17 Alimentary tract and pancreatic disease 747-830

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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY
OESOPHAGUS


Figure 17.1 The oesophagus: anatomy and function. The swallowing wave.
The oesophagus is a muscular tube 25 cm long which extends from the cricoid cartilage to the cardiac orifice of the stomach. It has an upper and a lower sphincter. A peristaltic swallowing wave propels the food bolus into the stomach (see Fig. 17.1).




Integration link: The gut contains smooth muscle fibers

Taken from Cell Biology




STOMACH AND DUODENUM (see Fig. 17.2)
The stomach acts as a 'hopper', retaining and grinding food, then actively propelling the contents into the upper small bowel.
Gastric secretion
Hydrogen ions, accompanied by chloride ions, are secreted in response to the activity of the hydrogen-potassium ATPase ('proton pump') from the apical membrane of the parietal cells (see Fig. 17.3). Acid sterilises the upper gastrointestinal tract and converts pepsinogen to pepsin. Pepsinogen is secreted by chief cells. The glycoprotein intrinsic factor, secreted in parallel with acid, is necessary for vitamin B12 absorption.
Gastrin and somatostatin
The hormones gastrin, produced by G cells in the antrum, and somatostatin, secreted from D cells throughout the stomach, interact to modulate gastric secretion and motility. Gastrin stimulates whilst somatostatin suppresses acid secretion.
Protective factors
Bicarbonate ions and mucus together protect the gastroduodenal mucosa from the ulcerative properties of acid and pepsin.
SMALL INTESTINE
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Figure 17.2 Normal gastric and duodenal anatomy.


Figure 17.3 Control of acid secretion. The parietal cell secretes acid in response to cholinergic activity, histamine and gastrin. Hydrogen ions are secreted in exchange for potassium ions from the apical membrane of the cell and chloride ions passively diffuse to maintain electroneutrality. (VIP = vasoactive intestinal polypeptide; GIP = gastric inhibitory polypeptide)
The small bowel extends from the ligament of Treitz to the ileocaecal valve (see Fig. 17.4, p. 752). In the fasted state, muscular activity is absent for at least 80% of the time. Every 1-2 hours a wave of peristaltic activity, called the migrating motor complex, passes down the small bowel. Entry of food into the gastrointestinal tract stimulates small bowel peristaltic activity.
Functions of the small intestine are:
digestion
absorption-the products of digestion, water, electrolytes and vitamins
protection against ingested toxins-immunological, mechanical, enzymatic and peristaltic.

Digestion and absorption
Fat
Dietary fat comprises:
long-chain triglycerides (a glycerol 'backbone' bound to three fatty acid molecules)
cholesterol esters
fat-soluble vitamins (A, D, K and E).

Digestion and absorption involve multiple, interrelated steps as food passes through the gastrointestinal tract (see p. 306).
Stomach. Churning activity emulsifies the fat. Limited hydrolysis of triglycerides to diglycerides and fatty acid occurs due to the activity of swallowed, lingual lipase.
Duodenum. Secretin is released in response to acid exposure. This stimulates pancreatic bicarbonate secretion, producing alkaline duodenal contents. Intraluminal fat releases cholecystokinin (CCK). This hormone stimulates gallbladder contraction and relaxes the sphincter of Oddi, resulting in entry of bile into the duodenum. Bile further emulsifies lipids to form chyme.
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Figure 17.4 Small intestine: anatomy. Epithelial cells are formed in crypts and differentiate as they migrate to the tip of the villi to form enterocytes (absorptive cells) and goblet cells.


Figure 17.5 Hydrolysis of triglycerides to monoglycerides and free fatty acids-the jejunal phase of fat digestion.
Upper jejunum. Pancreatic lipase and colipase hydrolyse triglycerides to monoglycerides and free fatty acids (see Fig. 17.5). Phospholipids and cholesterol esters are hydrolysed by other pancreatic enzymes. The lipid mixture is now emulsified by the bile acids as 'mixed micelles'.
Distal small intestine. The lipid contents of the mixed micelles pass across cell membranes into enterocytes. Bile salts remain in the lumen and are absorbed in the terminal ileum, pass via the portal vein back to the liver and are then recycled (the enterohepatic circulation). Within enterocytes, fatty acids, monoglycerides and diglycerides are re-esterified to form triglycerides. These are coated with apoproteins, phospholipids and cholesterol in the endoplasmic reticulum to form chylomicrons which leave the cells by exocytosis and eventually enter the portal circulation via lymphatics.
Carbohydrates
Dietary carbohydrate largely comprises the polysaccharide starch, some sucrose and lactose. Starch is hydrolysed by salivary and pancreatic amylases to alpha-limit dextrins containing 4-8 glucose molecules; to the disaccharide maltose; and to the trisaccharide maltotriose.
Disaccharides are digested by enzymes fixed to the microvillous membrane to form the monosaccharides glucose, galactose and fructose. Glucose and galactose enter the cell by an energy-requiring process involving a carrier protein. Fructose enters by simple diffusion.
Protein
Intragastric digestion by pepsin is quantitatively modest but nevertheless important because the resulting polypeptides and amino acids are sufficient to stimulate CCK release from the mucosa of the proximal jejunum. CCK stimulates secretion of pancreatic trypsinogen into the duodenum.
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Figure 17.6 Glucose/sodium cotransport. Glucose/sodium cotransport across the apical membrane of the enterocyte involving an energy-dependent pump on the basolateral membrane and a carrier for glucose and sodium on the apical membrane. Passive movement of water and electrolytes through tight junctions occurs as a consequence of electrochemical gradients.
Trypsinogen is activated by enterokinase, a hormone fixed to the duodenal mucosa, to produce the active proteolytic enzyme, trypsin. Trypsin subsequently activates a range of other pancreatic proenzymes and these digest proteins to form small polypeptides and amino acids. The enzymes comprise the endopeptidases trypsin, chymotrypsin and elastase, which hydrolyse bonds within proteins, and exopeptidases, which hydrolyse the carboxyl terminus. Peptidases on the microvilli then digest polypeptides to form dipeptides and amino acids, which are absorbed by sodium-dependent active transport systems. Within the enterocytes, cytosolic peptidases further digest dipeptides to amino acids.
Water and electrolytes
Both absorption and secretion of electrolytes and water occur throughout the intestine. Net transport is the difference between absorption and secretion; in health, absorption predominates. Electrolytes and water are transported by two pathways (see Fig. 17.6):
the paracellular route, in which flow through tight junctions between cells is a consequence of osmotic, electrical or hydrostatic gradients
the transcellular route across apical and basolateral membranes by energy-requiring specific active transport carriers (pumps).

Vitamins and trace elements
Water-soluble vitamins are absorbed throughout the intestine. The absorption of folic acid, vitamin B12, calcium and iron is described on pages 322-324.
Protective function of the small intestine
Immunology
B and T lymphocytes, macrophages and mast cells are found throughout the gastrointestinal mucosa. Mucosa-associated lymphoid tissue (MALT) constitutes 25% of the total lymphatic tissue of the body.


Figure 17.7 Migration of gut lymphoid tissue in response to antigen exposure.
Luminal macromolecules and viral particles are transported by specialised (M) cells to Peyer's patches (see Fig. 17.7). These comprise lymphoid follicles with a well-defined structure. B lymphocytes within Peyer's patches differentiate to plasma cells following exposure to the antigens, and these cells migrate to mesenteric lymph nodes, thence to the blood stream via the thoracic duct and then return to the lamina propria of the gut, bronchial tree and other lymph nodes. They subsequently release IgA, which is transported into the lumen of the intestine after linkage to secretory piece. This neutralises the antigen.
The role of T lymphocytes is less clear, but these cells probably help localise the plasma cells to the site of antigen exposure as well as producing inflammatory mediators. Macrophages phagocytose foreign materials and secrete a range of cytokines which mediate inflammation. Activation of mast cell surface IgE receptors leads to degranulation and release of other molecules involved in inflammation.
Mucosal barrier
The epithelium of the gastrointestinal tract constitutes a barrier to luminal contents. This barrier comprises mucus, secreted by goblet cells, the membranes of the enterocytes and the tight junctions between them. These cells are constantly renewed, those of the small intestine every 48 hours.
PANCREAS (see Box 17.1)
17.1 PANCREATIC ENZYMES
Enzyme Substrate Product
Amylase Starch and glycogen Limit dextrans
Maltose
Maltriose
Lipase Triglycerides Monoglycerides and free fatty acids
Colipase
Proteolytic enzymes Proteins and polypeptides Short polypeptides
Trypsinogen
Chymotrypsinogen
Proelastase
Procarboxypeptidases

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Figure 17.8 Pancreatic structure and function. Ductular cells secrete alkaline fluid in response to secretin. Acinar cells secrete digestive enzymes from zymogen granules in response to a range of secretagogues. The photograph shows a normal pancreatic duct and side branches as defined at ERCP.


Figure 17.9 The normal colon, rectum and anal canal.
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The exocrine pancreas is necessary for the digestion of fat, protein and carbohydrate. Inactive proenzymes are secreted from acinar cells in response to circulating gastrointestinal hormones (see Fig. 17.8) and are then activated by trypsin. Bicarbonate-rich fluid is secreted from ductular cells to produce an optimum, alkaline pH for enzyme activity.
COLON
The colon (see Fig. 17.9) absorbs water and electrolytes. It also acts as a storage organ and has contractile activity. Two types of contraction occur. The first of these is segmentation (ring contraction), which leads to mixing but not propulsion; this facilitates absorption of water and electrolytes. Propulsive (peristaltic contraction) waves cause mass movement several times a day and propel the faecal bolus to the rectum. All activity is stimulated after meals, probably in response to release of motilin and CCK.
Faecal continence depends upon maintenance of the anorectal angle and tonic contraction of the external anal sphincters. Relaxation of these muscles, increased intra-abdominal pressure from a Valsalva manoeuvre and contraction of abdominal muscles, with relaxation of the anal sphincters, result in defaecation.
CONTROL OF GASTROINTESTINAL FUNCTION
Secretion, absorption, motor activity, growth and differentiation are modulated by nervous and hormonal factors.
17.2 GUT NEUROPEPTIDES
Neuropeptide Action
Opioids Pain perception
Decrease motility, regulate sphincter activity
Increase acid secretion
Modulate electrolyte and water absorption
Substance P Propagates peristaltic activity
Stimulates lower oesophageal sphincter
Pain modulation
Vasoactive intestinal polypeptide (VIP) Smooth muscle relaxation
Vasodilatation
Gastrin-releasing polypeptide Mediate gastrin release
Bombesin
Cholecystokinin (CCK) Controls satiety
Release of acetylcholine and ?-aminobutyric acid (GABA) from myenteric plexus
Neuropeptide Y Vasocontraction of splanchnic circulation
Reduces small bowel secretions

17.3 GUT HORMONES
Hormone Origin Stimulus Action
Gastrin Stomach (G cell) Products of protein digestion
Suppressed by acid and somatostatin Stimulates gastric acid secretion
Stimulates growth of gastrointestinal mucosa
Somatostatin Throughout GI tract (D cell) Fat ingestion Inhibits gastrin and insulin secretion
Decreased acid secretion
Decreased absorption
Cholecystokinin Duodenum and jejunum Products of protein digestion Stimulates pancreatic enzyme secretion
Fat and fatty acids Gallbladder contraction
Suppressed by trypsin Sphincter of Oddi relaxation
Satiety
Decreased gastric acid secretion
Reduced gastric emptying
Regulates pancreatic growth
Secretin Duodenum and jejunum Duodenal acid Stimulates pancreatic fluid and bicarbonate secretion
Fatty acids Decreased acid secretion
Reduced gastric emptying
Motilin Duodenum and jejunum Fasting Regulates peristaltic activity
Dietary fat
Gastric inhibitory polypeptide (GIP) Duodenum and jejunum Nutrients Stimulates insulin release
Inhibits acid secretion
Pancreatic polypeptide Duodenum and jejunum Protein digestive products Inhibits pancreatic secretions
Gastric distension
Enteroglucagon lleum and colon Unknown Modulates insulin release
Trophic effect
Neurotensin Ileum and colon Unknown May regulate ileal motility in response to fat
Peptide Y Ileum and colon Intestinal fat Decreases pancreatic and gastric secretion
Vasoactive intestinal polypeptide (VIP) Nerve fibres throughout GI tract Unknown Regulates blood flow

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17.4 CONTRAST RADIOLOGY IN THE INVESTIGATION OF GASTROINTESTINAL DISEASE
Barium swallow Barium meal Barium follow-through Barium enema
Indications Dysphagia Dyspepsia Diarrhoea and abdominal pain of small bowel origin Altered bowel habit
Heartburn Epigastric pain Rectal bleeding
Chest pain Anaemia Possible obstruction by strictures etc. Anaemia
Possible motility disorder Vomiting
Possible perforation (non-ionic contrast)
Major uses Strictures Gastric, duodenal ulcers Malabsorption Neoplasia
Hiatus hernia Gastric cancer Crohn's disease Diverticulosis
Gastro-oesophageal reflux and motility disorders, e.g. achalasia Outlet obstruction Strictures, e.g. ischaemic
Gastric emptying disorders Megacolon
Limitations Risk of aspiration Low sensitivity for early cancer Time-consuming Difficult in frail elderly or incontinent patients
Poor mucosal detail Unable to biopsy or assess Radiation exposure Uncomfortable
Unable to biopsy Helicobacter pylori Sigmoidoscopy also necessary to evaluate rectum
Possibly misses polyps <1 cm
Less useful in inflammatory bowel disease





Figure 17.10 Examples of contrast radiology. A A long irregular stricture (arrow) caused by oesophageal cancer. B A polypoid carcinoma demonstrated as a filling defect arising from the gastric body (arrow). C A long Crohn's stricture in the terminal ileum (large arrow) and also an adjacent fistulous tract (small arrow). D Colon cancer demonstrated as an 'apple core' stricture in the caecum (arrow).
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THE ENTERIC NERVOUS SYSTEM
Extrinsic innervation is provided by sympathetic nerves which release noradrenaline, and by parasympathetic, vagal nerves which release acetylcholine. In general, sympathetic pathways stimulate contraction and secretion, whilst parasympathetic pathways are inhibitory.
Extrinsic nerves interact with the intrinsic plexuses of the gastrointestinal tract (Auerbach's and Meissner's plexuses). Neuropeptides produced by these nerves exert a wide range of activities (see Box 17.2) through neurocrine, paracrine and autocrine mechanisms; some (e.g. VIP, CCK) also have endocrine actions.
GUT HORMONES
The origin, action and control of the major gut hormones are summarised in Box 17.3.
17.5 ULTRASOUND SCANNING, CT AND MRI IN GASTROENTEROLOGY
Investigation Ultrasound CT MRI
Major uses Abdominal masses, e.g. cysts, tumours, abscesses Assessment of pancreatic disease Hepatic tumour staging
Hepatic tumour deposits Magnetic resonance cholangiopancreatography (MRCP)
Organomegaly Tumour staging Pelvic/perianal
Ascites Assessment of vascularity of lesions Crohn's fistulae
Biliary tract dilatation
Gallstones
Guided needle aspiration and biopsy of lesions
Limitations Low sensitivity for small lesions Expensive Role in gastrointestinal disease not fully established
Little functional information High radiation dose Limited availability
Operator-dependent May understage some tumours, e.g. oesophago-gastric Time-consuming
Gas and obesity may obscure view 'Claustrophobic' for some Contraindicated in presence of metallic prosthesis, cardiac pacemaker





Figure 17.11 Examples of ultrasound, CT and MRI. A Ultrasound of normal liver with hepatic veins entering the inferior vena cava (arrow). B CT showing a stent in the common bile duct (arrow). (L = liver; GB = gallbladder; K = kidneys; S = stomach; P = pancreas; V = vertebra; A = aorta; I = inferior vena cava) C Normal pelvic MRI (sagittal image). (B = bladder; R = rectum; U = uterus)
INVESTIGATION OF GASTROINTESTINAL DISEASE
A wide range of tests are available for the investigation of patients with gastrointestinal symptoms. These can be classified broadly into tests of structure, tests of infection and tests of function.
TESTS OF STRUCTURE: IMAGING
Plain radiographs
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Plain radiographs of the abdomen show the distribution of gas within the small and large intestines and are useful in the diagnosis of intestinal obstruction or paralytic ileus where dilated loops of bowel and (in the erect position) fluid levels are seen. The outlines of soft tissues such as liver, spleen and kidneys may be visible, and calcification of these organs as well as pancreas, blood vessels, lymph nodes and calculi may be detected. Abdominal radiographs do not help in cases of gastrointestinal bleeding. A chest radiograph shows the diaphragm, and erect films may detect subdiaphragmatic free air in cases of perforation. Unexpected pulmonary problems such as pleural effusions will also be revealed.
Contrast studies
Barium sulphate is inert and provides good mucosal coating and excellent opacification. It can, however, solidify and impact proximal to an obstructive lesion. Water-soluble contrast is used to opacify bowel prior to abdominal computed tomography and in cases of suspected perforation but is less radio-opaque and is also irritant if aspirated into the lungs. Contrast studies are carried out under fluoroscopic control, which allows assessment of motility and correct patient positioning. The double contrast technique improves mucosal visualisation by using gas to distend the barium-coated intestinal surface.
Barium studies are useful for detecting filling defects, which may be intraluminal (e.g. food or faeces), intramural (e.g. carcinoma) or extramural (e.g. lymph nodes). Strictures, erosions, ulcers and motility disorders can all be detected.
The major uses and limitations of various contrast studies are shown in Box 17.4 and Fig. 17.10.
Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI)
These are increasingly used in the evaluation of intra-abdominal disease. They are non-invasive and offer detailed images of the abdominal contents. Their main applications are summarised in Box 17.5 and Fig. 17.11.
Endoscopy
In recent years video endoscopy has replaced fibreoptic endoscopes. Images are displayed on a colour monitor. Endoscopes have controls to allow steering of the tip and also possess channels for suction and insufflation of air and water. An increasing array of instruments can be passed down the endoscope to allow both diagnostic and therapeutic procedures, some of which are illustrated in Figure 17.12.
Upper gastrointestinal endoscopy
After the patient has fasted for at least 4 hours, this is performed under light intravenous benzodiazepine sedation, or using only local anaesthetic throat spray. With the patient in the left lateral position the entire oesophagus (excluding pharynx), stomach and first two parts of duodenum can be seen. Indications, contraindications and complications are given in Box 17.6.
Enteroscopy


Figure 17.12 Examples of therapeutic techniques in endoscopy.
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17.6 UPPER GASTROINTESTINAL ENDOSCOPY
Indications
Dyspepsia (especially aged over 55 years)
Upper abdominal pain
Atypical chest pain
Dysphagia
Vomiting
Weight loss
Acute or chronic gastrointestinal bleeding
Suspicious barium meal
Duodenal biopsies in the investigation of malabsorption
Contraindications
Severe shock
Recent myocardial infarction, unstable angina, cardiac arrhythmia
Severe respiratory disease
Atlantoaxial subluxation
Possible visceral perforation
Complications
Cardiorespiratory depression due to sedation
Aspiration pneumonia
Perforation
Bleeding
Infective endocarditis (use antibiotic prophylaxis in those with previous endocarditis or a prosthetic heart valve)


Using a longer endoscope (enteroscope) it is possible to visualise a large portion of the small intestine. Enteroscopy is of special value in the assessment of obscure, recurrent gastrointestinal bleeding.
Sigmoidoscopy and colonoscopy
Sigmoidoscopy can be carried out either in the outpatient clinic using a 20 cm rigid plastic sigmoidoscope or in the endoscopy suite using a 60 cm flexible instrument following a disposable enema for bowel preparation. When sigmoidoscopy is combined with proctoscopy, accurate detection of haemorrhoids, ulcerative colitis and distal colorectal neoplasia is possible. After full bowel cleansing it is possible to examine the entire colon and often the terminal ileum using a longer colonoscope. Indications, contraindications and complications of colonoscopy are listed in Box 17.7.
Endoscopic retrograde cholangiopancreatography (ERCP)
Using a side-viewing duodenoscope, it is possible to cannulate the main pancreatic duct and common bile duct. The procedure is valuable in defining the ampulla of Vater, biliary tree and pancreas. Its main uses include investigation of obstructive jaundice, biliary pain and suspected pancreatic disease, such as chronic pancreatitis and pancreatic cancer. Obstruction of the common bile duct by stones can be treated by stone extraction after sphincterotomy, and strictures may be stented. The procedure is technically demanding and carries a significant risk of pancreatitis (3-5%), haemorrhage (4% after sphincterotomy) and perforation (1%). Diagnostic ERCP is being replaced by magnetic resonance cholangiopancreatography (MRCP), which provides comparable images of the biliary tree and pancreas.
17.7 COLONOSCOPY
Indications
Suspected inflammatory bowel disease
Altered bowel habit
Rectal bleeding or anaemia
Assessment of abnormal barium enema
Colorectal cancer surveillance
Therapeutic procedures


Contraindications
Severe shock
Recent myocardial infarction, unstable angina, cardiac arrhythmia
Severe respiratory disease
Possible visceral perforation
Severe, active ulcerative colitis

Complications
Cardiorespiratory depression due to sedation
Perforation
Bleeding
Infective endocarditis (use antibiotic prophylaxis in those with previous endocarditis or a prosthetic heart valve)


ISSUES IN OLDER PEOPLE
ENDOSCOPY
Endoscopic procedures are generally well tolerated even in very old people.
Older people are more sensitive to side-effects from sedation with pethidine and/or midazolam; respiratory depression, hypotension and prolonged recovery times are more common.
Bowel preparation for colonoscopy can be difficult in frail, immobile people. Sodium phosphate-based preparations can cause dehydration or hypotension and should be avoided in those with underlying cardiac or renal failure.
Hyoscine should be avoided in those with glaucoma and can also cause tachyarrhythmias. Glucagon is preferred if an antiperistaltic agent is needed.


Histology
Biopsy material obtained during endoscopy or percutaneously can provide useful information (see Box 17.8).
17.8 REASONS FOR BIOPSY OR CYTOLOGICAL EXAMINATION
Suspected malignant lesions
Assessment of mucosal abnormalities
Diagnosis of infection (e.g. Candida, Helicobacter pylori, Giardia lamblia)
Measurement of enzyme contents (e.g. disaccharidases)
Analysis of genetic mutations (e.g. oncogenes, tumour suppressor genes)


TESTS OF INFECTION
Bacterial cultures
Stool cultures are essential in the investigation of diarrhoea, especially when it is acute or bloody, to identify pathogenic organisms (see Ch. 1).
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Serology
Detection of antibodies plays a limited role in the diagnosis of gastrointestinal infection caused by organisms such as Helicobacter pylori, Salmonella species and Entamoeba histolytica.
Breath tests
Non-invasive breath tests for H. pylori infection are discussed on page 761. Breath tests for suspected small intestinal bacterial overgrowth are discussed on page 795.
TESTS OF FUNCTION
A number of dynamic tests can be used to investigate aspects of gut function, including digestion, absorption, inflammation and epithelial permeability. Some of those more commonly used are listed in Box 17.9. In the assessment of suspected malabsorption, blood tests (full blood count, erythrocyte sedimentation rate (ESR), folate, B12, iron status, albumin, calcium and phosphate) are essential. Endoscopy with distal duodenal biopsy is also indicated in most cases.
17.9 DYNAMIC TESTS OF GASTROINTESTINAL FUNCTION
Process Test Principle Comments
Absorption
Fat 14C-triolein breath test Measurement of 14CO2 in breath after oral ingestion of radio-labelled fat Fast and non-invasive but not quantitative
3-day faecal fat Quantification of stool fat while patient ingests 100 g/day fat. Normally <20 mmol/day Non-invasive but slow and unpleasant for all
Lactose Lactose H2 breath test Measurement of breath H2 content after 50 g oral lactose. Undigested sugar is metabolised by colonic bacteria in hypolactasia, and expired hydrogen is measured Non-invasive and accurate; may provoke pain and diarrhoea in sufferers
Bile acids 75SeHCAT test Isotopic quantification of 7-day whole-body retention of oral dose 75Se-labelled homocholyltaurine (> 15% = normal, < 5% = abnormal) Accurate and specific but requires two visits and involves radiation. Can be equivocal. Serum cholestenone is as sensitive and specific
Pancreatic exocrine function Pancreolauryl test Pancreatic esterases cleave fluoroscein dilaurate after oral ingestion. Fluoroscein is absorbed and quantified in urine Accurate and avoids duodenal intubation. Takes 2 days. Accurate urine collection essential
Faecal chymotrypsin or elastase Immunoassay of pancreatic enzymes on stool sample Simple, quick and avoids urine collection. Does not detect mild disease
Mucosal inflammation/permeability 51Cr-EDTA Urinary quantification of label after oral dose. More is absorbed through 'leaky' mucosa Relatively non-invasive and accurate but involves radioactivity; limited availability
Sugar tests (lactulose: rhamnose) Small intestine absorbs mono- but not disaccharides unless inflamed. Urinary excretion of oral dose of two sugars expressed as ratio (normal < 0.04) Non-invasive test of small bowel mucosal integrity (e.g. coeliac, Crohn's). Accurate urine collection essential
Calprotectin A protein secreted non-specifically by neutrophils into the colon in response to inflammation or neoplasia Useful screening test for colonic disease

Gastrointestinal motility
A range of diverse radiological, manometric and radioisotopic tests exist for investigation of gut motility but many are research tests of limited value in daily clinical practice.
Oesophageal motility
A careful barium swallow can give useful information about oesophageal motility. Videofluoroscopy, with joint assessment by a speech and language therapist and a radiologist, may be necessary in difficult cases. Oesophageal manometry (see Fig. 17.1, p. 750), often in conjunction with 24-hour pH measurements, is of value in diagnosing cases of refractory gastro-oesophageal reflux, achalasia and non-cardiac chest pain.
Gastric emptying
Delayed gastric emptying (gastroparesis) may be responsible for some cases of persistent nausea, vomiting, bloating or early satiety. Endoscopy and barium studies are often normal. Calculating the amount of radioisotope retained in the stomach after a test meal containing solids and liquids labelled with different isotopes (see Fig. 17.13) is often useful.
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Figure 17.13 Gastric emptying study. The body of the stomach churns solids into small particles which are then actively expelled by antral peristaltic activity. Gastric emptying is decreased by (a) fats, (b) high osmolality and (c) acid.
Small intestinal transit
This is much more difficult to quantify and is seldom necessary in clinical practice. Barium follow-through examination can give a rough estimate by noting the time taken for contrast to reach the terminal ileum (normally 90 minutes or less). Orocaecal transit can be assessed by the lactulose-hydrogen breath test. Lactulose is a disaccharide which normally reaches the colon intact; here, breakdown by colonic bacteria results in hydrogen production. The time at which this occurs, as measured in expired air, is a measure of orocaecal transit.
Colonic and anorectal motility
A plain abdominal radiograph taken on day 5 after ingestion of different-shaped inert plastic pellets on days 1-3 gives an estimate of whole gut transit time. The test is useful in the evaluation of chronic constipation when the position of any retained pellets can be observed, and helps to differentiate cases of slow transit from those due to obstructed defaecation. The mechanism of defaecation and anorectal function can be assessed by anorectal manometry, electrophysiological tests and defaecating proctography.
RADIOISOTOPE TESTS
Many different radioisotope tests are used (see Box 17.10). In some, structural information is obtained, e.g. localisation of a Meckel's diverticulum or distribution of activity in inflammatory bowel disease. Others use radioisotopes for functional information, e.g. rates of gastric emptying or ability to reabsorb bile acids. Yet others are tests of infection and rely on the presence of bacteria to hydrolyse a radio-labelled test substance followed by detection of the radioisotope in expired air (e.g. urea breath test for H. pylori).
17.10 COMMONLY USED RADIOISOTOPE TESTS IN GASTROENTEROLOGY
Test Isotope Major uses and principle of test
Gastric emptying study 99mTc-sulphur Used in assessment of gastric emptying, particularly for possible gastroparesis
111In-DTPA
Urea breath test 14C- or 13C-urea Used in non-invasive diagnosis of Helicobacter pylori. Bacterial urease enzyme splits urea to ammonia and CO2 which is detected in expired air
Meckel's scan 99mTc-pertechnate Diagnosis of Meckel's diverticulum in cases of obscure Gl bleeding.
Isotope is injected i.v. and localises in ectopic parietal mucosa within diverticulum
Labelled red cell scan 51Cr-labelled erythrocytes Diagnosis of obscure and recurrent Gl bleeding. Labelled erythrocytes seen extravasating into intestine from bleeding vessel
Labelled leucocyte scan 111In- or 99mTc-HMPAO-labelled leucocytes Localisation of abscess collections and distribution of activity in inflammatory bowel disease. Patient's white cells are labelled in vitro, are reinfused and migrate to site of inflammation or infection


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > DISEASES OF THE MOUTH AND SALIVARY GLANDS
DISEASES OF THE MOUTH AND SALIVARY GLANDS
APHTHOUS ULCERATION
Aphthous ulcers are superficial and painful; they occur in any part of the mouth. Recurrent ones afflict up to 30% of the population and are particularly common in women prior to menstruation. The aetiology is unknown, but in severe cases other causes of oral ulceration must be considered (see Box 17.23). Occasionally, biopsy is necessary for diagnosis.
17.23 CAUSES OF ORAL ULCERATION
Aphthous
Idiopathic
Premenstrual

Infection
Fungal, e.g. candidiasis
Viral, e.g. herpes simplex
Bacterial, e.g. Vincent's angina, syphilis

Gastrointestinal diseases
Crohn's disease
Coeliac disease

Dermatological conditions
Lichen planus
Pemphigoid
Pemphigus

Drugs
Hypersensitivity, e.g. Stevens-Johnson syndrome (see p. 33)
Cytotoxics

Systemic diseases
Systemic lupus erythematosus (see p. 1034)
Behçet's syndrome (see p. 1044)

Neoplasia
Carcinoma
Leukaemia
Kaposi's sarcoma


Topical corticosteroids (such as 0.1% triamcinolone in Orabase) or choline salicylate (8.7%) gel can effect healing. Symptomatic relief is achieved using local anaesthetic mouthwashes. A few patients have very severe, recurrent aphthous ulcers and need oral steroids.
VINCENT'S ANGINA
This is characterised by painful, deep, sloughing ulcers which principally affect the gums. It is due to invasion of the mucous membranes by organisms such as Borrelia vincenti and other commensals. Invasion occurs when host resistance is low and oral hygiene is poor. Malnutrition, general debility and the acquired immunodeficiency syndrome (AIDS) predispose. The illness is associated with halitosis, and many patients are feverish and systemically unwell. Local treatment with hydrogen peroxide mouthwashes and broad-spectrum antibiotics are required.
CANDIDIASIS
The yeast Candida albicans is a normal mouth commensal but it may proliferate to cause thrush. This occurs in babies, debilitated patients, patients receiving corticosteroid or antibiotic therapy, diabetics and immunosuppressed patients, especially those receiving cytotoxic therapy and patients with AIDS. White patches are seen on the tongue and buccal mucosa. Painful swallowing (odynophagia) or dysphagia suggests pharyngeal and oesophageal candidiasis. A clinical diagnosis is sufficient to instigate therapy, although brushings or biopsies can be obtained for mycological examination.
Oral thrush is treated using nystatin or amphotericin suspensions or lozenges. Resistant cases or immunosuppressed patients may require oral fluconazole.
PAROTITIS
Parotitis is due to viral or bacterial infection. Mumps causes a self-limiting acute parotitis (see p. 36). Bacterial parotitis usually occurs as a complication of major surgery. It is a consequence of dehydration and poor oral hygiene and can be avoided by good post-operative care. Patients present with painful parotid swelling and this can be complicated by abscess formation. Broad-spectrum antibiotics are required, whilst surgical drainage is necessary for abscesses. Other causes of salivary gland enlargement are listed in Box 17.24.
17.24 CAUSES OF SALIVARY GLAND SWELLING
Infection
Mumps
Bacterial (post-operative)
Calculi
Tumours
Benign: pleomorphic adenoma (95% of cases)
Intermediate: mucoepidermoid tumour
Malignant: carcinoma
Sjögren's syndrome (see p. 1038)
Sarcoidosis


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ISSUES IN OLDER PEOPLE
ORAL HEALTH
Around 40% of healthy older people complain of dry mouth.
Gustatory and olfactory sensation declines with age and chewing power is diminished.
Baseline salivary flow falls with age but stimulated salivation is unchanged.
Root caries and periodontal disease are common in old age, partly because oral hygiene deteriorates with increasing frailty.
In the very frail, Gram-negative anaerobic infection in the periodontal pockets can lead to bacteraemia and septicaemia.


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > DISEASES OF THE OESOPHAGUS
DISEASES OF THE OESOPHAGUS
GASTRO-OESOPHAGEAL REFLUX DISEASE
Gastro-oesophageal reflux resulting in heartburn affects approximately 30% of the general population.
Pathophysiology
Occasional episodes of gastro-oesophageal reflux are common in health. Reflux is followed by oesophageal peristaltic waves which efficiently clear the gullet, alkaline saliva neutralises residual acid, and symptoms do not occur. Gastro-oesophageal reflux disease develops when the oesophageal mucosa is exposed to gastric contents for prolonged periods of time, resulting in symptoms and, in a proportion of cases, oesophagitis. Several factors are known to be involved (see Fig. 17.21).
Abnormalities of the lower oesophageal sphincter
In health, the lower oesophageal sphincter is tonically contracted, relaxing only during swallowing (see p. 750).
Some patients with gastro-oesophageal reflux disease have reduced lower oesophageal sphincter tone, permitting reflux when intra-abdominal pressure rises. In others, basal sphincter tone is normal but reflux occurs in response to frequent episodes of inappropriate sphincter relaxation.
Hiatus hernia


Figure 17.21 Factors associated with the development of gastro-oesophageal reflux disease.
17.25 IMPORTANT FEATURES OF HIATUS HERNIA
Occurs in 30% of the population over the age of 50 years
Often asymptomatic
Heartburn and regurgitation can occur
Gastric volvulus may complicate large para-oesophageal hernias




Figure 17.22 Types of hiatus hernia.
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Hiatus hernia (see Box 17.25 and Fig. 17.22) causes reflux because the pressure gradient between the abdominal and thoracic cavities, which normally pinches the hiatus, is lost. In addition, the oblique angle between the cardia and oesophagus disappears. Many patients who have large hiatus hernias develop reflux symptoms, but the relationship between the presence of a hernia and symptoms is poor. Hiatus hernia is very common in individuals who have no symptoms, and some symptomatic patients have only a very small or no hernia. Nevertheless, almost all patients who develop oesophagitis, Barrett's oesophagus or peptic strictures have a hiatus hernia.
Delayed oesophageal clearance
Defective oesophageal peristaltic activity is commonly found in patients who have oesophagitis. It is a primary abnormality, since it persists after oesophagitis has been healed by acid-suppressing drug therapy. Poor oesophageal clearance leads to increased acid exposure time.
Gastric contents
Gastric acid is the most important oesophageal irritant and there is a close relationship between acid exposure time and symptoms.
Defective gastric emptying
Gastric emptying is delayed in patients with gastro-oesophageal reflux disease. The reason for this is unknown.
Increased intra-abdominal pressure
Pregnancy and obesity are established predisposing causes. Weight loss may improve symptoms.
Dietary and environmental factors
Dietary fat, chocolate, alcohol and coffee relax the lower oesophageal sphincter and may provoke symptoms. There is little evidence to incriminate smoking or NSAIDs as causes of gastro-oesophageal reflux disease.
Clinical features
The major symptoms are heartburn and regurgitation, often provoked by bending, straining or lying down. 'Waterbrash', which is salivation due to reflex salivary gland stimulation as acid enters the gullet, is often present. A history of weight gain is common. Some patients are woken at night by choking as refluxed fluid irritates the larynx. Others develop odynophagia or dysphagia. A few present with atypical chest pain which may be severe, can mimic angina and is probably due to reflux-induced oesophageal spasm.
Complications
Oesophagitis
A range of endoscopic findings, from mild redness to severe, bleeding ulceration with stricture formation, is recognised (see Fig. 17.23). There is a poor correlation between symptoms and histological and endoscopic findings. A normal endoscopy and normal oesophageal histology are perfectly compatible with significant gastro-oesophageal reflux disease.
Barrett's oesophagus


Figure 17.23 Reflux oesophagitis. The gullet is inflamed and ulcerated (small arrows) and there is early stricturing (large arrow).


Figure 17.24 Barrett's oesophagus. Pink columnar mucosa extends up the gullet. Small islands of squamous mucosa remain (arrow).
Background. Barrett's oesophagus ('columnar lined oesophagus'-CLO) is a pre-malignant glandular metaplasia of the lower oesophagus, in which the normal squamous lining is replaced by columnar mucosa composed of a cellular mosaic containing areas of intestinal metaplasia (see Fig. 17.24). It occurs as an adaptive response to chronic gastro-oesophageal reflux and is found in 10% of patients undergoing gastroscopy for reflux symptoms. Community-based epidemiological and autopsy studies suggest the true prevalence may be up to 20 times greater as the condition is often asymptomatic until first discovered when the patient presents with oesophageal cancer. CLO principally occurs in Western Caucasian males and is rare in other racial groups. It is the major risk factor for oesophageal adenocarcinoma, with a lifetime cancer risk of around 10%. The cancer incidence is estimated at 1 in 200 patient years (0.5% per year). The absolute risk is low, however, and more than 95% of patients with CLO die of causes other than oesophageal cancer. The epidemiology and aetiology of CLO are poorly understood. The prevalence is increasing, and it is more common in men (especially white) and those over 50 years of age. It is weakly associated with smoking but not alcohol. Recent studies suggest that cancer risk is related to the severity and duration of reflux rather than the presence of CLO per se but this remains to be proven. Recent attention has focused on the importance of duodenogastro-oesophageal reflux, containing bile, pancreatic enzymes and pepsin in addition to acid. The molecular events underlying the progression of CLO from metaplasia to dysplasia to cancer are not well understood but E-cadherin polymorphisms, p53 mutations, transforming growth factor-ß (TGF-ß), epidermal growth factor (EGF) receptors, COX-2 and tumour necrosis factor-a (TNF-a) may play roles in neoplastic progression.




Integration link: Barrett's metaplasia

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e




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Diagnosis requires multiple systematic biopsies to maximise the chance of detecting intestinal metaplasia and/or dysplasia.
Management. Neither potent acid suppression nor antireflux surgery will stop progression or induce regression of CLO, and treatment is only indicated for symptoms of reflux or complications such as stricture. Endoscopic ablation therapy or photodynamic therapy can induce regression but 'buried islands' of glandular mucosa may persist underneath the squamous epithelium and cancer risk is not eliminated. At present these therapies remain experimental but show promise; they are used in patients with high-grade dysplasia (HGD) or early malignancy that is not suitable for surgery.
Regular endoscopic surveillance is often performed to detect dysplasia and prevent malignancy or diagnose it at a curable stage. Surveillance can detect tumours at earlier stages and improve 2-year survival but, because most CLO is undetected until cancer develops, surveillance strategies are unlikely to influence the overall mortality rate of oesophageal cancer. Surveillance is expensive and cost-effectiveness studies have been conflicting. Surveillance is currently recommended every 1-2 years for those without dysplasia and 6-12-monthly for those with low-grade dysplasia. Oesophagectomy is widely recommended for those with HGD as the resected specimen harbours cancer in up to 40%. This may be an over-estimate and recent data suggest that HGD often remains stable and may not progress to cancer, at least in the medium term. Close follow-up with biopsies every 3 months is an alternative strategy for those with HGD. Further studies are required to confirm recent evidence suggesting that more selective surveillance at longer intervals may be safe and more cost-effective.
Anaemia
Iron deficiency anaemia occurs as a consequence of chronic, insidious blood loss from long-standing oesophagitis. Almost all such patients have a large hiatus hernia. Nevertheless, hiatus hernia is very common and other causes of blood loss, particularly colorectal cancer, must be considered in anaemic patients, even when endoscopy reveals oesophagitis and a hiatus hernia.
Benign oesophageal stricture
Fibrous strictures develop as a consequence of long-standing oesophagitis. Most patients are elderly and have poor oesophageal peristaltic activity. They present with dysphagia which is worse for solids than for liquids. Bolus obstruction following ingestion of meat can lead to absolute dysphagia. A history of heartburn is common but not invariable; many elderly patients presenting with strictures have no preceding heartburn.
Diagnosis is made by endoscopy, and biopsies of the stricture are taken to exclude malignancy. Endoscopic balloon dilatation or bouginage is undertaken. Subsequently, long-term therapy with a proton pump inhibitor drug at full dose should be started to reduce the risk of recurrent oesophagitis and stricture formation. The patient should be advised to chew food thoroughly, and it is important to ensure adequate dentition.
Investigations
Young patients who present with typical symptoms of gastro-oesophageal reflux, without worrying features such as dysphagia, weight loss or anaemia, can be treated empirically.
Investigation is advisable if patients present in middle or late age, if symptoms are atypical or if a complication is suspected. Endoscopy is the investigation of choice. This is performed to exclude other upper gastrointestinal diseases which can mimic gastro-oesophageal reflux, and to identify complications. A normal endoscopy in a patient with compatible symptoms should not preclude treatment for gastro-oesophageal reflux disease.
When, despite endoscopy, the diagnosis is unclear or if surgical intervention is under consideration, 24-hour pH monitoring is indicated. This involves tethering a slim catheter with a terminal radiotelemetry pH-sensitive probe above the gastro-oesophageal junction. The intraluminal pH is recorded whilst the patient undergoes normal activities, and episodes of pain are noted and related to pH. A pH of less than 4 for more than 6-7% of the study time is diagnostic of reflux disease.
Management
Lifestyle advice, including weight loss, avoidance of dietary items which the patient finds worsen symptoms, elevation of the bed head in those who experience nocturnal symptoms, avoidance of late meals and giving up smoking are recommended but rarely needed.
Proprietary antacids and alginates, which are said to produce a protective mucosal 'raft' over the oesophageal mucosa, are taken with considerable symptomatic benefit by most patients. H2-receptor antagonist drugs (see p. 786) help symptoms without healing oesophagitis. They are well tolerated, and the timing of medication and dosage should be tailored to individual need.
Proton pump inhibitors (see p. 786) are the treatment of choice for severe symptoms and for complicated reflux disease. Symptoms almost invariably resolve and oesophagitis heals in the majority of patients. Recurrence of symptoms is common when therapy is stopped and some patients require life-long treatment at the lowest acceptable dose.
EBM
GASTRO-OESOPHAGEAL REFLUX DISEASE-role of pharmacological intervention
'A meta-analysis of available RCT data indicates that proton pump inhibitors are significantly better than H2-receptor antagonists in both healing oesophagitis and relieving symptoms. Proton pump inhibitors heal oesophagitis resistant to long-term therapy with H2-receptor antagonists.'
Chiba N, de Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterol 1997; 112:1798-1810.
Bate CM, Green JR, Axon AT, et al. Omeprazole is more effective than cimetidine in the prevention of recurrence of GERD-associated heartburn and the occurrence of underlying oesophagitis. Aliment Pharmacol Ther 1998; 12:41-47.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

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Figure 17.25 Treatment of gastro-oesophageal reflux disease: a 'step-down' approach.
Patients who fail to respond to medical therapy, those who are unwilling to take long-term proton pump inhibitors and those whose major symptom is severe regurgitation should be considered for anti-reflux surgery. This can be undertaken by an open operation but is increasingly being carried out laparoscopically. Although heartburn and regurgitation are alleviated in most patients, a proportion develop complications such as inability to vomit and abdominal bloating ('gas-bloat syndrome'). A treatment algorithm is outlined in Figure 17.25.
ISSUES IN OLDER PEOPLE
GASTRO-OESOPHAGEAL REFLUX DISEASE
The prevalence of gastro-oesophageal reflux disease is higher in older people and complications are more common.
The severity of symptoms does not correlate with the degree of mucosal inflammation in old age.
Late complications such as peptic strictures or bleeding from oesophagitis are more common in older people.
Aspiration from occult gastro-oesophageal reflux disease should be considered in older patients with recurrent pneumonia.


OTHER CAUSES OF OESOPHAGITIS
Infection
Oesophageal candidiasis occurs in debilitated patients and those taking broad-spectrum antibiotics or cytotoxic drugs. It is a particular problem in AIDS patients, who are also susceptible to a spectrum of oesophageal infections (see p. 116).
Corrosives
Suicide attempt by strong household bleach or battery acid is followed by painful burns of the mouth and pharynx and by extensive erosive oesophagitis. This is complicated by oesophageal perforation leading to mediastinitis and by stricture formation. At the time of presentation treatment is conservative, based upon analgesia and nutritional support. Vomiting should be avoided and endoscopy should not be carried out at this stage because of the high risk of oesophageal perforation. Following the acute phase, a barium swallow is performed to demonstrate the extent of stricture formation. Endoscopic dilatation is usually necessary, although it is difficult and hazardous because strictures are often long, tortuous and easily perforated.
Drugs
Potassium supplements and NSAIDs may cause oesophageal ulcers when the tablets are trapped above an oesophageal stricture. Liquid preparations of these drugs should be used in such patients. Bisphosphonates, especially alendronate, cause oesophageal ulceration and should be used with caution in patients with known oesophageal disorders.
MOTILITY DISORDERS
PHARYNGEAL POUCH
Incoordination of swallowing within the pharynx leads to herniation through the cricopharyngeus muscle and formation of a pouch. Most patients are elderly and have no symptoms, although regurgitation, halitosis and dysphagia can occur. Some notice gurgling in the throat after swallowing. A barium swallow demonstrates the pouch and reveals incoordination of swallowing, often with pulmonary aspiration. Endoscopy may be hazardous since the instrument may enter and perforate the pouch. Surgical myotomy and resection of the pouch are indicated in symptomatic patients.
ACHALASIA OF THE OESOPHAGUS
Pathophysiology
Achalasia is characterised by:
a hypertonic lower oesophageal sphincter which fails to relax in response to the swallowing wave
failure of propagated oesophageal contraction, leading to progressive dilatation of the gullet.

The cause is unknown, although failure of non-adrenergic, non-cholinergic (NANC) innervation related to abnormal nitric oxide synthesis within the lower oesophageal sphincter has been found. Degeneration of ganglion cells within the sphincter and the body of the oesophagus occurs. Loss of the dorsal vagal nuclei within the brain stem can be demonstrated in later stages.
Chagas disease (see p. 60) is endemic in South America; infestation with the protozoan organism Trypanosoma cruzi leads to myocarditis and a range of motility disorders of the gastrointestinal tract. Destruction of the myenteric plexus causes a syndrome which is clinically indistinguishable from achalasia.
Clinical features
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Achalasia is an unusual disease affecting 1:100 000 people in Western populations. It usually develops in middle life but can occur at any age. Dysphagia develops slowly, and is initially intermittent. It is worse for solids and is eased by drinking liquids, standing and moving around after eating. Heartburn does not occur, since the closed oesophageal sphincter prevents gastro-oesophageal reflux. Some patients experience episodes of severe chest pain due to oesophageal spasm ('vigorous achalasia'). As the disease progresses dysphagia worsens, the oesophagus empties poorly and nocturnal pulmonary aspiration develops. Achalasia predisposes to squamous carcinoma of the oesophagus.
Investigations
A chest radiograph may be abnormal in late disease, with widening of the mediastinum from gross oesophageal dilatation and features of aspiration pneumonia. A barium swallow shows tapered narrowing of the lower oesophagus. In late disease the oesophageal body is dilated, aperistaltic and food-filled (see Fig. 17.26A). Endoscopy must always be carried out to distinguish these radiological appearances from carcinoma. A strategically placed carcinoma of the cardia can mimic the presentation and radiological and manometric features of achalasia ('pseudo-achalasia'). Manometry in achalasia confirms the high-pressure, non-relaxing lower oesophageal sphincter with poor contractility of the oesophageal body (see Fig. 17.26B).
Management
Endoscopic
Forceful pneumatic dilatation using a 30-35 mm diameter fluoroscopically positioned balloon disrupts the oesophageal sphincter and improves symptoms in 80% of patients. Some patients require more than one dilatation but those requiring frequent dilatation are best treated surgically. Endoscopically directed injection of botulinum toxin into the lower oesophageal sphincter induces clinical remission, but late relapse is common.




Figure 17.26 Achalasia. A Radiograph showing a dilated, barium-filled oesophagus (O) with tapering, and a closed lower oesophageal sphincter (LOS). (D = diaphragm) B Oesophageal manometry demonstrates an elevated resting LOS pressure (1), low-amplitude, non-propagated contractions in the oesophageal body (2), and failure of the LOS to relax on swallowing (3). Compare with Figure 17.1, page 750.
Surgical
Surgical myotomy ('Heller's operation') is done by open operation or by a laparoscopic approach and is an extremely effective although more invasive option. Both pneumatic dilatation and myotomy may be complicated by gastro-oesophageal reflux, and this can lead to severe oesophagitis because oesophageal clearance is so poor in these patients. For this reason Heller's myotomy is accompanied by a partial fundoplication anti-reflux operation. Acid-suppressing drug therapy, using a proton pump inhibitor, is often necessary following surgical or endoscopic intervention for achalasia to prevent oesophagitis.
OTHER OESOPHAGEAL MOTILITY DISORDERS
Diffuse oesophageal spasm presents in late middle age with episodic chest pain which may mimic angina, but is sometimes accompanied by transient dysphagia. Some cases occur in response to gastro-oesophageal reflux. Treatment is based upon the use of proton pump inhibitor drugs when gastro-oesophageal reflux is present. Oral or sublingual nitrates or nifedipine may relieve attacks of pain. Results of therapy are often disappointing and the alternatives of pneumatic dilatation and surgical myotomy are also poor.
'Nutcracker' oesophagus is a condition in which extremely forceful peristaltic activity leads to episodic chest pain and dysphagia. Treatment is based upon the use of nitrates or nifedipine.
Non-specific motility disorders represent a collection of oesophageal motility disorders which do not fall into a specific disease entity. Patients are usually elderly and present with dysphagia and chest pain. A range of manometric abnormalities from poor peristalsis to spasm occur.
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SECONDARY CAUSES OF OESOPHAGEAL DYSMOTILITY
In systemic sclerosis the muscle of the oesophagus is replaced by fibrous tissue. Consequently, oesophageal peristalsis fails and this leads to heartburn and dysphagia. Oesophagitis is often severe, and benign fibrous strictures occur. Such patients require long-term therapy with proton pump inhibitor drugs. Dermatomyositis, rheumatoid arthritis and myasthenia gravis are other causes of dysphagia.
BENIGN OESOPHAGEAL STRICTURE
Benign oesophageal stricture is usually a consequence of gastro-oesophageal reflux disease (see Box 17.26) and occurs most often in elderly patients who have poor oesophageal clearance. Rings, due to submucosal fibrosis, occur at the oesophago-gastric junction ('Schatzki ring') and cause intermittent dysphagia, often starting in middle age. A post-cricoid web is a rare complication of iron deficiency anaemia (Paterson-Kelly or Plummer-Vinson syndrome), and may be complicated by development of squamous carcinoma.
Benign strictures are treated by endoscopic dilatation, in which wire-guided bougies or balloons are used to disrupt the fibrous tissue of the stricture.
17.26 CAUSES OF OESOPHAGEAL STRICTURE
Gastro-oesophageal reflux disease
Webs and rings
Carcinoma of the oesophagus or cardia
Extrinsic compression from bronchial carcinoma
Corrosive ingestion
Post-operative scarring following oesophageal resection
Post-radiotherapy
Following long-term nasogastric intubation


TUMOURS OF THE OESOPHAGUS
BENIGN TUMOURS
The most common is a gastrointestinal stromal tumour (GIST). This is usually asymptomatic but may cause bleeding or dysphagia.
CARCINOMA OF THE OESOPHAGUS
Almost all are adenocarcinoma or squamous cancers. Small-cell cancer is a rare third type.
Squamous cancer
17.27 SQUAMOUS CARCINOMA: AETIOLOGICAL FACTORS
Smoking
Alcohol excess
Chewing betel nuts or tobacco
Coeliac disease
Achalasia of the oesophagus
Post-cricoid web
Post-caustic stricture
Tylosis (familial hyperkeratosis of palms and soles)


In Western populations squamous oesophageal cancer (see Box 17.27) is relatively rare (approximately 4 cases per 100 000), whilst in Iran, South Africa and China it is common (200 per 100 000). Squamous cancer can arise in any part of the oesophagus from the post-cricoid region to the cardia. Almost all tumours above the lower third of the oesophagus are squamous cancers.
Adenocarcinoma
This arises in the lower third of the oesophagus from Barrett's oesophagus or from the cardia of the stomach. The incidence of this tumour is increasing and is now approximately 5:100 000 in the UK; this is possibly because of the high prevalence of gastro-oesophageal reflux and Barrett's oesophagus in Western populations.
Clinical features
Most patients have a history of progressive, painless dysphagia for solid foods. Others present acutely because of food bolus obstruction. In late stages weight loss is often extreme; chest pain or hoarseness suggests mediastinal invasion. Fistulation between the oesophagus and the trachea or bronchial tree leads to coughing after swallowing, pneumonia and pleural effusion. Physical signs may be absent but even at initial presentation cachexia, cervical lymphadenopathy or other evidence of metastatic spread is common.
Investigations
The investigation of choice is upper gastrointestinal endoscopy (see Fig. 17.27) with cytology and biopsy. A barium swallow demonstrates the site and length of the stricture but adds little useful information.
Once a diagnosis has been achieved, investigations are performed to stage the tumour and define operability. Thoracic and abdominal CT are carried out to identify metastatic spread and local invasion. Invasion of the aorta and other local structures may preclude surgery. Unfortunately, CT tends to understage tumours and the most sensitive modality is endoscopic ultrasound (EUS), in which an ultrasound transducer is incorporated into the tip of a modified endoscope (see Fig. 17.28). These investigations will define the TNM stage of the disease (see Ch. 5).
Management
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Figure 17.27 Adenocarcinoma of the lower oesophagus. A Adenocarcinoma in association with Barrett's oesophagus (arrow). B Histology: clumps of invasive malignant cells are seen below areas of intestinal metaplasia (arrow).


Figure 17.28 Endoscopic ultrasound staging of oesophageal carcinoma. The tumour (T) has extended through the oesophageal wall (T3, arrows). A small peri-tumoral lymph node (LN) is also seen (arrow). (Ao = aorta; LA = left atrium; E = echoendoscope)
Despite modern treatment, the overall 5-year survival of patients presenting with oesophageal cancer is 6-9%. Survival following oesophageal resection depends on stage. Tumours which have extended beyond the wall of the oesophagus and have lymph node involvement (T3, N1) are associated with a 5-year survival of around 10% after surgery. However, this figure improves significantly if the tumour is confined to the oesophageal wall and there is no spread to lymph nodes. Overall survival following 'potentially curative' surgery (all macroscopic tumour removed) is about 30% at 5 years, but recent studies have suggested that this can be improved by neoadjuvant (pre-operative) chemotherapy, including agents such as cisplatin and 5-fluorouracil. Although squamous carcinomas are radiosensitive, radiotherapy alone is associated with a 5-year survival of only 5%.
Approximately 70% of patients have extensive disease at presentation; in these, treatment is palliative and based upon relief of dysphagia and pain. Endoscopically directed tumour ablation using laser therapy or insertion of stents is the major method of improving swallowing. Palliative radiotherapy may induce shrinkage of both squamous cancers and adenocarcinomas but symptomatic response may be slow. Quality of life can be improved by nutritional support and appropriate analgesia.
PERFORATION OF THE OESOPHAGUS
The most common cause is iatrogenic perforation complicating dilatation or intubation. Malignant, corrosive or post-radiotherapy strictures are more likely to be perforated than peptic strictures. A perforated peptic stricture is usually managed conservatively using broad-spectrum antibiotics and parenteral nutrition; most heal within days. Malignant, caustic and radiotherapy stricture perforations require surgical resection or intubation.
Spontaneous oesophageal perforation ('Boerhaave's syndrome') results from forceful vomiting and retching. Severe chest pain and shock occur as oesophago-gastric contents enter the mediastinum and thoracic cavity. Subcutaneous emphysema, pleural effusions and pneumothorax develop. The diagnosis is made using a water-soluble contrast swallow and treatment is surgical. Delay in diagnosis is a key factor in the high mortality associated with this condition.

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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > DISEASES OF THE STOMACH AND DUODENUM
DISEASES OF THE STOMACH AND DUODENUM
GASTRITIS
Gastritis is a histological diagnosis, although it can sometimes be recognised at endoscopy.
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ACUTE GASTRITIS
Acute gastritis is often erosive and haemorrhagic. Neutrophils are the predominant inflammatory cell in the superficial epithelium. Many cases result from aspirin or NSAID ingestion (see Box 17.28). Acute gastritis often produces no symptoms but may cause dyspepsia, anorexia, nausea or vomiting, haematemesis or melaena. Many cases resolve quickly and do not merit investigation; in others, endoscopy and biopsy may be necessary to exclude peptic ulcer or cancer. Treatment should be directed to the underlying cause. Short-term symptomatic therapy with antacids, acid suppression (e.g. H2-receptor antagonists) or antiemetics (e.g. metoclopramide) may be necessary.
CHRONIC GASTRITIS DUE TO HELICOBACTER PYLORI INFECTION




Integration link: Helicobacter pylori and gastritis

Taken from Robbins Basic Pathology 7e




The most common cause of chronic gastritis is H. pylori (see Box 17.28). The predominant inflammatory cells are lymphocytes and plasma cells. Correlation between symptoms and endoscopic or pathological findings is poor. Most patients are asymptomatic and do not require any treatment. Patients with dyspepsia and H. pylori-associated gastritis may benefit from H. pylori eradication.
AUTOIMMUNE CHRONIC GASTRITIS
17.28 COMMON CAUSES OF GASTRITIS
Acute gastritis (often erosive and haemorrhagic)
Aspirin, NSAIDs
H. pylori (initial infection)
Alcohol
Other drugs, e.g. iron preparations
Severe physiological stress, e.g. burns, multi-organ failure, CNS trauma
Bile reflux, e.g. following gastric surgery
Viral infections, e.g. cytomegalovirus (CMV), herpes simplex virus in AIDS (see pp. 115-117)
Chronic non-specific gastritis
H. pylori infection
Autoimmune (pernicious anaemia)
Post-gastrectomy
Chronic 'specific' forms (rare)
Infections, e.g. CMV, tuberculosis
Gastrointestinal diseases, e.g. Crohn's disease
Systemic diseases, e.g. sarcoidosis, graft-versus-host disease
Idiopathic, e.g. granulomatous gastritis


This involves the body of the stomach, spares the antrum and results from autoimmune activity against parietal cells. The histological features are diffuse chronic inflammation, atrophy and loss of fundic glands, intestinal metaplasia and sometimes hyperplasia of enterochromaffin-like (ECL) cells. Circulating antibodies to parietal cell and intrinsic factor may be present. In some patients the degree of gastric atrophy is severe, and loss of intrinsic factor secretion leads to pernicious anaemia. The gastritis itself is usually asymptomatic but some patients have evidence of other organ-specific autoimmunity, particularly thyroid disease. There is a fourfold increase in the risk of gastric cancer development (see alsop. 789).
MÉNÉTRIER'S DISEASE
In this rare condition the gastric pits are elongated and tortuous, with replacement of the parietal and chief cells by mucus-secreting cells. As a result, the mucosal folds of the body and fundus are greatly enlarged. Most patients are hypochlorhydric. Whilst some patients have upper gastro-intestinal symptoms, the majority present in middle or old age with protein-losing enteropathy (see p. 798) due to exudation from the gastric mucosa. Barium meal shows enlarged, nodular and coarse folds which are also seen at endoscopy, although biopsies may not be deep enough to show all the histological features. Treatment with anti-secretory drugs may reduce protein loss but unresponsive patients require partial gastrectomy.
PEPTIC ULCER DISEASE
The term 'peptic ulcer' refers to an ulcer in the lower oesophagus, stomach or duodenum, in the jejunum after surgical anastomosis to the stomach, or, rarely, in the ileum adjacent to a Meckel's diverticulum. Ulcers in the stomach or duodenum may be acute or chronic; both penetrate the muscularis mucosae but the acute ulcer shows no evidence of fibrosis. Erosions do not penetrate the muscularis mucosae.
GASTRIC AND DUODENAL ULCER
Although the prevalence of peptic ulcer is decreasing in many Western communities, it still affects approximately 10% of all adults at some time in their lives. The male to female ratio for duodenal ulcer varies from 5:1 to 2:1, whilst that for gastric ulcer is 2:1 or less.
Aetiology
Helicobacter pylori
In the industrialised world the prevalence of H. pylori infection in the general population rises steadily with age, and in the UK approximately 50% of those over the age of 50 years are infected. In many parts of the underdeveloped world infection is much more common and is often acquired in childhood. Up to 90% of the population are infected by adult life in some countries. The vast majority of colonised people remain healthy and asymptomatic and only a minority develop clinical disease. Around 90% of duodenal ulcer patients and 70% of gastric ulcer patients are infected with H. pylori; the remaining 30% of gastric ulcers are due to NSAIDs.
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Pathogenesis and pathophysiology of infection. The organism's motility allows it to localise and live deep beneath the mucus layer closely adherent to the epithelial surface. Here the surface pH is close to neutral and any acidity is buffered by the organism's production of the enzyme urease. This produces ammonia from urea and raises the pH around the bacterium. Although it is non-invasive, the bacterium stimulates chronic gastritis by provoking a local inflammatory response in the underlying epithelium due to release of a range of cytotoxins (see Fig. 17.29). H. pylori exclusively colonises gastric-type epithelium and is only found in the duodenum in association with patches of gastric metaplasia.


Figure 17.29 Some factors which may influence the virulence of Helicobacter pylori.


Figure 17.30 Sequence of events in the pathophysiology of duodenal ulceration.
In most people H. pylori causes antral gastritis associated with depletion of somatostatin (from D cells) and gastrin release from G cells. The subsequent hypergastrinaemia stimulates acid production by parietal cells, but in the majority of cases this has no clinical consequences. In a minority of patients (perhaps those who inherit a large parietal cell mass) this effect is exaggerated, leading to duodenal ulceration (see Fig. 17.30). The role of H. pylori in the pathogenesis of gastric ulcer is less clear but H. pylori probably acts by reducing gastric mucosal resistance to attack from acid and pepsin. In approximately 1% of infected people, H. pylori causes a pangastritis leading to gastric atrophy and hypochlorhydria. This allows bacteria to proliferate within the stomach; these may produce mutagenic nitrites from dietary nitrates, predisposing to the development of gastric cancer (see Fig. 17.31). The reasons for different outcomes are unclear but bacterial strain differences and host genetic factors are both likely.
Diagnosis. Many different diagnostic tests for H. pylori infection are available (see Box 17.29). Some are invasive and require endoscopy; others are non-invasive. They vary in sensitivity and specificity. Overall, breath tests are best because of their accuracy, simplicity and non-invasiveness.


Figure 17.31 Consequences of H. pylori infection.
17.29 METHODS FOR THE DIAGNOSIS OF HELICOBACTER PYLORI INFECTION
Test Advantages Disadvantages
Non-invasive
Serology Rapid office kits available Lacks sensitivity and specificity
Good for population studies Cannot differentiate current from past infection
Urea breath tests High sensitivity and specificity 14C uses radioactivity
13C requires expensive mass spectrometer
Invasive (antral biopsy)
Histology Sensitivity and specificity False negatives occur
Takes several days to process
Rapid urease tests, e.g. CLO, Pyloritek Cheap, quick Lack sensitivity
Specificity
Microbiological culture 'Gold standard' Slow and laborious culture
Defines antibiotic sensitivity Lacks sensitivity

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Non-steroidal anti-inflammatory drugs (NSAIDs)
See page 989.
Smoking
Smoking confers an increased risk of gastric ulcer and, to a lesser extent, duodenal ulcer. Once the ulcer has formed, it is more likely to cause complications and less likely to heal on standard treatment regimens if the patient continues to smoke.
Acid-pepsin versus mucosal resistance
An ulcer forms when there is an imbalance between aggressive factors, i.e. the digestive power of acid and pepsin, and defensive factors, i.e. the ability of the gastric and duodenal mucosa to resist this digestive power (see Fig. 17.32). This mucosal resistance constitutes the gastric mucosal barrier. Ulcers occur only in the presence of acid and pepsin; they are never found in achlorhydric patients such as those with pernicious anaemia. On the other hand, severe intractable peptic ulceration nearly always occurs in patients with the Zollinger-Ellison syndrome (see p. 788), which is characterised by very high acid secretion.
Most duodenal ulcer patients have markedly exaggerated acid secretion in response to stimulation by gastrin, and H. pylori (as already discussed) leads to hypergastrinaemia. In gastric ulcer patients the effects of H. pylori are more complex, and impaired mucosal defence resulting from a combination of H. pylori infection, NSAIDs and smoking may have a more important role.
Pathology


Figure 17.32 Gastroduodenal mucosal protection. Prostaglandins (PG) stimulate bicarbonate and mucus secretion and increase mucosal blood flow. Bicarbonate ions are secreted into the unstirred mucus layer, neutralising hydrogen ions as they back-diffuse towards the epithelium. Rapid cell turnover and a rich mucosal blood supply are important protective elements.
Chronic gastric ulcer is usually single; 90% are situated on the lesser curve within the antrum or at the junction between body and antral mucosa. Chronic duodenal ulcer usually occurs in the first part of the duodenum just distal to the junction of pyloric and duodenal mucosa; 50% are on the anterior wall. Gastric and duodenal ulcers coexist in 10% of patients and more than one peptic ulcer is found in 10-15% of patients. A chronic ulcer extends to below the muscularis mucosa and the histology shows four layers: surface debris, an infiltrate of neutrophils, granulation tissue and collagen.
Clinical features
Peptic ulcer disease is a chronic condition with a natural history of spontaneous relapse and remission lasting for decades, if not for life. Although they are different diseases, duodenal and gastric ulcers share common symptoms which will be considered together.
The most common presentation is that of recurrent abdominal pain which has three notable characteristics: localisation to the epigastrium, relationship to food and episodic occurrence.
Occasional vomiting occurs in about 40% of ulcer subjects; persistent vomiting occurring daily suggests gastric outlet obstruction. In one-third of patients the history is less characteristic. This is especially true in elderly subjects under treatment with NSAIDs. In these patients pain may be absent or so slight that it is experienced only as a vague sense of epigastric unease. Occasionally, the only symptoms are anorexia and nausea, or a sense of undue repletion after meals. In some patients the ulcer is completely 'silent', presenting for the first time with anaemia from chronic undetected blood loss, as an abrupt haematemesis or as acute perforation; in others there is recurrent acute bleeding without ulcer pain between the attacks.
It should be noted that the diagnostic value of individual symptoms for peptic ulcer disease is poor, and the history is often a poor predictor of the presence of an ulcer.
Investigations
The diagnosis can be made by double-contrast barium meal examination or by endoscopy. Endoscopy is the preferred investigation because it is more accurate and has the enormous advantage that suspicious lesions and H. pylori status can be evaluated by biopsy. For those with a duodenal ulcer seen at barium meal, urea breath testing will accurately define H. pylori status. Very occasionally, a gastric ulcer may be malignant; therefore endoscopy and biopsy are mandatory when a gastric ulcer is detected on barium examination. Moreover, in gastric ulcer disease endoscopy must be repeated after suitable treatment to confirm that the ulcer has healed and to obtain further biopsies if it has not. In contrast, it is not necessary to repeat endoscopy after treating duodenal ulcers.
Management
The aims of management are to relieve symptoms, induce ulcer healing in the short term, and cure the ulcer in the long term. H. pylori eradication is the cornerstone of therapy for peptic ulcers, as this will successfully prevent relapse and eliminate the need for long-term therapy in the majority of patients.
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H. pylori eradication
All patients with proven acute or chronic duodenal ulcer disease and those with gastric ulcers who are H. pylori-positive should be offered eradication therapy as primary therapy. Treatment is based upon a proton pump inhibitor taken simultaneously with two antibiotics (from amoxicillin, clarithromycin and metronidazole) for 7 days. Compliance, side-effects and metronidazole resistance influence the success of therapy (see Box 17.30).
Second-line therapy should be offered to those patients who remain infected after initial therapy once the reasons for failure of first-line therapy (e.g. compliance) have been established. For those who are still colonised after two treatments, the choice lies between a third attempt with quadruple therapy (bismuth, proton pump inhibitor and two antibiotics) or long-term maintenance therapy with acid suppression.
Other indications for H. pylori eradication are shown in Box 17.31.
EBM
H. PYLORI ERADICATION-antibiotic regimens
'RCTs show that first-line therapy should include a proton pump inhibitor at standard dose (12-hourly), clarithromycin 500 mg 12-hourly, and amoxicillin 1 g 12-hourly or metronidazole 400 mg 12-hourly, for 7 days. In case of failure recommended second-line therapy is a proton pump inhibitor at standard dose (12-hourly), bismuth 120 mg 6-hourly, metronidazole 400 mg 12-hourly, and tetracycline 500 mg 6-hourly, for 7 days.'
Lind T, Veldhuyzen van Zanten SJO, Unge P, et al. Eradication of Helicobacter pylori using one week triple therapies combining omeprazole with two antimicrobials-the MACH 1 study. Helicobacter 1996; 1:138-140.
Megrand F, Lehn N, Lind T, et al. The MACH 2 study. Helicobacter pylori resistance to antimicrobial agents and its influence on clinical outcome. Gastroenterology 1997; 112:A216 (abstract).
Further information: www.bsg.org.uk
www.evidbasedgastro.com

17.30 COMMON SIDE-EFFECTS OF H. PYLORI ERADICATION THERAPY
Diarrhoea
30-50% of patients; usually mild but Clostridium difficile-associated colitis can occur
Metronidazole
Metallic taste (common), peripheral neuropathy (rare)
Flushing and vomiting when taken with alcohol
Nausea, vomiting
Abdominal cramp
Headache
Rash


17.31 INDICATIONS FOR H. PYLORI ERADICATION
Definite
Peptic ulcer
MALToma

Not indicated
Asymptomatic
Gastro-oesophageal reflux disease

Uncertain
Family history of gastric cancer
Non-ulcer dyspepsia
Long-term NSAID users


General measures
Cigarette smoking, aspirin and NSAIDs should be avoided. Alcohol in moderation is not harmful and no special dietary advice is required.
Short-term management
Many different drugs are available for the short-term management of acid peptic symptoms (see Box 17.32).
17.32 DRUGS COMMONLY USED IN PEPTIC ULCERS AND OTHER ACID DYSPEPTIC DISORDERS
Drugs Short term Maintenance Side-effects
Drugs which inhibit acid secretion
H2-antagonists
Cimetidine 400 mg 12-hourly or 800 mg at night 400 mg at night Confusion, diarrhoea, interaction with warfarin, phenytoin, theophylline
Ranitidine 150 mg 12-hourly or 300 mg at night 150 mg at night Confusion
H+/K+ ATPase inhibitors (proton pump inhibitors)
Omeprazole 20-40 mg once daily 20 mg at night Hypergastrinaemia, diarrhoea, interactions with warfarin, phenytoin
Lansoprazole 30 mg once daily 15 mg at night
Pantoprazole 40 mg once daily Not recommended Hypergastrinaemia; fewer drug interactions, headache, diarrhoea, rashes
Rabeprazole 20 mg once daily Not recommended
Drugs which enhance mucosal defence and prokinetic agents
Colloidal bismuth 125 mg 6-hourly Not recommended Blackens tongue, teeth and faeces; rarely, bismuth toxicity with prolonged use
Misoprostol 200 µg 6-hourly 200 µg 6-hourly Abortifacient, contraindicated in women of childbearing age; diarrhoea in up to 20%
Sucralfate 2 g 12-hourly Not recommended May bind and reduce absorption of digoxin, warfarin, tetracycline, phenytoin; cramps, diarrhoea, extrapyramidal effects
Domperidone 10-20 mg 8-hourly Not recommended Hyperprolactinaemia and acute dystonia

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Antacids. These are widely available for self-medication and are used for relief of minor dyspeptic symptoms. The majority are based on combinations of calcium, aluminium and magnesium salts, all of which have individual side-effects. Calcium compounds cause constipation, while magnesium-containing agents cause diarrhoea. Aluminium compounds block absorption of digoxin, tetracycline and dietary phosphates. Most have a high sodium content and can exacerbate congestive heart failure.
Histamine H2-receptor antagonist drugs. These are competitive inhibitors of histamine at the H2-receptor on the parietal cell. Dyspeptic symptoms remit promptly, usually within days of starting treatment, and 80% of duodenal ulcers will heal after 4 weeks. These drugs do not inhibit acid secretion to the same degree as the proton pump inhibitors but are useful for the short-term management of acid dyspeptic symptoms prior to investigation. They are moderately effective for the management of reflux disease. They have a proven safety record and several can now be purchased in the UK without prescription.
H+/K+ ATPase ('proton pump') inhibitors. These are substituted benzimidazole compounds that specifically and irreversibly inhibit the proton pump hydrogen/potassium ATPase in the parietal cell membrane. They are the most powerful inhibitors of gastric secretion yet discovered, with maximal inhibition occurring 3-6 hours after an oral dose. They have an excellent safety profile. After a few days of treatment virtual achlorhydria is achieved and rapid healing of both gastric and duodenal ulcers follows. Omeprazole and lansoprazole are important components of H. pylori eradication regimens. Proton pump inhibitors are also much more effective than H2-antagonists for healing and maintenance of reflux oesophagitis.
Colloidal bismuth compounds. Colloidal bismuth subcitrate (CBS) is an ammoniacal suspension of a complex colloidal bismuth salt. It has little, if any, effect on gastric acid secretion and its ulcer-healing effect is probably due to a combination of activity against H. pylori and enhancement of mucosal defence mechanisms.
Sucralfate. This is a basic aluminium salt of sucrose octasulphate. It has little effect on acid secretion but probably acts to protect the ulcer base from peptic activity in a number of ways. It binds to fibroblast growth factor and to the ulcer base, reducing the access of pepsin and acid. It may also enhance epithelial cell turnover. It should be taken 30-60 minutes before meals.
Synthetic prostaglandin analogues (misoprostol). Prostaglandins exert complex effects on the gastroduodenal mucosa. In low doses they protect against injury induced by aspirin and NSAIDs by enhancing mucosal blood flow, and by stimulating mucus and bicarbonate secretion and epithelial cell proliferation. At high doses acid secretion is inhibited. Misoprostol is effective for the prevention and treatment of NSAID-induced ulcers, but in clinical practice proton pump inhibitors are preferred, since they are at least as effective and have fewer side-effects.
Maintenance treatment
Continuous maintenance treatment should not be necessary after successful H. pylori eradication. For the minority who require maintenance treatment the lowest effective dose should be used.
Surgical treatment
The cure of most peptic ulcers by H. pylori eradication therapy and the availability of safe, potent acid-suppressing drugs have made elective surgery for peptic ulcer disease a rare event. The indications are listed in Box 17.33.
The operation of choice for a chronic non-healing gastric ulcer is partial gastrectomy, preferably with a Billroth I anastomosis, in which the ulcer itself and the ulcer-bearing area of the stomach are resected. The reason for this is to exclude an underlying cancer. Definitive anti-acid surgery in the form of vagotomy and drainage (pyloroplasty or gastroenterostomy) or highly selective vagotomy is no longer indicated for duodenal ulcer disease. In the emergency situation 'under-running' the ulcer for bleeding or 'oversewing' (patch repair) for perforation is all that is required. In the presence of giant duodenal ulcers partial gastrectomy using a 'Polya' or Billroth II reconstruction may be required.
17.33 INDICATIONS FOR SURGERY IN PEPTIC ULCER
Emergency
Perforation
Haemorrhage

Elective
Complications, e.g. gastric outflow obstruction
Recurrent ulcer following gastric surgery


Complications of gastric resection or vagotomy
Some degree of disability is seen in up to 50% of patients following peptic ulcer surgery. In most, the effects are minor but in 10% of cases they significantly impair quality of life.
Early satiety and vomiting. Rapid gastric emptying leads to distension of the proximal small intestine as the hypertonic contents draw fluid into the lumen. This leads to abdominal discomfort and diarrhoea after eating. Autonomic reflexes release a range of gastrointestinal hormones which lead to vasomotor features such as flushing, palpitations, sweating, tachycardia and hypotension ('early dumping'). Patients should therefore avoid large meals with high carbohydrate content.
Bile reflux gastritis. Duodenogastric bile reflux leads to chronic gastritis. This is usually asymptomatic but dyspepsia can occur. Symptomatic treatment with aluminium-containing antacids or sucralfate may be effective. A few patients require revisional surgery with creation of a Roux-en-Y loop to prevent bile reflux into the stomach.
Late dumping syndrome. Symptoms of dumping occur 90-180 minutes after eating. The pathogenesis is broadly similar to early dumping, but in addition reactive hypoglycaemia occurs and may cause mental confusion. Rapid emptying of carbohydrates into the proximal small intestine results in an exaggerated release of insulin with subsequent reactive hypoglycaemia. Other gut hormones and enteric peptides may also be involved. Treatment is similar to that of early dumping syndrome.
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Diarrhoea and maldigestion. Diarrhoea may develop after any peptic ulcer operation and usually occurs 1-2 hours after eating. Poor mixing of food in the stomach, with rapid emptying, inadequate mixing with pancreatic biliary secretions, reduced small intestinal transit times and bacterial overgrowth, may lead to malabsorption.
Diarrhoea often responds to dietary advice to eat small, dry meals with a reduced intake of refined carbohydrates. Antidiarrhoeal drugs such as codeine phosphate (15-30 mg 4-6 times a day) or loperamide (2 mg after each loose stool) are often helpful.
Weight loss. Most patients lose weight shortly after surgery and 30-40% are unable to regain all the weight which is lost. The usual cause is reduced intake because of a small gastric remnant, but diarrhoea and mild steatorrhoea also contribute.
Anaemia. Anaemia is common many years after subtotal gastrectomy. Although iron deficiency is the most common cause, folic acid and B12 deficiency are also seen. Inadequate dietary intake of iron and folate, lack of acid and intrinsic factor secretion, mild chronic low-grade blood loss from the gastric remnant and recurrent ulceration are responsible.
Metabolic bone disease. Both osteoporosis and osteomalacia occur as a consequence of calcium and vitamin D malabsorption.
Gastric cancer. An increased risk of gastric cancer has been reported from several epidemiological studies. The risk is highest in those with hypochlorhydria, duodenogastric reflux of bile, smoking and H. pylori infection. Although the relative risk is increased, the absolute risk of cancer remains low and endoscopic surveillance is not indicated following gastric surgery.
Complications of peptic ulcer disease
These are perforation, gastric outlet obstruction and bleeding.
Perforation
When free perforation occurs, the contents of the stomach escape into the peritoneal cavity, leading to peritonitis. Perforation occurs more commonly in duodenal than in gastric ulcers, and usually in ulcers on the anterior wall. About one-quarter of all perforations occur in acute ulcers and NSAIDs are often incriminated.
Clinical features. Perforation is often the first sign of ulcer, and a history of recurrent epigastric pain is uncommon. The most striking symptom is sudden, severe pain; its distribution follows the spread of the gastric contents over the peritoneum. Pain initially develops in the upper abdomen and rapidly becomes generalised; shoulder tip pain is due to irritation of the diaphragm. The pain is accompanied by shallow respiration due to limitation of diaphragmatic movements, and by shock. The abdomen is held immobile and there is generalised 'board-like' rigidity. Intestinal sounds are absent and liver dullness to percussion decreases due to the presence of gas under the diaphragm. After some hours symptoms may improve, although abdominal rigidity remains. Later the patient's condition deteriorates as general peritonitis develops.
In at least 50% of cases an erect chest radiograph shows free air beneath the diaphragm. If not, a water-soluble contrast swallow will confirm leakage of gastroduodenal contents.
Management and prognosis. After resuscitation, the acute perforation is treated surgically, either by simple closure, or by converting the perforation into a pyloroplasty if it is large. On rare occasions a 'Polya' partial gastrectomy is required. Following surgery H. pylori is treated (if present) and NSAIDs are avoided.
Perforation carries a mortality of 25%. This high figure reflects the high age and comorbidity of this population.
Gastric outlet obstruction
The causes are shown in Box 17.34. The most common is an ulcer in the region of the pylorus.
Clinical features. Nausea, vomiting and abdominal distension are the cardinal features of gastric outlet obstruction. Large quantities of gastric content are often vomited, and food eaten 24 hours or more previously may be recognised.
Physical examination frequently shows evidence of wasting and dehydration. A succussion splash may be elicited 4 hours or more after the last meal or drink. Visible gastric peristalsis is diagnostic of gastric outlet obstruction.
Investigations. Loss of gastric contents leads to dehydration with low serum chloride and potassium, and raised serum bicarbonate and urea concentrations. This results in enhanced renal absorption of Na+ in exchange for H+ and paradoxical aciduria. Nasogastric aspiration of at least 200 ml of fluid from the stomach after an overnight fast suggests the diagnosis.
Endoscopy should be performed after the stomach has been emptied by a wide-bore nasogastric tube. Endoscopic balloon dilatation of benign stenoses may be possible in some patients. In gastroparesis the pylorus is normal and the endoscope can be passed easily into the duodenum.
Barium studies are rarely advisable because they cannot usually distinguish between peptic ulcer and cancer. Moreover, barium remains in the stomach and is difficult to remove.
17.34 DIFFERENTIAL DIAGNOSIS AND MANAGEMENT OF GASTRIC OUTLET OBSTRUCTION
Cause Management
Fibrotic stricture from duodenal ulcer, i.e. 'pyloric stenosis' Balloon dilatation or surgery
Oedema from pyloric channel or duodenal ulcer Medical therapy
Carcinoma of antrum Surgery
Adult hypertrophic pyloric stenosis Surgery
Gastroparesis Investigate cause, prokinetic drugs

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Management. Nasogastric suction and intravenous correction of dehydration are undertaken. In severe cases at least 4 litres of isotonic saline and 80 mmol of potassium may be necessary during the first 24 hours. Correction of metabolic alkalosis is not required. In some patients proton pump inhibitor drugs heal ulcers, relieve pyloric oedema and overcome the need for surgery. In others partial gastrectomy is necessary although this is best done after a 7-day period of nasogastric aspiration which enables the stomach to return to normal size. A gastroenterostomy is an alternative operation but patients will then require long-term proton pump inhibitor therapy to prevent stomal ulceration unless a vagotomy is also carried out.
Bleeding
See pages 764-766.
ISSUES IN OLDER PEOPLE
PEPTIC ULCER DISEASE
Gastroduodenal ulcers have a manyfold greater incidence, admission rate and mortality in older people.
This results from the high prevalence of H. pylori and NSAID use, and impaired defence mechanisms.
Pain and dyspepsia are frequently absent or atypical so older people develop complications such as bleeding or perforation more frequently.
When bleeding does occur, older patients require more intensive management (including central venous pressure measurement) than younger patients because they tolerate hypovolaemic shock poorly.


ZOLLINGER-ELLISON SYNDROME
This is a rare disorder characterised by the triad of severe peptic ulceration, gastric acid hypersecretion and a non-beta cell islet tumour of the pancreas ('gastrinoma'). It probably accounts for about 0.1% of all cases of duodenal ulceration. The syndrome occurs in either sex at any age, although it is most common between 30 and 50 years of age.
Pathophysiology
The gastrinoma secretes large amounts of gastrin, which stimulates the parietal cells of the stomach to secrete acid to their maximal capacity and increases the parietal cell mass three- to sixfold. Pentagastrin does not increase the secretory rate much above basal values because the stomach is maximally secreting. The acid output may be so great that it reaches the upper small intestine, reducing the luminal pH to 2 or less. Pancreatic lipase is inactivated and bile acids are precipitated. Diarrhoea and steatorrhoea result.
Pathology
Around 90% of tumours occur in the pancreatic head or proximal duodenal wall, the latter site being more common. At least half are multiple, and tumour size can vary from 1 mm to 20 cm. Approximately one-half to two-thirds are malignant but are often slow-growing. Of these patients, 20-60% also have adenomas of the parathyroid and pituitary glands (multiple endocrine neoplasia, MEN type I; see p. 688).
Clinical features
Peptic ulcers are multiple, severe and may occur in unusual sites such as the post-bulbar duodenum, jejunum or oesophagus. There is a poor response to standard ulcer therapy. The history is usually short; bleeding and perforations are common. The syndrome may present as severe recurrent ulceration following a standard operation for peptic ulcer. Diarrhoea is seen in one-third or more of patients and can be the presenting feature. The diagnosis should be suspected in all patients with unusual or severe peptic ulceration, especially if a barium meal shows abnormally coarse gastric mucosal folds.
Investigations
Hypersecretion of acid under basal conditions with little increase following pentagastrin may be confirmed by gastric aspiration. Serum gastrin levels are grossly elevated (10- to 1000-fold). Injection of the hormone secretin normally causes no change or a slight decrease in circulating gastrin concentrations, but in Zollinger-Ellison syndrome there is a paradoxical dramatic increase in gastrin. Tumour localisation is best achieved by endoscopic ultrasound and use of radio-labelled somatostatin receptor scintigraphy.
Management
Approximately 30% of small and single tumours can be localised and resected but many tumours are multifocal. Some patients present with metastatic disease and surgery is inappropriate. Proton pump inhibitors have made total gastrectomy unnecessary and in the majority of patients continuous therapy with omeprazole heals ulcers and alleviates diarrhoea. Larger doses (60-80 mg daily) than those used to treat duodenal ulcer are required. The synthetic somatostatin analogue, octreotide, given by subcutaneous injection, reduces gastrin secretion and is sometimes of value. Overall 5-year survival is 60-75% and all patients should be monitored for the later development of other manifestations of MEN I.
FUNCTIONAL DISORDERS
NON-ULCER DYSPEPSIA
This is defined as chronic dyspepsia (pain or upper abdominal discomfort) with no evidence of organic disease on investigation (which must include endoscopy). Other commonly reported symptoms include early satiety, fullness, bloating and nausea. 'Ulcer-like' and 'dysmotility-type' subgroups are reported, but there is great overlap between these and also with irritable bowel syndrome, which often coexists.
Aetiology
The condition of non-ulcer dyspepsia probably covers a spectrum of mucosal, motility and psychiatric disorders.
Clinical features
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Patients are usually young (<40 years) and women are affected twice as commonly as men. Abdominal pain is associated with a variable combination of other 'dyspeptic' symptoms, the most common being nausea and bloating after meals. Morning symptoms are characteristic and pain or nausea may occur on waking. Direct enquiry may elicit symptoms suggestive of irritable bowel syndrome. Peptic ulcer disease must be considered, whilst in older subjects intra-abdominal malignancy is a prime concern.
There are no diagnostic signs, apart perhaps from inappropriate tenderness on abdominal palpation. Symptoms may appear disproportionate to clinical well-being and there is no weight loss. Patients often appear anxious and usually distraught, and it is sometimes possible to detect psychological symptoms.
A drug history should be taken and the possibility of a depressive illness should be considered. Pregnancy should be ruled out in young women before radiological studies are undertaken. Alcohol misuse should be suspected when early morning nausea and retching are prominent.
Investigations
The history will often suggest the diagnosis but in older subjects an endoscopy is necessary to exclude mucosal disease. While an ultrasound scan may detect gallstones, these are rarely responsible for dyspeptic symptoms.
Management
The most important elements are explanation and reassurance. Possible psychological factors should be explored and the concept of psychological influences on gut function should be explained. Idiosyncratic and restrictive diets are of little benefit, but fat restriction may help.
Drug treatment is not especially successful but merits trial. Antacids are sometimes helpful. Prokinetic drugs such as metoclopramide (10 mg 8-hourly) or domperidone (10-20 mg 8-hourly) may be given before meals if nausea, vomiting or bloating is prominent. Metoclopramide may induce extrapyramidal side-effects, including tardive dyskinesia in young subjects. H2-receptor antagonist drugs may be tried if night pain or heartburn is troublesome. Low-dose amitriptyline is sometimes of value. The role of H. pylori eradication remains controversial, although a minority (up to 20%) may benefit.
Symptoms which can be associated with an identifiable cause of stress (impending marriage or divorce, or financial or employment difficulties, for example) resolve with appropriate counselling. Some patients have major chronic psychological disorders resulting in persistent or recurrent symptoms and need behavioural or other formal psychotherapy (see p. 256).
FUNCTIONAL CAUSES OF VOMITING
Psychogenic vomiting may occur in anxiety neurosis. It starts usually on wakening or immediately after breakfast; only rarely does it occur later in the day. The disorder is probably a reaction to facing up to the worries of everyday life; in the young it can be due to school phobia. There may be retching alone or the vomiting of gastric secretions or food. Although functional vomiting may occur regularly over long periods, there is little or no weight loss. Early morning vomiting also occurs in pregnancy, alcohol misuse and depression.
In all patients it is essential to exclude other common causes (see p. 763). Tranquillisers and antiemetic drugs (e.g. metoclopramide 10 mg 8-hourly, domperidone 10 mg 8-hourly, prochlorperazine 5-10 mg 8-hourly) have only a secondary place in management. Antidepressants in full dose may be effective (see p. 257).
TUMOURS OF THE STOMACH
GASTRIC CARCINOMA
Although the incidence of gastric cancer in the UK has fallen markedly in recent years, it remains the leading cause of cancer death world-wide. There is marked geographical variation in incidence. It is extremely common in China, Japan and parts of South America (mortality rate 30-40 per 100 000), less common in the UK (12-13 deaths per 100 000) and uncommon in the USA. Studies of Japanese migrants to the USA have revealed a much lower incidence in second-generation migrants, confirming the importance of environmental factors. Gastric cancer is more common in men and the incidence rises sharply after 50 years of age.
Aetiology
H. pylori is associated with chronic atrophic gastritis and gastric cancer (see Fig. 17.33). H. pylori infection may be responsible for 60-70% of cases and acquisition of infection at an early age may be important. Although the majority of H. pylori-infected individuals have normal or increased acid secretion, a few become hypo- or achlorhydric and these people are thought to be at greatest risk. Chronic inflammation with generation of reactive oxygen species and depletion of the normally abundant antioxidant ascorbic acid are also important.


Figure 17.33 Gastric carcinogenesis: a possible mechanism.
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17.35 FACTORS PREDISPOSING TO GASTRIC CANCER
Smoking
Alcohol
H. pylori
Dietary associations (see text)
Autoimmune gastritis (pernicious anaemia)
Adenomatous gastric polyps
Previous partial gastrectomy (> 20 years)
Ménétrier's disease
Familial adenomatous polyposis


Diets rich in salted, smoked or pickled foods and the consumption of nitrites and nitrates are associated with cancer risk. Carcinogenic N-nitroso-compounds are formed from nitrates by the action of nitrite-reducing bacteria which colonise the achlorhydric stomach. Diets lacking fresh fruit and vegetables as well as vitamins C and A may also contribute.
Other recognised risk factors include smoking, heavy alcohol intake and a number of less common factors (see Box 17.35).
No predominant genetic abnormality has been identified, although cancer risk is increased two- to threefold in first-degree relatives of patients, and links with blood group A have been reported. Rare 'gastric cancer families' have also been described, in which diffuse gastric cancers occur in association with mutations of the E-cadherin gene. This is inherited as an autosomal dominant trait.
Pathology
Virtually all tumours are adenocarcinomas arising from mucus-secreting cells in the base of the gastric crypts. Most develop upon a background of chronic atrophic gastritis with intestinal metaplasia and dysplasia. Cancers are either 'intestinal', arising from areas of intestinal metaplasia with histological features reminiscent of intestinal epithelium, or 'diffuse', arising from normal gastric mucosa. Intestinal carcinomas are more common, and arise against a background of chronic mucosal injury. Diffuse cancers tend to be poorly differentiated and occur in younger patients.
Of gastric cancers, 50% occur in the antrum and 20-30% are situated in the gastric body, often on the greater curve. About 20% occur in the cardia and this type of tumour is becoming more common. Diffuse submucosal infiltration by a scirrhous cancer (linitis plastica) is uncommon. Macroscopically, tumours may be classified as polypoid, ulcerating, fungating or diffuse.
Early gastric cancer is defined as cancer confined to the mucosa or submucosa, regardless of lymph node involvement (see Fig. 17.34). It is often recognised in Japan, where widespread screening is practised. Over 80% of patients in the West present with advanced gastric cancer.
Clinical features
Early gastric cancer is usually asymptomatic but may occasionally be discovered during endoscopy for investigation of dyspepsia. Two-thirds of patients with advanced cancers have weight loss and 50% have ulcer-like pain. Anorexia and nausea occur in one-third, while early satiety, haematemesis, melaena and dyspepsia alone are less common features. Dysphagia occurs in tumours of the gastric cardia which obstruct the gastro-oesophageal junction. Anaemia from occult bleeding is also common.


Figure 17.34 Gastric carcinoma. A Endoscopic view of early cancer showing a shallow, depressed ulcer. B Advanced cancer seen as a large deep ulcer with rolled edges in the cardia.
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Examination may reveal no abnormalities, but signs of weight loss, anaemia or a palpable epigastric mass are not infrequent. Jaundice or ascites may signify metastatic spread. Occasionally, tumour spread occurs to the supraclavicular lymph nodes (Troisier's sign), umbilicus ('Sister Joseph's nodule') or ovaries (Krukenberg tumour). Paraneoplastic phenomena, such as acanthosis nigricans, thrombophlebitis (Trousseau's sign) and dermatomyositis, occur rarely. Metastases occur most commonly in the liver, lungs, peritoneum and bone marrow.
Diagnosis and staging
There are no laboratory markers of sufficient accuracy for the diagnosis of gastric cancer. Upper gastrointestinal endoscopy is the investigation of choice and should be performed promptly in any dyspeptic patient with 'alarm features' (see p. 763). Multiple biopsies from the edge and base of a gastric ulcer are required and exfoliative brush cytology also improves the diagnostic yield. Barium meal is a poor alternative approach but any abnormalities must be followed by endoscopy to obtain biopsy. Once the diagnosis is made, further imaging is necessary for accurate staging and assessment of resectability. CT may not demonstrate small involved lymph nodes, but will show evidence of intra-abdominal spread or liver metastases. Even with these techniques, laparoscopy is required to determine whether the tumour is resectable as it is the only modality that will detect peritoneal spread.
Management
Surgery
Resection offers the only hope of cure, which can be achieved in 90% of patients with early gastric cancer. For the majority who have locally advanced disease radical and total gastrectomy with lymphadenectomy is the operation of choice, preserving the spleen if possible. Proximal tumours involving the oesophago-gastric junction require an associated distal oesophagectomy. Small distally sited tumours can be managed by a partial gastrectomy with lymphadenectomy and either a Billroth I or Roux-en-Y reconstruction. More extensive lymph node resection may increase survival rates but carries greater morbidity. Even for those who cannot be cured, palliative resection may be safely performed with low morbidity and may be necessary when patients present with bleeding or gastric outflow obstruction. Between 80 and 85% of tumours recur, particularly if serosal penetration has occurred, although complete removal of all macroscopic tumours combined with lymphadenectomy will achieve a 50-60% 5-year survival. Neoadjuvant chemotherapy (based on 5-fluorouracil) may improve survival rates, although post-operative radiotherapy has no value.
Unresectable tumours
The management of inoperable, locally advanced cancer is unsatisfactory. Modest palliation of symptoms can be achieved in some patients with chemotherapy using FAM (5-fluorouracil, doxorubicin and mitomycin C) or ECF (epirubicin, cisplatin and 5-fluorouracil). Endoscopic laser ablation of tumour tissue for control of dysphagia or recurrent bleeding benefits some patients. Carcinomas at the cardia may require endoscopic dilatation, laser therapy or insertion of expandable metallic stents to allow adequate swallowing.
Prognosis
Apart from patients with early gastric cancer overall prognosis remains very poor due to advanced stage at presentation, with less than 30% surviving 5 years. Thus the best hope for improved survival lies in greater detection of tumours at an earlier stage. The low incidence of gastric carcinoma in many Western countries makes widespread endoscopic screening impractical but urgent referral and investigation of patients with new-onset dyspepsia over the age of 55, or those with 'alarm' features, are essential. If the important association with H. pylori proves to be causal, this offers the possibility of gastric cancer prevention by widespread eradication of the infection.
GASTRIC LYMPHOMA
Primary gastric lymphoma accounts for less than 5% of all gastric malignancies. The stomach is, however, the most common site for extranodal non-Hodgkin's lymphoma and 60% of all primary gastrointestinal lymphomas occur at this site. Lymphoid tissue is not found in the normal stomach but lymphoid aggregates develop in the presence of H. pylori infection. Indeed, H. pylori infection is closely associated with the development of a low-grade lymphoma ('MALToma'). Superficial MALTomas may be cured by H. pylori eradication.
The clinical presentation is similar to that of gastric cancer and endoscopically the tumour appears as a polypoid or ulcerating mass. While initial treatment of low-grade MALTomas consists of H. pylori eradication and close observation, high-grade lymphomas are treated by combination chemotherapy, surgery and/or radiotherapy. The prognosis depends on the stage at diagnosis. Features predicting a favourable prognosis are stage I or II disease, small resectable tumours, those with low-grade histology, and age below 60 years.
OTHER TUMOURS OF THE STOMACH
Gastrointestinal stromal cell tumours (GIST) are occasionally found at upper gastrointestinal endoscopy. They are benign and usually asymptomatic but may occasionally be responsible for dyspepsia; they can also ulcerate and cause gastrointestinal bleeding. A variety of polyps occur. Hyperplastic polyps and fundic cystic gland polyps are common and of no consequence. Adenomatous polyps are rare; they may be pre-malignant and should be removed endoscopically.
Occasionally, gastric carcinoid tumours (see p. 801) are seen in the fundus and body in patients with long-standing pernicious anaemia. These benign tumours arise from enterochromaffin-like (ECL) or other endocrine cells, and are often multiple but rarely invasive. Unlike carcinoid tumours arising elsewhere in the gastrointestinal tract, they usually run a benign and favourable course. However, large (>2 cm) carcinoids may metastasise and should be removed. Rarely, small nodules of ectopic pancreatic exocrine tissue are found. These 'pancreatic rests' may be mistaken for gastric neoplasms and usually cause no symptoms. Endoscopic ultrasound is the most useful investigation.

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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > DISEASES OF THE SMALL INTESTINE
DISEASES OF THE SMALL INTESTINE
DISORDERS CAUSING MALABSORPTION
COELIAC DISEASE
Coeliac disease is an immunologically mediated inflammatory disorder of the small bowel occurring in genetically susceptible individuals. It can result in malabsorption and responds to a gluten-free diet. The condition occurs world-wide but is more common in northern Europe. The prevalence in the UK is between 1:1000 and 1:1500. Improved awareness of non-classical presentations and better serological tests for diagnosis, however, suggest that the true prevalence may be nearer 1:300 in northern Europe. Some of these are undiagnosed 'silent' cases and there are probably also many cases of 'latent' coeliac disease. These are asymptomatic, genetically susceptible people who may later develop clinical coeliac disease.
Pathogenesis
The precise mechanism of damage causing coeliac disease is unclear but immunological responses to gluten play a key role (see Fig. 17.35). As yet unidentified environmental agents probably trigger small bowel inflammation, allowing gluten peptides (gliadin) access to the enzyme tissue transglutaminase (TTG) in the lamina propria. TTG modifies gluten and this allows it to bind to the antigen-binding groove of major histocompatibility complex (MHC) class II molecules on the surface of antigen presenting cells (APC). In turn the modified gluten peptide is now recognised as antigenic by CD4+ T cells. A TH1 response ensues with release of pro-inflammatory cytokines (e.g. interleukin-1, TNF-a and interferon-?). TTG is now recognised as the autoantigen for anti-endomysial antibodies.


Figure 17.35 Pathophysiology of coeliac disease.
Clinical features and associations
Coeliac disease presents at any age. In infancy it occurs after weaning on to cereals and often presents with classic features of diarrhoea, malabsorption and failure to thrive. It may be seen in older children with non-specific features such as delayed growth. Features of malnutrition are often found on examination and mild abdominal distension may be present. Affected children fail to thrive and have both growth and pubertal delay, leading to short stature in adulthood.
In adults peak onset is in the fifth decade and females are affected slightly more than males. The presentation is highly variable, depending on the severity and extent of small bowel involvement. Some patients have florid malabsorption while others develop non-specific symptoms such as tiredness, weight loss, folate deficiency or iron deficiency anaemia. Other recognised presentations include oral ulceration, dyspepsia and bloating.
Coeliac disease is associated with other human leucocyte antigen (HLA)-linked autoimmune disorders and with certain other diseases (see Box 17.36).
17.36 DISEASE ASSOCIATIONS OF COELIAC DISEASE
Insulin-dependent diabetes mellitus (2-8%)
Thyroid disease (5%)
Primary biliary cirrhosis (3%)
Sjögren's syndrome (3%)
IgA deficiency (2%)
Pernicious anaemia
Inflammatory bowel disease
Sarcoidosis
Myasthenia gravis
Neurological complications-encephalopathy, cerebellar atrophy, peripheral neuropathy, epilepsy
Dermatitis herpetiformis
Down's syndrome
Enteropathy-associated T-cell lymphoma
Small bowel carcinoma
Squamous carcinoma of oesophagus
Ulcerative jejunitis
Pancreatic insufficiency
Microscopic colitis
Splenic atrophy


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Investigations
These are performed to confirm the diagnosis and to look for consequences of malabsorption.
Duodenal or jejunal biopsy
Endoscopic small bowel biopsy is the gold standard. The histological features are usually characteristic but other causes of villous atrophy should also be considered (see Box 17.37 and Fig. 17.36).
Antibodies
Serum antigliadin (especially IgA) and anti-endomysial antibodies are detectable in most untreated cases. IgA anti-endomysial antibodies are detected by immunofluorescence. They are not quantitative, but are more sensitive (85-95%) and specific (approximately 99%) for the diagnosis, except in very young infants. IgG antibodies, however, must be analysed in patients with coexisting IgA deficiency. TTG assays may replace other blood tests in the future as they are easier to perform, semi-quantitative and more accurate in patients with IgA deficiency. These antibody tests constitute valuable screening in patients with diarrhoea but are not a substitute for small bowel biopsy; they usually become negative with successful treatment.
Haematology and biochemistry
17.37 IMPORTANT CAUSES OF SUBTOTAL VILLOUS ATROPHY
Coeliac disease
Tropical sprue
Dermatitis herpetiformis
Lymphoma
AIDS enteropathy
Giardiasis
Hypogammaglobulinaemia
Radiation
Whipple's disease
Zollinger-Ellison syndrome




Figure 17.36 Jejunal mucosa. A Normal. B Jejunum in coeliac disease showing subtotal villous atrophy and marked inflammatory infiltrate.
A full blood count may show microcytic or macrocytic anaemia from iron or folate deficiency and features of hyposplenism (target cells, spherocytes and Howell-Jolly bodies). Biochemical tests may reveal reduced concentrations of calcium, magnesium, total protein, albumin or vitamin D.
Other investigations
These are usually unnecessary. Barium follow-through radiographs may show dilated loops of bowel, coarse or diminished folds and sometimes flocculation of contrast. Sugar tests of intestinal permeability are abnormal and a modest degree of fat malabsorption is usual. Newly diagnosed patients should undergo baseline measurement of bone density by dual energy X-ray absorptiometry (DEXA scan) to look for evidence of metabolic bone disease.
Management
The aims are to correct existing deficiencies of iron, folate, calcium and/or vitamin D, and to commence a life-long gluten-free diet. This requires the exclusion of wheat, rye, barley and initially oats although oats may be reintroduced safely in most patients. Rice, maize and potatoes are satisfactory sources of complex carbohydrates. Initially, frequent dietary counselling is required to make sure the diet is being observed, as the most common reason for failure to improve with dietary treatment is accidental or unrecognised gluten ingestion. Mineral and vitamin supplements are also given when indicated but are seldom necessary when a strict gluten-free diet is adhered to. Booklets produced by coeliac societies in many countries, containing diet sheets and recipes for the use of gluten-free flour, are of great value. Regular monitoring of symptoms, weight and nutrition is essential. Patients who have an excellent clinical response with disappearance of circulating anti-endomysial antibodies probably do not need to undergo repeat jejunal biopsies. These should be reserved for patients who do not symptomatically improve or whose antibodies remain persistently positive.
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Rarely, patients are 'refractory' and require treatment with corticosteroids or immunosuppressive drugs to induce remission. Dietary compliance should be carefully assessed in patients who fail to respond but if their diet is satisfactory, other conditions such as pancreatic insufficiency or microscopic colitis should be sought, as should complications of coeliac disease such as ulcerative jejunitis or enteropathy-associated T-cell lymphoma.
Prognosis and complications
There is an increased risk of malignancy, particularly of enteropathy-associated T-cell lymphoma, small bowel carcinoma and squamous carcinoma of the oesophagus. A few patients develop ulcerative jejunoileitis characterised by deep ulcers in the jejunum with malabsorption. Fever, pain, obstruction or perforation may supervene. The diagnosis is rarely made by barium studies or enteroscopy, and laparotomy and full-thickness biopsy are necessary.
Treatment is difficult. Steroids are used with mixed success and some patients require surgical resection and parenteral nutrition. The course is often progressive and relentless.
Metabolic bone disease is common in patients with long-standing, poorly controlled coeliac disease and is a source of considerable morbidity. This complication is less common in patients who adhere strictly to a gluten-free diet.
DERMATITIS HERPETIFORMIS
This is characterised by crops of intensely itchy blisters over extensor surfaces of the limbs and back. Immunofluorescence shows granular or linear IgA deposition at the dermo-epidermal junction. Almost all patients have partial villous atrophy on jejunal biopsy, even though they usually have no gastrointestinal symptoms. In contrast, fewer than 10% of coeliac patients have evidence of dermatitis herpetiformis although both disorders are associated with the same histocompatibility antigen groups. The rash usually responds to a gluten-free diet but some patients require additional treatment with dapsone (100-150 mg daily).
TROPICAL SPRUE
Tropical sprue is defined as chronic, progressive malabsorption in a patient in or from the tropics, associated with abnormalities of small intestinal structure and function.
Aetiology
The disease occurs mainly in the West Indies and in Asia, including southern India, Malaysia and Indonesia. The epidemiological pattern and occasional epidemics suggest that an infective agent or agents may be involved. Although no single bacterium has been isolated, the condition often begins after an acute diarrhoeal illness. Small bowel bacterial overgrowth with Escherichia coli, Enterobacter and Klebsiella is frequently seen.
Pathology
The changes closely resemble those of coeliac disease. Partial villous atrophy is more common than subtotal villous atrophy.
Clinical features
There is diarrhoea, abdominal distension, anorexia, fatigue and weight loss. In visitors to the tropics the onset of severe diarrhoea may be sudden and accompanied by fever. When the disorder becomes chronic, the features of megaloblastic anaemia from folic acid malabsorption and other deficiencies are common. Remissions and relapses may occur. There may be oedema, glossitis and stomatitis.
The differential diagnosis in the indigenous tropical population is an infective cause of diarrhoea. The important differential diagnosis in visitors to the tropics is giardiasis (see p. 46).
Management
Tetracycline 250 mg 6-hourly for 28 days is the treatment of choice and brings about long-term remission or cure. In most patients pharmacological doses of folic acid (5 mg daily) improve symptoms and jejunal morphology. In some cases treatment must be prolonged before improvement occurs, and occasionally patients must leave the tropics.
SMALL BOWEL BACTERIAL OVERGROWTH ('BLIND LOOP SYNDROME')
The normal duodenum and jejunum contain less than 104/ml organisms which are usually derived from saliva. The count of coliform organisms never exceeds 103/ml. In bacterial overgrowth there may be 108-1010/ml organisms, and these are bacteria which are normally found only in the colon. Disorders which impair the normal physiological mechanisms controlling bacterial proliferation in the intestine predispose to bacterial overgrowth (see Box 17.38). The most important are loss of gastric acidity, impaired intestinal motility and structural abnormalities which allow colonic bacteria to gain access to the small intestine or provide a secluded haven from the peristaltic stream.
Clinical features
The patient presents with watery diarrhoea and/or steatorrhoea with anaemia due to B12 deficiency. These arise because of deconjugation of bile acids, which impairs micelle formation, and because of bacterial utilisation of vitamin B12. There may also be symptoms from the underlying intestinal cause.
17.38 CAUSES OF SMALL BOWEL BACTERIAL OVERGROWTH
Mechanism Examples
Hypo- or achlorhydria Pernicious anaemia
Partial gastrectomy
Long-term proton pump inhibitor therapy
Impaired intestinal motility Scleroderma
Diabetic autonomic neuropathy
Chronic intestinal pseudo-obstruction
Structural abnormalities Gastric surgery (blind loop after Billroth II operation)
Jejunal diverticulosis
Enterocolic fistulae (e.g. Crohn's disease)
Extensive small bowel resection
Strictures (e.g. Crohn's disease)
Impaired immune function Hypogammaglobulinaemia

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Figure 17.37 Early rise in breath hydrogen in small bowel bacterial overgrowth. Breath samples are analysed after ingestion of glucose. Bacteria within the small bowel release hydrogen as the glucose is digested.
Investigations
Serum vitamin B12 concentration is low, whilst folate levels are normal or elevated because the bacteria produce folic acid. Barium follow-through or small bowel enema may reveal blind loops or fistulae. Endoscopic duodenal biopsies exclude mucosal disease such as coeliac disease. During endoscopy, aspiration of jejunal contents for bacteriological examination is carried out; the laboratory analysis requires anaerobic and aerobic culture techniques. The diagnosis can often be made non-invasively using the glucose hydrogen or 14C-glycocholic acid breath tests. In these tests breath samples are serially measured after oral ingestion of the test material. Bacteria within the small bowel cause an early rise in breath hydrogen from glucose (see Fig. 17.37) or 14C from 14C-glycocholate.
Management
The underlying cause of small bowel bacterial overgrowth should be addressed. Tetracycline 250 mg 6-hourly for 7 days is the treatment of choice, although up to 50% of patients do not respond adequately. Metronidazole 400 mg 8-hourly or ciprofloxacin 250 mg 12-hourly are alternatives. Some patients require up to 4 weeks of treatment and, in a few, continuous rotating courses of antibiotics are necessary. Intramuscular vitamin B12 supplementation is needed in chronic cases.
Some specific causes of bacterial overgrowth (see Box 17.38)
Jejunal diverticulosis
This is sometimes seen on barium follow-through examinations in patients over the age of 50 years. The diverticula are usually asymptomatic but predispose to bacterial over-growth and subsequent malabsorption. Rarely, they may cause acute or chronic gastrointestinal bleeding, obstruction or perforation.
Diabetic diarrhoea
This results from diabetic autonomic neuropathy (see p. 676), which reduces small bowel motility and affects enterocyte secretion. In some diabetic patients coexisting pancreatic insufficiency or coeliac disease may be responsible. The diarrhoea is watery. It may be continuous or interrupted by bouts of constipation. It is often worse at night, frequently associated with faecal incontinence and may be refractory to antidiarrhoeal drugs. Treatment with antibiotics may be helpful but antidiarrhoeal drugs (diphenoxylate 5 mg 8-hourly orally or loperamide 2 mg 4-6-hourly orally) or opiates are usually needed. The a2-adrenergic agonist clonidine (50-100 µg 8-hourly) or the somatostatin analogue octreotide may benefit some patients.
Progressive systemic sclerosis (scleroderma)
The circular and longitudinal layers of the intestinal muscle are fibrosed, motility is abnormal and malabsorption due to bacterial overgrowth is common. The patient may also have features of chronic intestinal pseudo-obstruction (see p. 1037).
Hypogammaglobulinaemia
This rare disorder is characterised by a markedly reduced or absent IgA and IgM content in the serum and jejunal secretions. Chronic diarrhoea, malabsorption and respiratory infections are common. Diarrhoea is due to bacterial over-growth and recurrent gastrointestinal infections (particularly giardiasis).
The diagnosis is made by measurement of serum immunoglobulins and by intestinal biopsy which shows reduced or absent plasma cells and nodules of lymphoid tissue (nodular lymphoid hyperplasia). Some patients have the histological features of coeliac disease. Treatment involves control of giardiasis (see p. 46) and, if necessary, regular parenteral replacement of immunoglobulins.
WHIPPLE'S DISEASE
This rare condition is characterised by infiltration of small intestinal mucosa by 'foamy' macrophages which stain positive with periodic acid-Schiff (PAS) reagent. The disease is a multisystem one and almost any organ can be affected, sometimes long before gastrointestinal involvement becomes apparent (see Box 17.39).
Electron microscopy reveals small Gram-positive bacilli (Tropheryma whippelli) within the macrophages. Villi are widened and flattened; densely packed macrophages occur in the lamina propria. These may obstruct lymphatic drainage, causing fat malabsorption.
Clinical features
Middle-aged men are most commonly affected and the presentation depends on the pattern of organ involvement. Low-grade fever is common and most patients have joint symptoms to some degree. Occasionally, neurological manifestations may predominate.
Management
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17.39 CLINICAL FEATURES OF WHIPPLE'S DISEASE
Gastrointestinal
Diarrhoea, steatorrhoea, weight loss, bloating, protein-losing enteropathy, ascites, hepatosplenomegaly (<5%)
Musculoskeletal
Seronegative large joint arthropathy, sacroiliitis
Cardiac
Pericarditis (10%), myocarditis, endocarditis, coronary arteritis
Neurological
Apathy, fits, dementia, myoclonus, meningitis, cranial nerve lesions
Pulmonary
Chronic cough, pleurisy, pulmonary infiltrates
Haematological
Anaemia, lymphadenopathy
Other
Fever, pigmentation


Whipple's disease is often fatal if untreated but responds well, at least initially, to penicillin, tetracycline or sulphonamides. Symptoms resolve within a week and biopsy changes revert to normal in a few weeks. Long-term follow-up is essential, as relapse occurs in up to one-third of patients. This often occurs within the central nervous system, in which case 2 weeks of parenteral penicillin and co-trimoxazole, followed by 6-12 months of oral co-trimoxazole, are necessary.
INTESTINAL RESECTION
The long-term effects of small bowel resection depend on the site and the amount of intestine resected, and vary from trivial to life-threatening.
Ileal resection
This usually occurs following surgery for Crohn's disease. Vitamin B12 and bile salt malabsorption develops (see Fig. 17.38). Unabsorbed bile salts pass into the colon, stimulating water and electrolyte secretion and resulting in diarrhoea. If hepatic synthesis of new bile salts cannot keep pace with faecal losses, then fat malabsorption occurs. Another consequence is the formation of lithogenic bile, leading to gallstones. Renal calculi, rich in oxalate, develop. Normally, oxalate in the colon is bound to and precipitated by calcium. Unabsorbed bile salts preferentially bind calcium, leaving free oxalate to be absorbed with subsequent development of urinary oxalate calculi.
Patients have urgent watery diarrhoea or mild steatorrhoea. Contrast studies of the small bowel and tests of B12 and bile acid absorption (see pp. 760-761) are useful investigations. Parenteral vitamin B12 supplementation is necessary. Diarrhoea usually responds well to colestyramine, a resin which binds bile salts in the intestinal lumen. Aluminium hydroxide may also do this in those unable to tolerate colestyramine.
Massive resection (short bowel syndrome)
Short bowel syndrome is defined as malabsorption resulting from extensive small intestinal resection. Many factors determine the severity, including the extent and site of resection, the presence of underlying disease in the remaining intestine, the presence of the ileocaecal valve and the ability of the remaining small intestine to undergo 'adaptation'.
Aetiology and pathogenesis
The syndrome has many causes (see Box 17.40) but in adults it usually results from extensive surgery undertaken for Crohn's disease or mesenteric infarction.


Figure 17.38 Consequences of ileal resection.
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17.40 AETIOLOGY OF SHORT BOWEL SYNDROME
Children
Congenital anomalies (e.g. mid-gut volvulus, atresia)
Necrotising enterocolitis
Adults
Crohn's disease
Mesenteric infarction
Radiation enteritis
Volvulus


Loss of surface area for digestion and absorption is the key problem. These processes are normally completed within the first 100 cm of jejunum, and enteral feeding is usually possible if this amount of small intestine remains. The proximal small bowel normally reabsorbs around 8 of the 9 litres of fluid it receives daily, and patients with a high jejunostomy are at great risk of hypovolaemia, dehydration and electrolyte losses. The presence of some or all of the colon may markedly improve these losses by increased water reabsorption. The presence of an intact ileocaecal valve ameliorates the clinical picture by slowing small intestinal transit and reducing bacterial overgrowth. The remaining small bowel mucosa undergoes 'adaptation', whereby mucosal hyperplasia over months or years increases the effective surface area for absorption.
Clinical features
Severely affected patients have large volumes of jejunostomy fluid losses or, if the colon is preserved, diarrhoea and steatorrhoea. Dehydration and signs of hypovolaemia are common, as are weight loss, loss of muscle bulk and malnutrition. Some patients remain in satisfactory but precarious fluid balance until a minor intercurrent illness or intestinal upset occurs, when they can rapidly become dehydrated.
Management
In the immediate post-operative period, total parenteral nutrition (TPN) is started. Proton pump inhibitor therapy is given to reduce gastric secretions. Enteral feeding is cautiously introduced after 1-2 weeks under careful supervision and is slowly increased as tolerated.
The principles of long-term management are:
Detailed nutritional assessments at regular intervals.
Monitoring of fluid and electrolyte balance. Patients can usually be taught how to do this for themselves. A readily available supply of oral rehydration solution is useful for intercurrent illness.
Adequate calorie and protein intake. Fats are a good energy source and should be taken as tolerated. Medium-chain triglyceride supplements are often given first because they are more easily absorbed.
Replacement of B12, calcium, vitamin D, magnesium, zinc and folic acid.
Antidiarrhoeal agents, e.g. loperamide (2-4 mg 6-hourly) or codeine phosphate (30 mg 4-6-hourly).

Some patients are unable to maintain positive fluid balance. Octreotide (50-200 µg 8-12-hourly by subcutaneous injection) reduces gastrointestinal secretions and is useful in such individuals. Despite these measures, some patients require long-term home TPN for survival and this is best managed in specialist centres. Small bowel transplantation is an option in some patients but rejection and 'graft-versus-host' disease (see p. 934) remain significant hurdles to be overcome.
RADIATION ENTERITIS AND PROCTOCOLITIS
Intestinal damage occurs in 10-15% of patients undergoing radiotherapy for abdominal or pelvic malignancy. The risk varies with total dose, dosing schedule and the use of concomitant chemotherapy.
Pathology
The rectum, sigmoid colon and terminal ileum are most frequently involved. Radiation causes acute inflammation, shortening of villi, oedema and crypt abscess formation. These usually resolve completely but in some patients an obliterative endarteritis affecting the endothelium of submucosal arterioles develops over 2-12 months. Fibroblastic proliferation produces progressive ischaemic fibrosis over years and may lead to adhesions, ulceration, strictures, obstruction or fistula to adjacent organs.
Clinical features
In the acute phase there is nausea, vomiting, cramping abdominal pain and diarrhoea. When the rectum and colon are involved, rectal mucus, bleeding and tenesmus occur. The chronic phase develops after 5-10 years in some patients and produces one or more of the problems listed in Box 17.41.
17.41 CHRONIC COMPLICATIONS OF INTESTINAL IRRADIATION
Proctocolitis
Bleeding from telangiectasia
Small bowel strictures
Fistulae-rectovaginal, colovesical, enterocolic
Adhesions
Malabsorption-bacterial overgrowth, bile salt malabsorption (ileal damage)


Investigations
In the acute phase the rectal changes at sigmoidoscopy resemble those of ulcerative proctitis (see Fig. 17.50, p. 813). The extent of the lesion is determined by colonoscopy. Barium follow-through examination shows small bowel strictures, ulcers and fistulae.
Management
Diarrhoea in the acute phase is treated with codeine phosphate, diphenoxylate or loperamide in standard dosage. Local steroid enemas help proctitis, and antibiotics may be required for bacterial overgrowth. Nutritional supplements are necessary when malabsorption is present. Colestyramine (4 g as a single sachet) is useful for bile salt malabsorption. Endoscopic laser or argon plasma coagulation therapy may reduce bleeding from proctitis. Surgery should be avoided, if possible, because the injured intestine is difficult to resect and anastomose, but it may be necessary for obstruction, perforation or fistula.
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ABETALIPOPROTEINAEMIA
This rare autosomal recessive disorder results from deficiency of apolipoprotein B and subsequent failure of chylomicron formation. It leads to fat malabsorption and deficiency of fat-soluble vitamins. Jejunal biopsy reveals enterocytes distended with resynthesised triglyceride and normal villous morphology. Serum cholesterol and triglyceride levels are low. A number of other abnormalities occur in this syndrome, including acanthocytosis, retinitis pigmentosa and a progressive neurological disorder with cerebellar and dorsal column signs. Symptoms may be improved by a low-fat diet supplemented with medium-chain triglycerides and vitamins A, D, E and K.
ISSUES IN OLDER PEOPLE
MALABSORPTION
The following apply to coeliac disease in old age:
It tends to present with vague symptoms such as dyspepsia or isolated folate or iron deficiency; only 25% present classically with diarrhoea and weight loss.
Severe osteopenia and osteomalacia, or bleeding due to hypothrombinaemia are more common than in the young.
Small bowel lymphoma is more common when coeliac disease develops in the elderly.
Small bowel bacterial overgrowth is more prevalent in older than younger people because:
atrophic gastritis resulting in hypo- or achlorhydria becomes more prevalent with age
jejunal diverticulosis is prevalent in old age
the long-term effects of gastric surgery for ulcer disease are now being seen in older people.


MOTILITY DISORDERS
CHRONIC INTESTINAL PSEUDO-OBSTRUCTION
Small intestinal motility is disordered in conditions which affect the smooth muscle or nerves of the intestine. Many cases are 'primary' (idiopathic), while others are 'secondary' to a variety of disorders or drugs (see Box 17.42).
Clinical features
17.42 CAUSES OF CHRONIC INTESTINAL PSEUDO-OBSTRUCTION
Primary or idiopathic
Rare familial visceral myopathies or neuropathies
Congenital aganglionosis
Secondary
Drugs, e.g. opiates, tricyclic antidepressants, phenothiazines
Smooth muscle disorders, e.g. scleroderma, amyloidosis, mitochondrial myopathies
Myenteric plexus disorders, e.g. paraneoplastic syndrome in small-cell lung cancer
CNS disorders, e.g. Parkinsonism, autonomic neuropathy
Endocrine and metabolic disorders, e.g. hypothyroidism, phaeochromocytoma, acute intermittent porphyria


There are recurrent episodes of nausea, vomiting, abdominal discomfort and distension, often worse after food. Alternating constipation and diarrhoea occur and weight loss results from malabsorption (due to bacterial overgrowth) and fear of eating. There may also be symptoms of dysmotility affecting other parts of the gastrointestinal tract, e.g. dysphagia, and, in primary cases, features of bladder dysfunction. Some patients have obscure but severe abdominal pain which is extremely difficult to manage.
Investigations
The diagnosis is often delayed and a high index of suspicion is needed. Plain radiographs show distended loops of bowel and air-fluid levels but barium studies demonstrate no mechanical obstruction. Laparotomy is sometimes performed to exclude obstruction and to obtain full-thickness biopsies of the intestine. Electron microscopy, histochemistry and special stains define rare, specific syndromes.
Management
This is often difficult. Underlying causes should be addressed and further surgery avoided if at all possible. Metoclopramide or domperidone may enhance motility, and antibiotics are given for bacterial overgrowth. Nutritional and psychological support are also necessary.
MISCELLANEOUS DISORDERS OF THE SMALL INTESTINE
PROTEIN-LOSING ENTEROPATHY
This term is used when there is excessive loss of protein into the gut lumen, sufficient to cause hypoproteinaemia. Less than 10% of plasma protein is normally lost from the gastrointestinal tract. Protein-losing enteropathy occurs in many gut disorders but is most common in those where ulceration occurs (see Box 17.43). In other disorders protein loss results from increased mucosal permeability or obstruction of intestinal lymphatic vessels.
Patients present with peripheral oedema and hypoproteinaemia in the presence of normal liver function and without proteinuria. There may also be features of the underlying cause.
17.43 CAUSES OF PROTEIN-LOSING ENTEROPATHY
With mucosal erosions or ulceration
Crohn's disease
Ulcerative colitis
Radiation damage
Oesophageal, gastric or colonic cancer
Lymphoma

Without mucosal erosions or ulceration
Ménétrier's disease
Bacterial overgrowth
Coeliac disease
Tropical sprue
Eosinophilic gastroenteritis
Systemic lupus erythematosus

With lymphatic obstruction
Intestinal lymphangiectasia
Constrictive pericarditis
Lymphoma
Whipple's disease


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The diagnosis is confirmed by measurement of faecal clearance of a1-antitrypsin or 51Cr-labelled albumin after intravenous injection. Other investigations are performed to determine the underlying cause. Treatment is that of the underlying disorder, nutritional support and measures to control peripheral oedema.
INTESTINAL LYMPHANGIECTASIA
This may be primary, resulting from congenital malunion of lymphatics, or secondary to lymphatic obstruction due to lymphoma, filariasis or constrictive pericarditis. Impaired drainage of intestinal lymphatic vessels leads to discharge of protein and fat-rich lymph into the gastrointestinal lumen. The condition presents with peripheral lymphoedema, pleural effusions or chylous ascites, and steatorrhoea. Investigations reveal hypoalbuminaemia, lymphocytopenia and reduced serum immunoglobulin concentrations. Jejunal biopsies show greatly dilated lacteals, and lymphangiography shows lymphatic obstruction. Treatment consists of a low-fat diet with medium-chain triglyceride supplements.
ULCERATION OF THE SMALL INTESTINE
Small bowel ulcers are uncommon and are either idiopathic or secondary to underlying intestinal disorders (see Box 17.44).
Ulcers are more common in the ileum, and cause bleeding, perforation, stricture formation or obstruction. Barium studies and enteroscopy confirm the diagnosis.
17.44 CAUSES OF SMALL INTESTINAL ULCERS
Idiopathic
Inflammatory bowel disease, e.g. Crohn's
Drugs, e.g. NSAIDs, enteric-coated potassium tablets
Ulcerative jejunoileitis
Lymphoma and carcinoma
Infections, e.g. tuberculosis, typhoid, Yersinia
Others, e.g. radiation, vasculitis


EOSINOPHILIC GASTROENTERITIS
This disorder of unknown aetiology can affect any part of the gastrointestinal tract; it is characterised by eosinophil infiltration affecting the gut wall in the absence of parasitic infection or eosinophilia of other tissues. Peripheral blood eosinophilia is present in 80% of cases.
Inflammation and destruction affect mucosal, muscular and/or serosal layers.
Clinical features
There are features of obstruction and inflammation, such as colicky pain, nausea and vomiting, diarrhoea and weight loss. Protein-losing enteropathy occurs and up to 50% of patients have a history of other allergic disorders. Serosal involvement may produce eosinophilic ascites.
Diagnosis and management
The diagnosis is made by histological assessment of multiple endoscopic biopsies, although full-thickness biopsies are occasionally required. Other investigations are performed to exclude parasitic infection and other causes of eosinophilia. A raised serum IgE concentration is often seen.
Dietary manipulations are rarely effective although elimination diets, especially of milk, may benefit a few patients. Severe symptoms are treated with prednisolone 20-40 mg daily and/or sodium cromoglicate, which stabilises mast cell membranes. The prognosis is good in the majority of patients.
MECKEL'S DIVERTICULUM
This is the most common congenital anomaly of the gastrointestinal tract and occurs in 0.3-3% of people. Most patients are asymptomatic. The diverticulum results from failure of closure of the vitelline duct, with persistence of a blind-ending sac arising from the antimesenteric border of the ileum; it usually occurs within 100 cm of the ileocaecal valve, and is up to 5 cm long. Approximately 50% contain ectopic gastric mucosa; rarely, colonic, pancreatic or endometrial tissue is present.
Complications most commonly occur in the first 2 years of life but are occasionally seen in young adults. Bleeding results from ulceration of ileal mucosa adjacent to the ectopic parietal cells and presents as recurrent melaena or altered blood per rectum. Diagnosis can be made by scanning the abdomen using a gamma counter following an intravenous injection of 99m-technetium pertechnate, which is concentrated by ectopic parietal cells. Other complications include intestinal obstruction, diverticulitis, intussusception and perforation. Intervention is unnecessary unless complications occur. The vast majority of patients remain asymptomatic throughout life.
ADVERSE FOOD REACTIONS
Adverse food reactions are common and are subdivided into food intolerance and food allergy, the former being much more common.
FOOD INTOLERANCE
This involves adverse reactions to food which are not immune-mediated and result from a wide range of mechanisms. Contaminants in food, preservatives and lactase deficiency may all be involved.
LACTOSE INTOLERANCE
Human milk contains around 200 mmol/l of lactose which is normally digested to glucose and galactose by the brush border enzyme lactase prior to absorption. In most populations enterocyte lactase activity declines throughout childhood. The enzyme is deficient in up to 90% of adult Africans, Asians and South Americans, but only 5% of northern Europeans.
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In cases of racially determined (primary) lactase deficiency, jejunal morphology is normal. 'Secondary' lactase deficiency occurs as a consequence of disorders which damage the jejunal mucosa, e.g. coeliac disease and viral gastroenteritis. Unhydrolysed lactose enters the colon, where bacterial fermentation produces volatile short-chain fatty acids, hydrogen and carbon dioxide.
Clinical features
In most people lactase deficiency is completely asymptomatic. However, some complain of colicky pain, abdominal distension, increased flatus, borborygmi and diarrhoea after ingesting milk or milk products. Irritable bowel syndrome is often suspected but the diagnosis is suggested by clinical improvement on lactose withdrawal. The lactose hydrogen breath test is a useful non-invasive confirmatory investigation.
Dietary exclusion of lactose is recommended, although most sufferers are able to tolerate small amounts of milk without symptoms. Addition of commercial lactase preparations to milk has been effective in some studies but is costly.
DIARRHOEA DUE TO OTHER SUGARS
'Osmotic' diarrhoea can be caused by sorbitol, an unabsorbable carbohydrate which is used as an artificial sweetener. Fructose may also cause diarrhoea if consumed in greater quantities (e.g. in fruit juices) than can be absorbed.
FOOD ALLERGY
Food allergies are immune-mediated disorders due to IgE antibodies and type 1 hypersensitivity reactions. Up to 20% of the population perceive themselves as suffering from food allergy but only 1-2% of adults have genuine food allergies. The most common culprits are peanuts, milk, eggs, soya and shellfish.
Clinical manifestations occur immediately on exposure and range from trivial to life-threatening or even fatal anaphylaxis. In the 'oral allergy syndrome' contact with certain fresh fruit juices results in urticaria and angio-oedema of the lips and oropharynx. 'Allergic gastroenteropathy' has features similar to eosinophilic gastroenteritis, while 'gastrointestinal anaphylaxis' consists of nausea, vomiting, diarrhoea and sometimes cardiovascular and respiratory collapse. Fatal reactions to trace amounts of peanuts are well documented.
The diagnosis of food allergy is difficult to prove or refute. Skin prick tests and measurements of antigen-specific IgE antibodies in serum have limited predictive value. Double-blind placebo-controlled food challenges are the gold standard, but are laborious and are not readily available. In many cases clinical suspicion and trials of elimination diets are used.
Treatment of proven food allergy consists of detailed patient education and awareness, strict elimination of the offending antigen and in some cases antihistamines or sodium cromoglicate. Anaphylaxis should be treated as a medical emergency with resuscitation, airway support and intravenous adrenaline (epinephrine). Teachers and other carers of affected children should be trained in this. Patients should wear an information bracelet and be taught to carry and use a preloaded adrenaline (epinephrine) syringe.
INFECTIONS OF THE SMALL INTESTINE
TRAVELLERS' DIARRHOEA
See page 47.
GIARDIASIS
See page 46.
AMOEBIASIS
See page 45.
ABDOMINAL TUBERCULOSIS
Mycobacterium tuberculosis is a rare cause of abdominal disease in Caucasians but must be considered in immigrants from the underdeveloped world and in AIDS patients. Gut infection usually results from human M. tuberculosis which is swallowed after coughing. Many patients have no pulmonary symptoms and a normal chest radiograph.
The area most commonly affected is the ileocaecal region; presentation and radiological findings may be very similar to those of Crohn's disease. Abdominal pain can be acute or of several months' duration, but diarrhoea is less common in tuberculosis (TB) than in Crohn's disease. Low-grade fever is common but not invariable. Like Crohn's disease, TB can affect any part of the gastrointestinal tract, and perianal disease with fistula is recognised. Peritoneal TB may result in peritonitis with exudative ascites, associated with abdominal pain and fever. Granulomatous hepatitis occurs.
Diagnosis
Abdominal TB causes an elevated erythrocyte sedimentation rate (ESR); a raised serum alkaline phosphatase concentration suggests hepatic involvement. Histological confirmation is sought by endoscopy, laparoscopy or liver biopsy. Caseation of granulomata is not always seen and acid- and alcohol-fast bacteria are often scanty. Culture may be helpful but identification of the organism may take 6 weeks.
Management
When the presentation is very suggestive of abdominal TB, chemotherapy with four drugs, isoniazid, rifampicin, pyrazinamide and ethambutol (see p. 538), should be commenced even if bacteriological or histological proof is lacking.
CRYPTOSPORIDIOSIS
Cryptosporidiosis and other protozoal infections, including isosporiasis (Isospora belli) and microsporidiosis, are dealt with on pages 47 and 118-119.
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TUMOURS OF THE SMALL INTESTINE
The small intestine is rarely affected by neoplasia, and fewer than 5% of all gastrointestinal tumours occur here.
Benign tumours
The most common are adenomas, GIST, lipomas and hamartomas. Adenomas are most often found in the periampullary region and are usually asymptomatic, although occult bleeding or obstruction due to intussusception may occur. Transformation to adenocarcinoma is rare. Multiple adenomas are common in the duodenum of patients with familial adenomatous polyposis (FAP), who merit regular endoscopic surveillance. Hamartomatous polyps with almost no malignant potential occur in Peutz-Jeghers syndrome (see p. 822).
Malignant tumours
These are rare and include, in decreasing order of frequency, adenocarcinoma, carcinoid tumour, malignant GIST and lymphoma. The majority occur in middle age or later. Kaposi's sarcoma is seen in patients with AIDS.
Adenocarcinomas occur with increased frequency in patients with FAP, coeliac disease and Peutz-Jeghers syndrome. The non-specific presentation and rarity of these lesions often lead to delay in diagnosis. Barium follow-through examination or small bowel enema studies will demonstrate most lesions of this type. Enteroscopy, mesenteric angiography and CT also play a role in investigation.
CARCINOID TUMOURS
These are derived from enterochromaffin cells and are most common in the ileum. Localised spread and the potential for metastasis to the liver increase with primary lesions over 2 cm in diameter. Carcinoid tumours also occur in the rectum and in the appendix; those in the latter are usually benign. Overall, these tumours are less aggressive than carcinomas and their growth is usually slow.
The term 'carcinoid syndrome' refers to the systemic symptoms produced when secretory products of the neoplastic enterochromaffin cells reach the systemic circulation (see Box 17.45). When produced by the primary tumour they are usually metabolised in the liver and do not reach the systemic circulation. The syndrome is therefore only seen when 5-hydroxytryptamine (5-HT, serotonin), bradykinin and other peptide hormones are released by hepatic metastases.
Management
17.45 CLINICAL FEATURES OF THE CARCINOID SYNDROME
Small-bowel obstruction due to the tumour mass
Intestinal ischaemia (due to mesenteric infiltration or vasospasm)
Hepatic metastases causing pain, hepatomegaly and jaundice
Flushing and wheezing
Diarrhoea
Cardiac involvement (tricuspid regurgitation, pulmonary stenosis, right ventricular endocardial plaques) leading to heart failure
Facial telangiectasia
The diagnosis is made by detecting excess levels of the 5-HT metabolite, 5-HIAA, in a 24-hour urine collection.

The treatment of a carcinoid tumour is surgical resection. The treatment of carcinoid syndrome is palliative because hepatic metastases have occurred, although prolonged survival is common. Surgical removal of the primary tumour is usually attempted and the hepatic metastases can be excised as reduction of tumour mass improves symptoms. Hepatic artery embolisation retards growth of hepatic deposits. Octreotide 200 µg 8-hourly by subcutaneous injection is used to reduce tumour release of secretagogues. Cytotoxic chemotherapy has only a minor role.
LYMPHOMA
Non-Hodgkin's lymphoma (see p. 940) may involve the gastrointestinal tract as part of more generalised disease or may rarely arise in the gut, with the small intestine being most commonly affected. Lymphomas occur with increased frequency in patients with coeliac disease, AIDS and other immunodeficiency states. Most are of B-cell origin, although lymphoma associated with coeliac disease is derived from T cells (enteropathy-associated T-cell lymphoma).
Colicky abdominal pain, obstruction and weight loss are the usual presenting features and perforation is also occasionally seen. Malabsorption is only a feature of diffuse bowel involvement and hepatosplenomegaly is rare.
The diagnosis is made by small bowel biopsy, radiological contrast studies and CT. Staging investigations are performed. Surgical resection where possible is the treatment of choice, with radiotherapy and combination chemotherapy reserved for those with advanced disease. The prognosis depends largely on the stage at diagnosis, cell type, patient age and the presence of 'B' symptoms.
IMMUNOPROLIFERATIVE SMALL INTESTINAL DISEASE (IPSID)
Also known as 'alpha heavy chain disease', this rare condition occurs mainly in the Mediterranean, Middle East, India and Pakistan, and North America. The aetiology is unknown but it may be a response to chronic stimulation by bacterial antigens. The condition varies in severity from relatively benign to frankly malignant.
The small intestinal mucosa is diffusely affected, especially proximally, by a dense lymphoplasmacytic infiltrate. Enlarged mesenteric lymph nodes are also common. Most patients are young adults who present with malabsorption, anorexia and fever. Serum electrophoresis confirms the presence of alpha heavy chains (from the Fc portion of IgA). Prolonged remissions can be obtained with long-term antibiotic therapy but chemotherapy is required for those who fail to respond or who have aggressive disease.

pages 792 - 801


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > DISEASES OF THE PANCREAS
DISEASES OF THE PANCREAS
ACUTE PANCREATITIS
Acute pancreatitis accounts for 3% of all cases of abdominal pain admitted to hospital. It affects 2-28 per 100 000 of the population and may be increasing in incidence.
Pathophysiology
Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of regional tissues and remote organ systems. It occurs as a consequence of premature activation of zymogen granules, releasing proteases which digest the pancreas and surrounding tissue (see Fig. 17.39). The normal pancreas has only a poorly developed capsule, and adjacent structures, including the common bile duct, duodenum, splenic vein and transverse colon, are commonly involved in the inflammatory process. The severity of acute pancreatitis is dependent upon the balance between activity of released proteolytic enzymes and antiproteolytic factors. The latter comprise an intracellular pancreatic trypsin inhibitor protein and circulating ß2-macroglobulin, a1-antitrypsin and Cl-esterase inhibitors. Causes of acute pancreatitis are given in Box 17.46.
Acute pancreatitis may be mild, with minimal organ dysfunction and uneventful recovery. Alternatively, it may be severe and associated with local complications such as necrosis (often with infection), pseudocyst or abscess, and systemic complications leading to multi-organ failure.


Figure 17.39 Pathophysiology of acute pancreatitis.
17.46 CAUSES OF ACUTE PANCREATITIS
Common (90% of cases)
Gallstones
Alcohol
Idiopathic
Post-ERCP

Rare
Post-surgical (abdominal, cardiopulmonary bypass)
Trauma
Drugs (azathioprine, thiazide diuretics, sodium valproate)
Metabolic (hypercalcaemia, hypertriglyceridaemia)
Pancreas divisum (see p. 806)
Infection (mumps, Coxsackie virus)
Hereditary
Renal failure
Organ transplantation (kidney, liver)
Severe hypothermia


Clinical features
Severe, constant upper abdominal pain which radiates to the back in 65% of cases builds up over 15-60 minutes. Nausea and vomiting are common. There is marked epigastric tenderness but in the early stages (and in contrast to a perforated peptic ulcer), guarding and rebound tenderness are absent because the inflammation is principally retroperitoneal. Bowel sounds become quiet or absent as paralytic ileus develops.
In severe cases the patient becomes hypoxic and develops hypovolaemic shock with oliguria. Discoloration of the flanks (Grey Turner's sign) or the periumbilical region (Cullen's sign) are features of severe pancreatitis with haemorrhage. The differential diagnosis includes a perforated viscus, acute cholecystitis and myocardial infarction.
Complications


Figure 17.40 CT showing large pancreatic pseudocyst (arrow) developing from the body of the pancreas.
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17.47 COMPLICATIONS OF ACUTE PANCREATITIS
Complication Cause
Systemic
Systemic inflammatory response syndrome (SIRS): renal failure Increased vascular permeability from cytokine, platelet aggregating factor and kinin release, paralytic ileus, vomiting
Hypoxia Acute respiratory distress syndrome (ARDS) due to microthrombi in pulmonary vessels
Hyperglycaemia Disruption of islets of Langerhans with altered insulin/glucagon axis
Hypocalcaemia Sequestration of calcium in fat necrosis, fall in ionised calcium (? cause)
Reduced serum albumin concentration Increased capillary permeability
Pancreatic
Necrosis Non-viable pancreatic tissue and peripancreatic tissue death; frequently infected
Abscess Circumscribed collection of pus close to the pancreas and containing little or no pancreatic necrotic tissue
Pseudocyst Disruption of pancreatic ducts
Pancreatic ascites or pleural effusion Disruption of pancreatic ducts
Gastrointestinal
Upper gastrointestinal bleeding Gastric or duodenal erosions
Variceal haemorrhage Splenic or portal vein thrombosis
Erosion into colon
Duodenal obstruction Compression by pancreatic mass
Obstructive jaundice Compression of common bile duct

These are listed in Box 17.47. An acute pancreatic pseudocyst is a localised extrapancreatic collection of pancreatic juice and debris which usually develops in the lesser sac following inflammatory rupture of the pancreatic duct. The pseudocyst is initially contained within a poorly defined, fragile wall of granulation tissue which matures over a 6-week period to form a fibrous capsule (see Fig. 17.40). Small intrapancreatic cysts and pseudocysts are common features of both acute and chronic pancreatitis; they are usually asymptomatic and resolve as the pancreatitis recovers. Pseudocysts greater than 6 cm in diameter seldom disappear spontaneously. Large pseudocysts cause constant abdominal pain, can produce a palpable abdominal mass and may compress or erode surrounding structures including blood vessels to form pseudoaneurysms.
Pancreatic ascites occurs when fluid leaks from a disrupted pancreatic duct into the peritoneal cavity. Leakage into the thoracic cavity can result in a pleural effusion or a broncho-pancreatic fistula.
Diagnosis
The diagnosis of acute pancreatitis is based upon elevation of serum amylase or lipase concentrations and ultrasound or CT evidence of pancreatic swelling. Plain radiographs are taken to exclude other diagnoses such as perforation or obstruction and to identify pulmonary complications.
Amylase is efficiently excreted by the kidneys, and concentrations may have returned to normal if measured 24-48 hours after the onset of pancreatitis. In this situation the diagnosis can be made by demonstrating an elevated urinary amylase:creatinine ratio. A persistently elevated serum amylase concentration suggests pseudocyst formation. Peritoneal amylase concentrations are massively elevated in pancreatic ascites. Serum amylase concentrations are also elevated (but to a lesser extent) in intestinal ischaemia, perforated peptic ulcer and ruptured ovarian cyst, and the salivary isoenzyme of amylase is elevated in parotitis.
Ultrasound scanning confirms the diagnosis, although in the earlier stages the gland may not be grossly swollen. The ultrasound scan is also useful because it may show gallstones, biliary obstruction or pseudocyst formation.
CT between 3 and 10 days after admission is used to define the viability of the pancreas. Necrotising pancreatitis is associated with decreased pancreatic enhancement following intravenous injection of contrast material. The presence of gas within necrotic material suggests infection and impending abscess formation, in which case percutaneous aspiration of material for bacterial culture should be carried out. Involvement of the colon, blood vessels and other adjacent structures by the inflammatory process is best seen by CT.
Certain investigations stratify the severity of acute pancreatitis and have important prognostic value at the time of presentation (see Box 17.48). In addition, serial assessment of C-reactive protein (CRP) is a useful indicator of progress. A peak CRP >210 mg/l in the first 4 days predicts severe acute pancreatitis with 80% accuracy. It is worth noting that the serum amylase concentration has no prognostic value.
Management
Management comprises several related steps:
establishing the diagnosis and stratifying disease severity
early treatment according to whether the disease is mild or severe
detection and treatment of complications
treating the underlying cause-specifically gallstones.

The initial management is based upon analgesia using pethidine and correction of hypovolaemia using normal saline and/or colloids. All severe cases should be managed in a high-dependency or intensive care unit. A central venous line or Swan-Ganz catheter and urinary catheter are used to monitor patients with shock. Hypoxic patients need oxygen and patients who develop ARDS may require ventilatory support. Hyperglycaemia is corrected using insulin, but it is not necessary to correct hypocalcaemia by intravenous calcium injection unless tetany occurs.
Nasogastric aspiration is only necessary if paralytic ileus is present. Enteral feeding via a nasoenteral tube should be started at an early stage in patients with severe pancreatitis. These patients are in a severely catabolic state and need nutritional support. In addition enteral feeding decreases endotoxaemia and thereby may reduce systemic complications. Prophylaxis of thromboembolism with low-dose subcutaneous heparin is also advisable. Prophylactic, broad-spectrum intravenous antibiotics such as imipenem or cefuroxime may improve outcome in severe cases.
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Patients who present with cholangitis or jaundice in association with severe acute pancreatitis should undergo urgent ERCP to diagnose and treat choledocholithiasis. In less severe cases of gallstone pancreatitis ERCP may be carried out after the acute phase has resolved.
EBM
ACUTE PANCREATITIS-role of nutritional support
'Clinical improvement in patients with acute pancreatitis is greater in those receiving nasojejunal tube feeding rather than total parenteral nutrition.'
Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998; 42:431-435.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

EBM
ACUTE PANCREATITIS-role of ERCP
'Emergency ERCP with biliary sphincterotomy and stone extraction when stones are identified in the common bile duct improves outcome in severe acute pancreatitis. Greatest benefit occurs in those patients who have ascending cholangitis.'
Neoptolemos JP, London NJ, James D, et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 1988; ii:979-983.
Fan ST, Lai ECS, Mok FPT, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 1993; 328:278-282.
Folsch UR, Nitsche R, Ludtke R, et al. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. N Engl J Med 1997; 336:237-242.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

Management of complications
Patients who have developed necrotising pancreatitis or pancreatic abscess require urgent surgical débridement of the pancreas, followed by drainage of the pancreatic bed. Pancreatic pseudocysts are treated by drainage into the stomach or duodenum. This is usually done after at least 6 weeks, once a pseudocapsule has matured, using open surgery or endoscopic methods.
Prognosis (see Box 17.48)
17.48 ADVERSE PROGNOSTIC FACTORS IN ACUTE PANCREATITIS (GLASGOW CRITERIA)
Age > 55 years
PO2 < 8 kPa
White blood cell count (WBC) > 15 × 109/litre
Albumin < 32 g/l
Serum calcium < 2 mmol/l (corrected)
Glucose > 10 mmol/l
Urea > 16 mmol/l (after rehydration)
Alanine aminotransferase (ALT) > 200 U/l
Lactate dehydrogenase (LDH) > 600 U/l


Despite recent advances in management, the mortality has remained unchanged at 10-15%. About 80% of all cases are mild with a mortality less than 5%; 98% of deaths occur in the 20% of severe cases. One-third occur within the first week, usually from multi-organ failure. After this time the majority of deaths result from sepsis, especially that complicating infected necrosis.
CHRONIC PANCREATITIS
Chronic pancreatitis is a chronic inflammatory disease characterised by fibrosis and destruction of exocrine pancreatic tissue. Diabetes mellitus occurs in advanced cases because the islets of Langerhans are involved.
Pathophysiology
Around 80% of cases in Western countries result from alcohol misuse (see Fig. 17.41). In southern India severe chronic calcific pancreatitis occurs in non-alcoholics, possibly as a result of malnutrition and dietary cassava consumption. Other causes are listed in Box 17.49.


Figure 17.41 Pathophysiology of chronic pancreatitis.
17.49 CAUSES OF CHRONIC PANCREATITIS
Calcific
Alcoholism
Tropical
Obstructive
Stenosis of the ampulla of Vater
Pancreas divisum (see p. 806)
Cystic fibrosis
Hereditary
Idiopathic
N.B. Many patients have gallstones but these do not cause chronic pancreatitis.

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Clinical features
Chronic pancreatitis predominantly affects middle-aged alcoholic men. Almost all present with abdominal pain. In 50% this occurs as episodes of 'acute pancreatitis', although each attack results in a degree of permanent pancreatic damage. Relentless, slowly progressive chronic pain without acute exacerbations affects 35% of patients, whilst the remainder have no pain but present with diarrhoea. Pain is due to a combination of increased pressure within the pancreatic ducts and direct involvement of pancreatic and peripancreatic nerves by the inflammatory process. Pain may be relieved by leaning forwards or by drinking alcohol. Approximately one-fifth of patients chronically consume opiate analgesics.
Weight loss is common and results from a combination of anorexia, avoidance of food because of post-prandial pain, malabsorption and/or diabetes. Steatorrhoea occurs when more than 90% of the exocrine tissue has been destroyed; protein malabsorption only develops in the most advanced cases. Overall, 30% of patients are diabetic, but this figure rises to 70% in those with chronic calcific pancreatitis.
Physical examination reveals a thin, malnourished patient with epigastric tenderness. Skin pigmentation over the abdomen and back is common and results from chronic use of a hot water bottle (erythema ab igne). Many patients have features of other alcohol- and smoking-related diseases.
Complications are listed in Box 17.50.
Investigations
17.50 COMPLICATIONS OF CHRONIC PANCREATITIS
Pseudocysts and pancreatic ascites, which occur in both acute and chronic pancreatitis
Extrahepatic obstructive jaundice due to a benign stricture of the common bile duct as it passes through the diseased pancreas
Duodenal stenosis
Portal or splenic vein thrombosis leading to segmental portal hypertension and gastric varices
Peptic ulcer


17.51 INVESTIGATIONS IN CHRONIC PANCREATITIS
Tests to establish the diagnosis
Ultrasound
CT (may show atrophy, calcification or ductal dilatation)
Abdominal radiograph (may show calcification)
ERCP only if non-invasive tests are negative or equivocal (see Fig. 17.42)
Endoscopic ultrasound
Tests of pancreatic function
Collection of pure pancreatic juice after secretin injection (gold standard but invasive and seldom used)
Pancreolauryl or PABA test (see p. 760)
Faecal pancreatic chymotrypsin or elastase
Oral glucose tolerance test
Tests of anatomy prior to surgery
ERCP (see Fig. 17.42)


Investigations (see Box 17.51) are carried out to:
make a diagnosis of chronic pancreatitis
define pancreatic function
demonstrate anatomical abnormalities prior to surgical intervention.

Management
Alcohol misuse
Alcohol avoidance is crucial in halting the progression of the disease and reducing pain. Unfortunately, counselling and psychiatric intervention are rarely successful and the majority of patients continue to drink alcohol.
Pain relief
A range of analgesic drugs, particularly NSAIDs, are valuable, but the severe and unremitting nature of the pain often leads to opiate use with the risk of addiction. Oral pancreatic enzyme supplements suppress pancreatic secretion and their regular use reduces analgesic consumption in some patients.


Figure 17.42 ERCP in chronic pancreatitis. A Early pancreatitis with irregular dilated side branches (arrow). B Advanced disease. Dilated, irregular main duct (arrow A), with obstructed abnormal side branches (arrow B).
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17.52 INTERVENTION IN CHRONIC PANCREATITIS
Endoscopic therapy
Dilatation or stenting of main pancreatic duct
Removal of calculi (mechanical or shock-wave lithotripsy)
Surgical methods
Partial pancreatic resection, preserving the duodenum
Pancreatico-jejunostomy


Patients who are abstinent from alcohol and who have severe chronic pain which is resistant to conservative measures are considered for surgical or endoscopic pancreatic therapy (see Box 17.52). Coeliac plexus neurolysis or minimally invasive thoracoscopic splanchnicectomy sometimes produces long-lasting pain relief although relapse eventually occurs in the majority of cases.
In some patients ERCP does not show a surgically or endoscopically correctable abnormality and in these patients the only surgical approach is total pancreatectomy. Unfortunately, even after this operation, some patients will continue to experience pain. Moreover, the procedure causes diabetes which may be difficult to control, with a high risk of hypoglycaemia (since both insulin and glucagon release are absent), and this is a cause of significant morbidity and mortality.
Steatorrhoea
This is treated by dietary fat restriction (with supplementary medium-chain triglyceride therapy in malnourished patients) and oral pancreatic enzyme supplements. A proton pump inhibitor is added to optimise duodenal pH for pancreatic enzyme activity.
Diabetes
Diabetes requires carbohydrate restriction and insulin therapy.
Management of complications
Surgical or endoscopic therapy may be necessary for the management of pseudocysts, pancreatic ascites, common bile duct or duodenal stricture and the consequences of portal hypertension. Many patients with chronic pancreatitis also require treatment for other alcohol- and smoking-related diseases and for the consequences of self-neglect and malnutrition.
CONGENITAL ABNORMALITIES OF THE PANCREAS
PANCREAS DIVISUM
This is due to failure of the primitive dorsal and ventral ducts to fuse during embryonic development of the pancreas. As a consequence, most of the pancreatic drainage occurs through the smaller accessory ampulla rather than through the major ampulla.
Pancreas divisum occurs in 7-10% of the normal population and is usually asymptomatic. Some patients develop acute pancreatitis, chronic pancreatitis or atypical abdominal pain, possibly because drainage through the accessory papilla is restricted.
ANNULAR PANCREAS
In this congenital anomaly, the pancreas encircles the second/third part of the duodenum, leading to gastric outlet obstruction. Annular pancreas is associated with malrotation of the intestine, atresias and cardiac anomalies.
CYSTIC FIBROSIS
This disease is considered in detail on page 522. The gastro-intestinal manifestations of cystic fibrosis are pancreatic insufficiency and meconium ileus. Peptic ulcer, and hepatic and biliary disease also occur.
In cystic fibrosis pancreatic secretions are protein- and mucus-rich. The resultant viscous juice forms plugs which obstruct the pancreatic ductules, leading to progressive destruction of acinar cells. Steatorrhoea is universal and the large-volume bulky stools predispose to rectal prolapse. Malnutrition is compounded by the metabolic demands of respiratory failure and by diabetes which develops in 40% of patients by adolescence.
The majority of patients now survive well into adulthood and heart/lung transplantation can further prolong life. Optimal treatment of the cystic fibrosis patient depends upon an assiduous team approach to respiratory, nutritional and hepatobiliary complications. Nutritional counselling and supervision are important to ensure intake of high-energy foods, providing 120-150% of the recommended intake for normal subjects. Fats are an important calorie source and, despite the presence of steatorrhoea, fat intake should not be restricted. Supplementary fat-soluble vitamins are also necessary.
High-dose oral pancreatic enzymes are necessary, in doses sufficient to control steatorrhoea and stool frequency. A proton pump inhibitor aids fat digestion by producing an optimal duodenal pH. Diabetic patients usually require insulin injections rather than oral hypoglycaemic agents.
Meconium ileus
Mucus-rich plugs within intestinal contents can obstruct the small or large intestine. Meconium ileus is treated by the mucolytic agent N-acetylcysteine given orally, by gastrografin enema or by gut lavage using polyethylene glycol. In resistant cases of meconium ileus surgical resection may be necessary.
TUMOURS OF THE PANCREAS
Pancreatic carcinoma affects 10-15 per 100 000 in Western populations, rising to 100 per 100 000 in those over the age of 70. Men are affected twice as often as women. The disease is associated with smoking and chronic pancreatitis. Between 5 and 10% of patients have a genetic predisposition (hereditary pancreatitis, MEN, hereditary non-polyposis colon cancer-HNPCC).
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Pathology
Approximately 90% of pancreatic neoplasms are adenocarcinomas which arise from the pancreatic ducts. These tumours involve local structures and metastasise to regional lymph nodes at an early stage. The majority of patients have advanced disease at the time of presentation.
Ampullary or periampullary adenocarcinomas are rare neoplasms which arise from the ampulla of Vater or adjacent duodenum. These tumours are often polypoid and ulcerated. They infiltrate the duodenum but behave less aggressively than pancreatic adenocarcinoma.
Cystadenocarcinoma is a very rare, slowly growing tumour, usually arising from the head of the pancreas and characterised by mucinous cyst formation. It occurs most often in middle-aged women.
Clinical features


Figure 17.43 Features of pancreatic cancer.
The clinical features of pancreatic cancer are pain, weight loss and obstructive jaundice (see Fig. 17.43). The pain results from invasion of the coeliac plexus and is characteristically incessant and boring. It often radiates from the upper abdomen through to the back and may be eased a little by bending forwards. Almost all patients lose weight and many are cachectic. Weight loss is the consequence of anorexia, steatorrhoea and metabolic effects of the tumour. Around 60% of tumours arise from the head of the pancreas, and involvement of the common bile duct results in the development of obstructive jaundice, often with severe pruritus.
A few patients present with diarrhoea, vomiting from duodenal obstruction, diabetes mellitus, recurrent venous thrombosis, acute pancreatitis or depression.
Physical examination reveals clear evidence of weight loss. An abdominal mass due to the tumour itself, a palpable gallbladder or hepatic metastasis is commonly found. A palpable gallbladder in a jaundiced patient is usually the consequence of distal biliary obstruction by a pancreatic cancer (Courvoisier's sign).
Investigations
When a patient presents with biochemically confirmed cholestatic jaundice the diagnosis is usually made by ultrasound and CT (see Fig. 17.44). Diagnosis in non-jaundiced patients is often delayed because presenting symptoms are relatively non-specific.
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Figure 17.44 Carcinoma of the pancreatic head. CT obtained during biopsy of mass in pancreatic head.
Fit patients with small localised tumours should undergo staging to define operability. Laparoscopy with laparoscopic ultrasound will define tumour size, involvement of blood vessels and metastatic spread. In patients unsuitable for surgery because of advanced disease, frailty or comorbid disease, ultrasound or CT-guided cytology or biopsy may be used to confirm the diagnosis. Endoscopic ultrasound with fine-needle aspiration is used to define vascular invasion and obtain cytological proof of diagnosis.
ERCP is a sensitive method of diagnosing pancreatic cancer and is valuable when the diagnosis is in doubt, although differentiation between cancer and localised chronic pancreatitis can be difficult. The main role of ERCP is to insert a stent into the common bile duct to relieve obstructive jaundice.
Management
Surgical resection is the only method of effecting cure; adjuvant chemotherapy or radiotherapy confers no clear additional benefits. Unfortunately, a mere 15% of tumours are amenable to curative resection since most neoplasms are locally advanced at the time of diagnosis.
For the vast majority of patients therapy is based on palliation of pain and obstructive jaundice. Pain relief is achieved using analgesic drugs and, in some patients, coeliac plexus neurolysis by a percutaneous or endoscopic ultrasound-guided phenol injection. Jaundice is relieved by choledochojejunostomy in fit patients; percutaneous or endoscopic stenting is used in the elderly or in patients who have very advanced disease.
Around 25% of patients undergoing resection of ampullary or periampullary tumours survive for 5 years and this contrasts with 3-5% survival in patients who present with pancreatic ductal cancer.
ENDOCRINE TUMOURS
These arise from neuro-endocrine tissue within the pancreas. They may occur in association with parathyroid and pituitary adenomas (MEN I, see p. 688). The majority of endocrine tumours are non-secretory and, although malignant, grow slowly and metastasise late. Other tumours secrete hormones and present because of their endocrine effects (see Box 17.53). Neuro-endocrine pancreatic tumours may be single, but are frequently multifocal and arise from other clusters of neuro-endocrine cells derived from neural crest tissues. They are localised by CT and endoscopic ultrasound. 111In-labelled DTPA is very sensitive in the diagnosis of glucagonoma.
17.53 ENDOCRINE PANCREATIC TUMOURS
Tumour Hormone Effects
Gastrinoma Gastrin Peptic ulcer and steatorrhoea
Insulinoma Insulin Recurrent hypoglycaemia (see p. 732)
VIPoma VIP Watery diarrhoea and hypokalaemia
Glucagonoma Glucagon Diabetes mellitus, necrolytic migratory erythema
Somatostatinoma Somatostatin Diabetes mellitus and steatorrhoea


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > INFLAMMATORY BOWEL DISEASE
INFLAMMATORY BOWEL DISEASE
Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases which pursue a protracted relapsing and remitting course, usually extending over years. The diseases have many similarities and it is sometimes impossible to differentiate between them. A crucial distinction is that ulcerative colitis only involves the colon, while Crohn's disease can involve any part of the gastrointestinal tract from mouth to anus.
The incidence of inflammatory bowel disease (IBD) varies widely between populations; Crohn's disease appears to be very rare in the underdeveloped world yet ulcerative colitis, although still unusual, is becoming more common. In the West, the incidence of ulcerative colitis is stable at 10 per 100 000 while that of Crohn's disease is increasing and is now 5-7 per 100 000. Both diseases most commonly start in young adults, with a second incidence peak in the seventh decade.
Pathogenesis
Both genetic and environmental factors are implicated (see Box 17.54). The cellular events involved in the pathogenesis of Crohn's disease and ulcerative colitis involve activation of macrophages, lymphocytes and polymorphonuclear cells with release of inflammatory mediators, and these events represent targets for future therapeutic intervention (see Fig. 17.45).
17.54 FACTORS ASSOCIATED WITH THE DEVELOPMENT OF INFLAMMATORY BOWEL DISEASE
Genetic
More common in Ashkenazi Jews
10% have a first-degree relative or at least one close relative with inflammatory bowel disease
High concordance between identical twins
Associated with autoimmune thyroiditis and SLE
Four regions of linkage on chromosomes 16, 12, 6 and 14 ('IBD 1-4')
HLA-DR103 associated with severe ulcerative colitis
Ulcerative colitis and Crohn's patients with HLA-B27 commonly develop ankylosing spondylitis

Environmental
Ulcerative colitis-more common in non-smokers and ex-smokers
Crohn's-most patients are smokers (relative risk = 3)
Associated with low-residue, high refined sugar diet
Appendicectomy protects against ulcerative colitis


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Figure 17.45 Probable pathogenesis of inflammatory bowel disease. Dietary or bacterial antigens either are taken up by specialised M cells, pass between leaky epithelial cells or enter the lamina propria through ulcerated mucosa. Macrophages within Peyer's patches process the antigen and then secrete a series of cytokines. Tumour necrosis factor-alpha (TNF-a) up-regulates adhesion molecules (E-selectin and ICAM-1). These are localised on the vascular endothelium and cause circulating neutrophils to adhere to the endothelium and then pass through into the bowel wall. TNF-a is also largely responsible for the anorexia, malaise, fever and metabolic bone disease which characterise inflammatory bowel disease.Interleukin-1 (IL-1) also up-regulates adhesion molecules, thereby aiding neutrophil recruitment. In addition, IL-1 activates CD4 lymphocytes. These in turn secrete interleukins 3 and 4, which activate mast cells and plasma cells. Mast cells secrete molecules (platelet activating factor and leukotrienes), which are necessary for inflammation; plasma cells secrete IgG and IgE. IL-1 stimulates other CD4 cells to secrete gamma interferon (IFN-?) and this results in expression of HLA-DR antigens on the intestinal mucosa. Lastly, in Crohn's disease but not ulcerative colitis, IL-1, TGF-ß and IGF-1 (secreted from various sources) activate fibroblasts, thereby stimulating collagen metabolism, fibrosis and stricture formation. Interleukin-8 (IL-8) attracts, activates and degranulates neutrophils. Toxic proteases and reactive oxygen species are released; these are cytotoxic and cause ulceration. The regulatory cytokines IL-10 and transforming growth factor-ß (TGF-ß), produced by macrophages and mature T lymphocytes, down-regulate these inflammatory processes. These pathways occur in all normal individuals exposed to an inflammatory insult and this is self-limiting in healthy subjects. In genetically predisposed persons, dysregulation of these steps leads to chronic inflammatory bowel disease.
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Pathology
In both diseases the intestinal wall is infiltrated with acute and chronic inflammatory cells. There are important differences in the distribution of disease and in histological features (see Fig. 17.46).
Ulcerative colitis
Inflammation invariably involves the rectum (proctitis). It may spread proximally to involve the sigmoid colon (proctosigmoiditis) and in a minority the whole colon is involved (pancolitis). Inflammation is confluent and is more severe distally. In long-standing pancolitis the bowel becomes shortened and 'pseudopolyps' develop; these represent normal or hypertrophied residual mucosa within areas of atrophy.
Histologically, the inflammatory process is limited to the mucosa and spares the deeper layers of the bowel wall (see Fig. 17.47). Both acute and chronic inflammatory cells infiltrate the lamina propria and the crypts ('cryptitis'). Crypt abscesses are typical. Goblet cells lose their mucus and in long-standing cases glands become distorted. Dysplasia, characterised by heaping of cells within the crypts, nuclear atypia and increased mitotic rate, may herald the development of colon cancer.
Crohn's disease


Figure 17.46 Common patterns of disease distribution in inflammatory bowel disease. Overlap of distribution is common in Crohn's disease.
The sites most commonly involved, in order of frequency, are terminal ileum and right side of colon, colon alone, terminal ileum alone, ileum and jejunum. Characteristically, the entire wall of the bowel is oedematous and thickened. There are deep ulcers which often appear as linear fissures; thus the mucosa between them is described as 'cobblestone'. Deep ulcers may penetrate through the bowel wall to initiate abscesses or fistulae. Fistulae may develop between adjacent loops of bowel or between affected segments of bowel and the bladder, uterus or vagina and may appear in the perineum.
Characteristically, the changes are patchy. Even when a relatively short segment of bowel is affected, the inflammatory process is interrupted by islands of normal mucosa and the change from the affected part is abrupt. A small lesion separated in this way from a major area of involvement is referred to as a 'skip' lesion. The mesenteric lymph nodes are enlarged and the mesentery thickened.
Histologically, chronic inflammation is seen through all the layers of the bowel wall, which is thickened as a result (see Fig. 17.48). There are focal aggregates of epithelioid histiocytes, which may be surrounded by lymphocytes and contain giant cells. Lymphoid aggregates or microgranulomas are also seen, and when these are near to the surface of the mucosa they often ulcerate to form tiny aphthous-like ulcers.
Clinical features
Ulcerative colitis
The first attack is usually the most severe and thereafter the disease is followed by relapses and remissions. Only a minority of patients have chronic, unremitting symptoms. Emotional stress, intercurrent infection, gastroenteritis, antibiotics or NSAID therapy may provoke a relapse. The clinical features depend upon the site and activity of the disease.
Proctitis causes rectal bleeding and mucus discharge, sometimes accompanied by tenesmus. Some patients pass frequent, small-volume fluid stools, while others are constipated and pass pellety stools. Constitutional symptoms do not occur.
Proctosigmoiditis causes bloody diarrhoea with mucus. Almost all patients are constitutionally well but a small minority who have very active, limited disease develop fever, lethargy and abdominal discomfort.
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Figure 17.47 Histology of ulcerative colitis. Inflammation is confined to the mucosa with excess inflammatory cells in the lamina propria, loss of goblet cells, and crypt abscesses (arrow).


Figure 17.48 Histology of Crohn's disease. A Inflammation is 'transmural'; there is ulceration with loss of surface epithelium and deep fissuring ulcers extending into the submucosa (arrows). B At higher power a characteristic non-caseating granuloma is seen.
17.55 DISEASE SEVERITY ASSESSMENT IN ULCERATIVE COLITIS
Mild Severe
Daily bowel frequency <4>6
Blood in stools +/- +++
Stool volume (g/24 hrs) <200>400
Pulse (bpm) <90>90
Temperature (°C) Normal >37.8, 2 days out of 4
Sigmoidoscopy Normal or granular mucosa Blood in lumen
Abdominal radiograph Normal Dilated bowel and/or mucosal islands
Haemoglobin (g/l) Normal <100
ESR (mm/hr) Normal >30
Serum albumin (g/l) >35 <30

Extensive colitis causes bloody diarrhoea with passage of mucus. In severe cases anorexia, malaise, weight loss and abdominal pain occur, and the patient is toxic with fever, tachycardia and signs of peritoneal inflammation (see Box 17.55).
Crohn's disease
Presentation depends on the major site of disease involvement.
Ileal disease causes abdominal pain, principally because of subacute intestinal obstruction, although an inflammatory mass, intra-abdominal abscess or acute obstruction may be responsible. Pain is often associated with diarrhoea which is watery and does not contain blood or mucus. Almost all patients lose weight. This is usually because they avoid food since eating provokes pain. Weight loss may also be due to malabsorption, and some patients present with features of fat, protein or vitamin deficiencies.
Crohn's colitis presents in an identical manner to ulcerative colitis, with bloody diarrhoea, passage of mucus and constitutional symptoms including lethargy, malaise, anorexia and weight loss. Rectal sparing and the presence of perianal disease are features which favour a diagnosis of Crohn's disease rather than ulcerative colitis.
Many patients present with symptoms of both small bowel and colonic disease. A few have isolated perianal disease, vomiting from jejunal strictures or severe oral ulceration.
Physical examination often reveals evidence of weight loss, anaemia with glossitis and angular stomatitis. There is abdominal tenderness, most marked over the inflamed area. An abdominal mass due to matted loops of thickened bowel or an intra-abdominal abscess may occur. Perianal skin tags, fissures or fistulae are found in at least 50% of patients.
Complications
Intestinal
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Severe, life-threatening inflammation of the colon. This occurs in both ulcerative colitis and Crohn's disease. In the most extreme cases the colon dilates (toxic megacolon) and bacterial toxins pass freely across the diseased mucosa into the portal then systemic circulation. This complication occurs most commonly during the first attack of colitis and is recognised by the features described in Box 17.55. An abdominal radiograph should be taken daily because when the transverse colon is dilated to more than 6 cm (see Fig. 17.54, p. 815) there is a high risk of colonic perforation and subsequent generalised peritonitis and death.
Perforation of the small intestine or colon. This can occur without the development of toxic megacolon.
Life-threatening acute haemorrhage. Haemorrhage due to erosion of a major artery is a rare complication of both conditions.
Fistula and perianal disease. Fistulous connections between loops of affected bowel, or between bowel and bladder or vagina are specific complications of Crohn's disease and do not occur in ulcerative colitis. Enteroenteric fistulae cause diarrhoea and malabsorption due to blind loop syndrome. Enterovesical fistulation causes recurrent urinary infections and pneumaturia. An enterovaginal fistula causes a feculent vaginal discharge. Fistulation from the bowel may also cause perianal or ischiorectal abscesses, fissures and fistulae. These may sometimes be extremely severe and can be the source of great morbidity.
Cancer. Patients with extensive active colitis of more than 8 years' duration are at increased risk of colon cancer. The cumulative risk for ulcerative colitis may be as high as 20% after 30 years but is probably less for Crohn's colitis. Tumours develop in areas of dysplasia and may be multiple. Small bowel adenocarcinoma is a rare complication of long-standing small bowel Crohn's disease. Patients with long-standing, extensive colitis are therefore entered into surveillance colonoscopy programmes beginning 8-10 years after diagnosis. Multiple random biopsies are taken every 10 cm throughout the colon and additional biopsies are taken from raised or ulcerated areas. Dysplastic changes are graded by histopathologists as low-grade or high-grade. Assessment of biopsies is subjective and the presence of active inflammation makes analysis of dysplasia very difficult. Patients who have no evidence of dysplasia or only low-grade dysplasia are screened every year to every 2 years, while those with high-grade dysplasia should be considered for panproctocolectomy because of the high risk of colon cancer development.



Figure 17.49 Systemic complications of inflammatory bowel disease.
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Extraintestinal
Inflammatory bowel disease can be considered as a systemic illness and in some patients extraintestinal complications dominate the clinical picture. Some of these occur during relapse of intestinal disease; others appear unrelated to intestinal disease activity (see Fig. 17.49).
Differential diagnosis (see Boxes 17.56 and 17.57)
Ulcerative colitis
The major diagnostic difficulty is to distinguish the first attack of acute colitis from infection. In general, diarrhoea lasting longer than 10 days in Western countries is unlikely to be the result of infection. A history of foreign travel, antibiotic exposure (pseudomembranous colitis) or homosexual contact suggests infection. Stool microscopy, culture and examination for Clostridium difficile toxin or for ova and cysts, sigmoidoscopy and rectal biopsy, blood cultures and serological tests for infection are useful.
Small bowel Crohn's disease
17.56 CONDITIONS WHICH CAN MIMIC ULCERATIVE OR CROHN'S COLITIS
Infective
Bacterial
Salmonella
Shigella
Campylobacter jejuni
E. coli 0:157
Gonococcal proctitis
Pseudomembranous colitis
Viral
Herpes simplex proctitis
Chlamydia proctitis
Cytomegalovirus
Protozoal
Amoebiasis
Non-infective
Vascular
Ischaemic colitis
Radiation proctitis
Idiopathic
Collagenous colitis
Behçet's disease
Drugs
NSAIDs
Neoplastic
Colonic carcinoma
Other
Diverticulitis


17.57 DIFFERENTIAL DIAGNOSIS OF SMALL BOWEL CROHN'S DISEASE
Other causes of right iliac fossa mass
Caecal carcinoma
Appendix abscess
Infection (tuberculosis, Yersinia, actinomycosis)
Mesenteric adenitis
Pelvic inflammatory disease
Lymphoma


Crohn's disease can usually be diagnosed with confidence without histological confirmation in the appropriate clinical setting. Indium- or technetium-labelled white cell scanning may help identify inflamed intestinal segments. In atypical cases biopsy or surgical resection is necessary to exclude other diseases (see Box 17.57). This can often be done endoscopically by ileal intubation at colonoscopy, but sometimes laparotomy or laparoscopy with resection or full-thickness biopsy is necessary.
Investigations
These confirm the diagnosis, define disease distribution and activity, and identify specific complications.
Blood tests
Anaemia results from bleeding or malabsorption of iron, folic acid or vitamin B12. Serum albumin concentration falls as a consequence of protein-losing enteropathy, reflecting active and extensive disease, or because of poor nutrition. The ESR is raised in exacerbations or because of abscess. Elevation of CRP concentration is helpful in monitoring Crohn's disease activity.
Bacteriology
Stool cultures are performed to exclude superimposed enteric infection in patients who present with exacerbations of inflammatory bowel disease. Blood cultures are also advisable in patients with known colitis or Crohn's disease who develop fever.
Endoscopy
Sigmoidoscopy with biopsies is a simple and essential investigation in all patients who present with diarrhoea (see Fig. 17.50). Rectal sparing, perianal disease and discrete ulcers suggest Crohn's disease rather than ulcerative colitis.


Figure 17.50 Sigmoidoscopic view of moderately active ulcerative colitis. Mucosa is erythematous and friable with contact bleeding. Submucosal blood vessels are no longer visible.
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Colonoscopy may show active inflammation with pseudopolyps or a complicating carcinoma. Biopsies are taken to define disease extent, as this is underestimated by endoscopic appearances alone, and to seek dysplasia in patients with long-standing colitis. In ulcerative colitis the macroscopic and histological abnormalities are confluent and most severe in the distal colon and rectum. Stricture formation does not occur in the absence of a carcinoma. In Crohn's colitis the endoscopic abnormalities are patchy, with normal mucosa between the areas of abnormality. Aphthoid or deeper ulcers and strictures are common.
Barium studies
Barium enema is a less sensitive investigation than colonoscopy for the investigation of colitis. In long-standing ulcerative colitis the colon is shortened and loses haustra to become tubular, and pseudopolyps are seen (see Fig. 17.51). In Crohn's colitis a range of abnormalities occur. The appearances may be identical to those of ulcerative colitis but skip lesions, strictures and deeper ulcers are characteristic (see Fig. 17.52). Reflux into the terminal ileum may show stricture and ulcers.
Contrast studies of the small bowel are normal in ulcerative colitis, but in Crohn's disease affected areas are narrowed and ulcerated; multiple strictures are common (see Fig. 17.53).
Plain radiographs
A straight abdominal radiograph is essential in the management of patients who present with severe active disease. In colitis dilatation of the colon (see Fig. 17.54), mucosal oedema ('thumb-printing') or evidence of perforation may be found. In small bowel Crohn's disease there may be evidence of intestinal obstruction or displacement of bowel loops by a mass.
Radionuclide scans
Radio-labelled white cell scans show areas of active inflammation. They are less accurate than other imaging modalities with poor specificity but may be useful in severely ill patients in whom invasive tests are best avoided.


Figure 17.51 Barium enema showing shortened colon, loss of haustra, pseudopolyps and fine ulceration (arrow).


Figure 17.52 Ileocolonic Crohn's disease. Barium enema showing normal rectum and sigmoid colon, typical aphthous ulceration in the descending colon, ulceration (arrow) and lack of haustra in the transverse colon. The ascending colon and caecum are normal and there is typical Crohn's disease affecting the terminal ileum, with coarse ulceration, rigidity and lack of mucosal folds.


Figure 17.53 Barium follow-through showing terminal ileal Crohn's disease.
MRI
MRI scans are very accurate in delineating pelvic or perineal involvement by Crohn's disease.
Management
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Best treatment depends upon a team approach involving physicians, surgeons, radiologists and dietitians. Both ulcerative colitis and Crohn's disease are life-long conditions and have psychosocial implications; counsellors and patient support groups have important roles in education, reassurance and coping. The key aims are to:
treat acute attacks
prevent relapses
detect carcinoma at an early stage
select patients for surgery.



Figure 17.54 Plain abdominal radiograph showing a grossly dilated colon due to severe ulcerative colitis.
Drug treatment of colitis
The principles of drug treatment are similar for ulcerative colitis and Crohn's colitis. They are based upon the treatment of active disease and prevention of relapse.
Active colitis. Corticosteroids are the first-line treatment. Active proctosigmoiditis should be managed by steroid foam or liquid retention enemas, from which systemic corticosteroid absorption is clinically insignificant. Patients with very active proctosigmoiditis, those who are unable to retain enemas and those who have active, extensive colitis need oral corticosteroids. Prednisolone (30-40 mg/day orally) is given for 2 weeks and then reduced slowly over 8 weeks. Severe active colitis can be treated with intravenous methylprednisolone (60 mg daily by infusion). Once improvement occurs, the patient is converted to a reducing regimen of oral prednisolone.
Systemic steroid complications, such as mood changes, acne, weight gain and dyspepsia, are common but these resolve as the dose is reduced. Long-term, high-dose therapy must be avoided because of risks of the more severe steroid complications such as metabolic bone disease and infection.
Patients who relapse frequently after courses of steroids or who require maintenance steroid therapy may be considered for azathioprine treatment (1.5-2 mg/kg body weight daily). This immunosuppressant drug exerts its maximal effect only after 6-12 weeks, and corticosteroid therapy may have to be continued until this time. Treatment is sometimes complicated by bone marrow suppression, nausea, vomiting, myalgia or acute pancreatitis.
Antidiarrhoeal agents (codeine phosphate, loperamide or diphenoxylate) are sometimes useful but should be avoided in severe active disease.
Maintenance of remission. This is based upon the use of 5-aminosalicylic acid (5-ASA) which acts by modulating intestinal inflammatory activity. High concentrations of 5-ASA are delivered to the colon using the preparations mesalazine or olsalazine and these have replaced sulfasalazine which has a worse side-effect profile. Mesalazine is an enteric-coated form in which 5-ASA is slowly released from a cellulose-based or pH-dependent coating. Olsalazine comprises two molecules of 5-ASA bound by an azo bond to optimise delivery to the colon. 5-ASA liquid or foam retention enemas are also available and are as effective as steroid enemas for treating active proctitis.
EBM
ULCERATIVE COLITIS-role of 5-aminosalicylic acid (5-ASA)
'Six RCTs including a total of 485 5-ASA-treated patients and 401 placebo-treated patients indicate that active therapy is better than placebo (Chi Square 2.39).'
Jewell DP, Sutherland LR. Ulcerative colitis: diagnosis, prognosis and treatment. In: McDonald J, Burroughs A, Feagan B, eds. Evidence-based gastroenterology and hepatology. London: BMJ Books; 1999.
Further information: www.evidbasedgastro.org

Drug treatment of small bowel Crohn's disease
Drug treatment for active disease is based upon the use of oral corticosteroids (prednisolone 30-40 mg daily), reducing over 6-8 weeks. Patients who respond yet frequently relapse after stopping steroids, or who are steroid-dependent, are usually treated with azathioprine (1.5-2 mg/kg body weight daily). Steroid side-effects can be overcome by using budesonide; this is a potent synthetic corticosteroid which reduces mucosal inflammation. (9 mg is equivalent to 30 mg of prednisolone.) Following absorption, the drug undergoes extensive first-pass metabolism in the liver; adrenocortical suppression is minimised and steroid side-effects are reduced.
Some patients respond inadequately to steroids and azathioprine. In these, other immunosuppressive drugs such as methotrexate or immunomodulatory agents have a role. Antibodies to TNF-a ('infliximab') induce remission in 70-80% of patients whose disease is refractory to corticosteroids; this drug is particularly useful in healing fistulae associated with Crohn's disease. Unfortunately, most patients relapse after approximately 12 weeks and further infliximab infusions given at this time may cause anaphylactic reactions. Other genetically engineered immunomodulatory drugs, directed against other steps in the inflammatory cascade (see Fig. 17.45, p. 809), will inevitably be developed.
EBM
CROHN'S DISEASE-role of azathioprine
'Six RCTs examining the role of azathioprine in the maintenance of Crohn's disease (136 patients azathioprine, 183 patients placebo) have shown that active therapy is better than placebo (Chi Square 7.37).'
Feagan BG, McDonald JWD. Crohn's disease: treatment. In: McDonald J, Burroughs A, Feagan B, eds. Evidence-based gastroenterology and hepatology. London: BMJ Books; 1999.
Further information: www.evidbasedgastro.org

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EBM
CROHN'S DISEASE-role of monoclonal antibodies
'Anti-TNF antibody treatment (infliximab) induced clinical remission in 81.5% of patients who had Crohn's disease which was refractory to conventional therapies including corticosteroids. This compared to a 16.7% remission rate in placebo-controlled cases (p < 0.001; NNT 2). In a separate trial, 62% of patients receiving infliximab, compared to 26% of those receiving placebo, healed enterocutaneous Crohn's fistulae.'
Targan SR, Hanauer SB, Van Deventer SJH, et al. A short term study of chimeric monoclonal antibody CA2 to tumour necrosis factor for Crohn's disease. N Engl J Med 1997; 337:1029-1035.
Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398-1405.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

Metabolic bone disease
Inflammatory bowel disease patients, particularly those needing frequent courses of steroids and those who are malnourished, have a significant risk of bone demineralisation leading to osteopenia and osteoporosis, and a high risk of fracture. Details of management are given on page 1027.
Nutritional therapy
Many patients embark upon 'elimination diets' in which specific foods are avoided. Although some colitic patients do improve on a milk-free diet and a few others respond to avoidance of wheat, the best advice for the majority of patients is to eat a well-balanced, healthy diet and to avoid only those foods which, by experience, are poorly tolerated. Exceptions include patients with small bowel strictures, who should avoid nuts, pulses, raw fruit and vegetables which may precipitate intestinal obstruction, and patients with a combination of proctitis and constipation who benefit from increased dietary fibre.
Many patients who have severe chronic inflammatory bowel disease are undernourished. They require dietary assessment and appropriate calorie, protein, vitamin and mineral supplements. This is particularly important in children.
Specific nutritional therapy can induce remission in active Crohn's disease but not in ulcerative colitis. Elemental diets which contain simple sugars, triglycerides, amino acids, vitamins and trace elements, and polymeric diets which contain oligopeptides rather than amino acids, are both effective. Normal food is avoided for the 2-4 weeks of treatment. Possible modes of action include improved nutrition, exclusion of dietary antigens and avoidance of dietary fibre. Unfortunately, nutritional therapy is expensive, is often poorly tolerated and is usually followed by disease relapse on return to a normal diet.
Surgical treatment
Ulcerative colitis. Up to 60% of patients with extensive ulcerative colitis eventually require surgery. The indications are listed in Box 17.58. Impaired quality of life, with impact upon occupation and on social and family life, is the most important of these.
17.58 INDICATIONS FOR SURGERY IN ULCERATIVE COLITIS
Fulminant colitis
Disease complications, unresponsive to medical therapy
Arthritis
Pyoderma gangrenosum
Colon cancer or severe dysplasia
Impaired quality of life
Loss of occupation or education
Disruption of family life
Failure of medical therapy
Dependence upon oral corticosteroids
Complications of drug therapy


Surgery involves removal of the entire colon and rectum and cures the patient. Before surgery, patients must be counselled by doctors, stoma nurses and patients who have undergone similar surgery. The choice of procedure is either panproctocolectomy with ileostomy or proctocolectomy with ileal-anal pouch anastomosis. Surgical textbooks should be consulted for further details.
Crohn's disease. The indications for surgery are similar to those for ulcerative colitis. Operations are often necessary to deal with fistulae, abscesses and perianal disease, and may also be required to relieve small or large bowel obstruction.
Up to 80% of patients eventually need some form of surgical intervention but, unlike ulcerative colitis, surgery does not cure the patients and disease recurrence is the rule. Surgical intervention should therefore be as conservative as possible in order to minimise loss of viable intestine and to avoid creation of a short bowel syndrome.
Patients who have localised segments of Crohn's colitis may be managed by segmental resection. Others who have extensive colitis require total colectomy but ileal-anal pouch formation should be avoided because of the high risk of disease recurrence within the pouch and subsequent fistula, abscess formation and pouch failure.
Patients who have perianal Crohn's disease are managed as conservatively as possible by drainage of abscess and avoidance of resection or reconstructive procedures. Obstructing or fistulating small bowel disease may require resection of affected tissue. Patients who have multiple or recurrent strictures are considered for strictureplasty in which the stricture is not resected but instead incised in its longitudinal axis and sutured transversely.
Management of complications
Fulminant colitis. This is a life-threatening complication which demands intensive medical and surgical management. Patients should be monitored frequently for clinical signs of peritonitis, fever and tachycardia. Stool frequency and volumes are documented and abdominal radiographs are taken daily to seek evidence of toxic dilatation or perforation. The patient must also be counselled about the possibility of surgery.
If improvement has not occurred within 5-7 days, or if the patient deteriorates, urgent colectomy should be under-taken. The lower rectum can be left in situ for subsequent ileo-anal pouch reconstruction. Key steps in the management of fulminant ulcerative colitis are listed in Box 17.59.
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17.59 MANAGEMENT OF FULMINANT ULCERATIVE COLITIS
Intravenous fluids
Transfusion if Hb < 100 g/l
I.v. methylprednisolone (60 mg daily) or hydrocortisone
Antibiotics for proven infection
Nutritional support
Subcutaneous heparin for prophylaxis of venous thromboembolism
Avoidance of opiates and antidiarrhoeal agents


Perianal disease. The treatment of perianal disease, including fissure, fistula and abscess formation, is based upon a conservative approach. For many patients symptoms are few, even when the visible disease is apparently severe. In these the benefits of medical or surgical intervention are few and the relative risks of complications are high. Patients who have painful or discharging perineal disease are managed jointly by surgeons and physicians. Metronidazole or ciprofloxacin therapy may relieve pain and eliminate sepsis. Abscesses require drainage but radical procedures risk damage to the anal sphincters and faecal incontinence. Infliximab may induce remission in resistant cases.
Inflammatory bowel disease in special circumstances
Childhood
Ulcerative colitis and Crohn's disease can develop before adolescence. Chronic ill health results in growth failure, metabolic bone disease and delayed puberty. Loss of schooling and social contact, as well as frequent hospitalisation, can have important psychosocial consequences. Treatment is similar to that described for adults and may require use of corticosteroids, immunosuppressive drugs and surgery. Monitoring of height, weight and sexual development is important.
Pregnancy
The activity of inflammatory bowel disease is not usually affected by pregnancy although relapse may be more common after parturition. Drug therapy including aminosalicylates, corticosteroids and azathioprine can be safely continued throughout the pregnancy.
Prognosis
Life expectancy in patients with inflammatory bowel disease is now similar to that of the general population. Although many patients require surgery and admission to hospital for other reasons, the majority have an excellent work record and pursue a normal life. Around 90% of ulcerative colitis patients have intermittent disease activity, whilst 10% have continuous symptoms. One-third of those with pancolitis undergo colectomy within 5 years of diagnosis. Around 80% of Crohn's patients undergo surgery at some stage, and 70% of these require more than one operation during their lifetime. Clinical recurrence following resectional surgery is present in 50% of all cases at 10 years.
MICROSCOPIC COLITIS
Some patients experience watery diarrhoea as a consequence of microscopic ('lymphocytic') colitis. The colonoscopic appearances are normal but histological examination of biopsies shows a range of abnormalities.
Collagenous colitis is characterised by the presence of a thick submucosal band of collagen; a chronic inflammatory infiltrate is usually seen. The disease is more common in women and is associated with rheumatoid arthritis, diabetes and coeliac disease. Patients have a history of intermittent watery diarrhoea and treatment is based upon the use of antidiarrhoeal drugs, bismuth, aminosalicylates and topical steroid enemas.

pages 808 - 817


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > IRRITABLE BOWEL SYNDROME
IRRITABLE BOWEL SYNDROME
Functional gastrointestinal disorders are extremely common. They are defined as disorders of gut function in the absence of structural pathology. Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain is associated with defaecation or a change in bowel habit with features of disordered defaecation and distension.
Epidemiology
Approximately 20% of the general population fulfil diagnostic criteria for IBS but only 10% of these consult their doctors because of gastrointestinal symptoms. Nevertheless, IBS is the most common cause of gastrointestinal referral and accounts for frequent absenteeism from work and impaired quality of life. Young women are most often affected. There is wide overlap with non-ulcer dyspepsia, chronic fatigue syndrome, dysmenorrhoea and urinary frequency. A significant proportion of these patients have a history of physical or sexual abuse.
Aetiology
Irritable bowel syndrome encompasses a wide range of symptoms and a single cause is unlikely. It is generally believed that most patients develop symptoms in response to psychosocial factors, altered gastrointestinal motility, altered visceral sensation or luminal factors.
Psychosocial factors
Most patients seen in general practice do not have psychological problems but about 50% of patients referred to hospital meet criteria for a psychiatric diagnosis. A range of disturbances are identified, including anxiety, depression, somatisation and neurosis. Panic attacks are also common. Acute psychological stress and overt psychiatric disease are known to alter gastrointestinal motility in both irritable bowel patients and healthy people. There is an increased prevalence of abnormal illness behaviour with frequent consultations for minor symptoms (see p. 254).
Altered gastrointestinal motility
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A range of motility disorders are found but none is diagnostic. Patients with diarrhoea as a predominant symptom exhibit clusters of rapid jejunal contraction waves, rapid intestinal transit and an increased number of fast and propagated colonic contractions. Those who are predominantly constipated have decreased orocaecal transit and a reduced number of high-amplitude, propagated colonic contraction waves but there is no consistent evidence of abnormal motility.
Abnormal visceral perception
Irritable bowel syndrome is associated with increased sensitivity to intestinal distension induced by inflation of balloons in the ileum, colon and rectum, a consequence of altered CNS processing of visceral sensation.
Luminal factors
Between 10 and 20% of patients develop irritable bowel syndrome following an episode of gastroenteritis, while others may be intolerant of specific dietary components, particularly lactose and wheat.
Clinical features
17.60 FEATURES OF IRRITABLE BOWEL SYNDROME
Altered bowel habit
Colicky abdominal pain
Abdominal distension
Rectal mucus
Feeling of incomplete defaecation


The most common presentation is that of recurrent abdominal pain (see Box 17.60). This is usually colicky or 'cramping', is felt in the lower abdomen and is relieved by defaecation. Abdominal bloating worsens throughout the day; the cause is unknown but it is not due to excessive intestinal gas. The bowel habit is variable. Most patients alternate between episodes of diarrhoea and constipation but it is useful to classify patients as having predominantly constipation or predominantly diarrhoea. The constipated type tend to pass infrequent pellety stools, usually in association with abdominal pain or proctalgia. Those with diarrhoea have frequent defaecation but produce low-volume stools and rarely have nocturnal symptoms. Passage of mucus is common but rectal bleeding does not occur.
Despite apparently severe symptoms, patients do not lose weight and are constitutionally well. Many have other 'functional' symptoms including dyspepsia, urinary frequency, headaches, backache, dyspareunia, poor sleep and chronic fatigue syndrome. Physical examination does not reveal any abnormalities, although abdominal bloating and variable tenderness to palpation are common.
Diagnosis
Investigations are normal. A positive diagnosis can confidently be made in patients under the age of 40 years without resort to complicated tests. Full blood count, ESR and sigmoidoscopy are usually done routinely, but barium enema or colonoscopy should only be undertaken in older patients to exclude colorectal cancer. Those who present atypically require investigations to exclude organic gastrointestinal disease. Diarrhoea-predominant patients justify investigations to exclude microscopic colitis (see p. 817), lactose intolerance (see p. 799), bile acid malabsorption (see p. 760), coeliac disease (see p. 792) and thyrotoxicosis. All patients who give a history of rectal bleeding should undergo colonoscopy or barium enema to exclude colonic cancer or inflammatory bowel disease.


Figure 17.55 Management of irritable bowel syndrome.
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Management
The most important steps are to make a positive diagnosis and reassure the patient. Many patients are concerned that they have developed cancer, and a cycle of anxiety leading to colonic symptoms, which further heighten anxiety, can be broken by explanation that symptoms are not due to organic disease but are the result of altered bowel motility and sensation. In patients who fail to respond to reassurance, treatment is tailored to the predominant symptoms (see Fig. 17.55).
Patients with intractable symptoms sometimes benefit from several months of therapy with amitriptyline. This is given in doses (10-25 mg at night) which are much lower than those used to treat depression. Side-effects include dry mouth and drowsiness but these are usually mild and the drug is well tolerated. It may act by reducing visceral sensation and by altering gastrointestinal motility. Other drugs may overcome abnormalities of 5-HT signalling which have been identified in some IBS patients. These include 5-HT4 agonists. Hypnotherapy is reserved for the most difficult cases.
Most patients have a relapsing and remitting course. Exacerbations often follow stressful life events, occupational dissatisfaction and difficulties with interpersonal relationships.
EBM
IRRITABLE BOWEL SYNDROME-role of antidepressants
'Six placebo-controlled RCTs have shown benefit for tricyclic antidepressant therapy in irritable bowel patients. Patients whose major symptoms are pain and diarrhoea benefit most; those with constipation as a predominant symptom benefit least.'
Greenbaum DS, Magle JE, Vanegeren LE, et al. The effects of despiramine on IBS compared with atropine and placebo. Dig Dis Sci 1987; 32:257-266.
Myren J, Lovland B, Larssen SE. A double blind study of the effect of trimipramine in patients with the irritable bowel syndrome. Scand J Gastroenterol 1984; 19:835-843.
Ritchie JA, Tinelore SC. Comparisons of various treatments for irritable bowel syndrome. BMJ 1980; 281:257-266.
Tripathi BM, Misra NP, Gupta AK. Evaluation of tricyclic compound (trimipramine) vis-à-vis placebo in irritable bowel syndrome. J Assoc Physicians India 1989; 31:201-203.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

pages 817 - 819


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > DISORDERS OF THE COLON AND RECTUM
DISORDERS OF THE COLON AND RECTUM
TUMOURS OF THE COLON AND RECTUM
POLYPS AND POLYPOSIS SYNDROMES
Polyps may be neoplastic or non-neoplastic. The latter include hamartomas, metaplastic ('hyperplastic') polyps and inflammatory polyps. These have no malignant potential. Polyps may be single or multiple and vary from a few millimetres to several centimetres in size.
Colorectal adenomas are extremely common in the Western world and the prevalence rises with age; 50% of people over 60 years of age have adenomas, and in half of these the polyps are multiple. They are more common in the rectum and distal colon and are either pedunculated or sessile. Histologically, they are classified as either tubular, villous or tubulovillous, according to the glandular architecture.
Adenomas are usually asymptomatic and discovered incidentally. Occasionally, they cause bleeding and anaemia. Villous adenomas sometimes secrete large amounts of mucus, causing diarrhoea and hypokalaemia. The majority of cancers arise from adenomas ('adenoma-carcinoma sequence') over 5-10 years, although not all polyps carry the same degree of risk. Features associated with a higher risk of subsequent malignancy in colonic polyps are listed in Box 17.61.
17.61 RISK FACTORS FOR MALIGNANT CHANGE IN COLONIC POLYPS
Large size (>2 cm)
Multiple polyps
Villous architecture
Dysplasia


Discovery of a polyp at sigmoidoscopy is an indication for colonoscopy because proximal polyps are present in 40-50% of such patients. Colonoscopic polypectomy should be carried out wherever possible, as this considerably reduces subsequent colorectal cancer risk (see Fig. 17.57). Very large or sessile polyps which cannot be removed endoscopically require surgery. Once all polyps have been removed, patients should undergo surveillance colonoscopy at 3-5-year intervals, as new polyps develop in 50% of patients. Patients over 75 years of age do not require repeated colonoscopies, as their lifetime cancer risk is low.
Between 10 and 20% of polyps show histological evidence of malignancy. When cancer cells are found within 2 mm of the resection margin of the polyp, when the polyp cancer is poorly differentiated or when lymphatic invasion is present, segmental colonic resection is recommended because residual tumour or lymphatic spread may be present. Malignant polyps without these features can be followed up by surveillance colonoscopy.
EBM
COLONIC POLYPS-role of colonoscopic polypectomy in the reduction of subsequent risk of colorectal cancer
'In the US National Polyp Study, 1400 patients underwent follow-up for a mean of 5 years following colonoscopic polypectomy. The incidence of colorectal cancer was substantially less (75%) than expected; these data support the view that colonoscopic polypectomy reduces the risk of subsequent colorectal cancer development.'
Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. National Polyp Study Workgroup. N Engl J Med 1993; 329:1977-1981.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

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Figure 17.57 Adenomatous colonic polyps. A Before colonoscopic polypectomy (arrows show polyps). B After polypectomy.
Polyposis syndromes are classified by histopathology (see Box 17.62). It should be noted that, while the hamartomatous polyps in Peutz-Jeghers syndrome and juvenile polyposis are not themselves neoplastic, these disorders are associated with an increased risk of certain malignancies, e.g. breast, colon, ovary and thyroid.
Familial adenomatous polyposis (FAP)
This uncommon (1 in 8000-14 000) autosomal dominant disorder results from germ-line mutation of the APC gene on the long arm of chromosome 5. One-third of cases arise as new mutations and have no family history. Hundreds to thousands of adenomatous colonic polyps will develop in 50% of patients by age 16 (see Fig. 17.58). Of those affected, 90% will develop colorectal cancer by the age of 45 years.
17.62 GASTROINTESTINAL POLYPOSIS SYNDROMES
Neoplastic Non-neoplastic
Familial adenomatous polyposis Peutz-Jeghers syndrome Juvenile polyposis Cronkhite-Canada syndrome Cowden's disease
Inheritance Autosomal dominant Autosomal dominant Autosomal dominant in 1/3 None Autosomal dominant
Oesophageal polyps - - - + +
Gastric polyps + ++ + +++ +++
Small bowel polyps ++ +++ ++ ++ ++
Colonic polyps +++ ++ ++ +++ +
Other features see text see text see text Hair loss, pigmentation, nail dystrophy, malabsorption Many congenital anomalies, oral and cutaneous hamartomas, thyroid and breast tumours

Adenomatous polyps are also frequently found in the stomach (50%) and duodenum (over 90%). The latter are most common around the ampulla of Vater and may undergo malignant transformation to adenocarcinoma. Many extraintestinal features are also seen in FAP and these are summarised in Box 17.63.
17.63 EXTRAINTESTINAL FEATURES OF FAMILIAL ADENOMATOUS POLYPOSIS
Subcutaneous epidermoid cysts (extremities, face, scalp)
Lipomas
Benign osteomas, especially skull and angle of mandible
Desmoid tumours
Dental abnormalities (15-20%)
Congenital hypertrophy of the retinal pigment epithelium (CHRPE)


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Figure 17.58 Colonoscopic view in familial adenomatous polyposis. There are multiple small polyps throughout (arrows).
Desmoid tumours occur in 10% of patients and usually arise in the mesentery or abdominal wall. Although benign, they may become very large, may cause compression of adjacent organs and are difficult to remove. Congenital hypertrophy of the retinal pigment epithelium can be seen as dark, round, pigmented retinal lesions. When present in an at-risk individual, they are 100% predictive of the presence of FAP.
Clinically, several variants of FAP exist, including Gardner's syndrome, Turcot's syndrome and 'attenuated FAP', in which far fewer polyps are found and cancer development is delayed. In Gardner's syndrome, benign extraintestinal features are prominent, notably epidermoid cysts and osteomas. Turcot's syndrome was formerly thought to be a distinct genetic entity but the majority of patients also have APC mutations. The syndrome is characterised by FAP with brain tumours (astrocytoma or medulloblastoma).
Diagnosis and management
In newly diagnosed cases with new mutations, genetic testing by DNA linkage analysis confirms the diagnosis, and all first-degree relatives should also undergo testing (see p. 343). In families with known FAP, at-risk family members undergo direct mutation testing at 13-14 years of age. This is less invasive than regular sigmoidoscopy which is reserved for those known to have the mutation. Affected individuals should undergo colectomy after school or college education has been completed. The operation of choice is ileal pouch-anal anastomosis. Periodic upper gastrointestinal endoscopy is recommended to detect duodenal adenomas. Duodenal carcinoma is the most common cause of death in FAP patients who have undergone colectomy.
Peutz-Jeghers syndrome


Figure 17.59 Peutz-Jeghers syndrome. Typical lip pigmentation.
This is characterised by multiple hamartomatous polyps in the small intestine and colon, as well as melanin pigmentation of the lips, mouth and digits (see Fig. 17.59). Most cases are asymptomatic, although chronic bleeding, anaemia or intussusception is seen. There is a small but significant risk of small bowel adenocarcinoma, and of cancer of the pancreas, ovary, breast and endometrium.
Juvenile polyposis
Tens to hundreds of mucus-filled hamartomatous polyps are found in the colon and rectum. One-third of cases are inherited in an autosomal dominant manner and up to 20% of patients develop colorectal cancer before the age of 40. Colonoscopy with biopsies should be performed every 1-3 years.
COLORECTAL CANCER
Although relatively rare in the underdeveloped world, colorectal cancer is the second most common internal malignancy and the second leading cause of cancer deaths in Western countries. In the UK the incidence is 50-60 per 100 000, equating to 30 000 cases per year. The condition becomes increasingly common over the age of 50.
Aetiology
Both environmental and genetic factors are important in colorectal carcinogenesis (see Fig. 17.60).
Environmental factors
Environmental factors probably account for 80% of all 'sporadic' colorectal cancers. This figure is based on the wide geographic variation in incidence and the decrease in risk seen in migrants who move from high- to low-risk countries. Dietary factors are believed to be most important and these are summarised in Box 17.64; other recognised risk factors are listed in Box 17.65.
Genetic factors
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Colorectal cancer development results from the accumulation of multiple genetic mutations (see Fig. 17.61). Several important hereditary forms of colon cancer are recognised. Familial adenomatous polyposis (FAP) accounts for only 1% of cases of colonic cancer. In a further 10% there is a strong family history of colorectal cancer at an early age. Pedigrees of these families with 'hereditary non-polyposis colon cancer' (HNPCC, also known as Lynch's syndrome) indicate an autosomal dominant pattern of inheritance.
These patients have germ-line mutations in one or more genes (designated hMSH2, hMLH1, hPMS1 and hPMS2) involved in the repair of errors which normally occur during DNA replication. Failure of this DNA 'mismatch repair' system results in a genetically unstable phenotype and accumulation of multiple somatic mutations throughout the genome.


Figure 17.60 Risk factors in colon cancer development.


Figure 17.61 The multistep origin of cancer: molecular events implicated in colorectal carcinogenesis.
17.64 DIETARY RISK FACTORS FOR COLORECTAL CANCER DEVELOPMENT
Risk factor Comments
Increased risk
Red meat High saturated fat and protein content
Carcinogenic amines formed during cooking
Saturated animal fat High faecal bile acid and fatty acid levels
May affect colonic prostaglandin turnover
Decreased risk
Dietary fibre Effects vary with fibre type; shortened transit time, binding of bile acids and effects on bacterial flora proposed
Fruit and vegetables Green vegetables contain anticarcinogens, e.g. glucosinolates and flavonoids. Little evidence for protection from vitamins A, C, E
Calcium Binds and precipitates faecal bile acids
Folic acid Reverses DNA hypomethylation

17.65 NON-DIETARY RISK FACTORS IN COLORECTAL CANCER
Medical conditions
Colorectal adenomas (see p. 820)
Long-standing extensive ulcerative colitis (see p. 808)
Acromegaly
Pelvic radiotherapy

Others
Obesity and sedentary lifestyle-may be related to dietary factors
Alcohol and tobacco (weak association)


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The criteria necessary for diagnosing this condition are given in Box 17.66. The lifetime risk of colorectal cancer in affected individuals is 80%. The mean age of cancer development is 45 years, and two-thirds of tumours occur proximally, in contrast to sporadic colon cancer. In a subset of patients, there is also an increased incidence of cancers of the endometrium, urinary tract, stomach and pancreas.
Those who fulfil the criteria for diagnosis should be referred for pedigree assessment, genetic testing and colonoscopy. These should begin around 25 years of age or 5-10 years earlier than the youngest case of cancer in the family. Colonoscopy needs to be repeated every 1-2 years.
A further 10% of patients who do not have HNPCC still have a family history of colorectal cancer. The relative risks of cancer with one and two affected first-degree relatives are 1 in 12 and 1 in 6, respectively. The risk is even higher if relatives were affected at an early age. The genes mediating this increased risk are unknown.
Pathology
Most tumours arise from malignant transformation of a benign adenomatous polyp. Over 65% occur in the rectosigmoid and a further 15% recur in the caecum or ascending colon. Synchronous tumours are present in 2-5% of patients. Macroscopically, the majority of cancers are either polypoid and 'fungating', or annular and constricting. Spread occurs through the bowel wall. Rectal cancers may invade the pelvic viscera and side walls. Lymphatic invasion is common at presentation, as is spread through both portal and systemic circulations to reach the liver and, less commonly, the lungs. Tumour stage at diagnosis is the most important determinant of prognosis (see p. 217).
Clinical features
Symptoms vary depending on the site of the carcinoma. In tumours of the left colon, fresh rectal bleeding is common and obstruction occurs early. Tumours of the right colon present with anaemia from occult bleeding, or altered bowel habit, but obstruction is a late feature. Colicky lower abdominal pain is present in two-thirds of patients and rectal bleeding occurs in 50%. A minority present with features of either obstruction or perforation, leading to peritonitis, localised abscess or fistula formation. Carcinoma of the rectum usually causes early bleeding, mucus discharge or a feeling of incomplete emptying. Between 10 and 20% of all patients present solely with iron deficiency anaemia or weight loss.
On examination there may be a palpable mass, signs of anaemia or hepatomegaly from metastases. Low rectal tumours may be palpable on digital examination.
Investigations
17.66 CRITERIA FOR THE DIAGNOSIS OF HEREDITARY NON-POLYPOSIS COLON CANCER
Three or more relatives with colon cancer (at least one first-degree)
Colorectal cancer in two or more generations
At least one member affected under 50 years of age
Familial adenomatous polyposis (FAP) excluded




Figure 17.62 Colonoscopic view of a polypoid rectal carcinoma undergoing laser therapy (arrow) in a patient unfit for surgery.
Rigid sigmoidoscopy will detect approximately one-third of tumours. Colonoscopy (see Fig. 17.62) is the investigation of choice because it is more sensitive and specific than barium enema. Furthermore, lesions can be biopsied and polyps removed. Endoanal ultrasound or pelvic MRI stages rectal cancers accurately. CT colography ('virtual colonoscopy') is a promising non-invasive technique for diagnosing tumours and large polyps. CT is valuable for detecting hepatic metastases, although intraoperative ultrasound is being used increasingly for this purpose. A proportion of patients have raised serum carcinoembryonic antigen (CEA) concentrations but this is variable and so of little use in diagnosis. Measurements of CEA are valuable, however, during follow-up and can help to detect early recurrence.
Management
Surgery
The tumour is removed, along with adequate resection margins and pericolic lymph nodes. Continuity is restored by direct anastomosis wherever possible. Carcinomas within a few centimetres of the anal verge may require abdominoperineal resection and formation of a colostomy. All patients should be counselled pre-operatively about the possible need for a stoma. Solitary hepatic metastases are sometimes resected at a later stage.
Post-operatively, patients should undergo colonoscopy after 6-12 months and periodically thereafter to search for local recurrence or development of new 'metachronous' lesions, which occur in 6% of cases.
Adjuvant therapy
Two-thirds of patients have lymph node or distant spread (Dukes stage C, see Fig. 17.63) at presentation and are, therefore, beyond cure with surgery alone. Most recurrences are within 3 years of diagnosis.
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Figure 17.63 Staging and survival in colorectal cancer. (Modified Dukes classification. * Dukes' original staging only had stages A-C.)
Colonic cancers recur in lymph nodes, liver and peritoneum. Adjuvant chemotherapy with 5-fluorouracil and folinic acid (to reduce toxicity) improves both disease-free and overall survival in patients with Dukes C colon cancer. This combination also provides useful palliation for patients with metastatic disease and is usually well tolerated. A short pre-operative course of radiotherapy is given to patients with large, fixed rectal cancers to 'down-stage' the tumour. Dukes C and some Dukes B rectal cancers are given post-operative radiotherapy to reduce the risk of recurrence.
Prevention and screening
Evidence suggests that colorectal cancer is preventable. At present there are no guidelines in the UK for primary prevention by dietary or lifestyle changes.
Chemoprevention
No effective, safe, long-term agent yet exists. The most promising agents at present are aspirin, calcium and folic acid. COX-2 is over-expressed in many polyps and most colorectal cancers where it has anti-apoptotic actions. Selective COX-2 inhibitors may be useful chemopreventive drugs with a superior safety profile to standard NSAIDs.
Secondary prevention
Secondary prevention aims to detect and remove lesions at an early or pre-malignant stage. Several potential methods exist:
Widespread screening by regular faecal occult blood (FOB) testing reduces colorectal cancer mortality by 15-20% and increases the proportion of early cancers detected. These tests currently lack sensitivity and specificity and need to be improved. In the USA, annual FOB screening is recommended after the age of 50 years.
Colonoscopy remains the gold standard but requires expertise, is expensive and carries risks; many countries lack the resources to offer this form of screening.
Flexible sigmoidoscopy is an alternative option and has been shown to reduce overall colorectal cancer mortality by approximately 35% (70% for cases arising in the rectosigmoid). It is recommended in the USA every 5 years in all persons over the age of 50.
Screening by molecular genetic analysis is an exciting prospect but is not yet available.

EBM
SCREENING FOR COLORECTAL CANCER-role of faecal occult blood tests
'Data from three RCTs demonstrate that faecal occult blood testing every 1-2 years reduces the mortality from colorectal cancer by 15-33%.'
Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348:1472-1477.
Kronborg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996; 348:1467-1471.
Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328:1365-1371.
Further information: www.bsg.org.uk
www.evidbasedgastro.com

DIVERTICULOSIS
Diverticula are acquired and are most common in the sigmoid and descending colon of middle-aged people. Diverticulosis is present in over 50% of people above the age of 70 and is usually asymptomatic. Symptomatic or complicated diverticulosis ('diverticulitis') is much less common.
Aetiology
A life-long refined diet with a relative deficiency of fibre is widely thought to be responsible and the condition is rare in populations with a high dietary fibre intake, particularly in Africa and parts of Asia. It is postulated that small-volume stools require high intracolonic pressures for propulsion and this leads to herniation of mucosa between the taeniae coli (see Fig. 17.64).
Pathology
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Figure 17.64 The human colon in diverticulosis. The colonic wall is weak between the taeniae. The blood vessels that supply the colon pierce the circular muscle and weaken it further by forming tunnels. Diverticula usually emerge through these points of least resistance.
Diverticula consist of protrusions of mucosa covered by peritoneum. There is commonly hypertrophy of the circular muscle coat. Inflammation is thought to result from impaction of diverticula with faecoliths. This may resolve spontaneously or progress to cause perforation, local abscess formation, fistula and peritonitis. Repeated attacks of inflammation lead to thickening of the bowel wall, narrowing of the lumen and eventual obstruction.




Integration link: Morphology of diverticular disease

Taken from Robbins Basic Pathology 7e




Clinical features
Symptoms are usually the result of associated constipation or spasm. Colicky pain is usually suprapubic or felt in the left iliac fossa. The descending colon may be palpable and, in attacks of diverticulitis, there is local tenderness, guarding, rigidity and a palpable mass. During these episodes there may also be diarrhoea, rectal bleeding or fever. The differential diagnosis includes colorectal cancer, ischaemic colitis, inflammatory bowel disease and infection. Diverticular disease is complicated by perforation, pericolic abscess and acute rectal bleeding. These complications are more common in patients who take NSAIDs or aspirin.
Investigations
These are usually performed to exclude colorectal neoplasia. Barium enema confirms the presence of diverticula (see Fig. 17.65). Strictures and fistulae may also be seen. Flexible sigmoidoscopy is performed to exclude a coexisting neoplasm which is easily missed radiologically. Colonoscopy requires expertise and carries a risk of perforation. CT is used to assess complications.
Management
Diverticulosis which is asymptomatic and discovered coincidentally requires no treatment. Constipation can be relieved by a high-fibre diet with or without a bulking laxative (ispaghula husk, 1-2 sachets daily) taken with plenty of fluids. Stimulants should be avoided.


Figure 17.65 Barium enema showing severe diverticular disease. There is tortuosity and narrowing of the sigmoid colon with multiple diverticula (arrow).
An acute attack of diverticulitis requires 7 days of metronidazole (400 mg 8-hourly orally), along with either a cephalosporin or ampicillin (500 mg 6-hourly orally). Severe cases require intravenous fluids, analgesia and nasogastric suction. Emergency surgery is reserved for severe haemorrhage or perforation. Elective surgery is performed in patients after recovery from repeated acute attacks of obstruction, and resection of the affected segment with primary anastomosis is the procedure of choice.
CONSTIPATION AND DISORDERS OF DEFAECATION
The clinical approach to patients with constipation and its aetiology have been described on pages 770-771.
SIMPLE CONSTIPATION
This is extremely common and does not imply underlying organic disease. It usually responds to increased dietary fibre or the use of bulking agents; an adequate fluid intake is also essential. Many types of laxative are available, and these are listed in Box 17.67.
SEVERE IDIOPATHIC CONSTIPATION
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17.67 LAXATIVES
Class Examples
Bulk-forming Ispaghula husk
Methylcellulose
Stimulants Bisacodyl
Dantron (only for terminally ill patients)
Docusate
Senna
Faecal softeners Docusate
Arachis oil enema
Osmotic laxatives Lactulose
Lactitol
Magnesium salts
Others Polyethylene glycol (PEG)*
Phosphate enema*

* Used mainly for bowel preparation prior to investigation or surgery.
This occurs almost exclusively in young women and often begins in childhood or adolescence. The cause is unknown but some have 'slow transit' with reduced motor activity in the colon. Others have 'obstructed defaecation' resulting from inappropriate contraction of the external anal sphincter and puborectalis muscle (anismus).
The condition is often resistant to treatment. Bulking agents may exacerbate symptoms but prokinetic agents or balanced solutions of polyethylene glycol '3350' benefit some patients with slow transit. Glycerol suppositories and biofeedback techniques are used for those with obstructed defaecation. Rarely, subtotal colectomy is necessary as a last resort.
FAECAL IMPACTION
In faecal impaction a large, hard mass of stool fills the rectum. This tends to occur in disabled, immobile or institutionalised patients, especially the frail elderly or those with dementia. Constipating drugs, autonomic neuropathy and painful anal conditions also contribute. Megacolon, intestinal obstruction and urinary tract infections may supervene. Perforation and bleeding from pressure-induced ulceration are occasionally seen. Treatment involves adequate hydration and careful digital disimpaction after softening the impacted stool with arachis oil enemas. Stimulants should be avoided.
MELANOSIS COLI AND LAXATIVE MISUSE SYNDROMES
Long-term consumption of stimulant laxatives leads to accumulation of lipofuscin pigment in macrophages in the lamina propria. This imparts a brown discoloration to the colonic mucosa, often described as resembling 'tiger skin'. The condition is benign and resolves when the laxatives are stopped.
Prolonged laxative use may rarely result in megacolon or 'cathartic colon', in which barium enema demonstrates a featureless mucosa, loss of haustra and shortening of the bowel.
Surreptitious laxative misuse is a psychiatric condition seen in young women, some of whom have a history of bulimia or anorexia nervosa (see p. 267). They complain of refractory watery diarrhoea. Laxative use is usually denied and may continue even when patients are undergoing investigation. Screening of urine for laxatives may reveal the diagnosis.
MEGACOLON
Megacolon is characterised by dilatation of the colon and refractory constipation. It may be congenital (Hirschsprung's disease) or develop in later life (acquired megacolon).
Hirschsprung's disease
This is congenital aganglionosis of the large intestine, with an incidence of 1:5000. It may be local or diffuse and a family history is present in one-third of all cases. The condition results from failure of migration of neuroblasts into the gut wall during embryogenesis. Ganglion cells are absent from nerve plexuses, most commonly in a short segment of the rectum and/or sigmoid colon. As a result, the internal anal sphincter fails to relax. Constipation, abdominal distension and vomiting usually develop immediately after birth but a few cases do not present until childhood or adolescence. The rectum is empty on digital examination.
Barium enema shows a small rectum and colonic dilatation above the narrowed segment. Full-thickness biopsies are required to demonstrate nerve plexuses and confirm the absence of ganglion cells. Histochemical stains for acetylcholinesterase are also used. Anorectal manometry demonstrates failure of the rectum to relax with balloon distension. Treatment involves resection of the affected segment.
Acquired megacolon
This may develop in childhood as a result of voluntary withholding of stool during toilet training. In such cases it presents after the first year of life and is distinguished from Hirschsprung's disease by the urge to defaecate and the presence of stool in the rectum. It usually responds to osmotic laxatives.
In adults, acquired megacolon has several causes. It is seen in depressed or demented patients, either as part of the condition or as a side-effect of antidepressant drugs. Prolonged misuse of stimulant laxatives may cause degeneration of the myenteric plexus, while interruption of sensory or motor innervation may be responsible in a number of neurological disorders. Scleroderma and hypothyroidism are other recognised causes.
Most patients can be managed conservatively by treatment of the underlying cause, high-residue diets, laxatives and the judicious use of enemas. Prokinetics are helpful in a minority of patients. Subtotal colectomy is a last resort for the most severely affected patients.
ACUTE COLONIC PSEUDO-OBSTRUCTION (OGILVIE'S SYNDROME)
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17.68 CAUSES OF ACUTE COLONIC PSEUDO-OBSTRUCTION
Trauma, burns
Recent surgery
Drugs, e.g. opiates, phenothiazines
Respiratory failure
Electrolyte and acid-base disorders
Diabetes mellitus
Uraemia


This condition has many causes (see Box 17.68) and is characterised by relatively sudden onset of painless, massive enlargement of the proximal colon accompanied by distension; there are no features of mechanical obstruction. Bowel sounds are normal or high-pitched rather than absent. Left untreated, it may progress to perforation, peritonitis and death.
Plain abdominal radiographs show colonic dilatation with air extending to the rectum. A caecal diameter greater than 10-12 cm is associated with a high risk of perforation. Single-contrast or water-soluble barium enemas demonstrate the absence of mechanical obstruction.
Management consists of treating the underlying disorder and correcting any biochemical abnormalities. The anticholinesterase, neostigmine, is often effective by enhancing parasympathetic activity and gut motility. Decompression either with a rectal tube or by careful colonoscopy may be effective but needs to be repeated until the condition resolves. In severe cases, surgical or fluoroscopic defunctioning caecostomy is necessary.
CLOSTRIDIUM DIFFICILE INFECTION
Antibiotic-associated diarrhoea, antibiotic-associated colitis and pseudomembranous colitis are part of the same disease spectrum which results from disturbance of the normal intestinal flora. Cl. difficile can be isolated from a variable proportion of patients and is thought to be the cause in most cases. The organism is a Gram-positive, anaerobic, spore-forming bacterium. It is commonly found in hospital wards.
Pathogenesis
Around 5% of healthy adults and up to 20% of elderly patients in long-term care carry Cl. difficile. Infection is usually hospital-acquired and becomes established when the normal colonic bacterial flora is disrupted by antibiotic treatment. It can also occur, however, in debilitated patients who have not been exposed to antibiotics. Although almost any antibiotic may be responsible, the most commonly implicated are cephalosporins, ampicillin, amoxicillin and clindamycin.
The organism produces two cytotoxic and inflammatory exotoxins (A and B), both of which contribute to virulence. It is not known why some people are asymptomatic carriers whilst others develop fulminant colitis. Host antibody responses to Cl. difficile toxin A may play a role in determining the clinical response to infection.
Pathology
Initially the mucosa shows focal areas of inflammation and ulceration. In severe cases the ulcers become covered by a creamy-white adherent 'pseudomembrane' composed of fibrin, debris and polymorphs.
Clinical features
Around 80% of cases occur in people over 65 years of age, many of whom are frail with comorbid diseases. Symptoms usually begin in the first week of antibiotic therapy but can occur at any time up to 6 weeks after treatment has finished. The onset is often insidious, with lower abdominal pain and diarrhoea which may become profuse and watery. The presentation may resemble acute ulcerative colitis with bloody diarrhoea, fever and even toxic dilatation and perforation. Ileus is also seen in pseudomembranous colitis.
Diagnosis
The diagnosis should be suspected in any patient who is currently taking or has recently taken antibiotics. The rectal appearances at sigmoidoscopy may be characteristic, with erythema, white plaques or an adherent pseudomembrane. At other times the appearances resemble those of ulcerative colitis. In some cases the rectum is spared and the changes predominantly affect the proximal colon. Biopsies are carried out routinely.
Stool cultures isolate Cl. difficile in 30% of patients with antibiotic-associated diarrhoea and over 90% of those with pseudomembranous colitis. As some healthy people may harbour Cl. difficile, isolation of toxins A and B by cell cytotoxicity assays is required to prove the diagnosis. Culture and toxin isolation can be difficult and may take up to 72 hours.
Management
The offending antibiotic should be stopped and the patient should be isolated. Supportive therapy with intravenous fluids and bowel rest is often needed. Ill patients and those with evidence of ileus, dilatation or pseudomembranous colitis should be treated with antibiotics. These are most effective when given orally and there is little to choose between metronidazole 400 mg 8-hourly and vancomycin 125 mg 6-hourly. Seven to ten days of therapy are usually effective, although relapses occur in 5-20% and require repeated treatment. Intravenous immunoglobulin is sometimes given in the most severe cases. Preventative measures include the responsible use of antibiotics and improved ward hygiene, hand-washing and disinfection policies.
ENDOMETRIOSIS
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Ectopic endometrial tissue can become embedded on the serosal aspect of the intestine, most frequently in the sigmoid and rectum. The overlying mucosa is usually intact. Cyclical engorgement and inflammation result in pain, bleeding, diarrhoea, constipation and adhesions or obstruction. Low backache is frequent. The onset is usually between 20 and 45 years and is more common in nulliparous women. Bimanual examination may reveal tender nodules in the pouch of Douglas. Endoscopic studies only reveal the diagnosis if carried out during menstruation, when a bluish mass with intact overlying mucosa is apparent. In some patients laparoscopy is required. Treatment options include laparoscopic diathermy and hormonal therapy with progestogens (e.g. norethisterone), gonadotrophin-releasing hormone analogues or danazol.
PNEUMATOSIS CYSTOIDES INTESTINALIS
In this rare condition multiple gas-filled submucosal cysts line the colonic and small bowel walls. The cause is unknown but the condition may be seen in patients with chronic cardiac or pulmonary disease, pyloric obstruction, scleroderma or dermatomyositis. Most patients are asymptomatic, although there may be abdominal cramp, diarrhoea, tenesmus, rectal bleeding and mucus discharge. The cysts are recognised on sigmoidoscopy, plain abdominal radiographs or barium enema. Fasting breath hydrogen levels are elevated and fall with treatment. Therapies reported to be effective include prolonged high-flow oxygen, elemental diets and antibiotics.
ISSUES IN OLDER PEOPLE
CONSTIPATION
Particular attention should be paid to immobility, dietary fluid and fibre intake, drugs and depression in the evaluation of older people with constipation.
Immobility predisposes to constipation by increasing the colonic transit time; the longer this is, the greater the fluid absorption and the harder the stool.
In those with slow transit times, bulking agents can make matters worse and should be avoided.
If faecal impaction develops, paradoxical overflow diarrhoea may occur. If antidiarrhoeal agents are given, the underlying impaction may worsen and result in serious complications such as stercoral ulceration and bleeding.


pages 820 - 829


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Home > 2 SYSTEM-BASED DISEASES > 17 Alimentary tract and pancreatic disease > ANORECTAL DISORDERS
ANORECTAL DISORDERS
FAECAL INCONTINENCE
The normal control of anal continence is described on page 755. Common causes of incontinence are listed in Box 17.69.
Patients are often embarrassed to admit incontinence and may complain only of 'diarrhoea'. A careful history and examination, especially of the anorectum and perineum, may help to establish the underlying cause. Endoanal ultrasound is valuable for defining the integrity of the anal sphincters, while anorectal manometry and electrophysiology are also useful investigations if available.
17.69 CAUSES OF FAECAL INCONTINENCE
Obstetric trauma-childbirth, hysterectomy
Severe diarrhoea, faecal impaction
Congenital anorectal anomalies
Anorectal disease-haemorrhoids, rectal prolapse, Crohn's disease
Neurological disorders-spinal cord or cauda equina lesions, dementia


Management
This is often very difficult. Underlying disorders should be treated and diarrhoea managed with loperamide, diphenoxylate or codeine phosphate. Pelvic floor exercises and biofeedback techniques help some patients, and those with confirmed anal sphincter defects may benefit from sphincter repair operations.
HAEMORRHOIDS ('PILES')
Haemorrhoids arise from congestion of the internal and/or external venous plexuses around the anal canal. They are extremely common in adults. The aetiology is unknown, although they are associated with constipation and straining and may develop for the first time during pregnancy. First-degree piles bleed, while second-degree piles prolapse but retract spontaneously. Third-degree piles are those which require manual replacement after prolapsing. Bright red rectal bleeding occurs after defaecation. Other symptoms include pain, pruritus ani and mucus discharge. Treatment involves measures to prevent constipation and straining. Injection sclerotherapy or band ligation is effective for most, but a minority of patients require haemorrhoidectomy, which is usually curative.
PRURITUS ANI
This is common and can result from many causes (see Box 17.70), most of which result in contamination of the perianal skin with faecal contents.
17.70 CAUSES OF PRURITUS ANI
Local anorectal conditions
Haemorrhoids
Fistula, fissures
Poor hygiene

Infections
Threadworms
Candidiasis

Skin disorders
Contact dermatitis
Psoriasis
Lichen planus

Other
Diarrhoea or incontinence of any cause
Irritable bowel syndrome
Anxiety


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Itching may be trivial or severe and results in an itch-scratch-itch cycle which exacerbates the problem. When no underlying cause is found, all local barrier ointments and creams must be stopped. Good personal hygiene is essential, with careful washing after defaecation. The perineal area must be kept dry and clean. Bulk-forming laxatives may reduce faecal soiling.
SOLITARY RECTAL ULCER SYNDROME
This is most common in young adults and occurs on the anterior rectal wall. It is thought to result from localised chronic trauma and/or ischaemia associated with disordered puborectalis function and mucosal prolapse. The ulcer is seen at sigmoidoscopy and biopsies show a characteristic accumulation of collagen.
Symptoms include minor bleeding and mucus per rectum, tenesmus and perineal pain. Treatment is often difficult but avoidance of straining at defaecation is important and treatment of constipation may help. Marked mucosal prolapse is treated surgically.
ANAL FISSURE
In this common problem traumatic or ischaemic damage to the anal mucosa results in a superficial mucosal tear, most commonly in the midline posteriorly. Spasm of the internal anal sphincter exacerbates the condition. Severe pain occurs on defaecation and there may be minor bleeding, mucus discharge and pruritus. The skin may be indurated and an oedematous skin tag, or 'sentinel pile', adjacent to the fissure is common.
Avoidance of constipation with bulk-forming laxatives is important. Relaxation of the internal sphincter is normally mediated by nitric oxide, and 0.2% glyceryl trinitrate ointment, which donates nitric oxide, is effective in a proportion of patients. Manual dilatation under anaesthesia leads to long-term incontinence and has been superseded by lateral anal sphincterotomy for those requiring surgery.
ANORECTAL ABSCESSES AND FISTULAE
Perianal abscesses develop between the internal and external anal sphincters and may point at the perianal skin. Ischiorectal abscesses occur lateral to the sphincters in the ischiorectal fossa. They usually result from infection of anal glands by normal intestinal bacteria. Crohn's disease (see p. 808) is sometimes responsible.
Patients complain of extreme perianal pain, fever and/or discharge of pus. Spontaneous rupture may also lead to the development of fistulae. These may be superficial or may track through the anal sphincters to reach the rectum. Abscesses are drained surgically and fistulae are laid open with care to avoid sphincter damage.

pages 829 - 830


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