alternative to intravenous feeding in patients with complicated pancreatitis. Techniques for placing a gastrostomy tube endoscopically (PEG) are now routine and straightforward. After transabdominal puncture into a distended stomach under direct endoscopic vi- sion, a PEG tube with diameter from 8 to 24 F can be pulled back down the oesophagus through the stomach and a flange, balloon, or button will allow the tube to be anchored firmly up against the gastric mucosa. In patients where there is gastric stasis, or in pan- creatitis, a small jejunal extension tube can be inserted through the PEG tube and positioned endoscopically into the distal duo- denum or beyond the duodenojejunal flexure. Balloon-​assisted enteroscopy can be used to place percutaneous feeding tubes dir- ectly into the jejunum. Endoscopy and disorders of the pancreas and biliary tree Endoscopic retrograde cholangiopancreatography ERCP is performed using a combination of a side-​viewing duodenoscope (necessary to visualize the ampulla and access the pancreaticobiliary ducts on the medial wall of the duodenum), and a dynamic X-​ray (fluoroscopy) screening facility. Modern duodenoscopes are approximately 13 mm in diameter at the tip, with 120o four-​way tip angulation, and a 4.2-​mm working channel down which wires, contrast injection catheters, and stents, may be inserted. ERCP is an important tool in the care of patients with a range of problems, including bile duct stones, biliary stricturing diseases (e.g. primary sclerosing cholangitis, IgG4-​related cholangitis), malignant obstruction (e.g. pancreatic cancer, cholangiocarcinoma), and chronic pancreatitis (Fig. 15.3.2.5). Given the inherent risks associated with ERCP, and improved and alternative imaging modalities, ERCP should no longer be used as a diagnostic tool per se. Its primary role is in delivering therapy, at which time it may be used for tissue acquisition. Gallstones Gallbladder stones occur in 10 to 15% of the adult population, but remain asymptomatic in 80% of patients. Migration of stones into the bile duct (choledocholithiasis) may lead to obstructive jaundice, biliary colic, cholangitis, and acute pancreatitis. Bile duct stones require removal, and this is most usually performed through ERCP. Having positioned the tip of the duodenoscope within the duodenum, opposite the duodenal papilla (ampulla of Vater), a thin wire is passed through the sphincter and into the bile duct. Contrast dye is carefully injected into the duct to de- fine the exact number, site, and size of the bile duct stones. A dia- thermy cut is then applied through a wire on the end of the catheter (sphincterotome), which results in cutting through the ring of muscle within the ampulla (sphincterotomy). This may then allow the stones to be removed, by means of 8 to 15-​mm balloon trawls, or baskets (Fig. 15.3.2.6). Fig. 15.3.2.5  ERCP showing intrahepatic biliary strictures (bold arrow) and dilatation (dashed arrow) in IgG4-related sclerosing cholangitis. From Medical masterclass, 2nd edition, RCP London (2008) with permission.

15.3.2  Upper gastrointestinal endoscopy 2745 Large (>15  mm) stones may require additional approaches, including further balloon dilatation of the sphincter (e.g. 10–​18-​mm balloon sphincteroplasty) or baskets with metallic sheaths to crush the stones (mechanical lithotripsy). Difficulty in endoscopic stone clearance may relate to stone number, size (>10  mm), location (intrahepatic, within cystic duct, stones above strictures). For the approximate 10% of patients in whom stone clearance is not possible by conventional ERCP techniques, new innov- ations in cholangioscopy (small endoscopes, 3–​6 mm in diameter, which may be passed into the bile duct) allow direct visualization of stones, and intraduct laser or electrohydraulic lithotripsy are gaining wider use, and may avoid the need for surgical bile duct exploration. In patients with bile duct stones, cholecystectomy should be per- formed following ERCP and bile duct clearance. Sphincterotomy and pigtail stent insertion into the bile duct, alongside the stones, is an effective means to ensure relief of biliary obstruction and cholangitis. However, attempt should be made to clear the duct of stones, and biliary stenting (i.e. without duct clearance) is rarely an acceptable long-​term solution, except in the setting of extreme infirmity. A biliary leak may occur following 1 to 2% of cholecystectomies. This may occur from the cystic duct stump or relate to trauma to the bile duct or liver. ERCP may both define the site of leakage and allow closure of the leak by means of stent placement. Biliary strictures ERCP has an important role to play in the assessment and man- agement of biliary strictures. These may relate to a wide range of causes, which may be benign (e.g. postoperative anastomotic or iatrogenic strictures, primary sclerosing cholangitis, secondary to chronic pancreatitis) or malignant (e.g. cholangiocarcinoma, car- cinoma of head of the pancreas, hilar lymph nodes). Advancing the diagnosis may be achieved with noninvasive imaging (CT, mag- netic resonance cholangiopancreatography), and EUS, but ERCP remains central in most cases for endobiliary tissue acquisition and relief of biliary obstruction. Tissue acquisition Exfoliative biliary brush cytology has been the standard tech- nique for tissue sampling of biliary strictures at ERCP for more than 30 years. While providing high specificity (>95%), it carries low sensitivity (approximately 40%) for malignancy. Combining fluoroscopically directed endobiliary biopsies with brush cy- tology may improve sensitivity, as may additional tissue analysis techniques, such as fluorescence in situ hybridization, which uses fluorescently labelled DNA probes to evaluate the presence of chromosomal alterations. Direct intraductal visualization of strictures, using cholangioscopy, allows better targeted tissue sampling, and enhanced mucosal visualization techniques, such as confocal laser endomicroscopy, may help in the assessment of indeterminate strictures. Stricture management The management of biliary strictures depends on a range of fac- tors, including the stricture aetiology, site, complexity, and the ex- tent of biliary obstruction. ERCP plays an important role in the treatment of dominant biliary strictures (those causing significant obstruction, i.e. jaundice). a bb a c (a) (b) Fig. 15.3.2.6  Panel A: a duodenoscope is seen in position within the duodenum (a), from where a thin catheter is passed into the bile duct (b). Radiopaque contrast injection and X-​ray screening reveals multiple stones within the bile duct (arrows). Panel B: following cutting of the biliary sphincter using electrocautery (sphincterotomy), a balloon allows the stones to be cleared from the bile duct into the duodenum (c).

section 15  Gastroenterological disorders 2746 Balloon dilatation alone (using 4–​10-​mm balloons) may be an op- tion in some patients with known benign strictures (e.g. postsurgical stricture or primary sclerosing cholangitis), but biliary stenting is almost always required when strictures result in jaundice. A range of stents are available, with different indications. The wider a stent, the longer its likely patency. Straight plastic 6 to 18 cm long, 2 to 3 mm in diameter (7–​10 F) stents are inexpensive and effective, and may be used for strictures of any type, and at any location within the biliary tree. Stent patency is usually 3 to 6 months, hence these stents may be an appropriate choice for patients with malignant obstruction and expected poor prognosis. Biliary self-​expandable mesh metal stents are available, 4 to 10 cm long, 8 to 10 mm in diameter (Fig. 15.3.2.7). Fully covered self-​expandable mesh metal stents may be used to treat benign and malignant extrahepatic strictures (but not across the liver hilum, as they may block the contralateral liver ducts). They carry an ad- vantage of being removal up to 12 months after deployment. Fully covered self-​expandable mesh metal stents for benign disease may lead to stricture remodelling over 6 to 9 months, precluding the need for long-​term stenting or surgical management. Uncovered self-​expandable mesh metal stents should only be used in patients with known malignancy, who are not planned for surgery (as they are not generally removable), but provide good long-​term patency (>9  months). Tissue ingrowth through the stent, or overgrowth over the proximal end of the stent, can occur over time, requiring reintervention via ERCP. In patients with malignant stricturing at the liver hilum (e.g. cholangiocarcinoma), bilateral stents may be required, and the choice, location, and best route of deployment (i.e. ERCP or percutaneously) should be carefully coordinated through a spe- cialist multidisciplinary team. Pancreatic disease ERCP in patients with pancreatic disease should be confined to patients with clearly defined anatomical disease and significant symptoms, and these procedures should optimally be performed in specialist units. There may also be surgical options, which should be considered. In patients with chronic or recurrent pancreatitis, with pancreatic ductal obstruction due to a stricture or stone near to the ampulla, pancreatic sphincterotomy with stone removal or pancreatic duct stenting (5–​7-​F plastic stents) may be considered. Additional approaches to stone management, including extra- corporeal shock wave lithotripsy or intraductal lithotripsy, may be needed. Pancreatic fluid fistulae following acute pancreatitis, trauma, or surgery may sometimes benefit from ERCP and pancre- atic duct stenting. Drainage of peripancreatic fluid collections and pseudocysts may require EUS-​guided cystgastrostomy. Malignant duodenal obstruction Approximately 10% of patients with pancreatobiliary tumours will develop gastric outlet obstruction as a late complication, as tumour infiltrates the duodenum. While a surgical gastric bypass may relieve this obstruction, many patients are frail on presen- tation, with advanced malignancy, and avoiding surgery is op- timal. Uncovered self-​expandable mesh metal stents, 6 to 12 cm long, 20 to 22 mm in diameter, may be placed endoscopically using a therapeutic gastroscope/​duodenoscope, under direct vi- sion and fluoroscopic guidance. This may allow return to a soft or semiliquid diet, and a resolution of vomiting. c d a (a) (b) b Fig. 15.3.2.7  Panel A: a duodenoscope is seen in position within the duodenum (a), from where a balloon catheter is passed into the bile duct (b). Radiopaque contrast injection and X-​ray screening reveals a stricture of the bile duct (arrow) and pancreatic duct (dashed arrow), due to a tumour in the head of pancreas. Panel B: biliary obstruction is managed with a mesh metal biliary stent (c), deployed with distal flange in the duodenum (d).

15.3.2  Upper gastrointestinal endoscopy 2747 Endoscopic ultrasound Linear EUS and fine needle aspiration now plays a central role in the assessment of solid and cystic lesions within the pancreaticobiliary system. Using thin 18 to 22-​gauge fine needle aspiration needles, a definitive diagnosis may be obtained in 80 to 94% of solid pancreatic lesions. Larger core needles may provide formal histological samples, with high diagnostic yield. EUS now allows formal assessment of lesions within several centi- metres of the upper gastrointestinal tract, including oesophagus, mediastinum, gastric wall, retroperitoneum, pancreas, liver, gallbladder, and adrenal glands. EUS is increasingly being used for therapy, including coeliac plexus neurolysis for painful pancreatic disease, drainage of pancreaticobiliary collections (e.g. cystgastrostomy), targeted cancer therapies (e.g. placement of radiopaque fiducials to lo- calize radiotherapy, or EUS-​guided radiofrequency ablation), and drainage of obstructed pancreaticobiliary ducts, where not feasible through conventional endoscopy. Risks and complications of 
endoscopic procedures Risks associated with upper gastrointestinal endoscopy, EUS, and ERCP relate largely to issues of sedation, scope trauma during in- sertion, and complications specific to the particular intervention performed. Diagnostic upper gastrointestinal endoscopy carries very few risks. With careful attention to nursing techniques and sedation protocol, cardiorespiratory problems, such as hypoventilation or as- piration pneumonia, should be very rare, although they account for 60% of complications of upper gastrointestinal endoscopy. Perforation during diagnostic endoscopy occurs in approximately 1:10 000, and may relate to anterior osteophytes in the region of the cricopharyngeus, a malignant stricture, or an unrecognized pha- ryngeal or oesophageal pouch (a particularly hazard using the side-​ viewing duodenoscope). It carries a 2 to 36% mortality rate. Interventional upper gastrointestinal endoscopy The overall risk of oesophageal perforation following balloon or bougie dilatation of benign strictures is less than 2%, 2 to 5% for achalasia balloon dilatation, and up to 10% for malignant strictures. Endoscopic mucosal resection of oesophagogastric early neoplasia carries a 1 to 5% risk of bleeding/​perforation, but endoscopic sub- mucosal dissection, with en bloc resection, carries increased risks (2–​6% perforation, 11% bleeding). Oesophageal perforation may be suspected in the setting of pain or discomfort after oesophageal dilatation (palpable crepitus of the soft tissues of the neck, ‘surgical emphysema’, makes it a virtual cer- tainty), and is confirmed with an emergency CT scan. Management is by putting the patient nil by mouth, giving parenteral antibiotics, and intravenous feeding. Surgery or specialist endoscopic interven- tion may be necessary. PEG is associated with a 2 to 9% complication rate, including aspiration, free perforation, injury to internal organs (e.g. liver), wound infection, and 0.5% procedure-​related mortality (the overall 15% 30-​day mortality largely reflects underlying comorbidity linked to the indication for PEG placement). Endoscopic ultrasound Diagnostic EUS carries risks comparable with standard upper gastrointestinal endoscopy. Tissue or cyst sampling using fine needle aspiration is very safe, carrying less than a 1% risk of com- plications. The emerging field of interventional EUS is associated with increased risks of complications (10–​16% for EUS-​guided biliary or pancreatic duct intervention/​stenting), but this is likely to fall with experience. EUS-​guided cystgastrostomy carries a 2 to 10% risk of complications, most commonly bleeding, perforation, or infection. ERCP ERCP carries an overall 5% risk of complication, including post-​ERCP pancreatitis, bleeding, perforation, and infection. Pancreatitis may occur after any ERCP, irrespective of endosco- pist skill or experience, with the risk related largely to patient fac- tors. While the pancreatitis is mild/​moderate in the majority, it can be severe in 8 to 10%, and occasionally fatal. The useful adage that ‘ERCP is most dangerous in those who need it least’ reflects the 3-​ to 10-​fold increased risk of pancreatitis (to >20%) in cer- tain groups (e.g. female, <40 years, absence of jaundice, suspected functional pain), and reinforces the use of ERCP as a therapeutic, not a diagnostic, tool. While the use of prophylactic 5-​F plastic pancreatic stents may reduce the risks of postprocedural pancreatitis in high-​risk pa- tients, the most important recent change in practice is the uni- versal use of a single rectal nonsteroidal anti-​inflammatory suppository (e.g. 100 mg of indomethacin or diclofenac) at the time of ERCP. Significant bleeding occurs in less than 1% of patients, usually fol- lowing biliary sphincterotomy and inadvertent cutting of a branch of the gastroduodenal artery. Endoscopic haemostasis is usually achieved, but angiographic embolization, or even surgery, may rarely be necessary. Retroperitoneal perforation occurs in less than 1%, almost al- ways following sphincterotomy or balloon sphincter dilatation. It is difficult to diagnose clinically (CT is essential), and may present late with retroperitoneal abscess formation. It should be managed by putting the patient nil by mouth, intravenous antibiotics, radio- graphic drainage of collections, and parenteral nutrition until the perforation closes. Surgery is rarely indicated. Infection (usually cholangitis) following ERCP usually occurs due to inadequate biliary drainage. Prophylactic antibiotics are no longer indicated for all ERCPs, but should be given in cases where poor drainage may be predicted (e.g. primary sclerosing cholangitis, complex hilar biliary strictures), or in immunosuppressed patients, and should be given during/​after the procedure (and continued for 3–​5 days) if adequate drainage is not achieved. Cholangioscopy ap- pears to carry a slight increased risk of cholangitis (likely due to the need for retrograde fluid infusion), hence prophylactic antibiotics are given.

15.3.3 Radiology of the gastrointestinal tract 274

15.3.3 Radiology of the gastrointestinal tract 2748

section 15  Gastroenterological disorders 2748 FURTHER READING Allison MC, et al. (2009). Antibiotic prophylaxis in gastrointestinal endoscopy. Gut, 58, 869–​80. ASGE Standards of Practice Committee, et al. (2012). Adverse events of upper GI endoscopy. Gastrointest Endosc, 76, 707–​18. Dumonceau JM, et  al. (2014). Prophylaxis of post-​ERCP pancrea- titis:  European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy, 46, 799–​815. Veitch AM, et al. (2015). Optimizing early upper gastrointestinal cancer detection at endoscopy. Nat Rev Gastroenterol Hepatol, 12, 660–​7. 15.3.3  Radiology of the gastrointestinal tract Fiachra Moloney and Michael Maher ESSENTIALS The widespread introduction of endoscopic techniques has reduced the need for radiological examination of the intestinal tract and has almost completely rendered imaging of the stomach obsolete. There remains, however, a substantial role for radiological imaging in the investigation of the small and large bowel in the diagnosis of abdom- inal and gastrointestinal disease. The small intestine may be examined by a number of radio- logical techniques, including plain films, barium contrast studies, ultrasonography, CT, MRI, and nuclear medicine. Barium studies (follow-​through or small-​bowel enema) provide good morpho- logical detail of the mucosal surface of the bowel; cross-​sectional imaging (usually CT or MRI) is required for disease involving the wall of the bowel or outside it. CT is increasingly used as the pri- mary investigation in suspected bowel obstruction. Nuclear medi- cine studies have a role in the examination of the small bowel for the presence of inflammatory conditions, and for demonstration of potential bleeding sources. Colonoscopy has revolutionized imaging approaches to the colon because of its proven diagnostic efficacy and the added facility for biopsy of diffuse mucosal pathology and focal mucosal lesions, but is associated with a small risk of perforation. The use of barium enema continues to decline steadily. The advent of multidetector CT that allows three-​dimensional reconstruction has led to a large number of new applications, including virtual colonoscopy or colonography, use of which is steadily increasing and is particularly valuable in the setting of unsuccessful or incomplete optical colonoscopy, although it is disadvantaged by inability to perform biopsy. Introduction Traditionally, barium studies were the mainstay of gastrointestinal tract imaging. However, barium techniques are labour intensive, time-​consuming, sometimes technically demanding and unpleasant for the patient, and do not provide adequate extraluminal infor- mation and have thus largely been superseded by cross-​sectional imaging techniques, namely computed tomography (CT) and mag- netic resonance imaging (MRI). CT and MRI usually provide sat- isfactory luminal and mural information as well as detecting the presence of extraintestinal disease. Furthermore, there have been many technological advances in these imaging techniques in recent years including the development of enteric contrast agents that dis- tend the bowel, multiplanar and three-​dimensional imaging, and advanced imaging applications such as motility imaging, and radi- ation dose reduction techniques. An exception to the trend in the declining use of barium studies is the barium swallow. This technique is still commonly used in pa- tients intolerant of endoscopy and in the assessment of oesophageal function and motility (Fig. 15.3.3.1). Barium studies also have an important role in the evaluation of patients following gastrointes- tinal surgery to detect postoperative complications. Upper gastrointestinal endoscopy has effectively replaced radio- logical studies for imaging the stomach. Radiology continues to play a pivotal role in the investigation of small-​bowel pathology, as the small bowel is much less amenable to conventional endoscopy due to its length and tortuosity. The barium enema is the fluoroscopic procedure that has undergone the greatest decline in use with the emergence of CT colonography. This technique has a higher diagnostic accuracy than barium enema and may be used in patients intolerant of colonos- copy or as a screening tool. Fig. 15.3.3.1  Upright double-​contrast view of the oesophagus shows tapered, beak-​like narrowing of the distal oesophagus (arrow) due to incomplete opening of the lower oesophageal sphincter, with a standing column of barium proximally and slow emptying of barium into the stomach. There was no primary peristalsis in the body of the oesophagus at fluoroscopy. This constellation of findings is characteristic of achalasia. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.3.3  Radiology of the gastrointestinal tract 2749 Capsule endoscopy is a commonly used imaging technique that involves the ingestion of a pill camera that acquires high-​definition colour views of the bowel lumen. Although the technique provides excellent mucosal detail, it has a relatively high false-​positive rate (14%) due to mucosal breaks and erosions. In addition, it does not provide extraluminal information and its use is contraindicated in bowel obstruction and in patients with a history of bowel stric- tures. Many authorities advocate reserving capsule endoscopy for selected cases in which the suspicion of small-bowel disease re- mains high despite negative evaluations with endoscopy and radio- logical studies. The small bowel Small-​bowel imaging techniques CT enterography and enteroclysis CT enterography and enteroclysis can be used to image a spectrum of small-​bowel disorders including inflammatory bowel disease, coeliac disease, small-​bowel tumours, and bowel obstruction. Both techniques combine an enteral volume challenge with the advan- tages of modern multidetector CT scanners, which offer multiplanar and three-​dimensional reformatting capabilities with reduction in motion artefacts. CT enterography involves the oral administration of a neutral oral contrast agent approximately 1 hour prior to an abdominopel- vic CT examination. Patients are fasted for 8 to 12 hours prior to the study and drink 1.5 to 2 litres of oral solution. Neutral enteric contrast agents have similar attenuation properties to water (10–​20 Hounsfield units) and may include polyethylene glycol, mannitol, water–​methylcellulose solution, and milk, with polyethylene glycol being marginally favoured at many institutions. Reported side ef- fects include diarrhoea, vomiting, and abdominal cramps. CT enteroclysis involves inserting a nasojejunal tube under fluoroscopic guidance and infusing an enteral contrast agent at a controlled rate using an enteroclysis pump to a total volume of ap- proximately 2 litres. Postprocessing options with both techniques include multiplanar reformations and maximum intensity projections, which are useful to assess the mesenteric vasculature and highlight enhancing path- ology on coronal reconstructions. Although superior small-​bowel distension is routinely obtained with the enteroclysis technique, CT enterography has been found to be comparable in terms of diagnostic accuracy. Furthermore, given the invasive nature of the enteroclysis technique and the additional radiation exposure incurred during nasojejunal tube placement, CT enterography has become the preferred technique for the investiga- tion of suspected small-​bowel disease. CT lacks the mucosal detail of small-​bowel barium studies but pro- vides excellent depiction of the bowel wall and extraintestinal tissues. Other limitations include the need to administer intravenous contrast, possible poor toleration of the enteral contrast agent, and exposure to relatively high levels of ionizing radiation (up to 15 millisievert com- pared to 2 millisievert for a small-​bowel follow-​through). Exposure to ionizing radiation is a key consideration when decid- ing on the most appropriate imaging modality to investigate poten- tial small-​bowel disease. This is especially true in young patients and patients with chronic conditions such as Crohn’s disease that are at risk of high cumulative radiation doses from diagnostic imag- ing. Imaging modalities that do not involve exposure to ionizing ra- diation such as MRI and US should be used where possible in the first instance. However, CT is an appropriate technique when used judiciously in the correct clinical setting with consideration of the potential radiation dose to the patient and possible use of dose re- duction strategies to keep the dose as low as reasonably practical. Dose optimization strategies include limiting the number of imag- ing phases acquired, omitting unnecessary images at the peripheries of acquired series that do not contribute to diagnosis, and the use of modern image reconstruction techniques such as iterative recon- struction that reduce radiation dose while still acquiring diagnostic quality images (Fig. 15.3.3.2). Magnetic resonance enterography and enteroclysis MRI has many advantages that make it well suited for imaging the gastrointestinal tract: excellent tissue contrast, absence of ionizing radiation, and ultrafast sequences that facilitate the acquisition of real-​time cine sequences which can evaluate small-​bowel motility. The two imaging techniques most commonly used to achieve small-​bowel distension are magnetic resonance enterography with oral contrast administration and magnetic resonance enteroclysis with infusion of the contrast solution through a nasojejunal tube. Enteric agents are classified as being positive (gadolinium, manga- nese ions), negative (super-​paramagnetic iron oxides), or biphasic (water, polyethylene glycol) according to the signal intensity pro- duced on T1-​ and T2-​weighted images. Biphasic agents are the most commonly used and produce low signal on T1-​weighted images, which contrasts well to hyperenhancing inflammatory or neoplastic tissue on postgadolinium sequences (Fig. 15.3.3.3). As with CT en- teral contrast solutions, these agents may cause diarrhoea, vomiting, and abdominal pain. A routine MRI examination of the small bowel includes multiplanar T1-​ and T2-​weighted sequences, often supplemented by dynamic contrast-​enhanced sequences. Several new advanced imaging applications have been developed and investigated for small-​bowel imaging in recent years including diffusion-​weighted imaging, perfusion imaging, and motility imaging. Both diffusion and perfusion imaging have been shown to accurately discriminate normal from abnormal bowel, especially in inflammatory bowel dis- ease. Motility imaging, whereby real-​time short cine loops of bowel motility are acquired, are facilitated by several properties of MRI including a rapid acquisition time and absence of ionizing radiation (Fig. 15.3.3.4). Both MRI and CT frequently serve as a ‘one-​stop shop’ for imaging the small bowel offering satisfactory imaging of the bowel wall as well as the extraintestinal tissues. Compared with CT, MRI has su- perior contrast resolution and does not involve exposure to ionizing radiation, thus small-​bowel loops of interest can be reimaged sev- eral times until satisfactory assessment is achieved. Conversely, CT is more widely available and is less prone to motion artefact. A major disadvantage of CT, however, is that due to the limitation of radi- ation exposure, a single imaging acquisition can only be taken and thus distinction of small-​bowel stricture from normal peristalsis can sometimes be difficult. The choice of modality should be tailored to the individual patient with consideration of current guidelines. Both modalities are comparable in terms of diagnostic accuracy but given

section 15  Gastroenterological disorders 2750 the radiation dose incurred during a CT examination of the small bowel, MRI is recommended by most authorities as the preferred initial investigation. However, in the acute setting CT is frequently more appropriate. Barium studies There are two barium techniques that are utilized to image the small bowel: the barium follow-​through and the small-​bowel enema. The barium follow-​through involves the oral administration of a barium suspension followed by the acquisition of prone films every 20 to 30 min until barium reaches the terminal ileum. Fluoroscopic com- pression views of the terminal ileum to separate overlying small-​ bowel loops are then performed. For the small-​bowel enema technique, a nasojejunal tube is inserted and the barium suspension is infused to give better bowel distension. Patients are fasted prior to both procedures. Small-​bowel barium studies offer excellent mucosal detail at a lower radiation dose than CT. However, they provide very limited extraluminal information and patients often need to undergo fur- ther imaging with a cross-​sectional technique. Ultrasonography Ultrasonography offers many advantages when imaging the small bowel: absence of ionizing radiation, low cost, and the dynamic real-​ time nature of the technique provides high temporal resolution. The technique generally involves systematic scanning of the abdomen with the use of graded compression to displace air and overlying bowel loops with a low-​ to medium-​frequency ultrasound probe. Thickened, dilated bowel loops can often be identified but patient factors such as Fig. 15.3.3.2  Coronal reformatted images from a CT enterography in a 25-​year-​old female patient with Crohn’s disease. The left panel is from a conventional-​dose CT with standard reconstruction. The right panel is from a contemporaneously acquired low-​dose study performed at 18% of the conventional radiation dose study and reconstructed with pure model-​based iterative reconstruction. Both images demonstrate thickening of distal ileal loops with associated mucosal hyperenhancement and mesenteric fat stranding (arrows). An extraluminal abscess is clearly seen on both studies (arrowheads). Courtesy of Cork University Hospital, Cork, Ireland. Fig. 15.3.3.3  Coronal T1 fat-​saturation post-contrast magnetic resonance enterography in a 32-​year-​old male patient with Peutz–​ Jeghers syndrome demonstrates an ileoileal intussusception (arrow) secondary to an enhancing 4-​cm polyp (arrowheads); another polyp is also shown (arrowhead). Courtesy of Cork University Hospital, Cork, Ireland.

15.3.3  Radiology of the gastrointestinal tract 2751 obesity, guarding, and shadowing gas often limit complete evaluation. Furthermore, ultrasonography is operator dependent and may fail to identify disease in bowel loops located deep within the abdomen and pelvis and to detect complications such as fistulas and strictures. Contrast-​enhanced ultrasonography involving the intravenous injection of microbubbles and hydrosonography, whereby the small bowel is distended with oral contrast, are two additional ultrasound techniques that are gaining in popularity. Ultrasound elastography is a novel technique that exploits the fact that pathological processes have altered elastic properties. This change in elasticity is detected and im- aged using ultrasound elastography; this technique is currently under evaluation and may play a future role in small-​bowel imaging. Nuclear medicine The more commonly used nuclear medicine techniques in small-​ bowel assessment include labelled red and white cell studies, Meckel’s diverticulum scintigraphy, and position emission tomog- raphy (PET). Many of these play a role in patient assessment when the results of other modalities have been negative or equivocal. Scintigraphy with red blood cells involves labelling red blood cells with a radioactive substance that can be detected on a gamma camera to identify occult sites of gastrointestinal bleeding. This may be done in vivo, whereby the patient is administered 99mTc-​pertechnetate following an agent that reduces the radioisotope within the red blood cells or in vitro, whereby the binding process is performed after blood is taken from the patient and then reinjected. Bleeding rates of up to 0.1 ml/​min can be detected compared to 1 ml/​min for conventional angiography. Extravasated red blood cells within the small bowel lumen are identi- fied as a focus of activity that increases in intensity over time and moves along the expected anatomical course of the small bowel (Fig. 15.3.3.5). Labelled white cell scanning is another nuclear medicine tech- nique occasionally used in small-​bowel imaging to detect sites of inflammation. The labelling can be completed in vivo or in vitro and a number of agents including 99mTc-​pertechnetate and indium may be used. Meckel’s scintigraphy is performed to localize gastric mucosa in a Meckel’s diverticulum as a potential source of unexplained gastrointestinal bleeding. The technique involves the administra- tion of 99mTc-​pertechnetate with any radioactivity appearing at the same time as orthotopic gastric mucosa. Detection rates are often increased by the administration of pentagastrin, glucagon, or a H2 blocker around the time of the procedure. PET or hybrid PET-​CT with 18F-​FDG (fluorodeoxyglucose) may be used to detect the enhanced glucose metabolism associated with Fig. 15.3.3.4  Three consecutive images from a cine sequence acquired using a fast T2-​weighted steady-​state free procession imaging sequence in a 29-​year-​old male patient with Crohn’s disease. An apparent stricture (arrowheads) is seen to resolve (left panel to right panel) as it represents an area of peristalsis. Courtesy of Cork University Hospital, Cork, Ireland. Fig. 15.3.3.5  Fused images of a technetium red blood cell scan obtained by single-​photon emission CT show bleeding (arrows) in the right lower abdomen surgically proven to stem from within a Meckel’s diverticulum. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2752 inflammation, especially in patients with fever of unknown origin. 18F-​FDG can localize at sites of small-​bowel inflammation over the course of a few minutes. Radiological findings in small-​bowel disease Obstruction CT is the best investigation to diagnose the presence of small-​bowel obstruction and determine its cause, the key issue being to locate a transition point from distended (obstructed) bowel proximally to bowel that is normal or collapsed distally (Figs. 15.3.3.6 and 15.3.3.7). Crohn’s disease Crohn’s disease is a chronic, noncaseating granulomatous disease characterized by a chronic relapsing and remitting clinical course. Crohn’s disease may affect any part of the gastrointestinal tract from mouth to anus but in the majority of cases the small bowel is involved, especially the terminal ileum. Small-​bowel involve- ment is typically transmural with skip lesions being a character- istic feature. Imaging features of active Crohn’s disease include mural thick- ening (>3 mm), mucosal hyperenhancement, mesenteric inflam- matory fat stranding, strictures with proximal bowel dilatation, and prominence of the vasa recta (comb sign) (Fig. 15.3.3.8). Mural stratification is another feature on CT or MRI whereby hyperenhancement of the inner mucosal and outer serosal layers following intravenous contrast administration are separated by an interposed layer of lower attenuation/signal intensity submucosa which facilitates visualization of the bowel wall layers. The inter- vening submucosa may be of lower attenuation/signal intensity due to the presence of oedema in acute disease, fat in chronic dis- ease, or an inflammatory infiltrate. Ulceration is identified by clefts in the thickened bowel wall, which may penetrate the wall forming an abscess. Other extraenteric complications include bowel obstruction, bowel stricture, and sinus tract and fistula formation. Fistulas may Fig. 15.3.3.6  Small-​bowel obstruction from an adhesion. Intravenous contrast-​enhanced CT showing a small-​bowel obstruction with a transition point in the distal jejunum and abrupt change in calibre (arrow). To the left of the arrow the bowel is dilated; to the right, decompressed small bowel is seen. This was due to an adhesion. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.3.3.7  Small-​bowel obstruction from primary adenocarcinoma. Intravenous contrast-​enhanced CT showing a small-​bowel obstruction transition point that is abrupt, with no mass or distortion (arrow), but with circumferential rather than eccentric margins. This appearance is very nonspecific and could be due to an inflammatory or ischaemic stricture, nonsteroidal anti-​inflammatory drug diaphragm-​like stricture, or metastatic disease. In this case, it was due to a primary adenocarcinoma. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.3.3.8  Coronal T1 fat-​saturation post-contrast MR enterography image in a 23-​year-​old female patient with Crohn’s disease shows thickening with associated transmural enhancement of a long contiguous segment (20 cm) of the distal ileum (arrowheads) consistent with active inflammation. Courtesy of Cork University Hospital, Cork, Ireland.

15.3.3  Radiology of the gastrointestinal tract 2753 form between adjacent bowel segments, the anterior abdominal wall, vagina, and genitourinary tract. Features of chronic disease include fibrotic strictures, pseudosac­ culation, and submucosal fat deposition. Transmural extension of inflammation into the mesentery of the affected bowel segment in the acute phase resulting in asymmetric inflammation and fibrosis with pseudosacculation of the antimesenteric border is a hallmark feature. With long-​standing Crohn’s disease, there may be separ- ation of bowel loops due to fibrofatty proliferation of the perienteric and colonic fat. Findings in acute and chronic disease as well as extraenteric complications can be readily identified on both CT and MRI. Other associated conditions such as gallstones, sclerosing cholangitis, renal calculi, sacroiliitis, and adenocarcinoma may also be detected. Barium studies may demonstrate fold thickening, coarsening of the villous pattern, and aphthous ulceration, particularly along the mesenteric border. The gastrointestinal ‘string sign’ where luminal narrowing occurs secondary to fold thickening, oedema, spasm, and inflammation may also be seen. Tumours of the small bowel Small-​bowel tumours account for less than 5% of all gastrointestinal tract tumours. They may be classified as benign or malignant and often produce nonspecific clinical symptoms and signs resulting in delayed diagnosis. Benign These include benign gastrointestinal tumour (GISTs), hamar- tomas, and benign neuroendocrine tumours and adenomas and may present with bleeding or intussusception. A number of syn- dromes are associated with multiple small-​bowel polyps including Peutz–​Jeghers syndrome (multiple hamartomas) and Gardner’s syndrome (multiple adenomas). Malignant These include carcinoid, adenocarcinoma, lymphoma, gastrointes- tinal stromal tumours (GISTs), and metastatic disease. Presentation may be with bleeding, bowel obstruction, intussusception, and rarely perforation. • Carcinoid is the most common primary malignant small-​bowel tumour. Carcinoid tumours occur most frequently in the ileum and are typically intensely enhancing luminal polyps or enhanc- ing carpet lesions with mesenteric metastases being characteristic. The mesenteric disease incites a desmoplastic reaction producing a spiculated mass-​like appearance, which may calcify. • Adenocarcinoma has a predilection for the duodenum but also occur with decreasing frequency in the jejunum and ileum, and may appear as a focal area of annular narrowing, a tumour mass, or an ulcerated plaque (Fig. 15.3.3.9). • Lymphoma does not have a particular predilection for any small-​bowel territory. The imaging appearances are protean ranging from a solitary polypoid mass to segmental mural thickening with aneurysmal dilatation due to destruction of the myenteric plexus with associated adjacent lymphadenopathy (Fig. 15.3.3.10). • GISTs are typically extraluminal occurring most commonly in the stomach followed by the small bowel. It is often difficult to distinguish benign from malignant GISTs on imaging but cer- tain findings favour malignant disease including lesion size greater than 5 cm, heterogeneous enhancement, gastric location, necrotic components, and associated metastases. • Metastatic disease to the small bowel is encountered more frequently than primary tumours. Transcoelomic spread may occur from colonic, gastric, or ovarian malignancies while haematogenous metastasis may occur from breast, lung, or melanoma primaries (Fig. 15.3.3.11). Fig. 15.3.3.9  Coronal contrast-​enhanced CT following positive oral contrast administration shows a large soft tissue mass (arrowheads) centred in the proximal ileum with associated luminal narrowing. Biopsy confirmed adenocarcinoma of the small bowel. Courtesy of Cork University Hospital, Cork, Ireland. Fig. 15.3.3.10  Axial contrast-​enhanced CT enterography in a 39-​year-​ old male patient demonstrates segmental mural thickening within a loop of jejunum with aneurysmal luminal dilatation (arrowheads). Histology confirmed a diagnosis of small-​bowel lymphoma. Courtesy of Cork University Hospital, Cork, Ireland.

section 15  Gastroenterological disorders 2754 Immune-​mediated enteritis Coeliac disease Coeliac disease is a gluten-​related, immune-​mediated enteropathy occurring in susceptible individuals. The most common imaging finding is moderately dilated fluid-​filled loops of small bowel. The classic finding of jejunal fold atrophy with secondary hypertrophy of the ileal folds (jejunoileal fold reversal) is uncommonly encoun- tered. Characteristic findings on barium examinations occurring due to an excess of luminal fluid include air–​fluid levels and ag- gregation of coarse clumps of disintegrated barium, termed floc- culation. Other imaging features include transient small-​bowel intussusceptions and splenic atrophy. The primary role of imaging is the detection of enteropathy-​associated T-​cell lymphoma, espe- cially in patients with refractory disease. Findings vary from mul- tiple enhancing mural nodules to aneurysmal luminal dilatation due to destruction of the muscle wall and myenteric plexus. Patients with coeliac disease are also at an increased risk of developing small-​bowel adenocarcinoma. Another entity that has been described in coeliac disease is cavi- tating mesenteric lymph node syndrome. This consists of enlarged, rim-​enhancing, necrotic mesenteric lymph nodes in association with an ulcerative jejunoileitis, predominantly affecting the je- junum. On MRI, the centres of these lymph nodes may be bright on T2-​weighted images, in keeping with central cavitation within the lymph nodes. Ulcerative jejunoileitis results in diffuse mucosal ulceration and the appearances may closely simulate lymphoma or Crohn’s disease. Graft-​versus-​host disease (GVHD) Acute GVHD disease involves the small bowel in 75 to 100% of cases. The typical imaging findings are mild bowel wall thickening with dilatation, marked mucosal hyperenhancement, and mural stratification. Small-​bowel GVHD differs in appearance from other inflammatory pathologies in that the bowel wall thickening is gener- ally mild and disease involves a long segment often extending from the duodenum to the rectum. Eosinophilic gastroenteritis Eosinophilic gastroenteritis is a rare condition with over 50% of cases occurring in patients with atopy. The disease most commonly affects the small bowel and stomach with imaging findings of fold thickening, polyps, mucosal ulcers, stricture formation, ascites, omental thickening, and lymphadenopathy. Patients often respond well to an initial course of corticosteroids. Vascular diseases of the small bowel Small-​bowel ischaemia Small-​bowel ischaemia may result from arterial occlusion, venous occlusion, or low-​flow states such as cardiac failure or hypovol- aemia, with superior mesenteric artery occlusion accounting for over 50% of cases. The imaging manifestations vary according to the degree of vascular insufficiency. Occlusive arterial disease may re- sult in acute transmural infarction with absence of enhancement, mural thinning, and bowel dilatation. Pneumatosis intestinalis and portal venous gas are less commonly seen (Fig. 15.3.3.12). Conversely, nonocclusive disease may result in mural thickening and mucosal hyperenhancement related to reactive hyperaemia due to reperfusion injury. Venous occlusion, the least common cause of small-​bowel ischaemia, presents with marked mural thickening with hyperenhancement and associated vascular engorgement and mesenteric stranding. CT is the imaging modality of choice for the detection of acute mesenteric ischaemia with a reported high sensitivity (93%) and specificity (96%). CT also facilitates evaluation of the mesen- teric vessels detecting potential causes of ischaemia and guiding management. Systemic vasculitis may present with small-​bowel ischaemia. This should be suspected in young patients with recurrent symptoms, disease involving atypical sites such as the duodenum, and when additional findings such as aneurysms and solid visceral infarcts are present. Small-​bowel bleeding Angiodysplasia is the most common cause of occult gastrointestinal tract bleeding. It typically manifests on CT as an avidly enhanc- ing nodule or plaque during the arterial phase that fades during the delayed phase. Other potential causes of small-​bowel bleeding include tumours, other vascular malformations, and Meckel’s di- verticulum. Multiphase contrast-​enhanced CT has been shown to be effective in the detection of occult small-​bowel bleeding sites. Furthermore, it may guide interventional management by identi- fying the bleeding vessel facilitating selective catheterization and embolization. Capsule endoscopy may also be complementary in patients with suspected small-​bowel bleeding but is limited by long reporting times. Fig. 15.3.3.11  Coronal contrast-​enhanced CT following positive oral contrast administration shows a large soft tissue mass centred in the distal ileum (arrow). Biopsy at laparoscopy confirmed melanoma of the small bowel. Courtesy of Cork University Hospital, Cork, Ireland.

15.3.3  Radiology of the gastrointestinal tract 2755 The colon Radiological techniques to image the colon CT colonography CT colonography or virtual colonoscopy is gaining in popularity as an alternative or complementary investigation to conventional colo- nography for diagnosis and screening for colorectal carcinoma. Bowel preparation with dietary restriction and laxatives is re- commended in a similar fashion to colonoscopy. Additional faecal tagging with an oral enteric contrast agent is often performed. A rectal tube is inserted and room air or carbon dioxide is insuf- flated into the colon under controlled injection until satisfactory colonic distension is achieved. Patients are then scanned in the prone and supine positions with additional imaging being per- formed as required to ensure complete colonic imaging. Images undergo postprocessing on an integrated computer system to gen- erate three-​dimensional endoluminal or ‘fly-​through’ series from the two-​dimensional images. Disadvantages of the technique include the prerequisite exposure to ionizing radiation and in the event of a lesion being found, the pa- tient may need a second bowel preparation to undergo colonoscopy to perform biopsy or further treatment. However, the risk of bowel preparation is lower than with colonoscopy. Barium enema Although use of the barium enema has declined significantly in recent years with the advent of CT colonography, it may still be of use in selected patients to investigate altered bowel habit, inflam- matory bowel disease, and colorectal carcinoma. Patients undergo bowel preparation as for CT colonography. High-​density barium (100% w/​v) is administered per rectum via a rectal tube. This is then drained and air is administered followed by double-​contrast spot films of each colonic segment. The barium serves to coat the mucosa and absorb residual fluid in the colon. Before acquiring a spot image, barium is allowed to pass over the mucosal surface, the patient is turned to displace the barium pool, and air is insuf- flated. The volume of barium retained by the patient is important as excessive barium will obscure colonic lesions and a paucity of barium will result in poor mucosal coating. Incomplete filling of the right colon may also occur, resulting in the inability to exclude disease of the proximal colon. The technique may be poorly toler- ated by some patients due to abdominal cramps despite the use of an antispasmodic agent and/​or lax anal sphincter. Glucagon 1 mg or Buscopan 20 mg intravenously may be used to induce colonic hypotonia. MRI colonography Dark-​lumen magnetic resonance colonography is a rapidly evolv- ing, almost noninvasive method currently under evaluation for the assessment of colonic disease. The technique combines an aqueous enema with the intravenous administration of a gadolinium-​based contrast agent. This discriminates colonic pathology, which appears bright on T1-​weighted images post contrast, from the bowel lumen, which is rendered totally dark by the aqueous solution. Residual stool and air bubbles, which may mimic bowel pathology, also re- main dark. Patients undergo bowel preparation in a similar manner to colonoscopy. Approximately 2500 ml of warm tap water is instilled into the colon via a rectal enema tube following which scanning is performed in the prone position to reduce breathing artefacts. Multiplanar reformations are generated from pre-​ and post-contrast three-​dimensional data sets and virtual endoscopic fly-​through may be performed on a postprocessing workstation. Both antegrade and retrograde visual fly-​through is performed to ensure visualization of both sides of the haustral folds. Pathology of the colon Colorectal cancer CT colonography is the imaging modality of choice to detect colo- rectal cancer with a reported sensitivity of 96% and specificity of greater than 90%. CT can identify the tumour site, lesion length, de- gree of extension through the wall and into the mesentery, as well as the presence of nodal and distal metastatic disease in a single examination. The primary lesion may appear as a focal intraluminal mass, an area of asymmetric wall thickening, or an annular constriction of Fig. 15.3.3.12  Acute arterial occlusive mesenteric ischaemia. CT images during intravenous contrast in early arterial phase in a patient with proximal thrombotic occlusion of the superior mesenteric artery show portal venous gas (arrow on left image), mesenteric venous gas (arrows on right image), pneumatosis intestinalis, and a diffuse lack of bowel wall enhancement in keeping with bowel infarction. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2756 the colon. If the lesion causes a stricture, patients may present with large-​bowel obstruction. Extracolonic spread is detected by loss of the fat planes between the colon and surrounding tissue. Tumours may invade the mesentery, abdominal wall, retroperitoneum, or ad- jacent organs such as the stomach and liver. Inflammatory bowel disease The two main inflammatory bowel diseases are ulcerative colitis and Crohn’s disease. Although both can be readily diagnosed on barium studies due to its excellent mucosal detail, CT and MRI have become the imaging modalities of choice in suspected and known inflammatory bowel disease, especially for the detection of complications. There are imaging features specific to each disease that may help to distinguish them. Ulcerative colitis generally involves the rectum and extends proximally without skip lesions to in- volve the entire colon whereas Crohn’s disease tends to involve the right colon and small bowel. On CT, both conditions show mural thickening greater than 3 mm, submucosal oedema, mes- enteric hypervascularity, and fibrofatty proliferation of the ad- jacent pericolonic fat. Wall thickening in Crohn’s disease tends to be greater and is more often asymmetric involving the mes- enteric border predominantly, resulting in the formation of pseudodiverticula along the antimesenteric border. The wall also tends to enhance homogeneously. Wall thickening in ulcerative colitis tends to be diffuse and symmetric. In addition, a low-​ attenuation ring of submucosal fat (halo sign) is more commonly seen in ulcerative colitis. Complications of inflammatory bowel disease, which are more common in Crohn’s disease, that can be readily detected on CT and MRI include abscess, sinus tract, and fistula. Enterovesical, enterocutaneous, perianal, and rectovaginal fistulas may be detected with CT by the presence of enteric contrast within the fistula tract or adjacent organs. MRI is the investigation of choice for the de- tection and characterization of perianal fistula formation in Crohn’s disease. The differential diagnosis for inflammatory bowel disease of the colon includes pseudomembranous colitis, ischaemic colitis, infectious colitis, and radiation colitis. Ischaemic colitis The causes of colonic ischaemia are the same as small-​bowel is- chaemia. However, there are certain watershed areas that are par- ticularly susceptible to ischaemia from hypovolaemia including the splenic flexure (watershed between the superior and inferior mesenteric arteries) and rectosigmoid (watershed between the inferior mesenteric artery and superior rectal artery). These are regions of poor perfusion at the peripheries of major ar- terial territories with a poor collateral supply. Ischaemic colitis typically involves the left colon in the elderly patient with hypop- erfusion and the right colon in young patients with haemorrhagic shock. Findings on CT include symmetrical wall thickening, haustral fold enlargement, mural stratification, mesenteric in- flammation, pneumatosis coli, and portal venous gas. High at- tenuation within the wall indicates intramural haemorrhage. Pneumatosis coli is not specific to bowel ischaemia and may be seen in a wide range of nonischaemic conditions such as infection, inflammation, malignancy, respiratory disease, and also following endoscopic procedures. Thrombus may be identified within the splanchnic vessels in cases of occlusive arterial disease. Mural scarring and stricture formation may be seen in cases of chronic ischaemic colitis. Radiation colitis Findings of acute radiation colitis are nonspecific including bowel wall thickening and pericolic inflammatory change. However, the clinical history will help to make the diagnosis. The rectum and sigmoid are the most common sites of disease in patients who have undergone radiation therapy for prostate and cervical cancer. Chronic radiation colitis occurring secondary to radiation-​induced endarteritis generally presents more than 6 months following treat- ment. Findings on CT and MRI include bowel wall thickening, in- creased pelvic fat stranding, and thickening of the pericolic fibrous tissues. Strictures and fistulas are potential complications. Diverticular disease Diverticula are outpouchings of the colonic mucosa and sub- mucosa at the point where the vessels pierce the muscularis be- tween the mesenteric and antimesenteric taenia (Fig. 15.3.3.13). Diverticulosis appears on CT as multiple, small, air-​filled out- pouchings of the colonic wall, most prevalent in the sigmoid colon. The wall of the colon is often thickened due to circular muscle hypertrophy. Acute diverticulitis occurs when the neck of a diverticulum is occluded by stool leading to microperforation of the diverticulum and inflammation. CT is the imaging modality of choice to detect acute diverticulitis and its associated compli- cations. Imaging findings include segmental wall thickening, peri- colic inflammatory fat stranding, and injection of the mesenteric vessels. As acute diverticulitis occurs most commonly in the sig- moid colon, positive contrast material may be given per rectum to aid diagnosis. Potential complications include perforation, abscess (Fig. 15.3.3.14), and colovesical fistula formation. A  colovesi- cal fistula may be identified by the presence of air in the bladder, Fig. 15.3.3.13  A pelvic CT scan of mild diverticulitis showing mural thickening of the sigmoid colon, diverticula, and fluid in the combined interfascial plane (arrows). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.3.4 Investigation of gastrointestinal function

15.3.4 Investigation of gastrointestinal function 2757

15.3.4  Investigation of gastrointestinal function 2757 bladder wall thickening adjacent to the inflamed sigmoid colon, or enteric contrast within the bladder. FURTHER READING Ajaj W, Goyen M (2007). MR imaging of the colon: “technique, indica- tions, results and limitations”. Eur J Radiol, 61, 415–​23. Halligan S, Taylor SA (2007). CT colonography: results and limita- tions. Eur J Radiol, 61, 400–​8. Levine MS, Rubesin SE, Laufer I (2009). Barium studies in modern radiology: do they have a role? Radiology, 250, 18–​22. Masselli G, Gualdi G (2012). MR imaging of the small bowel. Radiology, 264, 333–​48. McLaughlin P, Maher M (2013). Nonneoplastic diseases of the small intestine:  clinical, pathophysiologic, and imaging characteristics. AJR Am J Roentgenol, 201, W382–​90. Pickhardt PJ, et al. (2011). Colorectal cancer: CT colonography and colonoscopy for detection—​systematic review and meta-​analysis. Radiology, 259, 393–​405. 15.3.4  Investigation of
gastrointestinal function Jervoise Andreyev ESSENTIALS There are two main reasons for investigating the gastro- intestinal (GI) tract:  first, to identify diseases at an early stage
(e.g. endoscopic screening for neoplasia); second, to diagnose and manage symptoms. A pathological process can potentially affect any part of the GI tract, but apart from mass lesions, pathological change per se hardly ever causes symptoms directly. Symptoms depend on whether critical physiological change has been triggered by the pathological insult. Individual symptoms or clusters of symptoms are not a re- liable indicator of the underlying cause, and different physio- logical changes can produce identical symptoms. Worrying symptoms indicative of significant GI tract pathology include ‘red
flag’ symptoms (e.g. a palpable mass, rectal bleeding, weight loss) and other symptoms that are frequently missed by pa- tients and clinicians alike (e.g. steatorrhoea, nocturnal waking to
defecate). Dietary intake requires systematic assessment. Routine inves- tigation should usually include thyroid function testing, vitamin B12 and vitamin D status, coeliac screen, iron studies, and inflam- matory markers. Endoscopy and cross-​sectional radiology provide excellent anatomical visualization but provide little information about the dynamic function and physiology of the GI tract, for which tests for specific physiological functions can be used. Failure to investigate adequately misses easily treated diagnoses and means ongoing symptoms for patients. For many patients with multiple comorbidities, there is often more than one cause for their GI symptoms, which will not improve unless all causes are identified and treated. Introduction The gastrointestinal (GI) tract is an extremely complex organ. It contains as many neurons as are found in the spinal cord. Specialized cells within the GI tract secrete a vast array of hor- mones, neurotransmitters, and enzymes. Within the GI tract lives a microbial—​bacterial, viral, and fungal—​population which contains substantially more DNA than is found in the rest of the human body. This microbial population is essen- tial for human health and normal intestinal function, but as yet how it interacts with its human host has barely started to be ex- plored. Keeping this microbial population under surveillance is an almost separate immune system to that found in the per- ipheral circulation and much remains to be understood as to how the intestinal immune system differentiates between useful commensals and dangerous pathogens. In addition, the GI tract has a vital role in nutrient metabolism, absorption, and in fluid homeostasis. It is extraordinary that of the order of 12 litres of fluid enters the GI tract daily yet rarely more than 200 ml is ex- creted. This is achieved through coordinated muscular activity, which allows mixing of nutrients for optimal digestion, propul- sion when mixed to appropriate areas for absorption, and excre- tion of waste. The normal physiology of the GI tract and some of the disorders of physiology which can occur are described in Fig. 15.3.4.1. Fig. 15.3.3.14  A pelvic CT scan showing an intramural abscess from diverticulitis. There is mural thickening of the sigmoid colon associated with a low-​density intramural abscess (arrow). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

section 15  Gastroenterological disorders 2758 Clinical context Defining abnormal GI function and the need for investigation In health, the GI tract allows the human being to thrive. Therefore, investigations are required if the human is not thriving, is losing weight, or starts to develop abnormal GI symptoms especially when empirical therapy to correct them is ineffective. The purpose of in- vestigations therefore, must be twofold: first to identify why the GI tract is behaving abnormally, and second, but equally critically, to define which treatment(s) are likely to be most effective at improving the patient’s outcome. Patients want disease processes to be diag- nosed accurately, but once a diagnosis of a disease is made, they often feel that their symptom burden and its effect on their quality of life are not addressed optimally. The role of investigations must be to enhance health gain for the patient. Why do GI symptoms occur? It is often poorly appreciated why people experience abnormal GI symptoms. However, the answer is simple. Abnormal symptoms are caused by an alteration in normal GI functioning, that is, a change in normal GI physiology. It is widely assumed that abnormal GI symptoms develop as a result of pathological change, processes which can involve inflammation, oedema, ulceration, atrophy, cell death, and infection. However, this is profoundly unhelpful as pathological change very rarely—​if ever—​causes symptoms directly. A pathological insult can potentially affect any part or all of the GI tract. Different parts of the GI tract have very different physio- logical roles. Therefore, for example, a pathological disease process affecting the proximal small bowel may have a very different effect to that in the distal small bowel (Fig. 15.3.4.2). Completely different physiological functions are at risk at the two sites within the GI tract. Pathological damage in the proximal small bowel may particularly affect carbohydrate malabsorption, while the same type of change in the distal small bowel may predominantly affect reabsorption of bile acids. However, both carbohydrate malabsorption and bile acid malabsorption may be characterized by identical symptoms, namely episodes of loose stool, bloating, and cramps. So, when investigating GI function, it is important to understand that while some pathological changes may lead indirectly to clinical symptoms, others remain subclinical. Whether the patient develops symptoms depends on whether critical physiological change has been triggered by the pathological insult or not. This explains why different pathological processes can produce identical symptoms. Even clusters of symptoms do not reliably define the underlying cause for those symptoms as the GI tract only responds to patho- logical damage in a limited variety of ways. Consider a very common clinical problem such as iron deficiency anaemia. Clearly, exclusion of GI tract malignancy as a cause for this is very important, however, the diagnostic process often stops at that point. Yet for the symp- tomatic patient, while they are no doubt reassured that they do not have cancer, identifying the reversible cause for iron deficiency (e.g. small-​bowel bacterial overgrowth, coeliac disease, or hookworm in- festation) will have a greater impact on their long-​term quality of life than undergoing a normal colonoscopy. Even if GI pathological changes cannot currently be reversed, for example, after therapeutic irradiation for cancer in the pelvis, there is no reason why symptoms cannot be treated through identification and correction of the physiological deficits that are induced by those pathological changes. Using the examples of proximal and distal small-​bowel physiological change previously cited, interventions to improve symptoms such as prescribing an antidiarrhoeal might be helpful, but why not investigate the patient in detail so as to be able Normal gut function aims to optimize nutrient absorption by balancing ... FLUID SECRETION FLUID REABSORPTION CONTRACTILITY PERMEABILITY ILEOCAECAL VALVE *altered microbiota *vitamin and bile acid malabsorption *altered motility *bacterial overgrowth *fat maIabsorption *pancreatic insufficiency *carbohydrate malabsorption UPPER GASTROINTESTINAL TRACT *altered motility *altered fermentation *altered sphincter control LOWER GASTROINTESTINAL TRACT ANY INSULT CAN CAUSE Fig. 15.3.4.1  The pictorial representation of the physiology of the gastrointestinal tract. The effect of disordered physiology is shown on the right-​hand side; the conditions seen in the small bowel are drawn in pink, and in the large bowel in blue. The diagnostic process has two aims: (1) to identify and treat the insult leading to physiological change and (2) to identify and treat any altered physiology which causes abnormal symptoms. Why gastrointestinal symptoms? Any insult Pathological change Cell death Atrophy Ischaemia Oedema Inflammation Fibrosis Affects specific gastrointestinal physiological functions depending on the affected site Symptoms Fig. 15.3.4.2  The physiological model for the development of abnormal gastrointestinal symptoms.

15.3.4  Investigation of gastrointestinal function 2759 to prescribe treatments which target the underlying cause for the symptom? This has the benefit that it allows the patient to under- stand why the symptom is occurring and to make lifestyle changes to reduce the risk of this happening. Carbohydrate malabsorption is abolished by reducing dietary intake of the nonabsorbed mono-​ or disaccharide or appropriate enzyme replacement with probiotics or presynthesized orally ingested disaccharidases while symptoms of bile acid malabsorption will not occur if people follow low-​fat diets and/​or use bile acid sequestrants. Understanding that GI symptoms are due to altered physiology helps focus investigations much more coherently, and this is per- haps best exemplified by the largest group of patients consulting with GI disorders in primary and secondary care, those potentially having ‘irritable bowel syndrome’. It has been clear for 30  years that in the large number of people referred with irritable bowel syndrome-​like symptoms but characterized by intermittent or con- stant loose stool, up to 80% have organic, treatable pathology which is very unlikely to be due to colorectal cancer or inflammatory bowel disease (Table 15.3.4.1). So, the traditional approach of lower GI endoscopy—​which excludes only colorectal cancer and inflamma- tory bowel disease—​before any other investigations, is inappropriate in this patient group, delays diagnosis and treatment, risks unneces- sary complications, and wastes significant amounts of money for both healthcare systems and patients. Taking a history to guide investigations Booking investigations must be guided by the history. Discussing GI symptoms can be very difficult for patients so history taking to help elicit GI symptomatology accurately requires a sensitive and systematic approach. It is useful to establish clearly at the outset what the patient considers as ‘normal’ (i.e. their premorbid GI bowel function) and when the current symptoms developed from that ‘normal’ state. The greatest problem in obtaining an accurate history is the poor agreement about the meaning of specific terms. For ex- ample, ‘indigestion’ may encompass reflux, regurgitation, dys- phagia, dyspepsia, bloating, or even flatulence. Many patients will term frequency of defecation if increased above normal lev- els as ‘diarrhoea’ even when the stool consistency is completely normal. A  critical marker of reversible GI tract pathology—​ intermittent or constant steatorrhoea—​is rarely identified as such by patients or clinicians and is often mistaken for diarrhoea. Table 15.3.4.2 describes the causes for diarrhoea and steatorrhoea. The two conditions need to be investigated differently. Some pa- tients will deny symptoms because they are too embarrassed or feel nothing can be done. For example, (faecal) ‘incontinence’ is con- sidered by many as highly stigmatizing and so will be denied, while asking about ‘accidents’, ‘soiling’, or ‘leakage’ may elicit an admission that it occurs. So, caution and rigor is needed in interpreting what the patient is saying. Dietary habits frequently contribute to the development of ab- normal GI symptoms. Careful questioning in six areas can often pay dividends:

  1. Is the alcohol intake excessive?
  2. What is the fibre intake (excessive/​inadequate)?
  3. Could lactose-​containing foods/​drinks trigger the symptoms?
  4. Is diarrhoea triggered by the intake of richer, fattier foods?
  5. Could nutritional supplements (e.g. excess selenium causing nausea, diarrhoea, and halitosis) trigger symptoms?
  6. Is the diet balanced? Discussion aids and physical examination Using simple tools to clarify what the patient means can be very illu- minating. Disordered GI function may have many ramifications for patients, so completing a holistic needs assessment questionnaire Table 15.3.4.1  Common missed organic causes for patients misdiagnosed with diarrhoea-​predominant irritable bowel syndrome. These data suggest that in patients with appropriate symptoms, that SeHCAT scanning, breath testing, stool for faecal elastase, and a coeliac screen are important first-​line investigations and that endoscopic assessment should be a second-​line test in a patient with no alarm symptoms Diagnosis % with this condition Best diagnostic tests for this condition Infectious diarrhoea <1 Stool culture Inflammatory bowel disease <1
  7. Inflammatory markers (e.g. CRP, faecal calprotectin)
  8. Colonoscopy/​capsule endoscopy/​enteroscopy
  9. Radiological assessment Cancer <1
  10. Colonoscopy
  11. Radiological assessment Coeliac disease <4
  12. Serum tissue transglutaminase levels
  13. Duodenal bulb biopsy
  14. Trial of a gluten free diet
  15. HLA testing Pancreatic insufficiency 6
  16. Faecal elastase levels
  17. Trial of pancreatic enzyme replacement
  18. Radiological imaging Small intestinal bacterial overgrowth 4–​78
  19. Glucose/lactulose hydrogen, methane breath testing
  20. Small-​bowel aspirate and culture Bile acid malabsorption 32
  21. SeHCAT scan Carbohydrate malabsorption/​maldigestion 35–​64
  22. Hydrogen breath testing for monosaccharide and disaccharide deficiency
  23. Small-​bowel biopsy for assessment of mucosal levels of monosaccharidases and disaccharidases

section 15  Gastroenterological disorders 2760 (Fig. 15.3.4.3) before their first appointment is a useful start- ing approach. Patients often volunteer information on question- naires which they may fail to voice during consultations. There are a number of validated questionnaires asking about GI symptoms. The Gastrointestinal Symptom Rating Scale is particularly helpful in focusing the consultation on the symptoms troubling the patient. The Bristol Stool Chart (Fig. 15.3.4.4) is often invaluable in helping a patient explain their bowel function. To explore the impact of diet, asking the patient to complete a 7-​day record of everything they eat and drink for assessment by a trained dietitian can some- times be helpful. Input from the patient’s partner or family during the consultation frequently improves the quality of the information Table 15.3.4.2  Diarrhoea and steatorrhoea: the differential diagnosis and most useful diagnostic investigations Condition Diagnostic investigation of choice Diarrhoea Autonomic neuropathy Autonomic testing Bile acid malabsorption SeHCAT scan Carbohydrate malabsorption

  1. Hydrogen breath testing for monosaccharide and disaccharide deficiency
  2. Small-​bowel biopsy for assessment of mucosal levels of monosaccharidases and disaccharidases Constipation with overflow Plain abdominal X-​ray Dietary/​alcohol problems Careful dietary history Drug side effects Careful drug history Endocrine abnormalities Measurement of renal function/​glucose levels/​glycosylated haemoglobin/​thyroid function tests/​morning cortisol levels/​short Synacthen test/​parathyroid levels Infection Stool for culture Urine dip sticks and midstream sample for culture Chest X-​ray Neoplasia
  3. Colonoscopy
  4. Radiological assessment
  5. Gut hormone screen plus chromogranin A and B Inflammatory bowel disease
  6. Inflammatory markers (e.g. CRP, faecal calprotectin)
  7. Colonoscopy/​capsule endoscopy/​enteroscopy
  8. Radiological assessment Laxative abuse/​factitious diarrhoea Low stool osmolality <290 mosmol/​kg High stool magnesium levels >45 mmol/​litre Stool sample for laxative screen Mesenteric ischaemia Digital subtraction angiography Microscopic colitis Colonoscopically directed biopsies Radiation enteropathy History of previous radiotherapy and typical symptoms Rapid transit Radiopaque marker study Short bowel syndrome Contrast small-​bowel meal with measurement of residual small-​bowel length Small-​bowel bacterial overgrowth
  9. Glucose hydrogen, methane breath testing
  10. Small-​bowel aspirate and culture Stricture formation Endoscopy/​radiology Steatorrhoea Bile acid malabsorption SeHCAT scan Intra-​ and extrahepatic bile duct disease Radiological imaging Intestinal lymphangiectasia Trial of a low-​fat/​low-​long-​chain triacylglycerol diet Lymphangiography Pancreatic insufficiency
  11. Faecal elastase levels
  12. Trial of pancreatic enzyme replacement
  13. Radiological imaging Small-​bowel bacterial overgrowth
  14. Glucose hydrogen, methane breath testing
  15. Small-​bowel aspirate and culture Free fatty acid malabsorption Trial of a low-​fat/​low-​long-​chain triacylglycerol diet Neuroendocrine tumour Serum gut hormone and chromogranin A and B levels Small-​bowel disease (e.g. lymphoma/​Crohn’s disease/​coeliac disease/​ amyloidosis/​cystic fibrosis/​tuberculosis/​chronic parasite infection
    (e.g. giardiasis) Typical changes on blood test/​radiology/​endoscopy/​biopsy/​stool culture Drug therapy (e.g. use of Benecol/​Orlistat/​Lanreotide/​Octreotide) Careful history

15.3.4  Investigation of gastrointestinal function 2761 obtained. Having precise data significantly enhances the choice of investigations. An appropriate physical examination is required. In patients who are acutely ill, this must include careful recording of their vital signs, while lying and standing blood pressures can be a useful measure of severity of dehydration. The ready availability and accuracy of flexible sigmoidoscopy requested urgently if required has meant that examination with rigid sigmoidoscopy has become largely unnecessary. Requesting investigations Before requesting investigations, a clinical decision needs to be made whether they are required urgently or whether they can be requested routinely. Is the expertise present to perform the appro- priate investigation safely and is the appropriate multidisciplinary team available to review and interpret the result? In addition, if mul- tiple investigations are required, should they all be requested at the same time or should they be requested sequentially? The guiding principle in so much of medical practice, Occam’s razor, is often interpreted to suggest that ‘diagnostic parsimony should be employed’, in other words that the simpler the hypoth- esis for the cause of the symptoms, the more likely it is to be true. Occam’s razor, however, is extremely unhelpful for determining the cause of GI symptoms especially in those who have complex dis- eases. In that situation, Hickam’s dictum that ‘patients can have as many diseases as they damn well please’ is much more appropriate. Basic investigations should usually include haematological and biochemical profiles including thyroid function, vitamin B12 and vitamin D status, a coeliac screen, iron studies, and inflammatory markers. Useful additional blood tests to consider when investigating abnormal GI function are listed in Table 15.3.4.3. Specific investigations should be tailored for the principal symp- toms and should reflect an understanding of the potential aetiolo- gies. There are two different types of tests available to the clinician: (1) tests which look at anatomical structure and (2) tests which examine dynamic and physiological function. Holistic Needs Assessment: Concerns Thermometer (over 25yrs) PREFERRED NAME: “I am coping well” YES PRACTICAL CONCERNS RELATIONSHIP CONCERNS EMOTIONAL CONCERNS SPIRITUAL/REUGIOUS CONCERNS SECONDLY, using the concerns list opposite, for each item please tick YES or NO to indicate if it has been a concern for you during the past week (including today). Please tick DISCUSS if you wish to speak further about your concern. No distress 0 1 2 3 4 5 6 7 8 9 10 Extreme distress FIRSTLY, please circle the number (0–10) that best describes how much distress you have been experiencing in the past week (including today). Caring responsibilities My appearance Bathing or dressing Breathing difficulties Passing urine Constipation Diarrhoea Eating or appetite Fatigue, exhaustion or extreme tiredness Feeling swollen High temperature or fever Getting around (e.g. walking) Indigestion Sore or dry mouth Nausea or vomiting Pain Sexual concerns Dry, itchy or sore skin Sleep problems Tingling in hands or feet Changes in how things taste Hot flushes Memory or concentration Wound care after surgery Other medical condition or disability Other concerns: YES NO Housing or Finances Transport or parking Work or Further Information needs Relationship with my children Relationship with my family Relationships Loneliness or isolation Sadness or depression Sadness or depression Anger or frustration Guilt Hopelessness Difficulty making plans Sexual concerns Loss of faith or other spiritual concern Loss of meaning of purpose in life Feeling regret about the past NO Discuss YES PRACTICAL CONCERNS NO Discuss YES NO PATIENT IDENTIF1ER: PATHWAY POINT: DATE: Fig. 15.3.4.3  An example of a holistic needs assessment questionnaire. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Distress Management V.2.2018. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

section 15  Gastroenterological disorders 2762 Tests investigating anatomical structure Anatomical examination using increasingly sophisticated tech- niques can be performed either endoscopically or by cross-​sectional imaging using radiation, ultrasonography, or magnetic resonance imaging. Technological innovation means that imaging devices including ultrasound systems, microscopes, and Doppler probes are increasingly incorporated into endoscopes and laparoscopes. However, while endoscopic assessment allows high-​quality visu- alization of the interior of the lumen of the GI tract, and allows sam- pling of tissues under direct vision, it offers no objective data about any structure which is beyond the field of vision (e.g. outside the lumen wall), nor does it offer accurate information about function. It usually requires specific preparation before it is performed, for example, fasting or bowel cleansing, which in their own right may cause alteration in function. It can also be misleading: for example, if inflammation is seen, that may not be the cause of the patient’s symptoms. In complex scenarios, luminal endoscopy can be com- bined with minimally invasive surgical techniques (laparoscopy) to give a more complete anatomical picture. Advances have allowed increased resolution of the human body when using cross-​sectional imaging techniques. However, the im- ages achieved even with the sophisticated contrast media available still need to be interpreted correctly taking the clinical context into account, a process which requires considerable experience and skill. While anatomical abnormalities can be imaged and reimaged easily, Bristol Stool Chart Type 1 Separate hard lumps, like nuts (hard to pass) Sausage-shaped but lumpy Like a sausage but with cracks on the surface Like a sausage or snake, smooth and soft Soft blobs with clear-cut edges Fluffy pieces with ragged edges, a mushy stool Watery, no solid pieces. Entirely Liquid Type 2 Type 3 Type 4 Type 5 Type 6 Type 7 Fig. 15.3.4.4  The Bristol Stool Chart. Copyright 2000 Rome Foundation, Inc. All rights reserved. Table 15.3.4.3  Potentially useful laboratory tests to investigate abnormal luminal GI function Type of test Name of the test Notes Haematology Full blood count Erythrocyte sedimentation rate INR May be abnormal in malabsorption Glycosylated haemoglobin level Associated with visceral neuropathy and small-​bowel bacterial overgrowth Biochemistry Urea and electrolytes Liver function tests Vitamin B12 Vitamin D Red blood cell folate Ferritin Transferrin saturation Coeliac screen HLA serotyping HLA DQ2 or DQ8 >95% of coeliac patients CRP Triglyceride levels Morning cortisol level If low requires Synacthen test IgG4 ? Autoimmune pancreatitis Amylase/​pancreatic lipase 7α-​hydroxy-​4-​cholesten-​3-​one (C4) ? Bile acid malabsorption Gut hormones, chromogranin A and B ? Neuroendocrine tumours Cancer markers Carcinoembryonic antigen/​CA125/​CA19-​9 Antibodies to intrinsic factor Vitamin B12 deficiency

15.3.4  Investigation of gastrointestinal function 2763 again almost no information is provided about function and espe- cially in younger patients, imaging techniques which involve ion- izing radiation increase the risk of subsequent radiation-​induced malignancy. Tests investigating gastrointestinal dynamic function and physiology While assessment of anatomy may be useful, assessing GI motility, peristalsis, and sphincter behaviour help define neuromuscular dis- orders of the digestive tract. However, remarkably frequently, the abnormalities detected in the various tests do not clearly relate to patients’ symptoms. Some people argue this may partly be because many of these tests have historically been performed without agree- ment as to the best methodology. Investigations which measure the effect of enzymes or analyse the gaseous by-​products of bacteria can also be useful ways to assess function. The range of tests is discussed in the following subsections. Oesophagus When there is no obvious anatomical abnormality, oesophageal manometry can accurately diagnose achalasia, diffuse oesophageal spasms, and nutcracker oesophagus and suggest the presence of scleroderma. Ambulatory oesophageal pH monitoring is the gold standard for the diagnosis of acid and nonacid gastro-​oesophageal reflux. Catheter-​free radio telemetric systems where available are now the diagnostic method of choice. Stomach Measuring gastric emptying can be performed by scintigraphic emptying of a test meal, by breath testing using stable isotopes, ultra- sonography, magnetic resonance scanning, or by wireless motility capsule. The results often differ from one another. The type of standard meal may need to be varied between patient groups. The presence of Helicobacter pylori infection can be assessed either by direct sampling of the gastric antral mucosa, by looking for helicobacter antigen in stool, or performing breath testing using13C, a stable isotope. Pancreas Many tests can accurately diagnose advanced pancreatic insuffi- ciency. The noninvasive tests are unreliable in those with early, mild disease. Some specialized invasive tests can reliably detect mild pan- creatic insufficiency but are only available at a few quaternary re- ferral centres. Stool chymotrypsin and elastase-​1 concentrations if very low (<15 μg/​g stool) indicate likely significant pancreatic exocrine insuf- ficiency, while if normal (>500 μg/​g stool) makes exocrine insuffi- ciency very unlikely. Measures of these stool enzymes in between the extremes are unreliable measures of pancreatic function. A 10-​day therapeutic trial of pancreatic enzyme replacement (10 000–​30 000 PhEur units of lipase with each and every snack—​including all drinks except black tea, black coffee, and water, and 30 000–​50 000 PhEur units with each main meal) can be helpful if the stool enzyme levels are not clear cut. More formal assessment tests such as the Lundth meal are essentially obsolete although some units still con- sider performing a secretin/​cholecystokinin stimulation test with or without MRI assessment of the pancreatic duct. Small intestine Small-​bowel transit time is difficult to quantify and can be affected by many factors. When a measurement is required, scintigraphy, hydrogen breath testing, and wireless capsule are the favoured methods. These are perhaps preferred over transit studies using radiopaque markers which require radiation exposure from serial abdominal radiographs. Glucose hydrogen breath testing will identify 65% of patients with small intestinal bacterial overgrowth. The addition of methane ana- lysis will identify a further 25% of patients. Small-​bowel aspiration with positive culture is particularly helpful at guiding appropriate antibiotic usage but is rarely performed routinely. A trial of broad-​ spectrum antibiotics (e.g. rifaximin 550 mg twice daily or ciproflox- acin 500 mg twice daily or doxycycline 200 mg day 1, 100 mg days 2 onwards for 7–​10 days) without any investigations is sometimes advocated but carries risks of unnecessary treatment and its com- plications; and if the antibiotic is not effective, does this mean that bacterial overgrowth is absent or that the organism is resistant? Mono-​ and disaccharide malabsorption is common. Protocols for fructose, lactose, galactose, and sucrose breath testing are described. If positive, exclusion diets can be prescribed, otherwise these disac- charides are sometimes replaced either by coadministration of these carbohydrates with the appropriate probiotics which contain the required enzymes or with the coadministration of presynthesized enzymes. Type of test Name of the test Notes Stool tests Faecal elastase If low possibly diagnostic of untreated Coeliac disease, pancreatic insufficiency or small intestinal bacterial overgrowth Faecal chymotrypsin Faecal α1 antitrypsin Protein-​losing enteropathy Faecal lactoferrin GI tract inflammatory marker Faecal calprotectin GI tract inflammatory marker Stool for culture and sensitivity Helicobacter pylori antigen Faecal occult blood testing Urine Urinary 5-​hydroxyindoleacetic acid (5-​HIAA) Table 15.3.4.3  Continued

section 15  Gastroenterological disorders 2764 Probably, the most reliable assessment tool of small-​bowel func- tion is the selenium homocholic acid taurine (SeHCAT) scan, which assesses for the condition ‘bile acid malabsorption/​diarrhoea’ which affects 1% of the population. Colon Scintigraphy correlates well with results obtained using radiopaque markers. However, scintigraphy may be particularly useful in demonstrating regional colon transit. Pelvic floor and rectoanal dynamics Barium defecography has been largely replaced by magnetic res- onance defecography. Dynamic imaging and new scanners allow studies in the seated position which provide detailed information about anatomical structures and how they integrate with function. Conclusion Understanding that abnormal GI symptoms arise as a result of al- tered physiological processes provides a rational approach to dealing with symptoms, particularly those that are complex. If abnormal symptoms are identified clearly, all relevant differential diagnoses are considered, and appropriate investigations performed, then ab- normal results allow treatments to be applied systematically. Such an approach has been shown to be effective in clinical studies and can easily be taught. All investigations carry a risk and inconvenience for the patient, from the test itself, from the possibility of false-​negative or false-​ positive results, from how the result is interpreted, from further investigations which it instigates, or from treatments which are then prescribed. In an era where more complex investigations are being ordered and the results reviewed by nonmedically qualified practi- tioners or nonspecialists, it is essential that all those requesting and reviewing tests work within their competency and understand when they need to seek additional advice, and where the sources of that advice are. FURTHER READING Andreyev HJN, et al. (2015). Guidance: the practical management of the gastrointestinal symptoms of pelvic radiation disease. Frontline Gastroenterol, 6, 53–​72. Camilleri M, et  al. (2008). American Neurogastroenterology and Motility Society consensus statement on intraluminal measure- ment of gastrointestinal and colonic motility in clinical practice. Neurogastroenterol Motil, 20, 1269–​82. Grace E, et  al. (2013). Review article:  small intestinal bacterial overgrowth-​prevalence, clinical features, current and develop- ing diagnostic tests, and treatment. Aliment Pharmacol Ther, 38, 674–​88. Jellema P, et al. (2009). Systematic review: accuracy of symptom-​based criteria for diagnosis of irritable bowel syndrome in primary care. Aliment Pharmacol Ther, 30, 695–​706. Slattery SA, et al. (2015). Systematic review with meta-​analysis: the prevalence of bile acid malabsorption in the irritable bowel syn- drome with diarrhoea. Aliment Pharmacol Ther, 42, 3–​11. Svedlund J, Sjödin I, Dotevall G (1988). GSRS—​a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syn- drome and peptic ulcer disease. Dig Dis Sci, 33, 129–​34.

15.4 Common acute abdominal presentations 2765

15.4 Common acute abdominal presentations 2765

15.4.1 The acute abdomen 2765

15.4.1 The acute abdomen 2765

CONTENTS 15.4.1 The acute abdomen  2765 Simon J.A. Buczacki and R. Justin Davies 15.4.2 Gastrointestinal bleeding  2771 Vanessa Brown and T.A. Rockall 15.4.1  The acute abdomen Simon J.A. Buczacki and R. Justin Davies ESSENTIALS The term ‘acute abdomen’ describes abdominal pain of rapid onset requiring urgent surgical assessment. No firm pathological diagnosis is made in many patients initially presenting in this way, but those that do, require rapid diagnosis and treatment to avoid potentially life-​threatening complications. Patients may present directly to medical specialties with an acute abdomen, or abdominal pain may occur in patients al- ready residing on medical wards. These patients are often old and their acute abdomen is likely to present on a background of other comorbidities. Understanding the interaction between risk factors and underlying pathological diagnosis is key to preventing misdiag- nosis in such cases. Although not eliminating the need for a sound focused his- tory and examination, spiral CT scanning allows rapid diagnosis of most causes. However, management of the diagnosed acute abdomen in medical patients can be extremely difficult, and there is no substitute for an experienced physician working together
with a thoughtful surgeon supported by anaesthetists and intensi­ vists. The key question is often ‘Does this patient need an op- eration?’, a decision which depends on many factors. It may be necessary to proceed straight to surgery without any supportive imaging in very sick patients who may be bleeding or who are profoundly septic. Introduction The acute abdomen can be defined as a rapid history of abdominal pain caused by a pathology usually requiring an invasive interven- tion. The vast majority of patients suffering with an acute abdomen are not seen by physicians as they are generally referred directly to surgeons. Nevertheless, patients under the care of physicians can suffer an acute abdomen or the acute abdominal pathology may be the underlying primary diagnosis in the first place. Diagnosing an acute abdomen requires an open-​minded approach to a patient suffering with abdominal pain and should include a readiness to reappraise a patient’s signs and symptoms. Given that many of the underlying pathologies can be life-​threatening, it is important to as- sess patients with acute abdominal pain expeditiously and request timely investigations with concurrent advice from an experienced surgeon. Delay in initiation of treatment and surgical intervention should be avoided at all costs, as this is directly related to overall outcome. Aetiology While many of the causes of the acute abdomen are bowel related, there are many others that are nonintestinal related (Table 15.4.1.1). The frequencies of the underlying pathology also vary according to a patient’s age and sex. Similar to many medical conditions, patients at the extremes of ages may not present with ‘textbook’ signs and symptoms of an acute abdomen, requiring even greater vigilance. Clearly, this has significant implications for the general physician whose patients will fall into these higher age groups. Clinical features The diagnosis of an acute abdomen is based on a sound, focused history together with a thorough examination supplemented by ap- propriate investigations. History The history compatible with an acute abdomen is typically short in onset (generally <48 h) with abdominal pain that may be general or 15.4 Common acute abdominal presentations

SECTION 15  Gastroenterological disorders 2766 localized. Particular attention should be drawn to patients with a short history of severe back pain which can suggest an underlying acute aortic pathology. Although the pain may be colicky or con- stant in nature, the pain associated with the acute abdomen does not commonly improve over time. Colicky pain suggests visceral contractions and stretch, mediated by general visceral afferents, with an associated blockage which may be biliary, ureteric, or in- testinal in cause. Constant abdominal pain, also mediated by these visceral nerves and/​or the somatic sensory system, may be central or lateralized. Central upper abdominal pain is typically associated with foregut-​derived viscera such as stomach and hepatobiliary structures. Central periumbilical pain is generated from the em- bryological midgut (D2 to two-​thirds along the transverse colon). Central lower abdominal pain will arise from the hindgut or pelvis. Migratory pain implies an evolving pathology with a change in nociceptive neuronal mediation from visceral referred to somatic in origin, the classic example being in appendicitis. Other associated symptoms may include anorexia and/​or nausea and vomiting. Feculent vomiting is a particularly ominous sign suggesting high-​grade small-​bowel obstruction. The patient may complain of abdominal bloating and/​or a change in bowel habit. Constipation, which may be absolute, and the inability to pass flatus suggests large-​bowel obstruction. Bloody diarrhoea is compatible with colonic ischaemia or an acute colitis. Urinary symptoms, although most commonly associated with urinary disorders, may also be caused by juxtaurinary tract path- ologies such as a large inflammatory sigmoid phlegmon (most often due to sigmoid diverticulitis) or classically the rapidly enlarging ab- dominal aortic aneurysm causing ureteric colic-​like symptoms. Examination On examination, the patient may appear shocked and/​or septic. Jaundice may be present and the combination of jaundice with sepsis should raise immediate concern of underlying cholangitis. The patient who is unwilling to move around on the couch, because this exacerbates their abdominal pain, is likely to have peritonism. On the other hand, the patient rolling around in agony with an in- ability to get comfortable is more likely to be suffering with ureteric colic. Peritonism is defined as irritation of the parietal peritoneum of the abdominal wall by an intra-​abdominal pathology. It is diag- nosed by eliciting the cardinal signs of guarding or rebound ten- derness. Guarding is the involuntary contraction of the abdominal musculature after gentle palpation whereas rebound tenderness is the generation of pain after rapid removal of the hand following deep palpation or percussion. Similar pain may be experienced on coughing or gentle percussion over the pathology in this clinical condition. Peritonism is pathognomonic of many aetiologies of the acute abdomen and therefore the discovery of these signs should warrant urgent surgical referral. As well as examining the anterior abdomen, it is important to add- itionally assess the other areas of the lower torso. The loins should be palpated for renal tenderness which can be caused by pyelonephritis or an obstructed urinary system. The hernial orifices should be pal- pated for the presence of inguinal or femoral herniae. Should these be found then attention should be paid as to whether they are (1) re- ducible and if not reducible (2) tender. The presence of an irredu- cible and tender hernia is diagnostic of acute strangulation which requires an immediate operation. Even in the absence of genital symptoms such as scrotal pain, it is essential that these structures should be examined. Acute testicular torsion can, albeit uncommonly, present with abdominal pain, and failure to diagnose this pathology is disastrous. Finally, a digital rectal examination should be performed to look for the presence or absence of stool, a collapsed or expanded rectal cavity, rectal mu- cosal pathologies and tenderness that could be associated with an extrarectal pelvic abscess, or an acutely inflamed appendix lying within the pelvis. Investigation Timely investigations are often key to diagnosing an acute abdomen as signs and symptoms may be equivocal. A high level of clinical suspicion should therefore be maintained, and management should be progressed to investigation rapidly to prevent any delay in diag- nosis. For most causes of the acute abdomen, patients’ outcomes are closely related to how far advanced the pathology is and the timeliness of treatment. Table 15.4.1.1  Common causes of the acute abdomen Anatomical location Cause Approximate incidence (%) Gastrointestinal Appendicitis 40 Small-​bowel obstruction (adhesions) Large-​bowel obstruction Perforated peptic ulcer Intestinal ischaemia Diverticulitis Strangulated hernia Sigmoid volvulus Hepatopancreaticobiliary Pancreatitis 12 Acute cholecystitis Biliary colic Obstructive jaundice ± cholangitis Urological Ureteric colic 8 Pyelonephritis Testicular torsion Urinary retention Gynaecological Ruptured ectopic pregnancy 1 Ovarian torsion Ovarian cyst ‘accident’ Salpingitis Vascular Ruptured abdominal aortic aneurysm 1 Aortic dissection Miscellaneous Nonspecific abdominal pain 38 ‘Medical’ (see ‘Medical causes of an acute abdomen’)

15.4.1  The acute abdomen 2767 Laboratory tests Investigations begin with bedside urine analysis, including a ß-​human chorionic gonadotropin pregnancy test in women. Laboratory tests will include a full blood count to look for anaemia or a leucocyt- osis, urea and electrolytes, liver function tests, a C-​reactive protein level, and an amylase level to exclude a diagnosis of acute pancrea- titis. Arterial blood gas analysis, looking for a metabolic acidosis, is often useful in aiding the diagnosis of acute mesenteric ischaemia where clinical signs can be very subtle; however, typically the pain remains significant. If the physician has particular concern that the patient may imminently need surgery, then a coagulation screen with a group and save can help prevent a delay in moving the patient to the operating theatre. Imaging Plain radiographs have a limited role in diagnosing acute surgical pathologies. The erect chest radiograph, however, remains a useful, easily acquired modality to diagnose free intra-​abdominal air, al- though it has less sensitivity than CT scanning (Fig. 15.4.1.1). The plain abdominal radiograph is only of use in monitoring patients with acute colitis for the development of toxic megacolon and has no role in the modern approach to the acute abdomen (Fig. 15.4.1.2). (a) (b) Fig. 15.4.1.1  Pneumoperitoneum on supine abdominal and upright chest radiographs. There is central lucency beneath the hemidiaphragm (arrow in (a)). The upright chest radiograph shows free intraperitoneal air beneath the hemidiaphragms (arrows in (b)). From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. (a) (b) Fig. 15.4.1.2  Plain abdominal X-​ray of a 68-​year-​old man with inflammatory bowel disease who presented with fever, abdominal pain, and bloody diarrhoea. The descending colon is grossly dilated (a), with a close up view (b) demonstrating a diameter of 10 cm, with loss of the normal mucosal pattern with irregular nodular contour (arrows). From Abujudeh HH (ed) (2014). Emergency radiology cases. By permission of Oxford University Press.

SECTION 15  Gastroenterological disorders 2768 Rapid access to 24/​7 radiology, in particular spiral CT scanning, has revolutionized the management of patients suspected of having an acute abdomen. Historically, many patients were managed by repeated clinical examination to assess for developing pathology—​ ‘masterful inactivity coupled with cat-​like observation’. Nowadays, with appropriate clinical concern, a CT scan can be performed in many centres within a few minutes if required. The contrast-​en- hanced CT scan is capable of diagnosing most causes of the acute ab- domen and a normal scan, although not eliminating all pathologies, is very reassuring. Some patients with severe sepsis and an acute ab- domen may still require emergency surgery without a prior CT scan, and this decision is generally best made by a senior surgeon. Of note, there are a few pathologies where other radiological modalities are of greater utility than standard contrast-​enhanced CT scanning: • Cholelithiasis (gallstones) and biliary obstruction—​transabdominal ultrasound scan has greater sensitivity than CT (Fig. 15.4.1.3) • Gynaecological pathology—​transvaginal ultrasound scan • Mesenteric ischaemia—​CT angiogram • Renal colic—​unenhanced CT (Fig. 15.4.1.4) Treatment Management of the individual pathologies is obviously specific to each, but there are some underlying principles behind the man- agement of all patients with an acute abdomen. Many patients with these acute pathologies are volume depleted from gastro- intestinal losses and sepsis. Rapid resuscitation is of great im- portance and should be guided by clinical examination and urine output. A urinary catheter is essential in most cases, and a naso- gastric tube should be passed if the patient is vomiting. The role of antibiotics is variable according to individual pathologies, but once an appropriate diagnosis has been made, or if the patient is clearly overwhelmingly septic, then antibiotics should immedi- ately be commenced. Often, however, the most important aspect of these patients’ management is assessment by an experienced surgeon to decide on whether or not they require an operation (Table 15.4.1.2). The acute abdomen on the medical ward There are some causes of the acute abdomen that are seen more frequently on the medical wards. Pseudo-​obstruction Colonic pseudo-​obstruction (also known as Ogilvie’s syn- drome) is not an uncommon pathology in the elderly or infirm. Predisposing factors include pneumonia, stroke, myocardial in- farction, hypothyroidism, electrolyte disturbance, or recent ortho- paedic surgical intervention. It manifests with signs and symptoms compatible with an acute large-​bowel obstruction, but there is in fact no obstructive process. Rather, there is a failure of correct autonomic supply to the colon leading to a failure of function and consequent acute dilatation. The patient will be suffering with absolute constipation and will have a grossly distended and tym- panic abdomen, although will commonly have minimal abdom- inal pain or tenderness. Importantly, rectal examination reveals a cavernous rectum. It is important to differentiate this condition from true mechan- ical large-​bowel obstruction, and a CT scan is the investigation of choice. Management is nonoperative, with correction of electro- lyte disturbances in the first instance. The parasympathomimetic neostigmine has been used successfully, although it carries a sig- nificant cardiac risk profile and should only be given in a moni- tored environment. Flexible sigmoidoscopic decompression can be used if there is concern over an enlarging colonic diameter (>10 cm). Immunosuppression Many medical patients are on immunosuppressive treatments such as corticosteroids, or suffer with inherent immunosuppres- sion consequent to an ongoing disease process such as a haem- atological malignancy. The immunosuppressed patient who is suffering with an acute abdominal pathology can present atyp- ically, with occult symptoms and signs. Further, these patients will present later and with more advanced disease. They tend to have a much poorer outcome from the abdominal pathology as in addition to the delayed presentation they are less able to fight any septic insult. Fig. 15.4.1.3  Ultrasound image of the gallbladder with posterior acoustic shadowing (arrow) due to gallstones. From Abujudeh HH (ed) (2014). Emergency radiology cases. By permission of Oxford University Press. Fig. 15.4.1.4  A large right renal calculus seen on an unenhanced CT scan. From Hamdy FC, Eardley I (eds) (2017). Oxford textbook of urological surgery.
By permission of Oxford University Press.

15.4.1  The acute abdomen 2769 Elderly patients Elderly patients present atypically. Not only are the signs and symp- toms more difficult to elucidate from patients who are commonly confused and distressed, but the sequelae of the disease process can be far more severe. A heightened sense of urgency should accom- pany the management of elderly patients suspected of having an acute abdomen. Liver disease Spontaneous bacterial peritonitis can occur in patients with chronic liver disease and associated ascites. Bacteria, either translocated from the gut or seeded from elsewhere, can infect the normally sterile as- cites. The patient will present in a septic manner with associated ab- dominal pain, although some may have minimal signs. Diagnosis is made by an ascitic tap demonstrating the presence of greater than 250 polymorphonuclear cells/​mm3. Treatment is nonsurgical with intra- venous antibiotics. Inflammatory bowel diseases Patients with inflammatory bowel disease can develop an acute abdomen as a result of disease progression. Those with acute col- itis can deteriorate, developing toxic megacolon or even more worryingly a perforation. Given these patients are likely to be on high doses of immunosuppression (see ‘Immunosuppression’) they may also present atypically. Patients suffering with Crohn’s disease can develop acute bowel obstruction or on occasion an intestinal perforation. Cardiac disease A patient who has suffered an acute cardiac event, be it a myo- cardial infarction or a cardiac arrhythmia, can develop acute mesenteric ischaemia as a result of either hypoperfusion or a thromboembolic event. These patients are at particular risk as they can seldom be managed conservatively, and the risk of having to undergo a laparotomy following any recent cardiac pathology is often not insignificant. Iatrogenic problems Medical patients undergoing interventions as part of their man- agement can develop complications, some of which will present with an acute abdomen. Ascitic taps, liver biopsies, and even intercostal chest drains can cause abdominal visceral injuries resulting in acute bleeds, or intestinal perforations requiring surgical intervention. ERCP results in postprocedural acute pancreatitis in approximately 10% of patients, the management of which is conservative. Other forms of endoscopy such as col- onoscopy can result in intestinal perforations, most commonly following the use of diathermy for polypectomy. These are some- times managed conservatively, but others will inevitably have to undergo laparotomy. Medical causes of an acute abdomen Diabetic ketoacidosis Abdominal pain is present in almost 50% of patients suffering diabetic ketoacidosis. In about one-​third of these patients, the cause of the pain is the precipitating factor inducing the diabetic crisis. In the remaining two-​thirds, the abdominal pain occurs secondary to the diabetic ketoacidosis, and here the abdom- inal pain rapidly resolves following correction of the underlying metabolic derangements. Radiological imaging is useful in differentiating those requiring surgical intervention from those who do not. Table 15.4.1.2  Surgical management of common causes of acute abdomen Pathology Management Acute appendicitis Urgent surgery to be considered, normally via a laparoscopic approach Conservative management (antibiotics) in selected cases (comorbidity, appendix mass, patient choice) Strangulated hernia Immediate surgery ± bowel resection if nonviable Small-​bowel obstruction Normally conservative approach (nasogastric tube and intravenous infusion) for up to 48 h in the absence of pain or a raised white cell count. If conservative approach fails, the patient will require laparotomy Large-​bowel obstruction Generally surgical resection with either primary anastomosis or stoma. Immediate in the presence of right iliac fossa tenderness as this suggests a closed-​loop obstruction with imminent caecal perforation Colonic stenting in selective cases determined by aetiology and comorbidity Intestinal ischaemia Immediate surgery with resection of nonviable bowel. On occasion, revascularization if bowel has not infracted Perforated peptic ulcer Urgent surgery (laparoscopic or laparotomy) with repair Conservative approach in the elderly with minimal abdominal signs Acute diverticulitis Antibiotics for uncomplicated diverticulitis Radiological drainage of abscesses Laparoscopy and washout may be considered for selected cases Laparotomy and surgical resection for free perforation with faecal contamination Sigmoid volvulus Flexible sigmoidoscopy and decompression with possible flatus tube insertion Acute pancreatitis Conservative and organ-​supportive management in the first instance Acute cholecystitis Either urgent ‘hot’ laparoscopic cholecystectomy or alternatively antibiotics and delayed surgery Biliary colic Analgesia and nonurgent laparoscopic cholecystectomy Obstructive jaundice ± cholangitis Urgent endoscopic retrograde cholangiopancreatography (ERCP) Ruptured abdominal aortic aneurysm Immediate endovascular aneurysm repair or open aneurysm repair if patient is medically fit

SECTION 15  Gastroenterological disorders 2770 Herpes zoster Shingles can generate an extremely painful, unilateral dermatomal eruption. Commonly the pain precedes the appearance of the rash by 2 to 3 days, when diagnostic confusion can arise. Acute urinary retention An acutely painful lower abdomen and inability to pass urine should raise suspicion of urinary retention, which can be confirmed by clin- ical examination and a bladder scan. However, on occasion urinary retention can occur secondary to an intra-​abdominal pathology, hence if the pain persists following catheterization then an alterna- tive explanation for the patient’s symptoms should be sought. Rectus sheath haematoma This relatively rare condition is characterized by the accumulation of a haematoma within the rectus sheath and is associated with anticoagulation, abdominal trauma, and coughing. More common in women, it presents with acute abdominal pain and a palpable abdominal mass. Ultrasonography or CT scanning can differen- tiate the haematoma from an intra-​abdominal source when there is diagnostic doubt. It is a self-​limiting condition that does not re- quire surgical/​radiological intervention, although correction of overanticoagulation may be needed. Pneumonia It is not uncommon for lower lobe pneumonia to present with upper abdominal pain. A chest radiograph can diagnose this, but it should be borne in mind that on occasion pneumonia can occur as a result of an upper intra-​abdominal pathology causing basal atelectasis and thus secondary infection. Gastroenteritis In addition to diarrhoea and/​or vomiting, patients may also suffer with abdominal pain. Laboratory tests and stool cultures can con- firm the diagnosis, and a CT scan can be a useful adjunct if there is diagnostic doubt. Constipation Constipation is common in the elderly, even more so in combination with neurological disease such as Parkinson’s disease. In addition to abdominal distension and failure to pass stool, the patient may complain of abdominal pain. The ongoing passage of flatus can be reassuring, but imaging may be required to exclude a mechanical blockage. Addisonian crisis Abdominal pain as a presenting sign in an acute adrenal crisis is a well-​recognized phenomenon. Diagnosis can be confirmed on la- boratory blood tests. If in doubt, intravenous hydrocortisone should be given immediately. Spontaneous splenic rupture This rare but life-​threatening condition can occur secondary to various aetiologies. It is most commonly associated with haematological malignancies and systemic infections such as infec- tious mononucleosis. There are rarer associations with local inflam- matory processes such as pancreatitis, pregnancy, and drug use (e.g. granulocyte colony-​stimulating factor). Most cases require imme- diate laparotomy and splenectomy. The overall mortality rate is ap- proximately 10%, although is significantly higher in those with an underlying neoplastic process. Cocaine abuse There are an estimated 1  million cocaine users in the United Kingdom. While there are many well-​recognized cardiovascular and respiratory conditions associated with its use, there are uncom- monly some severe, life-​threatening, intra-​abdominal conditions which are also related. Gastrointestinal perforations have been reported both near the gastric pylorus and mesenteric ischaemia in locations throughout the gut causing perforations secondary to acute vasoconstriction and subsequent infarction. Crack cocaine abuse more commonly causes upper gastrointestinal perforations and has also been associated with ischaemic colitis. Surgical man- agement is generally laparotomy and resection and mortality rates are high (approximately 20%). Acute porphyria The autosomally dominant inherited metabolic disorder por- phyria has an approximate incidence of 1 in 10 000. Abdominal pain is a common presenting symptom, but abdominal tenderness is seldom present. Diagnosis is made on biochemical analysis. Surgery should be avoided in the absence of convincing evidence of a surgically remediable cause. See Chapter  12.5 for further discussion. FURTHER READING ASGE Standards of Practice Committee (2011). Complications of col- onoscopy. Gastrointest Endosc, 74, 745–​52. Hansson J, et al. (2009). Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg, 96, 473–​81. Paterson-​Brown S (ed) (2013). Core topics in general and emergency surgery, 5th edition. Saunders/​Elsevier, Edinburgh. Renzulli P, et al. (2009). Systematic review of atraumatic splenic rup- ture. Br J Surg, 96, 1114–​21. Siegel JD, et al. (2005). Medical treatment of constipation. Clin Colon Rectal Surg, 18, 76–​80. Tiwari A, et al. (2006). Life threatening abdominal complications fol- lowing cocaine abuse. J R Soc Med, 99, 51–​2. UK Working Party on Acute Pancreatitis (2005). UK guidelines for the management of acute pancreatitis. Gut, 54, Suppl 3, iii1–​9. Umpierrez G, et al. (2002). Abdominal pain in patients with hypergly- caemic crises. J Crit Care, 17, 63–​7. Vennix S, et al. (2015). Laparoscopic peritoneal lavage or sigmoidectomy for perforated diverticulitis with purulent peritonitis: a multicentre, parallel-​group, randomised, open-​label trial (LADIES Trial). Lancet, 386, 1269–​77.

15.4.2 Gastrointestinal bleeding 2771

15.4.2 Gastrointestinal bleeding 2771

15.4.2  Gastrointestinal bleeding 2771 15.4.2  Gastrointestinal bleeding Vanessa Brown and T.A. Rockall ESSENTIALS Gastrointestinal bleeding (GIB) is a common emergency, which can be subdivided into upper and lower, and acute or chronic, with acute upper GIB further subdivided into variceal (11%) and nonvariceal (89%) bleeding. Risk stratification in acute upper GIB can be performed using simple clinical and endoscopic criteria that can be used to estimate the risk of mortality, but there are no validated systems for use in acute lower GIB. The immediate management of the hypovolaemic patient is first directed towards resuscitation and then to identification of the site and cause of bleeding. Most patients will stop bleeding spontan- eously and should then be investigated with either upper gastro- intestinal endoscopy or colonoscopy as appropriate. Patients with acute ongoing upper GIB require urgent investiga- tion by oesophagogastroduodenoscopy with a view to applying endoscopic haemostatic therapy, which is efficacious in up to 95% of patients. High-​dose proton pump inhibitor treatment should be given following successful endoscopic therapy to patients with major ulcer bleeding. If these techniques fail to arrest bleeding, then ei- ther selective mesenteric angiography with embolization or surgery is indicated. Patients who are unstable with acute lower GIB require early oesophagogastroduodenoscopy (to exclude an upper gastrointes- tinal cause) and then an interventional radiological procedure to embolize the bleeding vessel(s); surgery is generally a last resort. Introduction Gastrointestinal bleeding (GIB) is a common emergency, with approximately 85 000 cases per year in the United Kingdom. It is subdivided into upper and lower, and acute or chronic, with acute upper gastrointestinal haemorrhage further subdivided into variceal (11%) and nonvariceal (89%) bleeding. Despite significant advances in the management of GIB, particu- larly the introduction of proton pump inhibitors (PPIs) and advances in endoscopy, published mortality rates remain similar to the 1950s. This is because patients presenting with acute upper GIB are now older and have more comorbidities. The incidence of peptic ulcers in younger patients has fallen since the introduction of PPIs. Mortality therefore is often due to the complications associated with advanced age and multiple comorbidities as opposed to exsanguination. In-​ hospital mortality for patients admitted with acute upper GIB is 7%, but up to 15% of acute upper GIB occurs in established inpatients and is associated with a much higher mortality rate of approximately 30%. A recent report has recommended that patients with any acute GIB should only be admitted to hospitals with 24-​h on-​site endoscopy, GIB surgery, critical care, and 24-​h access to interventional radiology. Definition Acute gastrointestinal haemorrhage is classified by its origin, from either the upper or the lower gastrointestinal tract, anatomically de- marcated by the ligament of Treitz (at the junction of the duodenum and jejunum). Upper GIB is further subdivided into nonvariceal and variceal haemorrhage. Only when gastrointestinal bleeding is acute does it constitute an emergency. Chronic, low-​volume blood loss is usually subclinical until such time as it presents with iron deficiency anaemia. Acute upper gastrointestinal bleeding Aetiology and pathogenesis Many gastrointestinal lesions may result in haemorrhage but peptic ulcer is the most frequent cause of acute UGIB in the United Kingdom (Table 15.4.2.1). Each diagnostic group has its own aetiological factors. Peptic ulcer disease Peptic ulcer disease accounts for 35% of cases of acute upper GIB. Helicobacter pylori infection and ingestion of aspirin and nonsteroidal anti-​inflammatory drugs (NSAIDs) are important aetiological factors for peptic ulcer disease. Stress ulcers can de- velop in critically ill patients, for example, those in intensive care environments, and are caused by mucosal ischaemia. Ulceration may also occur at the site of surgical enterostomies (stomal ulcers) and in association with the Zollinger–​Ellison syndrome. Peptic ul- ceration at specific sites is associated with major haemorrhage due to the anatomical relation of major arteries—​the posterior wall of the first part of the duodenum (gastroduodenal artery), the lesser curve of the stomach (left gastric artery), and posterior wall of stomach (splenic artery). Varices Variceal bleeding is increasing in incidence. In Western countries, liver disease due to alcohol and hepatitis are the principal causes of portal hypertension, which leads to oesophageal varices; vari- ceal bleeding may rarely affect the stomach and the remaining Table 15.4.2.1  Diagnoses following acute upper gastrointestinal haemorrhage Diagnosis % Peptic ulcer 35–​50 Erosive disease 10–​15 Oesophagitis 10 Mallory–​Weiss tear 5–​10 Oesophageal varices 5–​10 Upper gastrointestinal malignancy <5 Vascular malformations 5 Other/​not established 5–​15

SECTION 15  Gastroenterological disorders 2772 gastrointestinal tract. Bleeding from varices is often severe and com- plications associated with underlying liver disease mean this patient group are best managed by specialists in the care of patients with liver disease. Mallory–​Weiss tears These are mucosal lesions at the oesophagogastric junction asso- ciated with profuse vomiting (most commonly from alcohol). The haematemesis that occurs follows a normal vomit, and is usually minor and nearly always self-​limiting. Erosive disease Oesophagitis due to gastro-​oesophageal reflux disease, gastritis, duodenitis, and gastroduodenal erosions are associated with the use of aspirin, NSAIDs, and H. pylori infection. Rare causes The most common malignant causes of upper gastrointestinal haem- orrhage are adenocarcinoma of the stomach and gastric lymphoma, but acute bleeding is an unusual presentation. Other causes include gastrointestinal stromal tumours, which may bleed when the mu- cosal surface ulcerates, angiodysplasia (and other vascular lesions), aortoduodenal fistula, haemobilia, and trauma. Epidemiology The incidence of acute upper GIB in the United Kingdom is approxi- mately 1 per 1000 adults/​year, accounting for 50 000 to 70 000 acute hospital admissions per year. Fifteen per cent of cases occur in patients already in hospital. The male incidence is twice that of the female in all age groups except older people, where they are similar. The annual in- cidence increases dramatically with age, in a recent nationwide survey of patients requiring 4 or more units of blood, the mean age for vari- ceal upper GIB was 53 and for nonvariceal was 73 years old. Prevention All patients with a peptic ulcer should be tested for H. pylori infec- tion, and if positive, eradication therapy should be prescribed. This significantly reduces the risk of ulcer recurrence. Patients in hospital, particularly elderly people and those who have had surgery, are at higher risk of acute upper GIB. For this group when prescribing NSAIDs, it is prudent to consider coprescription of a PPI. Variceal haemorrhage can be prevented through programmes of variceal eradication by injection or banding and also by transjugular intrahepatic portosystemic shunt, or ultimately liver transplantation where indicated. Clinical features History The most common presentation in major acute upper GIB is haema- temesis or ‘coffee-​ground’ vomiting, melaena (see Box 15.4.2.1), and a decrease in haemoglobin. Frank haematemesis indicates a severe bleed. It is not always a feature, but melaena will always follow a significant bleed. The absence of blood in the first vomit suggests a Mallory–​Weiss tear. In rapid bleeding, symptoms of hypovolaemia may precede haematemesis or melaena. These include postural hypotension, syn- cope, shock, and even death. It is particularly important to pursue the past medical history for evidence of liver disease (alcohol, risk factors for hepatitis). With re- gard to drug history, the patient should be asked about ingestion of aspirin and other NSAIDs, and anticoagulants. The use of β-​blockers may mask tachycardia associated with shock. Examination The first concern must be airway, breathing, circulation: the patient must be assessed rapidly for signs of hypovolaemic shock. Signs of liver disease may be present in patients with oesophageal varices, but this does not confirm the cause of blood loss since peptic ulcer is a common synchronous lesion. Rectal examination looking for fresh blood or evidence of melaena must not be neglected. Differential diagnosis In patients with rapid haemorrhage, usually accompanied by shock, fresh blood may be passed per rectum (haematochezia) and thus is difficult to distinguish from lower GIB. A large nasopharyngeal bleed, resulting in a significant volume of swallowed blood, can also present with haematemesis. Investigations Acute upper GIB is mainly a clinical diagnosis. Full blood count and coagulation tests In actively bleeding patients, the haemoglobin concentration will only fall after haemodilution has occurred, hence the initial haemo- globin estimation is not a useful indicator of the volume of blood loss. The haemoglobin level may be normal in a patient with a large, acute haemorrhage and cannot be relied upon to guide resuscita- tion. Equally, it may be low in a patient with iron deficiency anaemia resulting from chronic haemorrhage who presents with a small, acute bleed. The haemoglobin and haematocrit concentrations after volume resuscitation are more useful. Platelet count and coagula- tion studies are important to exclude a bleeding disorder and are of particular relevance in patients receiving therapeutic anticoagulants and in those with liver disease. Other blood tests Urea, creatinine, and electrolytes should be checked: the serum urea may rise disproportionately to the serum creatinine as the absorbed products of luminal blood are metabolized by the liver, and it is important to establish baseline renal function. Serum liver-​related tests are required as a marker of liver disease. Group and save, or cross-​match, may be required depending on clinical severity. Endoscopy Required for both diagnosis and treatment, as discussed later. Box 15.4.2.1  Melaena This is a clinical diagnosis made on the observation of black, tarry, offensive stool on rectal examination (or passed spontaneously). It occurs as the result of digestive enzymes and bacteria acting on haemoglobin. Although melaena is usually due to acute upper GIB, bleeding from the small bowel or right side of the colon may also pre- sent in this way.

15.4.2  Gastrointestinal bleeding 2773 Management The management of acute upper GIB falls into four principal stages (Box 15.4.2.2). A pathway for management is shown in Fig. 15.4.2.1. Resuscitation, assessment, and monitoring Resuscitation Resuscitation is as for any hypovolaemic patient, with the immediate aim of rapidly restoring blood volume. Tachycardia, vasoconstric- tion, sweating, hypotension (including a postural drop), tachyp- noea, and a low central venous pressure all indicate hypovolaemia. Large-​bore peripheral venous access, central venous access, and Resuscitation

  1. Adequate IV access - Large-bore peripheral venous access plus/minus central venous access
  2. Urinary catheter
  3. Balanced transfusion • Blood, platelets, and FFP as per local haematology guidelines • Activate massive transfusion protocol if necessary
  4. Correct coagulation abnormalities
  5. Monitoring - regular pulse, blood pressure, urine output and central venous pressure (if available). Transfer to high dependency setting if necessary
  6. Drugs • Terlipressin if risk of variceal bleeding • Consider Tranexamic acid
  7. Risk assessment
  8. Early involvement of anaesthetists and surgeons if ongoing haemodynamic compromise
  9. All patients should have a documented rebleed plan that should be updated after every intervention OGD Nonvariceal •Endoscopic treatment with dual therapy •Start PPI Variceal •Prophylactic anitbiotics •Oesophageal varices – band •Gastric varices – N-butyl-2- cyanoacrylate Second OGD Interventional Radiology? Mesenteric angiogram ± embolization Surgery TIPS Stable Unstable Rebleeding No Yes Rebleeding Fig. 15.4.2.1  Pathway for management of acute upper GIB. FFP, fresh frozen plasma; OGD, oesophagogastroduodenoscopy; PPI, proton pump inhibitor; TIPS, transjugular intrahepatic portosystemic shunt. Box 15.4.2.2  Management of acute upper GIB 1 Resuscitation, assessment, and monitoring 2 Diagnosis and haemostasis: —​ Endoscopy —​ Interventional radiology —​ Surgery —​ Drugs 3 Treatment of causative lesion: —​ Nonvariceal —​ Variceal 4 Prevention of recurrence

SECTION 15  Gastroenterological disorders 2774 placement of a urinary catheter will help in the resuscitation and monitoring of more severe cases and those with major cardiovas- cular and respiratory comorbidity. A haemoglobin concentration less than 7 g/​dl is associated with compromised cardiac function and impaired tissue oxygenation. However, overtransfusion may be as damaging as undertransfusion, particularly in elderly patients with multiple comorbidities, and there has been much recent debate regarding indications for blood transfusion. Recent studies with varying levels of evidence have concluded that a restrictive policy and low trigger threshold for transfusion is beneficial, and that even if there is no absolute clin- ical advantage of a restrictive practice, then—​as long as this is not detrimental—​avoidance of blood transfusion both reduces transfu- sion risk and saves the health economy money. Decisions on trans- fusion should be patient specific, taking into account underlying comorbidities and their ability to tolerate an aggressive restrictive transfusion strategy. All patients with massive bleeding should have replacement of blood, platelets, and clotting factors in order to restore volume and maintain clotting, which should be administered in line with local major transfusion protocols (Box 15.4.2.3). The National Institute for Health and Care Excellence (NICE) recommends that (1) plate- lets should be given to actively bleeding patients with platelet concentrations of less than 50 × 109 (but not to those that are haemodynamically stable and not actively bleeding), and (2) fresh frozen plasma should be given if the concentration of fibrinogen is less than 1 g/​litre (with cryoprecipitate offered if fibrinogen levels remain <1.5 g/​litre despite fresh frozen plasma) or if INR or acti- vated partial thromboplastin time are greater than 1.5 times the normal value. Assessment of risk There are several scoring systems to predict the need for interven- tion, risk of rebleeding, and risk of death. The simplest and most widely used scoring system is the Rockall score, which was devel- oped to stratify patients for the risk of death. The full Rockall score can only be calculated after endoscopy. The Blatchford score can be used prior to endoscopy and is a better predictor of rebleeding and the need for intervention. Both the Rockall score and the Blatchford score have been extensively externally validated. Recent NICE guidelines recommended that all patients with acute upper GIB should have a formal risk assessment with the Blatchford score at first assessment and the full Rockall score after endoscopy. Early discharge should be considered in patients with a Blatchford score of 0. Independent risk factors that accur- ately predict mortality have been identified (see ‘Prognosis’ and Tables 15.4.2.2 and 15.4.2.3). These include increasing age, comorbidity, shock, and endoscopic findings. Monitoring Once circulating blood volume has been restored, management should be aimed at monitoring the patient for continued or recur- rent bleeding, replacing blood, making a diagnosis, and instituting therapy. Regular pulse, blood pressure, central venous pressure, and urine output will give a good guide. High-​risk patients should be monitored in a high-​dependency unit or intensive therapy unit. Ten to fifteen per cent of patients with an acute upper GIB will have a rebleed, and all patients should have a documented rebleed plan that should be updated after every intervention. While further fresh haematemesis obviously indicates another acute haemorrhage, the passage of further melaena has to be interpreted in the light of the cardiovascular signs and repeated estimations of blood haemo- globin concentration. Table 15.4.2.2  The Rockall score: acute upper gastrointestinal haemorrhage scoring system Variable Score 0 1 2 3 Age (years) <60 60–​79 ≥80 Shock ‘No shock’ ‘Tachycardia’ ‘Hypotension’   Systolic BP (mmHg) ≥100 ≥100 <100   Pulse (beats/​min) <100 ≥100 Comorbidity No major comorbidity Cardiac failure Renal failure Ischaemic heart disease Liver failure Any major comorbidity Disseminated malignancy Diagnosis Mallory–​Weiss tear All other diagnoses Malignancy of upper
gastrointestinal tract No lesion identified and no stigmata of recent haemorrhage Major stigmata of recent haemorrhage None or dark spot only Blood in upper gastrointestinal tract Adherent clot Visible or spurting vessel Box 15.4.2.3  Definition of major haemorrhage—​when to activate the major transfusion protocol Loss of more than • 1 × blood volume in 24 h • 50% of blood volume in less than 3 h • Greater than 150 ml/​min

15.4.2  Gastrointestinal bleeding 2775 Diagnosis and haemostasis Haemostasis occurs spontaneously in most cases. When bleeding continues, haemostasis can be achieved by endoscopic, radiological, or surgical means. Endoscopy Endoscopy is the diagnostic and therapeutic investigation of choice in all patients with upper GIB (Box 15.4.2.4) but should only occur after optimal resuscitation. NICE (2013) recommends oesophagogastroduodenoscopy is performed within 2 h of op- timal resuscitation in those patients with haemodynamic com- promise, and within 24 h of all those with a presentation of an upper GIB. Patients in whom haemodynamic stability cannot be achieved despite adequate resuscitation should have concomitant oesophagogastroduodenoscopy and resuscitation. These patients should be discussed with anaesthetists early as they are at increased risk of aspiration and often require postprocedural critical care. Endoscopic haemostatic therapy may be given in the form of the following: • Injection of adrenaline—​this is performed in quadrants around the bleeding point, and then into the bleeding vessel, using a total of 4 to 16 ml of a 1:10 000 adrenaline solution in normal saline. Haemostasis is achieved in 95% of cases, although bleeding can recur in 15 to 20%. Adrenaline injection alone is inferior to dual-​ modality treatments or mechanical clipping. • Mechanical—​clips can be applied to bleeding points and are par- ticularly useful for actively bleeding large vessels (Fig. 15.4.2.2). • Thermal energy—​the application of heat energy in the form of a heater probe or diathermy is effective. The heater probe is useful because it includes a powerful water jet which aids clot removal. Laser therapy is no longer used. • Fibrin glue or thrombin works by encouraging clot formation and has been shown to be effective. • Injection of other agents such as sclerosants (e.g. polidocanol) or alcohol does not confer additional advantage, but does increase the risk of perforation There is good trial evidence that endoscopic therapy reduces the rate of rebleeding and mortality. The reported rate of rebleeding after endoscopic therapy is between 5 and 20%. A  peptic ulcer greater than 2 cm in size and hypotension are both risk factors for rebleeding. Endoscopic therapy can be repeated if a patient rebleeds and cur- rent evidence supports two attempts at endoscopic control in most cases. Repeat endoscopy confirms that bleeding has recurred and can allow further endoscopic treatment. It can also enable plan- ning as metal clips placed at the site of bleeding can be used to guide subsequent radiological management. The benefits of further endoscopic therapy need to be balanced against the risk of delaying definitive treatment should further bleeding occur. Patients who rebleed after endoscopic treatment and are unstable should have interventional radiology or urgent surgery if interven- tional radiology is not immediately available. There is no evidence from randomized controlled trials that planned, repeated endo- scopic therapy further reduces rebleeding in peptic ulcer. Repeated injection or banding has been shown to reduce rebleeding and mor- tality from oesophageal varices. A second attempt at endoscopic therapy should be made (espe- cially in young patients) before resorting to surgery, although there is rarely any place for a third attempt. Radiological studies and interventions Nuclear scintigraphy  Nuclear scintigraphy, discussed further in the section on acute lower GIM, can be used to detect active haem- orrhage but cannot determine the underlying cause (Fig. 15.4.2.3). Table 15.4.2.3  Observed rebleeding and mortality by risk score Score 0 1 2 3 4 5 6 7 8+ Rebleed (%) 4.9 3.4 5.3 11.2 14.1 24.1 32.9 43.8 41.8 Deaths no rebleed (%) 0 0 0.3   2.0   3.5   8.1   9.5 14.9 28.1 Deaths with rebleed (%) 0 0 0 10.0 15.8 22.9 33.3 43.4 52.5 Deaths total (%) 0 0 0.2   2.9   5.3 10.8 17.3 27.0 41.1 Box 15.4.2.4  The aim of endoscopy is: 1 To confirm the diagnosis and aetiology 2 To apply haemostatic therapy where appropriate 3 To assess the risk of further haemorrhage based upon the site, size, and nature of the lesion (including stigmata of recent haemorrhage) 4 To inform the radiologist or surgeon as to the site of the lesion in cases requiring urgent surgery due to rapid, ongoing blood loss, and to exclude varices in these cases Fig. 15.4.2.2  Clipped bleeding in Mallory–​Weiss tear. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press.

SECTION 15  Gastroenterological disorders 2776 In cases where maximal endoscopic therapy has failed, inter- ventional radiology and embolization of the bleeding vessel is the second-​line treatment. In those patients with a duodenal ulcer, this is often the gastroduodenal artery. Recent guidance stated ‘No pa- tient should undergo surgery for nonvariceal upper GI bleeding without first undergoing endoscopic treatment, and if this fails or is inappropriate, interventional radiology’ (Fig. 15.4.2.4). CT angiography can detect bleeding rates higher than 0.3 to 0.5 ml/​min. It allows assessment of the entire gastrointestinal tract and can delineate between upper and lower GIB when the diagnosis is in doubt. It has an accuracy of up to 89%, can be used to localize the site of bleeding, and can guide radiological or surgical inter- vention. Mesenteric catheter angiography allows identification and embolization of any bleeding points, but requires specialized skill to selectively cannulate often second-​ or third-​order arterial branches. As with endoscopy, these patients should be discussed with an- aesthetists early as they often require concomitant resuscitation and postprocedural critical care. Surgery Due to advances in endoscopic and radiological treatments, emer- gency surgery for acute upper GIB is now rarely undertaken and is generally considered a last resort. It is indicated in massive, acute bleeding not amenable to endoscopic therapy, or where endoscopic therapy fails to control active bleeding, with operative mortality being of the order of 30%. Elective or semielective surgery is indicated when malignancy is suspected or in lesions considered at high risk of perforation, and there is some evidence that early surgical intervention in those older than 60 is appropriate. It is important to inform an experi- enced surgeon about the possible need for surgery at an early stage. All patients should have a formal assessment of preoperative risk to inform postoperative care and treatment decisions, and a docu- mented rebleed plan should bleeding recur after surgery. Drugs Acid suppression  Patients in critical care should be given acid suppression with PPIs or H2 receptor antagonists to prevent upper GIB. This medication should be reviewed on discharge. Tranexamic acid  Tranexamic acid is recommended in patients with ongoing haemodynamic compromise or a delay in intervention. The HALT-​IT trial—​a randomized, double blind, placebo-​controlled trial which intends to recruit 12 000 patients—​is evaluating whether Fig. 15.4.2.3  Tagged red blood cell scan showing radiotracer activity in the right upper quadrant (black arrows) in a 48-​year-​old woman with a history of a roux-​en-​Y gastric bypass who presented with melaena. From Covey AM, Pua BP, Aguado A, Madoff DC (2014). Interventional radiology cases. By permission of Oxford University Press. (a) (b) Fig. 15.4.2.4  (a) Superselective arteriogram of a branch of the pancreaticoduodenal artery shows contrast extravasation into the duodenum (arrow) in the patient whose tagged red cell scan is shown in Fig. 15.4.2.3. (b) Following coil embolization to exclude the bleeding branch. From Covey AM, Pua BP, Aguado A, Madoff DC (2014). Interventional radiology cases. By permission of Oxford University Press.

15.4.2  Gastrointestinal bleeding 2777 the early administration of tranexamic acid to patients with acute GIB reduces mortality. It is due to finish recruitment in May 2019. Anticoagulants and antiplatelet agents  In life-​threatening haem- orrhage warfarin should be stopped and the INR corrected with vitamin K and prothrombin complex concentrate in line with local haematology protocols. In the acute bleeding phase, NSAIDs (including cyclooxygenase-​2 inhibitors) should be stopped until bleeding is controlled. Low-​dose aspirin for secondary prevention can be continued once haemostasis has been achieved. For patients on clopidogrel or dipyridamole, the risk and benefits of continuing should be discussed with the patient and the appropriate specialist. Treatment of causative lesion Treatment of the causative lesion should be started as soon as possible after diagnosis. Non variceal upper GIB Maintaining gastric pH higher than 6.5 enhances platelet aggrega- tion and stabilizes clot formation, but there is no evidence that the use of PPIs prior to endoscopy changes clinical outcomes; hence, in patients with major ulcer bleeding—​following successful endo- scopic therapy—​treatment with a high-​dose PPI is recommended in accordance with local hospital guidelines (e.g. omeprazole 80 mg immediately followed by an infusion of 8 mg hourly for 72 h). PPIs are effective in healing peptic ulcers and have been shown to reduce the risk of rebleeding in patients with a nonbleeding visible vessel, although studies have not demonstrated a significant reduction in overall mortality. Elective surgery may be indicated where the causative lesion is a tumour (benign or malignant). Angiodysplasia can be treated with laser or argon beam therapy. Specific treatments may be required for rarer causes such as Crohn’s disease or tuberculosis. Variceal upper GIB A recent report has shown that patients with alcoholic liver disease who present with an upper GIB are equally likely to have a variceal as a nonvariceal bleed. The oesophagus is the site of varices in 80% of patients with cirrhosis. Current guidelines recommend that patients with suspected or confirmed variceal bleeding should have terlipressin and prophy- lactic antibiotics at presentation. Terlipressin is a long-​acting ana- logue of vasopressin and works by reducing portal pressure by constricting splanchnic arterioles. When used in conjunction with endoscopic therapy it has been shown to improve mortality and de- crease rebleeding rates. It should be stopped after definitive haemo- stasis or after 5 days. Prophylactic antibiotics have been shown to reduce the incidence of bacteraemia and spontaneous bacterial peritonitis. Uncontrolled variceal haemorrhage may be controlled with a Sengstaken–​Blakemore tube as a temporary measure before more definitive treatment (Fig. 15.4.2.5). Endoscopic band ligation should be the first-​line therapy in all patents with oesophageal variceal upper GIB and has been shown to have a significant mortality benefit. Patients with bleeding gastric varices should be offered endoscopic injection of N-​butyl-​2-​cyanoacrylate. Transjugular intrahepatic portosystemic shunt is a minimally in- vasive method of creating a portosystemic shunt, thereby reducing portal pressure. It is the recommended therapy for bleeding oe- sophageal and gastric varices that are not responsive to endoscopic management (Fig. 15.4.2.6). Outcomes for patients with variceal upper GIB are affected by the severity of the underlying liver disease and the degree of bleeding; hence, patients with variceal upper GIB should have a formal assess- ment of the severity of cirrhosis by a Childs–​Pugh score and ideally be managed by a specialist hepatologist. Oesophageal transection is now rarely undertaken, but is occa- sionally life-​saving where all other attempts at haemostasis have failed, although is associated with a very high mortality. Fig. 15.4.2.5  Sengstaken–​Blakemore tube. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press. Fig. 15.4.2.6  Transjugular intrahepatic portosystemic shunt following deployment. The white arrows point to the ends of the shunt. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press.

SECTION 15  Gastroenterological disorders 2778 Prevention of recurrence Recurrent episodes of bleeding from peptic ulcers can be prevented by eradicating H.  pylori infection and through the avoidance of ulcerogenic drugs. Persistent ulceration despite these measures may require long-​term acid suppressive therapy. Zollinger–​Ellison syn- drome should be excluded. Prognosis Prognosis depends on many factors including the severity of the bleed, the age of the patient, the associated comorbidity of the patient, the diagnostic category, the endoscopic features (stigmata of recent haem- orrhage), and whether continued or recurrent bleeding is a feature. Overall, the crude mortality for patients presenting to emergency departments with acute upper gastrointestinal haemorrhage is about 10%, but is significantly higher (approximately 30%) among in- patients who develop GIB while hospitalized for other reasons. Most deaths occur in older people and those with severe comorbidity. Death in those under the age of 60 with no comorbidity is very low (0.1%) regardless of the severity of the haemorrhage. The factors that contribute to mortality have been combined in a prognostic risk score which is represented in Table 15.4.2.2. The mortality associ- ated with each risk score is represented in Table 15.4.2.3. Acute lower gastrointestinal bleeding Epidemiology Lower GIB accounts for approximately 1% of acute hospital admis- sions. It is three times less common than upper GIB and has a signifi- cantly lower mortality (2.2%). Lower GIB occurs more commonly in the elderly, with a mean age of 74 years at presentation in a recent national study in the United Kingdom. In contrast to upper GIB, pa- tients present with a higher haemoglobin concentration, less shock, and are less likely to require a blood transfusion. Approximately 15% of patients with acute severe rectal bleeding/​haematochezia will have an upper gastrointestinal source of bleeding. Most (80–​85%) acute lower GIBs will stop spontaneously, al- though 35% will require blood transfusion, 25% of those with severe lower GIB will have a rebleed, and 5 to 10% will require urgent sur- gical intervention. Aetiology As in upper gastrointestinal haemorrhage, several pathological causes are responsible. Most causative lesions are colonic or ano- rectal, with 0.7 to 9% originating in the small bowel (Table 15.4.2.4). In developed countries, diverticular disease represents the largest proportion of cases. Bleeding is not uncommonly associated with coagulopathy, but studies have shown the distribution of causative lesions in these cases to be the same, although in severe cases there may be generalized mucosal bleeding. Diverticular disease Acute colonic diverticular bleeding is common. The estimated risk of bleeding with this disease is about 15%. After a single bleed, the risk of recurrence is 25%, and after two bleeds it is 50%. Eighty per cent of all bleeds stop spontaneously and no therapy is indicated. Operative intervention should be considered after two major bleeds because the risk of further recurrence is high. However, many of these patients are frail and elderly, and continuation of conservative treatment for multiple, self-​limiting episodes may be appropriate. Inflammatory bowel disease This often manifests itself as bloody diarrhoea, but more rarely may present with profuse haemorrhage. This is more common in Crohn’s disease than in ulcerative colitis because the inflammation involves the whole thickness of the bowel wall, and up to 6% of patients with this disease may sustain a major haemorrhage. About 50% stop bleeding spontaneously, but of these 35% will rebleed. For this reason, urgent surgery is usually indicated for patients with a life-​threatening haemorrhage as a result of inflammatory colitis. The operation usually required is a subtotal colectomy, with the rectum usually being pre- served at this stage unless this is the site of major haemorrhage. Ischaemic colitis rarely causes severe haemorrhage. Bloody diar- rhoea is more usual and may be accompanied by pain. Colonic tumours Benign and malignant colonic tumours may present as profuse bleeding, although occult blood loss and minor fresh bleeding is more common. A history of change in bowel habit, weight loss, and pain are suggestive of colorectal cancer. Rarely is urgent surgical intervention required. Angiodysplasia Vascular anomalies occur with increasing frequency with age. They may originate from chronic, partial venous obstruction of sub- mucosal veins due to incompetence of the precapillary sphincters and arteriovenous malformations. These lesions are usually mul- tiple and are most frequent in the caecum and ascending colon. Bleeding is usually slow, intermittent, and recurrent, although it is occasionally massive (2–​15%). Most (90%) stop spontaneously, but 25 to 85% will recur. The treatment of choice is endoscopic coagu- lation if the lesions can be identified (Fig. 15.4.2.7). Colectomy is reserved for those with repeated major haemorrhage. Benign anorectal disease Benign anorectal disease does present as lower gastrointestinal haemorrhage and a careful examination of the anorectum (with proctosigmoidoscopy) is imperative before initiating more invasive Table 15.4.2.4  Source of lower gastrointestinal haemorrhage Diagnosis % Diverticulosis 35 Colonic polyp or cancer 15 Benign anorectal conditions (including haemorrhoids) 10 Inflammatory bowel disease (including ulcerative colitis, Crohn’s, infective colitis) 15 Ischaemic colitis 5 Angiodysplasia (including angiomas and arteriovenous malfunctions) 10 Small bowel (including Meckel’s diverticulum) 1–​2 Others (including rectal ulcer, postpolypectomy, radiation colitis, rectal varices) 10

15.4.2  Gastrointestinal bleeding 2779 examinations. However, anorectal lesions are common and com- plete colonic evaluation is usually required even after identifying an anorectal source such as haemorrhoids. Iatrogenic haemorrhage The risk of haemorrhage after polypectomy is estimated to be be- tween 0.2 and 3%. Haemorrhage is usually immediate but may be delayed by up to 2 weeks. When identified, endoscopic haemostatic techniques are usually successful (injection of adrenaline, resnaring, recoagulating, placement of a ligature or clip). Clinical features History A good history from the patient may give clues as to the cause of colo- rectal haemorrhage. Important points to explore include any prior history of bleeding; the exact nature of the bleeding, specifically the colour of the blood (bright red or altered), whether the blood is mixed with or separate from the stool, duration, and relationship to defeca- tion; and any associated change in bowel habit or mucus discharge. Bright red blood separate from the stool suggests an anorectal cause. Diarrhoea and mucous associated with darker blood mixed in with the stool suggests colitis or neoplasm. Bleeding from the small bowel or right colon can present with melaena. Other risk fac- tors which should be identified include a previous history of pelvic radiation which may suggest radiation colitis and personal history of liver cirrhosis with associated coagulopathy and varices. None of these clinical features, however, is absolutely diagnostic. It is also very important to explore comorbidities, which may signifi- cantly affect management, and drug usage, particularly of agents that affect coagulation or platelet function (aspirin, NSAIDs, and warfarin). Examination Aside from checking for evidence of hypovolaemia and shock, a full clinical examination should be performed, with particular focus on examination of the abdomen and rectum. Proctosigmoidoscopy is a simple bedside test and is mandatory to confirm or exclude ano- rectal causes of bleeding. Management A pathway for management of acute lower GIB is shown in Fig. 15.4.2.8. Resuscitation Immediate resuscitation is as for bleeding from the upper gastro- intestinal tract. In a patient with significant bleeding, it is essential that good intravenous access is established, even in the stable pa- tient. The patient should be catheterized, closely monitored, and if necessary transferred to a high-​dependency setting. Further management Since most lower GIBs stop spontaneously, initial management should be conservative with transfusion and correction of clotting abnormalities. Once haemorrhage has ceased, bowel preparation and colonoscopy can be undertaken in a stable patient and with a much higher chance of detecting the pathological lesion (>90%). In contrast to upper GIB, there are no validated scoring systems for lower GIB, but the following risk factors are associated with se- vere/​uncontrolled bleeding and/​or death: • Haemodynamic compromise including heart rate >100 bpm, systolic blood pressure <115 mm Hg, syncope • Age • Multiple comorbidities—​two or more doubles the risk of a severe bleed • Drugs that affect coagulation or platelet function (e.g. warfarin, NSAIDs, aspirin) • Second PR bleed within first 4 hours of admission • Inpatient lower GIB (mortality 23%) In the few patients in whom active colonic bleeding continues, in- vestigation to localize the source of the haemorrhage is indicated so that directed treatment can be administered in the form of endo- scopic therapy, interventional radiology, or surgery. Localization of bleeding Oesophagogastroduodenoscopy In a patient with significant lower GIB, it may be necessary to exclude an upper gastrointestinal source prior to evaluation of the colon. This is because massive upper GIB can masquerade as lower GIB, with up to 15% of patients presenting with haematochezia having an upper gastrointestinal source. An oesophagogastroduodenoscopy will ex- clude an upper gastrointestinal cause, although passing a nasogastric tube and checking the aspirate for blood was used historically. CT angiography CT angiography is now often the first line investigation for unstable LGIB with a sensitivity of 91–92%. This drops to 45% if the bleeding is intermittent. As in acute upper GIB, CT angiography can detect bleeding rates higher than 0.3 to 0.5 ml/​min. It can be used to differentiate be- tween upper and lower GIB, and can determine the underlying cause. The main use of CT angiography is to provide anatomical information about the site of bleeding and variance in vascular anatomy, as well as confirming active bleeding prior to invasive mesenteric angiography. It is a diagnostic tool only and is not therapeutic. Whilst it is re- peatable, CT angiography involves the use of iv contrast which can Fig. 15.4.2.7  Angiodysplasia on the ileocaecal valve. From Marks D, Harbord M (2013). Emergencies in gastroenterology and hepatology. By permission of Oxford University Press.

SECTION 15  Gastroenterological disorders 2780 have a detrimental effect on renal function and is associated with a risk of allergic reactions and exposure to ionizing radiation. Colonoscopy Colonoscopy can be both diagnostic and therapeutic and has a reported 90% sensitivity and 87% positive predictive value in identifying lower gastrointestinal sources of bleeding. However it is often technically challenging and its use in acute LGIB is there- fore often limited. The use of bowel preparation is still debated. In studies, some using bowel preparation and some without, the causative lesion was identified in approximately three-​quarters of patients. In a recent randomized controlled trial comparing urgent versus elective colonoscopy, there was little difference in outcomes. Treatment of bleeding in the right colon is associated with a higher perforation rate of 2.5%. Colonoscopy should be abandoned if massive haemorrhage obscures the diagnosis or severe mucosal or ischaemic colitis is encountered, as the risk of perforation in these cases is high. Control of active bleeding is an important therapeutic indi- cation for colonoscopy, with haemostasis achievable in many cases such as diverticular haemorrhage, angiodysplasia, and post­ polypectomy bleeding. In patients with postpolypectomy bleed­ ing where the approximate site of bleeding is known and can be endoscopically treated, colonoscopy should be considered as a first-line investigation as it has a reported technical success rate of 90 to 100%. Early OGD Interventional Radiology? Surgery Colonoscopy/ Flexible sigmoidoscopy Rigid sigmoidoscopy ± proctoscopy Mesenteric angiogram ± embolization Resuscitation

  1. Adequate IV access - Large-bore peripheral venous access plus/minus central venous access
  2. Urinary catheter
  3. Balanced transfusion • Blood, platelets, and FFP as per local haematology guidelines • Activate massive transfusion protocol if necessary
  4. Correct coagulation abnormalities
  5. Monitoring - regular pulse, blood pressure, urine output and central venous pressure (if available). Transfer to high dependency setting if necessary
  6. Drugs • Consider tranexamic acid
  7. Early involvement of anaesthetists and surgeons if ongoing haemodynamic compromise
  8. All patients should have a documented rebleed plan that should be updated after every intervention Stable Unstable Rebleeding Yes No Rebleeding Severe bleeding/ cannot be stabilized Rebleeding Fig. 15.4.2.8  Pathway for management of acute lower GIB. FFP, fresh frozen plasma; OGD, oesophagogastroduodenoscopy.

15.4.2  Gastrointestinal bleeding 2781 Control of bleeding can be accomplished with monopolar or bi- polar coagulation, heater probe, injection of various agents (such as adrenaline), use of Nd:YAG laser, and clipping. Endoscopic treatment of focal bleeding lesions in the colon is highly effective and safe, diminishing the need for surgical interven- tion. However, rebleeding rates have been reported of between 13 and 53%, and many patients require further treatments. Once LGIB has settled, urgent outpatient colonoscopy has an established role on determining the cause of the LGIB. Mesenteric angiography If colonoscopy fails to stop bleeding in acute lower GIB, selective mesenteric angiography is the second-​line treatment. About 10 to 15% of cases of acute lower GIB will eventually require endovascular intervention. Mesenteric angiography can detect a rate of bleeding of 0.5 to 1.0 ml/​min. The sensitivity of angiography reported in various studies ranges from 40 to 86%, although this may be increased by the use of so-​called provocative measures, such as vasodilators, heparin, or thrombolytic agents. Once the site of haemorrhage is identified, there is the therapeutic possibility of arterial selective embolization. Selective embolization using coil springs, polyvinyl alcohol foam, or gel foam into the most distal vessel results in high initial rates of haemostasis, and the rate of intestinal infarction is low. It is an especially good technique for patients with very high predicted operative mortality. Vasopressin infusion (via a catheter positioned in the artery sup- plying the site of bleeding)—​now less frequently used—​has con- siderable side effects including mesenteric thrombosis, intestinal infarction, myocardial ischaemia, hypertension, arrhythmias, and death. Nitroglycerine may be infused simultaneously to counteract the systemic effects of the drug. It can be used to treat bleeding from diffuse lesions or when superselective catheterization is not possible. Vasopressin infusion is successful in stopping bleeding in about 59 to 90% of patients, but is associated with a high rebleeding rate (36–​43%). Nuclear scintigraphy Nuclear scintigraphy can be used to detect active haemorrhage but cannot determine the underlying cause. It is very sensitive and can detect bleeding rates of 0.1 ml/​min and is therefore useful for inter- mittent bleeding. Sensitivity for scintigraphy is over 90%, although specificity is lower (76–​95%), and overall accuracy reported in the literature is between 41 and 94%. Technetium-​99m (99mTc)-​labelled sulphur colloid can be used, which has the advantage of not requiring preparation but the dis- advantage of a very short half-​life. If there is no active bleeding at the moment it is given, the test may be nondiagnostic, and its rapid enhancement of the liver and spleen can also obscure the diagnosis. A better method is the use of 99mTc-​labelled red cells. Unfortunately, although sensitive, this is also very nonspecific and localizes lesions very poorly. Its half-​life of up to 12 to 24 h means that, even if the bleeding is intermittent, the labelled blood cells can accumulate at the site of bleeding up to 24 h after injection and the patient can therefore be scanned multiple times within 24 hours. There is still controversy over the role of nuclear scintigraphy, and many surgeons are reluctant to proceed to a colectomy based solely on its results. It may be useful immediately before angiog- raphy (as scintigraphy can detect lower bleeding rates) to con- firm active haemorrhage before undertaking the more invasive procedure. Whenever there is massive, active haemorrhage, how- ever, this is unnecessary, and the patient should proceed directly to visceral angiography. Other aspects Surgery Surgery is a last resort in patients with LGIB as it is associated with a high morbidity and mortality. An emergency operation for lower gastrointestinal haemorrhage is required in 10 to 25% of patients. Indications for surgery include haemodynamic instability, clinical deterioration, transfusion requirements of greater than 6 units, and persistent or recurrent haemorrhage. In patients where the site of bleeding has been localized a directed segmental colectomy can be performed with an associated rebleed­ ing rate of 6% and a mortality of 4%. In patients where the bleeding site has not been localized a blind segmental colectomy is associated with much higher morbidity and a rebleeding rate of 75% and mor- tality of 50%. In these patients a subtotal colectomy could be con- sidered if deemed fit enough. Obscure bleeding In about 5% of cases the source of bleeding remains obscure, des- pite multiple attempts at localization. In many of these cases, the bleeding source is eventually found to be in the small bowel, with the commonest causes being angiodysplasia (accounting for 75% of episodes), Meckel’s diverticula, neoplasia, and Crohn’s disease. Additional investigations may include capsule endoscopy, small-​ bowel enteroscopy, or laparotomy with on-​table enteroscopy. Capsule endoscopy Wireless capsule endoscopy has been shown to be useful in the in- vestigation of recurrent obscure gastrointestinal bleeds. It is the most sensitive modality for identifying lesions in the small bowel. The videocapsule is a self-​contained unit, approximately 1 × 3 cm in size, and contains a miniature image-​capturing system, battery, light source, and transmitter. Likely future developments Rebleeding still occurs in 20% of cases of upper GIB. New thera- peutic endoscopic techniques such as endoscopic suturing devices may reduce the need for salvage surgery. There have been several promising case series on the use of high-​dose barium enema for the treatment of ongoing diverticular bleeding, and this may prove to be useful, particularly in patients with multiple comorbidities and high anaesthetic risk. A small ran- domized controlled trial from Japan has shown a reduction in recur- rence of bleeding. FURTHER READING British Society of Gastroenterology Endoscopy Committee (2005). Non-​variceal upper gastrointestinal haemorrhage: guidelines. Gut, 51 Suppl IV, iv1–​6. Calvet X, et al. (2004). Addition of a second endoscopic treatment following epinephrine injection improves outcome in high-​risk bleeding ulcers. Gastroenterology, 126, 41–​50.

SECTION 15  Gastroenterological disorders 2782 Hoedema RE, Luchtefeld MA (2005). The management of lower gastrointestinal hemorrhage. Dis Colon Rectum, 48, 2010–​24. Jensen DM, Machicado GA (2005). Endoscopic hemostasis of ulcer hemorrhage with injection, thermal, and combination methods. Tech Gastroint Endosc, 7, 124–​31. Jensen DM, et al. (1999). Prospective effectiveness study of an urgent endoscopic approach to diagnosis and treatment of patients hospi- talized with recurrent hematochezia. Gastrointest Endosc, 49, 331. Kahi CJ, et  al. (2005). Endoscopic therapy versus medical therapy for bleeding peptic ulcer with adherent clot:  a meta-​analysis. Gastroenterology, 129, 855–​62. Keeling D, et  al. (2011). Guidelines on oral anticoagulation with warfarin—​fourth edition Br J Hameatol, 154, 311–​24. Khorrani GJP, et al. (2004). H. pylori eradication therapy vs. antisecretory non-​eradication therapy (with or without long-​term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev, 2, CD004062. Martins NB, Wassef W (2006). Upper gastrointestinal bleeding. Curr Opin Gastroenterol, 22, 612–​19. National Confidential Enquiry into Patient Outcome and Death (NCEPOD) (2015). Time to get control? A review of the care received by patients who had a severe gastrointestinal haemorrhage. London: NCEPOD. National Institute for Health and Care Excellence (2012). Acute upper gastrointestinal bleeding in over 16s: management. Clinical guideline. (Last updated:  August 2016.) https://​www.nice.org.uk/​guidance/​ cg141 Palmer KR, Church NI (1999). Therapeutic endoscopy for upper gastrointestinal bleeding. Cont Med Ed J Gastroenterol Hepatol Nutr, 2, 75–​8. Ramaswamy RS, et al. (2014). Role of interventional radiology I the management of acture gastrointestinal bleeding. World J Radiol, 6, 82–​92. Rockall TA, et  al. (1995). Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. BMJ, 311, 222–​6. Rockall TA, et  al. (1996). Risk assessment following acute upper gastrointestinal haemorrhage. Gut, 38, 316–​21. Scottish Intercollegiate Guidelines Network (SIGN) (2008). 105: Management of acute upper and lower gastrointestinal bleeding. Edinburgh: SIGN. Vernava AM, et al. (1997). Lower gastrointestinal bleeding. Dis Colon Rectum, 40, 846–​58. Williams SG, Westaby D (1994). Management of variceal haemor- rhage. BMJ, 308, 1213–​17.

15.5 Immune disorders of the gastrointestinal trac

15.5 Immune disorders of the gastrointestinal tract 2783

ESSENTIALS Immune homeostasis in the gut is the result of a delicate balance between peaceful coexistence with commensal microbiota, immu- nomodulatory effects of dietary antigens, and appropriate responses to pathogens. Immune disorders of the gut arise when defects in the integrity of these components lead to a dysregulated immune re- sponse to the commensal environment. Immunodeficiency disorders Primary immunodeficiency syndromes can present with intestinal inflammation but are commonly characterized by an increased sus- ceptibility to infections in childhood. This heterogeneous group of diseases arise from genetic defects in the development of a specific part of the immune system; most are related to an antibody defect (e.g. selective IgA deficiency or common variable immunodefi- ciency). Secondary immunodeficiency can occur in a protein-​losing enteropathy where loss of immunoglobulins and lymphocytes in- crease susceptibility to infections, or as a result of metabolic diseases (e.g. diabetes or liver cirrhosis), infections (e.g. HIV), or drugs (e.g. chemotherapy). Therapy-​associated and autoimmune-​related gastrointestinal immune disorders Immunosuppressive medication can not only lead to secondary immunodeficiency but in the context of neutropenia, cytotoxic gastrointestinal mucosal injury can lead to neutropenic typhlitis. Graft-​versus-​host disease, which commonly affects the gut, arises from host antigen-​presenting cells engaging with donor T cells and triggering an inflammatory cascade. Immunotherapy with check- point inhibitors can have significant gastrointestinal immune-​related adverse effects, most notably enterocolitis. Autoimmune diseases can impact gastrointestinal function. Autoimmune dysautonomia can result in gastrointestinal-​specific dysmotility and systemic IgG4-​related disease can lead to auto- immune pancreatitis. Systemic autoimmune diseases (e.g. rheuma- toid arthritis, systemic lupus erythematosus) can have gastrointestinal manifestations related to the primary autoimmune process (e.g. mesenteric infarction) or as an adverse effect of treatment (e.g. non- steroidal anti-​inflammatory-​induced peptic ulceration). Food allergy and eosinophilic gastrointestinal disorders Hypersensitivity reactions to dietary antigens (e.g. peanuts) result in food allergies and can be either IgE or non-​IgE mediated. Food intolerance which is not immunologically mediated is the result of pharmacological (e.g. monosodium glutamate), enzyme-​related (e.g. lactose intolerance), or noncoeliac gluten sensitivity. Eosinophilic gastrointestinal tract disorders are often associated with a food al- lergen: treatment is with steroids and avoidance of the allergen. The immune system of the gastrointestinal tract The gastrointestinal tract is the largest mucosal organ in the human immune system and indeed home to the greatest accumulation of im- mune cells within the body. It has a vast surface area that is continually exposed to compounds from the diet and microbial life (e.g. bacteria, viruses, and parasites), which altogether are foreign antigens from an immune system’s perspective. The gastrointestinal tract contains an enormous density of microbial life (the intestinal microbiota), with the colonic lumen most densely populated, and hence is challenged with the formidable task of distinguishing potential pathogens from commensals. Indeed, crosstalk between the gut immune system and the commensal microbiota is a prerequisite for the normal devel- opment and function of the mucosal immune system. This delicate host—​microbial balance can be disrupted, such as during infection, but also in the context of immune-​related disorders that are charac- terized by mucosal inflammation and an inappropriate immune re- sponse involving the commensal flora. Gut immune homeostasis is hence key to the coexistence of commensal microbial communities in such close proximity to gut mucosal cells and is achieved through a combination of luminal barriers, the gut lymphoid system, and regu- lation by innate and adaptive immune cells (Fig. 15.5.1). Luminal barriers A single layer of intestinal epithelial cells (IECs) provides a phys- ical separation between mammalian hosts and the external environ- ment. IECs play an important role in dynamic barrier function and microbial sensing, and have emerged as key regulators of the mu- cosal immune system critically involved in maintaining intestinal 15.5 Immune disorders of
the gastrointestinal tract Joya Bhattacharyya and Arthur Kaser

SECTION 15  Gastroenterological disorders 2784 immune homeostasis. Although the majority of IECs are absorptive enterocytes adapted for metabolic and digestive functions, secretory IECs are specialized for maintaining the barrier function. Paneth cells are specialized secretory IECs that line the base of small in- testinal crypts that contribute to the intestinal gut barrier not only through their production of key factors that are crucial to help main- tain the stem cell niche thereby supporting the continual renewal of the epithelial surface, but also through the secretion of antimicro- bial peptides. Antimicrobial peptides function as endogenous anti- biotics that target and disrupt highly conserved features of bacterial proteins. Antimicrobial peptides such as regenerating islet-​derived protein IIIγ (REGIIIγ) are produced by most enterocytes but Paneth cells are capable of secreting a wide range of antimicrobial peptides, including defensins, cathelicidins, and lysozyme. Paneth cells also play an important bona fide immune role by secreting cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-​17. Intestinal barrier function is further reinforced by goblet cells se- creting highly glycosylated mucins into the lumen, the most abun- dant of these being mucin 2 (MUC2). This provides an extensive and thick layer of protective mucus which together with luminal Fig. 15.5.1  Anatomy of the intestinal mucosa and its immune apparatus. Reprinted by permission from Springer Nature: Mowat AM, Agace WA (2014). Regional specialization within the intestinal immune system. Nat Rev Immunol, 14, 667–​85, © 2014.

15.5  Immune disorders of the gastrointestinal tract 2785 secretion of antimicrobial peptides provides a physical and bio- chemical barrier. Central to their role in barrier function is the cap- acity of IECs for microbial sensing and the translation of microbial signals to immune cells. IECs express pattern recognition receptors such as toll ligand receptors (TLRs) and NOD-​like receptors (NLRs) that can directly sense specific bacterial ligands and provide distinct immunoregulatory response pathways. Polarized expression of pat- tern recognition receptors on apical and basolateral surfaces of IECs may help distinguish between commensal and pathogen signals. Commensal-​derived signals are also responsible for IECs producing immunoregulatory factors that promote development of tolerogenic immune cells. The lymphoid system The commensal microbiota is instrumental in the maturation of gut-​ associated lymphoid tissue (GALT); GALT and the draining lymph nodes serve as important immunosurveillance posts in the intes- tinal epithelium. Tissues of the GALT include Peyer’s patches, their equivalents in the cecum and colon, and isolated lymphoid follicles. The GALT is comprised of subepithelial lymphoid aggregates with an overlying follicle-​associated epithelium that contains microfold (M) cells. M cells are specialized epithelial cells that sample luminal contents and phagocytose and transcytose particulate antigens across the epithelium to the subepithelial dome, a dendritic cell-​rich region. Subsequent antigen presentation by dendritic cells is not only instru- mental in T-​cell priming but also in the production of secretory IgA against specific mucosal antigens. Secretory IgA is the most abun- dant isotype antibody found in the intestinal lumen of humans. In contrast to serum IgA, secretory IgA is mainly dimeric and chiefly derived from local synthesis. Secretory IgA is thought to prevent en- teric toxins and pathogens gaining access to the intestinal epithelium by receptor blockade, steric hindrance, and/​or agglutination followed by mucous entrapment and clearance through peristalsis. Innate and adaptive immune cells Within the intestinal mucosa there are two main compartments har- bouring bona fide immune cells. The intraepithelial layer consists mainly of T cells while the lamina propria contains B cells, T cells, and innate immune cell populations. Intraepithelial lymphocytes (IELs) consist mainly of T cells and in contrast to conventional naïve T cells are antigen experienced and on activation release cytokines or mediate killing of infected target cells. IELs constitutively express CD103 (also known as αE integrin) which binds to E-​cadherin expressed on intestinal entero- cytes. These T cells belong to T-​cell receptor (TCR) γδ+ and TCR αβ+ lineages. IELs are more abundant in the small intestine and are predominantly of the TCR γδ+ lineage and most express CD8αα in their activated phenotype. There are two subsets of IELs: ‘natural’ IELs (previously known as ‘type b’ IELs) which acquire their acti- vated phenotype during thymic development in the presence of self-​ antigens and ‘induced’ IELs (previously known as ‘type a’ IELs) which are derived from conventional T cells that are activated in response to exogenous antigens encountered in the periphery. Both subsets have protective roles in immune regulation, epithelial homeostasis, antimicrobial response, and tolerance to intestinal antigens. T cells in the lamina propria are of TCR αβ+ lineage and play an important role in oral tolerance and protective microbial responses. They display an effector memory phenotype and there are twice as many CD4+ T cells as CD8+ T cells. The CD4+ population is highly varied and include forkhead box P3 (FOXP3)+ T-​regulatory (Treg) cells and FOXP3− Treg cells subsets as well as IL-​2+, IL-​2+IFN-​ γ+, IL-​2−IFN-​γ−, IFN-​γ+, and IL-​17+ T cells. The most abun- dant leucocyte population in the lamina propria are macrophages which produce IL-​10. IL-​10 is not only important for maintaining immune homeostasis by blocking proinflammatory responses to TLR stimulation but also in promoting the function of FOXP3+ Treg cells. Intestinal dendritic cells are also found predominantly in the lamina propria. They can be classified based on expression on CD103 (also known as αE integrin) and CD11b. These distinct sub- sets are thought to have differing roles in intestinal immunity. Other immune cells in the lamina propria include plasma cells that pri- marily secrete IgA and members of the innate immune system such as innate lymphoid cells (ILCs), T cells with invariant TCR chains, eosinophils, and mast cells. ILCs are a recently described subset of the innate immune system. They are classified into three distinct groups identified by their dif- ferential expression of transcription factors, cytokine production, and cell surface markers. They are enriched in mucosal tissue and play an important role in maintaining intestinal immune homeo- stasis. Type 3 ILCs are an important source of IL-​22, important in maintaining intestinal barrier integrity. The IL-​22 receptor is exclu- sively expressed by the gut epithelium and activation leads to epithe- lial proliferation, repair, and the production of protective molecules, including antimicrobial peptides and mucins. Impact of dietary compounds and gut microbiota on gastrointestinal immune function There is regional variation in the distribution of immune cells in the gastrointestinal tract thought to at least partly reflect differing ex- posure to environmental influences. Immunomodulatory effects of dietary constituents are most evident in the small intestine. Dietary vitamin A is found in higher concentrations in the small intestine compared to the colon and is metabolized by gut epithelial cells to generate the vitamin A metabolite all-​trans retinoic acid. Retinoic acid plays an important role in the migration and differentiation of immune cell subsets. Dendritic cells in the small intestine receive enhanced retinoic acid signals and are primed to expressed CD103 and eventually become imprinted with the ability to produce ret- inoic acid. This in turn induces the expression of gut homing recep- tors, α4β7 integrin and CCR9 chemokine receptor, on T cells, which in the presence of transforming growth factor (TGF)-​β can amplify the development of FOXP3+ Treg cells. Retinoic acid also affects the relative populations of subsets of ILCs. There are two dominant tissue resident ILCs. ILC2s express the transcription factor GATA3 and constitute the majority of the ILCs present in the lungs and skin while ILC3s express the transcription factor RORγt and are the dominant subset in the gut. The presence of RA supports the expan- sion and maintenance of IL-​17-​ and IL-​22-​producing ILC3s, while suppressing the maturation of IL-​13-​producing ILC2. Another regulator of the ILC population is the aryl hydrocarbon receptor (AhR). AhR is a highly conserved transcription factor whose ac- tivity is regulated by environmental and dietary small molecule lig- ands, particularly the phytochemical indole-​3-​carbinol found in the Brassicaceae vegetable family. ILC3s express the AhR and signalling via this receptor promotes development of ILC3s and postnatal lymphoid follicle development.

SECTION 15  Gastroenterological disorders 2786 AhR and RORγt-​dependent expression of IL-​22 limits coloniza- tion by segmented filamentous bacteria. segmented filamentous bac- teria are commensal bacteria that preferentially colonize the terminal ileum, where they drive enhanced IgA production and via the presen- tation of segmented filamentous bacteria antigens by dendritic cells can increase T-​helper (Th)-​17 cell numbers. Similar to segmented filamentous bacteria, various other microorganisms can impact im- mune cell distribution along the intestine. Lactobacillus spp. can in- fluence secretion of IL-​22 by Th17 cells through generation of AhR ligand indole-​3-​aldehyde from tryptophan metabolism. In the colon, enhanced generation of Treg cells may be the result of a TGFβ-​rich environment promoted by certain anaerobic Clostridia spp. Short-​ chain fatty acids that are produced by colonic bacteria can influence immune function by driving the expansion of FOXP3+Treg cells. Monogenic immune disorders and the gastrointestinal tract The importance of these interrelated components of the mucosal immune system, which form an integrated, physiological, complex barrier that functionally extends vastly beyond being just an ana- tomical boundary, is most visibly revealed by a whole range of monogenic defects that are associated with intestinal inflamma- tion. The majority of these defects manifest in the gastrointestinal tract very early in life, and some of them are classified as ‘very early-​onset inflammatory bowel disease’ (VEOIBD). These defects affect genes involved in epithelial barrier function (e.g. X-​linked ectodermal dysplasia and immunodeficiency, IKBKG gene) and in phagocytic killing (e.g. chronic granulomatous disease, CYBB gene), defects leading to autoinflammation (e.g. mevalonate kinase deficiency (also known as hyper-​IgD syndrome), MVK gene; fa- milial Mediterranean fever, MEFV gene; X-​linked lymphopro- liferative syndrome 2, XIAP gene), T-​ and B-​cell (e.g. common variable immunodeficiency (CVID) type 1, ICOS gene; Wiskott–​ Aldrich syndrome, WAS gene) and Treg cell defects (e.g. immune dysregulation, polyendocrinopathy, enteropathy X-​linked (IPEX), FOXP3 gene; and VEOIBD due to CTLA4 mutations), IL-​10 sig- nalling defects (IL10RA, IL10RB, IL10 genes), and defects in in- testinal innervation (e.g. Hirschsprung’s disease, RET gene). As detailed in Table 15.5.1, gastrointestinal manifestations may in- clude continuous and discontinuous colitis, ileitis, and fistula and Table 15.5.1  Genetic defects associated with inflammatory bowel disease-​like immunopathology Group of defects (monogenic disorder) Gene Mode of inheritance Epithelial barrier and epithelial response defects X-​linked ectodermal dysplasia and immunodeficiency Hyper-​IgM syndrome, atypical inflammatory bowel disease-​like enterocolitis with villous atrophy and epithelial cell shedding Dystrophic epidermolysis bullosa Moderately severe colitis Kindler syndrome Haemorrhagic continuous colitis Adam-​17 deficiency Skin, hair, and gut pathology Familial diarrhoea Neonatal diarrhoea with discontinuous colitis IKBKG COL7A1 FERMT1 ADAM17 GUY2YC X-​linked Autosomal recessive Autosomal recessive Autosomal recessive Autosomal dominant Neutropenia and defects in phagocyte bacterial killing Chronic granulomatous disease Colitis with pigmented macrophages and granulomas Glycogen storage disease type 1b Neutropenia, defective chemotaxis, ileitis, and colitis Congenital neutropenia Neutropenia, discontinuous colitis Leucocyte adhesion deficiency 1 Defects in chemotaxis, phagocytosis, discontinuous ulcerative stomatitis, ileocolitis, fistulas, strictures, perianal abscess CYBB CYBA, NCF1, NCF2, NCF4 SLC37A4 G6PC3 ITGB2 X-​linked Autosomal recessive Autosomal recessive Autosomal recessive Autosomal recessive Hyper-​ and autoinflammatory disorders Mevalonate kinase deficiency Febrile attacks, lymphadenopathy, polyarthritis, hypogammaglobulinaemia, colitis Familial Mediterranean fever Periodic fevers, continuous colitis X-​linked lymphoproliferative syndrome 1 Gastrointestinal symptoms of colitis and gastritis X-​linked lymphoproliferative syndrome 2 Very early onset and fistulating disease Phospholipase Cγ2 defects Autoinflammatory disease with mild immunodeficiency, skin lesions, continuous colitis Familial haemophagocytic lymphohistiocytosis type 5 Fever, splenomegaly, hypogammaglobulinaemia, diffuse discontinuous colitis Hermansky–​Pudlak syndrome Oculocutaneous albinism and bleeding diathesis, neutropenia, lung fibrosis, granulomatous colitis MVK MEFV SH2D1A XIAP PLCG2 STXBP2 HPS1, HPS4, HPS6 Autosomal recessive Autosomal recessive X-​linked X-​linked Autosomal dominant Autosomal recessive Autosomal recessive

15.5  Immune disorders of the gastrointestinal tract 2787 abscess formation. While some defects affect mechanisms critic- ally involved in preventing autoimmunity, such as mutations in FOXP3 (encoding the transcription factor critically required for Treg cell development and function) which cause multiorgan auto- immunity prominently involving the gastrointestinal tract (some- times also referred to as autoimmune enteropathy), many of these genetic defects affect mechanisms involved in innate host defence and inflammatory functions. Typical examples are chronic granu- lomatous disease, caused by mutations in the reactive oxygen species-​producing NADPH oxidase system, or leucocyte adhesion deficiency, caused by mutations in an integrin gene which leads to defects in chemotaxis, phagocytosis, and bacterial killing. Of note, defects in innate immune function, and hyperactive adaptive immune function, both can result in intestinal inflammation as ex- emplified by these monogenic disorders. Interestingly, the group of genes mutations of which cause VEOIBD (defined as onset <6 years of age) are, with very few ex- ceptions (IL10, IL10RB, IL2RA), distinct from the susceptibility loci that have been associated with risk for inflammatory bowel disease, consistent with the difference in time of onset and clinical manifest- ation, and response to treatment, altogether showcasing difference in pathogenesis. Identifying the genetic cause of these monogenic disorders can sometimes guide or determine therapeutic options when the biological mechanisms involved are already known, for ex- ample, allogenic haematopoietic stem cell transplantation has been successfully performed in VEOIBD patients carrying mutations in genes encoding IL-​10 receptor subunits. Gastrointestinal manifestations of classical primary immunodeficiency disorders As monogenic disorders causing intestinal inflammation often also involve manifestations outside of the intestinal tract, there is some overlap with classical primary immunodeficiency disorders. Primary immunodeficiency disorders (Table 15.5.2) refer to a het- erogeneous group of diseases characterized by a genetic defect in the maturation or development of specific components of the immune system resulting in an increased susceptibility to infection. Primary immunodeficiency disorders commonly present in early childhood with recurrent infections. Common gastrointestinal manifestations include infections, but may also include intestinal inflammation of Group of defects (monogenic disorder) Gene Mode of inheritance B-​cell and antibody defects Common variable immunodeficiency (CVID) type 1 Autoimmunity (rheumatoid arthritis, psoriasis) and inflammatory bowel disease CVID type 8 Defective B-​cell activation, neutropenia, autoimmunity, duodenal villous atrophy, lymphocytic or discontinuous colitis Wiskott–​Aldrich syndrome Eczema, thrombocytopenia, vasculitis and ulcerative colitis-​like continuous inflammation Agammaglobulinaemia Reduced levels of antibodies, peripheral B cells, autoimmunity (arthritis, haemolytic arthritis, thrombocytopenia or neutropenia), discontinuous colitis Erythema nodosum, arthritis, colitis, complete absence of B cells in the bone marrow Hyper-​IgM syndrome Oral ulcers, chronic neutropenia, colitis Omenn syndrome Erythroderma, increased serum IgE, desquamation, lymphadenopathy, chronic ulcerating intestinal inflammation Hyper-​IgE syndrome Eczema, raised serum IgE, multiple allergies, buccal granulomatous disease Trichohepatoenteric syndrome Intractable diarrhoea, hepatopathy, trichorrhexis nodosa, low immunoglobulin levels, and defect in vaccine response PTEN hamartoma tumour syndrome Gastrointestinal lymphoid hyperplasia, inflammatory polyps, colitis ICOS LRBA WAS BTK PIK3R1 CD40LG DCLRE1C DOCK8 SKIV2L, TTC37 PTEN Autosomal recessive Autosomal recessive X-​linked X-​linked Autosomal recessive X-​linked Autosomal recessive Autosomal recessive Autosomal recessive Autosomal dominant Treg cell defects and immune dysregulation Immune dysregulation, polyendocrinopathy, enteropathy X-​linked (IPEX) Polyendocrinopathy, high IgE, colitis and subtotal villous atrophy IL-​10 signalling defects Bloody diarrhoea, perianal fistula, discontinuous colitis with deep ulcerations reminiscent of Crohn’s disease CTLA4 mutations Impaired Treg cells, hypogammaglobulinaemia, recurrent infections, multiple autoimmune clinical features FOXP3 IL2RA IL10, IL10RA, IL10RB CTLA4 X-​linked Autosomal recessive Autosomal recessive Autosomal dominant Defects in intestinal innervation Hirschsprung’s disease Enterocolitis with cryptitis and crypt abscesses RET Autosomal dominant Adapted by permission from BMJ Publishing Group Limited: Uhlig HH (2013). Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut, 62, 1795–​805, © 2013. Table 15.5.1  Continued

SECTION 15  Gastroenterological disorders 2788 Table 15.5.2  Specific primary immunodeficiency syndromes and their gastrointestinal manifestations Primary immunodeficiency disease and pathogenesis Infectious gastrointestinal complications Noninfectious gastrointestinal complications Antibody defect Selective IgA deficiency This is the most common primary immunodeficiency syndrome, with highest prevalence rates of 1:160–​1:300 reported for Caucasian populations. The genetic basis is not well defined and the IgA deficiency may result from immune dysregulation of terminal B cells’ maturation into IgA-​secreting plasma cells. Most patients are asymptomatic, possibly as a result of compensatory increase in IgM secretion Upper respiratory tract infections are more common, but there is an increased incidence of gastrointestinal infections, most notably with Giardia lamblia. Colonization by trophozoites in the small intestine results in bloating, cramping, excessive flatus, and watery diarrhoea. Chronic infection can lead to malabsorption of lipids resulting in steatorrhea and villus flattening. Diagnosis is made by stool examination or duodenal aspirates for Giardia lamblia cysts or trophozoites. Despite treatment with metronidazole, the parasitic load can be unremitting suggesting that luminal IgA may be required for parasite clearance There is an association with coeliac disease. Nodular lymphoid hyperplasia is a common feature Common variable immunodeficiency (CVID) syndrome CVID is the most common symptomatic primary immunodeficiency and characterized by low levels of IgG together with reduced levels of IgA and/​or IgM, poor response to immunizations and absence of other immunodeficiency states. In addition to recurrent bacterial respiratory tract infections, patients have a wide range of clinical manifestations: autoimmune diseases (e.g. immune thrombocytopenic purpura, autoimmune haemolytic anaemia), granulomatous/​lymphoid infiltrative disorders and increase risk of malignancy. Treatment is with monthly IgG infusions. CIVD is a pathophysiologically heterogeneous entity Diarrhoea is a common presenting symptom. Infective causes of acute diarrhoea include norovirus, campylobacter jejuni, or salmonella. Giardiasis can cause refractory diarrhoea with features of malabsorption and weight loss. Other causes of chronic diarrhoea include cytomegalovirus, cryptosporidium, or norovirus An inflammatory bowel disease-​like pathology and coeliac-​like sprue may develop. This can lead to a protein losing enteropathy and malabsorption. Other gastrointestinal manifestations include bacterial overgrowth, pernicious anaemia, nodular lymphoid hyperplasia, and lymphoma X-​linked agammaglobulinaemia This is a humoral immunodeficiency characterized by the absence of immunoglobulins. It results from genetic mutations in the signal transduction molecule Bruton tyrosine kinase (BTK) leading to a maturation block in B-​ cell development. Clinical presentation occurs after the age of 3 months (once maternal IgG is catabolized) and is characterized by recurrent bacterial infections and particularly affect the respiratory and nervous system. Treatment is with replacement immunoglobulin. Infections are treated with multiple and prolonged courses of antibiotics In the gastrointestinal tract Salmonella and Campylobacter spp. can cause gastroenteritis. Enteroviral pathogens such as ECHO virus and Coxsackievirus cause hepatitis, meningoencephalitis, and dermatomyositis. This is rare in the setting of immunoglobulin substitution therapy Small-​bowel strictures and fissures resembling Crohn’s disease can occur. There is an increased risk of colonic and gastric adenocarcinomas Hyper-​IgM syndrome This is a heterogeneous group of diseases characterized by defective class-​switch recombination resulting in increased IgM production and inability to generate other immunoglobulin subtypes. The two most common genetic defects include CD40 ligand or CD40 deficiency or a deficiency in activation-​induced cytidine deamidase (AID). Clinical features depend on the underlying genetic defect. Treatment options include immunoglobulin replacement; in CD40 ligand deficiency, haematopoietic stem cell transplantation offers a curative option Protracted and recurrent diarrhoea is a common clinical feature. In half of all cases the infectious agent cannot be identified. The most common pathogen is Cryptosporidium parvum. Infection with Giardia lamblia, salmonella, Entamoeba histolytica, and cytomegalovirus have also been described Chronic intestinal inflammation resembling inflammatory bowel disease may occur. In CD40 deficiency, aphthous stomatitis and an increased incidence of lymphoma, hepatocarcinoma, cholangiocarcinoma, and neuroectodermal tumours of the gastrointestinal system can develop Combined T-​ and B-​cell immunodeficiency Severe combined immunodeficiency (SCID) Genetic defects in the development of T cells, B cells, and in some cases natural killer cells lead to cellular and humoral immunodeficiency collectively termed SCID. Life-​threatening infections lead to overwhelming sepsis and high infant mortality. Haematopoietic stem cell transplantation is curative Persistent mucocutaneous candidiasis of oral cavities and the oesophagus can compromise oral intake leading to malnutrition and failure to thrive. Rotavirus is the most common cause of protracted and refractory diarrhoea. Other gastrointestinal pathogens include picornavirus, parvovirus, adenovirus, cytomegalovirus, salmonella, Giardia lamblia, Escherichia coli, and Cryptosporidium GVHD affecting the gastrointestinal tract can occur in response to blood transfusion Ataxia–​telangiectasia (AT) This is an autosomal recessive neurodegenerative disorder characterized by defective DNA repair resulting from mutations in the ataxia telangiectasia mutated (ATM) gene. Clinical features include neurological abnormalities, particularly progressive cerebellar ataxia and oculomotor problems, facial and conjunctival telangiectasia, and increased incidence of malignancy. Immunodeficiency is both cellular and humoral. Treatment is supportive, no cure is yet available Infections tend to be sinopulmonary and are not particularly a problem in the gastrointestinal tract. Dysphagia is often a feature together with dysarthria Increased susceptibility to develop adenocarcinomas and lymphoreticular malignancies of the gastrointestinal tract

15.5  Immune disorders of the gastrointestinal tract 2789 various types, nodular hyperplasia, and malabsorption. There is also an increased incidence of malignancies. Infections Primary immune defects can affect the humoral (B-​cell) response and cellular (T-​cell) immune system; both T-​ and B-​cell immunity or innate defects. The second most common site for infection is the gastrointestinal tract second only to the respiratory system. Clinical features include persistent diarrhoea, malabsorption, weight loss, and failure to thrive. Often the type of infective pathogen reflects the underlying immune defect. Viral and fungal infections are more common in T-​cell defects and bacterial infec- tions in B-​cell immune defects. The disease course can be frequent, more severe and prolonged compared to immunocompetent indi- viduals, often with unexpected recurrence after standard therapy (e.g. patients with selective IgA deficiency infection with Giardia lamblia often require multiple and longer courses of antibiotics). Infections with atypical or opportunistic pathogens are also more common (e.g. microsporidia, Cryptosporidium spp.). Autoimmune and inflammatory disorders Some primary immunodeficiency disorders may be associated with intestinal inflammation (Table 15.5.1). In some cases, gastrointes- tinal symptoms such as bloody diarrhoea, vomiting, and abdominal pain can be the primary presenting feature. Features that suggest an underlying primary immunodeficiency disease or monogenic dis- order include early age of onset with aggressive disease, failure to re- spond to conventional therapy, and histopathology that differs from classical findings. CVID (see Chapter  4.4) may present with sprue-​like disease. CVID sprue-​like disease presents with diarrhoea, malabsorption, and weight loss. Small-​bowel biopsies share findings common to classical coeliac disease (e.g. villous atrophy, increased intraepithelial lymphocytes, and crypt hyperplasia) but distinguishing features Primary immunodeficiency disease and pathogenesis Infectious gastrointestinal complications Noninfectious gastrointestinal complications Wiskott–​Aldrich syndrome This is an X-​linked disease characterized by recurrent infections, thrombocytopenia bleeding, and eczema. It results from genetic mutations in the Wiskott–​Aldrich syndrome protein gene (WASP), a key regulator of the actin cytoskeleton in haematopoietic cells. Loss of WASP signalling leads to impaired antibody production and T-​cell lymphopenia. Haematopoietic stem cell transplantation offers a cure Individuals are susceptible to infection by all classes of micro-​organisms. Infectious diarrhoea can occur but respiratory and ear infections are more common Bloody diarrhoea is common, especially in infancy and is related to thrombocytopenia Disorders of phagocytic function Chronic granulomatous disease (CGD) This genetic disorder arises from mutations in key genes that regulate the phagocytic oxidative metabolism. These mutations result in inactivation or loss of function in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex thereby impairing the generation of superoxide and the bactericidal capabilities of phagocytes. Clinical features include bacterial and fungal infections and hepatic and gastrointestinal disorders. The X-​linked mode of inheritance is more common than the autosomal recessive and therefore there is a male preponderance There is an increased susceptibility to pyogenic and fungal infections including salmonella, enterococci, and Candida Gastrointestinal manifestations are common in CGD, including granulomatous colitis. It can present with diarrhoea, abdominal pain, perianal abscesses, and fissures. Granulomata formation in the intestinal tract can resemble Crohn’s disease or cause obstructive symptoms Immune dysregulation syndromes Immune dysfunction, polyendocrinopathy, enteropathy, X-​linked (IPEX) This X-​linked immunodysregulatory syndrome is caused by loss-​of-​function mutations in transcription factor FOXP3. This leads to decreased and dysfunctional Treg cells. IPEX is characterized by a triad of clinical features: enteropathy, autoimmune endocrinopathy, and dermatitis. IPEX-​like syndromes, common causes include CD25, STAT2b deficiencies and lipopolysaccharide (LPS)-​ responsive beige-​like anchor (LRBA) mutations, share the similar clinical features Although infectious diarrhoea can occur, significant infections are more likely to be meningitis, pneumonia, and osteomyelitis Autoimmune and allergic enteropathy is a hallmark of IPEX syndrome. Diarrhoea is severe, watery, and mucoid or bloody. Malabsorption with electrolyte imbalance and protein loss often occurs. Histopathology findings are not specific, but resemble other immune-​related enteropathies (coeliac disease, GVHD) Food allergies have also been described and can be IgE or non-​IgE mediated Complement deficiency Hereditary angio-​oedema This results from deficiency or dysfunction of C1 esterase inhibitor resulting in excessive generation of bradykinin, a potent vasodilatory mediator. This leads to recurrent episodes of angio-​oedema predominantly affecting skin and the gastrointestinal and respiratory system. The most serious being laryngeal oedema leading to airway obstruction Gastrointestinal infections are not a feature of this condition Individuals commonly present with abdominal pain, vomiting and watery diarrhoea related to bowel wall oedema, which may present segmental Table 15.5.2  Continued

SECTION 15  Gastroenterological disorders 2790 include a reduced number of plasma cells in the lamina propria and preservation of IECs at the villous tip. In addition, there is a lack of antibodies to gliadin, tissue transglutaminase, endomysium, or reticulin, no association with HLA DQ2/​DQ8, and no clinical im- provement on dietary gluten withdrawal. Classical coeliac disease (see Chapter 15.10.3) can occur in se- lective IgA deficiency, a primary immunodeficiency syndrome (see Chapter 4.4), and although the clinical course is similar to immuno- competent individuals, diagnosis may be missed if screening with tissue transglutaminase IgA. To avoid this, screening should be done either by concomitantly measuring serum IgA concentrations or tissue transglutaminase IgA and IgG. Nodular lymphoid hyperplasia is characterized by the presence of nodules often found in multiples throughout the intestine, 5 mm or greater in diameter, which are associated with mucosal flattening and malabsorption. Occasionally these lesions can develop a size that may cause intestinal obstruction. Diagnosis is via small-​bowel radiological imaging or video capsule imaging. Nodular lymphoid hyperplasia is found in patients with CVID syndrome and selective IgA immunodeficiency, but may also be found in healthy individ- uals. These nodules contain numerous lymphoid follicles with ger- minal centres in lamina propria or submucosa with large numbers of B cells. Whether nodular lymphoid hyperplasia is a risk factor for the development of lymphoma is a matter of controversy. Malignancy Malignancy is the second most common cause of death in patients with primary immunodeficiency disorders, second to infections. Patients with primary immunodeficiency disorders can be at an in- creased risk of gastrointestinal malignancies (e.g. lymphoma and adenocarcinoma). The increased susceptibility to cancer is thought to arise from a variety of mechanisms that include Helicobacter pylori infection, atrophic gastritis, genetic instability, and decreased immunosurveillance and immune-​mediated clearance of oncogenic viruses such as human papilloma virus and Epstein–​Barr virus. The most common types of cancer include non-​Hodgkin’s lymphoma and Hodgkin’s lymphoma. Two primary immunodeficiency dis- orders account for the majority of primary immunodeficiency disorder-​associated cancers, CVID and ataxia–​telangiectasia. Malabsorption Malabsorption as a result of persistent diarrhoea is a common clin- ical feature of primary immunodeficiency disorders. The chronic impaired absorption of nutrients leads to electrolyte imbalances, malnutrition, and, in children, a failure to thrive. Treatment is by addressing the underlying immune defect and by nutritional sup- plementation which in some severe cases can include parenteral nutrition. Secondary immunodeficiency and the gastrointestinal tract Secondary immunodeficiency disorders are more common and can be the result of metabolic disease (e.g. diabetes mellitus, liver cirrhosis, and malnutrition), HIV infection, and malignancies (e.g. multiple myeloma and leukaemia). Other causes include immunosuppressive drugs (e.g. chemotherapy) and protein loss (e.g. nephrotic syndrome, protein-​losing enteropathy). In the gastrointestinal tract, secondary immunodeficiency can arise from a protein-​losing enteropathy (which can be primary or secondary). Gastrointestinal manifestations related to secondary immuno- deficiency include increased susceptibility to infections, especially opportunistic pathogens (e.g. cryptococcosis, candida, and cyto- megalovirus in HIV-​infected individuals). Protein-​losing enteropathy Immunodeficiency can arise from protein-​losing enteropathies of the gastrointestinal tract, characterized by a severe loss of serum proteins into the intestinal lumen outstripping protein synthesis leading to hypoalbuminaemia. Secondary immunodeficiency de- velops with loss of immunoglobulins and lymphocytes. This can be caused by intestinal mucosal disease (e.g. Menetrier’s disease, Crohn’s disease, or coeliac disease) or by impaired lymphatic drainage. The latter mechanism can be the result of granuloma- tous or malignant involvement of the lymphatic system or related to intestinal lymphangiectasia. Secondary causes of intestinal lym- phangiectasia include cardiac failure or retroperitoneal lymph node enlargement. Primary intestinal lymphangiectasia presents typically in childhood with persistent diarrhoea and oedema. Endoscopically white villi (dilated lacteals), white nodules, and submucosal elevations can be seen (Fig. 15.5.2). The diagnosis is histologically confirmed by demonstration of dilated lymphatics. Treatment is attempted with dietary modification to a low-​fat diet and substituting long-​chain fatty acids with medium-​chain fatty acids. Fig. 15.5.2  Wireless capsule endoscopy demonstrating plump, white intestinal villous tips containing chyle in a patient with protein-​losing enteropathy. From Mulliken JB, Burrows PE, Fishman SJ (eds) (2013). Mulliken and Young’s vascular anomalies: hemangionas and malformations. By permission of Oxford University Press.

15.5  Immune disorders of the gastrointestinal tract 2791 Acquired immunodeficiency syndrome: HIV Gastrointestinal manifestations of HIV infection are common, also consistent with the gastrointestinal tract being a major site for HIV replication. This is attributed to HIV preferentially targeting acti- vated memory CD4+ T cells expressing chemokine receptor 5 (the main coreceptor HIV uses to gain entry into target cells) which are plentiful in the gastrointestinal tract. Severe depletion of CD4+ lymphocytes in the lamina propria and of intraepithelial lympho- cytes occurs during primary infection and persists throughout the course of the infection, and highly active antiretroviral therapy may not lead to full restoration of the GALT. Over half of all affected individuals report gastrointestinal symptoms with a much higher prevalence in developing countries. The most common symptom is diarrhoea which can occur during seroconversion or with more ad- vanced disease. When CD4+ T-​cell numbers in peripheral blood fall to less than 100 to 200 cells/​mm3, opportunistic infections from a myriad of bacteria, viruses, fungi, or parasitic pathogens can ensue. Table 15.5.3 summarizes major gastrointestinal inflammatory, in- fectious, and neoplastic diseases associated with HIV infection. Highly active antiretroviral therapy has profoundly decreased the incidence of HIV-​ associated opportunistic intestinal infections. However, immune reconstitution in GALT is typically incomplete, often leading to reactivation and disease progression. This has been attributed to persistent viral replication, preferential depletion of Th17 cells, and increased microbial translocation secondary to de- fects in the intestinal mucosal barrier resulting in systemic immune activation. Once identifiable infections and other causes of diarrhoea have been excluded, an entity referred to as HIV/​AIDS enteropathy may be present in a small percentage of patients. This may present with profound diarrhoea, malnutrition, and wasting. HIV enteropathy is related to increased inflammation and immune activation associ- ated with decreased mucosal repair and regeneration. However, the precise aetiology of HIV enteropathy remains insufficiently under- stood, and might involve the HIV virus itself, but also atypical viral pathogens. Therapy-​associated immune-​mediated affection of the gastrointestinal tract Graft-​versus-​host disease Graft-​versus-​host disease (GvHD) is a multisystem autoimmune disease most commonly occurring in recipients of allogeneic haem- atopoietic stem cell transplants where the conditioning protocol leads to mucosal damage and in the gastrointestinal tract increased translocation of microbial signals that activate antigen-​presenting cells. These host antigen-​presenting cells engage with donor T cells that differentiate, proliferate, and trigger an effector cascade medi- ated by cytotoxic T cells and natural killer cells and a cytokine storm (e.g. TNFα) leading to tissue damage and destruction. Historically, GvHD was divided into acute and chronic GvHD if onset of symptoms was before or after 100 days following transplant- ation. However, a National Institutes of Health consensus has reclas- sified acute and chronic GvHD based on clinical findings. Acute GvHD is characterized by epithelial cell death, the most commonly affected organs being skin, liver, and gut. Gastrointestinal involvement of the lower gastrointestinal tract typically presents with secretory, voluminous diarrhoea and abdominal pain. Severity of the diarrhoea determines the degree of gastrointestinal involve- ment and can lead to a protein-​losing enteropathy. Upper gastro- intestinal manifestations include anorexia, nausea and vomiting, mucositis, and dyspepsia. CT findings are nonspecific and diagnosis is made on endoscopic appearance (denuded mucosal patches, ery- thema, and ulceration) and histopathological findings characterized by apoptotic epithelial cells and crypt loss. Treatment is supportive (e.g. enteral and parenteral nutrition), steroids and immunosuppres- sive medication and vigilance for secondary infective pathogens. The pathogenesis of chronic GvHD is less well understood. It is marked by sclerosis and fibrosis with a wider spectrum of organ involvement to also include lungs, eyes, and the musculoskeletal system. In the gastrointestinal system, the proximal part is more commonly affected and oesophageal reflux and dysphagia, small-​ bowel overgrowth, and mucositis are the predominant manifest- ations. Secondary opportunistic infections often occur as there is an immune deficiency associated with chronic GvHD related to various factors (conditioning-​induced and/​or age-​associated thymic involu- tion, thymic GvHD, or GvHD prophylaxis or treatment). Treatment strategies are similar to those for acute GvHD. Neutropenic enterocolitis Neutropenic enterocolitis (typhlitis) can occur in any patient with severe neutropenia. It most commonly occurs 7 to 10 days following chemotherapy and can affect any part of the gastrointestinal tract but has a predilection for the caecum. It is thought to be the re- sult of mucosal injury secondary to cytotoxic chemotherapy in the context of neutropenia and therefore impaired host defence often leading to polymicrobial infection of the bowel and occasional sys- temic dissemination. Candida spp. are the most common cause of fungaemia secondary to neutropenic enterocolitis. Patients pre- sent with fever, abdominal pain, and diarrhoea that can be watery or bloody. Diagnosis is made based on characteristic CT findings that include bowel wall oedema, thickening, mesenteric stranding, Table 15.5.3  Gastrointestinal site-​specific common HIV-​associated pathogens and processes Gastrointestinal site Common HIV-​associated pathogens and processes Oesophagus Candidiasis, cytomegalovirus (CMV) and herpes simplex virus (HSV) infection, Kaposi’s sarcoma (KS), and idiopathic ulceration Stomach CMV, Mycobacterium avium-​intracellulare (MAI), and neoplasia (KS, lymphoma) Small bowel MAI, protozoa (giardia, isospora, cryptosporidia, amoebae, microsporidia), and helminths (Strongyloides stercoralis) Large intestine Viral pathogens: CMV, HSV Bacterial pathogens: clostridia, salmonella, shigella, campylobacter. Fungal pathogens: cryptococcosis, histoplasmosis Neoplastic processes: KS, lymphoma

SECTION 15  Gastroenterological disorders 2792 and pneumatosis (Fig. 15.5.3). The rising incidence of neutropenic enterocolitis is attributed to the increased use of cytotoxic chemo- therapy agents that cause gastrointestinal mucositis. Treatment includes an antimicrobial regimen (including antibacterial and antifungal agents), supportive measures (transfusions, enteral and parenteral nutrition), and in severe cases, the use of granulo- cyte colony-​stimulating factor to enhance recovery of leucocyte numbers. Intestinal inflammation caused by
checkpoint inhibitors Blockade of the coinhibitory molecules cytotoxic T lymphocyte-​ associated antigen 4 (CTLA4) or programmed cell death protein 1 (PD-​1) dampens negative regulation of T cells and provides ef- fective treatment against tumours (e.g. melanoma). However, a large proportion of patients on such treatment develop immune-​ related adverse events, most prominently diarrhoea and entero- colitis. Up to one-​third of patients on anti-​CTLA4 monoclonal antibodies and slightly fewer on anti-​PD1 monoclonal antibodies develop diarrhoea within weeks and a few months of treatment. Clinical manifestations are abdominal pain, diarrhoea, and per rectal bleeding or mucus discharge. Cross-​sectional imaging shows mesenteric engorgement and bowel wall thickening. Endoscopy usually demonstrates diffuse inflammation, with the histological presentation characteristically lacking features of chronicity that are typically seen in ulcerative colitis. Therapy usually consists of corticosteroids, with escalation to anti-​TNF in case of clinical and endoscopic nonresponse. Discontinuation of checkpoint inhibitor therapy might need to be considered, and colectomy required in select cases. Food allergy It is important to distinguish between food allergy/​hypersensitivity and food intolerance. In contrast to food intolerance, food allergy is an immunologically mediated hypersensitive response to dietary proteins. Class 1 food allergens (e.g. cow’s milk, peanut, soybean, and fish) are primary sensitizers, a process that can occur in the gastrointestinal tract. They are heat stable and resistant to acid and proteolytic degradation. Class 2 allergens (e.g. Latex, banana, and avocado) cross react with plant-​derived proteins. They are heat labile and therefore the allergen may be tolerated in the heated form, but not in the raw state (e.g. egg allergy). The immunological process of food allergies can be classified as either IgE mediated or non-​IgE mediated. IgE mediated This is an immediate hypersensitivity reaction characterized by mast cell activation most commonly seen in children who often outgrow the allergy. The most common allergens include milk, soy, peanut, wheat, egg, and seeds. Diagnosis is confirmed with skin prick testing and serum IgE levels. Gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhoea is found less frequently. Extraintestinal manifestations can be life-​threatening and include urticaria, angio-​oedema, and atopic dermatitis. Fig. 15.5.3  Neutropenic enterocolitis in a bone marrow transplant patient with myeloma. Axial CT images following intravenous contrast show that the small bowel (arrows in lower images) as well as the walls of the cecum and ascending colon are thickened (arrows in upper images). Note pericaecal phlegmon and also abnormal bone trabeculae in vertebrae and pelvis from myeloma. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press.

15.5  Immune disorders of the gastrointestinal tract 2793 Oral allergy syndrome Oral allergy syndrome describes a condition where cross-​reactivity between pollen and certain food allergens results in individuals al- lergic to pollen experiencing hypersensitivity reactions following the ingestion of certain foods (Table 15.5.4). Non-​IgE mediated Non-​IgE-​mediated food allergy is a delayed immunological reaction which can be immune complex mediated or cell mediated. Food protein-​induced enterocolitis syndrome is a non-​IgE-​mediated gastrointestinal food hypersensitivity that presents in infancy. Clinical features include profuse, repetitive vomiting and diarrhoea, leading to dehydration and lethargy in the acute setting, or weight loss and failure to thrive in a chronic form. The most common food triggers are cow’s milk or soy protein. Other triggers include rice and oats. There are no definitive diagnostic tests and treatment is dietary elimination of the food trigger. Investigation and treatment strategies for food allergies Diagnosis of a food allergy involves reproducible symptoms after exposure to the allergen with evidence of an underlying immuno- logical mechanism. The depth of investigation depends on the age of the patient, the severity of symptoms, and the nutritional import- ance of the allergen. It may be more practicable to advocate food avoidance in some cases without investigations. The primary investigative modality is a skin prick test with food extract and control solution. A positive result is the formation of wheal and flare skin reaction. Serum-​specific IgE testing is another common test. Both these tests do not predict or correlate with se- verity of allergic reactions and only determine sensitization to a food allergen. Clinical food allergy can only be assessed in an oral food challenge study which is the next step after positive skin prick test or serum-​specific IgE testing. Patients are fed incrementally larger extracts of the food allergen and monitored for clinical signs. This test is contraindicated in patients with a history of food-​induced anaphylaxis. Ideally this should be performed in a double-​blind, placebo-​controlled manner to ensure reliable and unbiased results. Studies assessing primary preventative measures suggest that increasing maternal ingestion of common dietary food allergens and not delaying weaning beyond 4 to 6 months of age may possibly de- crease the development of food allergy. Treatment of food allergies involves avoidance of the food al- lergen. This entails education not only of the patient but often of their caregivers as food allergies are more common in children and allergens (e.g. milk and egg) may be hidden in foods. For those with food-​induced anaphylaxis, carriage of an adrenaline autoinjector is recommended. Immunotherapy can be used to desensitize individuals to certain allergens by building tolerance through continuous oral exposure. Immunotherapy for peanut allergy has received substantial media attention. Peanut allergy is common, lifelong, and exposure to small amounts can cause life-​threatening reaction. Recent randomized controlled trials have demonstrated that the majority of patients can achieve desensitization and although adverse events did occur, al- though they were mostly mild. Food intolerance Food intolerance is not immunologically mediated and is relatively common, affecting 20% of the general population with gastrointes- tinal symptoms being the most commonly reported. The most common functional gastrointestinal disorder at least partly attrib- uted to food intolerance is irritable bowel syndrome. Extraintestinal manifestations may include asthma, migraine, malaise, and eczema. Treatment for irritable bowel syndrome is often dietary manipula- tion, for example, an exclusion diet with gradual reintroduction to identify any food triggers or a low FODMAP (fermentable oligo-​, di-​, monosaccharide, and polyol) diet. FODMAPs are poorly absorbed, osmotically active, and fermented by intestinal bacteria to produce hydrogen instead of methane, which is thought to contribute to in- testinal distension, bloating, and dysmotility. The aetiology of food intolerance can be pharmacological, en- zyme/​transport related, or as a result of noncoeliac gluten sensitivity. There are a number of chemicals present in food that can potentiate pharmacological effects on the gastrointestinal neuroendocrine system leading to a myriad of symptoms. The most commonly de- scribed chemicals include salicylates, vasoactive amines (e.g. his- tamine), glutamates (e.g. monosodium glutamate), and caffeine. Lactose intolerance is the most common enzyme/​transport-​related food intolerance (see Chapter 15.10.5). Lactase-​phlorizin hydrolase, commonly referred to as lactase is a β-​galactosidase enzyme that catalyses the breakdown of lactose, a disaccharide in mammalian milk, to its constituent monosaccharides glucose and galactose. This enzyme is encoded by LCT and is secreted by the brush border cells of the small intestine. In most adults, this enzyme is downregulated post weaning and ingestion of milk or milk-​containing products leads to symptoms typical of lactose nonpersistence (lactose intoler- ance):  diarrhoea, abdominal pain, and flatulence. Approximately 30% of the world population display lactase persistence where lac- tase activity persists into adulthood. This genetic trait is geograph- ically distinct and strongly correlated with the dairying history of that population. Noncoeliac gluten sensitivity describes gastrointes- tinal symptoms attributed to the ingestion of gluten in the absence of any diagnostic features to suggest coeliac disease or a wheat al- lergy. Hereditary Fructose Intolerance is another genetic enzyme deficiency with a birth frequency of about 1 in 20 000 and leads to marked dietary idiosyncrasy (see Chapter 12.3.2). This recessive disease is caused by mutations in ‘liver’ aldolase B—an isozyme ex- pressed in small intestinal mucosa, liver and renal tubule. The disease is principally provoked by ingestion of fructose and sucrose, which induce a severe metabolic disturbance including hypoglycaemia with injury to the organs in which the aldolase is expressed. Since the con- dition can be reversed by dietary exclusion of the offending sugars, and is readily diagnosed by molecular analysis of the ALDOB gene, careful dietary history-taking is of paramount importance. Table 15.5.4  Typical cross-​reactivity associations between inhalant allergen and food allergens Allergen Food allergens Birch pollen Apple, raw potato, carrot, celery, hazelnut, pear, peach, plum, cherry Mugwort pollen Celery, apple, peanut, kiwi fruit, carrot, parsley, spices (fennel, coriander, aniseed, cumin) Ragweed pollen Melons (e.g., watermelon, cantaloupe, and honeydew), bananas Latex Avocado, kiwi fruit, chestnut, papaya, banana

SECTION 15  Gastroenterological disorders 2794 Eosinophilic gastrointestinal tract disorders Eosinophilic gastrointestinal tract disorders encompasses a wide range of diseases including eosinophilic esophagitis (EoO), eosino- philic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, and eosinophilic colitis in the absence of known causes for eosino- philia. EoO is discussed in more detail in the following subsection. Common presenting symptoms of the other eosinophilic disorders include abdominal pain, vomiting, and diarrhoea. Association with a food allergen is common and treatment is with steroids and dietary elimination. Eosinophilic oesophagitis Initially described in 1993 and thought to be a rare disease, EoO is a relatively new clinical entity in which the prevalence and interest has grown over the last 15 years. It is an immune-​mediated dis- ease characterized by a mainly Th2-​type immune response leading to eosinophilic recruitment. The subsequent eosinophil degranulation results in tissue remodelling that predisposes to fibrosis. Diagnosis is based on a combination of histological and clinical features. The histological hallmark is the presence of eosinophil-​predominant inflammation with a peak value of more than 15 eosinophils per high-​power field. The finding of eo- sinophils in the oesophageal squamous epithelium is abnormal and not specific to EoO as it is associated with other conditions (e.g. gastro-​oesophageal reflux disease, infections, drug hyper- sensitivity, autoimmune and connective tissue disorders, and hypereosinophilic syndrome). Multiple biopsies from the distal and proximal oesophagus as well as the antrum and duodenum can help distinguish EoO from other conditions. This together with classical clinical features is necessary for an accurate diag- nosis. Clinical characteristics include a male preponderance and history of atopic diathesis (asthma, food allergy, eczema, allergic rhinitis). In childhood, the main presenting symptoms are feeding difficulties, vomiting, and pain. Adults tend to present with solid food dysphagia, often with food bolus impaction necessitating endoscopic removal. At endoscopy, common findings are char- acteristic linear furrows, circular rings, whitish plaques, and pap- ules, although none of these are pathognomonic for EoO. In some cases, benign oesophageal strictures have been described and have been successfully endoscopically dilated. Initially treatment consists of an 8-​week trial of a proton pump inhibitor. If there is histological and symptomatic reso- lution following this, it is likely the diagnosis was either gastro-​ oesophageal reflux or proton pump inhibitor-​responsive oesophageal eosinophilia (PPI-​ROE). It is currently not clear if PPI-​ROE is a separate entity or a subtype of EoO. If repeat oesophageal biopsies reveal persistent eosinophilia, treatment with topical steroids (e.g. fluticasone or budesonide, swal- lowed instead of inhaled) is recommended and largely effective. Maintenance therapy is recommended as cessation often leads to symptomatic recurrence. In more aggressive cases, longer or higher doses of topical steroids, systemic steroids, or elimin- ation diets have been tried. There is little evidence for the role of mast cell stabilizers, leukotriene antagonists, or biological ther- apies yet. Identification of specific food allergic triggers either through elimination diets or patch testing is recommended, es- pecially in the paediatric population. Autoimmune conditions and the gastrointestinal tract Autoimmune gastrointestinal dysmotility Autoimmune gastrointestinal dysmotility is a gastrointestinal-​specific manifestation of autoimmune dysautonomia that can either be idio- pathic or paraneoplastic in origin. Autoimmune dysautonomia de- scribes the neural-​specific IgG or effector T cell-​mediated impaired function of peripheral autonomic synapses, ganglionic neurons, autonomic nerve fibres, and central autonomic pathways. Common symptoms relate to the underlying gastrointestinal dysmotility (gas- troparesis, constipation, diarrhoea, pseudo-​obstruction) and the onset can be acute or insidious. Investigations include nonspecific ob- jective assessment of gastrointestinal motility (gastrointestinal transit studies, gastroduodenal manometry, or colonic barostat testing to assess colonic contractions). Laboratory tests include serological testing for specific antibodies. The most specific autoantibody marker of autoimmune dysautonomia is the neuronal ganglionic alpha-​3-​ acetylcholine receptor (AChR) autoantibody. Additional markers of paraneoplastic or idiopathic dysautonomia include antineuronal nu- clear antibody-​type 1 (ANNA-​1), CRMP-​5-​IgG, N-​type voltage-​gated calcium channel, muscle AChR, striational, glutamic acid decarb- oxylase 65, and peripherin. Treatment may consist of pyridostigmine (a cholinesterase inhibitor) for pseudo-​obstruction, while immuno- therapy with intravenous immunoglobulin has also been trialled for this rare condition. Autoimmune pancreatitis Autoimmune pancreatitis (AIP) is a relatively rare fibroinflammatory disorder initially described in Japan in the 1960s. Over time it has become clear that there are two distinct clinical subtypes. Type 1 AIP is part of a multiorgan, systemic IgG4-​related disease and histologically characterized by lymphoplasmacytic sclerosing pan- creatitis rich in IgG4-​positive cells. Type 2 AIP is less common and defined by ductal neutrophilic infiltration, ductal destruction, and the classic ductal epithelial lesion with a paucity of IgG4-​positive cells. Despite the histological differences, both subtypes share similar clinical features and treatment strategies. AIP can present with features of obstructive jaundice secondary to pancreatic duct strictures, or more commonly a focal enlargement of the pancreatic head. Other presenting symptoms include acute pancreatitis and ab- dominal pain. In type 1 AIP, clinical features can suggest other organ involvement (e.g. Sjögren’s disease secondary to saliva gland infiltra- tion, interstitial nephritis, retroperitoneal fibrosis, and biliary dis- ease). In the presence of a pancreatic head mass, a common clinical scenario is distinguishing autoimmune pancreatitis from pancre- atic cancer. This is achieved through a combination of radiological imaging with assessment of serological markers. Typical radiological features of AIP include diffuse pancreatic enlargement with delayed enhancement, pancreatic ductal strictures without dilatation, and minimal peripancreatic fat stranding. Serological markers, such as raised IgG4 antibody levels and antiplasminogen-​binding protein,

15.5  Immune disorders of the gastrointestinal tract 2795 are helpful, but not specific to AIP and often histological confirm- ation is required. As AIP is extremely steroid responsive, response to therapy is part of the diagnostic criteria. There are several dif- ferent diagnostic criteria proposed, such as the Japanese guidelines, the Korean criteria, the Asian consensus criteria, the Italian criteria, and the Mayo Clinic HISORt (Histology, Imaging, Serology, Other organ involvement, and Response to steroids). Patients are treated with prolonged courses of steroids (up to 3 years). Relapse rates vary between 30 and 50% and can be treated with a further course of cor- ticosteroids and an immunomodulatory agent (e.g. azathioprine). Gastrointestinal manifestations
of systemic autoimmune diseases Systemic autoimmune diseases can have a number of gastrointestinal manifestations that either reflect the underlying autoimmune process or are related to treatment (Table 15.5.5). Common gastrointestinal manifestations of systemic vasculitides include intestinal ulceration, dysmotility, mesenteric ischaemia, and mesenteric infarction. As therapy often includes the use of nonsteroidal anti-​inflammatory and immunosuppressive agents, gastrointestinal complications of therapy include peptic ulceration and infectious causes of diarrhoea. FURTHER READING Agarwal S, Cunningham-Rundles C (2019). Gastrointestinal mani- festations and complications of primary immunodeficiency dis- orders. Immunol Allergy Clin North Am, 39, 81–​94. Agarwal S, Mayer L (2013). Diagnosis and treatment of gastrointes- tinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol, 11, 1050–​63. Artis D, Spits H (2015). The biology of innate lymphoid cells. Nature, 517, 293–​301. Cheroutre H, Lambolez F, Mucida D (2011). The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol, 11, 445–​56. Dellon ES, et al. (2013). ACG clinical guideline: evidenced based ap- proach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol, 108, 679–​92. Flanagan EP, et al. (2014). Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. Neurogastroenterol Motil, 26, 1285–​97. Ho MH, Wong WH, Chang C (2014). Clinical spectrum of food
allergies: a comprehensive review. Clin Rev Allergy Immunol, 46, 225–​40. Table 15.5.5  Gastrointestinal manifestations of systemic autoimmune diseases Systemic autoimmune disease Autoimmune process Gastrointestinal manifestations Systemic lupus erythematosus (SLE) Systemic vasculitis. Gastrointestinal manifestations tend to reflect active disease Oral ulcers can be discoid, ulcerative, or erythematosus. Gastrointestinal vasculitis includes features varying from segmental oedema to discrete ulceration, gangrene, and perforation. Intestinal dysmotility is common. Venous thrombosis can cause intestinal infarction. Other gastrointestinal features include protein-​losing enteropathy, pancreatitis, ascites, liver steatosis, chronic hepatitis and Budd–​Chiari syndrome Rheumatoid arthritis (RA) RA is characterized by inflammation of the synovium and surrounding structures. Rheumatoid vasculitis affects 5% of patients with intestinal involvement in approximately 20% Ischaemic ulcers, intestinal infarction, and pancolitis that closely resembles ulcerative colitis can occur. Upper gastrointestinal manifestations include oesophageal dysmotility and chronic atrophic gastritis associated with hypergastrinaemia and hypo-​ or achlorhydria. The latter can promote small-​bowel bacterial overgrowth. Chronic diarrhoea can result from secondary amyloidosis Sjögren’s syndrome Autoimmune disease with histological hallmark of lymphocytic infiltration of the exocrine glands resulting in acinar gland degeneration, necrosis, atrophy, and decreasing lacrimosalivary function Extraglandular involvement occurs in 5–​10% of patients and can present with dysphagia, dyspepsia, nausea, and dysmotility Behçet’s disease Multisystemic immune-​mediated disorder characterized by recurrent oral and/​or genital ulcers, arthritis, skin manifestations, and ocular, vascular, neurological, or intestinal involvement Intestinal ulcers can be found throughout the gastrointestinal tract, but are most common in the ileocecal region. As vasculitis is rarely observed in endoscopic or surgical specimens and there are no specific laboratory markers for intestinal Behçet’s disease, it is therefore challenging to distinguish from Crohn’s disease Systemic sclerosis (scleroderma) Immune activation, vascular damage, and excessive synthesis of extracellular matrix with deposition of increased amounts of structurally normal collagen leading to fibrosis Although any part of the gastrointestinal tract can be affected, 90% of patients will have oesophageal involvement. Oesophageal dysmotility commonly results in dysphagia and dyspepsia Henoch–​Schönlein purpura Small vessel vasculitis mediated by IgA immune complex deposition. Gastrointestinal symptoms in 75% of patients. Most common symptoms and signs are abdominal pain and haemorrhage secondary to intestinal mucosal ulceration. Polymyositis and dermatomyositis Connective tissue disorder characterized by inflammation of striated muscle (to a lesser extend smooth muscle) Patient often present with delayed oesophageal and gastric emptying Eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg–​Strauss syndrome) Allergic granulomatous angiitis 50% of patients report gastrointestinal symptoms which include bloody diarrhoea, ulcers and abdominal pain. Eosinophilic gastroenteritis can present in the prodromal phase

SECTION 15  Gastroenterological disorders 2796 Johnson DB, et al. (2016). Ipilimumab therapy in patients with ad- vanced melanoma and pre-​existing autoimmune disease. JAMA Oncol, 2, 234–​40. Kamisawa T, et al. (2013). Recent advances in autoimmune pancrea- titis: type 1 and type 2. Gut, 62, 1373–​80. Kaser A, Zeissig S, Blumberg RS (2010). Inflammatory bowel disease. Ann Rev Immunol, 28, 573–​621. Lee YM, Ayres JS (2018). Decoding the intestinal epithelium cell by cell. Nat Immunol, 19, 7–​9. Lomer MC (2015). Review article: the aetiology, diagnosis, mechan- isms and clinical evidence for food intolerance. Aliment Pharmacol Ther, 41, 262–​75. Mabbott NA, et  al. (2013). Microfold (M)  cells:  important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol, 4, 666–​77. Mantis NJ, Rol N, Corthésy B (2011). Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol, 4, 603–​11. Mowat AM, Agace WW (2014). Regional specialization within the in- testinal immune system. Nat Rev Immunol, 14, 667–​85. Peterson LW, Artis D (2014). Intestinal epithelial cells: regulators of bar- rier function and immune homeostasis. Nat Rev Immunol, 14, 141–​53. Schubert D, et al. (2014). Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med, 20, 1410–​18. Schwimmer D, Glover S (2019). Primary immunodeficiency and the gut. Gastroenterol Clin North Am, 48, 199–​220. Turnbull JL, Adans HN, Gorard DA (2015). Review article: the diag- nosis and management of food allergy and food intolerances. Aliment Pharmacol Ther, 41, 3–​25. Uhlig HH (2013). Monogenic diseases associated with intestinal in- flammation:  implications for the understanding of inflammatory bowel disease. Gut, 62, 1795–​805. Zeissig S, et al. (2015). Early onset Crohn’s disease and autoimmunity associated with a variant in CTLA-​4. Gut, 64, 1889–​97. Zeissig Y, et al. (2015). XIAP variants in male Crohn’s disease. Gut, 64, 66–​76.

15.6 The mouth and salivary glands 2797

15.6 The mouth and salivary glands 2797

ESSENTIALS Many systemic diseases are associated with oral symptoms or signs, hence thorough examination of the lips, gums, teeth, tongue, and oropharynx should be part of any complete physical examination of a patient. Dental caries, caused by bacterial action, is one of the com- monest human diseases and a cause of considerable misery. Chronic periodontal disease is the most important cause of dental loss in adults. In addition to describing these conditions, this chapter also covers potentially malignant lesions of the oral mucosa and oral cancer; viral, fungal, and bacterial infections; oral ulceration; oral manifestations of dermatological, gastroentero- logical, haematological, and multisystem disorders; orofacial pain syndromes; and salivary gland disorders. Diseases of the teeth, gums,
and supporting tissues Dental caries Dental caries is the destruction of dental hard tissues due to acidic and proteolytic microbial attack. The caries process is initiated in the biofilm (dental plaque) where acidogenic bacteria cause a local pH reduction sufficient to bring about dissolution of the hydroxy- apatite crystals in enamel with resultant demineralization. If the process continues for long enough and sufficient mineral is lost, progressive porosity and weakening of the tooth structure leads to cavitation. Cavitation of the enamel represents the point of no return and leads to further destruction of enamel followed by the dentine and this subsequently leads to involvement of the dental pulp. Pulpal inflammation is initiated by noxious stimuli from the carious lesion and, if the stimulus is not removed, leads to pulpal abscess and subsequent necrosis. Necrotic teeth can lead to infec- tion of the periapical tissues and beyond. Aetiology Dental caries is a multifactorial disease, the complex aetiology of which is represented diagrammatically in Fig. 15.6.1. The pathogenic biofilm Dental plaque is a polymicrobial biofilm which is adherent to the tooth structure. The biofilm is a microenvironment where bac- teria live a symbiotic existence offering mutual protection from the nonspecific immune response of the host as well as from chemicals and antibiotics. The early colonizers in dental plaque include Streptococcus mitis, S. salivarius, and S. oralis. These form the initial adherent layer which facilitates the development of the mature plaque with more patho- genic bacteria capable of rapid and prolonged acid production. The main bacterial species thought to be responsible for dental caries is S. mutans, although lactobacilli are also involved in the caries pro- cess once the lesion progresses into the dentine. S. mutans cariogenic potency comes from its ability to colonize teeth by adhering to sal- ivary glycoprotein and production of extracellular polysaccharides, 15.6 The mouth and salivary glands John Gibson and Douglas Robertson SES Income Saliva Education Lifestyle Stress Occupation Behaviour Oral hygiene AMPs Cortisol Noradrenaline SIgA Adrenaline Teeth Plaque microorganisms Diet (sugar) Time No caries No caries No caries No caries Caries Fig. 15.6.1  The complex multifactorial nature of dental caries. AMPS, antimicrobial peptides; SES, socioeconomic status; SIgA, secretory immunoglobulin A.

SECTION 15  Gastroenterological disorders 2798 its acidogenic ability to reduce the local pH to just above 4, and its aciduric ability to thrive in low-​pH environments. Experimental studies have shown that S. mutans can also induce dental caries in germ-​free mice. Recent molecular microbiology investigating the caries microbiome now indicates that S. mutans is not always pre- sent and other acidogenic bacteria can also be involved. Elevated levels of S. salivarius, S. sobrinus, and S. parasanguinis and Veillonella spp. are also associated with dental caries, especially in subjects with no or low levels of S. mutans. Bacterial community diversity is gen- erally reduced in advanced caries compared to health with reduced levels of oral commensals such as the S. mitis group, Neisseria spp., and S. sanguinis. Dental caries probably represents the endpoint of an acidogenic dysbiosis in the oral microbiome leading to cariogenic conditions in the mouth. Source of fermentable carbohydrate Consumption of nonmilk extrinsic sugars produces a rapid fall in the pH at the tooth surface to less than the critical pH of 5.5 at which tooth demineralization occurs. The most common carbohydrates in our diet are starch and sucrose, with smaller amounts of glucose, fructose, and lactose. The most important substrate in the human diet is sucrose which gives rise to heavy plaque formation with con- siderable amounts of extracellular polysaccharide favouring col- onization with aciduric cariogenic bacteria such as S. mutans and lactobacilli. The most important polysaccharide is dextran (glucan), which is synthesized in large amounts by the constitutive enzyme glucosyltransferase. Dextran may give plaque the necessary quality of stickiness to the enamel surface. Streptococci do not possess a cytochrome system but contain the Embden–​Meyerhof glyco- lytic enzymes, which will convert glucose to lactic and other or- ganic acids. The pH inside the plaque may fall within 2 to 3 min of rinsing the mouth with glucose or sucrose from a level of about 6.5 to 4.5. The oral environment is therefore in a constant state of flux with changes in oral pH occurring after every ingestion of food leading to disruption of the balance between demineralization and remineralization. There are associations between caries prevalence and quantity of sugar, frequency of sugar more than four times daily, the consistency (i.e. stickiness) of the applied sugar, and the time of exposure, such as prior to sleeping during which salivary flow is reduced. Other modifying factors The tooth may be susceptible due to its anatomy (normal or dis- ordered formation), iatrogenic factors such as filling margins and damaged enamel surfaces, or due to its local environment such as a reduction in salivary quantity or quality. Patients who suffer from xerostomia (dry mouth), due either to the effect of head and neck irradiation, medication, or autoimmune diseases such as Sjögren’s syndrome, are extremely susceptible to caries which can be rapidly destructive. Saliva plays a significant role in the prevention of dental caries both through its high buffering capacity and through growth in- hibition of dental plaque by nonspecific defence proteins such as lysozyme and lactoferrin. Specific antibacterial proteins such as secretory IgA, released through fluid derived from the gum pocket known as gingival crevicular fluid, also play a role in protection of the teeth from the colonization and maturation of plaque bacteria. The effectiveness of these factors varies between individuals. Serum IgG, IgA, and IgM antibodies, as well as cell-​mediated immunity to S. mutans, can be correlated with the DMF (decayed, missing, and filled teeth) index of caries. Salivary IgA antibodies are also found. The induction of salivary IgA antibodies through immunization may be related to a reduction in dental caries. Such salivary IgA antibodies can be induced by direct immunization of the minor salivary glands or by immunization of the gut-​associated lymphoid tissue or nasal-​associated lymphoid tissue. Systemic im- munization experiments with S. mutans have shown in the rhesus monkey model that caries can be reduced by immunization and the induction of serum IgG antibodies. Salivary or serum-​derived anti- bodies may prevent S. mutans from adhering to the tooth surface or inhibit glucosyltransferase activity and thereby prevent caries. Epidemiology Dental caries comprises the most common disease of humankind. In spite of reductions in the rate of decay in some Western societies in the last 50 years, the prevalence of caries in developed countries remains at more than 90% of the population and shows worrying signs of increasing once more. Epidemiologists report caries as DMFT or DMFS which represents the number of decayed, missing, or filled teeth or surfaces respectively. Caries is still increasing in the developing countries with the increased consumption of refined sugars. Caries is a disease of social inequalities and its prevalence is highest in poorer countries and in the lower socioeconomic groups in richer countries. In most populations, 80% of dental caries oc- curs in 20% of the population. The prevalence of caries is greatest in children and young adults where it affects the pits and fissures of the occlusal surfaces, and the enamel of the interproximal surfaces of teeth. Changing population demographics and tooth retention into later life is, however, leading to an increase in the prevalence of root caries (at the neck of the tooth) later in life. Dental caries is associated with socioeconomic factors such as low income, education, dental health attitudes, dental attendance, fluoride exposure, tooth-​brushing frequency, presence of fissure sealants, family and past caries experience, and maternal infection with S. mutans. Pathology Dental caries starts as a white spot on teeth which is virtually un- detectable to the untrained eye. It progresses to a brown spot which normally represents the uptake of exogenous stain. Due to the balance between demineralization and remineralization, caries can often take 3 to 4 years to progress through enamel. It is, however, possible for caries to occur within months of tooth eruption in highly caries-​active patients. This is due to the nature of newly erupted en- amel which is hypomineralized, lacks demineralization-​inhibiting contaminants of the hydroxyapatite lattice such as fluoride, and is often physically within a plaque-​trap location in children who may have less than perfect oral hygiene and a diet high in nonmilk ex- trinsic sugars. Early identification and institution of preventative measures that promote remineralization can arrest and reverse this process prior to surface breakdown or cavitation. Once cavitation occurs, there will be changes in the appearance of the tooth including chalky white demineralization, dark staining which can appear as brown or grey, and visible holes in the teeth. This dark stain within the tooth represents spread to the dentine core and will quickly progress to induce a reaction in the pulp below. There is

15.6  The mouth and salivary glands 2799 a fine balance between the speed of the advancing front of the den- tine lesion and the rate at which pulp-​dentine defences can be laid down to reduce the dentine permeability. In response to the micro- bial assault in the dentine, the cells of pulp will lay down a protective layer of tertiary dentine but may also become inflamed, a condition known as pulpitis. Dental caries is not normally painful until the carious lesion is 0.5 mm from the pulp. Depending on the duration and severity of the microbial assault, the developing pulpitis may be either reversible or irreversible depending on the pulp’s health and ability to resolve the inflammation. Acute periapical periodontitis or abscess usually occurs sec- ondary to dental caries and its sequelae (Fig. 15.6.2). After the in- tact pulp chamber is breached, colonization of the root canals occurs with a diverse mix of anaerobic bacteria. The walls of the necrotic root canals become colonized by a specialized mixed anaerobic bio- film. Asymptomatic necrosis is common and can lead to granuloma or periapical cyst formation but abscess formation occurs when the root canal microbiota and their toxic products enter the periapical tissues via the apical foramen and induce acute inflammation and pus formation. Clinical features Dental caries is diagnosed by visual examination of a clean dry tooth under good illumination and ideally magnification supplemented by intraoral radiographs showing radiolucencies within the crown and tactile investigation by a trained dental professional (Fig. 15.6.3). Sequelae of dental caries Pulpitis is characterized by severe pain in the mouth and jaw, which is stimulated by hot, cold, and sweet stimuli, and in later stages the tooth can feel sore during biting. The pain can be either sharp or dull and poorly localized and can radiate to the ear. It is often worse at night and when lying down. Crucially, there is no bacterial infection of the surrounding tissue, swelling, or suppuration. The inflamma- tion does not respond to antibiotics and analgesia is often ineffective. This condition requires management by a dentist which includes re- moval of dental caries and placement of a sedative dressing before definitive restoration. In cases of irreversible pulpitis, removal of the tooth or extirpation of the pulp (root canal treatment) is indicated. Periapical periodontitis is inflammation of the periodontal liga- ment and alveolar bone surrounding the end of the tooth without pus formation. Pain from periapical periodontitis is not induced by thermal or osmotic stimuli such as sweet foods and is normally well localized to the offending tooth. The treatment is either to carry out root canal treatment or to extract the tooth. The acute periapical (dental) abscess is a localized collection of pus in the alveolar bone and tissues around the tooth. It is character- ized by pain, swelling, erythema, and suppuration usually localized to the affected tooth, Treatment of the localized dental abscess re- quires tooth removal or drainage of pus either through an intraoral incision or the root canal. Occasionally, dental infection can spread through the fascial planes of the head and neck as a spreading cellulitis or abscess (Fig. 15.6.4). These serious infections are potentially life-​threatening and are associated with pyrexia, tachycardia or tachypnoea, trismus, Infection via carious cavity or traumatized crown Periodontal ligament Alveolar bone Apical foramen Periapical infection Infected or necrotic pulp Fig. 15.6.2  Periapical abscess formation. (a) (b) Fig. 15.6.3  Dental caries: (a) extensive destruction of the enamel and dentine; (b) cervical caries secondary to xerostomia (affecting the neck of the teeth, slightly above or below the junction between the root cementum and the enamel crown).

SECTION 15  Gastroenterological disorders 2800 raised tongue and floor of mouth, drooling, periorbital cellulitis, dif- ficulty with speaking, swallowing, and breathing, increased white blood cell count, lymphadenopathy, and dehydration. Such patients should be referred to an oral and maxillofacial surgeon without delay for incision and drainage of collections, tooth extraction, and airway management with adjunctive systemic antibiotics and medical care. Prevention Advice on prevention of dental caries is shown in Box 15.6.1. Gingival and periodontal diseases Gingival and periodontal diseases are a heterogeneous group of dis- eases that affect the supporting structures of the teeth known as the periodontium. The periodontium is made up of the gingivae (gums), cementum, periodontal ligament, and alveolar bone. In health, it is resistant to mechanical, microbiological, and chemical trauma and is responsible for maintaining the attachment of the teeth. The diseases affecting the periodontium encompass a wide range of possible pathologies, the classification of which is listed in Table 15.6.1. But the two most common conditions by far are plaque-​induced gingivitis and plaque-​induced periodontitis. This chapter will focus on three of the more common conditions, namely plaque-​induced gingivitis, plaque-​induced periodontitis, and necrotizing ulcerative gingivitis. Clinicians should also be aware that periodontitis may be a presenting feature of haemato- logical, nutritional, hormonal, and genetic systemic diseases. Periodontal diseases are some of the most common diseases af- fecting mankind resulting in tooth loss with a significant impact on function and quality of life. Plaque-​induced gingivitis is the presence of gingival inflammation without loss of the supporting tissues of the periodontium. Once the plaque is removed, the effects are entirely reversed. Plaque-​induced periodontitis represents the condition in the periodontium in sites of gingival inflammation where there has been subsequent irreversible bone and connective tissue loss. Nasal passage Orbit Maxillary sinus Maxilla Buccal sulcus Buccinator muscle Buccal sulcus Mandible Oral cavity Tongue Floor of mouth Mylohyoid muscle Fig. 15.6.4  Possible routes of spread of dental infection. Box 15.6.1  Advice on the prevention of dental caries • Teeth should be brushed twice a day using toothpaste containing at least 1000 to 1500 parts per million of fluoride, the toothpaste spat out, and water for rinsing the mouth avoided. Fluoride in toothpaste decreases the incidence of caries in children by up to 40%. • Fissure sealants and professionally applied fluoride varnish applica- tions are also effective. • One part per million of fluoride in the drinking water will decrease the incidence of caries in children by up to 60%. There is no evidence of toxicity from water fluoridation. • Both the quantity and the frequency of sugar intake should be de- creased; in particular sugary snacks should be avoided between meals and immediately before bedtime. • Nonsugar sweeteners should ideally be used in food and drink; if a sweetener is required, consider xylitol. • It is important for patients to register with a dentist and attend ac- cording to individual risk assessment. • Doctors should be aware of the risk of dental caries from sugared medicines and consider this when prescribing. • Nondental professionals should be aware of the noticeably increased risk of dental caries in the presence of dry mouth. • Low-​sugar artificial saliva or sugar-​free chewing gum should be con- sidered for patients with dry mouth as appropriate. • General practitioners should actively encourage patients at high risk of caries to attend for dental care.

15.6  The mouth and salivary glands 2801 Periodontitis can be classified as either chronic or aggressive. Chronic periodontitis is the most common and is generally con- sidered to be a slowly progressing form of the disease. Chronic periodontitis may be further described as mild, moderate, or severe. Aggressive periodontitis is a severe and widespread form of periodontal disease which is characterized by rapid attachment loss and bone destruction from an early age. The patient will be healthy apart from the periodontitis and there is a propensity to familial aggregation. Aggressive periodontitis is commonly diag- nosed in teenagers and young adults and can lead to early tooth loss. The effects of chronic periodontitis increase with age and un- treated this will progress slowly through life in a pattern of cyclical bursts of disease progression and quiescence resulting in a linear loss of attachment over time. The distinction between aggressive and chronic forms of disease is related to the earlier age of onset or detection, the more rapid rate of progression, the pattern of destruction with molars and incisors affected more severely, es- pecially in localized aggressive periodontitis, the signs of inflam- mation, and the relative amounts of plaque and calculus which are generally lower. Aetiology Plaque-​induced gingivitis and periodontitis are an inflammatory response to the accumulation of dental plaque on the teeth. While dental plaque is required, it is in itself not sufficient to cause peri- odontitis and acts as an initiating factor in susceptible individuals. Theories on the effect of plaque in periodontitis have varied over the years from the nonspecific plaque hypothesis which suggested that all plaque would lead to periodontitis over time, to the spe- cific plaque hypothesis which suggested that only infection with specific periodontal pathogens would lead to periodontitis. There is good evidence that Porphyomonas gingivalis, Tanerella forsy­ thensis, Treponema denticola, and Aggregatibacter actinomycetem­ comitans are associated with periodontitis and each have potent periodontopathic potential. However, the periodontal microbiome is incredible complex with hundreds of species of bacteria found in the mouth, half of which are yet to be cultured. The current view is that both of these views are simplistic and microbiome analysis now suggests polymicrobial synergy and dysbiosis as the current model. This hypothesis suggests that breakdown of periodontal host–​microbe homeostasis (i.e. ‘healthy plaque’) occurs due to in- fection with a keystone pathogen such as P. gingivalis or the occur- rence of immunoregulatory defects in the host response and this precipitates a dysbiosis (pathogenic plaque) and periodontitis in susceptible hosts. P. gingivalis is the predominant organism iso- lated from periodontal disease; it is capable of invasion and pro- duces powerful extracellular toxins. Smoking is a significant cause of periodontitis with odds ratios of between 1.2 and 7.1 reported, depending on smoking exposure. The mechanisms by which smoking has been proposed to damage the periodontium include alterations in the vasculature of the peri- odontal tissues in smokers, reduced neutrophil transmigration across the periodontal microvasculature, suppression of neutrophil chemokinesis, chemotaxis, and phagocytosis. Large studies of populations have found that periodontal dis- ease is affected by a number of risk factors including increasing age, smoking, psychosocial stress, genetics, race, sex, oral hygiene, socioeconomic status, obesity, hormonal changes, psychosocial stress, osteopenia and osteoporosis, Down’s syndrome, diabetes mellitus, as well as host genetic factors which predispose to an inef- fective, excessive, or inappropriate inflammatory response. Table 15.6.1  Classification of periodontal conditions I. Gingival diseases A. Dental plaque-​induced gingival diseasesa

  1. Gingivitis associated with dental plaque only a. without other local contributing factors b. with local contributing factors
  2. Gingival diseases modified by systemic factors a. associated with the endocrine system
  3. puberty-​associated gingivitis
  4. menstrual cycle-​associated gingivitis
  5. pregnancy-​associated a. gingivitis b. pyogenic granuloma
  6. diabetes mellitus-​associated gingivitis b. associated with blood dyscrasias
  7. leukaemia-​associated gingivitis
  8. other
  9. Gingival diseases modified by medications
  10. Gingival diseases modified by malnutrition B. Non-​plaque-​induced gingival lesions II. Chronic periodontitis A. Localized B. Generalized III. Aggressive periodontitis A. Localized B. Generalized IV. Periodontitis as a manifestation of systemic diseases A. Associated with haematological disorders
  11. Acquired neutropenia 2. Leukemias 3. Other B. Associated with genetic disorders
  12. Familial and cyclic neutropenia 2. Down syndrome 3. Leukocyte adhesion deficiency syndromes 4. Papillon–​Lefèvre syndrome 5. Chediak–​Higashi syndrome 6. Histiocytosis syndromes 7. Glycogen storage disease 8. Infantile genetic agranulocytosis 9. Cohen syndrome 10. Ehlers–​Danlos syndrome (types IV and VIII) 11. Hypophosphatasia 12. Other C. Not otherwise specified V. Necrotizing periodontal diseases A. Necrotizing ulcerative gingivitis B. Necrotizing ulcerative periodontitis VI. Abscesses of the periodontium VII. Periodontitis associated with endodontic lesions A. Combined periodontic-​endodontic lesions VIII. Developmental or acquired deformities and conditions a Can occur on a periodontium with no attachment loss or on a periodontium with attachment loss that is not progressing. Source data from Armitage GC (1999). Development of a classification system for periodontal diseases and conditions. Ann Periodontol, 4, 1–​6.

SECTION 15  Gastroenterological disorders 2802 Epidemiology Gingivitis is found in most adults while periodontitis is found in about one-​half of the middle-​aged or older population. Periodontitis is the most important cause of loss of teeth after the age of 40 years, when the incidence of dental caries has greatly diminished. Across the whole adult population between 5 and 20% of the population are affected. In most populations there are groups of individuals who are (1) strongly periodontally resistant (10%), (2) highly periodontally susceptible (10%), and (3) mod- erately periodontally susceptible (80%) despite poor oral hygiene. There is evidence that the prevalence of periodontitis in developed countries is reducing slightly although changes in patient prefer- ence for tooth retention and an ageing population could affect this trend. The prevalence of chronic periodontitis is higher in Asian, Hispanic, and African patients even in migrant populations, thus pointing to a genetic predisposition. Aggressive periodontitis There is a low prevalence of aggressive periodontitis in those under 35 years. Aggressive periodontitis was found in 0.1% of teenagers but the severity and extent increases in young adulthood; for ex- ample, in one study in young adults, the prevalence rose to 3.6%. Population studies have reported varying low levels of aggressive periodontitis in children throughout the world of less than 1% apart from Africa where the prevalence was 3.4% of the population. Studies show lower levels of aggressive periodontitis in Caucasians compared with other races. Pathology Periodontitis develops in well-​described histological stages as a re- sult of initial plaque accumulation and subsequent development of a pathogenic dysbiosis in the biofilm. Gingivitis Gingivitis develops after 7 to 14 days of plaque accumulation with pronounced vascular changes and an increase in extra- vascular neutrophils. The inflammatory infiltrate consists of numerous lymphocytes, predominantly T lymphocytes, im- mediately below the proliferating basal cells of the junctional epithelium. In order to facilitate the migration of neutrophils and lymphocytes, destruction of the gingival connective tissue occurs through apoptosis of fibroblasts and a reduction in the collagen fibre network of the marginal gingivae, via host-​ and pathogen-​derived matrix metalloproteinases. As the lesion be- comes more established, there is a shift in the cell population in the inflammatory infiltrate with large numbers of plasma cells being the main histological feature in older patients; in younger patients, the infiltrate continues to be dominated by lympho- cytes. The inflammatory infiltrate becomes more pronounced and clinically noticeable. T and B lymphocytes and antibodies and complement are present in the inflamed marginal gingivae and gingival sulcus. The junctional epithelium becomes hyperplastic and ulcerated at this stage and bleeding occurs on gentle probing or brushing. Chronic gingivitis always preceded periodontitis but may persist for many years without destruction of the periodontal ligament and supporting bone. Periodontitis Periodontitis occurs when the inflammatory lesion extends into the periodontal ligament and alveolar bone and there is destruction of connective tissue attachment to the tooth. The epithelium migrates down the root surface to form a periodontal pocket. While there is some evidence that highly virulent strains of bac- teria can invade the tissues this is not normally the case. Progression of periodontal destruction occurs largely as a result of an inappro- priate and ineffective host response leading to bystander damage. Some direct tissue damage can occur through direct cytotoxicity of bacterial products such as proteinases, collagenases, epitheliotoxin, cytolethal distending toxin, haemolysin, hydrogen sulphide, and ammonia. Dysregulation of host derived factors such as protein- ases and proteinase inhibitors, matrix metalloproteinases and tissue inhibitors of metalloproteinases, proinflammatory cytokines such as interleukin (IL)-​1α, IL-​1β, tumour necrosis factor (TNF)-​α and others, prostaglandins, and the products of polymorphonuclear leucocytes lead to damage to the connective tissue attachment. This is particularly the case where the immunoinflammatory response is unsuccessful in containing the bacterial biofilm and its products. Bone is destroyed through normal biological mechanisms involving physiological bone turnover and impaired repair. The alveolar bone is resorbed by osteoclasts creating a ‘safety zone’, 0.5 to 1 mm in width, of uninfiltrated connective tissue. Periodontitis represents a significant microbial and inflammatory burden to the host and there are a number of systemic diseases that seem to be adversely affected by the condition of the periodontium. These include atherosclerosis, diabetes mellitus, adverse pregnancy outcomes, obesity, metabolic syndrome, chronic kidney disease, and rheumatoid arthritis. Clinical features The symptoms of chronic gingivitis or periodontitis are usually so mild that they go unnoticed by the patient until at an advanced stage (Fig. 15.6.5). The symptoms and signs of periodontitis are described in Box 15.6.2. Differential diagnosis Chronic gingivitis is relatively painless. It can be differentiated from acute ulcerative gingivitis (see later) by the sudden onset, malaise, characteristic halitosis, pain, and ulceration of the gingiva in the latter. Herpetic gingivostomatitis occurs predominantly in children and again the onset is acute, with fever, malaise, pain, and ulceration of the gingiva and oral mucosa (see later). Desquamative gingivitis usually involves the full thickness of the gingivae and is associated with lichen planus or mucous membrane pemphigoid (see later) as well as several other diseases and may cause difficulties in differen- tial diagnosis. The points to bear in mind are that the attached gin- giva shows diffuse erosive areas and there may be evidence of lesions elsewhere in the oral mucosa. Management Gingivitis and periodontitis can largely be prevented by excellent oral hygiene with twice-​daily tooth-​brushing and daily flossing and interdental brush use. Because severe periodontitis only occurs in a subgroup of the population, individual risk assessment by a dentist is important.

15.6  The mouth and salivary glands 2803 Once deep periodontal pockets have been formed, the contamin- ated root surface must be debrided and the biofilm disrupted. The dental plaque below the gum line is removed using scalers which may be manual or powered. Systemic and, to a lesser degree, local antibiotics are used in cases of aggressive periodontitis and in those unresponsive to initial nonsurgical therapy. Periodontal surgery to access the root surfaces is also occasionally indicated. Host modula- tion therapies are also available, for example, the matrix metallopro- teinase inhibitor, low-​dose doxycycline. Course and prognosis If the bacterial plaque is not removed, the gingivitis may progress to periodontitis and after many years will progress to loss of teeth and resultant loss of function. This process may, however, be arrested by excellent plaque control and professional root surface debridement, as long as there is sufficient bone to support the teeth. Patients with widespread severe or aggressive disease and those who continue to smoke are at high risk of recurrence. Necrotizing periodontal diseases The necrotizing periodontal diseases include necrotizing ulcerative gingivitis (synonyms: Vincent’s gingivitis or acute fusospirochaetal gingivitis) and necrotizing ulcerative periodontitis. Both are char- acterized by necrosis but there is no permanent damage to the periodontium in necrotizing ulcerative gingivitis. Aetiology Necrotizing ulcerative gingivitis is caused by a complex mixture of spirochaetes and fusiforms aided by other Gram-​negative species. Fusobacterium and Treponema vincenti have been favoured on account of their presence in large numbers in direct examination of smears from the lesions. Prevotella intermedia, Porphyromonas gingivalis, Leptotrichia spp., and Selenomonas spp. can also com- monly be found. Whatever role microorganisms may play, a number of local and systemic predisposing factors are recognized. Of the local factors, poor oral hygiene, pre-​existing gingivitis, and smoking are most important. Necrotizing periodontal diseases are associated with nutritional deficiency, smoking, stress, debilitating disease, and HIV/​AIDS. A lowered systemic resistance may also predispose to the disease, as was commonly seen in trench war- fare during the First World War which is where the term ‘trench mouth’ derives. Pathology The necrotizing ulcerative gingivitis lesion is a nonspecific, acute necrotizing inflammation of the gingivae which involves the underlying connective tissue as well as the epithelium. There is an intense polymorphonuclear response and fibrinous exudate. This soon leads to necrosis of the epithelium, thrombosis of the small blood vessels, and replacement with a meshwork of bacteria, fibrin, necrotic epithelial cells, and polymorphonuclear neutrophils. This appears clinically as a pseudomembrane. Epidemiology Necrotizing ulcerative gingivitis occurs most commonly in pa- tients between 15 and 30 years of age. It is more common in lower socioeconomic groups and in developing countries, especially in Africa where it can also progress to necrotizing ulcerative peri- odontitis and cancrum oris or ‘noma’ in malnourished children. Epidemic-​like outbreaks can occur in populations although it has not been shown to be contagious. Clinical features Necrotizing ulcerative gingivitis is readily recognized by the sudden onset of painful, bleeding gums and a characteristic foul breath and metallic taste. It is also characterized by pyrexia, re- gional lymphadenitis, leucocytosis, loss of appetite, and significant malaise. Oral examination reveals grey, necrotic, punched-​out crater-​like ulcers covered in a grey pseudomembrane predominantly affecting the interdental gingiva and a generalized gingivitis (Fig. 15.6.6). (a) (b) Fig. 15.6.5  (a) Chronic gingivitis, with erythema and oedema of the gingival margin of the lower teeth and especially the right upper lateral incisor; (b) drug-​induced gingival hyperplasia due to ciclosporin. Box 15.6.2  Symptoms and signs of periodontitis • Occasional redness or bleeding of gums while brushing teeth, using dental floss or biting into hard food (e.g. apples) • Occasional gum swelling • Halitosis or bad breath • Persistent bad taste in the mouth • Recession of gums resulting in apparent lengthening of teeth (which may also be caused by heavy-​handed brushing) • Periodontal pockets between the teeth and the gums • Spacing of teeth • Loose, shaky teeth in later stages

SECTION 15  Gastroenterological disorders 2804 If untreated, necrotizing ulcerative gingivitis can lead on to peri- odontal destruction (necrotizing ulcerative periodontitis), recession and loss of the necrotic papilla. Management Necrotizing ulcerative gingivitis/​periodontitis can respond to gentle local debridement alone and this can be carried out with ultra- sonic scalers and chlorhexidine gluconate or hydrogen peroxide mouthwash. If it does not respond to this then a short course of metronidazole is effective. Given that it is a disease of immunosup- pression, it is important to identify the underlying cause, especially in recurrent cases. Pericoronitis Pericoronitis is inflammation of the soft tissues associated with the crown of a partially erupted tooth (‘operculum’) and is seen most commonly in relation to the mandibular third molar teeth and gen- erally occurs at the time of their eruption (15–​24 years). Clinical features Pericoronitis is associated with a complex mixture of Gram-​positive and Gram-​negative bacteria. Risk factors include the presence of partially erupted teeth with deep gum pocketing around the crown, trauma from contact with the opposing tooth, and poor oral hygiene. Pericoronitis may remain localized or may develop into a spreading infection involving the deep surgical spaces with associated systemic upset. Symptoms include pain, swelling and pus from the pericoronal tissues, trismus, bad taste/​breath, and lymphadenopathy. Management Treatment includes irrigation of pericoronal space with a sterile irrigant such as chlorhexidine, water, saline, or local anaesthetic agent, or local agents to cauterize the soft tissues. The opposing tooth can be removed if it is causing trauma. Patients should be prescribed nonsteroidal anti-​inflammatory drugs unless contraindicated and should use a 0.2% chlorhexidine mouthwash twice daily. A broad-​ spectrum antibiotic should be prescribed only in cases of severe local disease not responding to local measures or if there are signs of systemic upset (e.g. fever). Repeated episodes of pericoronitis are an indication for removal of the affected tooth. Potentially malignant lesions of the oral mucosa and oral cancer Potentially malignant lesions of the oral mucosa The World Health Organization (WHO) Collaborating Centre for Oral Cancer and Precancer has identified several oral mucosal disorders as potentially malignant. These include leucoplakia, erythroplakia, lichen planus, oral submucous fibrosis, discoid lupus erythematosus, and the hereditary disorders of dyskeratosis congenita and epidermolysis bullosa. This section will deal specific- ally with leucoplakia and erythroplakia. Epidemiology Detailed studies into the incidence and prevalence of leucoplakia and erythroplakia are surprisingly uncommon with the majority of such studies being carried out in India or Sri Lanka. Thus estimates on the incidence and prevalence of these conditions vary signifi- cantly depending on which population group or country is being studied. Combining the Indian studies, the incidence of leucoplakia ranged from 0.6 per 1000 to 30.2 per 1000 depending on the use of tobacco or other substances of habit. The prevalence of leucoplakia and erythroplakia is around 1 to 5% of the population, again depending on the population examined, with leucoplakia being significantly commoner than erythroplakia. There have been brave attempts to define the term leucoplakia over several decades with the WHO in 1978 defining leucoplakia as ‘white patch or plaque that cannot be characterized clinically or pathologically as any other disease’. This definition has changed over the years with a more modern definition now being ‘a white plaque of questionable risk having excluded (other) known diseases or dis- orders that carry no increased risk for mouth cancer’. As such, it is clearly important to identify any other potential differential diag- nosis and potential positive factors. A biopsy is therefore mandatory where a lesion persists, despite intervention, for 3 weeks in order to rule out other mucosal conditions and to assess the risk of malignant transformation. Aetiology The natural history of leucoplakias and erythroplakias remains largely unknown. However, it seems that the majority of such lesions have involvement of tobacco, alcohol, or betel quid (or other recre- ational substance or drug). Pathogenesis and pathology It is important to appreciate that the terms leucoplakia and erythroplakia are clinical terms with no specific histological fea- tures. The lesions may show atrophy or hyperplasia of the prickle cell layer of the oral epithelium and may or not show epithe- lial dysplasia. Historically, two types of leucoplakias have been described—​homogeneous and nonhomogeneous. It is thought that nonhomogeneous lesions carry a much higher risk of malig- nant transformation. These include ‘speckled’ variants, also called erythroleucoplakia. Clinical features These lesions, by definition, are white, red, or speckled. They can be flat, nodular, or verrucous. Fig. 15.6.6  Acute necrotizing ulcerative gingivitis.

15.6  The mouth and salivary glands 2805 Differential diagnosis A number of oral mucosal lesions require to be excluded in order to make a diagnosis of leucoplakia. These include white sponge naevus, frictional keratosis, leukoedema, cheek biting and chemical injury from substances such as aspirin, candidosis, lichen planus and lichenoid tissue reactions, discoid lupus erythematosus, hairy leucoplakia, and stomatitis nicotina (hyperkeratosis of the palatal mucosa related to tobacco use). A number of clinical features are considered important in predicting the risk of malignant transformation of leucoplakias and erythroplakias. These include duration, older age of patient, being female, clinical subtype (with nonhomogeneous lesions being more prone to transformation than homogeneous lesions), being sited on the lateral borders of the tongue, ventral surface of the tongue, and floor of mouth, a previous diagnosis of head and neck cancer and, surprisingly, the absence of smoking habits. It has been reported in some studies that larger lesions are more prone to malignant transformation. Other predictive factors, in recent studies, have suggested that the presence and severity of grade of epithelial dysplasia and/​or the presence of Candida albicans also predict that the lesion may show malignant transformation at a future date. Clinical investigation Biopsy of an identified leucoplakia or erythroplakia of the oral mucosa is mandatory. Some studies have suggested that the use of diagnostic aids such as toluidine blue may be helpful in identifying the salient site for biopsy. The emergence of data to support the rou- tine use of such aids has not been forthcoming to date. Management Patients should be encouraged to stop smoking as a matter of priority and it is frequently noted that smoking cessation can re- sult in the significant regression or disappearance of such lesions in short order. Surgical treatment of leucoplakia, either by ex- cision or laser ablation, appears to offer little protection for the future development of mouth cancer within the affected mouth. Similarly, there is little evidence that long-​term follow up pro- grammes for patients with oral leucoplakia or erythroplakia are very effective in preventing oral cancers developing. Regardless, practitioners and patients should be educated to look out for any change in the clinical appearance of these lesions, seeking early referral as soon as possible thereafter. There is much debate as to whether patients with potentially malignant lesions of the oral mucosa should be followed up by any primary or secondary care setting. Prognosis and outcome It is estimated that the risk of malignant transformation of oral leucoplakias is around 2% per annum and this represents a sig- nificant increase over the general population. The risk of malig- nant transformation is even higher in those with erythroplakia. As such, patients with these lesions identified in their mouths should be informed of the increased risk of mouth cancer and of the need to self-​monitor the oral mucosa and report any changes to a doctor or dentist with some urgency. Oral cancer Mouth cancers include those arising on the lip, the intraoral mu- cosal structures, and oropharyngeal—​arising from the tonsils or posterior one-​third of tongue. The WHO’s tenth edition of the International Classification of Diseases (ICD-​10) classifies cancers of the lip, tongue, and mouth as ICD-​10: C00-​06, and oropharynx as ICD-​10: C09-​10. Salivary gland tumours are classified under the ICD coding as C07-​08 with other pharyngeal sites as C11-​13. The most common cancers of the head and neck are those arising from the mouth with the sides of the tongue the most common site. Epidemiology Head and neck cancers, including those affecting the oral cavity and pharynx, are increasingly common with around 0.5  million new cases annually across the world and 300 000 deaths. The poor out- come with mouth cancer is largely related to delay in diagnosis with around 50% of patients having metastatic disease at the time of pres- entation. Therefore, the early diagnosis of oral cancer is crucial. Aetiology The majority of mouth cancers are squamous cell carcinomas, that is, arising from the epithelial keratinocytes. Such cancers are com- moner in people who smoke tobacco, use betel, and consume al- cohol to excess. There are concerns about mouth cancer occurring in younger age groups but, currently, the majority of patients with oral squamous cell carcinoma (OSCC) are older men. There is also an increased risk of OSCC in those with a previous experience of a cancer within the aero-​digestive tract or other sites within the gastrointestinal system. OSCC is also commoner in patients with a past history of potentially malignant lesions of the oral mucosa, including erythroplakia, leucoplakia, submucous fibrosis, lichen planus, and discoid lupus erythematosus. It has also been identified that lower educational status and lower income levels are associated with increased risk of developing mouth cancer. These variables are independent of smoking and alcohol consumption. Several genetic polymorphisms involved with the regulation of metabolic pathways are currently under consideration as being influential in the aeti- ology of mouth cancer. Higher levels of consumption of fruit and vegetables have been reported as significantly reducing the risk for mouth cancer. Pathogenesis and pathology The vast majority of mouth cancers are squamous cell in origin with a multifactorial aetiology including genetic and environmental factors. Clinical features The classical appearance of an OSCC is that of an indurated (hard), exophytic (outward growing) lump or nodule with an area of asso- ciated chronic ulceration. Often the ulcer has a rolled, raised border and the tissues often friable, bleeding easily on touching (Fig. 15.6.7). However, increasingly, the topography of mouth cancer is changing with all red, white, and speckled patches of the oral mucosa which lasts for 3 weeks or more being viewed with suspi- cion. Similarly, any unexplained lumps or bumps around the oral mucosa and unexplained lymphadenopathy of the head and neck

SECTION 15  Gastroenterological disorders 2806 should be considered suspicious with investigations instituted within a 3-​week time frame. Differential diagnosis A differential diagnosis for OSCC would include benign and malig- nant tumours arising from other tissue types, including lymphoma and melanoma. A smaller cohort of mouth cancers arising from the keratinocyte are known as verrucous carcinomas and these tend to be chronic, slow-​growing lesions with local destructive invasion and little opportunity for metastasis. Clinical investigation Biopsy is mandatory with staging of the tumour being made under the TNM (tumour, node, metastases) classification. Examination under anaesthesia allows the full extent of the lesion to be identi- fied, along with any other coexisting primary tumours. MRI and CT scanning will allow fuller delineation of the tumour locally with the identification of nodal or distant metastatic spread. Management The identification of potential aetiological factors with rapid cessation of such factors is required. This will include advice on smoking cessation and moderation of alcohol consumption. Similarly, where the use of other recreational drugs or ethnicity-​ based substances (e.g. betel) is identified, cessation advice should be offered. Treatment of OSCC is centred on local excision, with or without neck dissection. The TNM staging and the tumour hist- ology will determine whether radiotherapy, chemotherapy, or chemoradiotherapy is appropriate. Prognosis and outcome Advancements in surgical techniques mean a gradually improving 5-​year survival rate for patients with OSCC. However, the 5-​year survival rate still sits at around 50%. Regardless, current management strategies, including prosthetic rehabilitation, mean that even those patients with disseminated disease should have a decent quality of life throughout their remaining years. Special circumstances A particular type of oral cavity cancer, oropharyngeal cancer, ap- pears to be becoming more prevalent. This is also a squamous cell carcinoma and affects primarily the lymphoid tissue of the oro- pharynx and the posterior one-​third of tongue. The increasing prevalence of oropharyngeal cancer is thought to be related to an increase in carriage rates of human papilloma virus (HPV), par- ticularly serotypes 16 and 18. It is now routine practice to assess biopsy and resection specimens for the presence of HPV DNA. Such tumours tend to be of better prognosis. It is unclear how the current vaccination programme against HPV in teenage girls in some countries such as the United Kingdom for the prevention of cervical cancer may affect the prevalence of oropharyngeal cancer in the long term. Some countries, such as Australia, are assessing the veracity of a similar programme of vaccination against HPV in boys. Viral infections A number of viruses are responsible for manifestations around the head and neck. These are particularly the herpes group vir- uses (herpes simplex virus (HSV)-​1, HSV-​2, varicella zoster virus, human herpes virus 8, cytomegalovirus (CMV), and Epstein–​Barr virus), the group A Coxsackie viruses, and HIV. On an historic note, the Koplik’s spots associated with the measles virus acute infection are now very rarely seen in those countries where the mumps, mea- sles, and rubella vaccination programme is in place. Herpes simplex virus 1 and 2 HSV-​1 and -​2 are DNA viruses with high seroprevalence rates across all populations. Historically, HSV-​1 has been predominantly found in the tissues of the head and neck with HSV-​2 in the genital tissues as a sexually acquired infection. However, with changing sexual practices, HSV-​1 and -​2 are now known to cause primary infections and reactivations both orally and genitally. That said, HSV-​1 is still the predominant serotype identified with lesions of the head and neck. Epidemiology Around 70% of adults show seropositivity for HSV-​1. In addition, some 70% of the population have been shown to shed HSV-​1 in their saliva, regardless of seropositivity. Primary infection Aetiology A primary herpetic infection in the first 6 months of life is rare because of the transfer of neutralizing IgG antibodies to the virus transferred across the placenta in utero. Primary herpetic gingivostomatitis is the primary presentation, normally in children following exposure to the HSV-​1 virus. For those subsequently ex- posed to HSV-​2, a further primary herpetic gingivostomatitis may Fig. 15.6.7  Squamous cell carcinoma on the ventral surface of the tongue showing a necrotic centre and rolled indurated margins.

15.6  The mouth and salivary glands 2807 then occur—​often in adulthood corresponding with the onset of sexual activity. Pathogenesis and pathology Infection starts with HSV-​1 gaining entry into the epithelial cells of the mouth with subsequent viral replication taking place inside the nucleus. With progressively more epithelial cells becoming infected, dramatic degenerative and oedematous changes occur within each cell and in the affected tissues, giving rise to vesicle formation with subsequent breakdown to form erosions or ulceration. Where ves- icle formation does not occur, the oral soft tissues simply become red and oedematous. Clinical features Clinically, the affected patient is irritable and lethargic with the onset of a sore throat, fever, and lymphadenitis. Subsequently, the gingivae (gums) become bright red with the development of vesicles. A similar picture is repeated on any or all oral mucosal surfaces. The patient refuses to eat due to oral discomfort and dehydration is a very real problem. The vesicles deroof to become erosions of ulcers, these coalescing into larger areas of tissue sloughing. Differential diagnosis The clinical picture is largely diagnostic but early phases may be con- fused with other upper aerodigestive tract viral infections. There is potential for confusion with acute Coxsackie virus infections but these tend to present with lesions in the posterior part of the mouth and pharynx, whereas a primary herpetic gingivostomatitis occurs throughout the mouth. Severe recurrent aphthous stomatitis may also be confused with a primary herpetic gingivostomatitis, save for the extensive gingival involvement in the viral infection. Clinical investigation Where doubt exists, culture of the virus may assist in the diag- nosis but, as noted previously, there is also extensive shedding of the herpes virus in asymptomatic carriers. The conventional rise in antibody titre at 2 to 3 weeks after infection allows a retrospective diagnosis to be made as required. Management The mainstay of treatment is rest with an emphasis on adequate oral fluid intake. Healthcare practitioners should have a low threshold for referral to secondary care where adequate oral hydration cannot be guaranteed. Similarly, where there is any risk of associated her- petic keratitis or encephalitis, early referral is warranted. Pain control is normally achieved with a simple analgesic such as paracetamol elixir. An antiviral preparation such as aciclovir in elixir or tablet form at a dose of 200 mg five times daily is used for adults and children over the age of 2 years. Under the age of 2, the dose is halved. The antiviral preparation is normally continued for 5 days but may be extended if new lesions appear during treatment or if the healing phase is prolonged. Prognosis and outcome Patients with primary herpetic gingivostomatitis will normally be completely well again within 10 days. Reactivation HSV-​1 is a latent neurotropic virus, lying latent in the neuronal tissue of the corresponding dermatome or mucosatome affected in the pri- mary event. Reactivation can occur in four forms—​recurrent herpes labialis (cold sore), recurrent intraoral herpes, lower motor neuron facial nerve palsy and, rarely, a trigeminal sensory neuropathy. Aetiology It is anticipated that reactivation of the HSV-​1 occurs following an appropriate triggering event—​such as intercurrent illness, signifi- cant trauma, emotional distress, menstruation, or high levels of sun- light exposure. It has been suggested that reactivation of the virus may occur due to a defect in the local cell-​mediated immunological response at the neuroepithelial junction. There is no evidence that any impairment in antibody response to the HSV is responsible for reactivation and, indeed, there is little evidence of an antibody re- sponse during episodes of reactivation. Clinical features The lesion of a cold sore tends to occur as a small, single blister, or groups of blisters on the vermillion border of the lips, although it can occur anywhere on the facial skin and nose. The lesions tend to heal within 7 to 10 days, although frequent recurrences can be very distressing and problematic. Recurrent intraoral herpes tends to occur in a localized area of the oral mucosa with ulceration or erosions which are frequently very painful. There is increasing evidence in the literature that reactivation of HSV-​1 within the facial nerve may result in a lower motor neuron palsy. This appears to occur due to inflammation of the facial nerve as it passes through the stylomastoid foramen with resultant pressure effects on the nerve within the canal leading to axonal dysfunction. Trigeminal sensory neuropathies tend to be commoner in the spring and summer with the gradual onset of facial pain of limited duration. This presentation is infrequently associated with any mu- cosal or skin manifestations of viral reactivation. Erythema multiforme (EM) may be triggered, sometimes recur- rently, by reactivation of HSV-​1. Management There is little evidence that topical preparations of anything other than antiviral agents have any effect on cold sores. Aciclovir cream (5%) or penciclovir cream (1%) may be applied to the developing cold sore lesions as soon as possible in the prodromal phase—​every 4 h in the case of aciclovir and every 2 h with penciclovir. Where recurrent episodes of cold sores become the cause of stress or re- lationship difficulties, then prophylactic systemic antiviral prepar- ations may be offered. This is also true of recurrent intraoral herpes infection and recurrent EM. Aciclovir may be prescribed at a dose of 400 mg twice daily and valaciclovir at a dose of 500 mg daily. With regard to the management of Bell’s palsy (lower motor neuron facial nerve palsy) associated with reactivation of HSV-​1, antiviral therapy has been identified as unhelpful with regard to prognosis in several studies. Instead, in uncomplicated Bell’s palsy, the literature supports the prescription of oral corticosteroids within 72 h of symptom onset.

SECTION 15  Gastroenterological disorders 2808 Prognosis and outcome Where sunlight is known to be a precipitant for recurrent cold sores, then an appropriate barrier cream may be applied to the lips before sun exposure. Herpes zoster infection The varicella zoster virus has a primary form (chicken pox) with the recurrent type causing shingles (herpes zoster infection). Once again, after primary infection, the virus shows latency, lying dormant in neuronal tissues of the dorsal root ganglia or cranial nerve ganglia. Reactivation is relatively uncommon and it is antici- pated that shingles will become increasingly rarer as a result of vac- cination programmes in many countries across the world. Reactivation of the virus initially causes altered sensation along the distribution of the affected cranial nerve with vesicles appearing within 5 days on the corresponding dermatome or mucosatome. When shingles affects the ophthalmic division of the trigeminal nerve, the risk of damage to the eye is possible and so consultation with an ophthalmologist is appropriate. When reactivation of the virus affects the geniculate ganglion of the facial nerve, the so-​called Ramsay Hunt syndrome may occur with vesicle formation within the external auditory meatus and ip- silateral oropharynx (Fig. 15.6.8), along with a lower motor neuron facial palsy on the same side. Management Early treatment of active shingles infection is most important with an appropriate antiviral preparation being administered systemic- ally as soon as possible. This may be in the form of aciclovir at a dose of 800 mg five times daily for 7 days, famciclovir at a dose of 500 mg three times daily for 7 days, or valaciclovir at a dose of 1 g three times daily for 7 days. Cytomegalovirus Although CMV infection in neonates may cause devastating results, CMV infection in otherwise healthy children and adults is largely asymptomatic but can include the features of a generalized viraemia with mild pharyngitis and regional lymph node enlargement. CMV infection in immunocompromised patients can be life-​ threatening. The features include salivary gland enlargement and large irregular ulcers affecting the oral mucosa. Epstein–​Barr virus Close contact with the oral secretions of an infected individual or asymptomatic carrier may cause the features of infectious mono- nucleosis in teenagers and adults. This causes acute sore throat, fever, and regional lymph node enlargement. Associated features are oral ulcers and petechiae—​both tending to affect the palatal mucosa. Enlargement of the spleen and liver with deranged liver functions tests are not uncommon features. Oral hairy leucoplakia is also caused by Epstein–​Barr virus with these corrugated white lesions tending to affect the lateral surfaces of the tongue (Fig. 15.6.9). It was originally felt that oral hairy leucoplakia was pathognomonic of HIV disease but, more recently, this condition has been found in other causes of immunosuppres- sion and, in particular, local immunosuppression due to the use of corticosteroid inhalers in patients with asthma. Human herpes virus 8 This virus is associated with Kaposi’s sarcoma in immunosuppressed patients, particularly those with HIV. Within the mouth, Kaposi’s sarcoma tends to be found on the palate and the maxillary gingivae (Fig. 15.6.10). Fig. 15.6.8  Herpes zoster of the maxillary branch of the trigeminal nerve showing vesicular eruption on half of the palate. (a) (b) Fig. 15.6.9  (a) Oral hairy leucoplakia. Note the vertical lines of keratosis on the side of the tongue. These are characteristically bilateral. (b) Histological examination reveals frequent swollen epithelial cells due to infection by Epstein–​Barr virus in addition to acanthosis.

15.6  The mouth and salivary glands 2809 Coxsackie virus infections Herpangina This is a relatively rare infection caused by group A Coxsackie vir- uses with small vesicles, and subsequently ulcers, affecting the oral mucosa posteriorly—​particularly the soft palate and oropharynx. Children tend to be affected more often than adults with a similar presentation to that of primary herpetic gingivostomatitis, albeit that the lesions of primary herpetic gingivostomatitis tend to be significantly more widespread in the mouth. The diagnosis can be firmly established by isolating the virus from a lesion or by showing an increase in antibody titre. Importantly, the symptoms and signs are self-​limiting and no specific treatments, except for rest and oral analgesics, is required. Hand, foot, and mouth disease This is another viral infection caused by group A Coxsackie viruses—​ notably A5, A10, and A16. It is a relatively common infection, mild in presentation but sometimes causing small epidemics among school children. Once again, the mouth is uncomfortable or sore due to multiple small vesicles, which turn into ulcers. These lesions most commonly affect the hard palate, the tongue, and the buccal mucosae. Associated with these oral lesions are similar lesions affecting the skin of the hands and feet. As before the diagnosis is largely clinical but can be confirmed either by isolating the virus from lesional tissue or by demonstrating an increase in antibody titre over 2 to 3 weeks. The disease is largely self-​limiting within 10 to 14 days with no specific treatment required except for rest and oral analgesics. Human immunodeficiency virus The epidemiology, aetiology, and pathogenesis of HIV infection is discussed in Chapter 8.5.23. The at-​risk populations for the trans- mission of HIV are well established. The specific significance to dentists of the potential for oral transmission of HIV is self-​evident, working as they do with saliva and causing bleeding of the oral soft tissues. However, despite extensive studies across the world, there has been no confirmed case of a dental healthcare worker infected with HIV causing onward transmission of the virus to a patient during the course of normal professional activities. HIV affects predominantly CD4+ lymphocytes, causing significant dysfunction of these cells and their role in the wider immune system. The resultant immunodeficiency allows coinfection with several other viruses, bacteria and fungi. There is evidence to suggest that HIV also adversely affects local innate immunity within the oral cavity. Epidemiology The advent of highly active antiretroviral therapy (HAART) has changed the prevalence and type of the oral manifestations of HIV very significantly. Although oral lesions (HIV-​OLs) are still helpful pointers to the possibility of HIV, particularly to dentists and mem- bers of the wider oral healthcare team, once treatment begins with HAART, the HIV-​OLs in an individual patient change. Lack of ad- herence to strict definitions of the oral manifestations of HIV and indeed HAART versus antiretroviral therapy, variation between adult and paediatric populations and countries, and the duration of treatment makes sensible interpretation of the worldwide data on the prevalence of HIV-​OLs somewhat difficult, with studies re- porting anything from 5 to 75%. Pathogenesis/​pathology It is often difficult or impossible to define the exact route of HIV transmission in a patient with HIV disease. However, the risk of oral transmission of HIV during orogenital contact, even with ejaculation of infected semen into the recipient’s mouth, remains low. Similarly, there is little evidence to suggest that transfer of the virus occurs in saliva, which makes the risk of transferring HIV in a social setting with talking, coughing, and even kissing very low or negligible. The antiviral factors in saliva and the other secretions which make up the oral fluid pool (e.g. gingival crevicular fluid and blood from gingival bleeding), such as lysozyme and secretory leucocyte pro- tease inhibitor, make contact with saliva, in even the most intimate circumstances, an unlikely route of HIV transmission. Nonetheless, the presence of HIV in the oral fluid pool makes the risk of transmis- sion of HIV in saliva possible and so individuals may prefer to take appropriate precautions. Clinical features of HIV/​AIDS It is remarkable to note that, with some minor alterations to the classification of periodontal diseases, the classification of the oral manifestations of HIV-​related disease remains unchanged from (a) (b) Fig. 15.6.10  (a) Early Kaposi’s sarcoma on the palate. (b) Established Kaposi’s sarcoma on the gingiva.

SECTION 15  Gastroenterological disorders 2810 1993 when the classification and diagnostic criteria for oral lesions in HIV infection under the auspices of the EC-​Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus was published. The HIV-​OLs are classified according to their relative frequency: Group 1: lesions strongly associated with HIV infection (Fig. 15.6.11) Group II: lesions less commonly associated with HIV infection Group III: lesions seen in HIV infection This classification in given in Boxes 15.6.3, 15.6.4, and 15.6.5. Differential diagnosis The disadvantage of an updated classification of HIV-​OLs is that changes are taking place in the number and type of HIV-​OLs—​for example, hairy leucoplakia is now seen relatively commonly in non-​ HIV settings such as in long-​term corticosteroid inhaler users; also, the pattern of HPV-​related lesions is changing, with some evidence that such lesions may be re-​emerging in patients on HAART. Clinical investigation Clearly, establishing the reason for the clinical presentation will be required, including an HIV test, along with viral load. However, other reasons for immunosuppression should be considered and it must always be remembered that HIV-​positive patients are subject to other diseases in the same way as the general population (e.g. dia- betes and oral candidosis). With an increasing pattern of resistance emerging in the HIV-​ positive population to drugs such as the triazole antifungal drugs, Box 15.6.3  Group 1: lesions strongly associated with HIV infection • Candidiasis: —​ Erythematous —​ Pseudomembraneous • Hairy leucoplakia • Kaposi’s sarcoma • Non-​Hodgkin’s lymphoma • Periodontal disease: —​ Linear gingival erythema —​ Necrotizing (ulcerative) gingivitis —​ Necrotizing (ulcerative) periodontitis Box 15.6.4  Group II: lesions less commonly associated with HIV infection • Bacterial infections: —​ Mycobacterium avium-​intracellulare —​ Mycobacterium tuberculosis • Melanotic hyperpigmentation • Necrotizing (ulcerative) stomatitis • Salivary gland disease: —​ Dry mouth due to decreased salivary flow rate —​ Unilateral or bilateral swelling of major salivary glands • Thrombocytopenic purpura • Ulceration NOS (not otherwise specified) • Viral infections: —​ Herpes simplex virus —​ Human papilloma virus (warty-​like lesions): —​ Condyloma acuminatum —​ Focal epithelial hyperplasia —​ Verruca vulgaris —​ Varicella zoster virus: — Herpes zoster — Varicella (a) (b) (c) Fig. 15.6.11  Candidiasis in HIV-​positive patients. (a) Erythematous candidiasis of the dorsum of the tongue. (b) Pseudomembranous candidiasis of the lower alveolus. (c) Chronic hyperplastic candidiasis of the dorsum of the tongue.

15.6  The mouth and salivary glands 2811 appropriate microbiological sampling with a request for sensitivity testing is required, particularly in cases of nonresponse to empirical therapy. Management As stated before, the HIV-​OLs change with the commencement of HAART in the individual patient, often ‘melting away’. However, where HIV-​OLs remain or re-​emerge subsequently, appropriate therapy targeted at the HIV-​OLs should be commenced with the proviso that HAART comes with myriad interactions so these should be checked carefully before prescribing. Prognosis Before the commencement of HAART, the prognosis for HIV-​ positive patients was always guarded; however, the prognosis is now very good for those who adhere to, and cope with, prescribed HAART. The emergence of a changing pattern of HIV-​OLs in patients on long-​term HAART with the apparent re-​emergence of some of the ‘old guard’ of HIV-​OLs means that vigilance is required in moni- toring the oral manifestations of HIV diseases into the future. Fungal infections Candidosis Oral, and indeed orofacial, candidosis is common; also called can- didiasis or moniliasis. ‘Thrush’ is often used by healthcare workers and patients alike to refer to anything ‘white’ in the mouth and there is no doubt that oral candidosis is overdiagnosed by medical and dental practitioners alike. ‘Thrush’ is, of course, simply a particular variant of candidosis—​the pseudomembranous variant. Epidemiology The carriage of Candida spp. is almost ubiquitous in the mouths of human subjects—​estimated to be present in 40 to 80% of mouths. This carriage is asymptomatic and the presence of Candida spp. isolated from a swab or oral rinse in no way implies infection and must always be interpreted alongside clinical symptoms and signs. Candida is a diverse genus of yeasts with some species growing blastospores, hyphae, or pseudohyphae. Aetiology Candidosis is often referred to as ‘a disease of the diseased’ and there is no doubt that there are often predisposing factors as the com- mensal becomes pathogenic. These factors are best considered as (1) local and (2) systemic (see Table 15.6.2). Pathogenesis C. albicans is the commonest oral species, accounting for around 50% of cases of candidosis. Other oral species include C. glabrata, krusei, tropicalis, parapsilosis, and dubliniensis. The local and systemic fac- tors exhibited by the host are compounded by the virulence factors exhibited by the yeast. Most candidosis is experienced as a superficial infection with the yeasts residing in the superficial layers of the epi- thelium and only rarely invading beyond the basement membrane (although such invasion is seen in chronic hyperplastic candidosis and seems to add to the potentially malignant nature of this particular variant). Invasion is seen in immunosuppression, notably HIV. The pseudomembranous form’s pseudomembranes are made up of desquamated keratinocytes, keratin, leucocytes (especially neu- trophils), and candida hyphae. Optimal phagocytosis and resultant death of hyphae requires anticandidal antibodies as well as complement and the presence of CD4+ lymphocytes. Clinical features There are four main types of primary oral candidosis: • Pseudomembranous: often considered to be ‘acute’ but tips into a chronic form in the correct circumstances (e.g. poorly con- trolled or undiagnosed diabetes mellitus; prolonged use of inhaled corticosteroids). • Acute erythematous: most often seen following a course of oral antibiotics and, unlike the other types of oral candidosis, persist- ently uncomfortable or painful. Occurs at any mucosal site but most frequently on the tongue, associated with atrophy of the mucosa—​hence the pain generated. • Chronic erythematous:  also known as ‘denture stomatitis’ and most often seen on the palate under an upper denture (whether partial or complete). • Hyperplastic:  most commonly seen at the labial commissures bilaterally and associated with smoking. Occurs in two forms—​ homogeneous (smooth) or nodular. These lesions (and the asso- ciated dysplasia) can regress very quickly with smoking cessation and systemic antifungal therapy. Box 15.6.5  Group III: lesions seen in HIV infection • Bacterial infections: —​ Actinomyces israelli —​ Escherichia coli —​ Klebsiella pneumoniae • Cat scratch disease • Drug reactions (ulcerative, erythema multiforme, lichenoid, toxic epidermolysis) • Epithelioid (bacillary) angiomatosis • Fungal infection other than candidiasis: —​ Cryptococcus neoformans —​ Geotrichum candidum —​ Histoplasma capsulatum —​ Mucoraceae (mucormycosis/​zygomycosis) —​ Aspergillus flavus Table 15.6.2  Local and systemic factors in oral candidosis Local Systemic Wearing of a prosthetic appliance, e.g. denture or orthodontic Immature immunity (especially the young and the old) or altered immunity Decreased saliva flow, e.g. drug induced Diabetes mellitus Diet high in refined carbohydrate Cushing’s disease Use of corticosteroid inhaler for respiratory disease, e.g. chronic obstructive pulmonary disease Prescription of immunosuppressive therapy Use of antibiotics, especially long term Haematinic deficiency, especially iron

SECTION 15  Gastroenterological disorders 2812 There are also a number of secondary types of candidosis—​also known as candida-​associated lesions: • Angular cheilitis (also known as angular stomatitis): frequently in combination with Staphylococcus aureus and usually seen where there is a pre-​established intraoral candidosis. • Median rhomboid glossitis: a diamond-​shaped area of erythema- tous candidosis in the midline of the anterior two-​thirds of the dorsal surface of the tongue. Oral candidosis can also be seen as part of chronic mucocutaneous candidosis with involvement of the skin, nailbeds, and mucosal sur- faces. Chronic mucocutaneous candidosis is associated with specific T-​lymphocyte defects as part of a wider disease process. Chronic mucocutaneous candidosis is also seen in association with autoimmune endocrine disorders such as Addison’s disease, hypoparathyroidism, hypothyroidism, and pernicious anaemia. Differential diagnosis The diagnosis of pseudomembranous candidosis may be assisted by the gentle scraping of a lesion to remove the white patch, leaving a bleeding red area underneath. Chronic hyperplastic candida lesions may be confused with leu- coplakia and other types of white patches but their site at the an- gles of the mouth is usually confirmatory. However, confusion with hairy leucoplakia must be avoided due to the implied underlying aetiology. All lesions of suspected chronic hyperplastic candidosis must be biopsied to determine the degree of dysplasia. Clinical investigation Management of oral candidosis involves addressing potential local and systemic factors and the degree of investigation is deter- mined by an absence of clinical response to empirical treatment. See Table 15.6.3. Management Treatment is carried out in conjunction with assessing and managing the local and systemic contributory factors. Improved oral and denture hygiene is fundamental, with dentures being removed overnight and sterilized, and also stopping smoking. Topical antifungals must be used for fully 28 days as clinical resolution is evident before mycological resolution. For angular cheilitis, miconazole cream is appropriate as it is active against both Candida spp. and Staphylococci spp. Miconazole oral gel is useful for use inside the fitting surface of dentures. A systemic antifungal is necessary for chronic hyperplastic candidosis and should be given for orally for at least 14 days, while addressing smoking cessation and referral for biopsy. Prognosis The lesions of chronic hyperplastic candidosis should be viewed as potentially malignant lesions with biopsy and close follow-​up under specialist supervision mandatory. However, in reality, the develop- ment of malignancy in these circumstances is not common. Bacterial infections Tuberculosis Oral tuberculosis (TB) is rare but seems to be becoming more common, perhaps due to the emergence of multidrug-​resistant TB and/​or HIV-​associated TB. Oral TB lesions are thought to occur in less than 1% of TB-​infected patients but this is still a significant number worldwide. Aetiology/​pathology The causative organism is Mycobacterium tuberculosis and oral TB may be primary or secondary with the latter more common and following on from pulmonary TB. The infected sputum seems to make contact with the dorsal surface of the tongue and this is the commonest site in the mouth for the classical oral TB ulcer. Clinical features The classical oral TB ulcer of secondary TB tends to be indurated (hard), stellate, painful, with undermined margins. While the dorsal Table 15.6.3  Local and systemic factors, and action required in managing patients with oral candidosis How to address Local factor Wearing of a prosthetic appliance, e.g. denture or orthodontic Seek assessment by dental healthcare practitioner to determine appropriateness (e.g. fit) of the denture or appliance Decreased saliva flow, e.g. drug induced Consider systemic factors, e.g. Sjögren’s syndrome Diet high in refined carbohydrate Reduce intake of refined carbohydrate especially constant use of ‘boilings’ Use of corticosteroid inhaler for respiratory disease, e.g. chronic obstructive pulmonary disease Rinse out with tap water after each actuation of corticosteroid inhaler and/​or use of a spacer device Systemic factor Immature immunity (especially the young and the old) or altered immunity May require check of FBC (white cell series) HIV status, immunoglobulin levels Diabetes mellitus Check for diabetes mellitus Cushing’s disease Any other clinical signs? Prescription of immunosuppressive therapy Check patient is not oversuppressed Use of antibiotics, especially long term Check the need for antibiotics Haematinic deficiency, especially iron Check FBC (haemoglobin) and iron stores

15.6  The mouth and salivary glands 2813 tongue is the usual site, there have been reports of cases in most other parts of the mouth and also disseminated lesions affecting the maxilla and mandible. The ulcer of primary oral TB tends to occur on the lateral border of the tongue. Differential diagnosis The differential diagnosis would include trauma, syphilis, deep-​ tissue mycosis, and squamous cell carcinoma. Clinical investigation Given the rarity of this lesions and the importance of identifying a case of TB as early as possible, as well as excluding the other im- portant differential diagnoses, a biopsy of the ulcer is important to look for classical caseating granulomatous inflammation with the bacillus identified. Once confirmed as oral TB, the primary body system affected should be identified along with underlying cause, such as HIV infection. Management Oral TB lesions tend to respond to the same treatment regimens as systemic TB (e.g. ethambutol, isoniazid, pyrazinamide, and rifam- picin), although multidrug-​resistant TB is causing increasing issues worldwide. Syphilis Syphilis is caused by the spirochaete Treponema pallidum and the manifestation of the disease process may affect the mouth in each of the three established stages of infection. See Chapter 8.6.37 for fuller information on the epidemiology, clinical presentation, and treatment of syphilis. Primary stage A syphilitic chancre appears within 2 to 4 weeks of primary infec- tion. The lesion tends to appear at the site of primary exposure to the spirochaete, most commonly affecting the lip or tongue. The chancre is a painless, small nodule initially which subsequently breaks down and forms an ulcer with raised, indurated margins. Although rela- tively acute in onset, the lesion can resemble a squamous cell car- cinoma or actinic sun damage of the lip. A  chancre is typically painless with the regional lymph node showing discrete nontender enlargement. This stage is highly infectious and serological tests can be deceptively negative during the initial 3 to 4 weeks of infection. The chancre itself heals within 8 to 10 weeks. Secondary stage This develops 1 to 4 months after infection and present as a general- ized maculopapular rash with lymph node enlargement. Oral lesions at this stage are usually the so-​called snail-​track ulcers—​flat ulcers covered by a silver-​coloured fibrinous membrane. These affect the tongue, tonsils, and lips and the saliva of the patient at this juncture is highly infective. The serological tests for syphilis are now positive. Tertiary stage This is delayed by up to 15 years after infection with an onset which is insidious. The oral manifestations at this stage include gummas and white patches (inappropriately termed ‘syphilitic leucoplakia’). The gummas tend to affect the palate with initial swelling and sub- sequent necrosis with a resultant painless, punched-​out deep ulcer. These gummas can vary from one to several centimetres in diameter. They can also, rarely, affect the tongue and tonsils. The lesions can heal by scarring or, when affecting the palate, lead to perforation into the nasal cavity. The white patches usually affect the dorsal surface of the tongue and are irregular, diffuse, and not possible to remove by gentle scraping. The histological appearance at this stage is often nonspecific and so, once again, confirmation of the diagnosis is dependent on positive serology. Management The treatment of the oral lesions of syphilis is the same as that used for the systemic disease, with the response in the tertiary stage being correspondingly poorer. Cancrum oris Also called ‘noma’, this is rapidly spreading gangrene of the lips and cheeks, most commonly found in children in sub-​Saharan Africa. It is thought to be an extension of acute ulcerative gingi- vitis as described earlier. However, there is also concomitant im- mune system hypofunction due to other disease processes, most commonly thought to be viral. Malnutrition is also thought to be a concomitant factor. Parasitic infections The ease of international travel, coupled with an increasingly large volume of migrant workers, refugees, and those seeking asylum, means that rarer tropical diseases are emerging in all countries of the world. A good example of this is the emergence of lip leishmaniasis, although other parasitic infections with orofacial manifestations are appearing in developed countries too, often with unusual clinical presentation. As with all good medicine, history-​taking is the mainstay of good diagnosis with clear questioning on recent travel, country of origin, and contacts with others who have been unwell. Early biopsy of lesional tissue with an indication of possible diagnoses will assist the histopathologist with the process and differential diagnosis. Oral ulceration The oral mucosa offers a limited response to trauma or irritation with two main outcomes—​white patches due to increased depos- ition of keratin associated with acanthosis (hyperplasia of the prickle cell layer), and erosion or ulceration. There are various types of oral ulcers, with a classification offered in Table 15.6.4 related to underlying aetiology. Recurrent aphthous stomatitis Recurrent aphthous stomatitis is also known as recurrent oral ul- ceration or more colloquially as ‘aphthae’. It comes in three main forms: minor, major, and herpetiform

SECTION 15  Gastroenterological disorders 2814 Epidemiology The true prevalence of recurrent aphthous stomatitis is difficult to determine due to clear differences in how the condition is defined across studies, populations, and countries. Lifetime prevalence in Western cultures is somewhere between 10 and 60%, with a 20% chance of developing the disease if neither parent has recurrent aphthous stomatitis but a 90% chance if both parents have the condition. Aetiology It is fair to say that the aetiology of recurrent aphthous stoma- titis has not been established, despite several potential aetiolo- gies being suggested including genetic and environmental factors. It is likely to be an autoimmune or autoinflammatory disorder. There are doubtless familial and HLA-​related factors. Other pos- tulated factors include mucosal trauma, food hypersensitivity, stress, hormonal changes (in women there is often a clear pat- tern of immediately premenstrual onset after puberty with the ul- cers disappearing completely during pregnancy), and the sharing of cross-​reacting antigens with Gram-​positive oral organisms (e.g. the 65-​kDa heat shock protein in S. sanguinis) and epithelial cell structures. Several studies using molecular biological tech- niques have sought involvement of various viral and bacterial spe- cies with no consistent positive findings. It is established that stopping smoking may unmask recurrent aphthous stomatitis in a patient with no previous history of the condition, which has led to speculation that cigarette smoke in- duces some downregulation of mucosal immunity of relevance. Pathology The features are those of delayed hypersensitivity with an initial influx of lymphocytes and monocytes, followed subsequently by polymorphonuclear leucocytes. Immunohistochemical analysis has shown a significant population of CD4+ and CD8+ T lymphocytes, Langerhans’ cells, and macrophages with HLA DR expression in the associated epithelial cells. Clinical features The salient clinical features of the three types of recurrent aphthous stomatitis are given in Table 15.6.5. Table 15.6.4  Classification of oral ulceration related to underlying aetiology Recurrent ulceration Recurrent aphthous ulceration (RAU): • Major • Minor • Herpetiform RAU associated with orofacial granulomatosis RAU associated with Behçet’s disease RAU associated with HIV RAU associated with PFAPA syndrome Recurrent erythema multiforme HIV-​related Persistent and/​or recurrent ulceration Aphthous-​type: • Secondary to haematinic deficiency—​vitamin B12, folate or iron Aphthous-​type: • Secondary to food hypersensitivity Aphthous-​type: • Secondary to gastrointestinal disease: Crohn’s disease Ulcerative colitis Coeliac disease Secondary to dermatological conditions: Mucous membrane pemphigoid Pemphigus Lichen planus/​lichenoid tissue reaction Dermatitis herpetiformis Linear IgA disease Secondary to connective tissue disorders: • Lupus erythematosus (systemic and discoid) Single episode of ulceration Traumatic: • Physical/​thermal • Chemical Infective: • Viral (but may also be recurrent) • Bacterial: syphilis, TB • Fungal: deep mycoses Drug reaction: • E.g. nicorandil (may also be recurrent) Solitary persistent, chronic ulcer Squamous cell carcinoma Table 15.6.5  Differentiating features of the three types of recurrent aphthous stomatitis Minor aphthous ulcers Major aphthous ulcers Herpetiform ulcers Sex ratio female:male 1.5:1 1:1 3:1 Age of onset (peak incidence) (years) 10–​19 10–​19 20–​29 Number of ulcers 1–​5 2–​10 10–​100 Size of ulcers <10 mm

10 mm (some) 1–​2 mm but coalesce Duration (days) 4–​14 10–​30 7–​10 Healing with scars (%) 8 64 32 Recurrence 1–​4 months <monthly <monthly Sites Lips, cheeks, sides of tongue Lips, cheeks, tongue (dorsum), pharynx, palate, gums Lips, cheeks, tongue (ventral), pharynx, floor of mouth Associated oral lesions None Erythema migrans None Treatment Corticosteroids (local) Corticosteroids, immunosuppressives Tetracycline as mouthwash

15.6  The mouth and salivary glands 2815 Minor recurrent aphthous stomatitis About 80% of recurrent aphthous stomatitis is of this type, often presenting around puberty and extending into middle age. They are found more frequently in females than males. A burning or tin- gling sensation is often experienced by the patient 1 to 2 days before the onset of ulceration. The ulcers are round or oval with a classical erythematous halo and yellow or white fibrinous floor. They occur singly or up to five in number and can cause significant discomfort and pain, the most common sites of involvement of the oral mucosa are the inner aspect of the lips and cheeks and the lateral margins of the tongue (Fig. 15.6.12). The ulcers last 4 to 14 days with rates of recurrence varying from 1 to 4 months in an irregular pattern. For some women, ulcers occur consistently in the premenstrual phase, leading up to menstruation. Major recurrent aphthous stomatitis Around 10% of patients with recurrent aphthous stomatitis have this form of ulceration. Once again a prodromal phase is evident with ulcers larger than 1 cm in diameter becoming evident over the next few days. These ulcers are often sited around the soft palate and fauceal complex, causing the swallowing of food and liquid to be- come quite troublesome. These ulcers are most commonly single but can occur multiply. The margins are more irregular and the ulcers more cratered than the minor variant and so, to the unsuspecting, oral cancer may be mistakenly diagnosed (Fig. 15.6.13). This puta- tive diagnosis is further compounded by the duration of these ulcers since they can stay around for several months. In addition to the soft palate and fauces, the lips, cheeks, and tongue can also be involved. Scarring is a common finding in the healing phase. Herpetiform recurrent aphthous stomatitis These are recurrent crops of tiny ulcers up to 100 in number af- fecting any part of the mouth including the gums, palate, and tongue (Fig. 15.6.14). These are the least common type of recurrent aph- thous ulcers but present more commonly in women than men. They can be very persistent and chronically recurrent, with new ulcers appearing before the previous crop has healed. Differential diagnosis It is important to differentiate genuine recurrent aphthous stomatitis from similar types of ulceration found in patients with haematinic deficiency (seen in up to 20% of patients with recurrent aphthous stomatitis) and those with food hypersensitivity reactions. Similarly, it is important to exclude underlying local and systemic disease such as orofacial granulomatosis, Crohn’s disease, ulcerative cheilitis, and coeliac disease. It is also important to exclude, by way of blood test, any leuco- penic state, particularly that of cyclic neutropenia and drug-​induced neutropenia. (a) (b) Fig. 15.6.12  Minor aphthous ulceration of (a) the buccal mucosa and (b) the lower lip. Note the normal appearance of the mucosa away from the ulcers. (a) (b) Fig. 15.6.13  Major aphthous ulcers, which are more than 10 mm in diameter on (a) the tongue, with several smaller ulcers, and (b) the left buccal mucosa.

SECTION 15  Gastroenterological disorders 2816 Clinical investigation It is important to exclude local trauma in the initiation or promul- gation of recurrent aphthous stomatitis, this requiring examination by a dental healthcare practitioner. Inadequate dentures or broken down fillings may cause the development of recurrent mucosal ul- ceration. Similarly, by eliciting a full history from each patient, underlying contributory systemic disease can be excluded—​such as gastrointestinal disorders and the immunobullous disorders. A plan for investigation is shown in Table 15.6.6. Management The mainstay of treatment for recurrent aphthous stomatitis re- mains topical corticosteroids. These come in various preparations including pellets (hydrocortisone hemisuccinate), mouth rinse (betamethasone valerate), sprays (beclomethasone dipropionate), and creams (clobetasol propionate). Topical tetracycline can be useful in treating the herpetiform variant of recurrent aphthous stomatitis. Benzydamine hydro- chloride as a spray or mouth rinse, and chlorhexidine gluconate as a mouth rinse, can also be used to facilitate symptom relief and faster remission of ulceration. Not infrequently, recurrent aphthous stomatitis is sufficiently se- vere to merit the use of systemic prednisolone and, in the longer term, immunomodulation in the form of azathioprine. HIV-​related ulceration often responds well to thalidomide. Recent studies have shown that TNFα inhibitors may be helpful in treating patients with severe and complex recurrent aphthous sto- matitis which otherwise do not respond to standard topical and sys- temic therapy. Prognosis Recurrent aphthous stomatitis may occur from childhood and around puberty long into adulthood. Unfortunately, most patients simply accept their recurrent ulceration as a fact of life, frequently reinforced by the attitude of healthcare professionals. Recurrent aphthous ulceration can be a significantly debilitating disorder which demands appropriate investigation and management. Special circumstances A relatively new syndrome has emerged, known as PFAPA syn- drome, comprising periodic fever, aphthous ulceration of the oral mucosa, pharyngitis, and adenitis (inflammation and enlargement of the cervical lymph nodes). This condition appears to be com- moner than once thought and responds promptly to oral prednis- olone and, where there are significant recurrences, tonsillectomy has been shown to be beneficial. Recently, there has been some interest around low levels of vitamin D in patient with PFAPA syndrome with vitamin D supplementation claimed to reduce the number and severity of episodes. This will require further clinical investigation. Behçet’s disease Behçet’s disease or syndrome is described in Chapter  19.11.10 but it is important to highlight that recurrent aphthous stoma- titis remains the salient diagnostic feature of the disease. Although reported as a relatively uncommon disorder, it is probably sig- nificantly underdiagnosed and it is most important that patients with recurrent aphthous stomatitis are asked about genital ulcer- ation and episodes of red eye. Colchicine has been found useful in managing the mucosal ulceration associated with Behçet’s disease. Oral manifestations of dermatological and multisystem disorders Oral lichen planus and oral lichenoid tissue reactions Lichen planus may affect the skin, the genital mucosa, and/​or the oral mucosa. The dermatological aspects are dealt with in Chapter 23.5. Epidemiology Oral lichen planus (OLP) is a common disorder and most often found as a coincidental finding in asymptomatic individuals. It is said to affect around 2% of the adult population, predominantly middle-​age to older women. Aetiology OLP is increasingly considered to be an autoimmune disorder with a cell-​mediated response being initiated against, as yet, unidentified antigens in the basement membrane zone. An associated genetic pre- disposition linked to type 1 T-​helper cell cytokine polymorphisms Fig. 15.6.14  Herpetiform ulceration: there are many coalescing ulcers on the ventral surface of the tongue. Table 15.6.6  Investigation plan for patients with recurrent aphthous stomatitis Local Remove trauma, e.g. dentures Change to a sodium lauryl sulphate-​free toothpaste Check if patient has reduced or stopped smoking recently Systemic Blood tests: • FBC • Vitamin B12, folate, iron stores • Coeliac disease screen (e.g. tissue transglutaminase) Exclude systemic disease on systems questioning and examination Check current medication, e.g. nicorandil Check diet for intake of benzoates, cinnamaldehyde, chocolate, and sorbic acid

15.6  The mouth and salivary glands 2817 may augment the antigenic challenge, although the overall aetiology is still something of a mystery. An association between hepatitis C virus antibody positivity and lichen planus of the skin has been reported, particularly in the Mediterranean basin, although whether this is a causal relationship or an involvement of hepatitis C virus directly (or indirectly) in the pathogenesis of lichen planus has yet to be established. Evidence that OLP and hepatitis C virus may be linked is frequently contradictory but there is increasing opinion that patients with OLP should be screened for hepatitis C virus in ‘high-​risk’ patients, while accepting that many patients with asymptomatic hepatitis C virus have no ob- vious risk factors. Emotional stress has been shown to be a risk factor for OLP and it is likely that other ‘environmental’ factors are identified in due course as the autoimmune aspects of this condition are elucidated further. Toothpastes containing sodium lauryl sulphate may irritate (rather than initiate) the condition and a trial of a sodium lauryl sulphate-​free toothpaste is sensible. Pathology The histopathological picture of OLP is that of a well-​defined in- filtrate of predominantly T lymphocytes just under the rete-​pegs within the lamina propria. The so-​called saw-​tooth pattern of rete-​ pegs often seen in lichen planus of the skin is not so marked in OLP but there is often a prominent degeneration of the basal cell layer with apoptosis, and also acanthosis of the prickle-​cell layer. Surface changes are determined by the clinical variant and may be keratotic, hyperkeratotic, or erosive. Clinical features OLP comes in seven variants (Box 15.6.6), three types of which are shown in Fig. 15.6.15. Oral lesions most commonly present in isolation, but they can also present in association with skin lesions and/​or genital lesions. In these circumstances, the oral lesions tend to significantly outlast the skin or genital lesions, with a mean duration of around 7 years. Around 10% of patients with OLP have skin lesions—​notably a popular red or purple rash on the flexor surfaces of the wrists, with a superimposed network of Wickham’s striae (‘spider-​web’ appearance). OLP is considered to be a potentially malignant condition, and this risk is thought to be significantly greater in smokers and in those with the erosive or atrophic variants. Vulvovaginal-​gingival syndrome (with a similar entity affecting the glans penis in men) is a particularly distressing variant of OLP with symptomatic lichen planus affecting the gingivae (widespread erythema and sloughing of the gums with pain and bleeding) alongside symptomatic genital lichen planus. This subtype of lichen planus is thought to have an increased risk of both oral and genital malignancy. Differential diagnosis There are a number of conditions which present with a similar clinical and/​or histological appearance—​the so-​called lichenoid-​spectrum disorders. These include graft-​versus-​host disease which may occur after bone marrow transplantation and, indeed, after various types of organ transplantation. The appearance of a lichenoid-​like lesion (a) (b) (c) Fig. 15.6.15  Oral lichen planus: (a) reticular, (b) ulcerative, and (c) atrophic forms. Box 15.6.6  Variants of OLP • Reticular • Erosive (also called ulcerative) • Papular • Atrophic • Plaque • Bullous • Desquamative gingivitis (this is more a description than a type as it can occur with any of the above-​listed variants but is essentially an atro- phic variant; can also occur with some of the vesiculobullous disorders such as mucous membrane pemphigoid)

SECTION 15  Gastroenterological disorders 2818 at any time after organ transplantation should be viewed with sus- picion but particularly at times of reducing antirejection immuno- suppressive drug therapy. A  biopsy is required along with early notification to the transplant team about possible rejection. Oral lichenoid tissue reactions—​also called oral lichenoid lesions—​have a similar clinical presentation and similar histology (although some authors would suggest that plasma cells are more evident in lichenoid tissue reactions) but in circumstances where a likely aetiological factor has been identified (e.g. amalgam restor- ation or drug therapy). There is some evidence to support the removal of amalgam res- torations where an lichenoid tissue reaction has occurred locally to a restoration, with replacement by a nonmercury-​containing restora- tive material. However, where the lesions of OLP are widespread in the mouth (particularly in association with desquamative gingivitis) and/​or associated with skin/​genital lesions, amalgam replacement is unlikely to be of any value, particularly in the context of this being a condition of exacerbation–​remission anyway. Where doubt exists, cutaneous patch-​testing should be performed as this also allows al- ternative dental materials to be identified since there is increasing evidence that mucosal reactions to gold and other dental materials is commoner than once thought. However, it should also be under- stood that cutaneous patch-​testing may not always replicate the re- sponse of the oral immunological mechanisms. There is a growing list of drugs implicated in lichenoid tissue re- actions of the oral mucosa, including β-​blockers, diuretics, and oral hypoglycaemic drugs. Such putative associations offer greater cred- ibility where the reaction has occurred in short order after commen- cing therapy with the drug. In these circumstances, stopping the drug may prove helpful but is by no means always curative. Clinical investigation Asymptomatic reticular lesions do not require biopsy (unless the pa- tient is a smoker) but all other lesions should be biopsied, particularly in smokers. This will allow the formal diagnosis to be established but also any degree of dysplasia and any presence of fungal hyphae, since superimposed candidosis in OLP can worsen symptoms. Management The mainstay of treatment remains topical corticosteroids although there is still a paucity of randomized controlled trials to compare these preparations with placebo. Topical corticosteroid application can be in the form of tablets to dissolve in the mouth (e.g. hydro- cortisone hemisuccinate 2.5 mg), mouthwash (e.g. betamethasone 0.5-​mg tablets to be dissolved in water), sprays (e.g. beclomethasone dipropionate) and creams/​pastes (e.g. clobetasol in mucoadhesive paste). Topical therapy with tacrolimus or pimecrolimus has gained momentum although there are some contradictory study results regarding the efficacy of these preparations and their use remains ‘off-​licence’. Systemic therapies in common use for recalcitrant cases include prednisolone, azathioprine, and mycophenolate, although random- ized controlled trials are few and far between. Use of the biologicals, such as adalimumab and infliximab will doubtless gain momentum for the most severe cases but outcome measures are awaited. Importantly, all patients with OLP should be advised to stop smoking, given the increased risk of oral cancer. Areas of dysplasia should be followed up with repeat biopsies over time with a decision on early intervention by way of surgical or laser excision. There is little in the literature to determine whether or not topical or sys- temic immunosuppressive therapies decrease or increase the risk of malignant transformation in OLP and this should be a focus of future study. Prognosis Although there is an increased risk of malignant transformation in OLP, the main problem with this condition is its chronicity and lack of response to topical therapies. Much debate remains in the literature about whether patients with OLP require follow-​up and, if so, where that follow-​up should be—​primary or secondary care. Regardless, patients with OLP should be informed of the need for self-​monitoring of their oral mucosa with the requirement to report any changes to their dentist for assessment. Lupus erythematosus (systemic and chronic discoid) Both the systemic and chronic discoid variants of lupus erythematosus can manifest in the mouth, affecting the palatal and buccal mucosae predominantly. These are considered as ‘lichenoid spectrum’ disorders and so are often confused clinically with OLP. The oral lesions tend to be red and white—​an atrophic or erosive centre with a white, keratotic border. Histologically, the lesions have varying degrees of keratosis with areas of hyperplasia and atrophy affecting the lesions in equal measure. Submucosal collections of lymphocytes are evident and these are often focal (as opposed to the wide band in OLP) and around blood vessels—​the so-​called peri- vascular infiltrate. Chronic discoid lupus erythematosus is now considered to be po- tentially malignant and so it is important to differentiate this con- dition from other mucosal disorders by way of biopsy. Otherwise treatment is similar to that described for OLP previously. The lesions of systemic lupus erythematosus tend to respond to the systemic therapies instituted to treat the wider disease. Bullous lesions Mucous membrane pemphigoid Mucous membrane pemphigoid is not one disease but rather a group of blistering disorders of autoimmune origin manifesting with subepithelial splitting to form blood-​filled bullae. The bullae are primarily on the mucous membranes but skin involvement is also possible (bullous pemphigoid). The bullae tend to heal with scarring when they affect sites other than the mouth (and especially the eyes)—​hence the historic term of ‘cicatricial’ pemphigoid. Oral scarring is unusual and should not be used as a diagnostic feature. Epidemiology Mucous membrane pemphigoid is rare but its true epidemiology re- mains elusive. It is known to be significantly less common than OLP. It affects women more than men and appears in the 30 to 50 years age group, or older. Aetiology and pathogenesis The identification of a causative or triggering factor for this auto- immune blistering disorder has not been forthcoming, but this is not surprising given the heterogeneity of identified antigens in mucous

15.6  The mouth and salivary glands 2819 membrane pemphigoid. Many antigens have been identified; all components of the epithelial basement membrane hemidesmosome and its anchoring filaments, including BP180, laminin-​331 and -​332, alpha-​6 integrin, and beta-​4 integrin. The antibodies generated may be of the IgG, IgA, or IgM classes and there is often associated com- plement deposition. Circulating autoantibodies may be detected in serum, but not as frequently as in pemphigus. Clinical features The salient feature is blood-​filled blistering and, with oral mucous membrane pemphigoid, desquamative gingivitis (Fig. 15.6.16). Oral mucosal involvement is the commonest site followed by the eyes, nose, and oesophagus. The bullae tend to rupture within hours to leave a raw, uncomfortable area of mucosal erosion or ulceration. Antigenic epitopes are increasingly being identified as unique for each site of mucosal involvement. Differential diagnosis Differential diagnosis includes the other immunobullous disorders, such as pemphigus, linear IgA disease, and dermatitis herpetiformis; and the other dermatoses, such as bullous lichen planus. There is growing evidence that Linear IgA disease may simply be a subset of mucous membrane pemphigoid. An important differential diagnosis is that of angina bullosa haemorrhagica, a blood-​filled blistering disorder of unknown aetiology although the blisters are though to occur following minor trauma. They are also commoner in patients using inhaled corticosteroids for pulmonary disorders. It is imperative to ex- clude an underlying blood dyscrasia and coagulopathy. It is im- portant that patients with this condition are encouraged to have the confidence to burst the blister, particularly when it affects the soft palate as an enlarging blister at this site can induce panic about compromising the airway. Early deroofing of the blister also reduces the tension therein and the reduced likelihood of prom- ulgation of the blister. Clinical investigation Clinical investigations include two biopsies—​one for routine histo- pathology and the other for direct immunofluorescence. Linear de- position of immunoglobulin and/​or complement at the basement membrane zone, in conjunction with the clinical findings, will es- tablish the diagnosis. Indirect immunofluorescence, by way of a blood test, may also be helpful. Management As is frequently the case with oral mucosal disorders, good quality randomized controlled trials are largely lacking when it comes to establishing the best therapeutic regimen to treat patients with mu- cous membrane pemphigoid. Topical corticosteroids are the main- stay of treatment with the gingival variant frequently helped by the use of occlusive corticosteroid therapy administered in gingival ven- eers or soft occlusal splints. Systemic therapies known to be worthwhile include dapsone, azathioprine, and mycophenolate mofetil. Cyclophosphamide may be added when ocular disease is associated and particularly troublesome. Regarding the biologicals, rituximab (a monoclonal anti-​CD20 antibody) is deemed to be most effective although optimal regi- mens have yet to be established and whether its use should be in conjunction with other immunosuppressive agents. The use of intra- venous immunoglobulin is gaining some ground in the literature as an effective treatment for otherwise recalcitrant mucous membrane pemphigoid. Where a diagnosis of oral mucous membrane pemphigoid is es- tablished, it is important to have the patient seen by an ophthal- mologist to ensure there are no features of ocular pemphigoid, given the propensity for conjunctival scarring and possible deteri- oration in vision. Prognosis Spontaneous remission from mucous membrane pemphigoid has been recorded in several studies but the more likely outcome is local and/​or systemic therapies over many years. Pemphigus vulgaris Pemphigus vulgaris (PV) is a potentially fatal immunobullous dis- order which commonly affects the oral mucosa and, indeed, may first present with oral involvement. Epidemiology and aetiology PV is commoner in women than men with women tending to pre- sent earlier by age, around 50 years. Around a quarter of patients have an existing autoimmune disease at the time of presenting with PV, but its aetiology or triggering factors are unknown. (a) (b) Fig. 15.6.16  Mucous membrane pemphigoid showing irregular and persistent ulceration of (a) the palate and (b) the buccal mucosa.

SECTION 15  Gastroenterological disorders 2820 Pathogenesis The two major types of PV are mucocutaneous and mucosa-​alone. The autoantibodies target the keratinocyte adhesion proteins asso- ciated with desmosomes at the intercellular junctions, in particular desmoglein. Antidesmoglein-​3 antibodies are associated with the mucosa-​alone variant of the disease. It is thought that the develop- ment of antidesmoglein-​1 heralds the transition from mucosa-​alone PV to mucocutaneous PV. The predominant autoantibody is of the IgG class. The deposition of autoantibodies causes destruction of intercellular adhesion within the prickle-​cell layer with resultant acantholysis and bulla formation, above the basement membrane. Clinical features Around 40% of patients with PV only ever have the mucosa-​alone variant. The bullae tend to be superficial within the mucosa and filled with clear fluid as opposed to blood. They are fragile and rup- ture readily and quickly—​often within minutes of forming—​to leave a shallow ulcer which may persist for months (Fig. 15.6.17). The involvement of multiple oral sites is associated with a poorer prog- nosis with a more prolonged course of disease, often recalcitrant to multiple therapies. Historically, the use of Nikolsky’s sign has been used, whereby rub- bing the oral mucosa can induce bulla formation, but this sign is not reproducible and attempts to demonstrate it should not be performed. Differential diagnosis The initial phase of bulla formation in PV means that confusion be- tween PV and aphthous ulceration should not occur, albeit that they are both chronic ulcerating disorders. Other types of pemphigus (e.g. vegetans and foliaceus) only rarely affect the oral mucosa and can normally be differenti- ated from PV on the basis of clinical presentation and histology. However, the association of PV with underlying malignancy, and in particular lymphoproliferative disease, is worthy of mention. So-​ called paraneoplastic pemphigus may be the sole manifestation of an underlying malignant process. The antigens in this case are the plakins and indirect immunofluorescence is often most helpful. Familial benign chronic pemphigus, also called Hailey–​Hailey disease, is a rare genetic disorder which should be part of a differen- tial diagnosis of blistering conditions in children and young adults. It brings a poor quality of life and is often very challenging to treat. Clinical investigation Two biopsies of the oral mucosa are required—​one of an intact blister, if possible, for routine histopathology, and one of perilesional tissue for direct immunofluorescence. The histology shows a suprabasal split in the epithelium with an intraepithelial bulla and acantholytic cells evident within the cleft. Indirect immunofluorescence is also frequently positive, and can also be used to assess response to treat- ment, but patients can also give that information directly! Management Treatment is similar to that for pemphigoid with topical cor- ticosteroid therapy for mild disease confined to the oral cavity. Thereafter, with recalcitrant disease, prednisolone at high dose can be changed relatively quickly to combination therapy with an immu- nomodulating drug such as azathioprine or mycophenolate mofetil. Rituximab is emerging as the biological agent of choice. Prognosis The course of PV is that of exacerbations and remissions over a long period of time. The death rate from PV is around 5% over the lifetime of the patient with, nowadays, mortality more likely to be from the side effects of drug therapy rather than from the disease itself. (a) (b) (c) Fig. 15.6.17  Pemphigus vulgaris: erosions affecting (a) the palate and (b) the tongue. Direct immunofluorescence (c) on oral mucosa reveals intercellular IgG autoantibodies to desmoglein 3 (green staining).

15.6  The mouth and salivary glands 2821 Where response to therapy is slow or not evident at all, consider again the possibility of paraneoplastic pemphigus. Erythema multiforme EM is a potentially fatal mucocutaneous bullous disorder, thought to be hypersensitivity driven. It is subdivided into EM minor, EM major, and Stevens–​Johnson syndrome. Epidemiology and aetiology The prevalence rate of EM in its various forms is about 1%, affecting predominantly young adults aged 18 to 30 years, women more than men. Certain HLA types have been associated with EM, but not con- sistently. The role of HSV as a triggering factor is well documented but poorly understood. HSV DNA is detected by polymerase chain reaction in the skin biopsies and lesional scrapings from more than 50% of patients with the condition. Other triggers include Mycoplasma pneumoniae infection and drugs, such as nonsteroidal anti-​inflammatory drugs and anticonvulsants (e.g. carbamazepine). Recurrent EM is a recognized clinical entity, with HSV playing a role as well as hypersensitivity reaction to the food additive group the benzoates (E210–​E219). Pathogenesis T lymphocytes are predominant in the biopsy specimens of lesional tissue. These autoreactive T cells are recruited to the skin and mu- cous membranes with resultant tissue lysis and keratinocyte death, often with bulla formation. One difference between EM induced by HSV and that induced by drugs is that drug-​induced EM is negative for HSV DNA but positive for the production of TNFα. Separation of the basement membrane zone leads to the classic blood-​filled blis- ters which appear readily around the lips; otherwise small intraepi- thelial vesicles occur. Clinical features History taking may reveal the prescription of a new drug. EM minor affects one mucosal area with associated skin lesions, whereas EM major involves two or more mucosal areas and skin. Stevens–​Johnson syndrome is a severe variant of EM major and is potentially fatal. There are associated systemic symptoms, such as malaise, fever, and cough. Skin features are ‘target’ lesions (also called ‘iris’ lesions) which are present over the limbs symmetric- ally. Oral lesions occur in up to two-​thirds of cases of EM and include bullae and erosions (Fig. 15.6.18). Healing can take up to 5 to 6 weeks. Differential diagnosis The differential diagnosis includes primary herpetic gingivostomatitis as well as the immunobullous disorders and fixed drug eruptions. Clinical investigation There are none to clinch a diagnosis although other investigations might be appropriate, including white cell count and renal and liver function tests. HIV testing should be considered. Management Treatment is decided on the basis of severity of the illness, including the requirement for hospitalization. For milder cases, rest and copious oral fluids are required: severe cases need hospital admission, intravenous fluids, and corticosteroids, either orally or parenterally. Prognosis Most episodes of EM are entirely self-​limiting and nonrecurrent. However, a few patients with EM have recurrent disease. Such pa- tients should be considered for patch-​testing against the benzo- ates. A 6-​month trial of aciclovir, famciclovir, or valaciclovir should be tried at an appropriate prophylactic dose. Patients with severe, recurrent EM should be considered for immunomodulation. Thalidomide may be a useful drug, and a number of biologicals have also been used successfully. Oral manifestations of gastrointestinal disorders Given that the mouth is part of the gastrointestinal tract, it should come as no surprise that the gastrointestinal disorders can have primary manifestations (a direct extension of the disease) and sec- ondary manifestations (e.g. due to malabsorption or chronic blood loss) within the mouth. Crohn’s disease and orofacial granulomatosis Crohn’s disease is discussed in Chapter 15.11 but it is important to understand about the oral (and orofacial) manifestations of Crohn’s (a) (b) Fig. 15.6.18  Erythema multiforme: (a) haemorrhagic crusted upper lip; (b) diffuse erosions of the palate.

SECTION 15  Gastroenterological disorders 2822 disease as they may be the only manifestation of the underlying dis- ease process in the wider gastrointestinal tract and/​or their appear- ance in a patient with known underlying Crohn’s disease may herald a worsening of the systemic disease. Orofacial granulomatosis is a condition manifesting clinic- ally with chronic lymphoedema of the mouth and/​or face, notably swelling of the lips and oral mucosa, a full-​thickness, erythematous gingivitis, and mucosal ulceration of various clinical types. Biopsy of affected tissue shows lymphoedema with or without granuloma- tous inflammation. It is a condition which frequently responds to the exclusion of certain food-​related chemicals from the diet and, as such, is distinct from gastrointestinal Crohn’s disease (albeit that some patients followed-​up over time may be reclassified as having gastrointestinal Crohn’s disease), although the entity of Crohn’s dis- ease may have a similar clinical presentation and histology in the orofacial region. The exact relationship between Crohn’s disease and orofacial granulomatosis is currently unknown, although recently published immunogenetic studies have added further weight to these being discrete entities. Epidemiology It is estimated that up to 30% of patients with Crohn’s disease have orofacial signs of the disease, particularly oral ulceration and other mucosal changes, often asymptomatic. In various studies, clinical evidence of Crohn’s disease was found in around 20 to 50% of patients with orofacial granulomatosis, with an estimate of 15 to 20% of patients with this condition developing Crohn’s disease over a 10-​ to 15-​year follow-​up period. Some studies have also identified that most people with orofacial granulomatosis have underlying signs of ileocolonic inflammation, but in a different pattern to that found in Crohn’s disease. Aetiology The aetiology of Crohn’s disease is complex—​a combination of genetic, environmental, and mucosal regulatory factors. Food hypersensitivity reactions have long been implicated in orofacial granulomatosis, but compelling evidence has emerged linking al- lergy with orofacial granulomatosis and Crohn’s disease. Pathogenesis/​pathology Crohn’s disease is a chronic granulomatous disorder with the incon- sistent finding of noncaseating granulomas deep in biopsies—​often in the underlying muscle—​hence the need for deeper than usual biopsies of the oral mucosa. The commonest feature on biopsies is lymphoedema, although this is not diagnostic. T lymphocytes are the predominant cells in the histology of Crohn’s disease and orofacial granulomatosis, alongside multinucleated giant cells originating from macrophages. More recently, the array of dendritic cells of the mucosa has been identified alongside the IgE-​ expressing B lymphocytes and mast cells, thus highlighting the link with food allergy. There has been interest over several years in the systemic response of IgA to Saccharomyces cerevisiae in Crohn’s dis- ease as well as the local secretory IgA response in several subclasses in orofacial granulomatosis. The potential role of Mycobacterium paratuberculosis in Crohn’s disease is still being investigated, but this organism has been effectively excluded in orofacial granulomatosis using polymerase chain reaction technology. Clinical features Clinical features include upper and lower lip swelling, which is con- stant, rather than intermittent in nature (Fig. 15.6.19). That said, there can be fluctuations in episodes of lip swelling. Other features are oral ulceration of the aphthous type but also linear ulcers of the lower buccal sulci. These liner ulcers, as well as ‘staghorning’ of the sublingual folds are virtually pathognomonic of underlying gut Crohn’s disease. There is also cobblestoning of the buccal mucosae, papillary hyperplasia of the hard palate, mucosal tagging, angular cheilitis, and full-​thickness gingivitis (redness extending from the papillae between the teeth to the reflected gingivae in the buccal and labial sulci). Differential diagnosis The differential diagnosis includes other noncaseating granuloma- tous disorders such as sarcoidosis. Occasionally, with an acute ex- acerbation of lip or facial swelling, a dental abscess or angio-​oedema may have to be excluded, albeit that dental abscesses are painful and the swellings of Crohn’s disease are not. The historic entities of cheilitis granulomatosa of Miescher and Melkersson–​Rosenthal syndrome (with associated lip swelling, fis- sured tongue, and lower motor neuron palsy of the facial nerve) are now considered by many simply to be variants of orofacial granulomatosis. (b) (a) Fig. 15.6.19  Orofacial granulomatosis in a 15-​year-​old boy showing (a) enlarged lips and (b) hyperplastic gingivae.

15.6  The mouth and salivary glands 2823 Clinical investigation Orofacial granulomatosis is essentially a clinical diagnosis, based on the constellation of clinical features. However, biopsy may also prove helpful. It is important to exclude underlying inflammatory bowel disease in all patients with orofacial granulomatosis, using inflam- matory markers, faecal calprotectin levels, and direct imaging of the gut if required. Management In light of recent studies, diet avoidance of benzoates, cinnamon, and sorbates should be advised on an empirical basis with patch-​ testing being reserved for nonresponders. Thereafter, management is often difficult with prednisolone and azathioprine being the mainstay of systemic treatment. For lip swelling, a positive response is often seen with combination therapy of intralesional triamcinolone and topical tacrolimus or pimecrolimus. Recalcitrant disease may respond to biological agents such as infliximab or adalimumab. Prognosis Orofacial granulomatosis and orofacial Crohn’s disease remain dif- ficult diseases to treat, with patients best referred to oral medicine clinics for management. Liaising with gastroenterology colleagues is essential. Ulcerative colitis Oral manifestations of ulcerative colitis are almost always accom- panied by a flare-​up of the gut disease activity. The main manifestation is recurrent aphthous stomatitis, but other oral mucosal conditions include pyostomatitis vegetans and stomatitis gangrenosum. Coeliac disease The presentation and management of coeliac disease are dealt with in Chapter 15.10.3. The oral manifestation of coeliac diseases is pre- dominantly aphthous-​type oral ulceration with this reported in 25 to 40% of patients with coeliac disease. Where iron or folate defi- ciency results from malabsorption, signs of such deficiencies may also manifest (e.g. angular cheilitis and mucosal atrophy). Such defi- ciency manifestations are much rarer now with many societies aug- menting manufactured food with folic acid. Current guidance would support the screening of patients with prolonged, severe, or atypical oral ulceration for coeliac dis- ease with serological tests including total IgA and IgA antitissue transglutaminase antibodies. Paediatric patients with widespread enamel defects should also be screened. Several studies report prompt resolution of oral ulceration and other oral signs with the exclusion of gluten from the diet of con- firmed cases. Where haematinic deficiency has been identified, im- provement may only begin with the initiation of replacement therapy. Oral manifestations of haematological disorders Haematinic and other deficiencies Deficiencies in iron, folate, or vitamin B12 frequently cause oral manifestations including glossitis, oral ulceration, nonspecific sto- matitis, and red patches of the mucosa. Often such deficiencies are latent and so a full blood count will not necessarily reveal a problem as the haemoglobin concentration may be normal, if low, within the reference range. Assays of iron, folate, and vitamin B12 should be specifically requested. Such deficiencies or anaemia may cause glossitis (Fig. 15.6.20), soreness of the tongue or mouth more generally, angular cheilitis, or recurrent oral ulceration. Deficiencies in folate and/​or vitamin B12 may cause macroglossia. Iron deficiency is known to predispose to oral candidosis. At the other end of the scale, iron overload in haemochromatosis can present with oral ulceration, angular cheilitis, and sensory nerve deficit. Pain and discomfort are often associated with geographic tongue (also called benign migratory glossitis; Fig. 15.6.21)—​a condi- tion with histology very similar to that of psoriasis of the skin and thought to be commoner in patients with psoriasis although by no means always associated. Geographic tongue has been associated with zinc deficiency in one study but this has never been replicated. The lesions of geographic tongue may, however, be zinc responsive, whether topical or systemic. Fig. 15.6.20  Tongue showing depapillation due to iron deficiency. Fig. 15.6.21  Geographic tongue: a common benign lesion frequently misdiagnosed as candida infection or anaemia.

SECTION 15  Gastroenterological disorders 2824 Vitamin C deficiency appears to be becoming more common in industrialized societies despite the increasing availability of fruit and vegetables. Diets overwhelmed by convenience foods may be responsible. Oral manifestations include spontaneous haemorrhage of the gingivae and mucosa with enlargement and erythema of the interdental papillae. This is frequently followed by destruction of periodontal tissues and loosening of the teeth, perhaps due the need for vitamin C in the cross-​linking of collagen fibres. Where there is marked, sudden, and unexpected periodontitis, vitamin C levels should be checked by blood test. Blood malignancies Acute leukaemia, particularly of the myelomonocytic form, may present in young people with sore, bleeding gums with vari- able swelling of the gingivae—​particularly the interdental pa- pillae (Fig. 15.6.22). This can be confused with primary herpetic gingivostomatitis. Frequently, there will be no particular lack of good oral hygiene measures to explain the gingivitis—​a feature most often picked up by dental surgeons or dental hygienists. Myelodysplasias may present with peripheral sensory changes af- fecting the trigeminal nerve. Spontaneous gingival or prolonged oral bleeding after dental ex- traction may alert the clinician to an undiagnosed coagulopathy or acquired thrombocytopenia (e.g. due to drug therapy). Leucopenia and agranulocytosis may manifest in the mouth with ulceration which is often atypical. This is most commonly drug related. Oral purpura and blood-​blister formation following minimal trauma may be seen in thrombocytopenia from varying causes, including drug therapy. Orofacial pain syndromes Temporomandibular disorders Temporomandibular disorders should be considered an ‘umbrella term’ for the various types of disorders that affect the temporoman- dibular joint and investing musculature. The commonest condition, and one with increasing prevalence worldwide, is temporomandibular joint dysfunction syndrome—​seen so commonly in young women in many countries as to be considered almost a ‘rite of passage’. This presents variably with pain in the joint(s), muscular tenderness, limitation of jaw movement, and ‘clicking’ in the joint(s). The symptoms are often worse on wakening and are thought to be related to nocturnal clenching or grinding of the teeth—​habits that are believed to be stress related. Chewing gum is also thought to worsen the symptoms and this habit should be stopped. Simple analgesia with the fabrication of an occlusal appliance by a dentist may prove helpful, although systematic reviews have failed to identify any particular treatment of value. Where the above-​mentioned symptoms are accompanied by ‘locking’ open or closed of the jaw, then internal derangement of the temporomandibular joint should be considered and this will require referral to an appropriate specialist for management. Inflammatory and degenerative arthropathies should be con- sidered in the context of patients with an appropriate underlying disease process. Oral dysaesthesias The oral dysaesthesias are a diverse group of disorders, often pre- senting with oral burning or dryness (in the context of normal saliva flow). They are commoner in women by a ratio of around 9:1. They rarely occur under the age of 40 years. Where examination of the mouth reveals no abnormality, then a diagnosis of primary burning mouth syndrome may be considered. Burning may also be a symptom secondary to haematinic deficiency, oral candidosis, or elevated blood sugar. Occasionally, burning mouth may be seen as a reaction to drug therapy, such as angiotensin-​converting enzyme inhibitors and statins. The oral dysaesthesias are seen most commonly in women around the age of the menopause and are thought to be hormo- nally related, at least in part. Hormone replacement therapy does not tend to improve symptoms although treatment with oral α-​ lipoic acid in conjunction with gabapentin or pregabalin, cognitive behavioural therapy, and topical clonazepam have been shown in studies to be of some benefit. Treatment outcomes are frequently disappointing. Trigeminal neuralgia Trigeminal neuralgia classically presents with a sharp, shooting pain affecting one or more divisions of the trigeminal nerve, most com- monly the maxillary division, followed by the mandibular division and only very rarely the ophthalmic division. It tends to affect older patients with focal demyelination of the peripheral nerve being a common finding in affected patients on autopsy. The paroxysms of pain can be very debilitating, even though they last only for seconds. Patients under the age of 60 years and those unresponsive to drug therapy should undergo MRI scanning to exclude space-​occupying lesion and demyelination. MRI scan- ning with contrast will also identify those patients in whom there is an associated microvascular compressive loop. Such patients may benefit from a microvascular decompression procedure with long-​ term success, in term of pain relief, being claimed in 70% or more of patients. Otherwise, drug therapy is the mainstay of treatment—​ carbamazepine, oxcarbazepine, lamotrigine, and gabapentin being some of the drugs showing efficacy in studies. Fig. 15.6.22  Hyperaemic swollen gingivitis in a patient with leukaemia.

15.6  The mouth and salivary glands 2825 Other oral conditions Halitosis Halitosis seems to be being reported more often, which may be due to the relentless advertising of oral healthcare products and the desire to reach perfection in health. ‘Bad breath’ is a subjective standard, often worsened by fear of working in close proximity to colleagues, or fixation on sexual problems, fear of intimacy, or other psycho- logical problems. However, there can also be some physical causes, and increasing the oral intake of clear fluids daily, as well as the use of a triclosan-​containing toothpaste may help, as may gently brushing the dorsal surface of the tongue. Patients with halitosis should be checked out by a dentist to ensure that active gum disease is not a contributory factor, alongside other forms of oral sepsis. Assessment of the throat should be carried out to ensure that there is no focal sepsis related to chronic tonsillitis or, rarely, a pharyngeal pouch. Other diseases such as diabetes, gastro-​oesophageal reflux, and (rarely) trimethylaminuria can cause halitosis and should be ex- cluded if symptoms fail to settle with local interventions. Patients suspected of having ‘delusional’ halitosis should be referred for psy- chiatric assessment. Oral manifestations of drug therapy Drugs are increasingly being reported to have oral side effects, not least of all a reduction in salivary flow (see following section). Other side effects include oral ulceration (e.g. nicorandil), taste disturb- ance (e.g. angiotensin-​converting enzyme inhibitors), and tongue swelling (e.g. angiotensin-​converting enzyme inhibitors). Drugs should always be considered as possible causes for oral symptoms and signs and the corresponding literature checked. Salivary gland disorders Disorders affecting the salivary glands can be classified as intrinsic salivary gland diseases (e.g. Sjögren’s syndrome) and extrinsic sal- ivary gland diseases (e.g. drug-​induced dry mouth). Dry mouth (xerostomia) Dry mouth may be reported by a patient as a symptom but, simi- larly, reduction in salivary flow may be seen by a dental healthcare worker and reported as a clinical sign. Salivary gland hypofunction is common, and a major side effect of much drug therapy (e.g. anti- depressants, diuretics, and antihistamines). It is also seen in Sjögren’s syndrome (both primary and secondary variants) as well as other systemic diseases such as diabetes mellitus where the degree of dry- ness is related to the level of glycaemic control as well as the carriage of candidal organisms. Epidemiology The true prevalence of dry mouth is unknown but, with such a vast number of potential aetiologies, it is undoubtedly common and underreported by patients. The prevalence of primary Sjögren’s syndrome clearly depends on the population surveyed but is up to 2.5% and commoner in white women around the age of 30 to 40 years. The prevalence of secondary Sjögren’s syndrome again depends on the population surveyed but also on the commonality of the asso- ciated autoimmune disease, for example, up to 30% of patients with rheumatoid arthritis, and up to 15% of patients with systemic lupus erythematosus. Aetiology and pathogenesis Sjögren’s syndrome is a chronic autoimmune disorder which oc- curs in a stand-​alone form (primary) and in a form secondary to an underlying systemic autoimmune disorder such as rheumatoid arthritis and lupus. The lacrimal and salivary glands, along with all the exocrine glands, have a classical inflammatory infiltration with B lymphocytes. The associated marked inflammatory reaction causes scarring of glandular tissue with loss of acini and their replacement with fibrous tissue. See Chapter 19.11.4 for further discussion. Clinical features The classical presentation of Sjögren’s syndrome involves dryness of the mouth and/​or eyes. Primary Sjögren’s syndrome is often associ- ated with other features such as tiredness, arthralgia, and myalgia. Differential diagnosis The differential diagnosis of dry mouth includes sarcoidosis and, increasingly, the obstructive sleep apnoea–​hypopnoea syndrome. It has been suggested that a group of patients with generalized nodal osteoarthritis and sialadenitis also have xerostomia, but with no evi- dence of autoantibodies—​the so-​called SOX syndrome (sialadenitis, osteoarthritis, and xerostomia). The sialadenitis is nonspecific as op- posed to the lymphocytic infiltrate seen in Sjögren’s syndrome. This putative disorder requires further investigation. Clinical investigations Most current diagnostic criteria include the need for objective evi- dence of salivary gland and/​or lacrimal gland involvement, in add- ition to symptoms reported by the patient. Objective assessment includes the presence of autoantibodies in serum and/​or the pres- ence of focal lymphocytic sialadenitis on minor labial salivary gland biopsy. The use of noninvasive salivary gland ultrasound scanning is gaining popularity in diagnosis, rather than parotid salivary gland sialography, but requires ratification. Management The loss of saliva function is most debilitating and distressing, af- fecting taste, speech, chewing, swallowing, sexual intimacy, and leading to worsening dental caries, gum diseases, loss of teeth, and poor denture retention. It may also lead to recurrent oral infections with candidal or staphylococcal species. Treatment focuses on increasing salivary flow by the use of oral pilocarpine. Where there is no residual functioning salivary tissue, patients may benefit from using sips of water and a saliva substitute. In dentate patients, high-​concentration fluoride toothpaste should be used to avoid caries and tooth surface loss. Oral and dental hy- giene should be maximized. Regular dental and oral review by a dental professional will assist in identifying early any infections with candida or staphylococcal species. Where systemic involvement in primary Sjögren’s syndrome is marked, immunosuppressive drugs are often tried, including

SECTION 15  Gastroenterological disorders 2826 hydroxychloroquine and azathioprine. Given the pathophysiology of Sjögren’s syndrome, biological agents such as rituximab are showing promise. Prognosis Sjögren’s syndrome is a progressive disease characterized by worsening symptoms over time. There is an increased lifetime risk of the development of lymphoma, mostly non-​Hodgkin B-​cell type, predominantly of the marginal zone histological form, particularly in the primary variant of Sjögren’s syndrome, although various studies have failed to agree the specific increased risk. Such lympho- mas are frequently extranodal and originate in mucosa-​associated lymphoid tissue—​so-​called MALT lymphomas. It is known that the risk of developing lymphoma is higher in pa- tients with persistent unilateral or bilateral major salivary gland en- largement, persistent lymphadenopathy, evidence of vasculitis, and/​ or low complement levels and the presence of cryoglobulins. Where minor salivary gland biopsy has been carried out, histological evi- dence of germinal centres also appears to increase the risk of subse- quently developing lymphoma. Where persistent enlargement of the major salivary glands is pre- sent, these should be subject to regular review by way of ultrasound scanning, MRI scanning, and/​or fine needle aspiration biopsy to de- termine the development of focal lymphoma. Sialadenitis (acute and chronic) Bacterial or viral infections and rarely allergic reactions may cause inflammation of the salivary glands. These agents may give rise to acute, chronic, and allergic sialadenitis, and recurrent parotitis. One particular variant, of unknown aetiology, is recurrent parotitis of childhood which appears to resolve spontaneously after puberty. Aetiology Ascending infection of the parotid gland may occur due to obstruc- tion of the ductal system by a calculus (stone), stricture, or mucus plug. Acute parotitis may also follow the use of a drug causing xerostomia. The most common microorganisms involved are Staphylococcus aureus, Streptococcus milleri group, and other mem- bers of the oral flora. The most common acute viral parotitis was historically mumps but routine vaccination against this has seen the incidence drop dramatically in many countries. Salivary glands are sometimes affected by HIV infection, with an enlargement of the parotid glands giving a Sjögren’s-​like picture. Chronic sialadenitis is usually associated with duct obstruction. Pathology Acute sialadenitis shows an acute inflammatory reaction of the sal- ivary tissue, with a predominantly neutrophil infiltration, except in mumps, which shows an infiltration by mononuclear cells. In both chronic and recurrent sialadenitis there is a marked periductal and acinar infiltration by mononuclear cells, with some duct epithelial hyperplasia, accompanied by acinar atrophy and fibrosis. Clinical features The presenting symptom of acute sialadenitis is a painful swelling in one of the major salivary glands. Commonly the patient has a low-​grade fever, oedema and erythema of the cheek, trismus, and a purulent discharge may be evident at the duct opening. In chronic sialadenitis there are usually clinical features of duct obstruction of the affected glands. With involvement of the sub- mandibular salivary gland, there is pain and swelling in the sub- mandibular or retromandibular region, with a reddened duct orifice discharging pus. Differential diagnosis There is little clinical difficulty in the differential diagnosis between acute sialadenitis of the parotid or submandibular gland due to as- cending infection and mumps in hitherto healthy young patients. Any discharging pus should be sampled for organisms with anti- biotic sensitivity determined. Empirical prescribing is warranted with a drug such as amoxicillin. In chronic sialadenitis, there is usually clinical or radiological evi- dence of a calculus and ultrasound scanning may show duct dilatation. Management In acute, chronic, or recurrent bacterial sialadenitis the appropriate antibiotics should be used to control the infection, but occasionally surgical drainage may also be necessary. Careful oral hygiene meas- ures are important in all types of sialadenitis. There is no special treatment for mumps, but rest and isolation for about a week are indicated. In chronic sialadenitis, the cause of obstruction, such as a calculus, should be removed. Course and prognosis Acute sialadenitis will resolve with the aid of antibiotics and gen- eral management of the patient. Mumps will resolve spontaneously and second attacks are very rare. Chronic sialadenitis may persist for many years and may lead to destruction of the gland, unless the cause of duct obstruction is removed early. Recurrent parotitis in childhood may show spontaneous recovery after puberty. Salivary gland neoplasms The salivary gland neoplasms are a complex and diverse group which can affect the major and the minor salivary glands. Most are slow growing and benign, but some are malignant and aggressive with manifestations such as lower motor neuron palsy of the facial nerve as it passes through the parotid gland. FURTHER READING Arduino PG, Porter SR (2008). Herpes simplex virus type 1 infec- tion: overview on relevant clinic-​pathological features. J Oral Pathol Med, 37, 107–​21. Armitage GC (2004). Periodontal diagnosis and classification of peri- odontal diseases. Periodontol 2000, 34, 9–​21. Armitage GC, Cullinan MP (2010). Comparison of the clinical features of chronic and aggressive periodontitis. Periodontol 2000, 53, 12–​27. Atout RN, Todescan S (2013). Managing patients with necrotizing ul- cerative gingivitis. J Can Dent Assoc, 79, 46. Baccaglini L, et al. (2013). Urban legends series: lichen planus. Oral Dis, 19, 128–​43. Bradley PJ, McGurk M (2013). Incidence of salivary gland neoplasms in a defined UK population. Br J Oral Maxillofac Surg, 51, 399–​403. Brocklehurst P, et al. (2012). Systemic interventions for recurrent aph- thous stomatitis (mouth ulcers). Cochrane Database Syst Rev, 9, CD005411.

15.6  The mouth and salivary glands 2827 Consensus Statement (1993). Classification and diagnostic criteria for oral lesions in HIV infection. EC-​Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus. J Oral Pathol Med, 19, 289–​91. Di Zenzo G, Carrozzo M, Chan LS (2014). Urban legends series: mu- cous membrane pemphigoid. Oral Dis, 20, 35–​54. Field JK, Shaw RJ (2015). The management of oral epithelial dys- plasia: the Liverpool algorithm. Oral Oncol, 51, 883–​7. Hajishengallis G, Darveau RP, Curtis MA (2012). The keystone-​ pathogen hypothesis. Nat Rev Microbiol, 10, 717–​25. Jain P, Jain I (2014). Oral manifestations of tuberculosis: step towards early diagnosis. J Clin Diagn Res, 8, 18–​21. Kalavrezos N, Scully C (2015). Mouth cancer for clinicians part 1: cancer. Dent Update, 42, 250–​60. Kalavrezos N, Scully C (2015). Mouth cancer for clinicians part 2: epi- demiology. Dent Update, 42, 354–​9. Kalavrezos N, Scully C (2015). Mouth cancer for clinicians part 3: risk factors (traditional: tobacco). Dent Update, 42, 476–​83. Kassimos DG, et al. (1997). Chronic sialadenitis in patients with nodal osteoarthritis. Br J Rheumatol, 36, 1312–​17. Lazzerini M, Bramuzzo M, Ventura A (2014). Association between orofacial granulomatosis and Crohn’s disease in children: systematic review. World J Gastroenterol, 20, 7497–​504. Linden GJ, Herzberg MC (2013). Periodontitis and systemic dis- eases: a record of discussions of working group 4 of the Joint EFP/​ AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol, 40, Suppl 14, 20–​3. Macfarlane TV, et al. (2010). The aetiology of upper aerodigestive tract cancers among young adults in Europe: the ARCAGE study. Cancer Causes Control, 12, 13–​21. Mahesh C, et al. (2012). Recurrent aphthous stomatitis: a review. J Oral Pathol Med, 41, 577–​83. Manfredi M, et al. (2013). Urban legends series: oral candidosis. Oral Dis, 19, 245–​61. Napier SS, Speight PM (2007). Natural history of potentially malig- nant oral lesions and conditions: an overview of the literature. J Oral Pathol Med, 37, 1–​10. Patel P, et al. (2013). Clinical evidence for allergy in orofacial granuloma­ tosis and inflammatory bowel disease. Clin Transl Allergy, 3, 26. Patton LL, et al. (2013). Urban legends series: oral manifestations of HIV infection. Oral Dis, 19, 533–​50. Pitts NB, Ekstrand KR (2013). International Caries Detection and Assessment System (ICDAS) and its International Caries Classification and Management System (ICCMS)—​methods for sta- ging of the caries process and enabling dentists to manage caries. Community Dent Oral Epidemiol, 41, 41–​52. Robertson DP, et al. (2015). Management of severe acute dental infec- tions. BMJ, 350, h1300. Samim F, Zed C, Williams PM (2013). Erythema multiforme a review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin N Am,57, 583–​96. Sand FL, Thomsen SF (2013). Efficacy and safety of TNF-​ɑ inhibitors in refractory primary complex aphthosis: a patient series and over- view of the literature. J Dermatolog Treat, 24, 444–​6. Scully C, Bagan J (2008). Oral mucosal diseases: erythema multiforme. Br J Oral Maxillofac Surg, 46, 90–​5. Selwitz RH, Ismail AI, Pitts NB (2007). Dental caries. Lancet, 369, 51–​9. Seoane J, et al. (2016). Early oral cancer diagnosis: the Aarhus state- ment perspective. A  systematic review and meta-​analysis. Head Neck, 38, Suppl 1, E2182–​9. Stoopler ET (2005). Oral herpetic infections. Dent Clin N Am, 49, 15–​29. To VS, et  al. (2012). Review of salivary gland neoplasms. ISRN Otolaryngol, 2012, 872982. Wade WG (2013). The oral microbiome in health and disease. Pharmacol Res, 69, 137–​43. Warnakulasuriya S, Ariyawardana A (2016). Malignant transform- ation of oral leukoplakia:  a systematic review of observational studies. J Oral Pathol Med, 45, 155–​66. Warnakulasuriya S, et al. (2007). Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med, 36, 575–​80. Williams D, Lewis M (2011). Pathogenesis and treatment of oral candidosis. J Oral Microbiol, 3, 5771–​11. Wray D, et al. (2000). The role of allergy in oral mucosal diseases. QJM, 93, 507–​11.

15.7 Diseases of the oesophagus 2828

15.7 Diseases of the oesophagus 2828

ESSENTIALS Defective conduit function of the oesophagus readily induces clinical symptoms and may have serious effects on nutrition and the lungs, the latter resulting from aspiration of gastro-​oesophageal contents. Oesophageal pain and dysphagia caused by diseases of the muscular layer or epithelium are often disabling. The oesophagus is exposed to numerous hostile environments including carcinogens in food or those derived from tobacco, betel nuts, and other ingested sources and hence carcinomas can occur. Chronic reflux disease from exposure to corrosive upper gastrointestinal secre- tions is also associated with malignant disease—​adenocarcinoma—​as well as benign stricture formation related to the action of pepsin. Introduction The oesophagus is responsible for transporting food to the stomach without compromising the safety of the airway. Imprecise muscle coordination of the oropharynx and the oesophageal body can have serious consequences such as aspiration pneumonia and malnutri- tion. Diseases of the oesophagus generally present with symptoms of pain or dysphagia either alone or in combination (odynophagia). True oesophageal dysphagia should be distinguished from oropha- ryngeal dysphagia, an abnormality of transfer of food from the mouth to the oesophagus, by a careful history. Other symptoms and signs of oesophageal disease include weight loss, anaemia, cough, hoarse voice, and breathlessness secondary to aspiration pneumonia. The most common oesophageal disorder is gastro-​oesophageal reflux disease which should be taken seriously because of its profound im- pact on quality of life in some people and since it can be a precursor to oesophageal adenocarcinoma. The diagnosis of oesophageal dis- ease may generally be determined by a thorough history and a small number of focused investigations outlined in the next section. Investigation Diagnosis and treatment of suspected oesophageal disease has been enhanced by the introduction of endoscopic techniques, but in some circumstances radiological investigations and physiological studies of oesophageal function using manometry and pH-impedance provide essential guidance for diagnosis of motor disorders and nonerosive reflux disease, which can be related to systemic diseases such as systemic sclerosis. Endoscopy An oesophagogastroduodenoscopy is usually the first investigation of choice to determine whether there is a mechanical cause for the symptoms and whether there is any evidence of inflammation or mucosal damage. Direct visualization of the oesophagus, combined with biopsy as appropriate, offers immediate benefit for the diag- nosis of mucosal diseases such as (1) infections due to candida and herpes simplex virus; (2) benign and malignant strictures; (3) and bleeding lesions, including varices. Although the endoscopic ap- pearances may be suggestive of a motility disorder, this is not the investigation of choice for assessing oesophageal motor function. Endoscopic technology is advancing rapidly and enhanced magnifi- cation coupled with permutations in the parts of the light spectrum used for image processing (e.g. narrow band imaging) permit a more detailed analysis of the mucosa and superficial vasculature in real time. There is now evidence that these technologies can aid in the diagnosis of dysplasia and early oesophageal cancer. Endoscopic ultrasound is an important staging investigation for oesophageal cancer (discussed later in this chapter) and also has a role in characterizing submucosal lesions. Radiology The barium or Gastrografin radiographic swallow has largely been superseded by endoscopy for the diagnosis of structural abnormal- ities; however, it can be a useful guide prior to interventions such as endoscopic stent insertion, to evaluate conduit functioning postoperatively, and to exclude the presence of a pharyngeal pouch prior to endoscopy, especially in elderly patients. Useful information can also be obtained about the motor function of the pharynx and oesophagus by videotaping the images and analysing, in slow-​motion replay, repeated tests of standardized stimuli such as bread or barium tablets. Optimal results from radiology are achieved when there is a partnership between a clinician and a radiologist who both have a special interest in oesophageal motor disorders, so that the examin- ation technique can then be tailored accordingly. CT scanning and 15.7 Diseases of the oesophagus Rebecca C. Fitzgerald and Massimiliano di Pietro

15.7  Diseases of the oesophagus 2829 positron emission tomography, increasingly as part of a combined procedure (CT-​PET), are part of the staging investigations for oe- sophageal cancer (see ‘Staging’). A CT scanning with Gastrografin should be taken in cases where oesophageal perforation is suspected. MRI currently has a limited role for oesophageal disease. Oesophageal function testing Techniques are now available for the precise measurement of oe- sophageal motor function. These include oesophageal manometry, intraluminal pH-​impedance monitoring, video fluoroscopy, and high-​resolution oesophageal manometry with isocontour mapping. Together these techniques build a dynamic picture of the physio- logical sequence of events and the effectiveness of contraction which can be compared with resultant functional outcome. These tests may also have a clinical role for explaining symptoms to patients even in the absence of therapy. Oesophageal manometry provides the most direct indication of patterns of oesophageal motor function. It is most helpful in the diagnostic work up of patients with dysphagia, after exclusion of fixed, structural defects. Manometry may also be useful to confirm the placement of intraluminal devices such as pH probes and to as- sess pre-​ and postoperative results following surgery for achalasia or reflux. To determine the asso­ciation between reflux episodes and symptoms, pH-impedance catheters can be used to provide either a stationary or ambulatory recording. Wireless devices are also in- creasingly used. Ambulatory monitoring is particularly useful to determine the association between symptoms and episodes of acid and non-acid reflux in patients in whom the origin of troublesome symptoms is unclear. This test is generally performed off medication but may occasionally be useful to assess response to therapy. Radionuclide measurement of oesophageal transit Computerized scintigraphic analysis of the movement of swallowed radiolabelled boluses can give quantitative information about the patterns of movement of material down the oesophagus. However, its poor spatial resolution makes it an inadequate method for the display of oesophageal anatomy. If structural abnormalities have been adequately excluded, slow or interrupted transit suggests ab- normal motility, although patterns of transit are usually nonspecific. Gastro-​oesophageal reflux disease This is by far the most common oesophageal disorder, indeed the second most common outpatient gastrointestinal diagnosis according to a recent survey of nine American databases. Management should be tailored to the severity, which may vary considerably. Definition Some reflux of gastric and duodenal contents into the oesophagus oc- curs in everybody due to vagally mediated transient lower oesopha- geal sphincter relaxations. It should only be considered a disease when it gives rise to symptoms or complications sufficient to impair quality of life. Pathogenic reflux may occur without causing mucosal damage. The terms reflux or peptic oesophagitis should be reserved for circumstances when endoscopy demonstrates that the oesopha- geal mucosa is clearly breached by the action of the refluxed gastric contents. Minor changes such as erythema, oedema, or friability have been shown to be very unreliable indicators of the presence of oesophagitis. The disease can be further classified into oesophageal and extra-​oesophageal syndromes using the Montreal classification. According to this classification gastro-oesophageal reflux disease can either present with typical symptoms (regurgitation, heartburn or chest pain) or atypical ones (cough, hoarse voice and other respira- tory symptoms). While the link with typical symptoms is generally easy to establish, the correlation with atypical symptoms can be chal- lenging in clinical practice. Aetiology In most patients, reflux disease arises from the excessive exposure of the distal oesophagus to gastric contents which are primarily acid and/​or bile. This is usually because of an abnormal frequency or dur- ation of reflux episodes. In a few patients, however, symptoms arise with relatively normal levels of acid exposure, presumably because of sensitization of the oesophageal mucosa. In normal individuals, excessive reflux is prevented by the lower oesophageal sphincter and an external sphincter formed by the crural diaphragm. Pathological reflux generally occurs as a result of defective neural control of the lower oesophageal sphincter. Hiatus hernia is therefore common in patients with reflux disease and causes displacement of the sphincter from the hiatus formed by the diaphragmatic crura. Most reflux oc- curs during the day, usually after food, but lying down will impair the antireflux effect of gravity and nocturnal reflux can be a disabling symptom. Refluxate is cleared from the oesophagus by peristalsis and buffered by swallowed saliva. Slow clearance of oesophageal acidification contributes significantly to prolonged acid exposure in about 50% of patients. This can be an important contributor to se- vere gastro-​oesophageal reflux disease in systemic disorders such as scleroderma which affect gut motility. Risk factors for gastro-​oesophageal reflux disease include herit- ability (up to 30% of the risk), obesity, and age but not sex. Alcohol and smoking may play a role. Asthma increases the risk as do medi- cations which relax the lower oesophageal sphincter such as cal- cium channel antagonists, nitrates, anticholinergics, and methyl xanthines. Consequences of excessive reflux Symptoms These are an important source of disability. Evidence suggests that heartburn or regurgitations occurring on more than 2 days a week causes significant impairment of quality of life. However, presenta- tion may be with the less specific symptom of dyspepsia (or epigas- tric discomfort), chest pain, belching, nausea or regurgitation, and dysphagia due to either stricture or motor dysfunction of the oe- sophageal body. There are a number of extra-​oesophageal manifest- ations of reflux including respiratory symptoms such as hoarseness, persistent cough, globus, and asthma. Chronic sinusitis, otalgia, and glue ear may also be associated with reflux and—​according to some studies—​even idiopathic pulmonary fibrosis. Complications of reflux disease The chemical insult from excessive exposure of the mucosa to gastroduodenal contents leads to distal oesophageal erosion or ul- ceration in between 40 and 60% of patients with troublesome reflux symptoms and columnar-lined (Barrett’s) oesophagus in between 3 and 10% of individuals, as discussed in detail in the following section. The extent of ulceration varies greatly, from tiny patches of erosion to extensive circumferential ulceration in a small minority.

SECTION 15  Gastroenterological disorders 2830 Peptic stricture sufficient to cause dysphagia is typically only associ- ated with severe oesophagitis. When strictures are severe, this may lead to malnutrition. Bleeding from oesophagitis may occur but is rarely life-​threatening except when it occurs from a deep ulcer asso­ ciated with columnar metaplasia, in which case a neoplastic process is the likely cause of the ulceration. Diagnosis and assessment of severity History The history is pivotal for diagnosis because of the extremely high prevalence of reflux-​induced symptoms and the lack of a defini- tive, inexpensive diagnostic test for reflux disease. A trial of acid-​ suppression therapy can be used as an aid to diagnosis. Endoscopy When investigation is required, endoscopy is the first choice as it is the only test that can give sensitive recognition and grading of oe- sophagitis (e.g. Los Angeles classification system) and reliable diag- nosis of oesophageal columnar metaplasia (Barrett’s oesophagus). Endoscopy also allows for the effective identification of significant peptic strictures, other types of oesophagitis (discussed in later sections), and peptic ulcer disease as well as malignancies. The value of endoscopy as the initial investigation is greatly enhanced by the accurate diagnosis of endoscopic biopsy and, where indicated, cy- tology brushings. As discussed earlier, however, most patients with reflux disease do not have endoscopically visible mucosal damage, so a negative endoscopy does not exclude the diagnosis of reflux disease (so-​called nonerosive reflux disease). Oesophageal function tests The place of these is summarized in Fig. 15.7.1. Oesophageal manometry and ambulatory 24-​h pH monitoring have a limited but important role in the diagnosis of reflux disease (Fig. 15.7.2). Oesophageal pH monitoring is most useful in patients with trouble- some symptoms but without endoscopic signs of oesophagitis in whom a trial of therapy has failed, and patients with atypical symp- toms that cannot be clearly related to reflux. Patients with suspected reflux symptoms but with no endoscopic evidence of oesophagitis who are being considered for antireflux surgery should also undergo oesophageal pH monitoring to maximize the chances of successful symptom relief from this invasive intervention. Multichannel oesophageal impedance monitoring (Fig. 15.7.3) is increasingly available in clinical practice and has been shown to distin- guish reliably between swallowed or refluxed fluid and gas. Combined with pH monitoring, it may identify individuals with ‘nonacid reflux’ who fail to respond to treatment. Bile reflux can be assessed using Bilitec probes, but these are not routinely available anywhere and fur- ther studies are required to elucidate future clinical application. Barium swallow and meal This is an inappropriate primary diagnostic test; it is of no value for the detection of abnormal reflux, and is insensitive for the diagnosis of oesophagitis and cannot grade it. Other pathologies such as gas- tric ulcer and oesophageal stricture are demonstrated with reason- able sensitivity, but adequate evaluation of these findings requires endoscopic biopsy. However, barium swallow is the best method for recognizing extrinsic oesophageal compression which may be pro- ducing symptoms that could be interpreted as being due to reflux, and in the assessment of an anatomically complex hiatus hernia. The mere demonstration of hiatus hernia, however, does not necessarily indicate the presence of reflux disease. Principles of management The major aims of treatment are to provide adequate symptom- atic relief and control of oesophagitis. Reduction of oesophagitis to minor patchy erosions is probably sufficient to prevent the com- plications of oesophagitis, although adequate symptomatic relief is usually achieved only when oesophagitis is completely healed. Tailoring and titration of therapy The severity and frequency of symptoms and the endoscopic find- ings should be used to choose an appropriate level of initial therapy (Fig. 15.7.1). There is some debate about whether to treat patients with a high or low dose of acid-​suppressant drugs initially. An initial trial of low-​ to medium-​dose empirical therapy has the disadvan- tage of giving less precise diagnostic information, and often gives Symptoms mild and infrequent Reassure Nondrug measures Clear-cut history no alarm symptoms Symptoms troublesome PPI 4–8 weeks Good response Maintain PPI Titrate dose to response Endoscopy if not yet done Upper abdominal/ lower retrosternal symptoms Endoscopy ± pH studies Poor response Twice-daily PPI or surgery History indeterminate or alarm symptoms Oesophagitis No oesophagitis Symptoms typical Symptoms indeterminate Reflux disease Function tests Not reflux Manage accordingly Endoscopy Fig. 15.7.1  Principal decision paths for management of reflux disease.

15.7  Diseases of the oesophagus 2831 only slow relief of symptoms. Patients with severe oesophagitis will usually not respond adequately to low-​dose acid suppression. Initial high-​dose proton pump inhibitor (PPI) therapy is likely to give more immediate confirmation of the diagnosis and prompt relief of symp- toms. As per recent National Institute for Health and Care Excellence (NICE) guidance, in general it is recommended to offer a full dose of PPI (e.g. omeprazole/​esomeprazole 40 mg or lansoprazole 30 mg daily) for 4 to 8 weeks for the management of symptomatic reflux. If symptoms recur after stopping treatment, then a low-​dose PPI (e.g. omeprazole 20 mg daily) should be offered as maintenance. In cases of severe oesophagitis, an 8-​week course of full-​dose PPI should be offered, or high-​dose PPI (e.g. omeprazole 80 mg daily) MEAL (C) Chest pain (H) Heartburn C H H H H pH 7 5 3 1 11:00 12:00 13:00 14:00 15:00 Time Fig. 15.7.2  Section of a 24-​h oesophageal pH monitoring study showing the association of heartburn with episodes of acid reflux after a meal. (b) (a) (c) Fig. 15.7.3  Example impedance images obtained from six impedance arranged from top (most proximal) to bottom (most distal) and two pH channels (two tracers at the bottom) which are placed in the oesophagus and stomach, respectively. (a) Impedance changes for normal liquid swallow (arrow). Usually air (higher impedance signal) is ahead of liquid bolus (low impedance signal). (b) Mixed (gas and liquid) acid reflux episode. Mixed reflux is more frequent than liquid only reflux. Gas (belch) reflux is evidenced by a short rise in impedance migrating rapidly into the proximal oesophagus. Arrowhead shows a drop in the oesophageal pH. (c) Non-acid reflux. Oesophageal pH is unchanged, while impedance channels are showing a liquid reflux episode migrating into the proximal oesophagus (arrow). Courtesy of Qasim Aziz, Professor of Physiology, Barts and the London School of Medicine and Dentistry.

SECTION 15  Gastroenterological disorders 2832 in case of no or partial response. Full-​dose PPI may be required as maintenance therapy in patients presenting with severe oesopha- gitis. For optimum cost-​effectiveness and to reduce complications, high-​dose treatment should be followed by a step-​down approach to long-​term therapy as outlined in Fig. 15.7.1. Nondrug measures and antacids The efficacy of these traditional approaches is often overrated. The most useful measures are avoidance of large meals and provocative foods, drinks, and physical activities involving bending or lifting. Stopping smoking and weight loss (if overweight) are recom- mended to help reduce symptoms and for general health improve- ment. Elevation of the bed head may be helpful, if it can be tolerated. Antacids will not usually prevent symptoms, but may be effective in aborting episodes of heartburn. These low-​cost measures are worth a trial in patients with mild intermittent symptoms and should be used as part of maintenance therapy if they prove effective. Acid suppression Inhibition of secretion of gastric acid makes gastric juice less injurious but does not stop reflux. This has deservedly become the most widely used drug therapy because of its high efficacy and adjustability. PPIs are the mainstay of treatment because of their effectiveness in reduc- tion of food-​stimulated acid secretion and their greater overall efficacy in control of acid secretion compared with histamine-​2 receptor ant- agonists. However, histamine-​2 receptor antagonists can be a useful adjunct to PPIs for controlling nocturnal reflux. Long-​term treatment with acid suppressants maintains patients free of symptoms and oesophagitis indefinitely, but withdrawal is usually associated with prompt relapse. The maintenance dose ap- pears to be the same as the lowest effective healing dose. There have been concerns about the safety of long-​term acid suppression ever since the introduction of histamine-​2 receptor antagonists. These include possible associations with susceptibility to infections such as gastroenteritis and pneumonia, malabsorption of vitamins, and increased prevalence of bone fracture. However, meta-​analyses show significant study heterogeneity and confounding effects. To date, follow-​up of many patients treated continuously for 10 years or more with acid suppression has shown no definite evidence of any effects of significance, but in the context of patients who may require treatment with these agents for decades, more extensive follow-​up is still needed. In particular, rare idiosyncratic effects, such hypomag- nesaemia and interstitial nephritis, cannot be dismissed and need to be taken into consideration. With regard to drug interactions, following extensive investi- gation it has been concluded that coadministration of PPIs with antiplatelet agents appears to be safe. However, PPIs can delay methotrexate metabolism, leading to increased toxicity, hence a switch to histamine-​2 receptor antagonists should be considered before induction with this drug. Given these theoretical safety considerations and also drug cost, long-​term treatment of reflux disease with these agents should use the lowest effective dose. In some patients, use of PPIs is limited by side effects such as diarrhoea and this may lead to consideration of surgical antireflux therapy. Motility stimulants The best researched, most efficacious motility stimulant is cisapride, which is a parasympathomimetic that acts as a serotonin 5-​HT4 receptor agonist. It mainly acts through enhancing oesophageal acid clearance as well as increasing muscle tone in the lower oesophageal sphincter. Unfortunately, cisapride can have effects on cardiac con- ductance that may rarely lead to sudden death at peak serum levels, especially when various drugs are coadministered. Cisapride has therefore been withdrawn from the market in many countries and should only be used cautiously in severe cases. Alternative prokinetics such as metoclopramide and domperidone may be useful adjuncts, again when used in combination with acid-​suppression therapy. However, long-​term therapy with these agents is also not recom- mended due to safety concerns. Recent studies with other prokinetic drugs such as acotiamide and mosapride have yielded disappointing results. Endoscopic and minimally invasive antireflux procedures Several new techniques have been evaluated to restore barrier func- tion at the level of the lower oesophageal sphincter. These include endoscopically delivered sutures (Esophyx), an electrical stimu- lator device (Endostim), radiofrequency energy delivery (Stretta), magnetic bead implantation (Lynx), and submucosal prosthetic im- plants. Effectiveness has mainly been assessed in uncontrolled trials without long-​term follow-​up data. NICE is currently monitoring the evidence for the electrical stimulator device and recommends that the use of other therapies (such as Lynx and Esophyx) is restricted to research studies until further evidence on long-​term safety and efficacy are available. Antireflux surgery Antireflux surgery is a very effective long-term therapy. Negative factors are the dependence of the results on the expertise of the surgeon and the morbidity and small (approximately 0.5%) mor- tality associated with the surgery itself. Laparoscopic antireflux surgery (usually a Nissen fundoplication) is a major advance, as it achieves good control of reflux with a major reduction in the morbidity inherent in the more traditional approach. The recent Lotus trial (a randomized controlled trial comparing antireflux surgery vs esomeprazole 20/​40 mg daily) showed similar clinical efficacy for the two arms, with significantly lower oesophageal acid exposure in the surgical group (0.7 vs 1.9%, respectively), but at the expense of increased side effects (dysphagia, flatulence, and bloating) Choice between medical and surgical therapies Selection of a medical or surgical therapy should take account of the severity of disease and the risks of antireflux surgery specific to the patient. It should also take account of the patient’s age, both from the point of view of operative risk and the time over which the patient will need treatment for reflux disease, the cost of ef- fective medical therapy, possible intolerance to PPI therapy, and, naturally, the preferences of the patient. The choice between med- ical therapies should be largely governed by the local cost of the alternatives that give the necessary level of treatment, as all of the first-​line options are effective, safe, and well tolerated. Anti-reflux surgery should not be routinely performed if any doubt persists, based on physiological studies, that gastro-oesophageal reflux be the primary cause of patients symptoms, as well as in the pres- ence of moderately to severely impaired oesophageal motility based on pre-operative manometry, as this can result in persistent dysphagia.

15.7  Diseases of the oesophagus 2833 Management of complications of reflux disease The important complication of oesophageal columnar metaplasia is discussed in a separate section (see ‘Oesophageal columnar meta- plasia (Barrett’s oesophagus)’). Abnormalities of oesophageal anatomy Non-​neoplastic abnormalities which distort oesophageal anatomy may interfere with normal function or merely pose difficulties in the interpretation of imaging findings. Sliding hiatus hernia Around 90% of hiatus hernias are of this type, in which the gastro-​ oesophageal junction is displaced upwards into the thorax, giving a simple-​shaped pouch of intrathoracic stomach. This can be mis­ taken for a columnar-lined oesophagus at endoscopy unless the ana- tomical land­marks are clearly defined. These landmarks include the proximal extent of the gastric folds and the palisading of vessels in the squamous oesophagus. The phreno-​oesophageal ligament is ef- faced in sliding hiatus hernia, but it is not clear whether this is a pri- mary defect of gastric anchorage. Many patients with hiatus hernia are asymptomatic. Despite this, physiological studies indicate that herniation of the gastro-​ oesophageal junction impairs its function as an antireflux barrier by removing the normal diaphragmatic crural compression from the lower oesophageal sphincter. Thus, hiatus hernia can be taken as a risk factor for reflux disease, but not an abnormality that makes the diagnosis. When present, symptoms of gastro-​oesophageal re- flux are the only ones of major significance. These should be treated along conventional lines (see ‘Gastro-​oesophageal reflux disease’). Prognosis is that of any associated reflux disease. Rolling or paraoesophageal hiatus hernia A variable part of the stomach herniates through the hiatus along- side a normally situated gastro-​oesophageal junction. This pattern of herniation may produce a gross disturbance of gastric anatomy, usually with a narrow exit from the herniated pouch into the main stomach cavity. Some rolling hernias are also associated with dis- placement of the gastro-​oesophageal junction above the hiatus, in which case these are known as mixed hernias. Obstruction and distension of the pouch causes upper abdom- inal discomfort and can progress to strangulation. Trapping of food bolus into the hiatus hernia can cause symptoms of post- prandial fullness, epigastric discomfort and early satiety. Gastric volvulus can occur because of the laxity of the gastric anchorage and may obstruct the gastro-​oesophageal junction. Both of these problems have a very high mortality and demand urgent surgery (Fig. 15.7.4). There are no adequate data on the degree of risk associated with rolling hiatus hernia. It is controversial whether elective surgery should be performed to reduce and anchor rolling hiatus hernias in order to remove risks of complications. Schatzki ring A Schatzki ring is a characteristic short luminal stenosis which oc- curs at the gastro-​oesophageal junction. It is made up only of mucosa and submucosa, and may narrow the lumen to a few millimetres or cause a clinically insignificant minor indentation. Aetiology is un- known: they have been postulated to be congenital, although evi- dence now suggests that they can occur in later life. Reflux and pill oesophagitis have been implicated. With mechanically significant rings, intermittent dysphagia occurs on eating solids. Meat is often the culprit, leading to the common term of ‘steakhouse syndrome’. Episodes of bolus obstruc- tion are not unusual, with associated chest pain caused by powerful oesophageal contractions. Failure to recognize a Schatzki ring fre- quently leads to the incorrect diagnosis of primary diffuse oesopha- geal spasm. Endoscopy is the investigation of choice (Fig. 15.7.5). If barium studies are performed, adequate distal oesophageal Fig. 15.7.4  Mesenteroaxial volvulus on upper gastrointestinal examination. A supine image shows the distal stomach located in a paraoesophageal hiatal hernia. There is a rotation about the short axis in the body of the stomach (arrow). A nasogastric tube is in place. Note the downward-​pointing pylorus. From Levy AD, Mortele KJ, Yeh BM (eds) (2015). Gastrointestinal imaging. By permission of Oxford University Press. Fig. 15.7.5  Endoscopic appearance of a Schatzki ring. Courtesy of Dr Ewen Cameron, Consultant Gastroenterologist, Addenbrooke’s Hospital, Cambridge.

SECTION 15  Gastroenterological disorders 2834 distension during the barium swallow is essential for detection; this is best achieved by prone-​oblique views. No treatment may be necessary. Disruption of the ring by simple peroral dilatation or endoscopic diathermy or laser is very re- warding as the dysphagia and chest pain are cured, sometimes after many years of symptoms. However, there is a significant incidence of recurrence and repeated dilatations at intervals are often needed. Other rings and webs Other short oesophageal stenoses may develop because of peptic stricture, muscular rings, and cervical webs with iron-​deficiency an- aemia (Plummer–​Vinson syndrome) or without. Wide-​mouthed multiple diverticula are characteristic of sclero- derma oesophagus. In the nonsclerodermatous oesophagus, diver- ticula occur in the mid and distal oesophagus, both types probably being ‘blow-​outs’ secondary to hypercontraction motor disorders. These can become very large, but it is rare for them to cause symp- toms, although they may be associated with dysphagia and regur- gitation of retained contents. Unless symptoms are disabling, they are best left undisturbed because leakage is common following surgical removal. Multiple intramural outpouchings of barium are characteristic of intramural pseudodiverticulosis, which appears to be due to dilata- tion of the ducts of submucosal glands by an unknown process. Peptic stricture Dysphagia secondary to stricture formation needs to be distin- guished from the more common dysphagia seen in patients with reflux disease which is due to defective triggering and control of oesophageal body peristalsis (see ‘Nonspecific oesophageal motor disorders’). Peptic stricture is managed by a combination of peroral dilatation and healing of oesophagitis by either medical or surgical means. All strictures should be treated as malignant until proven otherwise by repeated biopsy. Provided oesophagitis is healed, stric- ture is usually not an ongoing problem. Respiratory complications Respiratory disease may occur either as a result of direct aspiration of refluxed gastric contents or from the effects of gastro-​oesophageal reflux on reflexes. It is difficult to prove that reflux disease which coexists with respiratory disease is actually the cause of the respira- tory problem. The best investigative approach is probably a trial of high-​level acid inhibition with at least a double dose of PPI and prokinetics for at least 2 months. Management of respiratory dis- ease by antireflux surgery is not guaranteed to be successful. The evidence on the link between reflux disease and chronic cough re- mains conflicting, although in same cases this can be demonstrated by pH-impedance. Regurgitation Voluminous regurgitation is the main symptom in a small subgroup of patients with reflux disease. They may present complaining of vomiting, but a detailed history reveals that there is no prior nausea, and no effort involved in the appearance of the gastric content in the mouth. The determinants of high-​volume reflux and regurgitation have not been well defined. Treatment with PPIs and prokinetics can have substantial benefits, but in more severe cases antireflux surgery is usually the only effective management. Chest pain: noncardiac Reflux is also an important cause of noncardiac chest pain (see ‘Noncardiac chest pain’). Oesophageal columnar metaplasia
(Barrett’s oesophagus) Definition and nomenclature Oesophageal columnar metaplasia (Barrett’s oesophagus) is defined as the conversion of the normal stratified squamous epithelium with a columnar-​lined mucosa which may have characteristics of gas- tric or intestinal epithelium. The lack of international consensus on the definition of this disease has led to confusion in the literature. However, it is widely accepted that it is the subtype characterized by intestinal metaplasia with goblet cells which has the highest risk for malignant progression and in many countries the term Barrett’s oesophagus and/​or the recommendation for surveillance has been restricted to this subtype. The extent of the metaplasia may vary from 1 cm to the entire oesophageal length and there appears to be a correlation between the length of the segment, the proximal extent of reflux exposure, and the risk of malignancy transformation. The metaplasia generally starts in the distal oesophagus although dis- crete columnar islands may occur. The accepted nomenclature for describing the endoscopic features is the Prague classification in which C indicates circumferential involvement in centimetres and M is the maximal disease extent in centimetres (e.g. C2, M5 for a 5 cm segment with 2 cm of confluent columnar epithelium and 3 cm of metaplastic tongues) (Fig. 15.7.6). Aetiopathogenesis Columnar metaplasia occurs in the context of chronic gastro-​ oesophageal reflux, and occurs more commonly in white males. Its incidence appears to have increased, even taking into account the more frequent use of endoscopy, and the reasons for this are still under intense scrutiny. Possible explanations include an increase in obesity leading to an increased susceptibility to reflux and the re- duced prevalence of Helicobacter pylori infection with a consequent increase in gastric acid secretion. Columnar metaplasia carries an increased risk for the development of oesophageal adenocarcinoma compared with the general population, which equates to an annual incidence of 0.1 to 0.4% in nondysplastic Barrett’s, depending on the length of the segment and the presence of intestinal metaplasia. The risk for cancer significantly increases with the presence of dysplasia (up to 10% per annum) and endoscopic surveillance is therefore generally advocated. Management Surveillance hinges on the subjective interpretation of dysplasia in multiple, random biopsies (usually quadrantic biopsies every 2 cm according to the Seattle protocol). The frequency of surveillance depends on the degree of dysplasia (Table 15.7.1). This arduous

15.7  Diseases of the oesophagus 2835 protocol has not been uniformly accepted since no data from ran- domized controlled trials support a reduction in population mor- tality from oesophageal adenocarcinoma using this approach. On the other hand, the outcome for individuals with symptom- atic invasive adenocarcinoma is universally poor compared with surveillance-​detected disease. Failure to discuss the risk for adeno- carcinoma and the option of endoscopic surveillance with a patient who has oesophageal columnar metaplasia could well be viewed as an indefensible lapse of practice, despite the uncertainties about cost-​effectiveness. The treatment of dysplasia in oesophageal columnar metaplasia has changed substantially in the past 10 years with the advent of ef­ficacious and safe endoscopic therapies. The key is to establish the correct diagnosis, since dysplasia is notoriously difficult to diagnose, with high levels of inter-​ and intraobserver variability. A diagnosis of dysplasia should therefore be corroborated by two independent pathologists, and the addition of p53 immunohistochemistry can be a useful diagnostic adjunct to the traditional histopathological diag- nosis (Table 15.7.1). The management of confirmed dysplasia should be discussed with the multidisciplinary team for oesophagogastric cancer, and the pa- tient should have an opportunity to discuss the options available to them. Increasingly, endoscopic mucosal resection can be used as a diagnostic adjunct for visible lesions to determine depth of invasion. This will inform management decisions and in some cases will turn out to be a therapeutic local excision. Endoscopic ultrasound may be useful but there is a danger of overestimating the depth of in- vasion. A systematic review has showed that in early oesophageal adenocarcinoma, endoscopic ultrasound staging corresponds to the pathological staging only in just over half of the cases, hence this technique is not recommended routinely in patients with high-​ grade dysplasia and early oesophageal adenocarcinoma. Management options will be determined by the extent of dys- plasia and the fitness of the individual, as well as local expertise. Oesophagectomy (which may be performed as a transhiatal or a lap- aroscopic procedure with a limited lymph node resection) is now generally reserved for invasive disease extending into the submucosa because endoscopic resection of localized lesions coupled with ab- lative therapy, generally using radiofrequency ablation, is now sup- ported by randomized control trial evidence with encouraging data on durability. For cases with confirmed low-​grade dysplasia, abla- tion therapy can also be offered following discussion with the patient about the risks and benefits of this procedure. Endoscopic ablation is generally very safe and effective, but multiple treatment sessions are usually required, especially for long segments, with a risk of stricture formation (5–​9%) requiring dilatation. Barrett’s oesophagus may also be associated with deep oesopha- geal ulceration within the columnar-​lined segment and strictures usually at the squamocolumnar junction, but these should be con- sidered malignant until proven otherwise. The diagnosis and management of invasive oesophageal adeno- carcinoma are discussed in the malignancy section. Nonreflux causes of oesophagitis Infective oesophagitis Infective oesophagitis has become more prevalent with the increasing number of people who are immunosuppressed through HIV infec- tion or chemotherapy. The more important causes of infective oe- sophagitis are summarized in Table 15.7.2. Immune status is a major determinant of the pattern of infection and simultaneous infection with two or more infective agents is not unusual (Table 15.7.2). H. pylori does not appear to be of any primary significance in the pathogenesis of oesophageal mucosal disease. Patients may present with pain or dysphagia. Viral oesophagitis can sometimes cause major haemorrhage. The dysphagia is gener- ally secondary to superficial mucosal damage and inflammation, but some disorders damage the full thickness of the oesophageal wall and so lead to stricturing. (b) (a) Fig. 15.7.6  Endoscopic appearance of Barrett’s oesophagus. (a) Columnar mucosa in the distal oesophagus on white light
imaging. (b) Corresponding image obtained with narrow band
imaging (note tongues and islands of pink mucosa amid pale white squamous mucosa).

SECTION 15  Gastroenterological disorders 2836 A full history to determine the setting in which the oesophageal problem occurs is often very helpful. Cutaneous or oral disease can inform the oesophageal diagnosis. Endoscopy is the investigation of choice since the mucosal appearance and the distribution of oe- sophageal lesions can be virtually diagnostic. In addition, biopsies and brushings allow for histological diagnosis and identification of fungal elements, viral inclusions, or rarely, pathogenic bacteria. Although infective oesophagitis may be severe in immunocom- petent patients, it is characteristically self-​limiting and topical therapy is normally all that is needed. Immunocompromised pa- tients usually need aggressive, systemic therapy to resolve the infec- tion (Table 15.7.2). Some infections tend to recur, which can cause major disability. Eosinophilic oesophagitis Eosinophilic oesophagitis (in the past sometimes referred to as al- lergic oesophagitis) affects children and adults worldwide, with a male preponderance. The incidence has increased in recent years in line with other associated allergic conditions such as asthma, hay fever, allergic rhinitis, and atopic dermatitis. Although the exact aetiology is not understood, there does seem to be an aberrant immune-​mediated response and activated eosinophils may cause activation of acetyl choline via histamine. During endoscopic exam- ination, oesophageal biopsies should routinely taken in all cases referred with dysphagia and with normal appearance of the oe- sophageal mucosa. Food impaction and dysphagia are the common presenting symp- toms. Heartburn is often present, but refractory to standard treat- ments for gastro-​oesophageal reflux disease. Approximately 50% of patients will have other allergic symptoms. Endoscopy is the investigation of choice and the findings range from grossly abnormal to normal. Findings include a small-​calibre oesophagus, proximal strictures, white exudates, oesophageal rings, longitudinal furrows, and fragile mucosa. However, the sensitivity of endoscopic findings for this diagnosis is suboptimal (15–​48%); hence, in case of clinical suspicion histological corroboration is man- datory. The diagnosis is made on oesophageal biopsy in which there is a dense eosinophilic infiltration within the epithelium (>15 per high power microscopy field) in both proximal and distal biopsies; and exclusion of other possible causes including proton pump-​responsive oesophageal eosinophilia (Fig. 15.7.7). If the eosinophilic infiltration is more generalized, this suggests eosinophilic gastroenteritis. Table 15.7.1  Surveillance protocol for columnar-​lined (Barrett’s) oesophagus for patients willing and fit to undergo regular endoscopy Histopathological diagnosis Endoscopy frequency Clinical management Intestinal metaplasia No dysplasia 2–​5 years depending on the length of Barrett’s and other risk factors for cancer Treat heartburn symptoms with PPI Intestinal metaplasia Indefinite intraepithelial neoplasia/​dysplasia 6 months after index finding. Annual if changes persist. Revert 2-​yearly when two consecutive endoscopies no dysplasia Ensure adequate acid suppression to prevent inflammation confounding diagnosis Low-​grade intraepithelial neoplasia Confirm diagnosis with assessment by two independent pathologists. Rescope in 6 months if treatment not instigated. Ensure adequate acid suppression to prevent inflammation confounding diagnosis Offer ablation treatment after two endoscopies with low-​grade dysplasia. Prior to treatment consider external pathologist for confirmation of diagnosis High-grade dysplasia and intramucosal adenocarcinoma Confirm diagnosis with assessment by two independent pathologists and discuss treatment options Consider endoscopic therapy—​method depending on comorbidity and focality of lesion If endoscopic resection shows disease extending into the submucosa, surgical resection is recommended Table 15.7.2  Major causes of infective oesophagitis Pathogen Management Remarks Immunocompetent patients Candida albicans Topical/​oral antifungals By far the most common, often associated with inhaled steroid use Herpes simplex Aciclovir if severe Unusual, may denude mucosa Varicella zoster Aciclovir if severe In association with chickenpox/​herpes zoster Bacteria Rare in well individuals, and microbiome of healthy individuals becoming
better characterized Immunocompromised patients Candida albicans Systemic antifungals Most common; oral disease almost diagnostic Cytomegalovirus Prophylaxis and treatment with ganciclovir or foscarnet Serpiginous to giant ulcers in distal half Herpes simplex Prophylaxis and treatment with aciclovir or foscarnet Circumscribed ulcers, raised edges to coalescence. Oral lesions Tuberculosis Conventional From miliary and local spread Gram-​positive cocci,
Gram-​negative bacilli Intravenous antibiotics Often with systemic infection Syphilis Conventional Associated with tertiary syphilis elsewhere. Inflammatory stricture

15.7  Diseases of the oesophagus 2837 There is now robust evidence from randomized controlled trials that topical steroid (swallowed fluticasone or budesonide) is su- perior to placebo for symptom control and rate of histological re- mission, and therefore is recommended by the American College of Gastroenterology as first-​line treatment. There is also evidence from cohort studies that foods such as milk, soy, egg, nuts, fish, and wheat can trigger the eosinophilic infiltration, and their elimination im- prove symptoms and histological findings. Hence, alternative strat- egies may include dietary elimination in consultation with an allergy assessment and steroids given topically or systemically in severe cases. However, given the lack of objective tests for the assessment of food allergy, the identification of specific foods requires multiple endoscopies and biopsies, making topical therapy with steroid more practical routinely. Endoscopic food disimpaction and dilatation may be necessary. There are some data on leukotriene inhibitors and anti-​interleukin-​5 antibody therapy, but conflicting evidence on their clinical efficacy and limited data on the long-​term outcome for these patients. Given the high rate of recurrence after discontinuing the treatment, maintenance therapy with topic steroids or a restric- tion diet should be considered in all patients, but particularly those with severe symptoms and rapid relapse after discontinuation of ini- tial treatment. Medication-​induced oesophagitis This entity was only recognized in 1970. The chemical properties of medications pose hazards to the oesophageal mucosa because of its relative susceptibility to injury through pH-​dependent mechanisms. This susceptibility arises in part from the high local concentrations of medications that occur in the oesophageal lumen, since pills move surprisingly slowly through the normal oesophagus especially at the level of the aortic arch. Defective oesophageal transport, poor pill design, increased mucosal susceptibility to injury, and poor pill-​ taking technique contribute to the problem. Medications known to have an especially high risk for oesophageal damage are listed in Table 15.7.3. Symptoms are those for any form of stricture-​associated oesopha- gitis, and much pill-​induced injury probably goes unrecognized. Injury at the distal oesophagus, the other common site of hold-​up, may be commonly misdiagnosed as being due to reflux disease. Medications and formulations with a high risk of injury should be identified and avoided if possible, especially in older patients with re- flux disease or abnormal oesophageal transit. Pill transit is facilitated if medications are taken in the erect position with plenty of water. Pharmaceutical companies need to pay more attention to the use of shapes, sizes, and coatings that can assist transit of pills through the oesophagus. Stricturing may occasionally require surgery. Caustic injury See ‘Caustic ingestion’. Primary oesophageal motor disorders Idiopathic achalasia and achalasia-​like states Definition These disorders are characterized by increased lower oesophageal sphincter tone, absence of lower oesophageal sphincter relaxation with swallowing, and impairment of peristalsis of the oesophageal body. Idiopathic achalasia, which was first described over 300 years ago, accounts for more than 95% of cases and has an annual inci- dence of approximately 1 to 2 per 100 000. It affects all ages, but is diagnosed most often in early to mid-​adult life. Primary familial (b) (a) Fig. 15.7.7  Histopathological appearance of eosinophilic oesophagitis: Low power (a) and high power (b). Courtesy of Vicki Save, Lothian University Hospital, NHS Trust. Table 15.7.3  Common causes of medication-​induced oesophagitis Severe injury—​high risk Slow-​release potassium chloride Aspirin and nonsteroidal
anti-​inflammatory drugs Doxycycline/​tetracycline Quinidine Alendronate Potassium chloride Less severe injury—​high risk Many antibiotics Iron supplements Occasional injury Ascorbic acid Mexiletine Slow-​release theophylline Captopril Phenytoin Zidovudine Corticosteroids

SECTION 15  Gastroenterological disorders 2838 achalasia, which is genetically transmitted, accounts for less than 1% of cases. There are a number of causes of secondary or pseudo-​achalasia. The most common are due to malignant infiltration of the gastro-​ oesophageal junction which has been reported with carcinoma of the stomach, oesophagus, lung, pancreas, and prostate, and with lymphoma. It may also be a manifestation of paraneoplastic neural dysfunction. Chagas’ disease is an important cause worldwide and can sometimes accompany the intestinal pseudo-​obstructive syn- drome. There are a number of other secondary causes including oe- sophageal amyloidosis and sarcoidosis. Achalasia can also occur in associated with neurodegenerative diseases including Parkinson’s disease and cerebellar ataxia. Aetiology Impairment of inhibitory neural control of the distal oesophagus is the universal abnormality. The clearest evidence is degeneration of myenteric inhibitory neurons which, in the early stages, is associated with an inflammatory response. There is increasing evidence that the resulting nitric oxide deficiency may be causative. Symptoms Dysphagia with solids is almost universal, but the symptoms may extend to include liquids and regurgitation is also prominent. The regurgitated material tastes bland because it never enters the stomach. Cramping chest pain occurs in some patients during an early hypercontracting phase of the disorder. Weight loss is seen in patients with disabling dysphagia. The course of symptoms over time is variable in contrast to the progressive symptoms in patients with a malignant cause. Over a prolonged period of a hypertonic lower oesophageal sphincter, continuing oesophageal dilatation may result with increasing regurgitation. When this occurs, respira- tory problems secondary to aspiration can become a major feature. Diagnosis Idiopathic achalasia is diagnosed on average 2 years after its first presentation. Oesophageal manometry is the only sensitive method for demonstration of the characteristic motor dysfunction. The recent advent of high-​resolution manometry has significantly changed the diagnostic criteria and the classification of motor dis- orders. The most important manometric parameter for a diagnosis of achalasia is the integrated relaxation pressure, which measures both the efficacy and the duration of relaxation of the lower oe- sophageal sphincter. The new Chicago classification for motor dis- order describes three types of achalasia (I, II, and III). These are all characterized by increased integrated relaxation pressure, ac- companied by different oesophageal body motility abnormalities (failed peristalsis, pan-​oesophageal pressurization, or oesophageal spasms, respectively). It is not unusual for manometry to be diagnostic of achalasia even though barium studies have been judged to be normal. In advanced disease, a barium swallow may reveal gross oesopha- geal dilatation with a gastro-​oesophageal junction that tapers smoothly to a closed sphincter, with occasional spurts of flow into the stomach (Fig. 15.7.8). As noted earlier, idiopathic achalasia and achalasia-​like states should be distinguished from constriction of the gastro-​oesophageal junction by an infiltrating or encasing malignancy at the cardia. This can be difficult to ascertain with certainty. If there are any grounds to suspect malignancy then an endoscopy should be per- formed, including multiple biopsies from the gastro-​oesophageal junction. CT scanning may also be helpful in these circumstances. Management There are three potential approaches to treatment:  drug therapy with agents that relax the lower oesophageal sphincter, mechanical disruption of the sphincter by either pneumatic dilatation or sur- gical/​endoscopic myotomy, and pharmacological poisoning of the remaining excitatory nerves to the sphincter with botulinum toxin. The results of reduction of lower oesophageal sphincter pressure with drugs such as calcium antagonists and β-​adrenergic agonists compare poorly with mechanical techniques. Oesophagomyotomy can now be performed as an endo- scopic, laparoscopic, or thoracoscopic procedure. Randomized controlled trial evidence shows that laparoscopic myotomy has similar efficacy to pneumatic dilation, and both procedures have a risk of leading to troublesome gastro-​oesophageal reflux (10–​ 20%). In patients having surgery, this risk can be minimized by the incorporation of an antireflux procedure. Cohort studies showed that the myotomy can also be performed endoscopically via tunnelization in the submucosal space and endoscopic dissec- tion of oesophageal muscle fibres. Randomized controlled studies (a) (b) (c) Fig. 15.7.8  Chest radiograph and barium studies from a case of advanced achalasia.

15.7  Diseases of the oesophagus 2839 are currently being performed to compare endoscopic and laparo- scopic techniques. Balloon dilatation is an attractive approach because of its sim- plicity and low cost, but it often needs to be repeated and may fail in up to 40% of patients, especially those who are young. A re- cent meta-​analysis compared the outcome of balloon dilatation and surgical myotomy and found that 10-​year remission rates were 48% and 80%, respectively. It also carries a risk of perforation of about 2%. Given the associated risk of perforation, dilatation should not be performed in patients who are not fit for surgical intervention. Endoscopic injection of the sphincter with botulinum toxin acts on residual excitatory nerves, thereby lowering sphincter pressure. Even though the initial response rate is as high as 75%, the effects tend to wear off. Sustained response at 12 months is seen in about 40% of patients, and the treatment needs to be repeated at 6-​ to 24-​month intervals. The toxin is relatively expensive, however, it is a simple, low-​risk procedure and most applicable to patients with significant coexisting morbidity which renders them unfit for dila- tation or myotomy. Per-oral endoscopic myotomy is an attractive minimally invasive alternative, which was introduced by the Japanese endoscopist Dr Inoue in 2008. This involves the creation of a submucosal tunnel from the mid oesophagus until beyond the oesophagogastric junc- tion, division of the inner muscle layer with an endoscopic knife, and closure of the mucosal entry with clips. Promising results have been seen in cohort studies, but definite evidence of long-​term response is currently lacking and hence this procedure is cur- rently recommended in Europe only within research trials or strict auditing programmes. When oesophageal dilatation is present, prompt treatment is indi- cated because of the morbidity and poor therapeutic outcome asso- ciated with gross oesophageal dilatation. Prognosis Results are excellent if effective treatment is applied before the de- velopment of major dilatation, despite the persistence of major physiological abnormalities. Achalasia carries a significantly in- creased risk for oesophageal malignancy (squamous cell and, more recently appreciated, adenocarcinoma) up to three decades later. The prevalence ranges from 2 to 7% (or a standardized incidence ratio of around 10) in the most comprehensive reports. There is no apparent reduction of this risk with treatment. It is not usual practice to undertake surveillance for this condition. Diffuse oesophageal spasm Definition Episodic chest pain and/​or dysphagia resulting from abnormal contractions of the distal half of the oesophageal body in the ab- sence of any precipitating structural stenosis. On high-​resolution manometry, diffuse oesophageal spasm is characterized by normal relaxation of the lower oesophageal sphincter and recurrent prema- ture high-​amplitude contractions. Aetiology The aetiology of this disorder is poorly understood. Stress is an un- likely primary precipitant but may exacerbate the problem. Good prevalence data are lacking but it affects all age groups. Symptoms Virtually all patients have episodic, crushing central retrosternal pain which can be excruciating and may be misinterpreted as car- diac ischaemia. Intermittent dysphagia occurs in about two-​thirds of patients and leads to temporary abandonment of eating until symptoms abate. Episodes of oesophageal obstruction usually last for approximately 30 min but can last for several hours. In most pa- tients, symptomatic episodes occur less than once a month but in severe cases these may occur several times a week, or each time food intake is attempted. Diagnosis Due to the intermittent nature of the problem, investigations may be normal. Most frequently the diagnosis is made on the basis of the history and the exclusion of other problems that may mimic diffuse oesophageal spasm such as myocardial ischaemia and a Schatzki ring. On oesophageal high-​resolution manometry, the typical finding is normal integrated relaxation pressure and inter- mittent vigorous premature contractions, interspersed with normal swallow-​induced peristalsis. The normal relaxation of the lower oe- sophageal sphincter allows a differential diagnosis of achalasia to be excluded. Ambulatory 24-​h manometry may improve diagnostic accuracy by increasing the likelihood of capturing symptomatic episodes. Barium swallow may show trapping of contrast beads in the distal oesophagus—​the ‘corkscrew oesophagus’—​or sustained obliter- ation of the distal oesophageal lumen. This is not the investigation of choice. Management There is no specific therapy. Smooth muscle relaxants such as ni- trites, nitrates (given as sublingual spray), and calcium antagonists may reduce symptoms but their use is often limited by side effects. In many patients, reassurance is the most important management since the intensity and nature of symptoms gives rise to great con- cern. Opiate therapy is sometimes necessary. Botox injection into the oesophageal body can offer symptomatic relief, but—​similarly to achalasia—​the response is short-​lived. In the rare case of frequent, disabling spasm, oesophagomyotomy can give good relief. Prognosis The major significance is impairment of quality of life and concern about life-​threatening cardiac disease. There is no consistent progres- sion over time. There are several reports of progression of diffuse oe- sophageal spasm to achalasia but in most of these it seems likely that achalasia was initially misdiagnosed as diffuse oesophageal spasm. Hypercontractile (jackhammer) oesophagus Definition This is defined purely by the manometric demonstration in a symp- tomatic patient of primary peristaltic pressure waves in the oesopha- geal body, with at least two swallows, that have peaks of very high amplitude involving the majority of the oesophagus (distal con- tractile integral of >8000 mmHg/​s per cm in the high-​resolution manometry) (Fig. 15.7.9). There is preservation of the normal peri- staltic pattern with a broad progression of the time of onset of the contraction wave in the oesophageal body.

SECTION 15  Gastroenterological disorders 2840 Aetiology It is not clear if this is a true motor disorder or whether it represents the upper end of a continuum of peristaltic wave amplitudes. It has been shown to vary over time within individuals. There are indica- tions that psychological factors can influence peristaltic amplitude. A  minority of patients with hypertensive peristalsis also experi- ence episodes of diffuse oesophageal spasm, suggesting that their underlying dysfunction may be related and involve neural control mechanisms. Symptoms The only clinical significance of hypertensive peristalsis is its rela- tionship to noncardiac chest pain. Hypertensive peristalsis alone does not produce dysphagia or derangement of oesophageal transit, because, by definition, peristalsis is preserved. Management and prognosis These are discussed in the section on noncardiac chest pain. Nonspecific oesophageal motor disorders Definition These are departures from normal patterns of oesophageal motor function which do not actually define specific diseases, but which are of clinical significance. These are separate from oe- sophageal dysmotility arising in association with diseases such as gastro-​oesophageal reflux disease, diabetes, and other autonomic neuropathies. Nonspecific oesophageal motor disorder is the com- monest single functional diagnosis made in most oesophageal manometric laboratories. Aetiology There are likely to be several mechanisms involved. The intermittent occurrence of dysfunctions suggests that they are due to defective neural control. Symptoms Swallow-​induced distal oesophageal body contraction waves with multiple peaks stand out from the other patterns not only functionally but also symptomatically. This pattern is loosely asso- ciated with the hypercontraction disorders of diffuse oesophageal spasm and hypertensive peristalsis, but sometimes does not appear to have any clinical significance. Hypocontraction dysfunctions, re- cently termed ‘ineffective’ peristalsis, are associated with defective triggering and progression of both primary and secondary peri- stalsis. Failure to develop a propagated pressure wave of sufficient strength to maintain closure of the oesophageal lumen leads to de- ranged oesophageal transit. This probably explains the association of these disorders with mild intermittent dysphagia which occurs characteristically with solids. The nonobstructive dysphagia and slow oesophageal acid clearance seen in gastro-​oesophageal reflux disease are due to such dysfunction. Secondary oesophageal body peristalsis has not yet been widely evaluated, but it is probably an important cause of intermittent dysphagia, since, at least in patients with nonobstructive dysphagia and reflux disease, dysfunction of secondary peristalsis is substantially more common than primary peristaltic dysfunction. Oesophageal manometry with an adequate number of recording points in the oesophageal body is the only sen- sitive means for diagnosis. Management In most cases patients seek reassurance and an explanation about the origin of their symptoms. Prokinetic agents may improve triggering and amplitude of peristaltic contractions and so, theoretically, of transit. Secondary peristaltic dysfunction may be more trouble- some, but there is no good information on the effect of prokinetic or other drugs on this. Prognosis These dysfunctions do not remit spontaneously. Patients are often helped by the measures outlined in the section on general manage- ment of oesophageal dysphagia, which minimize the demands on oesophageal transport mechanisms and provide propulsive forces that substitute for oesophageal contractions. Noncardiac chest pain Definition Implicit in this rather circuitous and negative label is the view that this pain has a cardiac-​like quality, but there is no evidence for a car- diac origin. The oesophagus is the next most likely origin, but it is unlikely that all such pain arises from the oesophagus. Aetiology Evidence for triggering of pain by reflux or oesophageal motor dysfunction has been found in between one-​fifth and one-​half of patients evaluated. Oesophageal mucosal pain due to gastro-​ oesophageal reflux is the most common and helpful diagnosis. Frank oesophageal spasm associated with achalasia and diffuse oe- sophageal spasm is an unusual but convincing cause of noncardiac chest pain. In the majority of patients, most episodes of pain occur independently of reflux and any motor abnormality, although many of these patients have nonspecific oesophageal motor dis- orders or hypertensive peristalsis (see earlier sections). Sustained contraction of the longitudinal muscle has been identified by pro- longed intraluminal ultrasonography in association with a high proportion of episodes of pain. Nevertheless, in many patients Pharynx (mmHg) 80 0 400 0 Oesophageal body 0 Time (s) 400 0 400 80 0 0 30 60 90 120 Fig. 15.7.9  Oesophageal manometric tracing in a patient with hypertensive peristalsis.

15.7  Diseases of the oesophagus 2841 noncardiac chest pain appears to be a primary oesophageal hyper- sensitivity disorder and any motor disorder may be an epiphenom- enon. Recent work to understand the neurophysiological basis for the hypersensitivity suggests that there may be distinct phenotypic subclasses of disease based on enhanced afferent transmission de- fects versus heightened secondary cortical processing. Symptoms By definition, the pain resembles cardiac pain in its sensation and distribution. It can be very intense and distressing, can disturb sleep, and may be worse during periods of emotional stress. Postprandial occurrence, in association with heartburn, suggests that it may be caused by reflux. When pain is associated with dysphagia, vigorous achalasia or oesophageal spasm are very possible. Diagnosis Myocardial ischaemia should first be excluded as the cause. Endoscopy should then be performed followed by oesophageal pH and motility studies when symptoms are disabling. Investigation can be unrewarding. Management Reassurance is essential to prevent repeated hospital admis- sions for fear of a cardiac cause. If the pain is triggered by gastro-​ oesophageal reflux, high-​level acid-​suppression therapy should be tried (see ‘Gastro-​oesophageal reflux disease’). Achalasia and dif- fuse oesophageal spasm should be treated on their own merits. In patients with no clear-cut diagnosis, treatment with anxiolytics and low dose antidepres­sants has been found to be moderately effective, given their properties in reducing nociception. Agents that reduce the strength of oesophageal contraction, such as calcium antagon- ists, appear ineffective in hypertensive peristalsis. Oesophageal motor disorders secondary to systemic disease Oesophageal motility may be affected by a number of systemic diseases (Table 15.7.4). These diseases may affect the striated or smooth muscle itself or the neural control. The division of the oesophageal musculature into striated and smooth muscle components is revealed clearly by the myopathic diseases that affect the oesophageal musculature. In patients with peripheral myopathy this would normally have already been diag- nosed. Weak or absent oesophageal contraction in the affected seg- ment has the expected adverse impact on oesophageal transit, with a pattern of symptoms similar to the hypocontraction states of nonspecific oesophageal motor disorders (see earlier discussion). The management of these dysfunctions is along general lines (see ‘General management of oesophageal dysphagia’). Table 15.7.4  Systemic diseases associated with disturbance to oesophageal symptoms Systemic diagnosis Oesophageal symptom(s) Pathophysiology Rheumatological disorders Systemic sclerosis (limited and diffuse types) Dysphagia, heartburn, regurgitation, weight loss Oesophageal dysmotility, lower oesophageal sphincter incompetence, oesophagitis, columnar-​lined oesophagus Mixed connective tissue disease Dysphagia Oropharyngeal and body dysmotility Sjögren’s syndrome Dysphagia Xerostomia, oesophageal mucosal dryness Polymyositis/​dermatomyositis Dysphagia, nasal regurgitation, aspiration Oropharyngeal and body dysmotility Systemic lupus erythematosus Dysphagia, odynophagia Hypotone of the lower oesophageal sphincter, oesophageal
body dysmotility, pill oesophagitis Seronegative spondyloarthropathies Dysphagia Oesophageal body dysmotility Rheumatoid arthritis Dysphagia, odynophagia Oesophageal body dysmotility, oesophageal vasculitis, atlantoaxial subluxation Neuromuscular disorders Dysphagia, chronic aspiration, disordered phonation Oropharyngeal and oesophageal dysmotility Myotonic dystrophy Dysphagia Oropharyngeal and oesophageal dysmotility Myasthenia gravis Dysphagia Oropharyngeal and oesophageal dysmotility Chronic intestinal pseudo-​obstruction Dysphagia Oesophageal dysmotility Other disorders Vasculitic syndromes Dysphagia, odynophagia, chest pain, haematemesis Oesophageal vasculitis, ulcers, pharyngeal stenosis Diabetes mellitus Dysphagia Oesophageal dysmotility Alcohol abuse Dysphagia, odynophagia, heartburn Oesophageal dysmotility, oesophagitis, varices and haematemesis Infiltrative disorders (amyloidosis, sarcoidosis) Dysphagia Oesophageal dysmotility

SECTION 15  Gastroenterological disorders 2842 Diseases of oesophageal smooth muscle Systemic sclerosis (scleroderma) Definition and aetiology Sixty per cent of cases are limited cutaneous scleroderma, previ- ously called CREST (calcinosis, Raynaud’s syndrome, (o)esopha- geal dysphagia, sclerodactyly, telangiectasia) syndrome. The remaining 40% of cases are now termed diffuse cutaneous sclero- derma, with widespread involvement of other organs apart from the skin. The timing of onset of symptoms from oesophageal in- volvement are very variable in relation to other manifestations but are sometimes the presenting complaint. Oesophageal muscle atrophy and fibrosis are the cardinal features, but neuropathic ab- normalities may also contribute to dysfunction. Smooth muscle peristalsis and the tone of the lower oesophageal sphincter are feeble or absent (Table 15.7.4). Symptoms Troublesome reflux symptoms are the most common consequence of loss of function. The pattern of dysphagia resembles that seen in nonspecific oesophageal motor disorder (see ‘Nonspecific oesopha- geal motor disorders’). If dysphagia is severe, peptic stricture should be excluded, as complete loss of oesophageal smooth muscle peri- stalsis rarely leads to disabling dysphagia. Treatment Reflux disease is frequently severe and should be managed by high-​level medical therapy in order to prevent complications such as stricture (discussed earlier). Antireflux surgery is relatively contraindicated because of the poor propulsive function of the oesophageal body. Other rheumatological disorders A scleroderma-​like picture of oesophageal dysfunction is some- times seen in other connective tissue disorders such as mixed connective tissue disease. The smooth muscle segment is also involved in systemic myopathies including polymyositis–​ dermatomyositis and myotonic dystrophy. It should be remem- bered that in addition to effects on motility, rheumatological disorders may also lead to oesophageal symptoms via a combin- ation of effects including mucosal dryness and associated reflux disease (Table 15.7.4). Other disorders Abnormal oesophageal motility is common in diabetes mellitus, and may be a feature of amyloidosis, chronic alcoholism, and the pseudo-​obstructive syndrome. In these disorders, the disturbance is believed to be primarily due to dysfunction of neural control mechanisms. Disorders of striated muscle Involvement of the striated muscle segment of the oesophagus is rare and patients usually present with high dysphagia, often in association with oropharyngeal dysfunction. The inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis), the muscular dystrophies (myotonic dystrophy and oculopharyngeal dystrophy), and myasthenia gravis are the most common causes. General management of oesophageal dysphagia Symptomatic treatment of dysphagia is frequently necessary be- cause of the limited options and efficacy of specific treatments for oesophageal disorders. Although these measures may appear ob- vious, this aspect of management is commonly neglected by both patient and physician. Optimization of bolus consistency Large particles of solid food may impact on strictures. Large boluses require greater propulsive force even in the absence of stricture, and may trigger oesophageal spasm. Boluses should therefore be small and, in some circumstances, reduced to semiliquid or liquid form. Poor dentition should be treated. In some patients, defects of oe- sophageal function may be so severe that the diet should be puréed. Consultation with a dietitian will assist patients in identifying and preparing suitable food and in maintaining nutrition. Assistance with oesophageal transit Liquids assist transit by reducing the viscosity of food and providing a pressure head in the oesophagus. Gas generated within the oesopha- geal body from effervescent drinks can act as a piston which displaces oesophageal contents into the stomach in the erect position and may be sufficient to overcome an achalasic sphincter. The value of gravity in assisting transit should never be forgotten. Patients with severely impaired oesophageal transit should be advised to swallow medica- tions in the upright position and with plenty of water so as to avoid injurious contact of the oesophagus with potentially corrosive tablets. Alternative/​supplementary approaches to feeding Rarely, the earlier mentioned measures fail to maintain nutrition. Percutaneous endoscopic gastrostomy should then be used. Oesophageal neoplasms The two most frequently occurring malignancies of the oesophagus are adenocarcinoma and squamous cell carcinoma, defined ac- cording to the histopathological characteristics. Occasionally mixed cell types are seen. Cure is only possible in the small minority (<20%) of patients whose disease presents early. Several approaches are possible for palliation, although data are somewhat conflicting about the relative merits of each. Oesophageal adenocarcinoma and tumours of the gastro-​oesophageal junction Definition Over 80% of adenocarcinomas arising in the oesophagus occur in association with oesophageal columnar metaplasia, or Barrett’s oe- sophagus (Fig. 15.7.10). In the cases with no coincident Barrett’s, the oesophageal mucous glands or the adjacent gastric cardia mucosa are presumably the source of malignant change. Aetiology As discussed previously, columnar oesophageal metaplasia occurs in the context of chronic gastro-​oesophageal reflux disease, often manifest as heartburn symptoms. The incidence of oesophageal

15.7  Diseases of the oesophagus 2843 adenocarcinoma has increased rapidly in Western countries over the past 20 to 30 years, surpassing the incidence of squamous cell car- cinoma in these populations. The disease has a marked male prepon- derance. An increase in the prevalence of reflux disease related to the rise in obesity and reduced prevalence of H. pylori infection, with con- sequent increase in gastric acid secretion, are plausible explanations but not proven. In approximately 7% of cases, Barrett’s oesophagus and oesophageal adenocarcinoma occur within familial clustering, al- though the genetic causes remain unknown and more likely related to the cumulative effect of multiple low-risk genetic polymorphisms. Given the lethality oesophageal adenocarcinoma at symptomatic presentation, endoscopic screening should be considered in the pres- ence of multiple risk factors (obesity, reflux symptoms, male sex and white race), particularly in the presence of positive family history. Clinical features Dysplasia and carcinoma in situ are asymptomatic and this has led to discussions about screening in high-​incidence areas of the world. Inexorable progression of dysphagia to solids, and eventu- ally to liquids, over several weeks is the almost universal presenta- tion. Dysphagia usually occurs only when the tumour has become circumferential or bulky. Sometimes, malignant mucosal ulceration presents with pain. Substantial weight loss has often occurred by the time of presentation. Endoscopy and biopsy is the first investigation of choice. The lesion may be stricturing or exophytic. Multiple biopsies should be taken to avoid a missed diagnosis due to sampling bias. In stricturing lesions, dilatation for diagnostic purposes should be avoided if possible due to the risk of perforation. Biopsies can usu- ally be taken from the proximal portion of the stricture even if in- tubation is limited. If performed, a barium swallow typically reveals a stricture with an irregular, lobulated mucosal outline. However, it is important to note that occasionally the barium appearance mimics a benign peptic stricture, and with modern endoscopy enabling intubation under direct vision, prior barium examination is no longer required. Occasionally, an asymptomatic oesophageal carcinoma is diag- nosed when endoscopy is done for some other reason. Early lesions arising in Barrett’s mucosa may be inconspicuous endoscopically or be associated with a nodule or ulcer. Staging Staging using the TNM system is essential for all patients fit for radical therapy in order to optimize management. The staging mo- dalities and criteria of gastro-​oesophageal junction tumours will depend on whether the cancer is thought to arise primarily in the oesophagus or proximal stomach. CT scanning is very useful to determine nodal status and the presence of any distant metastases which most commonly affect the liver, lungs, adrenal glands and peritoneum. In order to obtain the best views the stomach should be distended with water before scanning (Fig. 15.7.11). In the absence of metastatic disease on the CT scan, endoscopic ultrasound should be performed to determine the degree of invasion through the oe- sophageal wall (T stage) (Fig. 15.7.12). Mediastinal or abdominal lymph nodes can also be assessed and sampled if necessary using fine needle aspiration. Positron emission tomography can provide fur- ther information on whether lymph nodes are involved and to char- acterize distant spread. Ideally this is now increasingly performed in combination with CT (CT-​PET). Bronchoscopy or thoracoscopy can be useful to look for signs of airway infiltration in proximal dis- ease and combined with fine needle aspiration if required. For tu- mours with a significant gastric component, a laparoscopy should also be performed to document whether there is involvement of the serosa and peritoneum. Management For disease limited to the mucosa, endoscopic therapy may be suf- ficient as the risk of nodal involvement is lower than the mortality rate of an oesophagectomy (<2%). In early-​stage disease extending into the submucosa and beyond, surgery is the treatment of choice as it achieves high rates of cure. The surgical approach depends on the location of the tumour. A transthoracic approach is standard (Ivor Lewis) but increasingly the operation is performed wholly or partially laparoscopically, with improved recovery times. Other options such as a transhiatal or Merendino operation have a lower morbidity if a less radical lymph node resection is required. If lymph nodes are involved (N1) or if the cancer is invading through the muscularis and into the adventitia (T3) then multimodal therapy is usually required. By the time the disease is stage T2, it is usually associated with lymph node involvement. Multimodal therapy generally involves neoadjuvant chemotherapy, which in- creasingly is combined with radiotherapy prior to surgery if the (b) (a) Fig. 15.7.10  Barrett’s associated adenocarcinoma: (a) demonstrates the endoscopic view in which tongues of salmon pink columnar lined mucosa are seen extending beyond the exophytic tumour mass; (b) is the corresponding endoscopic ultrasound image of this case in which the tumour is seen to invade through the muscularis (T3).

SECTION 15  Gastroenterological disorders 2844 patient is fit enough, based on improved survival from randomized clinical trial data. Molecular targeted therapies have lagged behind other cancer types due to the heterogeneity of the disease and the lag-​time for clinical trial data. The precise treatment algorithm will depend on the details of the individual case and the local expertise. Combined modality therapies have significant morbidity and mor- tality and an expert multidisciplinary approach, which takes into account quality of life issues for the patient, is required to achieve the best results. When curative treatment is not possible, palliation of dysphagia poses many challenges and the field is hampered by a lack of crit- ical comparisons. Surgery is not a good palliative option because of its morbidity and mortality. Radiotherapy applied as external beam or internal brachytherapy can provide useful relief from dysphagia. There may, however, be a temporary worsening of symptoms due to mucositis and nasogastric feeding may be required over this period. Peroral dilatation of malignant strictures, except prior to stent in- sertion, should be avoided due to the risk of perforation. Peroral placement of stenting tubes (usually covered, to prevent tumour ingrowth), laser photocoagulation, argon plasma coagulation, in- jection of sclerosants, and radiotherapy (external beam or brachy- therapy) are all options for the management of dysphagia which have potential for improving the quality of life. Laser and injection therapies can be useful when there is an exophytic tumour compo- nent, but are not supported by a strong evidence base. Stent insertion has the advantage of being a once-​only treatment with immediate effect, although pain after insertion can sometimes be a problem. Alternative endoscopic therapies can provide more physiological improvements in swallowing. Oesophagopulmonary fistula is a distressing development which usually causes pneumonia and persistent cough and which can sometimes be controlled by stenting. Bleeding can be managed with radiotherapy and sometimes argon plasma coagulation, or laser. (a) (b) Fig. 15.7.11  (a) Transaxial CT staging of a type 3 tumour of the gastro-​ oesophageal junction (primarily within the proximal stomach and extending into the oesophagus). (b) Reformatted view of a gastro-​oesophageal junction tumour with extensive involvement of lower oesophagus extending into the proximal stomach with proximal oesophageal dilatation. Courtesy of Dr Nicholas Carroll, Consultant Radiologist, Addenbrooke’s Hospital Cambridge. (a) (b) Fig. 15.7.12  Lugol’s iodine spray reveals early squamous cell carcinoma as seen by white light (a). On narrow-band imaging with magnification the irregular vascular pattern can be highlighted and suggests superficial mucosal invasion (b).

15.7  Diseases of the oesophagus 2845 Embolization of relevant arteries should also be discussed with an interventional radiologist. Palliative chemotherapy can increase survival and help symptoms in carefully selected patients fit enough to withstand the treatment. This can be combined with HER2 inhibitors in ERBB2 amplified cases with a significant gastric component. Other critical aspects of palliative care include pain control as well as nutritional advice and support (e.g. oral supplements) which are best done within the con- text of an expert multidisciplinary team. Prognosis This remains dismal except where screening programmes identify early, asymptomatic cases. In patients presenting with symptomatic disease, only about one-​quarter of patients are deemed to be poten- tially curable by surgery, and the overall 5-​year survival rate is ap- proximately 13% for all comers, increasing to 30% in those treated with curative intent. Squamous cell carcinoma Squamous cell carcinoma has marked geographical variation. It is common in the developing world with an annual incidence of 6 in 100 000 men and 1.6 in 100 000 women. There are areas of especially high incidence (northern China, northern Iran, Kazakhstan, and the Transkei region of South Africa with >35/​100 000 cases per year). Its incidence is stable in Western countries where it is six times more common in black men than in white men. Aetiology The striking geographical variation in incidence suggests a major aetiological contribution from environmental factors. The risk fac­tors include heavy alcohol use, tobacco, and dietary factors such as high rates of consumption of very hot beverage and dietary carcinogens (nitrosamines and aflatoxins). Other factors implicated are previous treatment for head and neck cancers, Plummer–​Vinson syndrome, human papilloma virus infection, vitamin A deficiency, chronic can- dida infection, injury to the oesophageal mucosa due to ingestion of a corrosive substance years previously, and chronic irritation from oe- sophageal retention in achalasia. Invasive carcinoma is preceded by mucosal dysplasia and carcinoma in situ and there may be a lag phase of many years which affords the possibility for screening in high-​risk regions. Some patients may be genetically predisposed to this cancer. The best-​documented example is tylosis, which is an autosomal dom- inant condition with associated palmar and plantar hyperkeratosis. Linkage studies suggest that the causative gene is IRHOM2 which res- ides on chromosome 17q25. Symptoms and staging The presentation and investigation algorithms for squamous cell carcinoma are essentially as described for adenocarcinoma. Patients may present to the ear, nose, and throat department if the dysphagia is very high or if hoarseness is a key symptom. Orolaryngosocopy may reveal the cause but flexible oesophagoscopy is usually required and should not be delayed in a patient with progressive dysphagia. In very high-​risk areas, screening programmes have been set up which generally hinge on standard endoscopy coupled with Lugol’s iodine spray to highlight dysplastic mucosa for targeted bi- opsies. Nonendoscopic sampling methods have generally had low sensitivity and specificity due to reliance on a cytological diagnosis of atypia (Fig. 15.7.12). Management The treatment is essentially similar for all oesophageal malignan- cies. Squamous carcinomas are generally more radiosensitive than adenocarcinomas and chemoradiotherapy can be given as definitive treatment either alone or combined with surgery as triple modality therapy. Again, the precise algorithm will depend on the details of the individual case and the local expertise. Unfortunately, for many patients palliative therapy is all that can be offered. Critical aspects of palliative care include pain control as well as nutritional advice and support (e.g. oral supplements) which can be problematic for prox- imal cancers and are again best done within the context of an expert multidisciplinary team. Prognosis As for adenocarcinoma, this remains dismal except where screening programmes identify early, asymptomatic cases. The overall 5-​year survival rate is less than 20%. Other primary oesophageal tumours Other primary malignant tumours are rare and all have a poor prog- nosis. These include malignant melanoma, lymphoma, carcinoid, leiomyosarcoma, neuroendocrine carcinoma (small cell carcinoma), adenoid cystic carcinoma, and pseudosarcoma reflecting the cell types present within the oesophagus. These tumours show a mix- ture of polypoid and infiltrating features and are usually only clearly distinguished from the more common malignancies by histology. Although rare in the oesophagus, gastrointestinal stromal tu- mours (which were previously classified as smooth muscle tumours) can also occur and have a varying degree of malignant potential. Approximately one-​half of patients are asymptomatic and the re- mainder exhibit symptoms which may include dysphagia, retro- sternal chest pain, pyrosis, cough, odynophagia, and weight loss. Bleeding is unusual, in contrast to gastric gastrointestinal stromal tumours. They are usually intramural but can become peduncu- lated and they usually only cause symptoms if they are very large, or on a long pedicle. On endoscopy the mucosa is intact but there may be central umbilication or ulceration. Because of the submucosal nature of the lesion, biopsy is often negative and endoscopic ultra- sonography is a useful diagnostic tool which can be combined with fine needle aspiration. The majority have a gain-​of-​function muta- tion of the proto-​oncogene growth factor receptor c-​Kit. The malig- nant potential is determined by the size, mitotic index, and precise mutation. Most small lesions do not require treatment. Surgery should be considered in symptomatic patients or when the risk of malignant transformation is high. Treatment with a tyrosine kinase inhibitor can be useful for metastatic disease and is tailored to the specific mutation. Benign intramural tumours of the oesophagus include lipomas, leiomyomas and granular cell tumours. The main risk of these is that they are mistaken for malignant tumours and operated on inappropriately. Squamous cell papillomas of the mucosa can mimic a polypoid squamous carcinoma and so should be removed endoscopically for histological diagnosis.

SECTION 15  Gastroenterological disorders 2846 Extrinsic oesophageal compression This is a relatively common cause of dysphagia, and is most often a result of malignant mediastinal lymphadenopathy. Barium swallow or endoscopy usually shows a relatively long constriction of the oesophageal lumen of variable calibre, associated with a normal mucosal appearance. Dilatation of such a compression is usually unrewarding because of its elastic recoil. Mechanically significant extrinsic compression may also result from an enlarged heart, a di- lated or unfolded aorta, or an aortic aneurysm. Kyphosis may ac- centuate the mechanical impact of these abnormalities. Mechanical changes along the cervical spine can also interfere with swallowing such as atlantoaxial spurs, osteophytes associated with osteoarth- ritis, and Forestier’s disease. In patients with rheumatoid arthritis, atlantoaxial joint subluxation can lead to dysphagia and other signs of spinal cord compression (Table 15.7.4). Congenital vascular ab- normalities can also compress the oesophagus in adults, an aber- rant right subclavian artery being by far the most common. Mechanical, chemical, and radiation trauma Mallory–​Weiss tear These mucosal tears extend across the gastro-​oesophageal junction and are normally induced by vigorous straining associated with vomiting. Bleeding is the only consequence of significance. In 10% of cases, bleeding is severe enough to cause hypovolaemia. The his- tory is usually quite characteristic, but definitive diagnosis requires endoscopy. Continued bleeding usually responds to endoscopic in­jection or haemostatic clipping, electrocoagulation, vascular em- bolization, or vasopressin infusion. Very rarely, surgery is needed to under-​run a persistently bleeding artery at the base of the tear. Barogenic oesophageal rupture (Boerhaave’s syndrome) In this uncommon but serious condition, straining and vomiting cause oesophageal rupture, most often in the left lower third of the oesophagus. High-​volume spillage of the gastric contents into the pleural space causes shock and pain in the chest and upper abdomen with radiation to the back, left chest, or shoulder. The chest radio- graph becomes abnormal only some hours after rupture. Surgical repair and drainage are usually necessary, and if this is delayed be- yond 24 h the mortality is very high. Unfortunately, diagnostic delay is not unusual. Iatrogenic oesophageal perforation Physicians encounter this problem most often as a result of their involvement in dilatation of oesophageal strictures, pneumatic bag dilatation for achalasia, endoscopic resection of early oesophageal tumours, or through problems with the management of oesopha- geal varices by balloon tamponade. Even with meticulous technique and appropriate equipment, oesophageal perforation can occur. Perforation is strongly suggested by development of chest or epigas- tric pain directly after instrumentation, sometimes with dyspnoea. Pneumothorax and surgical emphysema are diagnostic. Any suspi­ cion of perforation should be acted upon by performing CT scan- ning with Gastrografin. This can demonstrate the presence of air in the mediastinum or direct leakage of water soluble contrast. Broad-​ spectrum antibiotics should be given on suspicion, as they are most effective in minimizing the risks of mediastinitis when given from the outset. Surgical consultation should occur promptly; the choice between conservative and surgical management needs to be indi- vidualized. Increasingly, instrumental perforation is being managed nonsurgically with nasogastric suction, antibiotics, and intravenous nutrition with good results, primarily because instrumental injury usually occurs when the stomach is empty. Metal clipping can be applied if the perforation is promptly recognized during the endo- scopic procedure to aid mucosal healing. Caustic ingestion Definition and aetiology Strong acids and alkalis are both very damaging to the oesophagus and are found in high concentrations in many agents commonly used in the household for cleaning and maintenance. Laryngeal and gastric injuries may overshadow oesophageal injury. Because of their relative lack of taste, alkaline solutions are more likely to be swallowed ac- cidentally in large amounts. Alkaline injury is especially deep; acid tends to form a superficial coagulant, which limits penetration. Symptoms The severity and extent of injury are immensely variable and cannot be predicted accurately from estimates of the volume ingested. Around one-​half of patients with a history of caustic ingestion have no significant injury. Oropharyngeal and laryngeal injury confirm caustic ingestion and can be a major threat to the airway, but do not predict the existence and severity of oesophageal injury which causes odynophagia, dysphagia, or haematemesis. Prompt fibreoptic pan-​endoscopy appears to be safe. This may be normal or show only patchy mucosal oedema, erythema, and small haemorrhagic ulcers, indicative of superficial damage with a good prognosis. Extensive and circumferential ulceration, and grey or brown/​black ulceration suggest transmural injury. Management Patients with severe injury must be observed closely for signs of perforation. Nasogastric suction should be used with the admin- istration of broad-​spectrum antibiotics as these appear to reduce the severity of infective complications. The use of steroids is con- troversial, the balance of evidence tending to oppose their use. Oesophageal stricture is to be expected with severe injury and ap- pears not to be prevented by routine dilatation in the first 2 weeks after injury. A barium study should be done at 2 to 3 weeks to screen for stricturing, and then subsequently at about 3-​monthly intervals thereafter for a year, so that the development of stricturing is rec- ognized at a stage when dilatation may have some impact. Prognosis The main short-​ to medium-​term risk is the development of stric- ture. Caustic strictures are difficult and hazardous to treat by peroral dilatation so that about half of patients require oesophageal resec- tion. In the long term (average onset 40  years after injury), car- cinoma of the oesophagus is a major hazard, the risk being 1000 to 3000 times the expected risk.

15.7  Diseases of the oesophagus 2847 Oesophageal problems caused by oncological therapies Chemotherapy causes oesophageal problems in several ways. Therapy may impair mucosal defences by affecting cell turnover leading to ‘mucositis’. This in turn may reduce resistance of the mucosa to damage from other agents, and increase susceptibility to infective oesophagitis from immune suppression. Oesophageal transit and acid clearance may be impaired through the neuro- toxic effects of some agents. Fistulation or perforation may occur through cytotoxic effects on a malignancy in the oesophageal wall. It has been reported that combination chemotherapy is associ- ated with the development of oesophageal columnar metaplasia in women being treated for breast cancer. Radiotherapy as treat- ment of oesophageal malignancy or for lung, breast or other me- diastinal tumours can induce chronic oesophageal inflammation (radiation oesophagitis). This can cause dysphagia and chest pain. Endoscopic findings corroborated by the oncological history are sufficient for the diagnosis. However, radiation oesophagitis can occasionally cause stricture and mimic the endoscopic appearance of oesophageal cancer. In these cases endoscopic biopsies help in the differential diagnosis. Other non-​neoplastic mucosal diseases Skin and systemic diseases associated with lesions of the oropharynx may also involve the oesophagus. These include epidermolysis bullosa, Behçet’s disease, lichen planus, pemphigus vulgaris, bullous pemphigoid, benign mucous membrane (cicatrial) pemphigoid, and drug-​induced disease (Stevens–​Johnson syndrome and toxic epi- dermal necrolysis). Chronic, and less frequently acute, graft-​versus-​host disease may cause severe oesophageal problems through mucosal desquamation or mural damage. Resultant stricturing shows considerable variation in appearance. Rarely, Crohn’s disease can cause indolent, craggy ulceration and/​or stricturing. Oesophageal sarcoidosis can mimic Crohn’s disease. FURTHER READING Bhat S, et  al. (2011). Risk of malignant progression in Barrett’s esophagus patients:  results from a large population-​based study.
J Natl Cancer Inst, 103, 1049–​57. Blaydon DC, et  al. (2012). RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet, 90, 340–​6. Boeckxstaens GE, et  al. (2011). Pneumatic dilation versus laparo- scopic Heller’s myotomy for idiopathic achalasia. N Engl J Med, 364, 1807–​16. Boerwinkel DF, et al. (2014). The clinical consequences of advanced imaging techniques in Barrett’s esophagus. Gastroenterology, 146, 622–​9. Clouse R, Diamant N (2006). Motor function of the esophagus. In: Johnson L (ed.) Physiology of the gastrointestinal tract, 4th edi- tion, pp. 913–​26. Elsevier, Boston, MA. Cowgill SM, et al. (2007). Ten-​year follow up after laparoscopic Nissen fundoplication for gastroesophageal reflux disease. Am Surg, 73, 748–​52. Decalmer S, et  al. (2012). Chronic cough:  relationship between microaspiration, gastroesophageal reflux, and cough frequency. Chest, 142, 958–​64. Dellon ES, et al. (2013). ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosino- philia and eosinophilic esophagitis (EoE). Am J Gastroenterol, 108, 679–​92. Desai TK, et al. (2011). The incidence of oesophageal adenocarcinoma in non-​dysplastic Barrett’s oesophagus:  a meta-​analysis. Gut, 61, 970–​6. Desai TK, et al. (2012). The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett’s oesophagus: a meta-analysis. Gut, 61(7), 970–6. Di Pietro M, et  al. (2015). Screening for Barrett’s Esophagus. Gastroenterology, 148(5), 912–23. Ellis FH Jr. (1998). Long esophagomyotomy for diffuse esophageal spasm and related disorders: an historical overview. Dis Esophagus, 11, 210–​14. Enzinger PC, Mayer RJ (2003). Esophageal cancer. N Engl J Med, 349, 2241–​52. Falk GWM, Fennerty B, Rothstein RI (2006). AGA Institute technical review on the use of endoscopic therapy for gastroesophageal reflux disease. Gastroenterology, 131, 1315–​36. Fang Y, et al. (2013). Cellular origins and molecular mechanisms of Barrett’s esophagus and esophageal adenocarcinoma. Ann N Y Acad Sci, 1300, 187–​99. Fitzgerald RC, Triadafilopoulos G (1997). Esophageal manifestations of rheumatic disorders. Semin Arthritis Rheum, 26, 641–​66. Fitzgerald RC, et al. (2014). British Society of Gastroenterology guide- lines on the diagnosis and management of Barrett’s oesophagus. Gut, 63, 7–​42. Frankell AM, et al. (2019). The landscape of selection in 551 esopha- geal adenocarcinomas defines genomic biomarkers for the clinic. Nat Gen, 51(3), 506–16. Galmiche JP, et  al. (2006). Functional esophageal disorders. Gastroenterology, 130, 1459–​65. Galmiche JP, et  al. (2011). Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. JAMA, 305, 1969–​77. Giuliano C et al. (2012). Are proton pump inhibitors associated with the development of community-​acquired pneumonia? A  meta-​ analysis. Expert Rev Clin Pharmacol, 5, 337–​44. Harvey PR, et al. (2019). Outcomes of pneumatic dilatation and Heller’s myotomy for achalasia in England between 2005 and 2016, Gut, Jan 3. Hvid-​Jensen F, et al. (2011). Incidence of adenocarcinoma among pa- tients with Barrett’s esophagus. N Engl J Med, 365, 1375–​83. Hobson AR, et al. (2006). Neurophysiologic assessment of esopha- geal sensory processing in noncardiac chest pain. Gastroenterology, 130, 80–​8. Jankowski JAZ, et al. (2018). Esomeprazole and aspirin in Barrett’s oesophagus (AspECT): a randomised factorial trial. Lancet, 392(10145), 400–8. Kahrilas PJ, et al. (2015). The Chicago Classification of esophageal mo- tility disorders, v3.0. Neurogastroenterol Motil, 27, 160–​74. Kahrilas PJ (2017). Expert consensus document: Advances in the management of oesophageal motility disorders in the era of high- resolution manometry: a focus on achalasia syndromes. Nat Rev Gastroenterol Hepatol, 14(11), 677–88. Katz PO, et al. (2013). Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol, 108, 308–​28.

SECTION 15  Gastroenterological disorders 2848 Lagergren J, et al. (1999). Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med, 340, 825–​31. Liacouras CA, et al. (2011). Eosinophilic esophagitis: updated con- sensus recommendations for children and adults. J Allergy Clin Immunol, 128, 3–​20.e6. Mainie I, et al. (2006). Acid and non-​acid reflux in patients with per- sistent symptoms despite acid suppressive therapy:  a multicentre study using combined ambulatory impedance-​pH monitoring. Gut, 55, 1398–​402. Malfertheiner P, et al. (2005). Prognostic influence of Barrett’s oe- sophagus and Helicobacter pylori infection on healing of erosive gastro-​oesophageal reflux disease (GORD) and symptom reso- lution in non-​erosive GORD: report from the ProGORD study. Gut, 54, 746–​51. Matthews PJ, Aziz Q (2005). How useful are proton-​pump inhibitors for diagnosis and therapy of patients with noncardiac chest pain? Nat Clin Pract Gastroenterol Hepatol, 2, 506–​7. Mulhall BP, Wong RK (2003). Infectious esophagitis. Curr Treat Options Gastroenterol, 6, 55–​70. National Institute for Health and Care Excellence (2014). Dyspepsia and gastro-​oesophageal reflux disease: Investigation and management of dyspepsia, symptoms suggestive of gastro-​oesophageal reflux di­ sease, or both. http://​www.nice.org.uk/​guidance/​cg184 Ngamruengphong S, et al. (2011). Proton pump inhibitors and risk of fracture: a systematic review and meta-​analysis of observational studies. Am J Gastroenterol, 106, 1209–​18. Pandolfino JE, et al. (2006). Obesity: a challenge to esophagogastric junction integrity. Gastroenterology, 130, 639–​49. Pandolfino JE, et al. (2006). Transient lower esophageal sphincter re- laxations and reflux: mechanistic analysis using concurrent fluor- oscopy and high-​resolution manometry. Gastroenterology, 131, 1725–​33. Pech O, et al. (2014). Long term efficacy and safety of endoscopic re- section for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology, 146, 652–​60. Peery AF, et al. (2015). Burden of Gastrointestinal, Liver, and Pancreatic Diseases in the United States. Gastroenterology, 149, 1731–​41. Phoa KN, et al. (2014). Radiofrequency ablation vs endoscopic surveil- lance for patients with Barrett esophagus and low-​grade dysplasia: a randomized clinical trial. JAMA, 311, 1209–​17. Rastogi A, et al. (2007). Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-​grade dysplasia: a meta-​ analysis. Gastrointest Endosc, 67, 394–​8. Ross WA, et al. (2007). Evolving role of self-​expanding metal stents in the treatment of malignant dysphagia and fistulas. Gastrointest Endosc, 65, 70–​6. Ross-​Innes CS, et  al. (2015). Whole-​genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma. Nat Genet, 47, 1038–​46. Ruigómez A, et al. (2007). Endoscopic findings in a cohort of newly diagnosed gastroesophageal reflux disease patients registered in a UK primary care database. Dis Esophagus, 20, 504–​9. Scottish Intercollegiate Guidelines Network (SIGN) (2006) Manage­ ment of oesophageal and gastric cancer. http://​www.sign.ac.uk Shaheen NJ, et  al. (2009). Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med, 360, 2277–​88. Shapiro J, et al. (2015). Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol, 16(9), 1090–8. Sharma P, et al. (2006). The development and validation of an endo- scopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology, 131, 1392–​9. Sheikh M, et al. (2019). Individual and Combined Effects of Environ­ mental Risk Factors for Esophageal Cancer Based on Results From the Golestan Cohort Study. Gastroenterology, Jan 3. Spechler SJ (2007). Screening and surveillance for Barrett’s esophagus—​an unresolved dilemma. Nat Clin Pract Gastroenterol Hepatol, 4, 470–​1. Vakil N, et al. (2006). The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-​based consensus. Am J Gastroenterol, 101, 1900–​20. Weber CE, et al. (2012). Medium and long-​term outcomes after pneu- matic dilation or laparoscopic Heller myotomy for achalasia: a meta-​ analysis. Surg Laparosc Endosc Percutan Tech, 22, 289–​96. Young PE, et  al. (2010). Endoscopic ultrasound does not accur- ately stage early adenocarcinoma or high-​grade dysplasia of the esophagus. Clin Gastroenterol Hepatol, 8, 1037–​41. Zendehdel K, et  al. (2007). Risk of esophageal adenocarcinoma in achalasia patients, a retrospective cohort study in Sweden. Am J Gastroenterol, 102, 1–​5.

15.8 Peptic ulcer disease 2849

15.8 Peptic ulcer disease 2849

ESSENTIALS Helicobacter pylori infection, use of nonsteroidal anti-​inflammatory drugs (NSAIDs) including aspirin, and smoking are the most im- portant causes of peptic ulcer disease. Peptic ulcer disease is characterized by a history of waxing and waning symptoms of localized, dull, aching pain in the upper ab- domen. Bleeding is the most common complication; free perfor- ation of the stomach or duodenum into the peritoneal cavity is uncommon but serious. The diagnosis of peptic ulcer disease is made by endoscopy, which offers an opportunity for biopsy of gastric ulcers (which may be ma- lignant) and reveals important prognostic indicators in patients with bleeding ulcers. A single daily dose of a proton pump inhibitor gives quick relief of symptoms and effective healing of peptic ulcers in 4 to 6 weeks. The management of patients with upper gastrointestinal haem- orrhage requires a multidisciplinary medical and surgical approach. Early risk stratification based on clinical and endoscopic criteria al- lows delivery of appropriate care, with endoscopic intervention now widely accepted as the first line of therapy. This should be followed by administration of a high dose of an intravenous proton pump in- hibitor to further reduce recurrent bleeding. Treatment of H. pylori is a cure for peptic ulcer disease in most patients. This usually requires at least two antimicrobial agents, with the most popular triple therapy combining a proton pump inhibitor with any two of amoxicillin, metronidazole, and clarithromycin for 7 to 14 days. Eradication of H. pylori infection, avoidance of high-​dose NSAIDs or aspirin, and the maintenance use of proton pump inhibi- tors in high-​risk individuals are the best ways to prevent recurrence of ulcer and ulcer complications. Introduction Peptic ulcer is defined as a distinct breach in the mucosa of the gastrointestinal tract as a result of caustic effects of acid and pepsin in the lumen. The term ‘peptic ulcer disease’ usually refers to ul- ceration of the stomach, duodenum, or both but it can also occur in the oesophagus in gastro-​oesophageal reflux disease and in the distal ileum as a result of a Meckel’s diverticulum lined with an acid-​ secreting gastric epithelium. Histologically, peptic ulcer is identi- fied as necrosis of the mucosa extending through the muscularis mucosae into the submucosa. In the endoscopic or radiological view, there is an appreciable depth of the lesion. When the break of epithe- lial lining is confined to the mucosa without penetrating through the muscularis mucosae, the superficial lesion is called ‘erosion’. For more than a century, peptic ulcer disease has been a major cause of morbidity and mortality. The Schwarz dictum introduced in 1910 says ‘no acid, no ulcer’, indicating that the presence of acid is essential for peptic ulceration. Indeed, peptic ulcers rarely develop in patients with achlorhydria. Thus the therapy has always been fo- cused on acid neutralization or suppression of acid secretion. The discovery of Helicobacter pylori in the highly acidic environment by Marshall and Warren in 1984 has revolutionized the concept of ulcerogenesis. In many cases, peptic ulcer disease is an infectious disease which can be cured by a single course of antimicrobial therapy. In recent decades, however, there has been a rapid change in the epidemiology of peptic ulcer disease. With the improvement in sanitary conditions in many countries, there has been a dramatic de- cline in H. pylori infection and hence the associated peptic disease in the stomach and duodenum. On the other hand, with the increasing use of aspirin and nonsteroidal anti-​inflammatory drugs (NSAIDs), a new epidemic of peptic ulcer disease and complications has arisen. Our understanding of peptic ulcer disease is not complete. With the decline of H. pylori infection, peptic ulcers emerge that are not re- lated either to H. pylori or to NSAIDs. Aetiology, pathogenesis, and pathology Gastric acid and pepsin Despite the importance of H. pylori infection and ulcerogenic drugs such as NSAIDs and aspirin as the initiating events in the devel- opment of peptic ulcer disease, gastric acid and pepsin remain the ultimate injurious factors in the development of peptic ulcers. Ulceration is a result of an imbalance between the damaging effects of acid and pepsin and the defensive effects of bicarbonate and mucin 15.8 Peptic ulcer disease Joseph Sung

SECTION 15  Gastroenterological disorders 2850 on the mucosal surface. Factors that may account for increased se- cretion of acid and pepsin include increased parietal cell mass, in- creased stimulation of acid secretion (e.g. gastrin), increased parietal cell sensitivity to stimuli, and attenuated inhibition of acid secretion (e.g. somatomedin). Patients with peptic ulcer disease often have higher parietal cell mass, leading to increased basal and nocturnal unstimulated acid output as well as peak acid output under stimu- lation by food and gastrin. Several of these abnormal physiological responses are probably related to H. pylori infection (hypersecretion of gastrin, raised basal and gastrin-​releasing peptide-​stimulated acid output, decreased inhibitory drive mediated by somatostatin and hypersecretion of pepsinogen) as they disappear after successful cure of H. pylori infection. It is known that even peptic ulcer disease induced by NSAIDs or aspirin is an acid-​dependent process. In the low secretory state, NSAID and aspirin exposure are less likely to induce peptic ulcer in the upper gastrointestinal tract. With high exposure to gastric acid, epithelium of the duodenal bulb develops gastric metaplasia. Wyatt and colleagues postulated that gastric metaplasia is essential for the colonization of H. pylori in the duodenum and subsequent development of duodenal ulcer- ation. H. pylori is found colonizing only part of the duodenum with gastric metaplasia, setting off duodenitis and eventually duodenal ulcer. However, the data for the correlation of intragastric pH with occurrence of gastric metaplasia in the duodenum are inconsistent. Duodenal bicarbonate secretion Patients with duodenal ulcer are found to have impaired bicar- bonate secretion in the proximal duodenum in the face of influx of gastric acid. This impaired response is reversed by the eradication of H. pylori. The mechanism by which H. pylori hampers duodenal bicarbonate secretion is not understood. One proposed mechanism is that nitric oxide synthase activity in the duodenum interferes with bicarbonate secretion. Helicobacter pylori Since the discovery of H. pylori in the stomach of patients with gastritis and peptic ulcer, this bacteria has been reported in approximately 90% of cases of duodenal ulcer and 60% of cases of gastric ulcer. H. pylori is a slow-​growing, microaerophilic, highly motile, Gram-​negative spiral organism aetiologically linked to gastritis, peptic ulcer disease, gastric lymphoma, and adenocarcinoma of the stomach. H. pylori infection has a long latent period before symptomatic disease appears. H. pylori is tropic for gastric epithelium (i.e. stomach and areas of gastric meta- plasia outside the stomach) and is found either attaching to the surface epithelium through a pedestal or dwelling within the mucous coating on the surface of gastric epithelium. A very small proportion of or- ganisms can be found intracellularly, but the significance of this in relation to the inflammatory response and evasion of antimicrobial therapy is still under investigation. H. pylori infection elicits robust chronic active inflammatory and immune responses that continue throughout life. H. pylori produces abundant amount of urease, which is important for its colonization and survival in the stomach. H. pylori infection is primarily acquired in childhood, such that the prevalence at the age of 20 approximates the prevalence of that birth cohort throughout life. Acquisition during adulthood is rare, with estimates ranging from 0.3 to 0.5% per year, and recurrence of infection after successful eradication is therefore uncommon. The primary mode of transmission is person to person, probably via a gastro-​oral route (through vomitus) or oro-​oral route (through contamination of saliva). There are links between the bacterial geno- type, its virulence factor, and the development of gastroduodenal disease. CagA, a 120-​ to 140-​kDa highly antigenic protein, is en- coded by the cagA gene as part of the cag pathogenicity island. In Western countries, 60 to 80% of H. pylori express CagA, compared to 90% of isolates from Asian patients. The presence of the cag pathogenicity island is associated with a more prominent inflamma- tory tissue response than is seen with strains lacking this virulence factor. This increase in inflammation is associated with an increased risk of developing of peptic ulcer disease and adenocarcinoma of the stomach. The cag pathogenicity island encodes a type IV secretory apparatus that injects CagA and possibly other bacterial proteins into mammalian cells. CagA undergoes phosphorylation in the cell and is responsible for the changes in actin polymerization seen in the infected cell, resulting in conformational change. Besides cyto- skeletal changes, CagA also enhances inflammatory response which is mediated through NF-​κB. Attachment of H. pylori to the cell is re- quired for cagA-​positive H. pylori to elicit an interleukin-​8 (IL-​8) re- sponse in the gastrointestinal epithelium triggering gastritis. Beside CagA, approximately 50% of H. pylori strains produce a protein that induces vacuole formation in eukaryotic cells. This protein, which is called VacA, has been purified and the gene vacA has been cloned. The vacA gene has two families of alleles of the middle region (m1, m2) and at least three families of alleles of the signal sequence (s1a, s1b, s2). The vacA genotype s1 is strongly, but not exclusively, associ- ated with the cagA gene. So far, studies have not found an important role for VacA in relation to histological findings, or risk of H. pylori-​ related disease. The function of VacA remains unclear. Despite the establishment of a strong association between H. pylori infection and peptic ulcer disease, it is still unclear why some pa- tients develop duodenal ulcer and others gastric ulcer. McColl and El-​Omar proposed an intriguing paradigm (Fig. 15.8.1). In patients Gastrin ↑ Gastrin ↑ No atrophy Atrophy, cancer H. pylori infection DU GU or gastric cancer Acid ↓ Acid ↑ Body predominant gastritis Antral predominant gastritis Fig. 15.8.1  Association between pattern of H. pylori gastritis and disturbance in gastric physiology. Antral-​predominant gastritis is associated with duodenal ulcer (DU), body-​predominant gastritis with gastric ulcer (GU) or cancer. Modified from McColl KEL, El-​Omar E (2000). Mechanism involved in the development of hypochlorhydria and pangastritis in Helicobacter pylori infection. In: Hunt RH, Tytgat GNJ (ed) Helicobacter pylori: basic mechanisms to clinical cure. Kluwer, Dordrecht.

15.8  Peptic ulcer disease 2851 with duodenal ulcer, H. pylori colonizes mainly the antrum. The antral-​predominant gastritis stimulates production of gastrin-​ releasing peptide, triggering secretion of gastrin leading to exces- sive output of gastric acid. Profuse amount of acid flooding in the duodenum leads to gastric metaplasia, which allows colonization of H. pylori in the duodenum. This sets up an intense inflammation in the duodenum, further weakening mucosal protection and eventu- ally developing into duodenal ulcer. On the other hand, in patients with gastric ulcer, H. pylori is often found throughout the entire body of the stomach, leading to diffuse gastritis. The intense inflam- mation in the body of stomach tends to reduce gastric acid secre- tion as a result of glandular atrophy. In these patients other bacterial virulence factors come into play, leading to development of either gastric ulcer or adenocarcinoma in the distal stomach. Although this schema is probably oversimplified, it provides a broad-​brush picture explaining how an infection can induce two distinctly dif- ferent diseases. The ultimate proof of a causal relationship between H.  pylori and peptic ulcer disease comes from interventional studies. If peptic ulcer disease is merely a result of altered gastric physiology in bacterial infection, eradication of H. pylori in the stomach and duodenum should rectify the physiological change and cure the dis- ease. And, if reinfection with H. pylori is rare, peptic ulcer disease should not recur. Indeed, this has been proved in clinical trials. In a study that randomized duodenal ulcer patients to receive either 1-​week bismuth triple therapy or bismuth triple therapy plus 4-​week therapy with proton pump inhibitor, ulcers healed in 90 to 95% of cases with or without acid suppressive therapy. Similarly, when non-​ NSAID-​related gastric ulcer was treated by 1-​week bismuth triple therapy or 4-​week proton pump inhibitor therapy, ulcer healing was higher with anti-​Helicobacter therapy. More importantly, ulcer re- currence was much lower after patients received anti-​Helicobacter therapy with successful eradication than with a full course of proton pump inhibitor. Studies have also shown that peptic ulcer bleeding and bowel perforation does not recur, obviating the need for acid-​ reduction surgery. Ulcerogenic drugs In the last three decades, NSAIDs and antiplatelet agents have be- come increasingly important as a cause of peptic ulcer disease. It has been estimated that NSAIDs and aspirin increase the risk of gastric ulcer fourfold and the risk of gastrointestinal bleeding threefold. The risk of drug-​induced peptic ulcer is substantially higher in older people and those with previous history of peptic ulcer disease. Patients who are taking concomitant NSAIDs, as- pirin, anticoagulants, and corticosteroids are also exposed to a higher risk of peptic ulcer disease. H. pylori infection further in- creases the risk of peptic ulcer and ulcer complication in users of NSAIDs and aspirin. Aspirin and acidic NSAIDs were initially believed to have only a topical injurious effect by direct damage to the gastric epithelium as a result of intracellular accumulation of these drugs in an ionized state. However, the fact that enteric-​coated formulations, prodrugs, and systemic administration of NSAIDs fail to reduce the frequency of gastroduodenal ulceration implies that the chief mechanism of in- jury might not be a local action. NSAIDs reduce the hydrophobicity of mucous gel on the intestinal epithelium and this may hamper the defensive mechanism of the gut. The most important mechanism of drug-​induced peptic ulcer disease is inhibition of prostaglandin synthesis by NSAIDs. Prostaglandins regulate mucosal blood flow, epithelial cell proliferation, and basal acid secretion as well as mucus and bicarbonate secretion. The rate-​limiting enzyme in prosta- glandin synthesis is cyclooxygenase (COX). Most NSAIDs are found to suppress prostaglandin synthesis via reversible inhibition of COX, but aspirin acetylates COX and inhibits its enzyme activity irrevers- ibly in a dose-​dependent manner. In the early 1990s, two struc- turally related COX isoforms, COX-​1 and COX-​2, were identified. COX-​1 is found in most of the body’s tissues, including the gastro- intestinal tract and the kidney, and COX-​2 is an inducible enzyme produced principally in inflammation. The discovery of these iso- forms has prompted the development of COX-​2 selective inhibitors as anti-​inflammatory analgesics, with the aim of protecting against gastrointestinal damage. Yet this approach is an oversimplification, as evidence indicates that both COX-​1 and COX-​2 must be inhibited for gastric ulceration to occur. Selective suppression of COX-​1 does not cause gastric damage. Clinical trials have shown that COX-​2 selective inhibitors cause less peptic ulcer and ulcer bleeding than nonselective NSAIDs. Yet, in high-​risk patients with a history of peptic ulcer disease, ulcer complication as a result of using COX-​2 selective inhibitors is still a possibility. Gastric acid exacerbates NSAID injury by disrupting the base- ment membrane to produce deep injury, impairing platelet aggre- gation and potentiating enzymatic erosion of pepsin. It is therefore logical that suppression of acid secretion by potent agents such as proton pump inhibitors can confer at least partial protection against injury induced by NSAIDs and aspirin. More recently, attention has been focused on the role of nitric oxide in maintenance of intestinal mucosal blood flow. Like pros- taglandins, nitric oxide has been shown to increase blood flow, stimulate mucin secretion, and inhibit neutrophil adherence. It may thus protect the gastroduodenal tract against injury by aspirin and NSAIDs. Nitric oxide-​releasing NSAIDs have been developed and found to produce less gastric damage than their parent drugs. Tobacco, alcohol, and stress Cigarette smoking increases the risk of peptic ulcer diseases and their complications. As with NSAID usage, tobacco decreases pros- taglandin production and inhibits acid-​stimulated bicarbonate secretion in the duodenum. Increase in gastric acidity, reduction in epithelial cell proliferation, and impairment of mucosal blood flow have also been demonstrated with consumption of tobacco. Cigarette smokers are found to have slower healing of peptic ulcers and higher relapse rate of the disease. However, when H. pylori is eradicated, the effects of tobacco appear to be mitigated. It is a misconception that alcohol as such increases the risk of peptic ulcer disease. There are no convincing data in the literature supporting this notion. Although high concentrations of alcohol can cause damage to mucosa in animal studies, normal drinks such as wine and beer do not contain a high enough concentration of al- cohol to cause ulceration in the stomach and duodenum. However, peptic ulcer disease is more common in liver cirrhosis and alcohol consumption is certainly one of the most important underlying causes of this condition. The mechanism of peptic ulcer develop- ment in cirrhosis remains to be elusive. Psychological stress has always been implicated in peptic ulcer dis- ease but there is little scientific evidence to confirm the correlation.

SECTION 15  Gastroenterological disorders 2852 After all, stress is difficult to measure and its effects are hard to as- sess. Historical records during natural disasters (e.g. earthquakes and tsunami) and wars report an upsurge of peptic ulcer disease. During peacetime, however, stress seldom reaches high enough levels to lead to peptic ulcers. However, hospitalized patients with multiple illnesses and critical medical conditions can develop peptic ulcer and complications such as bleeding. Stress related to serious medical conditions and multiorgan failure is likely to produce peptic ulcer bleeding and the mortality of these patients has been estimated to be 10 times higher than for those without comorbid illnesses. Other causes Zollinger–​Ellison syndrome consists of a gastrin-​secreting islet cell tumour (gastrinoma) leading to marked hypergastrinaemia, out- pouring of gastric acid, and recurrent peptic ulceration. Most cases of Zollinger–​Ellison syndrome are sporadic but some are associated with multiple endocrine neoplasia syndrome type I (MEN-​1). As well as peptic ulcer disease, these patients may complain of diar- rhoea, steatorrhoea, symptoms of gastro-​oesophageal reflux, weight loss, and other presentations of MEN-​1 (e.g. hypercalcaemia and renal stones). The diagnosis is confirmed by finding a markedly raised serum gastrin level stimulated by secretin and radiological identification of tumour in the pancreas. Beside H.  pylori, other infections such as cytomegalovirus or Helicobacter heilmannii may lead to peptic ulcer disease. H. heilman­ nii has been found to cause intense inflammation in the stomach and occasionally peptic ulcers, especially in children. Helicobacter felis, a species that usually infects dogs and cats, has also been reported to cause peptic ulcer in pet owners. Crohn’s disease affects the whole gastrointestinal tract and may be a cause of peptic ulcer disease in the stomach, duodenum, or even the oesophagus. With the rising incidence of Crohn’s disease in Asia, peptic ulcers related to it are more commonly seen. Epidemiology It is hard to follow the temporal trend and geographical variation of peptic ulcer disease as the condition may not manifest itself in clin- ical settings. From records of peptic ulcer perforation, it has been suggested that this disease was uncommon before the 19th century. Over the ensuing decades, the incidence of peptic ulcer disease es- calated. By the end of the 19th century, duodenal ulcer frequency had surpassed gastric ulcer disease in frequency. The incidence of peptic ulceration rose dramatically throughout the first half of the 20th century, and then started to decline again in the second half of the century. Thus peptic ulcer disease appears to follow the trend of urbanization. The temporal trends of frequency of peptic ulcer disease are best studied by following birth cohorts. In Western coun- tries and in Japan, the risk of developing peptic ulcer disease rose in birth cohorts born before the turn of 20th century and then declined in subsequent generations. In addition to changes in the prevalence of peptic ulcer disease over time, there is also evidence that it shows geographical variations. For example, it is more common in Scotland and northern England than in southern England. Similarly, ulcers are more common in the south of India than in the north. Environmental factors are likely to play an important role in the development of peptic ulcer disease. Human-​to-​human transmission of H. pylori in urban dwellers, im- provement of sanitation in recent decades, and increased consump- tion of tobacco and analgesics might be important factors affecting the changing epidemiology of the disease. The incidence of bleeding resulting from peptic ulcer disease is much better documented than uncomplicated peptic ulcers. Based on the American Society of Gastrointestinal Endoscopy survey and two large United Kingdom audits made available in the 1990s, the reported incidence of gastrointestinal bleeding is approximately 100 per 100 000 population. The national United Kingdom audit was a population-​based, prospective collection of data on 4185 cases in 74 acute hospitals over a 4-​month period. Acute upper gastrointestinal bleeding is a disease primarily affecting the older age groups. In this audit, 68% of patients were older than 60 years and 27% were more than 80 years of age. In comparison with historic British series, a steady rise in the incidence over the last few decades was observed. The crude mortality rate increased from 9.9% in the 1940s to 11% in the 1990s. It is often argued that advances in the care of patients with upper gastrointestinal bleeding have been offset by an ageing population. A large survey of over 10 000 peptic ulcer bleeding pa- tients shows that mortality is often related to nonbleeding causes. Cardiopulmonary decompensation, multiorgan failure, and malig- nancy account for three-​quarters of the deaths and gastrointestinal bleeding is merely a terminal event in these patients. There has also been a trend towards increasing hospital admissions among older subjects and a corresponding decline for younger patients, resulting in little change in the overall admission rate. Hospital statistics from the United Kingdom Office of National Statistics revealed that from 1989 to 1999, admission rates for peptic ulcer haemorrhage increased among older people. Over this period, admissions increased by one-​ third among older women and by almost 50% among older men. The epidemiology of peptic ulcer disease has changed in the last two decades. With the declining prevalence of H. pylori infection in the developed countries, the proportion of patients with ulcers attributed to the use of aspirin and NSAIDs as well as H. pylori-​ negative ‘idiopathic’ ulcers is on the rise. However, there is evi- dence suggesting that between 20 and 40% of peptic ulcers in North America are not associated with H. pylori infection, nor the use of aspirin or NSAIDs. Is there truly a rise in non-​H. pylori, non-​NSAID ulcer, or does this merely reflects the declining trend of the disease and therefore a proportionate rise in idiopathic ulcers? The existing evidence suggests that the prevalence of these idiopathic ulcers is probably increasing. Two prospective cohort studies in Hong Kong, each lasting 1 year, looked at idiopathic ulcers in 1997 to 1998 and 2000 to 2001. The total number of bleeding peptic ulcers was more than 1500. Comparing the two time periods, the total number of bleeding ulcers per year had decreased by 33.1% and the number of H. pylori-​associated ulcers by over 30%. On the other hand, the absolute number of idiopathic ulcers increased 4.5-​fold. Patients suffering from idiopathic ulcers are older and sicker, and the ulcers more frequently developed after patients had been admitted to hos- pital for other medical conditions. Up to one-​half of idiopathic ulcer patients have major medical conditions such as advanced cardiopul- monary or liver disease. Ulcer recurrence is higher in patients with idiopathic ulcers than for H. pylori-​associated ulcers treated with eradication therapy.

15.8  Peptic ulcer disease 2853 Clinical features Dyspepsia Peptic ulcer disease is characterized by a history of waxing and waning symptoms of localized, dull, aching pain in the upper ab- domen, which is called dyspepsia. Many patients notice that symp- toms often worsen in winter. Eating spicy food and drinking coffee and tea may aggravate the symptoms, but these dietary habits do not lead directly to ulcer formation. Pain may occur sooner after meals in gastric ulcers than in duodenal ulcers, and is not necessarily relieved by food and antacids. The relationship between symptoms and eating is an unreliable predictor of peptic ulcer disease. Gastric ulcers are more often found in older patients, especially those taking NSAIDs or aspirin. Approximately 20% of complicated ulcers pre- sents without dyspeptic symptoms. These ‘silent’ ulcers are more common in individuals consuming NSAIDs, due to their analgesic effects. The lack of warning signs in these ulcers make them more dangerous. Haemorrhage Gastrointestinal bleeding is the most common complication as- sociated with peptic ulcer disease (Fig. 15.8.2). Vomiting of fresh blood, or haematemesis, indicates that bleeding originates from a site proximal to the suspensory muscle of the duodenum (liga- ment of Treitz). A history of fresh haematemesis usually implies a significant bleed and the patients may go into haemodynamic instability due to hypovolaemia. ‘Coffee ground’ vomiting, usu- ally arising from altered black blood, often indicates that active bleeding may have ceased. Melaena is the passage of black tarry stool. It occurs when haemoglobin in the gut is converted to haem- atin by bacterial degradation. As little as 200 ml of bleeding inside the digestive tract can produce melaena. Although melaena gen- erally connotes bleeding proximal to the suspensory muscle of the duodenum, bleeding from small bowel or proximal colon may also cause it, especially when colonic transit is slow. Haematochezia, passage of pure red blood or blood admixed with stool, occurs when bleeding comes from the lower gastrointestinal tract. It can also present in a massive upper gastrointestinal bleeding. When a substantial amount of blood is lost into the gastrointestinal lumen, pulses start to rise and blood pressure drops. The haemoglobin levels at this stage may not reflect the actual amount of blood loss before haemodilution sets in. A close monitoring of vital signs and estimation of volume of vomitus offer a better prognostic indicator of the severity of the illness. Perforation Free perforation of the stomach or duodenum into the peritoneal cavity is a rare but serious complication. It is more commonly found in older patients using aspirin or NSAIDs, leading to life-​ threatening catastrophe. The use of cocaine has also been related to peptic ulcer perforation. The classic presentation is a sudden onset of intense abdominal pain at the onset with gastric juice pouring into peritoneal cavity. This is followed a period of stabilization and amelioration of symptoms. Ulcer perforation may be concealed by the omentum. However, signs of peritonitis such as guarding and rebound tenderness persist. Bowel sounds are silent and liver dull- ness to percussion diminishes. A plain abdominal radiograph may demonstrate free gas between the upper border of the liver and the diaphragm and may also outline the serosal surfaces of the bowel wall. If prompt treatment is not provided, the patient will develop frank peritonitis and severe sepsis. Body temperature will rise and breathing becomes shallow. Leucocytosis and acidosis may appear at this stage. 55 43 22 10 5 0 20 40 60 80 100 Active Bleeder NBVV Clot Dot Clean Base Risk of recurrent bleeding (%) Fig. 15.8.2  Features of bleeding ulcers and the risk of recurrent bleeding. NBVV, nonbleeding visible vessel. From Lau JY, et al. (1998). The evolution of stigmata of hemorrhage in bleeding peptic ulcers: a sequential endoscopic study. Endoscopy, 30, 513–​18. © Georg Thieme Verlag KG.

SECTION 15  Gastroenterological disorders 2854 Besides free perforation, peptic ulcer may also penetrate into ad- jacent organs such as the pancreas, the bile duct, or even the colon, resulting in pancreatitis or gastrobiliary or gastroenteric fistula. With prompt medical attention, these complications are rarely seen nowadays. Obstruction In patients with recurrent peptic ulceration at the prepyloric an- trum, pylorus, and duodenal bulb, oedema and/​or scarring of the tissue may lead to obstruction of the gastric outlet. Pyloric obstruc- tion usually presents with bloating, early satiety, and vomiting. The patient may recognize food ingested several days ago in their vom- itus. Weight loss may be profound and dehydration with electrolyte disturbance (metabolic alkalosis with acidic urine) is common. On examination of the abdomen, an audible splash of the gastric content can be demonstrated by shaking the patient’s abdomen (succussion splash). Aspiration of gastric content through a nasogastric tube will empty litres of fluid and undigested food from the stomach, giving quick relief for the patient. Obstruction due to acute peptic ulcer and tissue oedema usually resolve in a few weeks as the ulcer heals. On the other hand, severe scarring of the pylorus and duodenum leads to permanent gastric outflow obstruction and requires endoscopic or surgical treatment. Differential diagnosis Symptoms are neither sensitive nor specific for the diagnosis of peptic ulcer disease. A wide range of conditions ranging from func- tional dyspepsia to malignancy of the gastrointestinal tract can pro- duce symptoms mimicking peptic ulcer disease. Pancreatitis and cholecystitis often produce more severe pain than peptic ulcer, so the differentiation may not be difficult. On the other hand, it is a disaster to miss a diagnosis of malignancy of the stomach, pancreas, or hepatobiliary tract. A high index of suspicion, especially in older patients with anorexia and weight loss, is needed to minimize the possibility of missing the diagnosis. In countries where the preva- lence of gastric cancer is high, symptom of dyspepsia should be managed carefully. Clinical investigation With the advent of endoscopy, barium studies are less frequently used in the diagnosis of dyspepsia. Endoscopy serves three pur- poses in diagnosis and evaluation of the patients. First, it confirms the diagnosis of peptic ulcer disease by its morphology, location, and, in the case of gastric ulcer, offering an opportunity for biopsy. Endoscopic features of bleeding ulcers are important prognostic in- dicators. The presence of signs of recent bleeding in an ulcer con- firms the source of bleeding. The Forrest classification categorizes ulcers into those that are actively bleeding, show signs of recent bleeding, or simply have a clean base: • Forrest class I ulcers are actively bleeding, either spurting (Forrest class IA) or oozing (Forrest class IB). • Forrest class  II ulcers show signs of recent bleeding including nonbleeding visible vessel (Forrest class  IIA), adherent clots (Forrest class IIB), or flat pigmented spots (Forrest IIC). • Forrest III ulcers have a clean base. The risk of continuous or recurrent bleeding of these ulcers is related to their appearance (Fig. 15.8.3). An evolutionary scheme for the natural history of signs of haem- orrhage for peptic ulcers has been proposed. Major bleeding from a peptic ulcer is arterial in origin. A sentinel clot (a term used syn- onymously with ‘visible vessel’) plugs the bleeding point. This can initially be contiguous with a larger overlying clot, which resolves in time. The clot may be variable in colour: initially it is red, but it darkens in time and subsequently the colour disappears leaving a plug of fibrin and platelets. Eventually the plug disappears, as the healing process is complete (Fig. 15.8.3). Ulcers with an adherent clot or protuberant vessels have a 20 to 40% chance of recurrent bleeding without proper endoscopic or pharmacological therapy. Endoscopic features, including the size and the site of bleeding ul- cers, should be interpreted along with clinical factors. Ulcers at the lesser curve of the stomach or posterior duodenal bulb are a high risk because of their proximity to the left gastric artery and the gastroduodenal artery respectively.

  1. Arterial bleeding
  2. Large red clot contiguous with sentinel clot/vv
  3. Small red sentinel clot/vv
  4. Dark sentinel clot/vv
  5. White sentinel clot
  6. Clot disappears Fig. 15.8.3  Evolution of signs of recent haemorrhage. vv, visible vessel. From Johnston JH (1990). Endoscopic risk factors for bleeding peptic ulcer. Gastrointest Endosc, 36 Suppl, S16–​20.

15.8  Peptic ulcer disease 2855 Gastric outlet obstruction due to recurrent peptic ulcer disease may produce a pinhole pylorus and dilated stomach. The endoscope may not be able to pass through the area of obstruction, leading to difficulty in assessment. Radiological imaging such as contrast studies is useful in this situation. Management Treatment of peptic ulcer disease can be divided into two stages: (1) treatment of acute symptoms and complications such as pain and bleeding, and (2) treatment of the underlying cause to prevent ulcer recurrence. Relief of symptoms and healing of peptic ulcer Before the 1970s treatment of peptic ulcer relied on antacids, anti- cholinergics, a bland diet, and bed rest. The therapeutic efficacy was low and many patients resorted to surgery such as partial gastrec- tomy and vagotomy. H2-​receptor antagonists In 1977, the first H2-​receptor antagonist, cimetidine, was introduced. Subsequently, ranitidine, famotidine, and nizatidine became available. These are effective acid-​suppressive agents, easy to use with an excellent safety profile. H2-​receptor antagonists quickly became the treatment of choice for peptic ulcer disease, but they have several disadvantages. Cimetidine has mild antiandrogenic effects, leading to gynaecomastia and impotence in some patients. The ability of cimetidine to bind to hepatic enzyme cytochrome P450 has also led to many interactions with other drugs, altering the pharmacokinetics of medications. Cimetidine is reported to interact with theophylline, phenytoin, lido- caine, warfarin, β-​blockers, tricyclic antidepressants, benzodiazep- ines, and many others. A variety of neurological reactions have also been reported such as headache, lethargy, depression, memory im- pairment, and confusion, especially in older patients. Furthermore, the reversible competitive inhibition of histamine-​stimulated acid secretion provides only a modest suppression of acid secretion. The postprandial acidity of the stomach is still relatively high. ‘Cytoprotective’ agents In addition to the acid-​suppressive agents, drugs claimed to have ‘cytoprotective’ activities were developed in the 1980s. Sucralfate is a complex salt of sucrose in which the eight hydroxyl groups of sucrose are replaced by sulphate and aluminium hydroxide. It is insoluble in water, forming a thick, tenacious paste that covers the surface of gastro- intestinal mucosa. Sucralfate has no acid-​suppressing effects and is be- lieved to work by coating the luminal surface of the ulcer, absorbing bile salts and pepsin and protecting the injured mucosa from further insult by erosive substances in the stomach. However, its ulcer healing effect is slow. Because of its aluminium content, it is considered unsafe in patients with chronic renal insufficiency. Acute aluminium toxicity has been reported in patients with end-​stage renal failure. Sucralfate is now rarely used in the clinical management of peptic ulcers. Bismuth salts have been used for many years for the treatment of diarrhoea, dyspepsia, and abdominal pain. As in case of sucralfate, bismuth has no effect on acid secretion in the stomach. The mech- anism of action is unknown but it is found to preferentially cover the ulcer crater. In the early 1980s, bismuth was found to inhibit the growth of H. pylori, which may partially explain its ulcer healing activity. Colloidal bismuth subcitrate and bismuth subsalicylate are available for clinical use. The use of bismuth subcitrate will blacken stool which might be confusing for patients suffering from gastro- intestinal bleeding. There are isolated reports of neurotoxicity re- lated to the use of bismuth subcitrate and bismuth subsalicylate when used in large doses in older patients. Otherwise, bismuth is a fairly safe drug. Its use is now mainly confined to the treatment of H. pylori infection in combination with other antimicrobial agents. Prostaglandin analogues Prostaglandins are derivatives of unsaturated fatty acid known as eicosanoids. The human gastrointestinal tract synthesizes several prostaglandins such as PGE2 and PGF2. Prostaglandins have been found to have a modest effect in inhibiting acid secretion in the stomach as well as stimulating the production of bicarbonate and mucin. Misoprostol has been developed as a prostaglandin analogue for human use. The standard dose of the drug is 800 µg/​day taken in four divided doses. The ulcer-​healing effect is not as potent as other acid-​suppressive agent and the regimen is inconvenient, but because of the nature of its action misoprostol offers one of the best treatments for NSAID-​related ulcers and prevention of this condi- tion. Diarrhoea is the most common side effects and limits the use of misoprostol in daily practice. It is also contraindicated in pregnancy as it may induce abortion. Uterine bleeding has been reported in a substantial proportion of patients. Proton pump inhibitors The discovery of proton pump inhibitors was major advance in the treatment of acid-​related gastrointestinal disorders. The final step of hydrogen ion secretion by the parietal cells is accomplished by H+,K+-​ APTase, an acid pump that exchanges hydrogen for potassium. These pumps are located at the apical membrane of tubulovesicular appar- atus of the parietal cells. Proton pump inhibitors such as omepra­ zole, lansoprazole, pantoprazole, and rabeprazole are substituted benzimidazoles that bind to the acid pump irreversibly. These drugs turn off acid secretion stimulated by any kind of stimulants. Recovery of acid secretion requires synthesis of new enzyme in the acid pump. The most effective way of administering a proton pump inhibitor is to take the drug before meals, that is, before acid secretion is trig- gered by food. Usually, a single daily dose gives quick relief of symp- toms and effective healing of peptic ulcers in 4 to 6 weeks. Compared to misoprostol and H2-​receptor antagonists, proton pump inhibi- tors such as omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole are more effective in healing the ulcer as well as preventing further peptic ulcerations and erosions. As the most po- tent inhibitors of acid secretion, proton pump inhibitors are also the treatment of choice for Zollinger–​Ellison syndrome. They have also been found to suppress the growth of H. pylori and form an integral part in combination therapy to eradicate H. pylori in the stomach (‘proton pump inhibitor triple therapy’). Newer PPIs have been de- veloped, including dexlansoprazole modified release, instant release omeprazole as well as novel molecules such as tenatoprazole have also been developed and achieve more effective control of intragastric pH especially at night. Initial suspicion that prolonged suppression of the proton pump leads to enterochromaffin-​like cell hyperplasia has not been proved in humans. There are recent reports on potential side effects of the long-​term use of proton pump inhibitors. These include osteoporosis and bone fracture, hypomagnesaemia, enteric infection (e.g. Clostridium difficile), and pneumonia. Most of these associations

SECTION 15  Gastroenterological disorders 2856 are based on cohort studies and retrospective analysis. The evidence for serious side effects is poor and the risk is low. Potassium-competitive acid blockers (P-CABs) There are needs to overcome the shortcomings of PPI namely, the delayed release of the drug, short plasma half-lives, requirement to be given before a meal and show poor control of nocturnal acid secretion. The major advance has been the development of the po- tassium channel acid blocking drugs (P-CABs) which block the K+,H+-ATPase K+ channel. P-CABs are food independent, revers- ible, have a rapid onset of action, and maintain a prolonged and con- sistent elevation of intragastric pH. Vonoprazan, the first P-CAB, has been introduced only into a small number of Asian countries. It is in general, safe and efficacious in gastric acid secretion. Its clinical indications are still to be developed. Ulcer bleeding The management of patients with upper gastrointestinal haemor- rhage requires a multidisciplinary approach mandating cooperation among medical and surgical gastroenterologists with access to skills in endoscopic and surgical haemostasis. Endoscopic treatments Endoscopic therapy is often the first treatment in the manage- ment algorithm. Approximately 80 to 85% of upper gastrointestinal bleeding stops spontaneously. The remaining 15 to 20% continue to bleed or develop recurrent bleeding and these patients constitute the high-​risk group with substantial increased morbidity and mor- tality. Early risk stratification of patients with upper gastrointestinal bleeding based on clinical and endoscopic criteria allows delivery of an appropriate level of care to patients. Endoscopic therapy is now widely accepted as the first line of therapy for upper gastrointestinal bleeding. It should be applied to actively bleeding ulcers or ulcers covered with an adherent clot (Forrest class IIB). Many clinical trials and at least two meta-​analyses have confirmed the efficacy of endo- scopic haemostasis with dual therapy. Endoscopic therapy reduces recurrent bleeding and the need for surgical intervention. Endoscopic therapy can be broadly categorized into endoscopic injection, thermal coagulation, and mechanical haemostasis. Combining endoscopic injection with either thermal coagulation or mechanical haemostasis represents the best endoscopic therapy, with an overall success rate of around 90%. Endoscopic injection Epinephrine, polidocanol, sodium tetradecyl sulphate, absolute al- cohol, and even saline solution have been used for injection. No single agent for endoscopic injection is superior to another for achieving haemostasis. The mechanism of action is mostly related to a tamponade effect produced by the solution injected. The haemo- static effect of endoscopic injection is only transient, as the solution will be absorbed by the tissue. Injection is therefore not recom- mended as the sole therapy for peptic ulcer bleeding. Combination with other modalities is required. Thermal coagulation Thermal devices include heated probes; electrocoagulation is re- quired to secure haemostasis. Thermal devices seal blood ves- sels underneath the ulcer base by pressure and heat energy. This combined pressure–​thermal energy effect is called ‘coaptive coagu- lation’. Like endoscopic injection, no single method of endoscopic coaptive therapy is superior to the others. Mechanical haemostasis Endoscopic clipping or (in some cases) banding ligation can achieve mechanical haemostasis. The latest development is a device called over-​the-​scope clips, which takes a bigger area of ulcer base with a firmer grip on the bleeding vessel. The results appear promising. Mechanical haemostasis is found to be as effective as thermal device in controlling peptic ulcer bleeding. Haemostatic spray (Hemospray) is an inert particle which swells on exposure to water and stimulates platelet aggregation. It can be applied through an endoscope and achieve temporary control of bleeding from peptic ulcers. It is a useful stop-​gap treatment when other endoscopic methods fail. Angiographic embolization Angiographic embolization has been used as a salvage procedure when endoscopic method fails to control peptic ulcer bleeding. When compare to surgery, angiographic embolization is less ef- fective in securing haemostasis but leads to lower morbidity re- lated to procedures. Recent study has also suggested that in treating patients with large (>1.5 cm) ulcer with visible blood vessels, pre-​ emptive embolization (i.e. before recurrent bleeding occurs) after initial endoscopic haemostasis might reduce mortality of patients. Proton pump inhibitors As an acidic environment in the stomach and duodenum inhibits platelet aggregation and activates enzymatic activity of pepsinogen, suppression of acid, especially in the early phase of peptic ulcer bleeding, is useful as an adjuvant therapy. Randomized studies and a subsequent systematic review have confirmed that a high-​dose intra- venous proton pump inhibitor offers an effective inhibition of gas- tric acid secretion and reduces recurrent bleeding. Patients receiving these intravenous infusions require less blood transfusion, fewer re- peated endoscopic treatments, and fewer surgical operations. Recent data suggest that the use of an intravenous proton pump inhibitor in the early phase of bleeding, before endoscopy, may reduce the re- quirement for endoscopic therapy and shorten hospital stay. Peptic ulcer bleeding Forrest I IV PPI Endo Rx IV PPI Endo Rx Oral PPI No Endo Rx Repeat Endo Rx or angiographic emobolization Surgery Forrest II a/b Forrest IIc, III Fig. 15.8.4  Management strategy for peptic ulcer bleeding. Endo Rx, endoscopic treatment; IVPPI, intravenous proton pump inhibitor. Adapted from Sung J (2006). Current management of peptic ulcer bleeding. Nat Clin Pract Gastroenterol Hepatol, 3, 24–​32.

15.8  Peptic ulcer disease 2857 There have been debates about the possible benefit of using oral instead of intravenous proton pump inhibitors in the management of bleeding peptic ulcer. While the acid-​suppressing effects of oral medi- cation are similar to intravenous administration, in the early phase of the emergency, anti-​acid effect of oral proton pump inhibitors might not be adequate. A recent randomized study, however, showed that a high-​dose oral proton pump inhibitor might be useful as an alterna- tive to intravenous bolus plus infusion of proton pump inhibitors in patients who are not candidates for high-​dose intravenous therapy. An algorithm for the management of peptic ulcer bleeding is proposed in Fig. 15.8.4. When endoscopic haemostasis fails, angiographic intervention may help to control bleeding in patients who are old and considered as a high risk for surgery. Strategy of blood transfusion Replacement of lost blood and volume with red cell transfusion has always been an important part in the resuscitation and man- agement of ulcer bleeding. In many cases of severe bleeding, transfusion of blood is considered a life-​saving measure. There is some recent data, however, indicating that restricted transfu- sion may be appropriate in some settings. In a randomized con- trolled trial in which patients were given either liberal transfusion or transfusion only when haemoglobin level dropped to less than 7 g/​dL, evidence showed that those who received restrictive trans- fusion had better survival. In this study, however, only about half of the patients had peptic ulcer bleeding. Survival benefit was more significant in those who suffered from bleeding related to portal hypertension. Prevention of ulcer recurrence Management of H. pylori infection Treatment of H. pylori is a cure for peptic ulcer disease in most patients. H. pylori is susceptible to many different antimicrobials and a variety of combinations have been used successfully. Those that have proved effective include amoxicillin, metronida- zole, tetracycline, clarithromycin, and furazolidone. Other less commonly used antimicrobials include rifabutin and several fluoroquinolones. Successful cure of infection usually requires two antimicrobial agents. Cure rates with single antimicrobial agents are poor, ranging from 0 to 35%, and monotherapy is also associated with the rapid development of antibiotic resistance, hence it is not recommended. In principle, only those regimens that give high cure rates (>80%) should be used as first-​line therapy. Generally, higher doses and longer durations provide better results. Antibiotic resistance leads to reduced efficacy of therapy, hence the antimicrobial resistance pattern of H. pylori should be moni- tored and made known in each locality. The patient’s compliance with therapy is very important for successful cure of the infec- tion, so regimens should be simple and with as few side effects as possible. The treatment of H. pylori infection has gone through substantial evolution, primarily because of the issues of antibiotic drug resistance and patient (non)compliance. The choice of therapy should depend on regional drug resistance pattern (especially to clarithromycin and metronidazole), previous treatment received by the patient, and antibiotic-​sensitivity testing of individual cases (Fig. 15.8.5). First-​line therapy Triple therapy with a proton pump inhibitor remains the first choice in areas where clarithromycin resistance is low (<15%). The regimen contains a proton pump inhibitor (omeprazole 20 mg twice daily, lansoprazole 30 mg twice daily, pantoprazole 40 mg twice daily, or rabeprazole 20 mg twice daily) plus amoxicillin (1 g twice daily) plus clarithromycin (500 mg twice daily). This regimen is simple, easy to take, and well tolerated by patients. The efficacies of 7-​day, 10-​day, or 14-​day therapy are comparable. The differences between proton pump inhibitors are minimal. H. pylori is rarely resistant to amoxicillin. Metronidazole can be used to substitute amoxicillin in penicillin-​allergic patients. Quadruple therapy that combines bismuth subsalicylate (534 mg four times daily) plus a proton pump inhibitor plus two antibiotics (usually metronidazole 250 mg four times daily and tetracycline 500 mg four times daily) given for 10 to 14 days is useful as first-​line therapy in areas where clarithromycin resistance is common. If bis- muth is not available, a proton pump inhibitor with three antibiotics (including clarithromycin), or so-​called concomitant therapy, is an option. Capsules that combine various antibiotics with bismuth or proton pump inhibitor are useful as they improve compliance. Sequential therapy using two-​phases of proton pump inhibitor–​ antibiotic combinations has recently been shown to improve effi- cacy. Lansoprazole 30 mg plus amoxicillin 1 g for the first 5 to 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metro- nidazole 500 mg for another 5 to 7 days appears to be superior to lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 400 mg for 14 days. Second-​line therapy Approximately 20% of patients fail responding to first-​line therapy and eradication of H. pylori cannot be achieved. Strategies to manage treat- ment failure include (1) not repeating clarithromycin unless in vitro Peptic ulcer disease with confirmed H. Pylori infection Region with Clarithromycin Resistance ≤15% PPI-Clari-Amox/Metro or Bismuth Quadruple PPI-Levo-Amox or PPI-Rifa-Amox or Bismuth Quadruple PPI-Levo-Amox or PPI-Rifa-Amox Based on antibiotic susceptibility testing For the choice of combination therapy Bismuth Quadruple or Sequential therapy or concomitant therapy Region with Clarithromycin Resistance >15% Fig. 15.8.5  A schematic diagram for H. pylori therapy.

SECTION 15  Gastroenterological disorders 2858 sensitivity testing prove that H. pylori is still susceptible to it, (2) anti- biotics used in initial therapy should be avoided, (3) tetracycline can be used, and (4) drug compliance of patients should be checked. After failure of a proton pump inhibitor–​clarithromycin triple therapy, a bismuth-​containing quadruple therapy (bismuth subci- trate 240 mg, omeprazole 20 mg, tetracycline 500 mg, metronidazole 500 mg all given twice daily for 14 days) is recommended. In areas of high clarithromycin resistance (where proton pump inhibitor–​ clarithromycin was therefore not used but bismuth-​containing quadruple therapy failed), levofloxacin-​containing triple therapy is recommended. A 10-​day course of proton pump inhibitor plus rifab- utin (300 mg twice daily) plus amoxicillin (1 g twice daily) has also been claimed to be effective. Sequential therapy for 14 days may be considered preferable in regions where clarithromycin resistance is high and metronidazole resistance is low. Levofloxacin-​containing sequential therapy may also be considered in a sequential regimen when clarithromycin resistance is high in the region. H. pylori resistance to antibiotics Treatment of H. pylori is becoming more difficult nowadays be- cause of emerging resistance to antimicrobials. Metronidazole and clarithromycin resistance rates are alarming but vary among popu- lations. Tetracycline and amoxicillin resistance are much lower in most countries. H. pylori resistance can be detected by phenotypic or by molecular methods. Different break points may be used when performing an antimicrobial susceptibility test, so comparing resist- ance among different populations is challenging. Eradication rates are dependent on the susceptibility of the strain to metronidazole and clarithromycin, being lower in patients infected with a resistant strain. Choice of therapy should be guided by prevalence of resist- ance to antibiotics (clarithromycin in particular) in that locality. Testing for antibiotic resistance Routine culture and testing for antibiotic sensitivity for H. pylori is not recommended. However, in patients who have received at least two courses of combination therapy and fail to cure the infection, testing of drug sensitivity seems logical. Culture of H. pylori can be done by obtaining a piece of biopsy tissue and placing it on a single drop of sa- line. A culture can also be obtained on the biopsy used for CLO test if the specimen is removed from the gel within 1 h and sent immediately to the laboratory. Choice of antimicrobial should then be guided by the sensitivity testing results. However, patients should be cautioned that even in vitro culture sensitivity-​guided therapy does not guarantee 100% success as in vivo activities of these drugs might be influenced by many other factors, including acidity and food in the stomach. Prevention of NSAID-​associated ulcer NSAID-​associated ulcer and ulcer complications are more com- monly reported in high-​risk individuals, that is, older people and those with history of peptic ulcer disease or chronic medical illness. Concomitant use of NSAIDs with aspirin, anticoagulants, or cor- ticosteroid also increases the risk of bleeding from peptic ulcers. Special caution has to be exercised before prescribing NSAIDs to these patients. Various prophylactic strategies to reduce gastroduodenal injury by NSAIDs have been investigated. These include concurrent treatment with H2-​receptor antagonist, misoprostol, proton pump inhibitor, and substitution of conventional NSAIDs by COX-​2 selective inhibitors. Systematic review pooling over 30 randomized controlled clinical trials of misoprostol, H2-​receptor antagonist, or proton pump in- hibitor for the prevention of gastroduodenal ulcer showed that these drugs have different efficacy. H2-​receptor antagonists reduce the risk of duodenal ulcer, but not of gastric ulcer, except at very high dose. Misoprostol at 80 µg per day can reduce ulcer and ulcer complication but its side effects are significant. Proton pump inhibitors can reduce the risk of both duodenal and gastric ulcers associated with NSAIDs and they are much better tolerated than misoprostol. The interaction between H. pylori and NSAIDs in the develop- ment of peptic ulcer disease is complex. Clinical studies reported by different investigators have yielded conflicting results. Part of the confusion stems from the recruitment of different patient groups and use of different outcome measurement. Meta-​analysis of 16 studies showed that H. pylori infection and NSAID use increase the risk of ulcer bleeding by 1.8-​fold and 4.8-​fold respectively. The risk of ulcer bleeding increases to around sixfold when both factors are present. This implies that NSAIDs and H. pylori are independent but addi- tive risk factors for ulcer development. H. pylori-​infected individ- uals taking NSAIDs will have an increased risk of peptic ulcer and ulcer complications. If a patient known to have H. pylori infection requires a NSAIDs, eradicating H. pylori before using the NSAID may substantially reduce the risk of peptic ulcer disease. However, simply curing H. pylori infection may not be sufficient to protect the stomach and duodenum from ulcer formation in high-​risk individ- uals. In elderly patients with history of ulcer complication, concomi- tant use of a proton pump inhibitor is warranted. In these patients, even the use of COX-​2 selective inhibitors is not entirely safe. The risk of recurrent bleeding with celecoxib is comparable to the use of diclofenac combined with omeprazole, according to one study. In patients with a history of ulcer bleeding, a combination of COX-​ 2 selective inhibitors with a proton pump inhibitor offers the best safety profile for the gastrointestinal tract (Table 15.8.1). Table 15.8.1  Recommendations for reducing the risk of ulcer and ulcer complications in high-​risk patients (NSAID and aspirin users) Strategies NSAID users Aspirin users Choice of medication Choose less ulcerogenic NSAID (e.g. ibuprofen) or short-​term COX-​2 selective inhibitors Use low-​dose aspirin (80–​100 mg/​day) H. pylori infection Eradicate H. pylori infection with proton pump inhibitor triple therapy Eradicate H. pylori infection with proton pump inhibitor triple therapy Concomitant medication Avoid combining with aspirin, anticoagulants, and steroid Avoid combining with NSAID, clopidogrel, COX-​2 selective inhibitors, anticoagulant, and steroid Ulcer-​preventing drugs Proton pump inhibitor or high-​dose H2-​receptor antagonist in high-​risk individuals Proton pump inhibitors in high-​risk individuals

15.8  Peptic ulcer disease 2859 Prevention of ulcer associated with antiplatelet agents Aspirin and clopidogrel are increasingly used in the prevention of cardiovascular and cerebrovascular diseases. Aspirin-​induced peptic ulcer disease is dose dependent, so the lowest dose of aspirin should be prescribed. Aspirin is often used in elderly patients who require NSAID or COX-​2 selective inhibitors for musculoskeletal pain. Combinations of aspirin with NSAIDs and COX-​2 selective inhibitors have been shown to increase the risk of ulcer bleeding substantially. The gastric sparing effect of COX-​2 inhibitors is offset by the concomitant use of low-​dose aspirin, so this combination should be avoided if possible. Eradication of H. pylori infection has been shown to reduce the risk of peptic ulcer bleeding in high-​risk individuals (Table 15.8.1). Recent study shows that if aspirin is dis- continued for a prolonged period after peptic ulcer bleeding, patient survival may be jeopardized as a result of cardiovascular or cere- brovascular conditions. Clinicians are advised to exercise discretion and balance the risk and benefit of discontinuing antiplatelet agents in these patients. Clopidogrel has an improved gastrointestinal safety profile com- pare to aspirin in general use. However, in high-​risk individuals (e.g. elderly patients with a history of ulcer or ulcer complication), the risk of peptic ulcer with clopidogrel should not be underestimated. In a head-​to-​head comparison between clopidogrel and low-​dose aspirin combined with proton pump inhibitors, the risks of peptic ulcer bleeding were shown to be similar for both strategies. In recent years, there has been a trend to combine aspirin and clopidogrel in the management of patients with myocardial infarction, especially after percutaneous coronary interventions with stenting. A com- bined use of two antiplatelet agents is recommended for at least 6 months after the procedures. The combination of clopidogrel and aspirin is expected to further increase the gastrointestinal risk, so the benefit of using these antiplatelet agents must be balanced against the risk of causing gastrointestinal toxicity in these patients. This could be a difficult decision in elderly patients with life-​threatening cardiovascular disease and a history of ulcer complication in the past. In patients with bleeding peptic ulcers who have significant car- diovascular disease, discontinuing antiplatelet agents may increase the risk of cardiovascular mortality. At least one antiplatelet agent should be continued under the cover of proton pump inhibitors. Although data suggest that interactions between some proton pump inhibitors and clopidogrel at least have the potential to increase the frequency of cardiovascular events, randomized trials and a recent meta-​analysis have not revealed such an effect, and more clinical evidence will be required to reach this conclusion with certainty. New anticoagulants and risk of ulcer bleeding New anticoagulants including dabigatran, rivaroxaban, and apixaban differ from warfarin with their fixed oral dose and no requirement for routine monitoring, hence attract a lot of usage among patients who requires anticoagulation therapy. Dabigatran has been asso- ciated with an increased risk in gastrointestinal bleeding (which is probably not shared by rivaroxaban) and hence should be used with caution in patients who have a history of peptic ulcer disease. When bleeding occurs, the use of coagulation factors (fresh frozen plasma, prothrombin complex concentrates, or recombinant activated factor VII) is more successful in reversing the activity of rivaroxaban than dabigatran. Surgery and peptic ulcer complications With the improvement of ulcer treatment using proton pump in- hibitors and anti-​Helicobacter therapy, the role of ulcer surgery has diminished. Classical operative procedures such as partial gastrec- tomy (Billroth I and Billroth II gastrectomy) and vagotomy are now rarely performed except for unhealed or recurrent peptic ulcers in the stomach or duodenum. As a result, postgastrectomy complica- tions such as afferent loop syndrome, dumping syndrome, postva- gotomy diarrhoea, and bile reflux gastropathy are disappearing in clinical practice. Surgery is still the most effective method of treating peptic ulcer bleeding arising from ulcers at difficult positions or large submucosal vessels (e.g. the gastroduodenal artery). Plication of the bleeding vessels and/​or removal of part of the stomach or duodenum remain the definitive method of controlling bleeding that cannot be stopped by pharmacological and endoscopic measures. Often, this is a life-​ saving procedure. The decision to operate is best made by a team of experienced gastroenterologists and gastrointestinal surgeons with a close working relationship. Repeated, unsuccessful attempts at endoscopic haemostasis lead to undue delay in surgery, massive blood transfusion, and multiorgan failure, jeopardizing the patient’s survival. In a study comparing second-​attempt endoscopic therapy versus surgery, ulcer surgery showed a superior haemostasis result although postoperative complications were frequent. An individual-​ based decision and the exercise of clinical discretion are therefore required. Despite initial enthusiasm for endoscopic dilatation of pyloric stenosis, the long-​term result is disappointing. Gastric outlet ob- struction often recurs months or years after endoscopic balloon dilatation. Partial gastrectomy and vagotomy may solve the problem of obstruction once and for all, saving the patient repeated admis- sions to hospital. Free perforation of the ulcer into the peritoneum is another indication for ulcer surgery. Repair of perforation and vagotomy is usually adequate to control the disaster. Treatment of H. pylori infection and a maintenance dose of proton pump in- hibitor are indicated as follow-​up therapy. Areas of uncertainty and future development We have come a long way in the last two decades in the under- standing of pathogenesis of peptic ulcer disease and its management. Substantial improvements have been made in preventing recurrent disease and in the treatment of its associated complications. There are, however, areas of uncertainty and room for future improvement. Although H. pylori has been identified as the major cause of peptic ulcer disease in individuals who do not use NSAIDs or aspirin, it is still not clear why only a relatively small proportion of infected sub- jects develop peptic ulcer disease. Bacterial factors (other than the cag pathogenicity island) and host factors (other than IL-​1B poly- morphism) need further studies to elucidate the difference in out- come. With rapid emergence of antimicrobial resistance in H. pylori, cure cannot be assumed without confirmation. An effective second-​ line therapy is still much needed. The best strategy for high-​risk individuals requiring antiplatelet, NSAIDs, or COX-​2 inhibitors needs further studies. There are, at pre- sent, very few data on the effective protection of the gastrointestinal

SECTION 15  Gastroenterological disorders 2860 tract when patients are prescribed double antiplatelet agents. Scepticism still persists about the safety of eradicating H. pylori as the only prophylaxis for aspirin users. In view of the complicated interaction between NSAIDs, COX-​2 inhibitors, and antiplatelet agents in vascular and gastrointestinal safety, a matrix for choice of therapy under different circumstances is much desired. Guidelines need to be developed for primary care physicians, cardiologists, and gastroenterologists looking after these patients. The role of nitric oxide is receiving more attention in under- standing the gastrointestinal toxicity of NSAIDs and analgesics. The development of NSAIDs and aspirin coupled with a molecule of nitric oxide is an exciting area that opens up a new horizon in the management of peptic ulcer disease in those who requires anti-​ inflammatory medication and antiplatelet therapy. The efficacy and safety of these drugs can only be confirmed by carefully designed clinical studies. Despite the advances in pharmacological and endoscopic therapy, the mortality of ulcer bleeding remains at 7 to 10%. Especially in the elderly patients, death is often related to nonbleeding causes such as cardiopulmonary conditions, multiorgan failure, and terminal malignancy. Clinicians are reminded to manage the comorbid ill- ness instead of focusing on bleeding lesions alone. In difficult cases of ulcer bleeding, endoscopy and surgery are the two common ap- proaches available at this stage. The role of radiological intervention, that is, embolization of the feeding artery at the ulcer base, deserves more careful investigation. FURTHER READING Abraham NS, et al. (2013). Novel anti-​coagulants: bleeding risk and management strategies. Curr Opin Gastroenterol, 29, 676–​83. Bhatt DL, et al. (2010). Clopidogrel with or without omeprazole in cor- onary heart disease. N Engl J Med, 363, 1909–​17. Blaser MJ (1996). Role of vac A and the cag A locus of Helicobacter pylori in human disease. Aliment Pharmacol Ther, 10, 73–​77. Calvet X, et al. (2004). Addition of a second endoscopic treatment following epinephrine injection improve outcome in high-​risk bleeding ulcers. Gastroenterology, 126, 441–​50. Chan FKL, et al. (2001). A randomised comparison of Helicobacter pylori eradication and omeprazole for the prevention of recurrent upper gastrointestinal bleeding in chronic users of low-​dose aspirin and non-​aspirin non-​steroidal anti-​inflammatory drugs. N Engl J Med, 344, 967–​73. Chan FKL, et al. (2002). Celecoxib versus diclofenac and omeprazole in preventing recurrent ulcer bleeding in patients with arthritis. N Engl J Med, 347, 2104–​10. Chan FKL, et al. (2002). Screen-​and-​treat Helicobacter pylori to reduce the risk of peptic ulcers for patients starting long-​term non-​steroidal anti-​inflammatory drug treatment:  a double blind randomised placebo-​controlled trial. Lancet, 359, 9–​13. Chan FKL, et al. (2005). Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med, 352, 238–​44. Chan HLY, et al. (2001). Is non-​Helicobacter non-​NSAID peptic ulcer a common cause of upper gastrointestinal bleeding? A prospective study of 977 patients. Gastroint Endosc, 53, 438–​42. Cook DJ, et al. (1992). Endoscopic therapy for acute non-​variceal upper gastrointestinal haemorrhage:  a meta-​analysis. Gastroenterology, 102, 139–​48. Dorward S, et al. (2006). Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev, CD005415. El-​Omar EM, et al. (1995). Helicobacter pylori infection and abnor- malities of acid secretion in patients with duodenal ulcer disease. Gastroenterology, 109, 681–​91. El-​Omar EM, et al. (1997). Helicobacter pylori infection and chronic gastric acid hypo-​secretion. Gastroenterology, 113, 15–​24. European Helicobacter pylori Study Group. (1997). Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. Gut, 41, 8–​13. Forrest JA, Finlayson ND, Shearman DJ. (1974). Endoscopy in gastro- intestinal bleeding. Lancet, 2, 392–​7. Graham DY, Yamaoka Y (2000). Disease-​specific Helicobacter pylori virulence factors—​the unfulfilled promise. Helicobacter, 5, 3–​9. Hawkey CJ (1990). Non-​steroidal anti-​inflammatory drugs and peptic ulcers. BMJ, 300, 764. Hawkey CJ, et  al. (1998). Omeprazole compared with misoprostol for ulcer associated with non-​steroidal anti-​inflammatory drugs. Omeprazole versus misoprostol for NSAID-​induced ulcer manage- ment (OMNIUM) study group. N Engl J Med, 338, 727–​34. Hosking SW, et al. (1994). Duodenal ulcer healing by eradication of Helicobacter pylori without anti-​acid treatment: randomized con- trolled trial. Lancet, 343, 508–​10. Huang JQ, Sridhar S, Hunt RH (2002). Role of Helicobacter pylori in- fection and non-​steroidal anti-​inflammatory drugs in peptic ulcer disease: a meta-​analysis. Lancet, 359, 12–​22. Hung LCT, et al. (2005). Long-​term outcome of H. pylori-​negative bleeding ulcers: a prospective cohort study. Gastroenterology, 128, 1845–​50. Kwok CS, et  al. (2013). No consistent evidence of differential car- diovascular risk amongst proton pump inhibitors when used with clopidogrel: meta-​analysis. Int J Cardiol, 167, 965–​74. Lanas A, et al. (2006). Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-​oxygenase 2 inhibitors, traditional non-​aspirin non-​steroidal anti-​inflammatory drugs, aspirin and combinations. Gut, 55, 1731–​8. Lau JYW, et  al. (1999). Endoscopic re-​treatment versus surgery in patients rebleeding after initial endoscopic ulcer hemostasis:
a prospective randomized controlled trial. N Engl J Med, 340, 751–​6. Lau JYW, et al. (2000). A comparison of high-​dose omeprazole infu- sion to placebo after endoscopic hemostasis to bleeding peptic ulcer. N Engl J Med, 343, 310–​316. Lau JYW, et al. (2007). Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med, 356, 1631–​40. Leontiadis G, Sharma VK, Howden CW (2006). Proton pump in- hibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev, CD002094. Liou JM, et al. (2013). Sequential versus triple therapy for the first-​ line treatment of Helicobacter pylori: a multicentre, open-​label, ran- domised trial. Lancet, 381, 205. Malfertheiner P, et al. (2011). Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-​ based triple therapy:  a randomised, open-​label, non-​inferiority, phase 3 trial. Lancet, 377, 905–​13. Malfertheiner P, et al. (2012). Management of Helicobacter pylori in- fection –​ the Maastricht IV/​Florence Consensus Report. Gut, 61, 646–​64.

15.8  Peptic ulcer disease 2861 Marmo R, et al. (2007). Dual therapy versus monotherapy in the endo- scopic treatment of high-​risk bleeding ulcers:  a meta-​analysis of controlled trials. Am J Gastroenterol, 102, 270–​89. Marshall BJ, Warren JR (1984). Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1, 1311–​15. Masferrer JL, et  al. (1994). Selective inhibition of inducible cyclooxygenase-​2 in vivo is anti-​inflammatory and non-​ulcerogenic. Proc Natl Acad Sci U S A, 91, 3228–​32. McColl KE, El-​Omar E (1996). Helicobacter pylori and disturbance of gastric function associated with duodenal ulcer disease and gastric cancer. Scand J Gastroenterol Suppl, 215, 32–​7. Patrono C, et  al. (2005). Low dose aspirin for the prevention of atherothrombosis. N Engl J Med, 353, 2373–​83. Rockall TA, et al. (1995). Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage, BMJ, 311, 222–​6. Rostom A, et al. (2002). Prevention of NSAID-​induced gastroduodenal ulcers. Cochrane Database Syst Rev, 4, CD002296. Sacks HS, et al. (1990). Endoscopic haemostasis: an effective therapy for bleeding peptic ulcers. JAMA, 264, 494–​9. Silverstein FE, et al. (1981). National ASGE survey on upper gastro- intestinal bleeding:  study design and baseline data. Gastrointest Endosc, 27, 73–​9. Silverstein FE, et  al. (1995). Misoprostol reduces serious gastro- intestinal complications in patients with rheumatoid arthritis receiving non-​steroidal anti-​inflammatory drugs. A  random- ized double-​blind placebo-​controlled trial. Ann Intern Med, 123, 241–​9. Sonnenberg A. (1995). Temporal trends and geographical variations of peptic ulcer disease. Aliment Pharmacol Ther, 9 Suppl 2, 3. Sung JJY, et al. (1995). Antibacterial treatment of gastric ulcers associ- ated with Helicobacter pylori. N Engl J Med, 332, 139–​42. Sung JJY, et  al. (2007). Endoscopic clipping versus injection and thermo-​coagulation in the treatment of non-​variceal upper gastro- intestinal bleeding: a meta-​analysis. Gut, 56, 1364–​73. Sung JJY, et al. (2009). Intravenous esomeprazole for prevention of re- current peptic ulcer bleeding: a randomized trial. Ann Intern Med, 150(7), 455–​64. Sung JJY, et  al. (2010). Causes of mortality in patients with peptic ulcer bleeding:  a prospective cohort study of 10,428 cases. Am J Gastroenterol, 105(1), 84–​9. Sung JJY, et al. (2010). Continuation of low-​dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med, 152, 1–​9. Sung JJY et al. (2014). Effects of intravenous and oral esomeprazole in the prevention of recurrent bleeding from peptic ulcers after endo- scopic therapy. Am J Gastroenterol, 109(7), 1005–​10. Taha AS, et al. (1996). Famotidine for the prevention of gastric and duodenal ulcers caused by non-​steroidal anti-​inflammatory drugs. N Engl J Med, 334, 1435–​9. Vane JR (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-​like drugs. Nat New Biol, 231, 232–​5. Villanueva C, et  al (2014). Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med, 368, 11–​21. Walan A, et al. (1989). Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N Engl J Med, 320, 69–​75. Wallace JL, et al. (2000). NSAID-​induced gastric damage in rats: require- ment for inhibition of both cyclooxygenase 1 and 2. Gastroenterology, 119, 706. Wyatt JI, et al. (1987). Campylobacter pyloridis and acid induced gastric metaplasia in the pathogenesis of duodenitis. J Clin Pathol, 40, 841–​8. Yeomans ND, et  al. (1998). A comparison of omeprazole with ra- nitidine for ulcers associated with nonsteroidal anti-​inflammatory drugs. Acid suppression trial:  Ranitidine versus omeprazole for NSAID-​associated ulcer treatment (ASTRONAUT) study group. N Engl J Med, 338, 719–​26.

15.9 Hormones and the gastrointestinal tract 2862

15.9 Hormones and the gastrointestinal tract 2862

15.9.1 Hormones and the gastrointestinal tract 286

15.9.1 Hormones and the gastrointestinal tract 2862

CONTENTS 15.9.1 Hormones and the gastrointestinal tract  2862 Rebecca Scott, T.M. Tan, and S.R. Bloom 15.9.2 Carcinoid syndrome  2870 B. Khoo, T.M. Tan, and S.R. Bloom 15.9.1  Hormones and the gastrointestinal tract Rebecca Scott, T.M. Tan, and S.R. Bloom ESSENTIALS The gastrointestinal tract is the largest endocrine organ in the body, with its component cells dispersed along its length rather than being clustered in glands. More than 20 gut peptides integrate gastrointestinal function by regulating the actions of the epithe- lium, muscles, and nerves; they also affect the growth and devel- opment of the gut and have a major role in appetite control. They mostly work in an autocrine or paracrine manner. Gastrointestinal hormones include the gastrin–​cholecystokinin family, the secretin superfamily, preproglucagon derivatives, the motilin–​ghrelin family, the pancreatic polypeptide-​fold family, and various other gut peptides. Gastrointestinal and other diseases may cause abnormalities of these gut peptides, for example: (1) achlorhydria (from atrophic gastritis or drug-​induced) causes elevation of circulating gastrin; (2) malabsorptive conditions are associated with a decrease in the amount of peptides produced in the affected region, and a com- pensatory elevation of other peptides; and (3) obesity is associated with an imbalance of orexigenic (appetite-​stimulating) versus less ­satiating hormonal changes, and the beneficial effects of bariatric surgery are partly explained through alterations in gut hormones. Introduction William Bayliss and Ernest Starling discovered secretin, the first recognized hormone, from a section of dog jejunum in 1902. The gastrointestinal tract is now recognized as the largest endocrine organ in the body. It produces more than 20 substances that act as hormones or neurotransmitters within the gastrointestinal tract and its associated nervous system. These substances have a diverse range of roles, from gastrointestinal motility, absorption, and growth to control of glucose homeostasis, appetite, and metabolism. Recent advances, such as the identification of REG4 and NEUROG3 genes as markers of hormone-​producing enteroendocrine cells, will help identify further hormone-​secreting cells and possibly new gastro- intestinal hormones. This chapter will describe the gut peptide hormones and neuro- transmitters in terms of their structure and function. It will then look at the effects of gastrointestinal disease on gut hormones. The end of the chapter will focus on alterations of gut hormones after bariatric surgery, and their potential therapeutic uses. Gut peptides The enteroendocrine cells that secrete gut hormones are widely dis- persed throughout the gut and pancreas (Fig. 15.9.1.1). Traditionally, enteroendocrine cells have been characterized by their location, morphology, and the hormones they secrete. Recent studies have suggested that there is greater overlap between cells, with multiple hormones being transcribed in each cell. This may provide the in- testine with a degree of adaptability. Nevertheless, as individual cells tend to produce one hormone in greater quantities than others, and cells that produce the same hormone typically cluster together, the traditional delineation of which enteroendocrine cell produces which hormone will be used here. Electron microscopy demonstrates that hormones are stored in specific peptide storage granules within cells, which are subse- quently released by exocytosis (Fig. 15.9.1.2). Enteroendocrine cells can be divided into two types: open-​type and closed-​type cells. The open-​type cells have direct contact with the intestinal lumen via ap- ical cytoplasmic processes, while the closed-​type cells do not directly 15.9 Hormones and the gastrointestinal tract

15.9.1  Hormones and the gastrointestinal tract 2863 contact the intestinal lumen. The interplay of luminal, hormonal, and neural signals affects the function of both of these cell types. Molecular cloning techniques have shown that many peptides originate from the same precursor or family. The gut peptides will now be classified according to their common structure or precursor. Gastrin–​cholecystokinin family Gastrin Gastrin is made in G cells of the gastrointestinal tract. Most G cells are found in the antrum of the stomach. Gastrin is initially pro- duced as 101-​amino acid preprogastrin, but subsequently cleaved to a number of active peptides. These include G6, G14, G17, G34, G54 and G71, though G17 and G34 are the predominant forms in the circulation. The biological activity resides in the four C-​terminal amino acids of all these forms. Gastrin release is stimulated by several factors including gas- tric distension, luminal contents (in particular amino acids and calcium), vagal stimulation, and the presence of gastrin-​releasing peptide. Release is inhibited by somatostatin and secretin. Gastrin activates the cholecystokinin (CCK)-​2 receptor, found mainly on enterochromaffin-​like cells and parietal cells. It simulates gastric acid secretion, mainly via a paracrine effect on the enterochromaffin-​like cells, which then release histamine that activates the parietal cells. Additionally, gastrin has proliferative effects on the gastric mucosa, and also causes gastric remodelling, which may be involved in the development of gastric cancers. Cholecystokinin CCK is produced by I cells in the duodenum, jejunum, and proximal ileum, and also the myenteric plexus and brain. CCK and gastrin contain five identical amino acids at the C-​terminus, but the speci- ficity of CCK is determined by the adjacent three amino acids, such that the octapeptide is the biologically active form (Fig. 15.9.1.3). Like gastrin, CCK refers to a family of biologically active peptides. It is initially produced as prepro-​CCK, a 115-​amino acid polypep- tide, but cleaved to peptides 58, 39, 33, 22, 12, and 8 amino acids in length. Release is stimulated by luminal products of the digestion of fat and protein, and by the pancreatic secretory trypsin inhibitor-​1 (monitor peptide). CCK is a ligand for CCK-​1 and CCK-​2 receptors. These are widely distributed, being found in the intestine, pancreas, gallbladder, oe- sophagus, brain, and peripheral nerves. CCK has multiple func- tions. These include stimulation of pancreatic enzyme secretion, trophic effects on the pancreas, potentiation of secretin-​induced bicarbonate production, contraction of the gallbladder, relaxation of the sphincter of Oddi, inhibition of gastric acid secretion, regu- lation of bowel motility, and delay in gastric emptying. Clinically it is used to measure pancreatic exocrine secretion, sphincter of Oddi manometry, and in radiological examination of the gallbladder. CCK rises postprandially and acts as a satiety signal; however, clinical trials of CCK analogues as an antiobesity therapy have not been successful. Secretin superfamily The secretin superfamily includes secretin, vasoactive intestinal peptide (VIP), glucose-​dependent insulinotropic peptide/​gastric inhibitor peptide (GIP), peptide histidine-​isoleucine amide/​peptide GLP-1 GLP-2 Oxyntomodulin Glicentin PYY(3–36) Somatostatin Large intestine Cholecystokinin Secretin GIP Motilin Somatostatin Small intestine Ghrelin Gastrin Obestatin Stomach Insulin Glucagon Pancreatic polypeptide Amylin Somatostatin Pancreas Fig. 15.9.1.1  The gastrointestinal tract releases a number of hormones from different areas. These hormones signal to the periphery and to the central nervous system to affect a number of biological functions. Fig. 15.9.1.2  Electron micrograph showing the typical morphology of an endocrine cell of the gut mucosa, with well-​developed microvilli at the luminal border and secretory granules grouped towards the basal membrane (magnification ×5500). Gastrin (G-17) (pyro) E-G-P-W-L-E-E-E-E-E-A-Y-G-W-D-F-NH2 K-A-P-S-G-R-V-S-M-I-K-N-L-Q-S-L-D- P-S-H-R-I-S-D-R-D-Y-M-G-W-M-D-F-NH2 SO3H SO3H Cholecystokinin Fig. 15.9.1.3  Amino acid sequences of gastrin (G-​17) and cholecystokinin, demonstrating the shared pentapeptide tail, and the three additional amino acids that confer activity to cholecystokinin.

SECTION 15  Gastroenterological disorders 2864 histidine methionine amide, orexins, growth hormone-​releasing factor, pituitary adenylate cyclase-​activating polypeptide (PACAP), and preproglucagon derivatives. Secretin Secretin is a 27-​amino acid polypeptide produced by S cells scattered through the duodenum and jejunum. Secretin-​immunoreactive cells are also found in the brain. Secretin acts on a G protein-​coupled receptor found in the brain, pancreas, intestine, kidney, and biliary epithelium. Hydrochloric acid potently stimulates secretin release, and a duodenal pH less than 4.5 causes significant secretin production. Additional stimulants to release are bile and the products of fat di- gestion. Secretin reduces gastric acid production and stimulates the release of a bicarbonate-​rich, alkaline pancreatic fluid. It also re- duces gastric motility, stimulates bile secretion, and induces insulin release. Secretin may play a role in the developing gastrointestinal tract, with high concentrations in the early postnatal period. Glucose-​dependent insulinotropic peptide GIP is a 42-​amino acid peptide secreted from intestinal K cells that are found most abundantly in the proximal small intestine. GIP re- lease is stimulated by food consumption, particularly glucose, long-​ chain fatty acids, and their monoglycerides. At pharmacological doses, GIP inhibits gastric secretions, hence its original name of gastric inhibitor peptide. However its pre- dominant physiological role is as an incretin, enhancing glucose-​ stimulated insulin secretion (Fig. 15.9.1.4). The incretin effect in type 2 diabetes is reduced in part due to a reduction in the effect of GIP. GIP increases insulin production and pancreatic beta-​cell proliferation, and reduces beta-​cell apoptosis; but it also causes glucagon secretion, and subsequent hyperglycaemia, preventing it being a diabetes treatment. The additional physiological effects of GIP are still debated. GIP receptors are found on adipose tissues, but studies have shown GIP to both promote fat deposition and to cause lipolysis. GIP reduces bone resorption, and a common mutation in the GIP receptor increases bone fracture risk. GIP receptors are also widely expressed in the brain, and may have a role in memory. There is increasing evidence suggesting drugs that are combined agonists at the GIP, glucagon-​like peptide (GLP)-​1, and glucagon receptors may be effective treatments for diabetes and obesity. Vasoactive intestinal polypeptide VIP is a 28-​amino acid neurotransmitter widely produced in the in- testine, as well as the nervous, respiratory, and reproductive systems. It acts on VIP receptors type 1 and 2 (VPAC1 and VPAC2), which are widely expressed, reflecting the diverse actions of VIP. Within the gastrointestinal tract it stimulates secretion of water and elec- trolytes in the gastrointestinal lumen, and increases gastrointestinal motility. It has insulinotropic and antiapoptotic effects on the pan- creas. VIP affects food intake and fat deposition, and affects release of other gastrointestinal hormones including GLP-​1 and peptide tyrosine-​tyrosine (PYY). Peptide histidine isoleucine amide This 27-​amino acid peptide derives its name from an N-​terminal his- tidine, and a C-​terminal isoleucine amide. It is produced throughout the intestine, with highest concentrations in the colon, but is also found in the brain, respiratory system, and reproductive system. It colocalizes with VIP and has a range of actions, including stimu- lating the secretion of pancreatic juice and amylase, the release of glucagon, and augmenting water and electrolyte transport in the jejunum. Neurotransmitters of the secretin family: orexins, GHRF, and PACAP PACAP is a neurotransmitter of 38 amino acids, which has signifi- cant homology to VIP. PACAP is present in several peripheral tis- sues, including the gastrointestinal tract, adrenal gland, and testes. It acts on VIP receptors and PAC1 receptors. PACAP stimulates salivary, gastrointestinal and pancreatic secretions; relaxes gastro- intestinal smooth muscle; and suppresses food intake. It is also in- volved in the control of circadian rhythm, learning, memory, and anxiety. Orexins A and B (also known as hypocretins) are, respectively, 33-​ and 28-​amino acid peptides, formed from post-​translational processing of the same precursor. Their highest concentration is in the hypothalamus, but they are widely expressed, including in the gastrointestinal tract. Orexin B has an appetite-​stimulating effect, while orexin A is involved in sleep control, with defects being asso- ciated with narcolepsy. CCK downregulates orexin expression, and may reduce food intake in this way. Growth hormone-​releasing factor, a 44-​amino acid peptide, is found predominantly in the hypothalamus. At low doses it stimu- lates feeding, while at high doses it suppresses feeding. Preproglucagon derivatives The preproglucagon gene is found on chromosome 2. The trans- lated 180-​amino acid polypeptide is expressed in the alpha-​cells of the pancreas, L-​cells of the intestine, and within the brain. Within the pancreas, the enzyme proconvertase 2 converts this polypep- tide into glucagon, glicentin-​related pancreatic peptide, and major proglucagon fragment. In the intestine and brain, proconvertase 1/​3 cleaves the prohormone into a number of related peptides: glicentin Blood glucose Plasma insulin Time Plasma insulin after oral administration of glucose Plasma insulin after oral administration of glucose Blood glucose after oral administration of glucose Blood glucose after IV administration of glucose Fig. 15.9.1.4  Representation of the incretin effect. Administration of the same amount of glucose as an oral dose (green lines) compared to an intravenous dose (blue lines) causes a similar change in plasma glucose level (solid lines), but a relatively greater increase in insulin releases (dashed lines). This is due to glucose within the intestine leading to GLP-​1 and GIP release, which stimulate insulin secretion.

15.9.1  Hormones and the gastrointestinal tract 2865 (also known as enteroglucagon), GLP-​1, GLP-​2, and oxyntomodulin (Fig. 15.9.1.5). Glicentin This is a 69-​amino acid peptide, containing a glucagon molecule with an N-​terminal extension (glicentin-​related pancreatic polypep- tide). It is released from the L cells of the intestine after a mixed meal, particularly of carbohydrate and long-​chain fatty acids. The amount of glicentin secreted is proportional to the amount of unabsorbed food entering the colon, so high glicentin concentrations are found in conditions where the absorptive capacity of the small intestine is lost. It acts to reduce digestive secretions, delay gastric emptying, and increase insulin secretion, and it has a trophic effect on the gut. Glucagon-​like peptide-​1 GLP-​1 is secreted as GLP-​11–​37, GLP-1 (7-36) amide and GLP-​17–​37. The GLP-1 (7-36) amide and GLP-​17–​37 moieties have biological activity, and are rapidly degraded in the plasma by the enzyme dipeptidylpeptidase-​4 (DPP-​4). GLP-​1 is secreted following direct contact of nutrients with the intestinal lumen, and by a neuroendo- crine circuit involving the vagus nerve and the hormone GIP. GLP-​1 stimulates insulin release and lowers blood sugar. Endo­ genous GLP-​1 is an incretin, enhancing insulin release following oral consumption of glucose. Long-​acting analogues of GLP-​1 are widely used to treat type 2 diabetes, as are DPP-​4 inhibitors, which act by enhancing the action of endogenous GLP-​1. GLP-​1 has additional effects in the pancreas, enhancing beta-​cell proliferation, inhibiting glucagon secretion, and reducing apoptosis. Evidence that GLP-​1 analogues may lead to acute pancreatitis and pancreatic cancer has been equivocal, hence clinical vigilance is suggested. GLP-​1 induces satiety through actions on the vagus nerve and the central nervous system (Fig. 15.9.1.6), and GLP-​1 analogues are now being used to treat obesity by reducing appetite. GLP-​1 is found in the taste cells of the gastrointestinal tract, and modulates preference for sweet food. Glucagon-​like peptide-​2 GLP-​2 has trophic effects on the intestine, enhancing crypt cell pro- liferation and reducing enterocyte apoptosis. It also enhances nutrient absorption and increases intestinal blood flow, and GLP-​2-​based drugs are used clinically to enhance nutrient absorption in patients with short bowel syndrome. Oxyntomodulin Oxyntomodulin is a 37-​amino acid polypeptide that consists of a glucagon molecule with a C-​terminal extension. There is no known oxyntomodulin-​specific receptor, but it activates both the GLP-​1 and glucagon receptors, though to a lesser extent than either cog- nate ligand. It is released postprandially, and is a potent inhibitor of gastric motility and gastric acid secretion. Its actions on the GLP-​1 receptor mean it induces satiety, while activation of the glucagon receptor increases energy expenditure. In humans, the increase in energy expenditure caused by oxyntomodulin may be via increased physical activity, whereas animal data suggests it increases resting energy expenditure. Drugs that mimic the actions of oxyntomodulin are in development as potential treatments for obesity. PS GRPP GRPP GRPP Glucagon Glucagon Glucagon Glucagon IP1 IP1 Oxyntomodulin Glicentin IP1 GLP-1 GLP-1 GLP-1 Major Proglucagon Fragment Pancreas (proconvertase 2) Brain/intestine (proconvertase 1/3) GLP-2 GLP-2 GLP-2 IP2 IP2 Fig. 15.9.1.5  Major active derivatives of the preproglucagon gene. In the pancreas, proconvertase 2 predominantly produces glucagon; additional fragments include glicentin-​related polypeptide (GRPP) and the major proglucagon fragment (GRPP + glucagon + IP1). In the central nervous system and the intestine, alternative processing by proconvertase 1/​3 produces GLP-​1, GLP-​2, oxyntomodulin, and glicentin. Fig. 15.9.1.6  Section showing c-​fos staining of the paraventricular nucleus in mice after administration of the GLP-​1 analogue Exendin-​4.

SECTION 15  Gastroenterological disorders 2866 Motilin–​ghrelin family Preproghrelin is subsequently processed into either the 28-​amino acid peptide ghrelin, or the 23-​amino acid amidated peptide obestatin. Motilin is a 22-​amino acid peptide that shares 50% hom- ology with ghrelin. Ghrelin and motilin act on receptors that are part of the same G protein-​coupled receptor family. The receptor for obestatin remains uncertain, and early reports of it acting on the GPR39 receptor have not been replicated. Motilin Motilin is a 22-​amino acid peptide produced by intestinal M cells. These are found in the jejunum, duodenum, and to a lesser degree the stomach antrum. Motilin is released in the interdigestive period, in as- sociation with period 3 of the migrating motor complex that controls gastrointestinal motility. After meals, it is released in response to duo- denal acidification, and also to mechanical influences on the gastro- intestinal tract. Motilin acts to enhance gastrointestinal motility. Erythromycin activates the motilin receptor and is the basis for its role in gastric motility, helping those with delayed gastric emptying. Motilin agonists are in phase II trials in the treatment of gastroparesis. Ghrelin Ghrelin is a 28-​amino acid peptide that is n-​octanoylated on the third residue by the enzyme Ghrelin-O-acyltransferase (GOAT). It is produced predominantly by the X/​A-​like cells of the stomach, though is found in small amounts in the intestine, pancreas, kid- neys, pituitary, and hypothalamus. Ghrelin was first characterized as a growth hormone secretagogue, but its major action is to stimu- late food intake. Ghrelin is the only known orexigenic (appetite-​ stimulating) hormone (as opposed to an autocrine or paracrine agent), with endogenous levels rising during fasting and falling postprandially. The rise in ghrelin also stimulates growth hormone release which protects blood glucose levels during fasting. Ghrelin has potential to stimulate appetite in chronic conditions associated with anorexia such as cancer, renal failure, and dialysis; antagonists have been trialled as obesity therapies, but have not been successful. Ghrelin causes a preference for sweet food, though the mechanism by which this happens is not yet understood. Additionally, ghrelin inhibits nausea and increases gastric emptying. Obestatin Obestatin is 23-​amino acid amidated peptide produced by the stomach. Initial rodent studies found obestatin suppresses food in- take and reduces body weight, but subsequent studies refuted this. Obestatin may be involved in processes such as sleep, memory, and anxiety; it may also have protective effects in the gastrointes- tinal tract, reducing development of acute pancreatitis, colitis, and helping the healing of gastric ulcers. Pancreatic polypeptide-​fold family The pancreatic polypeptide-​fold (PP-​fold) family includes the gut hormone peptide tyrosine-​tyrosine (PYY), the neurotransmitter neuropeptide Y, and pancreatic polypeptide found in pancre- atic islets. All are 36-​amino acid peptides that require C-​terminal amidation for bioactivity, and share the PP-​fold structural motif. They interact with the Y family of receptors that couple to inhibitor G proteins and are probably derived from a common ancestral gene. Peptide tyrosine-​tyrosine PYY is secreted as PYY1–​36 by the L cells of the intestine, and is con- verted to the biologically active PYY3–​36 by dipeptidylpeptidase 4 in plasma. PYY3–​36 is a specific agonist for the Y2 receptor, which is densely expressed in the arcuate nucleus of the hypothalamus. It is released following a meal in proportion to energy content con- sumed; protein stimulates PYY release more than other macronutri- ents. PYY is a satiety signal, with levels falling during fasting. It also delays gastric emptying, decreases intestinal motility, and inhibits gastric acid secretion. PYY modulates the rewarding properties of food, and higher endogenous levels are associated with disordered eating. Neuropeptide Y Neuropeptide Y (NPY) is a widely expressed neurotransmitter, often colocalized with noradrenaline. It is found in the extrinsic adren- ergic nerves of the myenteric plexus, and in the intrinsic nerves of the myenteric and submucosal plexi, with highest concentrations in the upper intestine and distal colon. In the gut it is a potent vasocon- strictor, it inhibits intestinal secretion, and it depresses colonic mo- tility. NPY is an important neurotransmitter in the central nervous system, and expression within the hypothalamus stimulates feeding. Pancreatic polypeptide Pancreatic PP is secreted by PP cells of the endocrine pancreas, and in small amounts by the distal intestine. It binds to the Y4 receptor, which is widely distributed in the central nervous system. PP is released in response to oral nutrients, and through vagal stimula- tion during the cephalic phase of ingestion. PP inhibits pancreatic exocrine secretion of enzymes and bicarbonate, and enhances the insulin-​induced decrease in hepatic glucose output. It acts as a sa- tiety signal and slows gastric emptying. Other gut peptides Bombesin and the gastrin-​releasing peptides Bombesin is a 1620-​Da peptide of 14 amino acids, isolated from amphibian skin. It stimulates gastrin release and hence gastric acid secretion. Mammalian bombesin has not been isolated, but a number of peptides which share the biologically active C-​terminal sequence have been found. These include gastrin-​releasing pep- tide, neuromedin B, and neuromedin C. Gastrin-​releasing peptide (GRP) is 27 amino acids long and found in the intrinsic neurons of the myenteric and submucosal plexi, particularly in the stomach and pancreas, and also in the mammalian central nervous system. It reduces food intake, and affects circadian rhythm, the sensation of itch, memory, smooth muscle contractions, and sexual behaviour. Neuromedin B is expressed in the hypothalamus and controls the stress, thyroid, and reproductive axes. It also reduces food intake. Neuromedin B and GRP work on the BB1 and BB2 receptors re- spectively. A BB3 receptor has been cloned, though its endogenous ligand has not been isolated; however, the receptor may have a role in glucose homeostasis. Neuromedin C affects pancreatic exocrine and endocrine secretion. Opioids The opioids met-​enkephalin, leu-​enkephalin, β-​endorphin, and dynorphin are found in enteric neurons and mucosal endocrine

15.9.1  Hormones and the gastrointestinal tract 2867 cells. The μ, κ, and δ-​opioid receptors are found throughout the gastrointestinal tract. Their effects include delaying transit through the small and large intestine, inhibiting gastric emptying, and inhibiting fluid and electrolyte secretion. These combine to cause constipation: opioids have been used to treat diarrhoea for centuries. Endogenous opioids reduce inflammation within the gastrointes- tinal tract, and maintain gastric mucosal integrity, so modulation of this system may be useful in inflammatory bowel disease. Endocannabinoids Humans produce a large number of endogenous endocannabinoids. These act on CB1 and CB2 receptors. The CB1 receptor is important in energy homeostasis, as activation increases food intake. Some obese people have been shown to have mutations in the gene coding for the FAAH enzyme, which leads to increased activity of the CB1 receptor. The inverse agonist for the CB1 receptor, rimonabant, has been used as a treatment for obesity. Endocannabinoids also regu- late gut motility, inflammation, and pain. Tachykinins There are two tachykinin genes: preprotachykinin A (TAC1) which encodes substance P and neurokinin A, and preprotachykinin B (TAC3) which encodes neurokinin B. These are excitatory neuro- transmitters which are released in response to inflammation and in- fection, and regulate pain, secretion, and motility. The tachykinins are responsible for the diarrhoea and gastrointestinal side effects seen after chemotherapy, radiotherapy, and certain infections. NK1-​ R receptor antagonists have been approved to treat nausea associ- ated with chemotherapy and radiotherapy. Neurotensin Neurotensin is a 13-​amino acid peptide found in the CNS, en- teric neurons, and N cells of the gastrointestinal tract. N cells are predominantly found in the ileum, but are spread throughout the gastrointestinal tract. Release is stimulated by intestinal fatty acids. Central and peripheral administration of neurotensin reduces appetite in rodent models. It helps protect the gastric mucosa by stimulating growth and preventing apoptosis, reducing acid secre- tion, and decreasing gastric motility. It also enhances pancreatic secretion and insulin release, and prevents apoptosis in pancreatic acinar cells. Somatostatin Somatostatin is cleaved from a 122-​amino acid precursor to a number of different forms. The 28-​amino acid form is secreted by D cells that are widely distributed in the gastrointestinal tract and pancreas; in enteric neurons the 14-​amino acid form predomin- ates. Release is stimulated by food consumption, particularly fat and proteins. Somatostatin has a wide range of roles, but importantly it suppresses all the activities of the gastrointestinal tract. It reduces secretions from the salivary glands, biliary tree, the stomach, and pancreas. It suppresses hormone release, including gastrin, secretin, motilin, enteroglucagon, CCK, VIP, GIP, intrinsic factor, pepsin, neurotensin, insulin, PP, and glucagon. It inhibits gastrointestinal motility, reduces visceral blood flow, and limits cell growth and re- newal within the gastrointestinal tract. Somatostatin analogues have a number of clinical uses, including the treatment of acromegaly and imaging of neuroendocrine tumours. Amylin Also known as islet amyloid polypeptide, amylin is a 37-​amino acid peptide released from pancreatic beta-​cells in response to food consumption. Amylin primarily reduces blood glucose levels, but pharmacological dosing leads to reduced food intake. Synthetic amylin has been approved in for use in the United States of America in diabetic patients treated with insulin and trials of amylin com- bined with other potential weight loss drugs, including leptin and sibutramine, continue. Peptide neurotransmitters Calcitonin gene-​related peptide (CGRP) is a 37-​amino acid peptide formed by alternative processing of the calcitonin gene transcript, and is related to amylin. It is found in the extrinsic sensory neurons and intrinsic neurons of the intestine. It reduces food intake, gastric acid and pancreatic secretion, protects against gastric ulcers, and af- fects gastrointestinal motility. It also plays a role in detection of co- lonic pain and inflammation. Nesfastin-​1 is an 82-​amino acid peptide produced from the pre- cursor nucleobindin-​2 in the pancreas and gastric mucosa, and is also expressed in the brain. It reduces food intake and controls gastrointestinal motility. Galanin is a 30-​amino acid peptide in humans, found in enteric neurons. It acts through three distinct G-​coupled protein recep- tors, and within the gastrointestinal tract, stimulates feeding, re- duces gastric acid secretion, influences gastric emptying, and affects gastrointestinal motility. Endothelins comprise three different peptides: ET-​1, ET-​2, and ET-​3. ET-​1 is expressed in multiple gastrointestinal tissues including vascular endothelium, submucosal stroma, and muscle. It causes both contraction and relaxation of the gastrointestinal tract depending on which receptor is activated, and has effects on vascular tone and perfusion. ET1 is elevated in a number of inflammatory conditions, including inflammatory bowel disease and peptic ulcer disease, and this may reduce perfusion to the intestinal mucosa and slow healing. Alterations in hormones in gastrointestinal
and other diseases Gastric pathology and hypergastrinaemia Achlorhydria refers to a condition of low or absent secretion of hydrochloride acid within gastric secretions. It has a number of causes, including atrophic gastritis, bacterial overgrowth, intes- tinal metaplasia, pernicious anaemia, uraemia, long-​term use of proton pump inhibitors, and H2 inhibitors. The lack of feedback from acid secretion causes hyperplasia of gastrin-​secreting G cells. The subsequent elevation in gastrin levels causes hyperplasia of enterochromaffin-​like cells (Fig. 15.9.1.7), which leads to carcinoid tumours; there is also an increased risk of gastric cancer. To date, there is no evidence that long-​term proton pump inhibitor or H2 inhibitor use causes gastric carcinoids. Peptic ulcer disease is not normally associated with abnormal- ities in gut peptide secretion. However, in some studies, gastrin release is increased by Helicobacter pylori infection. CCK-​B re- ceptor antagonists, which block the effects of gastrin, may be useful in the treatment of gastric ulcers. Additionally, reduced

SECTION 15  Gastroenterological disorders 2868 somatostatin levels in patients infected with H. pylori may influ- ence the paracrine regulation of gastric function. Dumping syndrome Subsequent to vagotomy or gastrectomy, there is increased speed of gastric emptying and food enters the small intestine rapidly. This may manifest itself as the symptoms of ‘dumping syndrome’, with sweating, fainting, flushing, weakness, feelings of hunger, and rapid heart rate. In those with dumping syndrome, there is a concurrent alteration in gut hormone response, with VIP, glicentin, and neurotensin all rising above the levels expected after a meal, while motilin release is reduced. The increase in VIP and neurotensin may contribute to the postprandial hypotension associated with dumping syndrome. Inflammatory bowel disease Altered levels of gut hormones are found in inflammatory bowel dis- ease. In ulcerative colitis, colonic PYY levels are reduced, in favour of the L-​cells producing higher levels of enteroglucagon and GLP-​1. There is increased release of GIP, gastrin, glicentin, ghrelin, motilin, and pancreatic polypeptide. In contrast, tachykinin levels are reduced. In Crohn’s disease, there are increased numbers of terminal ileal cells containing GLP-​1, but no increase in plasma GLP-​1. However, there are raised levels of GIP, ghrelin, motilin, and enteroglucagon, while PYY is reduced. Changes in gastrointestinal hormones may be re- sponsible for altered appetite and nutrient handling in inflammatory bowel disease. Elevated levels of endothelin have been reported in both ulcerative colitis and Crohn’s disease, and oral administration of an endothelin receptor antagonist in a model of colitis has been found to ameliorate diarrhoea and tissue damage. Endocannabinoids reduce inflammation, and research continues as to their therapeutic value in inflammatory bowel disease. Irritable bowel syndrome Irritable bowel syndrome is characterized by diarrhoea, constipation, bloating, and abdominal discomfort. Levels of enteric hormones do change, but the exact pattern varies in patients depending on the predominant phenotype. In most, CCK and VIP levels are raised, while PYY and NPY are reduced. However motilin and gastrin immunoreactivity appear higher in those with diarrhoea-​ predominant irritable bowel syndrome. Malabsorption Malabsorptive conditions are associated with a decrease in the amount of peptides produced in the affected region, and a com- pensatory elevation in other peptides, particularly those trophic peptides implicated in the bowel’s adaptation to loss of absorptive surface, such as enteroglucagon (Fig. 15.9.1.8). In coeliac disease, PYY, ghrelin, enteroglucagon, and neurotensin are elevated while GLP-​1, amylin, secretin, and GIP are reduced. Elevated enteroglucagon has a trophic effect on the small intestinal mucosa, while increased PYY may affect pancreatic and biliary se- cretion. In tropical sprue, PYY and enteroglucagon are also elevated, as are motilin levels, but the other hormone levels are normal. In both sprue syndromes, treatment normalizes gut hormones. The malabsorption associated with pancreatic exocrine insuf- ficiency of any cause leads to an excess of nutrients in the colon, and as a result, the concentrations of enteroglucagon, PYY, and neurotensin are raised. The gut adaptation resulting from the effects of these peptides may contribute to the improvement in absorptive function with age in patients with cystic fibrosis. Neuropathic disease In conditions where there is destruction of intrinsic enteric nerves, neuroendocrine peptides are also affected. In Hirschsprung’s disease, where children have aganglionic bowel segments, VIP, substance P, PACAP, and neurotensin levels are reduced, while NPY-​ containing neurons are not. These changes may contribute to the defect in intestinal relaxation. There are also increased numbers of neuroendocrine cells producing PYY, somatostatin, and serotonin, which contribute to sustained intestinal contraction. Fig. 15.9.1.7  Histological section of gastric fundus (oxyntic mucosa) from a patient with pernicious anaemia. Long-​standing achlorhydria has led to hyperplasia of enterochromaffin-​like cells, demonstrated by immunostaining of the general endocrine cell marker chromogranin. In addition to the abnormally high number of cells in the mucosa, small nodules (microcarcinoids) have formed in the submucosa (magnification ×180). % 1400 1200 1000 800 600 400 200 Normal Gastrin HPP Insulin GIP Secretin Motilin Neurotensin Enteroglucagon Fig. 15.9.1.8  The percentage incremental rise in gut hormones following a standard test breakfast in patients with coeliac disease compared with normal controls.

15.9.1  Hormones and the gastrointestinal tract 2869 In Chagas’ disease there is destruction of enteric nerves due to chronic infection with Trypanosoma cruzi. There is a general re- duction in neural innervation, and greatly reduced levels of sub- stance P in biopsies from these areas. However, there is a relative increase in neurons that express VIP within the myenteric plexus, and this may be essential in allowing Chagas’ patients to survive for many years, as VIP is essential for the maintenance of mucosal integrity. Diarrhoea In infants with acute gastroenteritis, there is an increase in enteroglucagon, glucagon, PYY, and motilin levels, while galanin-​1 is responsible for increased colonic secretion in rodent models of rotavirus, Salmonella typhimurium, shigella, and Escherichia coli in- fections. In patients with functional diarrhoea, pancreatic polypep- tide levels are increased. Obesity Many of the gut hormones have effects on food intake and energy expenditure—​PYY, PP, GLP-​1, oxyntomodulin, and CCK—​are anorexigenic, while ghrelin is orexigenic. These act via the ‘gut–​brain axis’, transmitting signals from the gastrointestinal tract to the hypo- thalamus and brainstem directly, and indirectly via the vagus nerve. These should work to keep weight stable, with energy intake and expenditure equal, but given the increasing prevalence of obesity it is clear that this system is not flawless. In obesity, the hormonal milieu changes to be orexigenic and less satiating, with lower fasting levels of PYY3–​36, PP, and CCK, lower postprandial rises in PYY and GLP-​1, while there is a higher proportion in ghrelin in the active, acylated state, and ghrelin levels fail to fall after eating. Moreover, these changes are exacer- bated in dieting: fasting ghrelin and NPY increase, while GIP, PP, and amylin all fall. The reduced levels of satiety hormones may contribute to the rebound in body weight commonly seen when people stop dieting. After gastrointestinal surgery The changes seen postoperatively depend on the type and extent of surgery. After subtotal gastrectomy for early gastric cancer, there is a rapid change in the levels of gut hormones ghrelin, obestatin, and PYY, but these normalize in 3 days, suggesting that there are com- pensatory mechanisms. After total gastrectomy, PYY levels tend to increase overall, possibly to compensate for the rapid gastric transit. In short bowel syndrome, levels of PYY, enteroglucagon, and VIP have been reported to change, but increments or decrements depend on the extent of the resection. Bariatric surgery Bariatric surgery is at present the most effective and long-​lasting treatment for obesity. This is in part through alterations in gut hor- mones to produce a more anorexigenic environment (Table 15.9.1.1). After Roux-​en-​Y bypass, GLP-​1, PPY, oxyntomodulin, glucagon, and CCK levels are all increased, while ghrelin levels fall. There is some evidence that gastrin levels fall as nutrients have less contact with G cells, but most patients are commenced on proton pump in- hibitor therapy which subsequently elevates gastrin. The increase in GLP-​1 may cause the early resolution of diabetes seen after gastric bypass, before there is any change in body weight. FURTHER READING Afroze S, et al. (2013). The physiological roles of secretin and its re- ceptor. Ann Transl Med, 1, 29. Besterman H, et al. (1983). Gut hormones in inflammatory bowel dis- ease. Scand J Gastroenterol, 18, 845–​52. Bloom S, Long R (eds) (1982). Radioimmunoassay of gut regulatory peptides. Saunders, London. Cegla J, Bloom S (2014). Gastrointestinal tract and appetite control. In: Lomer M (ed) Advanced nutrition and dietetics in gastroenter- ology, pp. 48–​54. Wiley-​Blackwell, Chichester. Ceranowicz P, Warzecha Z, Dembinski A (2015). Peptidyl hormones of endocrine cells origin in the gut—​their discovery and physiological relevance. J Physiol Pharmacol, 66, 11–​27. Chandra R, Liddle R (2007). Cholecystokinin. Curr Opin Endocrin Diabetes Obes, 14, 63–​7. Dacha S, et  al. (2015). Hypergastrinemia. Gastroenterol Rep (Oxf), 3, 201–​8. Dimaline R, Varro A (2014). Novel roles of gastrin. J Physiol, 592, 2951–​8. Gribble F, Reimann F (2015). Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol, 78, 277–​99. Harrison E, Lal S, McLaughlin J (2013). Enteroendocrine cells in gastrointestinal pathophysiology. Curr Opin Pharmacol, 13, 941–​5. Hay D, et al. (2015). Amylin: pharmacology, physiology and clinical potential. Pharmacol Rev, 67, 564–​600. Holzer P (2009). Opioid receptors in the gastrointestinal tract. Regul Pept, 155, 11–​17. Kirchgessner A (2002). Orexins in the brain-​gut axis. Endocr Rev, 23, 1–​15. Larsson L (1994). Hirschsprung’s disease—​immunohistochemical findings. Histol Histopathol, 9, 615–​29. Loh K, Herzog H, Shi Y (2015). Regulation of energy homeostasis by the NPY system. Trends Endocrinol Metab, 26, 125–​35. Mustain W, Rychahou P, Evers B (2011). The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes, 18, 75–​82. Rai U, et  al. (2015). Therapeutic uses of somatostatin and its ana- logues:  current view and potential applications. Pharmacol Ther, 152, 98–​110. Table 15.9.1.1  Gut hormones levels in obesity and after Roux-​en-​y gastric bypass. In obesity, the satiety signals are reduced, including PYY, PP, GLP-​1, and CCK; this may lead to further food intake. After Roux-​en-​Y bypass, many of these responses are restored, which will aid weight loss. The enhanced GLP-​1 release after bypass contributes to the improvement in glucose tolerance seen after bariatric surgery. Hormone Obesity Roux-​en-​Y surgery PYY ↓ postprandial rise ↑ postprandial response PP ↓ ↓ GLP-​1 ↓ postprandial rise ↑ postprandial response Oxyntomodulin ↑ postprandial response CCK ↓ ↑ postprandial response Ghrelin ↓ but fails to fall postprandially ↓ GIP ↔ ↓ Gastrin ↔ ↓ but elevated by proton pump inhibitor treatment

15.9.2 Carcinoid syndrome 2870

15.9.2 Carcinoid syndrome 2870

SECTION 15  Gastroenterological disorders 2870 Ramos-​Álvarez I, et al. (2015). Insights into bombesin receptors and ligands: highlighting recent advances. Peptides, 72, 128–​44. Sandoval D, D’Alessio D (2015). Physiology of proglucagon pep- tides: role of glucagon and GLP-​1 in health and disease. Physiol Rev, 95, 513–​48. Sanger G, Furness J (2015). Ghreline and motilin receptors as drug targets for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol, 13, 38–​48. Seino Y, Fukushima M, Yabe D (2010). GIP and GLP-​1, the two incretin hormones: similarities and differences. J Diabetes Investig, 1, 8–​23. Steinhoff M, et al. (2014). Tachykinins and their receptors: contribu- tions to physiological control and the mechanisms of disease. Physiol Rev, 94, 265–​301. Troke R, Tan T, Bloom S (2014). The future of gut hormones in the treatment of obesity. Ther Adv Chronic Dis, 5, 4–​14. Vaudry D, et al. (2009). Pituitary adenylate cyclase-​activating polypep- tide and its receptors: 20 years after the discovery. Pharmacol Rev, 61, 283–​357. Zhang H, et  al. (2008). Correlation of gut hormones with irritable bowel syndrome. Digestion, 78, 72–​6. 15.9.2  Carcinoid syndrome B. Khoo, T.M. Tan, and S.R. Bloom ESSENTIALS Carcinoid syndrome is a paraneoplastic syndrome caused by the re- lease of 5-​hydroxytryptamine (5-​HT or serotonin) and other vasoactive substances from neuroendocrine tumours (NETs), typically those arising from the duodenum, jejunum, ileum, and also from bronchial NETs. Characteristic clinical features, which typically arise when tumours have metastasized to the liver, are flushing and secretory diarrhoea, and occasionally wheezing. Carcinoid crisis is an acute and life-​threatening manifestation with sustained flushing, hyperdynamic shock, and acute kidney injury. Carcinoid heart disease typically manifests in the right side of the heart with valvular insufficiency and heart failure. Diagnosis is made by a combination of the characteristic clinical syndrome, biochemical markers such as 5-​hydroxyindoleacetic acid (a metabolite of 5-​HT), histopathological examination of tissue from tumour deposits, and imaging with conventional cross-​sectional modalities as well as somatostatin receptor scintigraphy. Treatment is most often directed at control of symptoms, with the standard of care for control of the carcinoid syndrome being a somatostatin analogue. Symptomatic therapies are used to palliate diarrhoea. Niacin supplements should be given to forestall the de- velopment of pellagra. Multiple modalities for treatment of NETs exist, which should be dir- ected by a multidisciplinary team. Their general prognosis is good with median overall survival of 9.3 years, but the presence of carcinoid syn- drome reduces this to 5.0 years, and is reduced even more in the pres- ence of heart disease. Early identification and management of carcinoid syndrome and heart disease is key to improving survival and quality of life. Introduction and terminology The term Karzinoide was originally used by Obendorfer in 1907 to describe tumours of the gastrointestinal tract with the histopatho- logical features of carcinoma but with a radically different behaviour with slow growth and a reduced tendency to metastasize. The term ‘carcinoid’ has now been superseded by ‘neuroendocrine tumour’ (NET) or ‘neuroendocrine neoplasm’ (NEN), which are defined as epithelial cell tumours arising from cells with predominant neuro- endocrine differentiation. The term ‘neuroendocrine carcinoma’ (NEC) is applied to those NETs which are relatively undifferentiated and demonstrate a high proliferation rate and/​or aggressive behav- iour. Nevertheless, the name lives on in the ‘carcinoid syndrome’, first described by Ransom in 1912, and in the term ‘carcinoid heart disease’. This chapter focuses primarily on those NETs associated with these two presentations. Other NETs are sometimes associated with specific functional syndromes due to the hypersecretion of other hormones such as, for example, gastrin, insulin, glucagon, somatostatin, pancreatic poly- peptide, glucagon-​like peptide-​1 (GLP-​1), ACTH, and parathyroid hormone-​related peptide. Most patients (81%) presenting with NETs do not have the car- cinoid syndrome. In the 19% who do have carcinoid syndrome, the most common type of NET are gastroenteropancreatic (GEP)-​NETs originating from the duodenum, jejunum, and ileum in 40%, fol- lowed by lung/​bronchial NETs in 13%, colon/​rectum GEP-​NETs in 10%, caecal GEP-​NETs in 5%, and appendix GEP-​NETs in 2%. Other subtypes of NET account for 30%. Rarely, pancreatic NETs can cause the carcinoid syndrome. The carcinoid syndrome does not develop when the tumour drains through a normal liver due to first-​pass metabolism of the tumour metabolites, and so GEP-​NETs associated with carcinoid syndrome have almost always metastasized, usually to the liver, be- fore symptoms develop. By contrast, tumours that drain directly into the systemic circulation such as bronchial NETs may cause the syn- drome without liver metastasis. The carcinoid syndrome, where present, has a clear impact on pa- tient quality of life, with increased fatigue, poorer general health, poorer physical function compared to NET patients who do not have the syndrome. In addition, there is a palpable cognitive impairment associated with the syndrome, linked to niacin deficiency. Carcinoid syndrome is associated with a higher mortality, hence identification and treatment of the syndrome is of clinical importance. Clinical manifestations Flushing The classical feature of the carcinoid syndrome is the flush, which occurs in 60 to 85% of patients with the syndrome. It predominantly involves the head and upper thorax, and is usually associated with tachycardia, hypotension, and increased skin temperature. Rarely, flushing extends to the trunk and limbs. Attacks are paroxysmal and usually unprovoked, although precipitating factors include al- cohol or food ingestion, stress, emotion, or exertion. Flushing ini- tially lasts for only a few minutes, but as the disease progresses, it may become almost continuous, and such patients often develop a

15.9.2  Carcinoid syndrome 2871 chronically reddened and cyanotic facial hue, with widespread tel- angiectasia, the ‘leonine facies’. This fixed flush is more commonly seen with bronchial NETs. When bronchial NETs trigger flushing, this can cause severe attacks lasting for hours or days, occasionally with profound hypotension and even anuria. Other symptoms such as tremor, periorbital oedema, tearing from the eye, salivation, and peripheral oedema may occur with bronchial NETs. Diarrhoea and gastrointestinal symptoms The other characteristic feature of the syndrome is secretory diar- rhoea, which occurs in 60 to 80%. This may be profuse and accom- panied by electrolyte disturbance, cramping abdominal pain, nausea, and vomiting. Hepatic metastases may cause right hypochondrial pain, particularly if the liver capsule is involved or stretched, and acute exacerbations may occur if metastases become ischaemic and undergo autonecrosis. Weight loss and, in the later stages, cachexia are common because of anorexia, malabsorption, and increased catabolism. Pellagra Pellagra with dermatitis of sun-​exposed areas may occur, due to the increased consumption of tryptophan by the tumour, limiting the availability of this amino acid for niacin synthesis, and causing deficiency (see Chapter 11.2). Heart disease Carcinoid heart disease affects about 20% of patients with the car- cinoid syndrome; historically this prevalence was as high as 50%, but the picture appears to have been modified by the widespread use of somatostatin analogues. The heart disease is due to the ­deposition of plaques of myofibroblasts and smooth muscle cells in a collagenous stroma on the endocardial surface of valvular cusps and leaflets, cardiac chambers, and occasionally the intimal surface of the pul- monary artery or aorta. The pathogenesis is thought to be activation of 5-​hydroxytryptamine (HT)2b receptors on valvular interstitial cells, leading to secretion of extracellular matrix and the develop- ment of fibrosis. The valves and other endocardial surfaces on the right side of the heart are most often involved, for example, in the form of tricuspid regurgitation and pulmonary stenosis, leading to right ventricular failure, manifesting as peripheral ­oedema, ascites, and dyspnoea. This tropism occurs as the causative mediators flow directly from metastases in the liver to the right side of the heart; the left side is protected by inactivation of the mediators in the lung capillary beds. Left-​sided cardiac damage occurs in 10% of cases, in association with bronchial NETs, which drain into the left atrium, or atrioseptal defects with right-​to-​left shunting. Uncommonly, in 4% of patients, a NET metastasis in the heart is the cause of the ­carcinoid heart disease. Other features The other causes of breathlessness in association with the carcinoid syndrome are bronchospasm, which affects a small number of pa- tients, often occurring with flushing attacks, and metastatic involve- ment of the lung and pleura. An atypical carcinoid syndrome is sometimes seen with type III gastric NETs, where the flushing is associated with raised, local- ized, wheal-​like rashes, which are usually pruritic and which may migrate. The ‘carcinoid crisis’ is an acute, life-​threatening manifestation of the carcinoid syndrome, manifesting as flushing, hyperdynamic shock, and acute kidney injury. It can be provoked during tumour biopsy, tumour surgery, or even anaesthesia for unrelated surgical procedures. It is also reported after embolization procedures, radio- nuclide therapy, or chemotherapy. Biochemistry The biologically active metabolite characteristically produced by those NETs associated with the carcinoid syndrome is 5-​HT (sero- tonin), synthesized from the amino acid tryptophan (Fig. 15.9.2.1). 5-​HT probably plays a part in the pathogenesis of some of the symp- toms of the carcinoid syndrome, particularly the diarrhoea and bronchoconstriction. It is metabolized to 5-​hydroxyindoleacetic acid (5-​HIAA), which accounts for 95% of the urinary excretion of 5-​HT. A variety of other vasoactive substances are implicated in the pathogenesis of the flush. Flushing can be provoked by intravenous noradrenaline, which has been shown to activate kallikrein in the tumour, leading to synthesis and release of bradykinin. Other possible mediators of the flush include histamine, the tachykinins substance P, neurokinin A and neuropeptide K, and prostaglandins E and F, although the flush is rarely affected by inhibitors of prosta- glandin synthesis, such as indomethacin. Gastric NETs are derived from histamine-​producing enterochromaffin-​like cells and hista- mine is likely the cause of the characteristic wheal-​like flush seen with these tumours. Fig. 15.9.2.1  Biochemical pathway for the synthesis and degradation of 5-​hydroxytryptamine.

SECTION 15  Gastroenterological disorders 2872 Investigations Biochemical tests The diagnosis of carcinoid syndrome is made based on the char- acteristic syndrome in association with elevated concentrations of 5-​HIAA in an acidified 24-​h urine collection. Urinary 5-​HIAA acts as a marker of disease progression. Plasma 5-​HIAA measurement is currently being evaluated for its diagnostic performance. Various foods, including avocados, bananas, aubergines, pineapples, plums, walnuts, and pecans should be avoided while collecting specimens to prevent false-​positive results. Several drugs and other substances can interfere with the assay: paracetamol, ephedrine, phenobarbital, diazepam, nicotine, and caffeine can give false-​positive results, and aspirin, phenothiazines, methyldopa, monoamine oxidase inhibi- tors, and tricyclic antidepressants false negatives. Chromogranin A, an acidic glycoprotein, is present in the secretory granules of enterochromaffin cells and NETs, and which is secreted into circula- tion, is often raised in NETs. Histopathology The gold standard for diagnosis is histopathological examination of the primary tumour or metastatic deposits. Typically, the NETs as- sociated with carcinoid syndrome are well-​differentiated tumours with relatively uniform cells containing abundant neuroendocrine granules, and which are arranged in trabecular, gyriform, or nested patterns. The classic histochemical argentaffin stain of Masson and Gosset is based on the capacity of 5-​HT to reduce silver salts. However, immunostaining for neuroendocrine markers such as the chromogranins A, B, and C, synaptophysin, and neuron-​specific enolase are used more routinely to classify these tumours as NETs. Assessment of proliferation indices (e.g. Ki-​67 immunopositivity, mitotic index) is essential for the grading of NETs according to the World Health Organization (2010) criteria. Structural imaging The initial imaging modality of choice is a triple-​phase CT scan, with images obtained precontrast, during the arterial phase (20 s after intravenous contrast medium is injected) and during the portal venous phase (70 s after injection; Fig. 15.9.2.2). Typically, with mid-​gut NETs, a mesenteric metastatic mass is frequently observed with a characteristic desmoplasia around the mass (Fig 15.9.2.3). CT scanning is 82% sensitive and 86% specific. Enhancement of otherwise isodense liver metastases can be ob- served during the arterial phase with a drop in enhancement during the portal venous phase: the sensitivity of CT for this pur- pose is 84% with a specificity of 92%. NET metastases are quite often detected as metastatic masses on ultrasound scanning of the liver, which is useful for guiding biopsy. Where expert interpretation is available, MRI is an alternative modality that enables serial imaging for restaging of NETs without incurring ionizing radiation exposure. Radionuclide imaging Somatostatin receptor scintigraphy with tracers such as 111-​In octreotide, 68-​Ga DOTATATE, 68-​Ga DOTANOC, and 68-​Ga DOTATOC exploits the fact that most differentiated NETs express receptors for somatostatin (particularly subtype 2a), enabling tracer uptake into tumours and metastases (Fig 15.9.2.2). Positron emission tomography (PET) scanning with the aforementioned 68-​Ga labelled tracers, where available, increases the sensitivity to greater than 90% due to the higher spatial resolution of the technique versus single-​positron emission computed tomography (SPECT; Fig 15.9.2.2). Other tracers have higher affinity for other somatostatin receptor subtypes such as 5 for DOTATOC, and 3 and 5 for DOTANOC. Positive somatostatin receptor scintigraphy imaging also opens the possibility of peptide receptor radionuclide therapy. 18-​F fluorodeoxyglucose (FDG) PET scanning is occasionally useful, especially in the case of NECs. Fig. 15.9.2.2  Comparison of imaging modalities (A, arterial phase CT; PV, portal venous phase CT; SPECT, 111-​In octreotide SPECT/​CT; PET, 68-​Ga DOTATATE PET/​CT) for NET metastases to liver in the same patient. Thick, red arrows indicate two major liver metastases which are appreciated on arterial phase CT (anterior metastasis has some enhancement, posterior metastasis remains isodense) and portal venous CT (anterior metastasis becomes isodense, posterior metastasis becomes hypodense). 111-​In octreotide SPECT/​CT scan shows uptake of tracer in anterior metastasis with poorer uptake in posterior metastasis. Metastases are better appreciated in 68-​Ga DOTATATE PET/​CT scanning. Fig. 15.9.2.3  CT scan from patient with an ileal NET, demonstrating mesenteric mass (thick arrow), surrounded by desmoplasia (thin arrows).

15.9.2  Carcinoid syndrome 2873 In those cases where the syndrome occurs in the absence of liver metastases, a careful search using a combination of CT scanning and somatostatin receptor scintigraphy (especially 68-​Ga based PET) is invaluable in locating the primary, which may be amenable to curative resection. Screening for cardiac disease Patients with markedly elevated 5-​HIAA excretion (>300 µmol/​24 h) and/​or frequent flushing with three or more episodes per day are particularly at risk of carcinoid heart disease and should be screened. N-​terminal pro-​B-​type natriuretic peptide (NT pro-​BNP) levels are a useful and simple biomarker for screening during the follow-​up of patients with NETs. Where NT pro-​BNP levels are elevated, such pa- tients should have a transthoracic echocardiogram by a practitioner experienced in the evaluation of carcinoid heart disease. Cardiac CT and MRI, where available, are valuable adjunctive investigations for the estimation of valvular heart disease burden, ventricular func- tion, and for the detection of cardiac metastases. Management Patients with NETs should be treated by multidisciplinary teams that include surgeons (upper gastrointestinal, hepatopancreaticobiliary, colorectal, thoracic), gastroenterologists, endocrinologists, onco- logists, palliative medicine specialists, interventional radiologists, nuclear medicine physicians, and specialist nurses. In those uncommon cases where the carcinoid syndrome is pre- sent with no metastases, for example, in the case of an isolated bronchial NET, a curative resection may eliminate the syndrome entirely. However, most cases present with numerous, unresectable liver metastases and hence the realistic aim of therapy is control of symptoms and reduction of complications. Control of symptoms Somatostatin analogues The standard treatment is a somatostatin analogue (SSTA), such as octreotide or lanreotide. These are effective at alleviating symp- toms in more than 90% of patients. They are commonly adminis- tered as monthly slow-​release injections, for example, octreotide LAR (given as a deep intramuscular injection) or lanreotide Autogel (given as a deep subcutaneous injection). Octreotide can additionally be administered as short-​acting subcutaneous injec- tions, every 8 h, if the long-​acting injections fail to give adequate symptom control. SSTAs act by binding to somatostatin receptor subtypes 2 and 5, inhibiting secretion from the tumours, and leading to a reduction in 5-​HIAA excretion. An added benefit of these analogues is that they slow the growth of NETs and extend progression-​free survival, as demonstrated by the PROMID Phase III and CLARINET trials. SSTAs are remarkably well tolerated. Common side effects include steatorrhoea due to iatrogenic pan- creatic exocrine deficiency, solved by enzyme supplements, and the development of gallstones, which rarely causes significant issues. Interferon-​α Interferon-​α is occasionally used for the treatment of GEP-​NETs, with an overall response rate of 20% and a biochemical response rate of 63%. However, its adverse effects—​flu-​like symptoms, myelotoxicity, weight loss and fatigue, depression, and on occasion, suicidal ideation—​limit the dose and duration of treatment. Reduction of tumour mass Cytoreductive surgery is advocated by some authorities, but re- mains controversial. Hepatic transarterial embolization with bland microspheres (TAE), with microspheres and chemotherapy (TACE), or even with 90-​Y labelled microspheres (selective in- ternal radioembolization therapy [SIRT]), can reduce tumour and symptom burden in selected patients, but requires suitable radio- logical expertise. Patients undergoing such embolization should be pretreated with high-​dose octreotide to reduce the risk of car- cinoid crisis. Peptide receptor radionuclide therapy Peptide receptor radionuclide therapy with 177-​Lu DOTATATE has recently been shown in a phase III trial (the NETTER-​1 study) to ex- tend progression-​free survival and to be associated with an objective tumour size response in 18% versus 3% for high-​dose octreotide LAR. Where available, this treatment should be considered for pa- tients who demonstrate radiological progression in their NET des- pite maximal SSTA therapy. Peptide receptor radionuclide therapy is generally well tolerated but is associated with fatigue, abdom- inal pain, diarrhoea, neutropenia, and thrombocytopenia, which is generally temporary. The number of doses that can be given in the long term is limited by bone marrow suppression (and possible myelodysplasia) as well as renal toxicity. Other types of radionuclide therapy such as 90-​Y octreotate peptide receptor radionuclide therapy and 131-​I MIBG therapy have been used in the past but have been largely superseded by 177-​Lu-​based agents. Chemotherapy Chemotherapy with conventional cytotoxic agents is not commonly used as response rates are poor, but may be considered where other treatments have failed to halt progression, or in the case of NECs with high proliferation indices. Symptomatic treatments Symptomatic treatments such as codeine phosphate and loperamide may help to control diarrhoea. Peripheral 5-​HT antagonists such as cyproheptadine, a 5-​HT2 receptor blocker, and the 5-​HT3 receptor antagonist ondansetron can alleviate diarrhoea and nausea. In the case of gastric NET-​associated atypical carcinoid syndrome, H1-​ and H2-​receptor blockade may be useful. Telotristat etiprate is a selective inhibitor of peripheral tryptophan hydroxylase and therefore the synthesis of 5-​HT, and has been shown to be effective at reducing the frequency of diarrhoea. It is currently licensed in the United States of America for the relief of carcinoid syndrome diarrhoea. Carcinoid crisis In cases where patients present with carcinoid crisis, they should be admitted immediately to high dependency or intensive care units for appropriate monitoring and treatment of fluid and electrolyte status. High-​dose octreotide infusions are given to suppress tumour secretion, and glucocorticoids may be given to improve haemo- dynamics. Although theoretically catecholamines may increase the

SECTION 15  Gastroenterological disorders 2874 output of vasoactive factors, in practice, inotropes may be given with monitoring. Avoidance and treatment of complications Vitamin supplements Vitamin supplements containing niacin are necessary when pa- tients have pellagra, and these can be given prophylactically. Supplementation with the fat-​soluble vitamins A, D, E, and K should be considered in patients who are being given SSTAs. Heart disease The medical treatment of carcinoid heart disease is the same as for right-​sided cardiac failure of other causes, for example, diuretics and mineralocorticoid antagonists. Although renin–​angiotensin–​ aldosterone axis blockade, digoxin, and vasodilators can be con- sidered, they have no clear effect on mortality in this population. Valve replacement is currently the most effective treatment option for advanced carcinoid heart disease. It is presently unclear whether telotristat might be useful in delaying carcinoid heart disease progression. Bony metastases Patients with bony metastases may benefit from palliative radio- therapy if the metastases are painful, and should be given antiresorptive agents such as zoledronic acid and denosumab, as for other patients who have solid tumour metastases in bone. Prognosis Most NETs follow an indolent course, and the median overall survival of all patients with NETs is 9.3 years (including those with localized disease). However, the presence of carcinoid syndrome does shorten median overall survival to 5.0 years. Active treatment of the carcinoid syndrome is very worthwhile in these patients, in terms of improving quality of life, and delaying or preventing the development of carcinoid heart disease. The prognosis is especially poor in those patients with untreated carcinoid heart disease, with a 3-​year survival of 31% compared to 68% without heart disease. Proactive screening and management (e.g. with valve replacement) is key to improving the prognosis of patients with heart disease. FURTHER READING Dasari A, et  al. (2017). Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol, 3, 1355–​42. de Herder WW, et al. (2016). A short history of neuroendocrine tu- mours and their peptide hormones. Best Pract Res Clin Endocrinol Metab, 30, 3–​17. Halperin DM, et al. (2017). Frequency of carcinoid syndrome at neuro- endocrine tumour diagnosis:  a population-​based study. Lancet Oncol, 18, 525–​34. Hicks RJ, et  al. (2017). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology, 105, 295–​309. Pavel M, et al. (2017). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms:  systemic therapy—​ biotherapy and novel targeted agents. Neuroendocrinology, 105, 266–​80. Sundin A, et al. (2017). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: radiological, nuclear medicine and hybrid imaging. Neuroendocrinology, 105, 212–​44.

Contents

Contents

Contents Volume 1 List of abbreviations  xxxv List of contributors  xlv SECTION 1 Patients and their treatment Section editors: John D. Firth, Christopher P. Conlon,
and Timothy M. Cox 1.1 On being a patient  3 Christopher Booth† 1.2 A young person’s experience of chronic
disease  6 1.3 What patients wish you understood  8 Rosamund Snow† 1.4 Why do patients attend and what do they want from the consultation?  14 Des Spence 1.5 Medical ethics  20 Mike Parker, Mehrunisha Suleman, and Tony Hope 1.6 Clinical decision-​making  26 Timothy E.A. Peto and Philippa Peto SECTION 2 Background to medicine Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 2.1 Science in medicine: When, how, and what  33 William F. Bynum 2.2 Evolution: Medicine’s most basic science  39 Randolph M. Nesse and Richard Dawkins 2.3 The Global Burden of Disease: Measuring the health of populations  43 Theo Vos, Alan Lopez, and Christopher Murray 2.4 Large-​scale randomized evidence: Trials and meta-​analyses of trials  51 Colin Baigent, Richard Peto, Richard Gray, Natalie Staplin, Sarah Parish, and Rory Collins 2.5 Bioinformatics  67 Afzal Chaudhry 2.6 Principles of clinical pharmacology and drug therapy  71 Kevin O’Shaughnessy 2.7 Biological therapies for immune, inflammatory, and allergic diseases  100 John D. Isaacs and Nishanthi Thalayasingam 2.8 Traditional medicine exemplified by traditional Chinese medicine  108 Fulong Liao, Tingliang Jiang, and Youyou Tu 2.9 Engaging patients in therapeutic development  118 Emil Kakkis and Max Bronstein 2.10 Medicine quality, physicians, and patients  124 Paul N. Newton 2.11 Preventive medicine  127 David Mant 2.12 Medical screening  137 Nicholas Wald and Malcolm Law 2.13 Health promotion  152 Evelyne de Leeuw † It is with great regret that we report that Christopher Booth died on 13 July, 2012 and Rosamund Snow died on 2 February, 2017.

Contents xiv 2.14 Deprivation and health  157 Harry Burns 2.15 How much should rich countries’ governments spend on healthcare?  161 Allyson M. Pollock and David Price 2.16 Financing healthcare in low-​income developing countries: A challenge for equity in health  168 Luis G. Sambo, Jorge Simões, and Maria do Rosario O. Martins 2.17 Research in the developed world  177 Jeremy Farrar 2.18 Fostering medical and health research in resource-​constrained countries  181 Malegapuru W. Makgoba and Stephen M. Tollman 2.19 Regulation versus innovation in medicine  185 Michael Rawlins 2.20 Human disasters  188 Amartya Sen 2.21 Humanitarian medicine  193 Amy S. Kravitz 2.22 Complementary and alternative medicine  201 Edzard Ernst SECTION 3 Cell biology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 3.1 The cell  209 George Banting and Jean Paul Luzio 3.2 The genomic basis of medicine  218 Paweł Stankiewicz and James R. Lupski 3.3 Cytokines  236 Iain B. McInnes 3.4 Ion channels and disease  246 Frances Ashcroft and Paolo Tammaro 3.5 Intracellular signalling  256 R. Andres Floto 3.6 Apoptosis in health and disease  266 Mark J. Arends and Christopher D. Gregory 3.7 Stem cells and regenerative medicine  281 Alexis J. Joannides, Bhuvaneish T. Selvaraj, and
Siddharthan Chandran 3.8 The evolution of therapeutic antibodies  296 Herman Waldmann and Greg Winter 3.9 Circulating DNA for molecular diagnostics  299 Y.M. Dennis Lo and Rossa W.K. Chiu SECTION 4 Immunological mechanisms Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 4.1 The innate immune system  307 Paul Bowness 4.2 The complement system  315 Marina Botto and Matthew C. Pickering 4.3 Adaptive immunity  325 Paul Klenerman and Constantino López-​Macias 4.4 Immunodeficiency  337 Sophie Hambleton, Sara Marshall, and Dinakantha S. Kumararatne 4.5 Allergy  368 Pamela Ewan 4.6 Autoimmunity  379 Antony Rosen 4.7 Principles of transplantation immunology  392 Elizabeth Wallin and Kathryn J. Wood SECTION 5 Principles of clinical oncology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 5.1 Epidemiology of cancer  411 Anthony Swerdlow and Richard Peto 5.2 The nature and development of cancer: Cancer mutations and their implications  445 James D. Brenton and Tim Eisen 5.3 The genetics of inherited cancers  456 Rosalind A. Eeles 5.4 Cancer immunity and immunotherapy  471 Charles G. Drake 5.5 Clinical features and management  487 Tim Eisen and Martin Gore† 5.6 Systemic treatment and radiotherapy  497 Rajesh Jena and Peter Harper † It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contents xv 5.7 Medical management of breast cancer  505 Tim Crook, Su Li, and Peter Harper SECTION 6 Old age medicine Section editor: Finbarr C. Martin 6.1 Ageing and clinical medicine  511 Claire Steves and Neil Pendleton 6.2 Frailty and sarcopenia  521 Andrew Clegg and Harnish Patel 6.3 Optimizing well-​being into old age  532 Steve Iliffe 6.4 Older people and urgent care  539 Simon Conroy and Jay Banerjee 6.5 Older people in hospital  548 Graham Ellis, Alasdair MacLullich, and Rowan Harwood 6.6 Supporting older peoples’ care in surgical and oncological services  563 Jugdeep Dhesi and Judith Partridge 6.7 Drugs and prescribing in the older patient  571 Miles Witham, Jacob George, and Denis O’Mahony 6.8 Falls, faints, and fragility fractures  579 Fiona Kearney and Tahir Masud 6.9 Bladder and bowels  589 Susie Orme and Danielle Harari 6.10 Neurodegenerative disorders in older people  601 John Hindle 6.11 Promotion of dignity in the life and death of older patients  612 Eileen Burns and Claire Scampion SECTION 7 Pain and palliative care Section editor: Bee Wee 7.1 Introduction to palliative care  623 Susan Salt 7.2 Pain management  629 Marie Fallon 7.3 Symptoms other than pain  634 Regina McQuillan 7.4 Care of the dying person  639 Suzanne Kite and Adam Hurlow SECTION 8 Infectious diseases Section editor: Christopher P. Conlon 8.1 Pathogenic microorganisms and the host  651

8.1.1 Biology of pathogenic microorganisms  651 Duncan J. Maskell and James L.N. Wood

8.1.2 Clinical features and general management of patients with severe infections  656 Peter Watkinson and Duncan Young 8.2 The patient with suspected infection  662

8.2.1 Clinical approach  662 Christopher J. Ellis

8.2.2 Fever of unknown origin  664 Steven Vanderschueren

8.2.3 Nosocomial infections  669 Ian C.J.W. Bowler and Matthew Scarborough

8.2.4 Infection in the immunocompromised host  673 Jon Cohen and Elham Khatamzas

8.2.5 Antimicrobial chemotherapy  684 Maha Albur, Alasdair MacGowan, and Roger G. Finch 8.3 Immunization  706 David Goldblatt and Mary Ramsay 8.4 Travel and expedition medicine  713 Susanna Dunachie and Christopher P. Conlon 8.5 Viruses  723

8.5.1 Respiratory tract viruses  723 Malik Peiris

8.5.2 Herpesviruses (excluding Epstein–​Barr virus)  734 J.G.P. Sissons†

8.5.3 Epstein–​Barr virus  754 Alan B. Rickinson and M.A. Epstein

8.5.4 Poxviruses  764 Geoffrey L. Smith

8.5.5 Mumps: Epidemic parotitis  769 B.K. Rima

8.5.6 Measles  772 Hilton C. Whittle and Peter Aaby

8.5.7 Nipah and Hendra virus encephalitides  784 C.T. Tan † It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016.

Contents xvi

8.5.8 Enterovirus infections  787 Philip Minor and Ulrich Desselberger

8.5.9 Virus infections causing diarrhoea and vomiting  797 Philip R. Dormitzer and Ulrich Desselberger

8.5.10 Rhabdoviruses: Rabies and rabies-​related lyssaviruses  805 Mary J. Warrell and David A. Warrell

8.5.11 Colorado tick fever and other arthropod-​borne reoviruses  819 Mary J. Warrell and David A. Warrell

8.5.12 Alphaviruses  821 Ann M. Powers, E.E. Ooi, L.R. Petersen, and D.J. Gubler

8.5.13 Rubella  827 Pat Tookey and J.M. Best

8.5.14 Flaviviruses excluding dengue  830 Shannan Lee Rossi and Nikos Vasilakis

8.5.15 Dengue  845 Bridget Wills and Yee-​Sin Leo

8.5.16 Bunyaviridae  852 James W. Le Duc and D.A. Bente

8.5.17 Arenaviruses  862 Jan H. ter Meulen

8.5.18 Filoviruses  870 Jan H. ter Meulen

8.5.19 Papillomaviruses and polyomaviruses  877 Raphael P. Viscidi, Chen Sabrina Tan, and
Carole Fakhry

8.5.20 Parvovirus B19  886 Kevin E. Brown

8.5.21 Hepatitis viruses (excluding hepatitis C virus)  889 Matthew Cramp, Ashwin Dhanda, and
Nikolai V. Naoumov

8.5.22 Hepatitis C virus  896 Paul Klenerman, Katie J.M. Jeffery, Ellie J. Barnes, and
Jane Collier

8.5.23 HIV/​AIDS  901 Sarah Fidler, Timothy E.A. Peto, Philip Goulder, and Christopher P. Conlon

8.5.24 HIV in low-​ and middle-​income countries  933 Alison D. Grant and Kevin M. De Cock

8.5.25 HTLV-​1, HTLV-​2, and associated diseases  941 Kristien Verdonck and Eduardo Gotuzzo

8.5.26 Viruses and cancer  945 Robin A. Weiss

8.5.27 Orf and Milker’s nodule  947 Emma Aarons and David A. Warrell

8.5.28 Molluscum contagiosum  949 David A. Warrell and Christopher P. Conlon

8.5.29 Newly discovered viruses  951 Susannah J.A. Froude and Harriet C. Hughes 8.6 Bacteria  958

8.6.1 Diphtheria  959 Delia B. Bethell and Tran Tinh Hien

8.6.2 Streptococci and enterococci  965 Dennis L. Stevens and Sarah Hobdey

8.6.3 Pneumococcal infections  975 Anthony Scott

8.6.4 Staphylococci  991 Kyle J. Popovich, Robert A. Weinstein, and Bala Hota

8.6.5 Meningococcal infections  1010 Petter Brandtzaeg

8.6.6 Neisseria gonorrhoeae  1025 Jackie Sherrard and Magnus Unemo

8.6.7 Enterobacteria and bacterial food poisoning  1032 Hugh Pennington

8.6.8 Pseudomonas aeruginosa  1041 G.C.K.W. Koh and Sharon J. Peacock

8.6.9 Typhoid and paratyphoid fevers  1044 Christopher M. Parry and Buddha Basnyat

8.6.10 Intracellular klebsiella infections (donovanosis and rhinoscleroma)  1051 John Richens and Nicole Stoesser

8.6.11 Anaerobic bacteria  1055 Anilrudh A. Venugopal and David W. Hecht

8.6.12 Cholera  1060 Aldo A.M. Lima and Richard L. Guerrant

8.6.13 Haemophilus influenzae  1066 Esther Robinson

8.6.14 Haemophilus ducreyi and chancroid  1071 Nigel O’Farrell

8.6.15 Bordetella infection  1073 Cameron C. Grant

8.6.16 Melioidosis and glanders  1076 Sharon J. Peacock

8.6.17 Plague: Yersinia pestis  1081 Michael Prentice

8.6.18 Other Yersinia infections: Yersiniosis  1086 Michael Prentice

8.6.19 Pasteurella  1088 Marina S. Morgan

8.6.20 Francisella tularensis infection  1091 Petra C.F. Oyston

Contents xvii

8.6.21 Anthrax  1094 Arthur E. Brown

8.6.22 Brucellosis  1102 Juan D. Colmenero and Pilar Morata

8.6.23 Tetanus  1109 C. Louise Thwaites and Lam Minh Yen

8.6.24 Clostridium difficile  1115 David W. Eyre and Mark H. Wilcox

8.6.25 Botulism, gas gangrene, and clostridial gastrointestinal infections  1120 Dennis L. Stevens, Michael J. Aldape, and Amy E. Bryant

8.6.26 Tuberculosis  1126 Richard E. Chaisson and Jean B. Nachega

8.6.27 Disease caused by environmental mycobacteria  1150 Jakko van Ingen

8.6.28 Leprosy (Hansen’s disease)  1154 Diana N.J. Lockwood

8.6.29 Buruli ulcer: Mycobacterium ulcerans infection  1167 Bouke de Jong, Françoise Portaels, and Wayne M. Meyers

8.6.30 Actinomycoses  1170 Klaus P. Schaal

8.6.31 Nocardiosis  1176 Roderick J. Hay

8.6.32 Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection)  1179 Andrew F. Woodhouse

8.6.33 Lyme borreliosis  1181 Gary P. Wormser, John Nowakowski, and
Robert B. Nadelman

8.6.34 Relapsing fevers  1188 David A. Warrell

8.6.35 Leptospirosis  1198 Nicholas P.J. Day

8.6.36 Nonvenereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta  1204 Michael Marks, Oriol Mitjà, and David Mabey

8.6.37 Syphilis  1210 Phillip Read and Basil Donovan

8.6.38 Listeriosis  1223 Herbert Hof

8.6.39 Legionellosis and Legionnaires’ disease  1226 Diego Viasus and Jordi Carratalà

8.6.40 Rickettsioses  1230 Karolina Griffiths, Carole Eldin, Didier Raoult, and Philippe Parola

8.6.41 Scrub typhus  1252 Daniel H. Paris and Nicholas P.J. Day

8.6.42 Coxiella burnetii infections (Q fever)  1257 Thomas J. Marrie

8.6.43 Bartonellas excluding B. bacilliformis  1262 Bruno B. Chomel, Henri-​Jean Boulouis, Matthew J. Stuckey, and Jean-​Marc Rolain

8.6.44 Bartonella bacilliformis infection  1272 A. Llanos-​Cuentas and C. Maguiña-​Vargas

8.6.45 Chlamydial infections  1278 Patrick Horner, David Mabey, David Taylor-​Robinson, and Magnus Unemo

8.6.46 Mycoplasmas  1295 Jørgen Skov Jensen and David Taylor-​Robinson

8.6.47 A checklist of bacteria associated with infection
in humans  1307 John Paul 8.7 Fungi (mycoses)  1338

8.7.1 Fungal infections  1338 Roderick J. Hay

8.7.2 Cryptococcosis  1359 William G. Powderly, J. William Campbell, and
Larry J. Shapiro

8.7.3 Coccidioidomycosis  1361 Gregory M. Anstead

8.7.4 Paracoccidioidomycosis  1364 M.A. Shikanai-​Yasuda

8.7.5 Pneumocystis jirovecii  1371 Robert F. Miller and Christopher P. Eades

8.7.6 Talaromyces (Penicillium) marneffei infection  1375 Romanee Chaiwarith, Khuanchai Supparatpinyo, and Thira Sirisanthana

8.7.7 Microsporidiosis  1378 Louis M. Weiss 8.8 Protozoa  1384

8.8.1 Amoebic infections  1384 Richard Knight

8.8.2 Malaria  1395 Nicholas J. White and Arjen M. Dondorp

8.8.3 Babesiosis  1414 Philippe Brasseur

8.8.4 Toxoplasmosis  1416 Oliver Liesenfeld and Eskild Petersen

8.8.5 Cryptosporidium and cryptosporidiosis  1424 Simone M. Cacciò

8.8.6 Cyclospora and cyclosporiasis  1432 Paul Kelly and Ralph Lainson† † It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Contents xviii

8.8.7 Cystoisosporiasis  1436 Louis M. Weiss

8.8.8 Sarcocystosis (sarcosporidiosis)  1438 John E. Cooper

8.8.9 Giardiasis and balantidiasis  1440 Lars Eckmann and Martin F. Heyworth

8.8.10 Blastocystis infection  1449 Richard Knight

8.8.11 Human African trypanosomiasis  1451 Reto Brun and Johannes Blum

8.8.12 Chagas disease  1459 Michael A. Miles

8.8.13 Leishmaniasis  1467 Antony D.M. Bryceson and Diana N.J. Lockwood

8.8.14 Trichomoniasis  1475 Jane Schwebke 8.9 Nematodes (roundworms)  1478

8.9.1 Cutaneous filariasis  1478 Gilbert Burnham

8.9.2 Lymphatic filariasis  1487 Richard Knight

8.9.3 Guinea worm disease (dracunculiasis)  1495 Richard Knight

8.9.4 Strongyloidiasis, hookworm, and other gut strongyloid nematodes  1500 Michael Brown

8.9.5 Gut and tissue nematode infections acquired
by ingestion  1506 Peter L. Chiodini

8.9.6 Angiostrongyliasis  1516 Richard Knight 8.10 Cestodes (tapeworms)  1520

8.10.1 Cestodes (tapeworms)  1520 Richard Knight

8.10.2 Cystic hydatid disease (Echinococcus
granulosus)  1529 Pedro L. Moro, Hector H. Garcia, and
Armando E. Gonzalez

8.10.3 Cysticercosis  1533 Hector H. Garcia and Robert H. Gilman 8.11 Trematodes (flukes)  1540

8.11.1 Schistosomiasis  1540 David Dunne and Birgitte Vennervald

8.11.2 Liver fluke infections  1551 Ross H. Andrews, Narong Khuntikeo,
Paiboon Sithithaworn, and Trevor N. Petney

8.11.3 Lung flukes (paragonimiasis)  1558 Udomsak Silachamroon and Sirivan Vanijanonta

8.11.4 Intestinal trematode infections  1562 Alastair McGregor 8.12 Nonvenomous arthropods  1568 John Paul 8.13 Pentastomiasis (porocephalosis,
linguatulosis/​linguatuliasis, or tongue
worm infection)  1582 David A. Warrell SECTION 9 Sexually transmitted diseases Section editor: Jackie Sherrard 9.1 Epidemiology of sexually transmitted infections  1589 David Mabey and Anita Vas-​Falcao 9.2 Sexual behaviour  1597 Catherine H. Mercer and Anne M. Johnson 9.3 Sexual history and examination  1600 Gary Brook, Jackie Sherrard, and Graz A. Luzzi 9.4 Vaginal discharge  1603 Paul Nyirjesy 9.5 Urethritis  1606 Patrick Horner 9.6 Genital ulceration  1610 Patrick French and Raj Patel 9.7 Anogenital lumps and bumps  1613 Henry J.C. de Vries and Charles J.N. Lacey 9.8 Pelvic inflammatory disease  1622 Jonathan D.C. Ross 9.9 Principles of contraception  1626 Zara Haider Index

Contents xix Volume 2 List of abbreviations  xxxv List of contributors  xlv SECTION 10 Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres 10.1 Environmental medicine, occupational medicine, and poisoning—​Introduction  1637 Jon G. Ayres 10.2 Occupational health  1638

10.2.1 Occupational and environmental health  1638 Raymond Agius and Debasish Sen

10.2.2 Occupational safety  1652 Lawrence Waterman

10.2.3 Aviation medicine  1656 Michael Bagshaw

10.2.4 Diving medicine  1664 David M. Denison and Mark A. Glover

10.2.5 Noise  1671 David Koh and Tar-​Ching Aw†

10.2.6 Vibration  1673 Tar-​Ching Aw† 10.3 Environment and health  1677

10.3.1 Air pollution and health  1677 Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres

10.3.2 Heat  1687 Michael A. Stroud

10.3.3 Cold  1689 Michael A. Stroud

10.3.4 Drowning  1691 Peter J. Fenner

10.3.5 Lightning and electrical injuries  1696 Chris Andrews

10.3.6 Diseases of high terrestrial altitudes  1701 Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch

10.3.7 Radiation  1709 Jill Meara

10.3.8 Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions  1713 Peter J. Baxter

10.3.9 Bioterrorism  1718 Manfred S. Green 10.4 Poisoning  1725

10.4.1 Poisoning by drugs and chemicals  1725 John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman

10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals  1778 David A. Warrell

10.4.3 Poisonous fungi  1817 Hans Persson and David A. Warrell

10.4.4 Poisonous plants  1828 Michael Eddleston and Hans Persson 10.5 Podoconiosis (nonfilarial elephantiasis)  1833 Gail Davey SECTION 11 Nutrition Section editor: Katherine Younger 11.1 Nutrition: Macronutrient metabolism  1839 Keith N. Frayn and Rhys D. Evans 11.2 Vitamins  1855 Tom R. Hill and David A. Bender 11.3 Minerals and trace elements  1871 Katherine Younger 11.4 Severe malnutrition  1880 Alan A. Jackson 11.5 Diseases of affluent societies and the need for dietary change  1891 J.I. Mann and A.S. Truswell 11.6 Obesity  1903 I. Sadaf Farooqi 11.7 Artificial nutrition support  1914 Jeremy Woodward † It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Contents xx SECTION 12 Metabolic disorders Section editor: Timothy M. Cox 12.1 The inborn errors of metabolism: General aspects  1929 Timothy M. Cox and Richard W.E. Watts† 12.2 Protein-​dependent inborn errors of metabolism  1942 Georg F. Hoffmann and Stefan Kölker 12.3 Disorders of carbohydrate metabolism  1985

12.3.1 Glycogen storage diseases  1985 Robin H. Lachmann and Timothy M. Cox

12.3.2 Inborn errors of fructose metabolism  1993 Timothy M. Cox

12.3.3 Disorders of galactose, pentose, and pyruvate metabolism  2003 Timothy M. Cox 12.4 Disorders of purine and pyrimidine metabolism  2015 Anthony M. Marinaki, Lynette D. Fairbanks, and Richard W.E. Watts† 12.5 The porphyrias  2032 Timothy M. Cox 12.6 Lipid disorders  2055 Jaimini Cegla and James Scott 12.7 Trace metal disorders  2098

12.7.1 Hereditary haemochromatosis  2098 William J.H. Griffiths and Timothy M. Cox

12.7.2 Inherited diseases of copper metabolism:
Wilson’s disease and Menkes’ disease  2115 Michael L. Schilsky and Pramod K. Mistry 12.8 Lysosomal disease  2121 Patrick B. Deegan and Timothy M. Cox 12.9 Disorders of peroxisomal metabolism in adults  2157 Anthony S. Wierzbicki 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias  2174 Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure 12.11 A physiological approach to acid–​base disorders: The roles of ion transport and body fluid compartments  2182 Julian Seifter 12.12 The acute phase response, hereditary periodic fever syndromes, and amyloidosis  2199

12.12.1 The acute phase response and C-​reactive protein  2199 Mark B. Pepys

12.12.2 Hereditary periodic fever syndromes  2207 Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins

12.12.3 Amyloidosis  2218 Mark B. Pepys and Philip N. Hawkins 12.13 α1-​Antitrypsin deficiency and the serpinopathies  2235 David A. Lomas SECTION 13 Endocrine disorders Section editor: Mark Gurnell 13.1 Principles of hormone action  2245 Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell 13.2 Pituitary disorders  2258

13.2.1 Disorders of the anterior pituitary gland  2258 Niki Karavitaki and John A.H. Wass

13.2.2 Disorders of the posterior pituitary gland  2277 Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass 13.3 Thyroid disorders  2284

13.3.1 The thyroid gland and disorders of thyroid function  2284 Anthony P. Weetman and Kristien Boelaert

13.3.2 Thyroid cancer  2302 Kristien Boelaert and Anthony P. Weetman 13.4 Parathyroid disorders and diseases altering calcium metabolism  2313 R.V. Thakker 13.5 Adrenal disorders  2331

13.5.1 Disorders of the adrenal cortex  2331 Mark Sherlock and Mark Gurnell

13.5.2 Congenital adrenal hyperplasia  2360 Nils P. Krone and Ieuan A. Hughes 13.6 Reproductive disorders  2374

13.6.1 Ovarian disorders  2374 Stephen Franks, Kate Hardy, and Lisa J. Webber

13.6.2 Disorders of male reproduction and male hypogonadism  2386 P.-​M.G. Bouloux

13.6.3 Benign breast disease  2406 Gael M. MacLean † It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.

Contents xxi

13.6.4 Sexual dysfunction  2408 Ian Eardley 13.7 Disorders of growth and development  2416

13.7.1 Normal growth and its disorders  2416 Gary Butler

13.7.2 Normal puberty and its disorders  2428 Fiona Ryan and Sejal Patel

13.7.3 Normal and abnormal sexual differentiation  2435 S. Faisal Ahmed and Angela K. Lucas-​Herald 13.8 Pancreatic endocrine disorders and multiple endocrine neoplasia  2449 B. Khoo, T.M. Tan, and S.R. Bloom 13.9 Diabetes and hypoglycaemia  2464

13.9.1 Diabetes  2464 Colin Dayan and Julia Platts

13.9.2 Hypoglycaemia  2531 Mark Evans and Ben Challis 13.10 Hormonal manifestations of nonendocrine disease  2541 Thomas M. Barber and John A.H. Wass 13.11 The pineal gland and melatonin  2553 J. Arendt and Timothy M. Cox SECTION 14 Medical disorders in pregnancy Section editor: Catherine Nelson-​Piercy 14.1 Physiological changes of normal pregnancy  2563 David J. Williams 14.2 Nutrition in pregnancy  2568 David J. Williams 14.3 Medical management of normal pregnancy  2575 David J. Williams 14.4 Hypertension in pregnancy  2583 Fergus McCarthy 14.5 Renal disease in pregnancy  2589 Kate Wiles 14.6 Heart disease in pregnancy  2597 Catherine E.G. Head 14.7 Thrombosis in pregnancy  2606 Peter K. MacCallum and Louise Bowles 14.8 Chest diseases in pregnancy  2613 Meredith Pugh and Tina Hartert 14.9 Liver and gastrointestinal diseases of pregnancy  2619 Michael Heneghan and Catherine Williamson 14.10 Diabetes in pregnancy  2627 Bryony Jones and Anne Dornhorst 14.11 Endocrine disease in pregnancy  2638 David Carty 14.12 Neurological conditions in pregnancy  2642 Pooja Dassan 14.13 The skin in pregnancy  2648 Gudula Kirtschig and Fenella Wojnarowska 14.14 Autoimmune rheumatic disorders and vasculitis in pregnancy  2655 May Ching Soh and Catherine Nelson-​Piercy 14.15 Maternal infection in pregnancy  2671 Rosie Burton 14.16 Fetal effects of maternal infection  2678 Lawrence Impey 14.17 Blood disorders in pregnancy  2687 David J. Perry and Katharine Lowndes 14.18 Malignant disease in pregnancy  2696 Robin A.F. Crawford 14.19 Maternal critical care  2701 Rupert Gauntlett 14.20 Prescribing in pregnancy  2706 Lucy MacKillop and Charlotte Frise 14.21 Contraception for women with medical diseases  2711 Aarthi R. Mohan SECTION 15 Gastroenterological disorders Section editor: Jack Satsangi 15.1 Structure and function of the gastrointestinal tract  2721 Michael E.B. FitzPatrick and Satish Keshav† 15.2 Symptoms of gastrointestinal disease  2727 Jeremy Woodward 15.3 Methods for investigation of
gastroenterological disease  2734

15.3.1 Colonoscopy and flexible sigmoidoscopy  2734 James E. East and Brian P. Saunders † It is with great regret that we report that Satish Keshav died on 23 January, 2019.

Contents xxii

15.3.2 Upper gastrointestinal endoscopy  2740 James E. East and George J. Webster

15.3.3 Radiology of the gastrointestinal tract  2748 Fiachra Moloney and Michael Maher

15.3.4 Investigation of gastrointestinal function  2757 Jervoise Andreyev 15.4 Common acute abdominal presentations  2765

15.4.1 The acute abdomen  2765 Simon J.A. Buczacki and R. Justin Davies

15.4.2 Gastrointestinal bleeding  2771 Vanessa Brown and T.A. Rockall 15.5 Immune disorders of the gastrointestinal tract  2783 Joya Bhattacharyya and Arthur Kaser 15.6 The mouth and salivary glands  2797 John Gibson and Douglas Robertson 15.7 Diseases of the oesophagus  2828 Rebecca C. Fitzgerald and Massimiliano di Pietro 15.8 Peptic ulcer disease  2849 Joseph Sung 15.9 Hormones and the gastrointestinal tract  2862

15.9.1 Hormones and the gastrointestinal tract  2862 Rebecca Scott, T.M. Tan, and S.R. Bloom

15.9.2 Carcinoid syndrome  2870 B. Khoo, T.M. Tan, and S.R. Bloom 15.10 Malabsorption  2875

15.10.1 Differential diagnosis and investigation of malabsorption  2875 Alastair Forbes and Victoria Mulcahy

15.10.2 Bacterial overgrowth of the small
intestine  2879 Stephen J. Middleton and Raymond J. Playford

15.10.3 Coeliac disease  2884 Peter D. Mooney and David S. Sanders

15.10.4 Gastrointestinal lymphomas  2892 Kikkeri N. Naresh

15.10.5 Disaccharidase deficiency  2902 Timothy M. Cox

15.10.6 Whipple’s disease  2909 Florence Fenollar and Didier Raoult

15.10.7 Effects of massive bowel resection  2911 Stephen J. Middleton, Simon M. Gabe, and
Raymond J. Playford

15.10.8 Malabsorption syndromes in the tropics  2916 Vineet Ahuja and Govind K. Makharia 15.11 Crohn’s disease  2925 Miles Parkes and Tim Raine 15.12 Ulcerative colitis  2937 Jeremy Sanderson and Peter Irving 15.13 Irritable bowel syndrome  2951 Adam D. Farmer and Qasim Aziz 15.14 Colonic diverticular disease  2960 Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and
Neil J.McC. Mortensen 15.15 Congenital abnormalities of the gastrointestinal tract  2967 Holm H. Uhlig 15.16 Cancers of the gastrointestinal tract  2977 Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira 15.17 Vascular disorders of the gastrointestinal tract  2997 Ray Boyapati 15.18 Gastrointestinal infections  3008 Sarah O’Brien 15.19 Miscellaneous disorders of the bowel  3025 Alexander Gimson 15.20 Structure and function of the liver, biliary tract, and pancreas  3032 William Gelson and Alexander Gimson 15.21 Pathobiology of chronic liver disease  3043 Wajahat Z. Mehal 15.22 Presentations and management of liver disease  3049

15.22.1 Investigation and management of
jaundice  3049 Jane Collier

15.22.2 Cirrhosis and ascites  3058 Javier Fernández and Vicente Arroyo

15.22.3 Portal hypertension and variceal bleeding  3068 Marcus Robertson and Peter Hayes

15.22.4 Hepatic encephalopathy  3080 Paul K. Middleton and Debbie L. Shawcross

15.22.5 Liver failure  3089 Jane Macnaughtan and Rajiv Jalan

15.22.6 Liver transplantation  3100 John G. O’Grady 15.23 Hepatitis and autoimmune liver disease  3108

15.23.1 Hepatitis A to E  3108 Graeme J.M. Alexander and Kate Nash

Contents xxiii

15.23.2 Autoimmune hepatitis  3119 G.J. Webb and Gideon M. Hirschfield

15.23.3 Primary biliary cholangitis  3127 Jessica K. Dyson and David E.J. Jones

15.23.4 Primary sclerosing cholangitis  3135 Kate D. Lynch and Roger W. Chapman 15.24 Other liver diseases  3142

15.24.1 Alcoholic liver disease  3142 Ewan Forrest

15.24.2 Nonalcoholic fatty liver disease  3147 Quentin M. Anstee and Christopher P. Day

15.24.3 Drug-​induced liver disease  3155 Guruprasad P. Aithal

15.24.4 Vascular disorders of the liver  3166 Alexander Gimson

15.24.5 The liver in systemic disease  3169 James Neuberger

15.24.6 Primary and secondary liver tumours  3178 Graeme J.M. Alexander, David J. Lomas,
William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison

15.24.7 Liver and biliary diseases in infancy and childhood  3191 Richard J. Thompson 15.25 Diseases of the gallbladder and biliary tree  3196 Colin Johnson and Mark Wright 15.26 Diseases of the pancreas  3209

15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay

15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen

15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira Index Volume 3 List of abbreviations  xxxv List of contributors  xlv SECTION 16 Cardiovascular disorders Section editor: Jeremy Dwight 16.1 Structure and function  3241

16.1.1 Blood vessels and the endothelium  3241 Keith Channon and Patrick Vallance

16.1.2 Cardiac physiology  3253 Rhys D. Evans, Kenneth T. MacLeod,
Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden 16.2 Clinical presentation of heart disease  3276

16.2.1 Chest pain, breathlessness, and fatigue  3276 Jeremy Dwight

16.2.2 Syncope and palpitation  3284 K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe 16.3 Clinical investigation of cardiac disorders  3294

16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray

16.3.2 Echocardiography  3314 James D. Newton, Adrian P. Banning, and
Andrew R.J. Mitchell

16.3.3 Cardiac investigations: Nuclear, MRI, and CT  3326 Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer

16.3.4 Cardiac catheterization and angiography  3339 Edward D. Folland 16.4 Cardiac arrhythmias  3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and
Gregory Y.H. Lip 16.5 Cardiac failure  3390

16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390 Theresa A. McDonagh and Kaushik Guha

16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397 Andrew L. Clark and John G.F. Cleland

16.5.3 Chronic heart failure: Definitions, investigation, and management  3407 John G.F. Cleland and Andrew L. Clark

Contents xxiv

16.5.4 Cardiorenal syndrome  3421 Darren Green and Philip A. Kalra

16.5.5 Cardiac transplantation and mechanical circulatory support  3428 Jayan Parameshwar and Steven Tsui 16.6 Valvular heart disease  3436 Michael Henein 16.7 Diseases of heart muscle  3459

16.7.1 Myocarditis  3459 Jay W. Mason and Heinz-​Peter Schultheiss

16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular  3468 Oliver P. Guttmann and Perry Elliott

16.7.3 Specific heart muscle disorders  3489 Oliver P. Guttmann and Perry Elliott 16.8 Pericardial disease  3501 Michael Henein 16.9 Cardiac involvement in infectious
disease  3509

16.9.1 Acute rheumatic fever  3509 Jonathan R. Carapetis

16.9.2 Endocarditis  3519 James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast

16.9.3 Cardiac disease in HIV infection  3534 Peter F. Currie

16.9.4 Cardiovascular syphilis  3539 Krishna Somers 16.10 Tumours of the heart  3544 Thomas A. Traill 16.11 Cardiac involvement in genetic disease  3551 Thomas A. Traill 16.12 Congenital heart disease in the adult  3559 S.A. Thorne 16.13 Coronary heart disease  3596

16.13.1 Biology and pathology of atherosclerosis  3596 Robin P. Choudhury, Joshua T. Chai, and
Edward A. Fisher

16.13.2 Coronary heart disease: Epidemiology and prevention  3603 Goodarz Danaei and Kazem Rahimi

16.13.3 Management of stable angina  3616 Adam D. Timmis

16.13.4 Management of acute coronary syndrome  3626 Rajesh K. Kharbanda and Keith A.A. Fox

16.13.5 Percutaneous interventional cardiac procedures  3655 Edward D. Folland

16.13.6 Coronary artery bypass and valve surgery  3666 Rana Sayeed and David Taggart 16.14 Diseases of the arteries  3674

16.14.1 Acute aortic syndromes  3674 James D. Newton, Andrew R.J. Mitchell, and
Adrian P. Banning

16.14.2 Peripheral arterial disease  3680 Janet Powell and Alun Davies

16.14.3 Cholesterol embolism  3688 Christopher Dudley 16.15 The pulmonary circulation  3691

16.15.1 Structure and function of the pulmonary circulation  3691 Nicholas W. Morrell

16.15.2 Pulmonary hypertension  3695 Nicholas W. Morrell 16.16 Venous thromboembolism  3711

16.16.1 Deep venous thrombosis and pulmonary embolism  3711 Paul D. Stein, Fadi Matta, and John D. Firth

16.16.2 Therapeutic anticoagulation  3729 David Keeling 16.17 Hypertension  3735

16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735 Bryan Williams and John D. Firth

16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753 Bryan Williams and John D. Firth

16.17.3 Secondary hypertension  3778 Morris J. Brown and Fraz A. Mir

16.17.4 Mendelian disorders causing
hypertension  3796 Nilesh J. Samani and Maciej Tomaszewski

16.17.5 Hypertensive urgencies and emergencies  3800 Gregory Y.H. Lip and Alena Shantsila 16.18 Chronic peripheral oedema and lymphoedema  3811 Peter S. Mortimer 16.19 Idiopathic oedema of women  3823 John D. Firth

Contents xxv SECTION 17 Critical care medicine Section editor: Simon Finfer 17.1 The seriously ill or deteriorating patient  3829 Carole Foot and Liz Hickson 17.2 Cardiac arrest  3839 Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and
David A. Gabbott 17.3 Anaphylaxis  3849 Anthony F.T. Brown 17.4 Assessing and preparing patients with medical conditions for major surgery  3860 Tom Abbott and Rupert Pearse 17.5 Acute respiratory failure  3867 Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark Griffiths 17.6 Circulation and circulatory support in the critically ill  3881 Michael R. Pinsky 17.7 Management of raised intracranial pressure  3892 David K. Menon 17.8 Sedation and analgesia in the ICU  3898 Michael C. Reade 17.9 Metabolic and endocrine changes in acute and chronic critical illness  3906 Eva Boonen and Greet Van den Berghe 17.10 Palliative and end-​of-​life care in the ICU  3914 Phillip D. Levin and Charles L. Sprung 17.11 Diagnosis of death and organ donation  3918 Paul Murphy 17.12 Persistent problems and recovery after critical illness  3925 Mark E. Mikkelsen and Theodore J. Iwashyna SECTION 18 Respiratory disorders Section editor: Pallav L. Shah 18.1 Structure and function  3933

18.1.1 The upper respiratory tract  3933 Pallav L. Shah, J.R. Stradling, and S.E. Craig

18.1.2 Airways and alveoli  3937 Peter D. Wagner and Pallav L. Shah 18.2 The clinical presentation of respiratory disease  3947 Samuel Kemp and Julian Hopkin 18.3 Clinical investigation of respiratory disorders  3956

18.3.1 Respiratory function tests  3956 G.J. Gibson

18.3.2 Thoracic imaging  3970 Susan J. Copley and David M. Hansell

18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy  3992 Pallav L. Shah 18.4 Respiratory infection  4004

18.4.1 Upper respiratory tract
infections  4004 P. Little

18.4.2 Pneumonia in the normal host  4008 Wei Shen Lim

18.4.3 Nosocomial pneumonia  4022 Wei Shen Lim

18.4.4 Mycobacteria  4026 Hannah Jarvis and Onn Min Kon

18.4.5 Pulmonary complications of HIV
infection  4031 Julia Choy and Anton Pozniak 18.5 The upper respiratory tract  4040

18.5.1 Upper airway obstruction  4040 James H. Hull and Matthew Hind

18.5.2 Sleep-​related breathing disorders  4048 Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind 18.6 Allergic rhinitis  4059 Stephen R. Durham and Hesham A. Saleh 18.7 Asthma  4067 Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew Menzies-​Gow 18.8 Chronic obstructive pulmonary
disease  4098 Nicholas S. Hopkinson 18.9 Bronchiectasis  4142 R. Wilson and D. Bilton 18.10 Cystic fibrosis  4151 Andrew Bush and Caroline Elston

Contributors

Contributors

Contributors Peter Aaby Bandim Health Project, INDEPTH Network, Bissau, Guinea-​Bissau, West Africa 8.5.6: Measles Emma Aarons Consultant Virologist and Infectious Disease Physician, Rare and Imported Pathogens Laboratory, Public Health England, Salisbury, Wiltshire, UK 8.5.27: Orf and Milker’s nodule Tom Abbott William Harvey Research Institute, Queen Mary University of London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Ade Adebajo Faculty of Medicine, Dentistry and Health, University of Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist Raymond Agius Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health S. Faisal Ahmed School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Shahzada K. Ahmed Department of Otorhinolaryngology, Queen Elizabeth Hospital, Birmingham, UK 13.2.2: Disorders of the posterior pituitary gland Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Guruprasad P. Aithal NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, The University of Nottingham, Nottingham, UK 15.24.3: Drug-​induced liver disease Sara Ajina Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.6.1: Visual pathways Tyler Albert VA Puget Sound Health Care System, Division of General Internal Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Maha Albur University of Bristol, Bristol, UK 8.2.5: Antimicrobial chemotherapy Michael J. Aldape Veterans Affairs Medical Center, Infectious Diseases Section, Boise, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Graeme J.M. Alexander UCL Professor, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK 15.23.1: Hepatitis A to E; 15.24.6: Primary and secondary liver tumours Michael E.D. Allison Liver Unit, Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK 15.24.6: Primary and secondary liver tumours Carlo Ammendolia Faculty of Medicine, University of Toronto, Toronto, Canada; Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada 19.4: Back pain and regional disorders Chris Andrews Faculty of Medicine, University of Queensland, Herston, Qld 4029, Australia 10.3.5: Lightning and electrical injuries Ross H. Andrews Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Professor of Parasitology, Imperial College London, Faculty of Medicine, St Mary’s Campus, London, UK 8.11.2: Liver fluke infections Jervoise Andreyev Consultant Gastroenterologist, United Lincolnshire Hospitals Trust; Honorary Professor, The School of Medicine, University of Nottingham, UK 15.3.4: Investigation of gastrointestinal
function Gregory M. Anstead Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Immunosuppression and Infectious Diseases Clinics, Department of Medicine, South Texas Veterans Health Care System, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Quentin M. Anstee Professor of Experimental Hepatology and Honorary Consultant Hepatologist, Faculty of Medical Sciences, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Charles M.G. Archer Department of Dermatology, Oxford University Hospitals NHS Trust, Oxford, UK 23.15: Skin and systemic diseases Clive B. Archer Consultant Dermatologist and Honorary Senior Clinical Lecturer, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust & King’s College London, Guy’s Hospital, London, UK 23.15: Skin and systemic diseases Michael J. Arden-​Jones  Consultant
Dermatologist, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Mark J. Arends University of Edinburgh Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK 3.6: Apoptosis in health and disease J. Arendt Emeritus Professor of
Endocrinology, University of Surrey,
Guildford, UK 13.11: The pineal gland and melatonin James O. Armitage The Joe Shapiro Professor of Medicine, Division of Oncology/​Hematology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Vicente Arroyo Professor of Medicine at the University of Barcelona Medical School; Chairman of the European Association
for the Study of the Liver Chronic Liver
Failure Consortium (EASL-​CLIF
Consortium) and President of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF), Barcelona, Spain 15.22.2: Cirrhosis and ascites Daniel Aruch Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Frances Ashcroft Professor of Physiology, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 3.4: Ion channels and disease Caroline Ashley Lead Specialist Pharmacist, Centre for Nephrology, Royal Free Hospital, London, UK 21.19: Drugs and the kidney Shazad Q. Ashraf Consultant Colorectal Surgeon, Department of Colorectal Surgery, Queen Elizabeth Hospital, Birmingham University Hospitals, Birmingham, UK 15.14: Colonic diverticular disease

Contributors xlvi Paul Aveyard Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management; 26.6.3: Smoking cessation Tar-​Ching Aw† Abu Dhabi National Oil Company, United Arab Emirates 10.2.5: Noise; 10.2.6 Vibration Jon G. Ayres Emeritus Professor of Environmental and Respiratory Medicine, Universty of Birmingham, Birmingham, UK 10.1: Environmental medicine, occupational medicine, and poisoning; 10.3.1: Air pollution and health Juan Carlos Ayus Renal Consultants of Houston, Houston, TX, USA; University of California Irvine, Orange, CA, USA 21.2.1: Disorders of water and sodium homeostasis Qasim Aziz Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 15.13: Irritable bowel syndrome Trevor Baglin Previously Cambridge Haemophilia and Thrombophilia Centre, Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK 22.7.2: Evaluation of the patient with a bleeding tendency Michael Bagshaw Aviation Medicine, King’s College, London, UK 10.2.3: Aviation medicine Colin Baigent Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Kenneth F. Baker Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 19.5: Rheumatoid arthritis Bettina Balint Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, UK; Department of Neurology, University Hospital Heidelberg, University of Heidelberg, Germany 24.7.3: Movement disorders other than Parkinson’s disease Jay Banerjee College of Life Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Adrian P. Banning Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1 Acute aortic syndromes George Banting Medical Sciences Building, University of Bristol, Bristol, UK 3.1: The cell Thomas M. Barber University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK 13.10: Hormonal manifestations of non-​endocrine disease E.J. Barnes Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.5.22: Hepatitis C virus Michael Barnes University of Newcastle, Newcastle upon Tyne, UK; Christchurch Group, Janet Barnes Unit, Birmingham, UK 24.13.2: Spinal cord injury and its management Andrew J. Barr Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK 19.9: Osteoarthritis Jonathan Barratt Professor of Renal Medicine, University of Leicester; Honorary Consultant Nephrologist, University Hospitals of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP) Buddha Basnyat Oxford University Clinical Research Unit -​ Nepal; Patan Academy of Health Sciences, Nepal 8.6.9 Typhoid and paratyphoid fevers; 10.3.6: Diseases of high terrestrial altitudes D. Nicholas Bateman, Pharmacology, Toxicology and Therapeutics, University of Edinburgh, Edinburgh, UK 10.4.1: Poisoning by drugs and chemicals David Bates Clinical Neurology, Newcastle University, Newcastle on Tyne, UK 24.5.5: The unconscious patient; 24.9: Brainstem syndromes Robert P. Baughman University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Peter J. Baxter School of Clinical Medicine,
Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK 10.3.8: Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions Hannah Beckwith Specialist Registrar, Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, UK 21.10.3: The kidney in rheumatological
disorders Diederik van de Beek Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.1: Bacterial infections David A. Bender University College London, London, UK 11.2: Vitamins D.A. Bente University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Anthony R. Berendt Oxford University Hospitals NHS Foundation Trust, Oxford, UK 20.3: Osteomyelitis Stefan Berg Consultant in Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Goteborg, Sweden 12.12.2 Hereditary periodic fever syndromes David de Berker Bristol Dermatology
Centre, University Hospitals Bristol,
Bristol, UK 23.13: Hair and nail disorders Nancy Berliner H. Franklin Bunn Professor of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 22.3.1: Granulocytes in health and disease; 22.4.1: Introduction to lymphopoiesis Jessica Bertrand Experimental Orthopedics, University Hospital Magdeburg, Magdeburg, Germany 19.1: Joints and connective tissue—​structure
and function J.M. Best King’s College London, London, UK 8.5.13: Rubella Delia B. Bethell Oxford University Hospitals NHS Foundation Trust, Oxford, UK 8.6.1: Diphtheria Kailash Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, UK 24.7.3: Movement disorders other than
Parkinson’s disease Vijaya Raj Bhatt Assistant Professor, Division of Hematology-​Oncology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Joya Bhattacharyya Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract Paola Bianchi Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Rudolf Bilous Professor of Clinical Medicine, Newcastle University, Newcastle upon Tyne; Academic Centre, James Cook University Hospital, Middlesbrough, UK 21.10.1: Diabetes mellitus and the kidney D. Bilton Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.9: Bronchiectasis Jonathan I. Bisson Division of Psychological Medicine and Clinical Neurosciences, University of Cardiff, Cardiff, UK 26.5.9: Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder Carol M. Black Newnham College, Cambridge, UK 19.11.3: Systemic sclerosis (scleroderma) S.R. Bloom Head of Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome Johannes Blum Medical Services, Swiss
Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis † It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Contributors xlvii Kristien Boelaert University of Birmingham, Birmingham, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Eva Boonen Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Christopher Booth† Wellcome Institute for the History of Medicine, Wellcome Building, London, UK 1.1: On being a patient Marina Botto Professor, Imperial College London, London, UK 4.2: The complement system Ralph Bouhaidar Consultant Forensic Pathologist, NHS Lothian; Honorary Senior Lecturer, Edinburgh University, Edinburgh; Training Programme Director for Forensic Histopathology (Scotland), UK 27.1: Forensic and legal medicine Henri-​Jean Boulouis Ecole Nationale Vétérinaire d’Alfort, Maisons-​Alfort, France 8.6.43: Bartonellas excluding B. bacilliformis P.-​M.G. Bouloux Centre for Neuroendocrinology, University College London Medical School, London, UK 13.6.2: Disorders of male reproduction and male hypogonadism S.J. Bourke Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.3: Lymphocytic infiltrations of the lung; 18.14.4: Hypersensitivity pneumonitis; 18.14.5: Pulmonary Langerhans’ cell histiocytosis; 18.14.6: Lymphangioleiomyomatosis; 18.14.7: Pulmonary alveolar proteinosis; 18.14.8: Pulmonary amyloidosis; 18.14.9: Lipoid (lipid) pneumonia; 18.14.10: Pulmonary alveolar microlithiasis; 18.14.12: Radiation pneumonitis; 18.14.13: Drug-​induced
lung disease Ian C.J.W. Bowler Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Louise Bowles Consultant Haematologist, Barts Health NHS Trust, London, UK 14.7: Thrombosis in pregnancy Paul Bowness Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK 4.1: The innate immune system Ray Boyapati Department of Gastroenterology, Monash Health, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Vic, Australia 15.17: Vascular disorders of the gastrointestinal tract Sally M. Bradberry NPIS (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Marcus Bradley North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases Tasanee Braithwaite Locum Consultant, Moorfields Eye Hospital NHS Foundation Trust, London, UK 25.1: The eye in general medicine Thomas Brandt Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Petter Brandtzaeg Emeritus Professor, Department of Paediatrics, Oslo University Hospital, Oslo, Norway 8.6.5: Meningococcal infections Philippe Brasseur Institut de Recherche pour le Développement, Dakar, Sénégal, West Africa 8.8.3: Babesiosis Jürgen Braun Medical Director, Rheumazentrum Ruhrgebiet, Herne, Germany; Chair of Rheumatology, Ruhr University, Bochum, Germany 19.6: Spondyloarthritis and related
conditions Evan M. Braunstein Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis James D. Brenton Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications J.A. Bridgewater Professor and Consultant in Medical Oncology, UCL Cancer Institute, London, UK 15.16: Cancers of the gastrointestinal tract Frank Bridoux Professor of Nephrology, Department of Nephrology, Hôpital Jean Bernard, Poitiers, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Charlotte K. Brierley Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 22.3.2: Myelodysplastic syndromes Alice Brockington University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Max Bronstein Advocacy and Science
Policy, Every Life Foundation, Washington, DC, USA 2.9: Engaging patients in therapeutic development Gary Brook London North West University Healthcare NHS Trust, London, UK 9.3: Sexual history and examination Arthur E. Brown Research Consultant, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand 8.6.21: Anthrax Anthony F.T. Brown Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Qld, Australia 17.3: Anaphylaxis Kevin E. Brown Virus Reference Department, Public Health England, London, UK 8.5.20: Parvovirus B19 Michael Brown Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.9.4: Strongyloidiasis, hookworm, and other gut strongyloid nematodes Morris J. Brown Professor of Endocrine Hypertension, Queen Mary University of London, William Harvey Heart Centre, London, UK 16.17.3: Secondary hypertension Vanessa Brown Specialist Registrar, Royal Surrey County Hospital, Guildford, UK 15.4.2: Gastrointestinal bleeding Reto Brun Parasite Chemotherapy Unit, Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis Marco J. Bruno Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis Amy E. Bryant Research Professor, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Antony D.M. Bryceson London School of Hygiene and Tropical Medicine, London, UK 8.8.13: Leishmaniasis Nicolas C. Buchs Consultant Colorectal Surgeon, Clinic for Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland 15.14: Colonic diverticular disease Camilla Buckley MRC Clinician Scientist and Honorary Consultant, Department of Clinical Neurology, University of Oxford, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Simon J.A. Buczacki Honorary Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen Enrico Bugiardini MRC Centre for Neuromuscular Disease, University College London, London, UK 24.19.1: Structure and function of muscle Alan Burnett Former Professor of Haematology, Cardiff University, Cardiff, UK 22.3.3: Acute myeloid leukaemia Gilbert Burnham John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 8.9.1: Cutaneous filariasis Aine Burns Consultant Nephrologist and Director of Postgraduate Medical Education, Centre for Nephrology, Royal Free NHS Trust and University College Medical School, London, UK 21.19: Drugs and the kidney † It is with great regret that we report that Christopher Booth died on 13 July, 2012.

Contributors xlviii Eileen Burns Leeds Centre for Older People’s Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK 6.11: Promotion of dignity in the life and death of older patients Harry Burns University of Strathclyde, UK 2.14: Deprivation and health N.P. Burrows Consultant Dermatologist, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.2: Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan syndrome, and pseudoxanthoma elasticum Rosie Burton Khayelitsha District Hospital, Corner of Walter Sisulu and Streve Biko
Roads, Khayelitsha, Cape Town, Africa; Department of Medicine, University of Cape Town, Cape Town, Africa 14.15: Maternal infection in pregnancy Andrew Bush Imperial College London, London, UK; National Heart and Lung Institute, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK 18.10: Cystic fibrosis Kate Bushby Newcastle University John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Gary Butler University College London Hospital and UCL Great Ormond Street Institute of Child Health, London, UK 13.7.1: Normal growth and its disorders William F. Bynum Professor Emeritus, University College London, London, UK 2.1: Science in medicine: When, how,
and what Simone M. Cacciò European Union Reference Laboratory for Parasites, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy 8.8.5: Cryptosporidium and cryptosporidiosis Djuna L. Cahen Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis P.M.A. Calverley School of Clinical Sciences, University of Liverpool, Liverpool, UK 18.15: Chronic respiratory failure Jason Caplan Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine; Phoenix, AZ, USA 26.5.3: Organic psychoses Jonathan R. Carapetis Telethon Kids Institute, University of Western Australia and Perth Children’s Hospital, Perth, Australia 16.9.1: Acute rheumatic fever Jordi Carratalà Department of Infectious Diseases, Hospital Universitari de Bellvitge -​ IDIBELL, Division of Health Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain 8.6.39: Legionellosis and Legionnaires’ disease R. Carter Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Stuart Carter Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Carty Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK 14.11: Endocrine disease in pregnancy Jaimini Cegla Imperial College London, London, UK 12.6: Lipid disorders Joseph Cerimele University of Washington, Washington, DC, USA 26.5.6: Depressive disorder Joshua T. Chai Department of Cardiovascular Medicine, University of Oxford,
Oxford, UK 16.13.1: Biology and pathology of
atherosclerosis Richard E. Chaisson Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8.6.26: Tuberculosis Romanee Chaiwarith Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Ben Challis University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia Siddharthan Chandran Euan MacDonald Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine; 24.10.2: Demyelinating disorders of the central nervous system Keith Channon John Radcliffe Hospital, Oxford, UK 16.1.1: Blood vessels and the endothelium Roger W. Chapman Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis V. Krishna Chatterjee University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action Afzal Chaudhry Chief Clinical Information Officer, Cambridge University Hospitals, Cambridge, UK 2.5: Bioinformatics K. Ray Chaudhuri National Parkinson Foundation Centre of Excellence, King’s College, Denmark Hill Campus, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Patrick F. Chinnery University of Newcastle, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease Hector Chinoy University of Manchester, Manchester, UK 19.11.5: Inflammatory myopathies Peter L. Chiodini Hospital for Tropical Diseases, University College London Hospitals,
London, UK 8.9.5: Gut and tissue nematode infections acquired by ingestion Rossa W.K. Chiu Choh-​Ming Li Professor of Chemical Pathology, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Bruno B. Chomel School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Robin P. Choudhury University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Julia Choy National Health Service, London, UK 18.4.5: Pulmonary complications of HIV infection Lydia Chwastiak Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA 26.5.6: Depressive disorder Andrew L. Clark Chair of Clinical Cardiology
and Honorary Consultant Cardiologist,
Hull York Medical School, Castle Hill Hospital, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3: Chronic heart failure: Definitions, investigation, and management Andrew Clegg Academic Unit of Elderly Care and Rehabilitation, University of Leeds, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.2: Frailty and sarcopenia John G.F. Cleland National Heart and Lung Institute, Royal Brompton and Harefield Hospitals Trust London, UK; Hull York Medical School, University of Hull, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3 Chronic heart failure: Definitions, investigation, and management Gavin Clunie Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.5: Osteonecrosis, osteochondrosis, and osteochondritis dissecans S.M. Cobbe Previously Consultant Cardiologist, Glasgow Royal Infirmary; former BHF Walton Professor of Medical Cardiology, University of Glasgow, Glasgow, UK 16.2.2: Syncope and palpitation Fredric L. Coe The University of Chicago Medicine, Chicago, IL, US 21.1: Structure and function of the kidney Sian Coggle Consultant Physician, Cambridge University Hospitals, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures Jon Cohen Brighton and Sussex Medical School, Brighton, UK 8.2.4: Infection in the immunocompromised host

Contributors xlix Alasdair Coles Cambridge School of Clinical Medicine, Cambridge, UK 24.10.2: Demyelinating disorders of the central nervous system Jane Collier Consultant Hepatologist, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus; 15.22.1: Investigation and management of jaundice Rory Collins Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Juan D. Colmenero Infectious Diseases Service, Regional University Hospital, Málaga, Spain 8.6.22: Brucellosis Alastair Compston Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 24.1: Introduction and approach to the patient with neurological disease Juliet Compston University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.4: Osteoporosis Philip G. Conaghan Leeds University,
Leeds, UK 19.9: Osteoarthritis Christopher P. Conlon Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.4: Travel and expedition medicine; 8.5.23: HIV/​ AIDS; 8.5.28: Molluscum contagiosum Simon Conroy Department of Health Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Cyrus Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK 20.4: Osteoporosis John E. Cooper University of Cambridge, Cambridge, UK 8.8.8: Sarcocystosis (sarcosporidiosis) Robert Cooper University of Liverpool, Liverpool, UK 19.11.5: Inflammatory myopathies Mhairi Copland Professor of Translational Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Susan J. Copley Imperial College Healthcare NHS Trust, London, UK 18.3.2: Thoracic imaging Jeremy Cordingley Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Philip J. Cowen University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.4.1: Psychopharmacology in medical practice Timothy M. Cox Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK 1.1: An older patient’s story; 12.1: The inborn errors of metabolism: General aspects; 12.3.1: Glycogen storage diseases; 12.3.2: Inborn errors of fructose metabolism; 12.3.3: Disorders of galactose, pentose, and pyruvate metabolism; 12.5: The porphyrias; 12.7.1: Hereditary haemochromatosis; 12.8: Lysosomal disease; 13.11: The pineal gland and melatonin; 15.10.5: Disaccharidase deficiency; 22.6.4: Iron metabolism and its disorders S.E. Craig Oxford Sleep Unit, Churchill Hospital, Oxford, UK 18.1.1: The upper respiratory tract Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Derriford Hospital, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Robin A.F. Crawford Addenbrooke’s Hospital, Cambridge, UK 14.18: Malignant disease in pregnancy Daniel Creamer King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs Tim Crook North Middlesex Hospital,
London, UK 5.7: Medical management of breast cancer Paul Cullinan Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.7: Asthma Peter F. Currie Perth Royal Infirmary, Perth and Ninewells Hospital and Medical School, Dundee, UK 16.9.3: Cardiac disease in HIV infection Nicola Curry Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of
platelet function Goodarz Danaei Department of Global Health and Population, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 16.13.2: Coronary heart disease: Epidemiology and prevention Christopher J. Danpure Emeritus Professor of Molecular Cell Biology, University College London, London, UK 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Bhaskar Dasgupta University of Essex, Essex, UK; Anglia Ruskin University, East Anglia, UK; Southend University Hospital NHS Foundation Trust, Essex, UK 19.11.11: Polymyalgia rheumatica Pooja Dassan Consultant Neurologist, Imperial College Healthcare NHS Trust and London
North West University Healthcare NHS Trust, London, UK 14.12: Neurological conditions in
pregnancy Andrew Davenport Professor of Dialysis and ICU Nephrology, UCL Department of Nephrology, Royal Free Hospital, University College London, London, UK 21.4: Clinical investigation of renal disease Gail Davey Centre for Global Health Research, Brighton and Sussex Medical School,
Brighton, UK 10.5: Podoconiosis Alun Davies Imperial College School of Medicine, London, UK 16.14.2: Peripheral arterial disease Helen E. Davies University Hospital of Wales, Cardiff, UK 18.19.4: Mediastinal tumours and cysts R Justin Davies Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen P.D.O. Davies Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK 8.6.27: Disease caused by environmental mycobacteria R. Rhys Davies Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture Simon Davies Professor of Nephrology and Dialysis Medicine, Institute for Science and Technology in Medicine, Keele University, Keele; Consultant Nephrologist, University Hospital of North Midlands, Stoke-​on-​Trent, UK 21.7.2: Peritoneal dialysis Richard Dawkins New College, University of Oxford, Oxford, UK 2.2: Evolution: Medicine’s most basic science Christopher P. Day Vice-​Chancellor and President, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Nicholas P.J. Day Mahidol-​Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.6.35: Leptospirosis; 8.6.41: Scrub typhus Colin Dayan University of Cardiff, Wales, UK 13.9.1: Diabetes Marc E. De Broe Professor of Medicine, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Kevin M. De Cock Center for Global Health, Atlanta, GA, USA 8.5.24: HIV in low-​ and middle-​income
countries An S. De Vriese Division of Nephrology, AZ Sint-​Jan Brugge-​Oostende AV, Brugge, Belgium 21.8.4: Membranous nephropathy Patrick B. Deegan Consultant Metabolic Physician, Lysosomal Disorders Unit, Cambridge University Hospitals, Cambridge, UK 12.8 Lysosomal disease

Contributors l Christopher Deighton Royal Derby Hospital, Derby, UK 19.2 Clinical presentation and diagnosis of rheumatological disorders David M. Denison Emeritus Professor of Clinical Physiology, Royal Brompton Hospital and Imperial College London, London, UK 10.2.4: Diving medicine Christopher P. Denton Centre for Rheumatology, Division of Medicine, University College London (UCL) Medical School, Royal Free Hospital, London, UK 19.11.3: Systemic sclerosis (scleroderma) Ulrich Desselberger University of Cambridge, Cambridge, UK 8.5.8: Enterovirus infections; 8.5.9: Virus
infections causing diarrhoea and vomiting Patrick C. D’Haese Head of Laboratory of Pathophysiology, University of Antwerp, Campus Drie Eiken, Wilrijk, Belgium 21.9.2: Chronic tubulointerstitial nephritis Ashwin Dhanda Plymouth Hospitals NHS Trust, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Jugdeep Dhesi Guys and St Thomas’ Hospitals, London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Euan J. Dickson Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Michael Doherty University of Nottingham, Nottingham, UK 19.3: Clinical investigation; 19.10: Crystal-​related arthropathies Inderjeet S. Dokal Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health NHS Trust, London, UK 22.5.1: Inherited bone marrow failure
syndromes Jan Donck Department of Nephrology, AZ Sint-​ Lucas, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Arjen M. Dondorp Mahidol-​Oxford Tropical Medicine Research Unit, Bangkok,
Thailand 8.8.2: Malaria Basil Donovan University of New South Wales, NSW, Australia 8.6.37: Syphilis Philip R. Dormitzer Pfizer Vaccine Research and Development, Pearl River, NY, USA 8.5.9: Virus infections causing diarrhoea and vomiting Anne Dornhorst Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy Charles G. Drake New York Presbyterian and Columbia University Medical Center, New York, USA 5.4: Cancer immunity and immunotherapy Hal Drakesmith MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Christopher Dudley Consultant Nephrologist, The Richard Bright Renal Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 16.14.3: Cholesterol embolism Susanna Dunachie Oxford University Hospitals NHS Trust, Oxford, UK 8.4: Travel and expedition medicine Lisa Dunkley Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Dunne University of Cambridge,
Cambridge, UK; Wellcome Trust-​Cambridge, Centre for Global Health Research, UK; CAPREx, THRiVE-​Cambridge, and Cambridge-​Africa 8.11.1: Schistosomiasis Stephen R. Durham National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK 18.6: Allergic rhinitis Jeremy Dwight John Radcliffe Hospital, Oxford, UK 16.2.1: Chest pain, breathlessness, and fatigue Jessica K. Dyson Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Christopher P. Eades University College London, London, UK 8.7.5: Pneumocystis jirovecii Ian Eardley St James’s Hospital, Leeds, UK 13.6.4: Sexual dysfunction James E. East Consultant Gastroenterologist, Translational Gastroenterology Unit, John Radcliffe Hospital; Associate Professor of Gastroenterology and Endoscopy, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 15.3.1: Colonoscopy and flexible
sigmoidoscopy; 15.3.2: Upper gastrointestinal endoscopy Lars Eckmann Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA 8.8.9: Giardiasis and balantidiasis Michael Eddleston Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 10.4.4: Poisonous plants Mark J. Edwards St George’s University of London, London, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Richard Edwards School of Clinical Sciences, University of Bristol, Bristol, UK 24.19.4: Metabolic and endocrine disorders Rosalind A. Eeles The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK 5.3: The genetics of inherited cancers Tim Eisen Department of Oncology, University of Cambridge, Cambridge, UK; Oncology Early Clinical Development, AstraZeneca, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications; 5.5: Clinical features and management; 21.18: Malignant diseases of the urinary tract Wagih El Masri(y) Keele University, Newcastle-​ under-​Lyme, UK; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK 24.13.2: Spinal cord injury and its management Carole Eldin University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Perry Elliott St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Christopher J. Ellis Heart of England Foundation Trust, Birmingham, UK; University of Birmingham, Birmingham, UK 8.2.1: Clinical approach Graham Ellis Monklands Hospital, Airdrie, Lanarkshire, UK 6.5: Older people in hospital Monique M. Elseviers Centre for Research and Innovation in Care (CRIC), University of Antwerp, Antwerp; Heymans Institute of Clinical Pharmacology, Ghent University, Ghent, Belgium 21.9.2: Chronic tubulointerstitial nephritis Caroline Elston Respiratory Medicine and Adult Cystic Fibrosis, King’s College Hospital, London, UK 18.10: Cystic fibrosis M.A. Epstein Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK 8.5.3: Epstein–​Barr virus Steve Epstein MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington, DC, USA 26.5.8: Anxiety disorders Wendy N. Erber Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia 22.2.2: Diagnostic techniques in the assessment of haematological malignancies Ari Ercole Neurosciences Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Edzard Ernst Emeritus Professor, University of Exeter, Exeter, UK 2.22: Complementary and alternative medicine Andrew P. Evan Indiana University School of Medicine, Indianapolis, IN, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Mark Evans University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia

Contributors li Rhys D. Evans Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 11.1 Nutrition: Macronutrient metabolism; 16.1.2: Cardiac physiology Pamela Ewan Allergy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.5: Allergy David W. Eyre Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 8.6.24 Clostridium difficile Lynette D. Fairbanks Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4 Disorders of purine and pyrimidine metabolism Christopher G. Fairburn Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.10: Eating disorders Carole Fakhry Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses Marie Fallon St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, Edinburgh, UK 7.2: Pain management Sonia Fargue University of Alabama at Birmingham, Birmingham, AL, USA 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Adam D. Farmer Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London; Department of Gastroenterology, University Hospitals of North Midlands, Stoke-​on-​Trent, UK 15.13: Irritable bowel syndrome I. Sadaf Farooqi Wellcome-​MRC Institute of Metabolic Science, University of Cambridge, UK 11.6: Obesity Jeremy Farrar Wellcome Trust, London, UK 2.17: Research in the developed world; 24.11.2: Viral infections Ken Farrington Lister Hospital, East and North Hertfordshire NHS Trust, Stevenage, UK 21.3: Clinical presentation of renal disease Hiva Fassihi King’s College London,
London, UK 23.9: Photosensitivity John Feehally Emeritus Consultant Nephrologist, University Hospitals of Leicester; Honorary Professor of Renal Medicine, University of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP); 21.8.2: Thin membrane nephropathy Peter J. Fenner School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Qld, Australia 10.3.4: Drowning Florence Fenollar Aix-​Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU Méditerranée Infection, Marseille, France 15.10.6: Whipple’s disease Javier Fernández Consultant Hepatologist, Head of Liver ICU, Liver Unit, Hospital Clinic Barcelona; Associate Professor, University of Barcelona Medical School, Barcelona, Spain; Member of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF) 15.22.2: Cirrhosis and ascites Fernando C. Fervenza Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA 21.8.4: Membranous nephropathy Sarah Fidler Professor of HIV Medicine, Imperial College London, London, UK 8.5.23: HIV/​AIDS Richard E. Fielding Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon
Tyne, UK 21.3: Clinical presentation of renal disease Roger G. Finch Nottingham University Hospitals, NHS Trust, Nottingham, UK 8.2.5: Antimicrobial chemotherapy Simon Finney Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Helen V. Firth Addenbrookes Hospital Cambridge, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system John D. Firth Consultant Physician and Nephrologist, Cambridge University
Hospitals, Cambridge, UK 16.16.1: Deep venous thrombosis and pulmonary embolism; 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment; 16.19: Idiopathic oedema of women; 21.2.2: Disorders of potassium homeostasis; 21.5: Acute kidney injury; 21.7.3: Renal transplantation; 30.1: Acute medical presentations; 30.2: Practical procedures A.J. Fisher Professor of Respiratory Transplant Medicine, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK 18.16: Lung transplantation Edward A. Fisher Departments of Medicine, Pediatrics, and Cell Biology, Smilow Research Centre, New York, NY, USA 16.13.1: Biology and pathology of atherosclerosis Rebecca C. Fitzgerald Professor of Cancer Prevention and MRC Programme Leader, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael E.B. FitzPatrick Department of Gastroenterology, Oxford University Hospitals, Oxford; Senior Research Fellow, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract R. Andres Floto Molecular Immunity Unit, Department of Medicine, University of Cambridge, UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK 3.5: Intracellular signalling Edward D. Folland University of Massachusetts Medical School, MA, USA 16.3.4: Cardiac catheterization and angiography; 16.13.5: Percutaneous interventional cardiac procedures D. de Fonseka Academic Respiratory Unit, University of Bristol, Bristol, UK 18.17: Pleural diseases Carole Foot Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating patient Alastair Forbes Norwich Medical School,  University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption Ewan Forrest Consultant Hepatologist and Honorary Clinical Associate Professor, Department of Gastroenterology, Glasgow Royal Infirmary and the University of Glasgow, Glasgow UK 15.24.1: Alcoholic liver disease Rob Fowkes Royal Veterinary College,
London, UK 13.1: Principles of hormone action Keith A.A. Fox Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 16.13.4: Management of acute coronary
syndrome Stephen Franks Imperial College London, London, UK 13.6.1: Ovarian disorders Keith N. Frayn Radcliffe Department of Medicine, University of Oxford, Oxford, UK 11.1: Nutrition: Macronutrient metabolism Patrick French Mortimer Market Centre, Central and North West London NHS Trust, London, UK; University College London, London, UK 9.6: Genital ulceration Izzet Fresko Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Peter S. Friedmann Emeritus Professor of Dermatology, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Charlotte Frise Obstetric Medicine and Acute General Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20: Prescribing in pregnancy Susannah J.A. Froude Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Stephen J. Fuller Associate Professor, Medicine Sydney Medical School Nepean, The University of Sydney, Sydney, Australia 22.6.8: Anaemias resulting from defective maturation of red cells David A. Gabbott Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK 17.2: Cardiac arrest

Contributors lii Simon M. Gabe Consultant Gastroenterologist, Intestinal Failure and Academic Unit, St Mark’s Hospital, London, UK 15.10.7: Effects of massive bowel resection Patrick G. Gallagher Professor of Pediatrics, Genetics and Pathology, Yale University, New Haven, CT, USA 22.6.9: Disorders of the red cell membrane Shreyans Gandhi King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Hector H. Garcia Center for Global Health, Tumbes and Department of Microbiology, Universidad Peruana Cayetano Heredia, and Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus); 8.10.3: Cysticercosis Hill Gaston University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Rupert Gauntlett Critical Care Medicine and Obstetric Anaesthesia, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK 14.19: Maternal critical care John Geddes University of Oxford, Oxford, UK 26.5.7: Bipolar disorder William Gelson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.20: Structure and function of the liver, biliary tract, and pancreas Jacob George Department of Clinical Pharmacology and Therapeutics, University of Dundee, Dundee, UK 6.7: Drugs and prescribing in the older patient G.J. Gibson Newcastle University, Newcastle upon Tyne, UK 18.3.1: Respiratory function tests John Gibson Professor of Oral Medicine and Honorary Consultant in Oral Medicine, Institute of Dentistry, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK 15.6: The mouth and salivary glands J. van Gijn University Medical Center Utrecht, Utrecht, the Netherlands 24.10.1 Stroke: Cerebrovascular disease Ian Giles Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction Robert H. Gilman Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA 8.10.3: Cysticercosis Alexander Gimson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.19: Miscellaneous disorders of the bowel; 15.20: Structure and function of the liver, biliary tract, and pancreas; 15.24.4: Vascular disorders of the liver Matthew R. Ginks Oxford University Hospitals NHS Trust, Oxford, UK 16.4: Cardiac arrhythmias D.S. Giovanniello Medical Director, American Red Cross, Biomedical Services, Connecticut Blood Services Region, Farmington, CT, USA 22.8.1: Blood transfusion Mark A. Glover Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.2.4: Diving medicine Peter J. Goadsby NIHR-​Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK 24.8: Headache David Goldblatt University College London, London, UK 8.3: Immunization Armando E. Gonzalez Center for Global Health, Tumbes, Universidad Peruana Cayetano Heredia, and Department of Veterinary Epidemiology and Economics, School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus) E.C. Gordon-​Smith Professor of Haematology, St George’s Hospital, University of London, London, UK 22.8.2: Haemopoietic stem cell transplantation Martin Gore† The Royal Marsden, London, UK; The Institute of Cancer Research, University of London, London, UK 5.5: Clinical features and management Eduardo Gotuzzo Universidad Peruana Cayetano Heredia, Lima, Peru 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Philip Goulder University of Oxford, Oxford, UK 8.5.23: HIV/​AIDS Alison D. Grant Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.5.24: HIV in low-​ and middle-​income
countries Cameron C. Grant The University of Auckland, New Zealand; Starship Children’s Health, Auckland, New Zealand 8.6.15: Bordetella infection David Gray Department of Cardiovascular Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK 16.3.1: Electrocardiography Richard Gray Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials John R. Graybill Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Darren Green Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.5.4: Cardiorenal syndrome Manfred S. Green Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.9: Bioterrorism Christopher D. Gregory University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK 3.6: Apoptosis in health and disease Christopher E.M. Griffiths Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK 23.5: Papulosquamous disease Karolina Griffiths University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Mark Griffiths Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK; Imperial College London, London, UK 17.5: Acute respiratory failure William J.H. Griffiths Consultant Hepatologist, Department of Hepatology, Addenbrooke’s Hospital, Cambridge, UK 12.7.1: Hereditary haemochromatosis; 15.24.6: Primary and secondary liver tumours J.P. Grünfeld Hôpital Universitaire Necker, Paris, France 21.12: Renal involvement in genetic disease D.J. Gubler Director, Program on Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore; Asian Pacific Institute of Tropical Medicine and Infectious Diseases, University of Hawaii, Honolulu 8.5.12: Alphaviruses Richard L. Guerrant Center for Global Health, School of Medicine, University of Virginia, VA, USA 8.6.12: Cholera Kaushik Guha Portsmouth Hospitals NHS Trust, Portsmouth, UK 16.5.1: Epidemiology and general pathophysiological classification of
heart failure Nishan Guha Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1060, Hôpital Cochin, Assistance Publique–​ Hôpitaux de Paris, University Paris Descartes, Paris, France 19.11.8: Polyarteritis nodosa Mark Gurnell University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action; 13.5.1 Disorders of the adrenal cortex Oliver P. Guttmann St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular
Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Robert D.M. Hadden Consultant Neurologist, King’s College Hospital, London, UK 24.12: Disorders of cranial nerves; 24.16: Diseases of the peripheral nerves † It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contributors liii Zara Haider Kingston Hospital NHS Trust, Surrey, UK 9.9: Principles of contraception Sophie Hambleton Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK; Paediatric Immunology and Infectious Diseases, Great North Children’s Hospital, Newcastle upon Tyne, UK 4.4: Immunodeficiency Freddie C. Hamdy Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 21.18: Malignant diseases of the
urinary tract Michael G. Hanna National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.19.1: Structure and function of muscle David M. Hansell Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.3.2: Thoracic imaging Danielle Harari Guy’s and St Thomas’ Hospitals and King’s College London, London, UK 6.9: Bladder and bowels Kate Hardy Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, London, UK 13.6.1: Ovarian disorders Karen E. Harman Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Peter Harper London Oncology Centre, London, UK 5.6: Systemic treatment and radiotherapy; 5.7: Medical management of breast cancer Steve Harper Consultant Renal and Transplant Medicine, Southmead Hospital, Bristol; Honorary Professor, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK; Honorary Professor, School of Medicine, University of Exeter, Exeter, UK 21.1: Structure and function of the kidney James L. Harrison London Deanery, London, UK 16.9.2: Endocarditis Tina Hartert Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Christine Hartmann Institute of Musculoskeletal Medicine, University of Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Nicholas C. Harvey MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 20.4: Osteoporosis Rowan Harwood Nottingham University Hospitals NHS Trust and University of Nottingham, Queens Medical Centre, Nottingham, UK 6.5: Older people in hospital Helen Hatcher Consultant Medical Oncologist, Cambridge University Hospitals, Cambridge, UK 20.6: Bone cancer Chris Hatton Cancer and Haematology Centre, Churchill Hospital, Oxford, UK 22.1: Introduction to haematology; 22.3.9: Histiocytosis; 22.6.2: Anaemia: Pathophysiology, classification, and clinical features Philip N. Hawkins Professor of Medicine, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.2 Hereditary periodic fever syndromes; 12.12.3 Amyloidosis Keith Hawton Centre for Suicide Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm Deborah Hay Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK 22.6.7: Disorders of the synthesis or function of haemoglobin; 22.6.9: Disorders of the red cell membrane Roderick J. Hay King’s College London,
London, UK 8.6.31: Nocardiosis; 8.7.1: Fungal infections; 23.6: Dermatitis/​eczema; 23.10: Infections of the skin; 23.12: Blood and lymphatic vessel disorders Peter Hayes Professor of Hepatology, Liver Unit, University of Edinburgh; and Royal Infirmary of Edinburgh, Edinburgh, UK 15.22.3: Portal hypertension and variceal
bleeding Catherine E.G. Head Consultant Cardiologist, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 14.6: Heart disease in pregnancy Eugene Healy Dermatopharmacology, Southampton General Hospital, University of Southampton, UK 23.8: Disorders of pigmentation Nick Heather Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption David W. Hecht Loyola University Health System, IL, USA 8.6.11: Anaerobic bacteria Thomas Hellmark Department of Clinical Sciences, Lund University, Lund, Sweden 21.8.7: Antiglomerular basement membrane
disease Michael Heneghan Professor of Hepatology and Consultant Hepatologist, Institute of Liver Studies, King’s College Hospital, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Michael Henein Umeå University, Sweden; Canterbury Christ Church University, Canterbury, UK 16.6: Valvular heart disease; 16.8: Pericardial disease Martin F. Heyworth Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 8.8.9: Giardiasis and balantidiasis Liz Hickson Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating
patient Tran Tinh Hien Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.1: Diphtheria Katherine A. High Professor of Pediatrics Emerita, Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; President and Head of R&D, Spark Therapeutics, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Ingeborg Hilderson Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Tom R. Hill Population Health Sciences
Institute, Newcastle University, Newcastle
upon Tyne, UK 11.2: Vitamins David Hilton-​Jones Muscular Dystrophy Campaign, Muscle and Nerve Centre, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK 24.18: Disorders of the neuromuscular junction; 24.19.3: Myotonia; 24.19.4 Metabolic and endocrine disorders Matthew Hind Royal Brompton Hospital
and National Heart and Lung Institute,
Imperial College School of Medicine, London, UK 18.5.1: Upper airway obstruction; 18.5.2: Sleep-​ related breathing disorders John Hindle Betsi Cadwaladr University Health Board, Llandudno Hospital; School of Psychology, Bangor University, Bangor, UK 6.10: Neurodegenerative disorders in
older people N. Hirani Royal Infirmary, Edinburgh, UK 18.11.2: Idiopathic pulmonary fibrosis Gideon M. Hirschfield Lily and Terry Horner
Chair in Autoimmune Liver Disease Research,
Toronto Centre for Liver Disease,
Department of Medicine, University of
Toronto, Toronto General Hospital, Toronto, Canada 15.23.2: Autoimmune hepatitis Sarah Hobdey Veterans Medical Hospital, Boise, ID, USA 8.6.2: Streptococci and enterococci Herbert Hof MVZ Labor Limbach, Heidelberg, Germany 8.6.38: Listeriosis A.V. Hoffbrand Emeritus Professor of Haematology, University College, London, UK 22.6.6: Megaloblastic anaemia and miscellaneous deficiency anaemias

Contributors liv Ronald Hoffman Albert A. and Vera G. List, Professor of Medicine, Division of Hematology/​ Oncology; Director, Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Georg F. Hoffmann Department of General Pediatrics, University of Heidelberg, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Tessa L. Holyoake† Professor of Experimental Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Roel Hompes Consultant Colorectal Surgeon, Academic Medical Centre Amsterdam, University of Amsterdam, the Netherlands 15.14: Colonic diverticular disease Tony Hope St Cross College, University of Oxford, Oxford, UK 1.5: Medical ethics Julian Hopkin Medicine and Health, School of Medicine, Swansea University, Swansea, UK 18.2: The clinical presentation of respiratory disease P. Hopkins Medical Director, Queensland Lung Transplant Service, Chermside, Qld, Australia 18.16: Lung transplantation Nicholas S. Hopkinson National Heart and Lung Institute, Imperial College, London, UK 18.8: Chronic obstructive pulmonary disease Patrick Horner Population Health Sciences, University of Bristol, Bristol, UK 8.6.45: Chlamydial infections; 9.5: Urethritis Bala Hota Rush University, Chicago, IL USA 8.6.4: Staphylococci Andrew R. Houghton Grantham and District Hospital, Grantham, UK; University of Lincoln, Lincoln, UK 16.3.1: Electrocardiography Robert A. Huddart The Institute of Cancer Research, London, UK 21.18: Malignant diseases of the urinary tract Harriet C. Hughes Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Ieuan A. Hughes University of Cambridge, Cambridge, UK 13.5.2: Congenital adrenal hyperplasia James H. Hull The Royal Brompton Hospital, London, UK 18.5.1: Upper airway obstruction Adam Hurlow Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person Jane A. Hurst Great Ormond Street Hospital, London, UK 24.20: Developmental abnormalities of the central nervous system Alastair Hutchison Medical Director and Professor of Renal Medicine, Dorset County Hospital, Dorchester, UK 21.6: Chronic kidney disease Peter J. Hutchinson University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Steve Iliffe Research Department of Primary Care and Population Health, University College London, London, UK 6.3: Optimizing well-​being into old age Lawrence Impey Obstetrics and Fetal Medicine, The Women’s Centre, John Radcliffe Hospital, Oxford, UK 14.16: Fetal effects of maternal infection Jakko van Ingen Radboud University Medical Centre, Nijmegen, the Netherlands 8.6.27: Disease caused by environmental mycobacteria Peter Irving Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis John D. Isaacs Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7 Biological therapies for immune, inflammatory, and allergic diseases; 19.5: Rheumatoid arthritis David A. Isenberg Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction; 19.11.2: Systemic lupus erythematosus and related disorders Theodore J. Iwashyna Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Clinical Management Research, Department of Veterans Affairs,
Ann Arbor, MI, USA; Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia 17.12: Persistent problems and recovery after critical illness Arnaud Jaccard Service d’hématologie clinique et de thérapie cellulaire, CHU de Limoges—​Hôpital Dupuytren, Limoges, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Alan A. Jackson Southampton General Hospital, Southampton, UK 11.4: Severe malnutrition Thomas Jackson Queen Elizabeth Hospital, Birmingham, UK 26.3.1: Confusion Anu Jacob National Neuromyelitis Optica Service, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.13.1: Diseases of the spinal cord Caron A. Jacobson Division of Hematologic Malignancies, Dana-​Farber Cancer Institute, Boston, MA, USA 22.4.1: Introduction to lymphopoiesis N. Asger Jakobsen Clinical Research Fellow, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Rajiv Jalan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Hannah Jarvis Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 18.4.4: Mycobacteria M.K. Javaid Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions David Jayne Professor of Clinical Autoimmunity, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK 19.11.7: ANCA-​associated vasculitis; 21.10.2: The kidney in systemic vasculitis Susan Jebb Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management Katie J.M. Jeffery Oxford University Hospitals NHS Foundation Trust, Department of Microbiology, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus Rajesh Jena Cambridge University Hospitals, Cambridge, UK 5.6: Systemic treatment and radiotherapy Tom Jenkins University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Jørgen Skov Jensen Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark 8.6.46: Mycoplasmas Vivekanand Jha Executive Director, The George Institute for Global Health, New Delhi, India; Professor of Nephrology, University of Oxford, Oxford, UK 21.11: Renal diseases in the tropics Tingliang Jiang Professor, Department of Pharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Alexis J. Joannides University of Cambridge, Cambridge, UK 3.7: Stem cells and regenerative medicine Anne M. Johnson Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour † It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017.

Contributors lv Colin Johnson Emeritus Professor of Surgical Sciences, University of Southampton, Southampton, UK 15.15: Diseases of the gallbladder and biliary tree M.R. Johnson Professor of Neurology and Genomic Medicine, Faculty of Medicine, Department of Brain Sciences, Imperial College, London, UK 24.5.1: Epilepsy in later childhood and adulthood Elaine Jolly University of Cambridge, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures D. Joly Necker-​Enfants Malades Hospital, Paris, France 21.12: Renal involvement in genetic disease Bryony Jones Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy David E.J. Jones Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Bouke de Jong Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Menno De Jong Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.2: Viral infections Iain Jordan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.13: Personality disorders Emil Kakkis Ultragenyx Pharmaceutical Inc., Novato, CA, USA 2.9: Engaging patients in therapeutic development Philip A. Kalra Consultant and Honorary Professor of Nephrology, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 16.5.4 Cardiorenal syndrome; 21.10.10: Atherosclerotic renovascular disease Eileen Kaner Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Theodoros Karamitos Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Niki Karavitaki Queen Elizabeth Hospital, Birmingham, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland Steven B. Karch Consultant in Cardiac Pathology and Toxicology, Berkeley, CA, USA 27.1: Forensic and legal medicine Fiona E. Karet Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 21.15: The renal tubular acidoses Arthur Kaser Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the
gastrointestinal tract David Kavanagh Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome Fiona Kearney Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures David Keeling Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 16.16.2: Therapeutic anticoagulation Andrew Kelion Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Julia Kelly Royal Brompton and Harefield NHS Trust, London, UK 18.5.2: Sleep-​related breathing disorders Paul Kelly Professor of Tropical Gastroenterology, Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; TROPGAN Group, Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia 8.8.6: Cyclospora and cyclosporiasis David P. Kelsell London Medical School, London, UK 23.3: Inherited skin disease Samuel Kemp Royal Brompton Hospital, London, UK 18.2: The clinical presentation of respiratory disease Christopher Kennard Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.1: Introduction and approach to the patient with neurological disease; 24.6.1: Visual pathways Richard S.C. Kerr Oxford University Hospitals NHS Foundation Trust, Oxford, UK 24.11.3: Intracranial abscesses Satish Keshav† Department of Gastroenterology, Oxford University Hospitals NHS Foundation Trust, Oxford; Professor of Gastroenterology, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract Nigel S. Key Harold R. Roberts Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Rajesh K. Kharbanda John Radcliffe Hospital, Oxford, UK 16.13.4: Management of acute coronary syndrome Elham Khatamzas Regional Infectious Diseases Unit, NHS Lothian, Edinburgh, UK 8.2.4: Infection in the immunocompromised host Peng T. Khaw Professor and Consultant Ophthalmic Surgeon; Director of Research, Development and Innovation; Director, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK 25.1: The eye in general medicine B. Khoo University College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.2: Carcinoid syndrome Nine V.A.M. Knoers Professor in Clinical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands 21.16: Disorders of tubular electrolyte handling Stefan Kölker Consultant, Pediatric Metabolic Medicine, University Children’s Hospital, Heidelberg; Department of General Pediatrics, Division of Inborn Metabolic Diseases, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Nils P. Krone University of Sheffield,
Sheffield, UK 13.5.2: Congenital adrenal hyperplasia Narong Khuntikeo Director, Cholangiocarcinoma Research Institute (CARI), Director, Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Faculty of Medicine, Khon Kaen University, Thailand; Associate Professor, Department of Surgery, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections Gudula Kirtschig Tübingen, Germany 14.13: The skin in pregnancy Suzanne Kite Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person John L. Klein Guy’s and St Thomas’ NHS Foundation Trust, London, UK 16.9.2: Endocarditis Paul Klenerman Nuffield Department of Medicine, University of Oxford, Oxford, UK 4.3: Adaptive immunity; 8.5.22: Hepatitis
C virus Richard Knight Department of Microbiology, University of Nairobi, Nairobi, Kenya 8.8.1: Amoebic infections; 8.8.10: Blastocystis infection; 8.9.2: Lymphatic filariasis; 8.9.3: Guinea worm disease (dracunculiasis); 8.9.6: Angiostrongyliasis; 8.10.1: Cestodes (tapeworms) David Koh PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, SSH School of Public Health, National University of Singapore, Singapore 10.2.5: Noise G.C.K.W. Koh Diseases of the Developing World, Alternative Drug Development, GlaxoSmithKline, UK 8.6.8: Pseudomonas aeruginosa M.A. Kokosi Royal Brompton and Harefield NHS Trust, London, UK 18.11.4: The lung in autoimmune rheumatic disorders Onn Min Kon Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK 18.4.4: Mycobacteria † It is with great regret that we report that Satish Keshav died on 23 January, 2019.

Contributors lvi Adelheid Korb-​Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Vasilis Kouranos Royal Brompton and Harefield NHS Trust, London, UK 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia Christian Krarup Region Hovedstaden, Denmark 24.3.2: Electrophysiology of the central and peripheral nervous systems Amy S. Kravitz United States Agency for International Development (USAID), Washington DC, USA 2.21: Humanitarian medicine Dinakantha S. Kumararatne Depatment of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.4: Immunodeficiency Om P. Kurmi Hyperbaric Medicine Unit,
St Richard’s Hospital, Chichester, UK 10.3.1: Air pollution and health Robert A. Kyle Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Peter L. Labib Clinical Research Fellow, Institute for Liver and Digestive Health, Royal Free Campus, University College London, London, UK 15.16: Cancers of the gastrointestinal tract Charles J.N. Lacey Hull York Medical School, University of York, York, UK 9.7: Anogenital lumps and bumps Helen J. Lachmann Senior Lecturer, National Amyloidosis Centre and Centre for Acute Phase Proteins, University College London Medical School, London, UK 12.12.2: Hereditary periodic fever syndromes Robin H. Lachmann Consultant in Inherited Metabolic Disease, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 12.3.1: Glycogen storage diseases Ralph Lainson† Ex Director, the Wellcome Parisitology Unit, and research-worker, Department of Parasitology, Instiuto Evandro Chagas, Rodovia, Barro Levilầndia, Ananindeua, Pará, Brazil 8.8.6: Cyclospora and cyclosporiasis Kin Bong Hubert Lam University of Oxford, Oxford, UK 10.3.1: Air pollution and health D.A. Lane Faculty of Medicine, Department of Medicine, Imperial College London,
London, UK 16.4: Cardiac arrhythmias Peter C. Lanyon Nottingham University Hospitals Trust, Nottingham, UK 19.3: Clinical investigation Andrew J. Larner Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture; 24.5.4: Syncope; 24.13.1: Diseases of the spinal cord Malcolm Law Wolfson Institute of Preventive Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2.12 Medical screening Tim Lawrence Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.3: Traumatic brain injury; 24.11.3: Intracranial abscesses Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, Edinburgh, UK 26.5.11: Schizophrenia Alison M. Layton Harrogate and District NHS Foundation Trust, Harrogate, UK 23.11: Sebaceous and sweat gland disorders James W. Le Duc Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Susannah Leaver St George’s NHS Foundation Trust, London, UK 17.5: Acute respiratory failure Y.C. Gary Lee Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia, Perth, WA, Australia 18.17: Pleural diseases; 18.19.3 Pleural tumours; 18.19.4 Mediastinal tumours and cysts Haur Yueh Lee National Heart Centre Singapore, Singapore, China; Kings Drugs Reaction Group, King’s College London, London, UK 23.16: Cutaneous reactions to drugs Richard W.J. Lee Director, Uveitis and Scleritis Service, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK 25.1: The eye in general medicine Evelyne de Leeuw Centre for Health Equity Training, Research and Evaluation, UNSW Sydney, South Western Sydney Local Health District, Ingham Institute, Australia 2.13: Health promotion Yee-​Sin Leo National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore; Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Lee Kong Chian School of Medicine, Singapore 8.5.15: Dengue Phillip D. Levin Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Elena N. Levtchenko Professor in Pediatric Nephrology, Catholic University Leuven, Leuven, the Netherlands 21.16: Disorders of tubular electrolyte handling Su Li Department of Epidemiology, Guangxi Medical University, Nanning, Guangxi, China 5.7: Medical management of breast cancer Fulong Liao Professor, Biomechanopharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Ted Liao MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington DC, USA 26.5.8: Anxiety disorders Oliver Liesenfeld Roche Molecular Systems, Pleasanton, CA, USA 8.8.4: Toxoplasmosis Liz Lightstone, Professor of Renal Medicine, Centre for Inflammatory Disease, Faculty of Medicine, Imperial College London, London, UK 21.10.3: The kidney in rheumatological disorders Wei Shen Lim Consultant Respiratory Physician and Honorary Professor of Medicine, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK 18.4.2: Pneumonia in the normal host; 18.4.3: Nosocomial pneumonia Aldo A.M. Lima Biomedicine Center and Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil 8.6.12: Cholera Gregory Y.H. Lip Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 16.4: Cardiac arrhythmias; 16.17.5: Hypertensive urgencies and emergencies Mark A. Little Professor of Nephrology and Consultant Nephrologist, Trinity Health Kidney Centre, Trinity College Dublin; Tallaght and Beaumont Hospitals, Dublin, Ireland 21.8.5: Proliferative glomerulonephritis; 21.8.6: Membranoproliferative glomerulonephritis P. Little University of Southampton, Southampton, UK 18.4.1: Upper respiratory tract infections William A. Littler The Priory Hospital, Birmingham, UK 16.9.2: Endocarditis A. Llanos-​Cuentas School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Y.M. Dennis Lo Li Ka Shing Professor of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Diana N.J. Lockwood London School of Hygiene and Tropical Medicine, London, UK 8.6.28: Leprosy (Hansen’s disease); 8.8.13: Leishmaniasis David A. Lomas Vice Provost (Health) and Head of UCL Medical School, University College London, London, UK 12.13: α1-​Antitrypsin deficiency and the serpinopathies; 15.24.6 Primary and secondary liver tumours Alan Lopez University of Melbourne, Melbourne, Vic, Australia 2.3: The Global Burden of Disease: Measuring the health of populations † It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Contributors lvii Constantino López-Macias Mexican Society of Immunology, Mexico; University of Oxford, Oxford, UK 4.3: Adaptive immunity David A. Low Liverpool John Moores University, Liverpool, UK 24.14: Diseases of the autonomic nervous system Elyse E. Lower University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Katharine Lowndes Department of Haematology, Royal Hampshire County Hospital, Winchester UK 14.17: Blood disorders in pregnancy Angela K. Lucas-​Herald School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Sloan, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden 19.11.5: Inflammatory myopathies James R. Lupski Department of Molecular and Human Genetics, Department of Pediatrics, Human Genome Sequencing Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3.2: The genomic basis of medicine Raashid Luqmani Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford Rheumatology Department, Nuffield Orthopaedic Centre, Oxford, UK 19.11.6: Large vessel vasculitis Linda Luxon National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK 24.6.3: Hearing loss Jean Paul Luzio Cambridge Institute for Medical Research, Cambridge, UK 3.1: The cell Lucio Luzzatto Department of Haematology, Muhimbili University of Health and Allied Sciences Dar es Salaam, Tanzania 22.5.3: Paroxysmal nocturnal haemoglobinuria; 22.6.11: Glucose-​6-​phosphate dehydrogenase deficiency Graz A. Luzzi Wycombe General Hospital, High Wycombe, UK 9.3: Sexual history and examination Kate D. Lynch Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis David Mabey Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta; 8.6.45: Chlamydial infections; 9.1: Epidemiology of sexually transmitted infections Peter K. MacCallum Senior Lecturer in Haematology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK 14.7: Thrombosis in pregnancy Alasdair MacGowan Department of Medical Microbiology, North Bristol NHS Trust, Bristol, UK 8.2.5: Antimicrobial chemotherapy Lucy Mackillop Obstetric Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20 Prescribing in pregnancy Gael M. MacLean Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.6.3: Benign breast disease Kenneth T. MacLeod National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Alasdair MacLullich Edinburgh University, Edinburgh, UK 6.5: Older people in hospital Jane Macnaughtan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Robert Mactier Consultant Nephrologist, Glasgow Renal and Transplant Unit, South Glasgow University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK 21.7.1: Haemodialysis C. Maguiña-​Vargas School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Michael Maher Professor of Radiology, University College Cork and Consultant Radiologist, Cork University Hospital and Mercy University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract Malegapuru W. Makgoba National Health Ombud, Pretoria, South Africa; College of Health Science, University of KwaZulu-​Natal, Durban, South Africa; National Planning Commission of South Africa; Universities of Natal and KwaZulu-​Natal, Durban, South Africa; MRC (SA), Cape Town, South Africa 2.18: Fostering medical and health research in resource-​constrained countries Govind K. Makharia Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in
the tropics Hadi Manji The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.11.4: Neurosyphilis and neuro-​AIDS J.I. Mann Edgar Diabetes and Obesity Research Centre (EDOR), Department of Human Nutrition, University of Otago, Dunedin, New Zealand 11.5: Diseases of affluent societies and the need for dietary change David Mant University of Oxford, Oxford, UK 2.11: Preventive medicine G.A. Margaritopoulos Royal Brompton and Harefield NHS Trust, London, UK 18.11.5: The lung in vasculitis Anthony M. Marinaki Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4: Disorders of purine and pyrimidine metabolism Chiara Marini-​Bettolo Newcastle University
John Walton Centre for Muscular Dystrophy Research, Newcastle upon Tyne Hospital NHS Foundation Trust, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Michael Marks Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Paul Marks Honorary Consultant Neurosurgeon, Harrogate District Hospital, Harrogate;
Her Majesty’s Senior Coroner for the City
of Kingston upon Hull and the County of
the East Riding of Yorkshire; Vice President, Faculty of Forensic and Legal Medicine,
London, UK; Honorary Professor of Neurosurgery, College of Medicine,
University of Malawi, Malawi 27.1: Forensic and legal medicine Thomas J. Marrie Department of Medicine, Dalhousie University, Nova Scotia, Canada 8.6.42: Coxiella burnetii infections (Q fever) Judith C.W. Marsh King’s College Hospital, King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Sara Marshall Wellcome Trust, London, UK 4.4: Immunodeficiency Steven B. Marston National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Maria do Rosario O. Martins University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Thiviyani Maruthappu Kelsell Group, Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London, Queen Mary University of London, London, UK 23.3: Inherited skin disease Duncan J. Maskell University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms N.A. Maskell Academic Respiratory Unit,
University of Bristol, UK 18.17: Pleural diseases Jay W. Mason Cardiology Division, University
of Utah College of Medicine, Salt Lake City, UT, USA 16.7.1: Myocarditis Tahir Masud Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures Christopher J. Mathias Stoke Poges, UK 24.14: Diseases of the autonomic nervous
system

Contributors lviii Fadi Matta Associate Professor, Department of Osteopathic Medical Specialties, Collage of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Eric L. Matteson Division of Rheumatology, Divisions of Rheumatology and Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, USA 19.11.11: Polymyalgia rheumatica Kieran McCafferty Consultant Nephrologist, Barts Health NHS Trust, London, UK 21.17: Urinary tract obstruction Fergus McCarthy Division of Women’s Health, Women’s Health Academic Centre KHP, St. Thomas’ Hospital, London, UK 14.4: Hypertension in pregnancy Brian W. McCrindle University of Toronto, Toronto, Canada; The Hospital for Sick Children, Toronto, ON, Canada 19.11.12: Kawasaki disease Theresa A. McDonagh King’s College Hospital, Denmark Hill, London, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure A.D. McGavigan Flinders University,
SA, Australia 16.2.2: Syncope and palpitation; 16.4: Cardiac arrhythmias Fiona McGill Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections John A. McGrath Genetic Skin Disease Group, St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, UK 23.1: Structure and function of skin Alastair McGregor Department of Tropical Medicine and Infectious Diseases, London Northwest Hospitals NHS Trust, London, UK; Department of Medicine, Imperial College London, London, UK 8.11.4: Intestinal trematode infections Jane McGregor Clinical Senior Lecturer and Honorary Consultant Dermatologist, Blizard Institute, Barts and the London School Medicine and Dentistry, London, UK 23.9: Photosensitivity Iain B. McInnes University of Glasgow, Glasgow, UK 3.3: Cytokines C.J. McKay Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis William J. McKenna The Heart Hospital, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular Curtis McKnight Dignity Health Medical Group;
St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine,
Phoenix, AZ, USA 26.5.3: Organic psychoses Alison McMillan East and North Hertfordshire NHS Trust, Stevenage, UK 18.5.2: Sleep-​related breathing disorders Martin A. McNally The Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford University Hospitals, Oxford, UK 20.3: Osteomyelitis Regina McQuillan St Francis Hospice and Beaumont Hospital, Dublin, Ireland 7.3: Symptoms other than pain Simon Mead MRC Prion Unit, University College London, Institute of Prion Diseases; NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, Queen Square, London, UK 24.11.5: Human prion diseases Jill Meara Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.7: Radiation Wajahat Z. Mehal Section of Digestive Diseases Yale University, New Haven, CT, USA 15.21: Pathobiology of chronic liver disease Tobias F. Menne Consultant Haematologist, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia David K. Menon Division of Anaesthesia, University of Cambridge, UK; Neurosciences Critical Care Unit, Royal College of Anaesthetists, London, UK; Queens’ College, Cambridge, UK; National Institute for Health Research, UK 17.7: Management of raised intracranial pressure Andrew Menzies-​Gow Royal Brompton Hospital, London, UK 18.7: Asthma Catherine H. Mercer Professor of Sexual
Health Science, Centre for Population Research in Sexual Health and HIV, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour Vinod K. Metta Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Jan H. ter Meulen Philipps University Marburg, 35043 Marburg, Germany 8.5.17: Arenaviruses; 8.5.18: Filoviruses Wayne M. Meyers Department of Environmental and Infectious Disease Sciences, Armed
Forces Institute of Pathology, Washington DC, USA 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Paul K. Middleton Clinical Research Fellow, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Stephen J. Middleton Consultant Gastroenterologist, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge; Consultant Gastroenterologist (Hon.) St Mark’s Hospital, Harrow, London; Associate Professor (Hon.) Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Mark E. Mikkelsen Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 17.12: Persistent problems and recovery after critical illness Michael A. Miles Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.8.12: Chagas disease Robert F. Miller University College London, London, UK 8.7.5: Pneumocystis jirovecii Dawn S. Milliner Emeritus Professor of Medicine and Pediatrics at the Mayo Clinic Alix School of Medicine, Rochester, MN, USA 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias K.R. Mills King’s College London, London, UK 24.3.4: Investigation of central motor pathways: Magnetic brain stimulation Philip Minor National Institute for Biological Standards and Control (NIBSC), Ridge, UK 8.5.8: Enterovirus infections Fraz A. Mir Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK 16.17.3: Secondary hypertension Pramod K. Mistry Professor of Pediatrics and Medicine, Chief, Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Andrew R.J. Mitchell Jersey General Hospital, Jersey, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Oriol Mitjà Barcelona Institute for Global Health, University of Barcelona, Spain; Lihir Medical Centre, InternationalSOS, Lihir Island, Papua New Guinea 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Aarthi R. Mohan Obstetrics and Maternal Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, UK 14.21: Contraception for women with medical diseases Fiachra Moloney Consultant Radiologist, Department of Radiology, Cork University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract P.L. Molyneaux Royal Brompton and Harefield NHS Trust, London, UK 18.11.2: Idiopathic pulmonary fibrosis

Contributors lix Andrew J. Molyneux The Manor Hospital, Oxford, UK 24.3.3: Imaging in neurological diseases Peter D. Mooney Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Anthony V. Moorman Professor of Genetic Epidemiology, Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia Pilar Morata Department of Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain 8.6.22: Brucellosis Marina S. Morgan Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 8.6.19: Pasteurella Michael L. Moritz Professor of Pediatrics, University of Pittsburgh School of Medicine, Clinical Director, Division of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA 21.2.1: Disorders of water and sodium homeostasis Pedro L. Moro Immunization Safety Office, Division of Healthcare Quality Promotion, NCEZID, Centers for Disease Control and Prevention, Atlanta, GA, USA 8.10.2: Cystic hydatid disease (Echinococcus granulosus) Mary J. Morrell Imperial College London, London, UK 18.5.2: Sleep-​related breathing disorders Nicholas W. Morrell British Heart Foundation Professor of Cardiopulmonary Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK 16.15.1: Structure and function of the pulmonary circulation; 16.15.2: Pulmonary hypertension Emma C. Morris Professor, Division of Infection and Immunity, UCL Institute of Immunity and Transplantation, Royal Free Campus, Royal Free Hospital, London, UK and Honorary Consultant, University College London Medical School, London, UK 22.8.2: Haemopoietic stem cell transplantation Neil J.McC. Mortensen Professor of Colorectal Surgery, Nuffield Department of Surgery, University of Oxford; Honorary Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 15.14: Colonic diverticular disease Peter S. Mortimer St George’s University of London; St George’s Hospital, London; Royal Marsden Hospital, London, UK 16.18: Chronic peripheral oedema and lymphoedema; 23.12: Blood and lymphatic vessel disorders Ghulam J. Mufti King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Victoria Mulcahy Norwich Medical School, University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption David R. Murdoch Professor and Head of Pathology, University of Otago, Christchurch, New Zealand 10.3.6: Diseases of high terrestrial altitudes Paul Murphy NHS Blood and Transplant, Bristol, UK 17.11: Diagnosis of death and organ donation Christopher Murray University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Jean B. Nachega Departments of Epidemiology,
Infectious Diseases and Microbiology,
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA; Department of Medicine, Centre for Infectious Diseases,
Stellenbosch University, Tygerberg, Cape Town, South Africa 8.6.26: Tuberculosis Robert B. Nadelman Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA 8.6.33: Lyme borreliosis Alexandra Nanzer-​Kelly Guys and St Thomas’ Hospital, London, UK 18.7: Asthma Nikolai V. Naoumov Novartis Pharma, Basel, Switzerland 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Kikkeri N. Naresh Department of Histopathology, Imperial College Healthcare NHS Trust and Imperial College, London, UK 15.10.4: Gastrointestinal lymphomas Kate Nash University Hospital Southampton NHS Foundation Trust, Southampton, UK 15.23.1: Hepatitis A to E N. Navani University College Hospital,
London, UK 18.19.1: Lung cancer Catherine Nelson-​Piercy Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Randolph M. Nesse Center for Evolution and Medicine, Arizona State University, AZ, USA 2.2: Evolution: Medicine’s most basic science Peter J. Nestor German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany 24.4.1: Disturbances of higher cerebral function Stefan Neubauer Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT James Neuberger Hon Consultant Physician, Liver Unit, Queen Elizabeth Hospital, Birmingham, UK 15.24.5: The liver in systemic disease James D. Newton Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Paul N. Newton Lao-​Oxford-​Mahosot Hospital-​ Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR; Nuffield Department of Medicine, University of Oxford, Oxford; Infectious Diseases Data Observatory (IDDO), University of Oxford, Oxford, UK 2.10: Medicine quality, physicians,
and patients Wan-​Fai Ng Newcastle University and NIHR Newcastle Biomedical, Research Centre for
Ageing and Chronic Diseases, Newcastle upon Tyne, UK 19.11.4: Sjögren’s syndrome A.G. Nicholson Royal Brompton and Harefield NHS Trust; Professor of Respiratory Pathology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.11.2: Idiopathic pulmonary fibrosis Jerry P. Nolan Warwick Medical School, Coventry; Royal United Hospital, Bath, UK 17.2: Cardiac arrest John Nowakowski New York Medical College,
NY, USA 8.6.33: Lyme borreliosis Paul Nyirjesy Drexel University College of Medicine, Philadelphia, PA, USA 9.4: Vaginal discharge Sarah O’Brien Modelling, Evidence and Policy
Group, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK 15.18: Gastrointestinal infections Amy O’Donnell Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Nigel O’Farrell Ealing Hospital, London North West University Healthcare NHS Trust, London, UK 8.6.14: Haemophilus ducreyi and chancroid John G. O’Grady Institute of Liver Studies, King’s College Hospital, London, UK 15.22.6: Liver transplantation Denis O’Mahony Department of Medicine, University College Cork and Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland 6.7: Drugs and prescribing in the older patient E.E. Ooi Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 8.5.12: Alphaviruses Susie Orme Barnsley Hospital NHS Foundation Trust, Barnsley, UK 6.9: Bladder and bowels Kevin O’Shaughnessy Division of Experimental Medicine and Immunotherapeutics,
Department of Medicine, University of Cambridge, Cambridge, UK 2.6: Principles of clinical pharmacology and drug therapy

Contributors lx Edel O’Toole Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry; and Department of Dermatology, Barts and the London NHS Trust, London, UK 23.14: Tumours of the skin Petra C.F. Oyston Biomedical Sciences, DSTL Porton Down, Salisbury, UK 8.6.20: Francisella tularensis infection Jacqueline Palace Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.18: Disorders of the neuromuscular junction Thomas Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Jayan Parameshwar Consultant Cardiologist, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Daniel H. Paris University of Oxford, Oxford, UK; Rickettsial Research (Oxford Tropical Network); Mahidol-​Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.6.41: Scrub typhus Sarah Parish Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Mike Parker Ethox Centre, Oxford, UK 1.5: Medical ethics Miles Parkes Consultant Gastroenterologist, Cambridge University Hospitals,
Cambridge, UK 15.11: Crohn’s disease Philippe Parola University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Christopher M. Parry Clinical Sciences, Liverpool School of Tropical Medicine, and Institute of Infection and Global Health, University of Liverpool, UK; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan 8.6.9: Typhoid and paratyphoid fevers Judith Partridge Guys and St Thomas’ Hospitals London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Sant-​Rayn Pasricha MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Harnish Patel Academic Geriatric Medicine, University of Southampton, Southampton, UK 6.2: Frailty and sarcopenia Raj Patel Solent NHS Trust, Southampton, UK 9.6: Genital ulceration Sejal Patel Oxford Childrens Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 13.7.2: Normal puberty and its disorders John Paul SE region, National Infection Service, Public Health England, UK 8.6.47: A checklist of bacteria associated with infection in humans; 8.12: Non​venomous arthropods Jason Payne-​James Specialist in Forensic and Legal Medicine and Consultant Forensic Physician; Lead Medical Examiner, Norfolk and Norwich University Hospital, Norfolk, UK; Honorary Clinical Professor, William Harvey Research Institute, Queen Mary University of London, UK; Consultant Editor-​in-​Chief, Journal of Forensic and Legal Medicine; Director, Forensic Healthcare Services Ltd, Southminster, UK 27.1: Forensic and legal medicine Sharon J. Peacock University of Cambridge, Cambridge, UK 8.6.8: Pseudomonas aeruginosa; 8.6.16: Melioidosis and glanders Fiona Pearce Clinical Lecturer, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham City Hospital, Nottingham, UK 19.2: Clinical presentation and diagnosis of rheumatological disorders Rupert Pearse Queen Mary University of London, London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Malik Peiris School of Public Health, The University of Hong Kong, Hong Kong, Special Administrative Region of China 8.5.1: Respiratory tract viruses Neil Pendleton School of Biological Sciences, Faculty Biology Medicine and Health and Manchester Institute for Collaborative Research in Ageing, University of Manchester, Manchester, UK 6.1: Ageing and clinical medicine Hugh Pennington University of Aberdeen, Aberdeen, UK 8.6.7: Enterobacteria and bacterial food poisoning Mark B. Pepys Director, Wolfson Drug Discovery Unit, and Honorary Consultant Physician, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.1 The acute phase response and C-​reactive protein; 12.12.3 Amyloidosis Stephen P. Pereira Professor of Hepatology and Gastroenterology, Institute for Liver and Digestive Health, University College London; Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.16: Cancers of the gastrointestinal tract; 15.26.3: Tumours of the pancreas Gavin D. Perkins Warwick Medical School, Coventry; Intensive Care Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 17.2: Cardiac arrest David J. Perry Previously Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK 14.17: Blood disorders in pregnancy Hans Persson Swedish Poisons Centre, Stockholm, Sweden 10.4.3: Poisonous fungi; 10.4.4: Poisonous plants Eskild Petersen Department of Infectious Diseases and Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark 8.8.4: Toxoplasmosis L.R. Petersen Director, Division of Vector-borne Infectious Diseases, Centers for Disease
Control and Prevention, Fort Collins,
Colorado, USA 8.5.12: Alphaviruses Trevor N. Petney Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP),
Faculty of Medicine, Khon Kaen University,
Khon Kaen, Thailand; Department of Paleontology and Evolution, Organization/​ University State Museum of Natural History, Karlsruhe, Germany 8.11.2: Liver fluke infections Philippa Peto Consultant in Renal and Acute Medicine, Queen Elizabeth Hospital, Lewisham and Greenwich NHS Trust, London, UK 1.6: Clinical decision-​making Richard Peto Nuffield Department of Population Health, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials
and meta-​analyses of trials; 5.1: Epidemiology of cancer Timothy E.A. Peto Nuffield Department of Clinical Medicine, University of Oxford; John Radcliffe Hospital, Oxford, UK 1.6: Clinical decision-​making; 8.5.23: HIV/​AIDS John D. Pickard University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Matthew C. Pickering Imperial College London, London, UK 4.2: The complement system Massimiliano di Pietro Senior Clinical Investigator Scientist and Consultant Gastroenterologist,
MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre,
Cambridge, UK 15.7: Diseases of the oesophagus Michael R. Pinsky Professor Critical Care Medicine, Bio­engineering, Cardiovascular Disease and Anesthesiology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA 17.6: Circulation and circulatory support in the critically ill Julia Platts University of Cardiff, Cardiff, UK 13.9.1: Diabetes Raymond J. Playford, Professor of Medicine, University of Plymouth, Plymouth, UK; Vice President Research Strategy, Pantheryx Inc., Boulder, CO, USA 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Michael I. Polkey Royal Brompton and Harefield NHS Trust, London, UK 18.15: Chronic respiratory failure; 18.18 Disorders of the thoracic cage and diaphragm

Contributors lxi Eleanor S. Pollak Associate Professor of Pathology and Laboratory Medicine (retired), Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Andrew J. Pollard Professor of Paediatric Infection and Immunity at the University of Oxford,
Director of the Oxford Vaccine Group, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital,
Oxford, UK 10.3.6: Diseases of high terrestrial altitudes Aaron Polliack Emeritus Professor, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel 22.4.5: Chronic lymphocytic leukaemia Allyson M. Pollock Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Cristina Ponte Department of Rheumatology, Hospital de Santa Maria -​ CHLN, Lisbon Academic Medical Centre, Lisbon, Portugal; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 19.11.6: Large vessel vasculitis Kyle J. Popovich Rush University, Chicago,
IL, USA 8.6.4: Staphylococci Françoise Portaels Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection John B. Porter Professor of Haematology and Consultant Haematologist, University College London Hospitals, London, UK 22.6.4: Iron metabolism and its disorders Stephen Potts Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.5.5: Substance misuse William G. Powderly Division of Infectious Diseases and Institute for Public Health, Washington University in St. Louis, MO, USA 8.7.2: Cryptococcosis Janet Powell Department of Surgery and Cancer, Imperial College, London, UK 16.14.2: Peripheral arterial disease Amy Powers Associate Professor of Pathology, John A Burns School of Medicine, University of Hawaii, Department of Pathology, Honolulu, HI, USA 22.6.12: Acquired haemolytic anaemia Ann M. Powers Centers for Disease Control and Prevention, Atlanta, GA, USA 8.5.12: Alphaviruses Anton Pozniak Department of HIV and GUM, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK 18.4.5: Pulmonary complications of
HIV infection Bernard D. Prendergast John Radcliffe Hospital, Oxford, UK 16.9.2: Endocarditis Michael Prentice School of Microbiology, University College Cork, Cork, Ireland 8.6.17: Plague: Yersinia pestis; 8.6.18: Other Yersinia infections: Yersiniosis David Price Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Christopher Pugh Nuffield Department of Medicine, University of Oxford, Oxford, UK 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Meredith Pugh Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Graham Raftery South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK 19.7: Infection and arthritis Kazem Rahimi The George Institute for Global Health, University of Oxford,
Oxford, UK 16.13.2: Coronary heart disease: Epidemiology and prevention Anisur Rahman Centre for Rheumatology, University College London, London, UK 19.11.2: Systemic lupus erythematosus and related disorders Tim Raine IBD Lead and Consultant Gastroenterologist, Cambridge University Hospital, Cambridge, UK 15.11: Crohn’s disease K. Rajappan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.2.2: Syncope and palpitation S. Vincent Rajkumar Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Mary Ramsay Health Protection Agency,
London, UK 8.3: Immunization A.C. Rankin Glasgow Royal Infirmary, Glasgow, UK 16.2.2: Syncope and palpitation Didier Raoult University Hospital Institute  Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses; 15.10.6: Whipple’s disease Michael Rawlins Medicines and Healthcare Products Regulatory Agency, London, UK 2.19: Regulation versus innovation in medicine Phillip Read University of New South Wales, Kensington, NSW, Australia 8.6.37: Syphilis Michael C. Reade Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Qld, Australia; Joint Health Command, Australian Defence Force, Canberra, ACT, Australia 17.8: Sedation and analgesia in the ICU Paul J. Reading Department of Sleep Medicine, The James Cook University Hospital, Middlesbrough, UK 24.5.3: Sleep disorders Jeremy Rees National Hospital for Neurology and Neurosurgery, London, UK; UCL Institute of Neurology, London, UK 24.23: Paraneoplastic neurological syndromes; 24.10.4: Intracranial tumours P.T. Reid Respiratory Unit, Western General Hospital, Edinburgh, UK 18.13: Pneumoconioses Shelley Renowden North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases John Richens Research Department of Infection and Population Health, University College London, London, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) Alan B. Rickinson Institute for Cancer Studies, University of Birmingham, Birmingham, UK 8.5.3: Epstein–​Barr virus B.K. Rima Wellcome-​Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK 8.5.5: Mumps: Epidemic parotitis David J. Roberts Radcliffe Department of Medicine, University of Oxford; Department of
Haematology, Oxford University Hospitals
NHS Trust and NHS Blood and Transplant,
Oxford, UK 22.6.3: Anaemia as a challenge to world health Harold R. Roberts Sarah Graham Kenan Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Irene Roberts Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 22.5.1: Inherited bone marrow failure syndromes Douglas Robertson Senior Lecturer and Honorary Consultant in Restorative Dentistry, University of Glasgow, Glasgow, UK 15.6: The mouth and salivary glands Marcus Robertson Gastroenterologist and Hepatologist, Monash Health, Vic, Australia; Monash University Department of Medicine,
Vic, Australia 15.22.3: Portal hypertension and variceal
bleeding Esther Robinson Public Health England, Birmingham, UK 8.6.13: Haemophilus influenzae T.A. Rockall Professor of Colorectal Surgery, University of Surrey; Consultant Colorectal Surgeon, Royal Surrey County Hospital Guildford, UK 15.4.2: Gastrointestinal bleeding Edward Roddy Keele University, Keele, UK 19.10: Crystal-​related arthropathies Simon D. Roger Renal Physician, Conjoint Professor, School of Medicine and Public Health, University of Newcastle, Newcastle; Director, Department of Renal Medicine, Central Coast Local Health District, Gosford, NSW, Australia 21.9.1: Acute interstitial nephritis

Contributors lxii Jean-​Marc Rolain IHU Méditerranée Infection, Marseille, France 8.6.43: Bartonellas excluding B. bacilliformis Pierre Ronco Professor of Renal Medicine, University Pierre et Marie Curie, and Inserm Unit UMR_​S1155, Tenon Hospital, Paris, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Antony Rosen Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4.6: Autoimmunity Jonathan D.C. Ross University Hospitals Birmingham NHS Trust, Birmingham, UK 9.8: Pelvic inflammatory disease Shannan Lee Rossi Department of Pathology, Center for Biodefense and Emerging Infectious Diseases; Member, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Peter M. Rothwell Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.1 Stroke: Cerebrovascular disease Simon M. Rushbrook Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK 15.24.6: Primary and secondary liver tumours Nigel Russell Professor of Haematology, Nottingham University, Nottingham, UK 22.3.3: Acute myeloid leukaemia Fiona Ryan Oxford Childrens Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.7.2: Normal puberty and its disorders Nikant Sabharwal Department of Cardiology, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Alan D. Salama University College London, London, UK 21.8.5: Proliferative glomerulonephritis Moin Saleem Professor of Paediatric Renal Medicine, University of Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Hesham A. Saleh Charing Cross Hospital and Royal Brompton Hospital, London; Imperial College London, London, UK 18.6: Allergic rhinitis Susan Salt Trinity Hospice, Blackpool, UK 7.1: Introduction to palliative care Nilesh J. Samani Department of Cardiovascular Sciences, University of Leicester, Leicester, UK 16.17.4: Mendelian disorders causing hypertension Luis G. Sambo University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health David S. Sanders Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Jeremy Sanderson Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis Vijay G. Sankaran Associate Professor of Pediatrics, Harvard Medical School, Division of Hematology/​Oncology, Boston Children’s Hospital, Dana-​Farber/​Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA 22.6.1: Erythropoiesis Swati Sathe Rutgers New Jersey Medical School, Newark, NJ, USA 24.17: Inherited neurodegenerative diseases Brian P. Saunders Consultant Gastroenterologist, St Mark’s Hospital, North West London Hospitals Trust; Adjunct Professor of Endoscopy, Imperial College London, London, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy Kate E.A. Saunders University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm; 26.5.7: Bipolar disorder Rana Sayeed Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery John A. Sayer Institute Of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK 21.15: The renal tubular acidoses Claire Scampion Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.11: Promotion of dignity in the life and death of older patients Matthew Scarborough Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Klaus P. Schaal Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany 8.6.30: Actinomycoses Michael L. Schilsky Associate Professor of Medicine, Medical Director, Adult Liver Transplant, Yale-​New Haven Transplantation Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA 12.7.2: Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Jonathan M. Schott Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK 24.4.2: Alzheimer’s disease and other dementias Heinz-​Peter Schultheiss Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany 16.7.1: Myocarditis Jane Schwebke University of Alabama at Birmingham, AL, USA 8.8.14: Trichomoniasis Neil Scolding University of Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, UK 24.21: Acquired metabolic disorders and the nervous system; 24.22: Neurological complications of systemic disease Anthony Scott KEMRI-​Wellcome Trust Research Programme, Kilifi, Kenya; London School of Hygiene and Tropical Medicine,
London, UK 8.6.3: Pneumococcal infections James Scott Imperial College London, London, UK 12.6: Lipid disorders Rebecca Scott Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK 15.9.1: Hormones and the gastrointestinal tract Mårten Segelmark Professor of Nephrology, Department of Clinical Sciences, Lund
University and Department of Nephrology
Skane University Hospital, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Julian Seifter Associate Professor of Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA 12.11: A physiological approach to acid–base disorders: The roles of ion transport and body fluid compartments Bhuvaneish T. Selvaraj University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine Amartya Sen Harvard University, Cambridge, MA, USA 2.20: Human disasters Arjune Sen Oxford Epilepsy Research Group, NIHR Oxford Biomedical Research Centre,
John Radcliffe Hospital, Oxford, UK 24.5.1: Epilepsy in later childhood and adulthood Debasish Sen Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health Nicholas J. Severs National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Pallav L. Shah Imperial College London, London, UK 18.1.1: The upper respiratory tract; 18.1.2: Airways and alveoli; 18.3.3: Bronchoscopy, thoracoscopy, and tissue biopsy Muddassir Shaikh James Cook University Hospital, Middlesbrough, UK 19.7: Infection and arthritis Alena Shantsila University of Liverpool, Liverpool, UK 16.17.5: Hypertensive urgencies and
emergencies Susie Shapiro Consultant Haematologist,
Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and
Thrombosis Centre, Churchill Hospital,
Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Claire C. Sharpe Professor of Renal Medicine, Faculty of Life Sciences and Medicine, King’s College London, London, UK 21.10.7: Sickle cell disease and the kidney

Contributors lxiii Michael Sharpe Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.1: General introduction; 26.2: The psychiatric assessment of the medical patient; 26.3.3: Medically unexplained symptoms; 26.4.2: Psychological treatments; 26.5.12: Somatic symptom and related disorders; 26.7: Psychiatry, liaison psychiatry, and psychological medicine Pamela J. Shaw Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 24.15: The motor neuron diseases Debbie L. Shawcross Professor of Hepatology and Chronic Liver Failure, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Bart Sheehan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.3.1: Confusion; 26.5.1: Delirium; 26.5.2: Dementia Neil Sheerin Professor of Nephrology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 21.13: Urinary tract infection Mark Sherlock General Medicine and Emergency Medicine, NHS, UK; Médecins Sans Frontières (MSF), Paris, France 13.5.1: Disorders of the adrenal cortex Jackie Sherrard Wycombe General Hospital, High Wycombe, UK 8.6.6: Neisseria gonorrhoeae; 9.3: Sexual history and examination M.A. Shikanai-​Yasuda Faculdade Medicina, University of São Paulo (FMUSP), Brazil 8.7.4: Paracoccidioidomycosis Brian Shine Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management John M. Shneerson Papworth Hospital, Papworth Everard, UK 18.18: Disorders of the thoracic cage and diaphragm Volha Shpadaruk Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Joachim Sieper Free University, Berlin, Germany 19.6: Spondyloarthritis and related conditions Udomsak Silachamroon Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Leslie Silberstein Director, Transfusion Medicine, Boston Children’s Hospital, Boston, MA, USA 22.6.12: Acquired haemolytic anaemia Jorge Simões University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Alexandra Sinclair Institute of Metabolism and Systems Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Birmingham, UK 24.10.5: Idiopathic intracranial hypertension Rod Sinclair Department of Dermatology, University of Melbourne, Melbourne, Vic, Australia; Epworth Healthcare, Sinclair Dermatology Investigational Research, Education and Clinical Trials, East Melbourne, Vic, Australia 23.17: Management of skin disease Joseph Sinning Regional Cancer Care Associates, Hartford, CT, USA 22.3.1: Granulocytes in health and disease Thira Sirisanthana Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection J.G.P. Sissons† University of Cambridge School of Clinical Medicine, Cambridge, UK 8.5.2: Herpesviruses (excluding Epstein–​Barr virus) Paiboon Sithithaworn Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Professor Parasitology, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections James R.A. Skipworth Consultant HPB and General Surgeon, Bristol Royal Infirmary, University Hospitals Bristol NHS Trust, Bristol, UK 15.26.3: Tumours of the pancreas Geoffrey L. Smith University of Cambridge, Cambridge, UK 8.5.4: Poxviruses Roger Smyth Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.2: The psychiatric assessment of the medical patient Rosamund Snow† BMJ, Tavistock Square, London, UK 1.3: What patients wish you understood E.L. Snyder Professor, Laboratory Medicine, Yale University Medical School; Director, Transfusion/​ Apheresis/​Tissue/​Cell Processing Services,
Yale-​New Haven Hospital, New Haven, CT, USA 22.8.1: Blood transfusion Jasmeet Soar Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 17.2: Cardiac arrest May Ching Soh Silver Star Unit, Women’s Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Elisaveta Sokolov Kings College Hospital, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Tom Solomon Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections Krishna Somers Royal Perth Hospital, Perth, WA, Australia 16.9.4: Cardiovascular syphilis Danielle Southerst NYU Langone Health, New York, NY, USA 19.4: Back pain and regional disorders Cathy Speed Consultant in Rheumatology, Sport and Exercise Medicine, Senior Physician, English Institute of Sport, Cambridge Centre for Health and Performance, Cambridge, UK 28.1: Sport and exercise medicine Des Spence Barclay Medical Centre, Maryhill Health Centre, Glasgow, UK 1.4: Why do patients attend and what do they want from the consultation? G.P. Spickett Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.4: Hypersensitivity pneumonitis S.G. Spiro University College Hospital,
London, UK 18.19.1: Lung cancer; 18.19.2: Pulmonary metastases David P. Steensma Institute Physician, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-​Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA 22.3.2: Myelodysplastic syndromes Jerry L. Spivak Hematology Division,
Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis Charles L. Sprung Department of Anesthesiology, Critical Care Medicine and Pain Medicine, Hadassah Medical Center, Hebrew
University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Paweł Stankiewicz Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 3.2: The genomic basis of medicine Natalie Staplin Clinical Trial Service Unit, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Paul D. Stein Professor, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Chris Stenton Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK 18.14.11: Toxic gases and aerosols Dennis L. Stevens Infectious Diseases Section, VA Medical Center, Boise, ID, USA 8.6.2: Streptococci and enterococci; 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Claire Steves King’s College London, London, UK 6.1: Ageing and clinical medicine † It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016 and Rosamund Snow died on 2 February, 2017.

Contributors lxiv Carmel B. Stober University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Nicole Stoesser Nuffield Department of Medicine Medical Sciences Division, University of Oxford, Oxford, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) John R. Stradling Oxford Centre for Respiratory Medicine, John Radcliffe Hospital, Oxford, UK 18.1.1: The upper respiratory tract Michael A. Stroud Department of Medicine, University of Southampton, Southampton, UK 10.3.2: Heat; 10.3.3: Cold Michael Strupp Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Matthew J. Stuckey School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Peter H. Sugden National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Mehrunisha Suleman Ethox Centre,
Oxford, UK 1.5: Medical ethics Joseph Sung Professor of Medicine, lately President and Vice Chancellor, The Chinese University of Hong Kong, Shatin, Hong Kong, China 15.8: Peptic ulcer disease Khuanchai Supparatpinyo Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Erik R. Swenson VA Puget Sound Health Care System, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Anthony Swerdlow The Institute of Cancer Research, University of London, London, UK 5.1: Epidemiology of cancer David Taggart University of Oxford, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery Kathy Taghipour The Whittington Health NHS Trust, London, UK 23.4: Autoimmune bullous diseases Penelope Talelli Homerton University Hospitals NHS Trust, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Paolo Tammaro Associate Professor, Department of Pharmacology, University of Oxford, Oxford, UK 3.4: Ion channels and disease C.T. Tan University of Malaya, Kuala Lumpur, Malaysia 8.5.7: Nipah and Hendra virus encephalitides Chen Sabrina Tan Harvard Medical School, Boston, MA, USA 8.5.19: Papillomaviruses and polyomaviruses T.M. Tan Consultant in Diabetes, Endocrinology, and Metabolic Medicine, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome David Taylor-​Robinson Section of Retrovirology and GU Medicine, Department of Infectious Diseases, Wright-​Fleming Institute, Faculty of Medicine, Imperial College London, London, UK 8.6.45: Chlamydial infections; 8.6.46: Mycoplasmas F. Teo National University Hospital, National University Health System, Singapore, China 18.11.1: Diffuse parenchymal lung disease: An introduction R.V. Thakker Academic Endocrine Unit, University of Oxford, OCDEM, Churchill Hospital, Oxford, UK 13.4: Parathyroid disorders and diseases altering calcium metabolism Nishanthi Thalayasingam Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7: Biological therapies for immune, inflammatory, and allergic diseases Richard J. Thompson Professor of Molecular Hepatology, Institute of Liver Studies, King’s College London, London, UK 15.24.7: Liver and biliary diseases in infancy and childhood S.A. Thorne University Hospital, Birmingham, UK 16.12: Congenital heart disease in the adult Guy E. Thwaites Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam 24.11.1: Bacterial infections C. Louise Thwaites Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.6.23: Tetanus Adam D. Timmis Barts Heart Centre, Queen Mary University London, London, UK 16.13.3: Management of stable angina Stephen M. Tollman University of the Witwatersrand, Johannesburg, South Africa; MRC/​Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences; INDEPTH Network (International Network for the Demographic Evaluation of Populations and Their Health), Accra, Ghana, South Africa; Centre for Global Health Research, Umeå University, Sweden 2.18: Fostering medical and health research in resource-​constrained countries Maciej Tomaszewski Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.17.4: Mendelian disorders causing hypertension Charles Tomson Consultant Nephrologist,
Freeman Hospital, Newcastle upon
Tyne, UK 21.13: Urinary tract infection Pat Tookey Honorary Associate Professor, Population, Policy and Practice Research
and Teaching Department, University College London Institute of Child Health,
London, UK 8.5.13: Rubella Peter Topham Consultant Nephrologist,
John Walls Renal Unit, University Hospitals
of Leicester NHS Trust, Leicester, UK 21.8.2: Thin membrane nephropathy Nicholas Torpey Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.7.3: Renal transplantation Thomas A. Traill Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD, USA 16.10: Tumours of the heart; 16.11: Cardiac involvement in genetic disease A.S. Truswell University of Sydney, Sydney, NSW, Australia 11.5: Diseases of affluent societies and the need for dietary change Steven Tsui Consultant Cardiac Surgeon, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Youyou Tu Professor, Department of Chemistry, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine D.M. Turnbull Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease A. Neil Turner Professor of Nephrology,
University of Edinburgh, Queen’s Medical Research Institute (CIR), Edinburgh, UK 21.10.8: Infection-​associated nephropathies; 21.10.9: Malignancy-​associated renal disease Tabitha Turner-​Stokes MRC Clinical Research Fellow, Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK 21.8.6: Membranoproliferative glomerulonephritis Holm H. Uhlig Translational Gastroenterology Unit and Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, UK 15.15: Congenital abnormalities of the gastrointestinal tract Magnus Unemo WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden 8.6.6: Neisseria gonorrhoeae; 8.6.45 Chlamydial infections Robert Unwin Department of Renal Medicine, University College London, London, UK 21.1: Structure and function of the kidney

Contributors lxv John A. Vale National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit; City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Patrick Vallance GlaxoSmithKline, London, UK 16.1.1: Blood vessels and the endothelium Greet Van den Berghe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Steven Vanderschueren Leuven Research Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, Clinical Department of General Internal Medicine, University Hospital Leuven, B-​3000 Leuven, Belgium 8.2.2: Fever of unknown origin Sirivan Vanijanonta Department of Clinical
Tropical Medicine, Faculty of Tropical
Medicine, Mahidol University,
Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Anita Vas-​Falcao London School of Hygiene and Tropical Medicine, London, UK 9.1: Epidemiology of sexually transmitted infections Nikos Vasilakis Department of Pathology,
Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases,
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Diana Vassallo Specialist Registrar, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 21.10.10: Atherosclerotic renovascular disease Birgitte Vennervald Section for Parasitology and Aquatic Diseases, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 8.11.1: Schistosomiasis Vanessa Venning Department of Dermatology, Churchill Hospital, Oxford, UK 23.2: Clinical approach to the diagnosis of skin disease Anilrudh A. Venugopal Los Angeles, CA, USA 8.6.11: Anaerobic bacteria Kristien Verdonck Institute of Tropical Medicine, Antwerp, Belgium 8.5.25: HTLV-​1, HTLV-​2, and associated
diseases Christopher M. Verity Addenbrookes Hospital, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system Benjamin A. Vervaet Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Diego Viasus Division of Health Sciences, Faculty of Medicine, Universidad del Norte, Barranquilla, Colombia 8.6.39: Legionellosis and Legionnaires’ disease Angela Vincent Hon Cons Immunology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Raphael P. Viscidi Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses H. Josef Vormoor Clinical Director,
Department of Hemato-​oncology, Princess Máxima Center for Pediatric Oncology,
Utrecht, the Netherlands 22.4.2: Acute lymphoblastic leukaemia Theo Vos University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Henry J.C. de Vries Academic Medical Centre,
University of Amsterdam, Amsterdam, the Netherlands 9.7: Anogenital lumps and bumps Paresh Vyas Professor of Haematology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe
Department of Medicine, University of Oxford; Consultant Haematologist, Department of
Haematology, Cancer and Haematology
Centre, Churchill Hospital, Oxford
University Hospitals NHS Foundation Trust,
Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Peter D. Wagner Division of Physiology at the Department of Medicine, University of California San Diego, CA, USA 18.1.2: Airways and alveoli Nicholas Wald Institute of Health Informatics, University College London, London; Population Health Research Institute, St George’s University of London, London; Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Rhode Island, USA 2.12: Medical screening Herman Waldmann Sir William Dunn School of Pathology, University of Oxford, Oxford, UK 3.8: The evolution of therapeutic antibodies Jane Walker Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.2: The psychiatric assessment of the medical patient; 26.3.4: Low mood Matthew C. Walker National Hospital of Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK 24.5.2: Narcolepsy Elizabeth Wallin Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Sarah Walsh King’s College Hospital,
London, UK 23.16: Cutaneous reactions to drugs T.E. Warkentin Professor, Department of Pathology and Molecular Medicine and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada 22.7.5: Acquired coagulation disorders David A. Warrell Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses; 8.5.27: Orf and Milker’s nodule; 8.5.28: Molluscum contagiosum; 8.6.34: Relapsing fevers; 8.13: Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection); 10.4.2: Injuries, envenoming, poisoning, and allergic reactions caused by animals; 10.4.3: Poisonous fungi; 24.11.2: Viral infections Mary J. Warrell Oxford Vaccine Group, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses John A.H. Wass University of Oxford, Oxford, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland; 13.10: Hormonal manifestations of non-​endocrine disease Lawrence Waterman Loughborough University, Loughborough, UK; Park Health and Safety Partnership, Aylesbury, UK 10.2.2: Occupational safety Laurence Watkins The National Hospital for Neurology and Neurosurgery, London, UK 24.10.3: Traumatic brain injury Peter Watkinson Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Richard A. Watts Department of Rheumatology, Ipswich Hospital, Ipswich; Norwich Medical School, University of East Anglia, Norwich, UK 19.11.9: Small vessel vasculitis Richard W.E. Watts† Division of Inherited Metabolic Diseases, Northwick Park Hospital, London, UK 12.1: The inborn errors of metabolism: general aspects; 12.4: Disorders of purine and pyrimidine metabolism David J. Weatherall† Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.6.2: Anaemia: Pathophysiology, classification, and clinical features; 22.6.3: Anaemia as a challenge to world health; 22.6.7: Disorders of the synthesis or function of haemoglobin G.J. Webb Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 15.23.2: Autoimmune hepatitis Lisa J. Webber St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 13.6.1: Ovarian disorders George J. Webster Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.3.2: Upper gastrointestinal endoscopy † It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018 and David J. Weatherall died on 8 December, 2018.

Contributors lxvi Anthony P. Weetman University of Sheffield, Sheffield, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Robert A. Weinstein Rush University, Chicago, IL, USA 8.6.4: Staphylococci Louis M. Weiss Department of Pathology, Division of Parasitology and Tropical Medicine; Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY, USA 8.7.7: Microsporidiosis; 8.8.7: Cystoisosporiasis Robin A. Weiss University College London, London, UK 8.5.26: Viruses and cancer Peter F. Weller William Bosworth Castle Professor of Medicine, Harvard Medical School, Boston; Chief of the Infectious Diseases and the Allergy and Inflammation Divisions, Beth Israel Deaconess Medical Center, Boston, MD, USA 22.3.8: Eosinophilia A.U. Wells Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 18.11.1: Diffuse parenchymal lung disease: An introduction; 18.11.2: Idiopathic pulmonary fibrosis; 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia; 18.11.4: The lung in autoimmune rheumatic disorders; 18.11.5: The lung in vasculitis Simon Wessely Department of Psychological Medicine, King’s College London, London, UK 26.4.2: Psychological treatments Gilbert C. White, II Aster Chair for Medical Research, Executive Vice President for Research, Director, Blood Research Institute, Versiti; Professor of Medicine, Biochemistry, and Pharmacology, Associate Dean for Research, Medical College of Wisconsin, Milwaukee, WI, USA 22.7.1: The biology of haemostasis and thrombosis Nicholas J. White Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.8.2: Malaria Hilton C. Whittle Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.5.6: Measles Anthony S. Wierzbicki Department of Metabolic Medicine/​Chemical Pathology, Guy’s and St Thomas’ Hospitals, London, UK 12.9: Disorders of peroxisomal metabolism in adults Mark H. Wilcox Professor of Medical Microbiology, Microbiology, Old Medical School, Leeds General Infirmary, and University of Leeds, Leeds, UK 8.6.24: Clostridium difficile Kate Wiles Department of Women and Children’s Health, King’s College London, London, UK 14.5: Renal disease in pregnancy James S. Wiley Principal Research Fellow, Florey Institute of Neuroscience, and Mental Health Honorary Professor, University of Melbourne, Melbourne, Vic, Australia 22.6.8: Anaemias resulting from defective maturation of red cells R.G. Will Professor of Clinical Neurology, Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK 24.11.5: Human prion diseases Lisa Willcocks Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Bryan Williams University College London, London, UK 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment David J. Williams Obstetric Physician, Institute for Women’s Health, University College London Hospital, London, UK 14.1: Physiological changes of normal pregnancy; 14.2: Nutrition in pregnancy; 14.3: Medical management of normal pregnancy Catherine Williamson Professor of Women’s Health, King’s College London and Honorary Consultant in Obstetric Medicine, St Thomas’ and King’s College Hospitals, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Bridget Wills Centre for Tropical Medicine
and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.5.15: Dengue; 24.11.2: Viral infections R. Wilson Royal Brompton and Harefield NHS Trust, London, UK 18.9: Bronchiectasis Greg Winter MRC Laboratory of Molecular Biology, Cambridge, UK 3.8: The evolution of therapeutic antibodies Miles Witham AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK 6.7: Drugs and prescribing in the older patient Fenella Wojnarowska Nuffield Department of Medicine, University of Oxford, Oxford, UK 14.13: The skin in pregnancy; 23.4: Autoimmune bullous diseases Edwin K.S. Wong Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome James L.N. Wood University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms Jonathan Wood Substance Misuse Psychiatry, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK 26.5.4: Alcohol misuse Kathryn J. Wood Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Nicholas Wood University College London, London, UK 24.7.4: Ataxic disorders Andrew F. Woodhouse Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, UK 8.6.32: Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection) Jeremy Woodward Cambridge Intestinal Failure and Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 11.7: Artificial nutrition support; 15.2: Symptoms of gastrointestinal disease Elaine M. Worcester Professor of Medicine, Nephrology Section, Department of Medicine, University of Chicago, Chicago, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis B. Paul Wordsworth Emeritus Professor of Clinical Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions Gary P. Wormser New York Medical College, NY, USA 8.6.33: Lyme borreliosis Mark Wright Consultant Gastroenterologist, University Hospital Southampton, Southampton, UK 15.25: Diseases of the gallbladder and biliary tree Channa Jayasumana Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka 21.9.2: Chronic tubulointerstitial nephritis Muhammad M. Yaqoob Barts Health NHS Trust, Renal Unit, Royal London Hospital, London, UK 21.17: Urinary tract obstruction Hasan Yazici Department of Medicine (Rheumatology), Academic Hospital, Istanbul, Turkey 19.11.10: Behçet’s syndrome Lam Minh Yen Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.23: Tetanus Duncan Young Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Katherine Younger School of Biological and Health Sciences, Technological University Dublin, Dublin, Ireland 11.3: Minerals and trace elements Sebahattin Yurdakul Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Alberto Zanella Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Adam Zeman Professor of Cognitive and Behavioural Neurology, University of Exeter Medical School, Exeter, UK 24.2: Mind and brain: Building bridges between neurology, psychiatry, and psychology Clive S. Zent University of Rochester Medical Center, Rochester, NY, USA 22.4.5: Chronic lymphocytic leukaemia

SECTION 16 Cardiovascular disorders Section editor: Jeremy Dwight 16.1 Structure and function  3241 16.1.1 Blood vessels and the endothelium  3241 Keith Channon and Patrick Vallance 16.1.2 Cardiac physiology  3253 Rhys D. Evans, Kenneth T. MacLeod,
Steven B. Marston, Nicholas J. Severs,
and Peter H. Sugden 16.2 Clinical presentation of heart disease  3276 16.2.1 Chest pain, breathlessness, and fatigue  3276 Jeremy Dwight 16.2.2 Syncope and palpitation  3284 K. Rajappan, A.C. Rankin, A.D. McGavigan,
and S.M. Cobbe 16.3 Clinical investigation of cardiac disorders  3294 16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray 16.3.2 Echocardiography  3314 James D. Newton, Adrian P. Banning,
and Andrew R. J. Mitchell 16.3.3 Cardiac investigations: Nuclear, MRI,
and CT  3326 Nikant Sabharwal, Andrew Kelion,
Theodoros Karamitos, and Stefan Neubauer 16.3.4 Cardiac catheterization and angiography  3339 Edward D. Folland 16.4 Cardiac arrhythmias  3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan,
and Gregory Y.H. Lip 16.5 Cardiac failure  3390 16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390 Theresa A. McDonagh and Kaushik Guha 16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397 Andrew L. Clark and John G.F. Cleland 16.5.3 Chronic heart failure: Definitions, investigation, and management  3407 John G.F. Cleland and Andrew L. Clark 16.5.4 Cardiorenal syndrome  3421 Darren Green and Philip A. Kalra 16.5.5 Cardiac transplantation and mechanical circulatory support  3428 Jayan Parameshwar and Steven Tsui 16.6 Valvular heart disease  3436 Michael Henein 16.7 Diseases of heart muscle  3459 16.7.1 Myocarditis  3459 Jay W. Mason and Heinz-​Peter Schultheiss 16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular  3468 Oliver P. Guttmann and Perry Elliott 16.7.3 Specific heart muscle disorders  3489 Oliver P. Guttmann and Perry Elliott 16.8 Pericardial disease  3501 Michael Henein 16.9 Cardiac involvement in infectious disease  3509 16.9.1 Acute rheumatic fever  3509 Jonathan R. Carapetis 16.9.2 Endocarditis  3519 James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast 16.9.3 Cardiac disease in HIV infection  3534 Peter F. Currie 16.9.4 Cardiovascular syphilis  3539 Krishna Somers 16.10 Tumours of the heart  3544 Thomas A. Traill 16.11 Cardiac involvement in genetic disease  3551 Thomas A. Traill

16.12	 Congenital heart disease in the adult  3559

S.A. Thorne 16.13 Coronary heart disease  3596 16.13.1 Biology and pathology of atherosclerosis  3596 Robin P. Choudhury, Joshua T. Chai,
and Edward A. Fisher 16.13.2 Coronary heart disease: Epidemiology
and prevention  3603 Goodarz Danaei and Kazem Rahimi 16.13.3 Management of stable angina  3616 Adam D. Timmis 16.13.4 Management of acute coronary syndrome  3626 Rajesh K. Kharbanda and Keith A.A. Fox 16.13.5 Percutaneous interventional cardiac procedures  3655 Edward D. Folland 16.13.6 Coronary artery bypass and valve surgery  3666 Rana Sayeed and David Taggart 16.14 Diseases of the arteries  3674 16.14.1 Acute aortic syndromes  3674 James D. Newton, Andrew R.J. Mitchell,
and Adrian P. Banning 16.14.2 Peripheral arterial disease  3680 Janet Powell and Alun Davies 16.14.3 Cholesterol embolism  3688 Christopher Dudley 16.15 The pulmonary circulation  3691 16.15.1 Structure and function of the pulmonary circulation  3691 Nicholas W. Morrell 16.15.2 Pulmonary hypertension  3695 Nicholas W. Morrell 16.16 Venous thromboembolism  3711 16.16.1 Deep venous thrombosis and pulmonary embolism  3711 Paul D. Stein, Fadi Matta, and John D. Firth 16.16.2 Therapeutic anticoagulation  3729 David Keeling 16.17 Hypertension  3735 16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735 Bryan Williams and John D. Firth 16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753 Bryan Williams and John D. Firth 16.17.3 Secondary hypertension  3778 Morris J. Brown and Fraz A. Mir 16.17.4 Mendelian disorders causing hypertension  3796 Nilesh J. Samani and Maciej Tomaszewski 16.17.5 Hypertensive urgencies and emergencies  3800 Gregory Y.H. Lip and Alena Shantsila 16.18 Chronic peripheral oedema and lymphoedema  3811 Peter S. Mortimer 16.19 Idiopathic oedema of women  3823 John D. Firth Section 16  Cardiovascular disorders

Copyright

Copyright

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2020 The moral rights of the authors have been asserted First Edition published in 1983 Second Edition published in 1987 Third Edition published in 1996 Fourth Edition published in 2003 Fifth Edition published in 2010 Sixth Edition published in 2020 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018933144 Set ISBN: 978–0–19–874669–0 Volume 1: 978–0–19–881533–4 Volume 2: 978–0–19–881535–8 Volume 3: 978–0–19–881537–2 Volume 4: 978–0–19–884741–0 Only available as part of a set Printed in Malaysia by Vivar Printing Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Foreword

Foreword

Foreword Professor Sir John Bell, Regius Professor of Medicine, University of Oxford In 1983, David Weatherall, John Ledingham, and David Warrell launched the first edition of the Oxford Textbook of Medicine. That era of medicine looked entirely different from today but the need for a scholarly repository of medical knowledge remains as important as ever. Medicine is now firmly in a digital age; sources of information abound and are readily available and the field is moving so quickly that it is harder than ever to provide up to date relevant informa- tion for the profession. Despite this, the sixth edition of the Oxford Textbook of Medicine still provides the foundation of knowledge upon which good clinical practice is based. Never before has there been such a rapid advance of medical know- ledge and practice. Since the first edition of the Oxford Textbook of Medicine, medical practice has reduced cardiovascular mortality by up to 70% in Western countries, there are now multiple new ther- apies for diseases such as rheumatoid arthritis and multiple scler- osis, disorders where the descriptions of therapeutic options in the first edition were necessarily brief. Cancer is now increasingly man- aged with immune and targeted therapies. Whole new diseases have appeared (Hepatitis C and HIV) and have been either controlled or conquered with drug therapy. The sequencing of the human genome seemed an impossible dream in 1983 while today we have sequenced more than a million genomes and have had insights into rare disease and cancer that were unimaginable then. Life expectancy has risen by nine years for men and ten for women in the United Kingdom, creating a demographic shift that will fundamentally change society and medicine forever. The pace of change has been dramatic. The Oxford Textbook of Medicine gained a reputation by moving medical practice forward from the Oslerian view of medicine ori- ginally expounded in his text book the Principles and Practice of Medicine into an era of more molecular and scientifically based understanding of disease. Constrained by the lack of tools for ex- ploring the molecular basis of pathogenesis, Osler was limited in how he could describe the world of disease, largely based on bed- side observations or those from the post-​mortem room. The Oxford Textbook of Medicine shifted this focus and aligned it with the emerging field of molecular medicine which has begun to create a new taxonomy of disease but also an approach to therapy which is based on pathogenesis. There has been a wave of new information, with new insights appearing weekly into the underlying molecular events associated with disease. Diseases characterized by phenotype are now broken down into multiple subtypes and disease is being individualized. This is rapidly leading to a very significant change in our perception of pathogenesis as well as the classification and nomenclature of disease, all crucial roles for a textbook of medicine. We now are aware that many of the classic definitions of diseases such as diabetes or cancer were descriptions of phenotypic charac- teristics. Interrogation of these disorders at a molecular level has demonstrated that these terms mask disease subtypes defined by molecular pathology where natural history and response to therapy may differ. Combine this with the explosion of new diseases coming from studies of rare disease and there is a challenge to conventional disease nomenclature. This molecular precision creates real oppor- tunities for targeted highly effective therapies, but it also creates challenges for the model of drug discovery when novel treatments can only be used in increasingly small patient populations. These are major issues for medicine, health systems, but also textbooks such as this one where, historically, the stewardship of disease nomenclature has been maintained. The therapeutic options available to practising clinicians have also advanced beyond all recognition since the first edition of the Oxford Textbook of Medicine. We have seen an era of biologic therapy which has provided important new therapeutic alternatives for many hard-​ to-​treat diseases including cancer. We are now entering a new era where modalities such as gene therapy and interfering RNA thera- peutics have demonstrated their utility in the clinic. Similarly, an era of cell therapy has also begun which will provide important new alternatives to some diseases. These new therapeutic alterna- tives and other opportunities for improving healthcare using med- ical technology or novel diagnostics such as sequencing also bring with them the challenge of how healthcare systems can continue to be affordable, either for individuals in private healthcare settings, or in state-​funded, single-​payer systems. In this context, it is remark- able that the authors and editors of the Oxford Textbook of Medicine have managed to sustain both its relevance and the accuracy of its content. The pace at which our understanding of disease, our therapeutic options, and our healthcare systems are likely to change makes it nearly impossible for a textbook of medicine to be truly comprehen- sive given the speed of change, the impact of new innovations and the multiple additional sources of information available to practi- tioners. The Oxford Textbook of Medicine has provided remarkable levels of detail in this rapidly changing world but, more importantly, the textbook continues to provide a source for readers to access information on the fundamental features of disease. This founda- tional knowledge remains crucial to our ability to understand, diag- nose, and treat patients whether they are in the developing world or

Foreword vi Western healthcare systems. Having a source of such information across all major diseases accessible in a single source remains the bedrock of both teaching and practising medicine. The foundations provided by the Oxford Textbook of Medicine form a core of know- ledge which practising clinicians will continue to need. The editors of this edition have been faithful to the vision of the original three editors. Science, in all its forms, is at the heart of our understanding of disease and has enabled progress in clinical medi- cine to occur at a remarkable pace. By providing a textbook that describes the foundations of our understanding of disease and its management, the editors have successfully given us an authoritative text which practising clinicians will find invaluable to support their day-​to-​day decisions. David Weatherall, one of the three original editors and who died in 2018, would be gratified by this new edition.

List of abbreviations xxxv

List of abbreviations xxxv

Abbreviations 5-​FU 5-​fluorouracil 5-​HIAA 5-​hydroxyindoleacetic acid 5-​HT 5-​hydroxytryptamine 5-​HT 5-​hydroxytryptamine AAA acquired aplastic anaemia AAFB acid-​ and alcohol-​fast bacilli AASLD American Association for the Study of Liver Diseases AAV antineutrophil cytoplasm autoantibody-associated vasculitis (also aplastic anaemia ABC ATP-​binding cassette ABCDE airway, breathing, circulation, disability, and exposure ABG arterial blood gas ABMR antibody-​mediated rejection ABPA allergic bronchopulmonary aspergillosis ABPM ambulatory blood pressure measurement ACE angiotensin-​converting enzyme AChE acetylcholinesterase, define at first mention ACPA anticitrullinated peptide/​protein antibodies ACR American College of Rheumatology (also albumin:creatinine ratio) ACS acute coronary syndromes ACTH adrenocorticotropic hormone AD Alzheimer’s disease ADEM acute disseminated encephalomyelitis ADH antidiuretic hormone ADL activities of daily living ADME absorption, distribution, metabolism, and excretion ADPKD autosomal dominant polycystic kidney disease ADR adverse drug reaction ADRT advanced decision to refuse treatment AECA antiendothelial cell antibodies AF atrial fibrillation AFP α-​fetoprotein AGT alanine–​glyoxylate aminotransferase aGVHD acute graft-​versus-​host disease AHA American Heart Association aHUS atypical haemolytic uraemic syndrome AIF apoptosis-​inducing factor AIHA autoimmune haemolytic anaemia AIN acute interstitial nephritis AIP autoimmune pancreatitis (also acute interstitial pneumonia) AIS androgen insensitivity syndromes AKI acute kidney injury ALD alcoholic liver disease ALF acute liver failure ALL acute lymphoblastic leukaemia alloSCT allogeneic stem cell transplantation ALP alkaline phosphatase ALS amyotrophic lateral sclerosis ALT alanine aminotransferase AMA antimitochondrial antibody AML acute myeloid leukaemia AMLR autologous mixed lymphocyte reactions AMT Abbreviated Mental Test ANA antinuclear autoantibodies ANC absolute neutrophil count ANCA antineutrophil cytoplasmic antibodies ANP atrial natriuretic peptide AOSD adult-​onset Still’s disease AP alternative pathway APA aldosterone-​producing adenoma APC antigen presenting cell APCM active physiological conservative management APL acute promyelocytic leukaemia APS antiphospholipid syndrome APTT activated partial thromboplastin time AR androgen receptor ara-​C cytosine arabinoside ARB angiotensin receptor blocker ARDS adult respiratory distress syndrome ARF acute renal failure ARH autosomal recessive hypercholesterolaemia ARPKD autosomal recessive polycystic kidney disease ART antiretroviral therapy ARVC arrhythmogenic right ventricular cardiomyopathy ARVD atherosclerotic renovascular disease AS ankylosing spondylitis ASAS Assessment of SpondyloArthritis International Society ASCT autologous stem cell transplantation ASD atrial septal defect ASH Action on Smoking and Health ASOT antistreptolysin O titre AST aspartate aminotransferase ATG antithymocyte globulin ATP adenosine triphosphate ATRA all-​trans-​retinoic acid AV aortic valve AVN arteriovenous nipping

Abbreviations xxxvi AVSD atrioventricular septal defect AZA azacitidine BCAA branched-​chain amino acid BCC basal cell carcinoma BCG bacillus Calmette–​Guérin BEN Balkan endemic nephropathy BH4 tetrahydrobiopterin BHS British Hypertension Society BICC betaferon in chronic viral cardiomyopathy BKV BK polyomavirus BM bone marrow BMD bone mineral density BMF bone marrow failure BMI body mass index BMP bone morphogenic protein BNF British National Formulary BNP B-​type natriuretic peptide BOS bronchiolitis obliterans syndrome BP blood pressure BPG biphosphoglycerate BRAO branch artery occlusion BRVO branch retinal vein occlusion BSEP haemolysis, elevated liver enzymes, and low platelet count BSP bromosulphthalein BTS British Thoracic Society BUN blood urea nitrogen CA carbohydrate antigen CABG coronary artery bypass grafting CAF Comprehensive Assessment for Frailty CAH congenital adrenal hyperplasia CAM Confusion Assessment Method CAMT congenital amegakaryocytic thrombocytopenia CAP community-​acquired pneumonia CAPS cryopyrin-​associated periodic syndromes CaR calcium-​sensing receptor CAT COPD assessment test CBT cognitive behaviour therapy CCB calcium channel blocker CCK cholecystokinin CCP anticyclic citrullinated peptide CCQ Clinical COPD questionnaire CCV clathrin-​coated vesicles CCyR complete cytogenetic response CD cluster of differentiation CDA congenital dyserythropoietic anaemia CDC donation after circulatory death CEA carcinoembryonic antigen CETP cholesteryl ester transfer protein CF cystic fibrosis CFA cryptogenic fibrosing alveolitis cfDNA cell-​free DNA CFS Clinical Frailty Scale CFTR cystic fibrosis transmembrane regulator CFU colony forming unit CGA comprehensive geriatric assessment CGRP calcitonin gene-​related peptide cGVHD chronic graft-​versus-​host disease CHAD cold haemagglutinin disease CHD coronary heart disease CHF congestive heart failure CHM Commission on Human Medicines CINAC chronic interstitial nephritis in agricultural communities CINCA chronic infantile neurological, cutaneous, and articular syndrome CISN coumarin-​induced skin necrosis CK creatine kinase CKD chronic kidney disease CKD-​EPI Chronic Kidney Disease Epidemiology Collaboration CLL chronic lymphocytic leukaemia CML chronic myeloid leukaemia CMR cardiac magnetic resonance CMS congenital myasthenic syndrome CMT Charcot–​Marie–​Tooth disease CMV cytomegalovirus CNI calcineurin inhibitor CNS central nervous system CNSHA congenital non-​spherocytic haemolytic anaemia CO cardiac output CoA coenzyme A COPD chronic obstructive pulmonary disease COX cyclooxygenase CPAP continuous positive airway pressure CPM central pontine myelosis CPP central precocious puberty CPPS chronic pelvic pain syndrome CPR cardiopulmonary resuscitation CR complete remission CRDQ Chronic Respiratory Disease Questionnaire CREST calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, telangiectasia CRF chronic renal failure CRH corticotropin-​releasing hormone CRIM cross-​immunoreactive material CRP C-​reactive protein CRT cardiac resynchronization therapy CS continuous smokers CSF cerebrospinal fluid/​colony-​stimulating factor CT computed tomography CTA computed tomography angiography CTCA computed tomography coronary angiography CTD connective tissue disease CTEPH chronic thromboembolic pulmonary hypertension CTL cytotoxic T-​lymphocyte CVD cardiovascular disease CVID common variable immunodeficiency CVS chorionic villus sampling CXR chest radiograph CYP cytochrome P450 CZT cadmium zinc telluride DAEC diffusely adherent Escherichia coli DALY disability-​adjusted life year DAMP damage-​associated molecular pattern DASH Dietary Approaches to Stop Hypertension DAT direct antiglobulin test

  Abbreviations xxxvii DBA Diamond–​Blackfan anaemia DBD donation after brain death DBP diastolic blood pressure DC dyskeratosis congenita (also dendritic cell) DCA directional coronary atherectomy DCCT Diabetes Control and Complications Trial DCD donation after circulatory death DCI decompression illness dcSSc diffuse cutaneous systemic sclerosis DCT distal convoluted tubule DDAVP 1-​deamino-​8-​d-​arginine vasopressin DDD dense deposit disease DECAF dyspnoea, eosinopenia, consolidation, acidosis, and atrial fibrillation DGP deamidated gliadin peptide DHG dihydroxyglutarate DIC disseminated intravascular coagulation DIC disseminated intravascular coagulation DILI drug-​induced liver injury DILV double-​inlet left ventricle DIP desquamative interstitial pneumonia DISC death-​initiating signalling complex DISH diffuse idiopathic skeletal hyperostosis DLB dementia with Lewy bodies DLBCL diffuse large B-​cell lymphoma DMARD disease-​modifying antirheumatic drug DMD disease-​modifying drugs (can also mean Duchenne muscular dystrophy) DMSA dimercaptosuccinic acid DNACPR do-​not-​attempt-​cardiopulmonary resuscitation DNR do not resuscitate DOAC direct oral anticoagulant DOCA desoxycorticosterone DOPPS Dialysis Outcomes and Practice Patterns Study DORV double-​outlet right ventricle DPI dry powder inhalers DRE digital rectal examination DRESS drug reaction with eosinophilia and systemic symptoms dRTA distal renal tubular acidosis DSA donor-​specific antibodies DTC direct to consumer DTPA diethylenetriaminepentaacetic acid DVT deep vein thrombosis DXA dual energy X-​ray absorptiometry EACTS European Association for Cardio-​Thoracic Surgery EAggEC enteroaggregative Escherichia coli EANM European Association of Nuclear Medicine EAPCI European Association of Percutaneous Cardiovascular Interventions EASL European Association for the Study of the Liver EATL enteropathy-​associated T-​cell lymphoma EBV Epstein–​Barr virus ECD extended criteria donor ECF extracellular fluid ECG electrocardiogram ECLAM European community lupus activity measure ECM extracellular matrix ECV extracellular volume EDMD Emery–​Dreifuss muscular dystrophy EDRF endothelial-​derived relaxing factor EDTA European Dialysis and Transplant Association EDV end-​diastolic volume EEG electroencephalography EELV end expiratory lung volume EGF epidermal growth factor eGFR estimated glomerular filtration rate EGPA eosinophilic granulomatosis with polyangiitis EIEC enteroinvasive Escherichia coli EIS endoscopic injection sclerotherapy ELCA excimer laser coronary atherectomy ELISA enzyme-​linked immunosorbent assay EM erythema multiforme (also electron microscopy) EMA endomysial antibody EMG electromyography EMS early morning urethral smear ENA extractable nuclear antigens ENaC epithelial sodium channel ENT ear, nose, or throat EOL end of life EoO eosinophilic oesophagitis EPCR endothelial cell protein C receptor EPEC enteropathogenic Escherichia coli EPO erythropoietin ER endoplasmic reticulum ERA European Renal Association ERC endoscopic retrograde cholangiography ERCP endoscopic retrograde cholangiopancreatography ERNV equilibrium radionuclide ventriculography ERS European Respiratory Society ESA erythropoiesis-​stimulating agent ESC European Society of Cardiology ESGE European Society of Gastrointestinal Endoscopy ESH European Society of Hypertension ESKD end-​stage kidney disease ESR erythrocyte sedimentation rate ESRD end-​stage renal disease ESS EULAR sicca score ESWL extracorporeal shock-​wave lithotripsy ETEC enterotoxigenic Escherichia coli EUS endoscopic ultrasonography EVLP ex-​vivo lung perfusion EVO endoscopic variceal obturation FA Fanconi’s anaemia FACIT fibril-​associated collagen with interrupted triple FAK focal adhesion kinase FAP familial adenomatous polyposis FBC full blood count FCAS familial cold autoinflammatory syndrome FCHL familial combined hyperlipidaemia FDA Food and Drug Administration FDG fluorodeoxyglucose FDG-​PET fluorodeoxyglucose-​positron emission tomography FDP fibrinogen-​degradation product FEV forced expiratory volume FEV1 forced expiratory volume in 1 s

Abbreviations xxxviii FFR fractional flow reserve FGF fibroblast growth factor FH familial hypercholesterolaemia FISH fluorescent in situ hybridization FL follicular lymphoma FLC free light chain FMF familial Mediterranean fever FMTC familial medullary thyroid carcinoma FNAB fine needle aspiration biopsy FNH focal nodular hyperplasia FOB faecal occult blood FODMAPs fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FRC functional residual capacity FSGS focal segmental glomerulosclerosis FSH follicular stimulating hormone FTD frontotemporal dementia FVC forced vital capacity FVU first voided urine G6PD glucose-​6-​phosphate dehydrogenase GABA γ-​aminobutyric acid GAD generalized anxiety disorder GALT gut-​associated lymphoid tissue GAVE gastric antral vascular ectasia GBD Global Burden of Disease GBM glomerular basement membrane G-​CSF granulocyte colony-​stimulating factor GCA giant cell arteritis GCS Glasgow Coma Score GDF growth differentiation factors GEP gastroenteropancreatic GFB glomerular filtration barrier GFR glomerular filtration rate GH growth hormone GI gastrointestinal GIB gastrointestinal bleeding GIE glucocorticoid inhibitory element GIP gastric inhibitor peptide GIST gastrointestinal stromal tumour GLP glucagon-​like peptide GM-​CSF granulocyte–​macrophage colony-​stimulating factor GM/​MS gas chromatography–​mass spectrometry GN glomerulonephritis GnRH gonadotropin-​releasing hormone GOLD Global Initiative for Obstructive Lung Disease GOMMID glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits GORD gastro-​oesophageal reflux disease GOV gastro-​oesophageal varices GP glycoprotein (also general practitioner) GPA granulomatosis with polyangiitis GPCR G-​protein-​coupled-​receptors GPI glycosylphosphatidylinositol GRACE Global Registry of Acute Coronary Events GRADE Grading of Recommendations, Assessment, Development and Evaluations GRHPR glyoxylate/​hydroxypyruvate reductase GSD glycogen storage disease GSGS focal segmental glomerulosclerosis GSH glutathione GU gonococcal urethritis GUM genitourinary medicine GVHD graft-​versus-​host disease GVL graft-​versus-​leukaemia GWAS genome-​wide association study H&E haematoxylin and eosin stain HAART highly active antiretroviral therapy HAND HIV-​associated neurocognitive disorder HAV hepatitis A virus HBc hepatitis B core HBeAG hepatitis B e antigen HBIg hepatitis B immunoglobulin HBPM home blood pressure measurement HBsAG hepatitis B surface antigen HBV hepatitis B virus HCC hepatocellular carcinoma HCG human chorionic gonadotropin HCV hepatitis C virus HD haemodialysis HDF haemodiafiltration HDL high-​density lipoprotein HDL-​C high-​density lipoprotein cholesterol HDU high-​dependency unit HDV hepatitis D virus HE hepatic encephalopathy or hereditary elliptocytosis HELLP haemolysis, elevated liver enzymes and low platelets HES hypereosinophilic syndrome hESC human embryonic stem cell HETE hydroxyeicosatetraenoic acid HEV hepatitis E virus HF haemofiltration HFA Heart Failure Association HFnEF heart failure with a normal ejection fraction HFOV high-​frequency oscillatory ventilation HFV high-​frequency ventilation HHT hereditary haemorrhagic telangiectasis/​ 15-​hydroxy-​5,8,10-​hepatrotrienoic acid HHV human herpesvirus HIF hypoxia-​inducible factors HIV human immunodeficiency virus HIV-​OL human immunodeficiency virus oral lesion HK high molecular weight kininogen HL hepatic lipase HLA human leucocyte antigen HLH haemophagocytic lymphohistiocytosis HLHS hypoplastic left heart syndrome HMA hypomethylating agent HOGA 4-​hydroxy-​2-​oxoglutarate aldolase HPA hypothalamic-​pituitary-​adrenal HPG hypothalamic-​pituitary-​gonadal HPLC high-​performance liquid chromatography HPP hereditary pyropoikilocytosis HPRT hypoxanthine-​guanine phosphoribosyltransferase HPV human papillomavirus

  Abbreviations xxxix HRA high-​resolution anoscopy HRCT high-​resolution computed tomography HRT hormone replacement therapy HS hereditary spherocytosis HSC haematopoietic stem cell or hepatic stellate cell HSCT haemopoietic stem cell transplantation HSP Henoch–​Schönlein purpura HSPC haematopoietic stem and progenitor cell HSV herpes simplex virus HUS haemolytic uraemic syndrome HUV hypocomplementaemic urticarial vasculitis IADL instrumental activities of daily living IAS insulin autoimmune syndrome IBD irritable bowel disease IBS irritable bowel syndrome IBS-​C irritable bowel syndrome with constipation IBS-​D irritable bowel syndrome with diarrhoea IBS-​M irritable bowel syndrome with alternating constipation and diarrhoea IC intercalated cell ICAM intercell adhesion molecules ICD implantable cardioverter-​defibrillator ICP intracranial pressure ICS inhaled oral corticosteroids ICU intensive care unit IDA iminodiacetic acid IDL intermediate-​density lipoprotein IEC intestinal epithelial cell IF intrinsic factor IFG impaired fasting glucose IFN interferon Ig immunoglobulin IgAN immunoglobulin A nephropathy IgE immunoglobulin E IGF insulin-​like growth factors IgG4-​RD immunoglobulin G4-​related disease IgG4-​SC immunoglobulin G4-​related sclerosing cholangitis IGV isolated gastric varices IHD ischaemic heart disease IHME Institute for Health Metrics and Evaluation IIH idiopathic intracranial hypertension IIP idiopathic interstitial pneumonias IL interleukin ILC innate lymphoid cell ILD interstitial lung disease IMA inferior mesenteric artery INR international normalized ratio IPAF interstitial pneumonitis with autoimmune features IPEX immunodysregulation polyendocrinopathy enteropathy X-​linked IPF idiopathic pulmonary fibrosis IPI International Prognostic Index iPSC induced pluripotent stem cell IPSID immunoproliferative small intestinal disease IRIDA iron-​refractory iron deficiency anaemia IRIS immune reconstitution inflammatory syndrome IRM immunoradiographic assay IRV Inspiratory and expiratory reserve volume ISH International Society of Hypertension ISHLT International Society for Heart and Lung Transplantation ISIS International Study of Infarct Survival ISWT incremental shuttle walking test ITP immune thrombocytopenia ITU intensive care unit IV intravenous IVC inferior vena cava IVF in vitro fertilization IVIG intravenous immunoglobulin IVU intravenous urography JE Japanese encephalitis JIA juvenile idiopathic arthritis JNC Joint National Committee KDIGO Kidney Disease: Improving Global Outcomes LA left atrium LAMA long-​acting antimuscarinic agents LBBB left bundle branch block LCAT lecithin–​cholesterol acyltransferase LCH Langerhans’ cell histiocytosis lcSSc limited cutaneous systemic sclerosis LDH lactate dehydrogenase LDL low-​density lipoprotein LDL-​C low-​density lipoprotein cholesterol LFT liver function test LGE late gadolinium enhancement LGMD limb-​girdle muscular dystrophy LGV lymphogranuloma venereum LH luteinizing hormone LIC liver iron content LINQ Lung Information Needs Questionnaire LIP lymphocytic interstitial pneumonia LKM liver–​kidney microsomal LMICs low-​ and middle-​income countries LMN lower motor neuron LMWH low molecular weight heparin LMWP low molecular weight protein LOLA l-​ornithine l-​arginine LP lumbar puncture LPL lipoprotein lipase LPLR lipoprotein lipase receptor LTOT long-​term oxygen therapy LV left ventricle LVDD left ventricular diastolic dysfunction LVEF left ventricular ejection fraction LVOT left ventricular outflow tract LVRS lung volume reduction surgery LVSD left ventricular systolic dysfunction MAG3 mercaptoacetyltriglycine MAGIC MAGnesium in Coronaries MAHA microangiopathic haemolytic anaemia MALT mucosa-​associated lymphoid tissue MAO monoamine oxidase inhibitor MAP mean arterial pressure MAPK mitogen-​activated protein kinase MBD mineral and bone disorder M-​CSF macrophage colony-​stimulating factor

Abbreviations xl MCHC mean cell haemoglobin concentration MCL mantle cell lymphoma MCNS minimal change nephrotic syndrome MCpEF myocarditis with preserved left ventricular ejection fraction MCV mean corpuscular volume MDE myeloma-​defining event MDI metered dose inhalers MDRD Modification of Diet in Renal Disease MDS myelodysplastic syndrome MED minimal erythema dose MELD Model for End-​Stage Liver Disease MEN multiple endocrine neoplasia MERFF myoclonic epilepsy and ragged red fibres mESC mouse embryonic stem cell MGRS monoclonal gammopathy of renal significance MGUS monoclonal gammopathy of undetermined significance MHC major histocompatibility complex MHRA Medicines and Healthcare Products Regulatory Agency MIC minimum inhibitory concentration MIDD monoclonal immunoglobulin deposition diseases MKD mevalonate kinase deficiency MM malignant melanoma MMA methylmalonic acid MMF mycophenolate mofetil MMP matrix metalloproteinase MMR mismatch repair MN membranous nephropathy MND motor neuron disease MoCA Montreal Cognitive Assessment MPA microscopic polyangiitis MPO myeloperoxidase MPS mucopolysaccharidosis (also myocardial perfusion scintigraphy) MR magnetic resonance MRA magnetic resonance angiography (can also be medicine regulatory authority) MRC Medical Research Council MRCP magnetic resonance cholangiopancreatography MRI magnetic resonance imaging MRSA methicillin-​resistant Staphylococcus aureus MS multiple sclerosis MS/​MS tandem mass spectroscopy MSA multiple-​system atrophy MSC mesenchymal stromal cell MSH melanocyte-​stimulating hormone MSU midstream urine MTC medullary thyroid carcinoma mTOR mammalian target of rapamycin MUS medically unexplained symptoms MWS Muckle–​Wells syndrome NAAT nucleic acid amplification testing NABQI N-​acetyl-​p-​benzoquinone imine NADH reduced nicotinamide-​adenine dinucleotide NADPH reduced nicotinamide-​adenine dinucleotide phosphate NAFLD nonalcoholic fatty liver disease NAIT neonatal alloimmune thrombocytopenia NASH nonalcoholic steatohepatitis NCAM neural-​cell adhesion molecule NEP neutral endopeptidase NET neuroendocrine tumour or neutrophil extracellular trap NETT National Emphysema Therapy Trial NEWS National Early Warning Score NGF nerve growth factor NGS next-​generation sequencing NHDL-​C non-​high-​density lipoprotein cholesterol NHL non-​Hodgkin’s lymphoma NHS National Health Service (UK) NICE National Institute for Health and Care Excellence NIPPV non-​invasive nasal positive-​pressure ventilation NIPT non-​invasive prenatal testing NIV non-​invasive ventilation NK natural killer NKT natural killer T NLST National Lung Screening Trial NMS neuroleptic malignant syndrome NMSC non-​melanoma skin cancer NNH number needed to harm NNT number needed to treat NOTT Nocturnal Oxygen Treatment Trial NREM non-​rapid eye movement NRT nicotine replacement therapy NSAID non-​steroidal anti-​inflammatory drug NSCLC non-​small cell lung cancer NSIP non-​specific interstitial pneumonia NSTEMI non-​ST-​elevation myocardial infarction NTD neural tube defect NTM non-​tuberculous mycobacterial NT-​proBNP N-​terminal B-​type natriuretic peptide NYHA New York Heart Association OAF osteoclast-​activating factor OAPR odds of being affected given a positive result OB obliterative bronchiolitis OCD obsessive–​compulsive disorder OCT optical coherence tomography OD once daily OECD Organisation for Economic Cooperation and Development OED other eating disorders OLP oral lichen planus OMIM Online Mendelian Inheritance in Man OMT optimal medical therapy OPAT outpatient parenteral antibiotic therapy OR odds ratio OS overall survival OSA obstructive sleep apnoea OTB oral tuberculosis PA pernicious anaemia (also pulmonary artery) PACAP pituitary adenylate cyclase activating polypeptide PAF platelet activating factor PAH polycyclic aromatic hydrocarbons (can also mean pulmonary hypertension)

  Abbreviations xli PAOP pulmonary artery occlusion pressure PAS periodic acid–​Schiff PASI Psoriasis Area and Severity Index PASP pulmonary artery systolic pressure PBD polyglucosan body disease PBM peripheral blood mononuclear cell PCC prothrombin complex concentrate PCH paroxysmal cold haemoglobinuria (also pulmonary capillary haemangiomatosis) PCI percutaneous coronary intervention PCNSL primary central nervous system lymphoma Pco partial pressure of carbon dioxide PCP Pneumocystis jirovecii pneumonia PCR polymerase chain reaction (also protein:creatinine ratio) PCT proximal convoluted tubule PCV pneumococcal conjugate vaccine PCWP pulmonary capillary wedge pressure PD peritoneal dialysis (also Parkinson’s disease) PDA patent ductus arteriosus PDC pyruvate dehydrogenase complex PDD Parkinson’s disease dementia PDGF platelet-​derived growth factor PE pleural effusion (can also mean pulmonary embolism) PEACH Pelvic Inflammatory Disease Evaluation and Clinical Health PEEP positive end expiratory pressure PEF peak expiratory flow PEG percutaneous endoscopic gastrostomy PET position emission tomography PFO patent foramen ovale PFS progression-​free survival PGK phosphoglycerate kinase PHARC polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract PICS post-​intensive care syndrome PID pelvic inflammatory disease PIGN postinfectious glomerulonephritis PK pyruvate kinase PKD pyruvate kinase deficiency (also polycystic kidney disease) PKU phenylketonuria PLA2R phospholipase A2 receptor PMN polymorphonuclear neutrophil PMR polymyalgia rheumatica PNH paroxysmal nocturnal haemoglobinuria Po2 partial pressure of oxygen POC point of care POMC pro-​opiomelanocortin PP polypeptide PPI proton pump inhibitor ppm parts per million PPS Palliative Performance Scale PPV porcine parvovirus PR3 proteinase 3 PRCA pure red cell aplasia PRI population reference intake PRPP phosphoribosyl pyrophosphate PRR pattern-​recognition receptor PRrP parathyroid-​hormone-​related protein PSA prostate-​specific antigen PSC primary sclerosing cholangitis PSP primary spontaneous pneumothorax PT prothrombin time PTC percutaneous transhepatic cholangiography PTCA percutaneous transluminal coronary angioplasty PTH parathyroid hormone PTHrP PTH/​PTH-​related peptide PTLD post-​transplant lymphoproliferative disorder PTP post-​transfusion purpura PTSD post-​traumatic stress disorder PUVA psoralen ultraviolet A PV pemphigus vulgaris (also plasmas viscosity test) PVE prosthetic valve endocarditis PVOD pulmonary veno-​occlusive disease PVR pulmonary vascular resistance PYY peptide tyrosine-​tyrosine QALY quality-​adjusted life year RA rheumatoid arthritis (can also mean right atrium) RAAS renin–​angiotensin–​aldosterone system RAS renin–​angiotensin system (also renal artery stenosis or restrictive allograft syndrome RAVV right atrioventricular valve RBBB right bundle branch block RBF rat bite fevers RCA right coronary artery RCC renal cell carcinoma RCDP rhizomelic chondrodysplasia punctata RCT randomized controlled trial RDA recommended dietary allowance REM rapid eye movement RF rheumatoid factor RI resistivity index RNA ribonucleic acid RNI reference nutrient intake RNP ribonucleoprotein ROC receiver–​operator characteristic RP ribosomal protein RRT renal replacement therapy RTA renal tubular acidosis RV residual volume (also right ventricle) RVOTO right ventricular outflow tract obstruction SA short-​axis SABR stereotactic ablative body radiotherapy SBP spontaneous bacterial peritonitis (also systolic blood pressure) SCC squamous cell carcinoma SCD sickle cell disease (also sudden cardiac death) SCI spinal cord injuries SCID severe combined immunodeficiency SCLC small cell lung cancer SCMR Society for Cardiovascular Magnetic Resonance SCN sickle cell nephropathy or severe congenital neutropenia sdLDL small dense low-​density lipoprotein SDS Shwachman–​Diamond syndrome

Abbreviations xlii SEER Surveillance, Epidemiology, and End Results SGRQ St George’s Respiratory Questionnaire SHBG sex hormone binding globulin SHEC Shiga toxin-​producing Escherichia coli SIADH syndrome of inappropriate antidiuretic hormone secretion SIRS systemic inflammatory response syndrome SLB surgical lung biopsy SLE systemic lupus erythematosus SM smouldering myeloma SMA superior mesenteric artery (also smooth muscle antibody) SMC smooth muscle cell sMDRD simplified Modification of Diet in Renal Disease SMR standardized mortality ratio SNGFR single-​nephron glomerular filtration rate SNP single nucleotide polymorphism SNS sympathetic nervous system SOD sphincter of Oddi disorder SPC Summary of Product Characteristics SPD storage pool deficiency SPECT single-​positron emission computed tomography SPF sun protection factor SSc systemic sclerosis SSD somatic symptom disorder SSFP steady-​state free precession SSRI selective serotonin reuptake inhibitor STEMI ST elevation myocardial infarction STI sexually transmitted infection STOPP/​START set of inappropriate combinations of medicines and disease (STOPP) and a set of recommended treatments for given conditions (START) suPAR soluble urokinase plasminogen activating receptor SVC superior vena cava SVR systemic vascular resistance TACE transarterial chemoembolization TAE transarterial embolization TALH thick ascending limb of Henle TAR thrombocytopenia with absent radii TAVI transcatheter aortic valve implantation TB tuberculosis TBLC transbronchial lung cryobiopsy TBM tuberculous meningitis TC total cholesterol TCA tricyclic antidepressant TCPC total cavopulmonary connection TCR T-​cell receptor TCT thrombin clotting time TdT terminal deoxyribonucleotidyl transferase TEC transient erythroblastopenia of childhood TEN toxic epidermal necrolysis TF transcription factor (also tissue factor) TFPI tissue factor pathway inhibitor TG triglyceride TGF transforming growth factor TGFα, TGFβ transforming growth factor-​α, -​β TGN trans Golgi network THR total hip replacement THRIVE Treatment of HDL to Reduce the Incidence of Vascular Events TIA transient ischaemic attack TIBC total iron-​binding capacity TIMI thrombolysis in myocardial infarction TINU tubulointerstitial nephritis uveitis TIPS transjugular intrahepatic portosystemic shunt TK tyrosine kinase TKI tyrosine kinase inhibitor TKR total knee replacement TLC total lung capacity TLR Toll-​like receptor TMA thrombotic microangiopathy t-​MDS therapy-​related myelodysplastic syndrome(s) TNF tumour necrosis factor TNFα tumour necrosis factor-​α tPA tissue plasminogen activator TPN total parenteral nutrition TPN total parenteral nutrition TRAIL TNF-​related apoptosis-​inducing ligand TRAPS tumour necrosis factor receptor-​associated periodic syndrome Treg regulatory T (cell) TROPHY Trial of Preventing Hypertension TSH thyroid-​stimulating hormone TTD thiazide-​type diuretic tTG tissue transglutaminase TTIP Transatlantic Trade and Investment Partnership TTKG transtubular potassium concentration gradient TTP thrombotic thrombocytopenic purpura TURBT transurethral resection of bladder tumour TV tricuspid valve UAER urinary albumin excretion rate UCB umbilical cord blood UDCA ursodeoxycholic acid UDP uridine diphosphate UI urinary incontinence UIP usual interstitial pneumonia UKELD United Kingdom Model for End-​Stage Liver Disease UKM urea kinetic modelling UKMEC UK Medical Eligibility Criteria UKPDS United Kingdom Prospective Diabetes Study ULN upper limit of normal UMN upper motor neuron UPR unfolded protein response URR urea reduction ratio URTI upper respiratory tract infection UTI urinary tract infection UV ultraviolet UVL ultraviolet light UVR ultraviolet radiation V/​Q ventilation/​perfusion VARD video-​assisted retroperitoneal debridement VATS video-​assisted thoracoscopic surgery VC vital capacity vCJD variant Creutzfeldt–​Jakob disease

  Abbreviations xliii VDRL Venereal Diseases Research Laboratory VEGF vascular endothelial growth factor VEOIBD very early-​onset inflammatory bowel disease VIP vasoactive intestinal peptide VKA vitamin K antagonist VLA vertical long axis VLCFA very long-​chain fatty acid VLDL very low-​density lipoprotein VSD ventricular septal defect VTE venous thromboembolism VWD von Willebrand’s disease VWF von Willebrand factor VZV varicella zoster virus WBC white blood cell WCC white cell count WGS whole genome sequencing WHO World Health Organization WM Waldenström’s macroglobulinaemia X-​ALD X-​linked adrenoleukodystrophy XLH X-​linked hypophosphataemia YLDs years lived with disability YLL years of life lost ZASP Z-​line associated protein

Oxford Textbook of Medicine- Volume 3, 6e (May 6,

Oxford Textbook of Medicine- Volume 3, 6e (May 6, 2020)(0198746695)(Oxford University Press)

Oxford Textbook of Medicine

Oxford Textbook of Medicine

1 Oxford Textbook of Medicine SIXTH EDITION Volume 3: Sections 16–21 EDITED BY John D. Firth Christopher P. Conlon Timothy M. Cox

Preface

Preface

Preface Changes in medicine The Oxford Textbook of Medicine is published online and has been regularly updated for many years, but the production of a new and very substantially updated edition provides a moment when it is nat- ural and proper to reflect on what has changed in medicine—​and what has not—​in recent years. In the context of burgeoning social changes and inequality across the world, we have cause to weigh and consider exactly what modern medicine has to offer patients and their doctors. Here we reflect on aspects of Medicine that are chan- ging rapidly and set out a vision for this in the sixth edition of the Oxford Textbook of Medicine. Demand, capacity, magic solutions, and the need for perspective Within all healthcare systems, in rich and poor nations alike, most physicians feel the inexorable rise in demand and are strug- gling to provide adequate ‘capacity’—​the term commonly applied by healthcare managers charged with the impossible task of con- straining expenditure while serving political masters who, almost without exception, promise more and more and blame inefficiency and ‘unwarranted variation’ for the failure to deliver. In response to the difficulties, claims are made that some new technological advance, be it sequencing of patients’ genomes, healthcare apps, the application of artificial intelligence or ‘Quality Improvement’ methodology, will provide the solutions. In the Oxford Textbook of Medicine, we do not shy away from these aspects and have several new chapters that consider how rich and ‘resource-​poor’ countries might best invest their revenues on health. It is often very hard for practising physicians, who care for patients as individuals, to maintain their bearings within the unfamiliar and depersonalized world of modern healthcare management. Many are left wondering whether those who organize health services ‘live on this planet’, or ‘did any working doctor check out that latest directive from above?’. When clinical outcomes that really matter are diffi- cult to quantify, doctors find themselves and their services judged by spurious measures of ‘productivity’ in the process of healthcare ‘de- livery’. Unrealistic and often clinically irrelevant targets might drive the thinking of the insurers, managers, and politicians, but who can determine the human and clinical value of the care provided? Timeliness of care is important and sometimes crucial for salutary outcomes, but disaster strikes when clock-​driven targets are blindly pursued for all patients irrespective of clinical urgency and to the ex- clusion of all else, including patients with greater clinical need. In the morass created by financial constraints and zealous pol- itical control of health services exercised by those without clinical responsibility, it is rare for doctors be able to stand back and perceive genuine improvements. However, it is certainly true that today we have greater potential to prevent and treat disease and to maintain health than ever before. It is our hope that the Oxford Textbook of Medicine will inform doctors about these changes and provide good guidance as to how they can be translated into clinical practice. Advances in biomedical sciences We seek to embody advances in understanding and practice that have arisen through scientific research. In the ten years since publication of the last edition of this book there has been spec- tacular progress in the application of science in medicine, espe- cially the understanding of genomics and molecular cell biology. These include: in diagnostics, non-​invasive prenatal diagnosis of chromosome abnormalities and monogenic disease by sampling maternal plasma for cell-​free fetal DNA, a technique which also holds promise for screening and monitoring of cancers; in meta- bolic disease, the introduction of molecular therapies that address the defective chloride transport in cystic fibrosis; in oncology, in- creased understanding of cancer immunity leading to the develop- ment of immunotherapies for cancers. Our authors include the very best in their fields. The founding editor and author in this edition, the late David Weatherall, was a recipient of the Lasker-​Koshland Special Achievement Award in Medical Science. Two new authors have received the Nobel Prize recently—​Professor Tu Youyou the 2015 prize for Medicine or Physiology, and Sir Greg Winter the 2018 prize for Chemistry. Another new author, Professor Y.M. Dennis Lo, was one of two winners of China’s inaugural Future Science Prize in 2016. Beyond scientific development, the introduction of new technolo- gies into practice typically leads to a sequence of events including initial ‘hype’ from many in the field, with extravagant claims of po- tential benefit. After an interval, these claims are followed by a more realistic assessment of what the technology can—​and cannot—​ provide. Frequently, this familiar pattern is driven by powerful com- mercial influences which can corrupt thinking in a manner that generates a climate in which those with views contrary to the big battalions are inevitably marginalized. In this edition of the Oxford Textbook of Medicine we have strived to bring an authentic perspec- tive and realism to recommendations for treatment. We sense, for in- stance, that the excitement generated by the sequencing of patients’ genomes continues to increase, but that this trajectory is flattening and expectations becoming more realistic. For patients very likely to have genetic disorders, diagnoses can be made for a proportion that was unimaginable until recently, but for most patients with the degenerative and/​or polygenic diseases that are the greatest burden

Preface viii to health, evidence of clinical benefit from genome sequencing re- mains elusive. Beyond the progress in genomics and cell biology there has been immense interest in bioinformatics and, especially with the enthu- siasm of major biomedical charities such as The Wellcome Trust, for ‘big data’, and the opportunities that these bring to the practice of medicine. However, while there are plentiful examples of gen- omics and cell biology having been translated productively from the bench to the bedside, with enormous benefit to patients, examples of transforming clinical impact from big data and bioinformatics are sparse. But examples there are, such as in the analysis of out- breaks of the scourges Clostridium difficile and methicillin-​resistant Staphylococcus aureus (MRSA). These discoveries give hope for the future as we learn which problems are tractable with this type of approach and which are not. Clinical skill Until recently, it would have been, to paraphrase Thomas Jefferson, regarded as self-​evident that the key requirements of a good phys- ician are the ability and will to obtain an informative history, carry out a thorough physical examination, formulate a relevant differ- ential diagnosis, instigate appropriate investigations, advise and administer correct treatment, including best efforts to relieve symp- toms in all cases. These skills, and the commitment to use them, are often forgotten when healthcare is described in the commercial terms of demand and capacity. While advances in biomedical sciences have dramatically im- proved the outcome for some diseases, and Paul Erhlich’s century-​ old magische Kugel (magic bullet) has whetted our appetite for wonder, it is prudent to recall Thomas Szasz: ‘Formerly, when reli- gion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medi- cine for magic’. The term ‘personalized’ medicine imputes remark- able and as yet unproven powers, excepting in a very few cases, to gene sequencing and molecular therapies, while the patient wants to be treated as a person. It is also alarming to us that some medical curricula increasingly focus on process, ‘behaviours’, and ‘communi- cation skills’, to the detriment of medical content or mature guidance and attitudes to lifelong learning. There is a tendency to forget the very essence of being, and how to become, a physician in the time-​ honoured understanding of the role. In the Oxford Textbook of Medicine we unashamedly emphasize the primacy of history, examination, differential diagnosis, investi- gation, and treatment. Without a firm grasp of these essentials the doctor cannot provide good care for patients, and nor can anyone else. Furthermore, having a firm understanding of clinical context and a well-​informed clinical perspective is an essential prerequisite for driving biomedical research into avenues that really matter. The broader context of health and disease The world has become a smaller place. We are now in an era when many regard not having a smartphone as an index of deprivation. An event that has happened on a different continent can, as a re- sult of social media, become known to millions of people within hours—​the term ‘viral’ has been rightfully translated from commu- nicable illness to global phenomenon. Narratives transmitted in this way often concern disasters, wars, and disease, and they are typically handled by the media in a sensationalized and superficial manner. One hundred and fifty years ago, Darwin’s 1859 masterpiece on evolution was entitled ‘On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life’. The ‘less favoured’ undoubtedly have poorer health outcomes, due largely to the persistent social ill of inequality, in poor as well as ostensibly rich countries. Continuing the tradition of previous edi- tions, we have contributions that discuss the impact of social deter- minants of health, also thoughtful chapters on human disasters (by another Nobel laureate, Prof Amartya Sen), and the practical and critically important aspects of humanitarian medicine. In addition, the modern problems of pollution and climate change are exam- ined. We contend that all doctors would benefit from reading these chapters. Patients and their expectations There are continuing changes in patients’ expectations, particularly those of articulate patients suffering from long-​term conditions and residing in countries with a rich provision of healthcare. A paternal- istic medical approach is no longer acceptable, and several patients have contributed greatly to the book by taking the opportunity to tell us how they think doctors should behave towards them and care for them. However, we are very aware that one size does not fit all, and that many patients want a doctor who will give them clear recom- mendations and not keep repeating a bewildering (to the patient) variety of options and ask them to choose. The mature and able physician will be alert and sensitive to those patients who want this and will provide them with clear advice, and we have endeavoured to ensure that the Oxford Textbook of Medicine will assist. Access to medical knowledge The ever-​expanding world of the smartphone and tablet device gives patients, families, doctors, and other healthcare professionals ready access to more information about medicine than all but a very few would have thought possible a decade ago. This has many benefits but often leaves users of the internet thoroughly perplexed, and some desperate people vulnerable to online quackery. Those wanting de- tails of particular studies will naturally refer to the original literature. Those wanting in-​depth reviews of particular subjects can refer to diverse resources: these are typically good at apprising the reader of plentiful options for investigation, diagnosis, or management, but often leave them uncertain of what a clinically experienced expert in the field would actually recommend. In the sections that form the bulk of the Oxford Textbook of Medicine, we have selected experts with specific clinical experience and given them this task, and we contend that they have met the challenge. Acknowledgements The Oxford Textbook of Medicine is a large undertaking: this edition, the most substantial so far, comprises 647 chapters and covers 6654 printed pages, and its production has required an extraordinary co- ordination of effort from many quarters. In darker moments the edi- tors feared that the process would never end, but as we have read and edited the chapters along the way, we have experienced the joy of learning a huge amount of medicine, often in fields far removed from our own. For this we are very grateful to our contributors, including those whose submissions were delayed!

Preface ix We wish to make particular acknowledgement of our friend and senior colleague, David Warrell, an editor from the first edition of this textbook, senior editor of the fourth and fifth editions, and au- thor in this edition. We and our readers, notably those seeking in- formation on tropical diseases and especially any who have been bitten by snakes, about which his knowledge is truly prodigious, owe him a great debt. We thank Helen Liepman, with whom we remain good friends: she has overseen and directed matters at Oxford University Press and coped in a steadfastly pleasant and professional way with expres- sions of editorial frustration caused by our failure to understand a publishing process that at times seemed to be Byzantine in its com- plexity, as might perhaps be expected in an ancient university. We also thank Anna Kirton, Jamie Oates, and Jess White at Oxford University Press for their considerable efforts on behalf of the book. Finally, we record that the editors’ personal lives have remained calm, and we are very grateful to Helen, Jenny, and Sue for their in- dulgence of our bizarre editorial pursuit. John D. Firth Christopher P. Conlon Timothy M. Cox

Section editors Jon G. Ayres  Emeritus Professor of Environmental
and Respiratory Medicine, University of Birmingham, Birmingham, UK Section 10: Environmental medicine, occupational medicine, and poisoning Christopher P. Conlon  Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 8: Infectious diseases; Section 25: Disorders of the eye; Section 29: Biochemistry in medicine Cyrus Cooper  MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK Section 20: Disorders of the skeleton Timothy M. Cox  Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 12: Metabolic disorders Jeremy Dwight  Previously John Radcliffe Hospital, Oxford, UK Section 16: Cardiovascular disorders Simon Finfer  Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, and The George Institute for Global Health, University of New South Wales, Sydney, Australia Section 17: Critical care medicine John D. Firth  Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 21: Disorders of the kidney and urinary tract; Section 27: Forensic medicine; Section 28: Sport and exercise medicine; Section 30: Acute medicine Mark Gurnell  University of Cambridge Medical School, Cambridge, UK Section 13: Endocrine disorders Chris Hatton  Cancer and Haematology Centre, Churchill Hospital, Oxford, UK Section 22: Haematological disorders Deborah Hay  Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 22: Haematological disorders Roderick J. Hay  King’s College London, London, UK Section 23: Disorders of the skin Christopher Kennard  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Section 24: Neurological disorders Finbarr C. Martin  Population Health Sciences, King’s College London, London, UK Section 6: Old age medicine Catherine Nelson-Piercy  Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK Section 14: Medical disorders in pregnancy Jack Satsangi  Oxford Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 15: Gastroenterological disorders Pallav L. Shah  Imperial College London, London, UK Section 18: Respiratory disorders Michael Sharpe  Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK Section 26: Psychiatric and drug-related disorders Jackie Sherrard  Wycombe General Hospital, High Wycombe, Bucks, UK Section 9: Sexually transmitted diseases Richard A. Watts  Department of Rheumatology, Ipswich Hospital, Ipswich, UK; Norwich Medical School, University of East Anglia, Norwich, UK Section 19: Rheumatological disorders Bee Wee  Associate Professor of Palliative Care, University of Oxford, Oxford, UK Section 7: Pain and palliative care Katherine Younger  School of Biological and Health Sciences, Technological University Dublin, Ireland Section 11: Nutrition

cover

cover

2 ONLY FOR SALE IN INDIA, BANGLADESH, SRI LANKA, NEPAL, BHUTAN, AND MYANMAR
AND NOT FOR EXPORT THEREFROM. NOT FOR SALE IN ANY OTHER COUNTRY IN THE WORLD SIXTH EDITION VOLUME 3 edited by John D. Firth Christopher P. Conlon Timothy M. Cox Oxford Textbook of Medicine INTERNATIONAL EDITION

Oxford Textbook of Medicine