PHARMACEUTICAL CARE WHEN DISPENSING OTC MEDICATIONS FOR THE SYMPTOMATIC TREATMENT OF DISEASES OF THE DIGESTIVE SYSTEM
In developed countries gastrointestinal symptoms are a common reason for attendance to primary care clinics and to hospital outpatients. Approximately 75% of these consultations are for non-organic symptoms. The clinician’s main task is therefore to recognize when organic disease must be sought or excluded, remembering that 20% of all cancers occur in the gastrointestinal tract. In developing countries, malnutrition and poor hygiene make infection a more probable diagnosis. The cliniciaeeds to recognize and treat these infections promptly and also help with prevention by encouraging good hygiene.
GASTROINTESTINAL SYMPTOMS AND SIGNS
Dyspepsia and indigestion
Dyspepsia is an inexact term used to describe upper abdominal
symptoms such as heartburn, acidity, pain or discomfort, nausea, wind, fullness or belching. Patients refer to all of these as ‘indigestion’, but may also include other symptoms such as constipation and the presence of undigested vegetable material in the stool. ‘Indigestion’ is common; 80% of the population will say they have had indigestion at some time.
‘Alarm’ features are suggestive of serious diseases such as cancer. They are:
■ dysphagia
■ weight loss
■ protracted vomiting
■ anorexia
■ haematemesis or melaena.
However among patients investigated for dysphagia, anorexia, weight loss and vomiting, only a minority have significant gastrointestinal pathology. Even among patients with a history of vomiting blood or melaena, organic disease is by no means invariable. Nonetheless, concern about missing treatable cancer is so great that most patients with alarm symptoms will be recommended to undergo endoscopy.
Vomiting
Vomiting centres are located in the lateral reticular formation of the medulla and are stimulated by the chemoreceptor trigger zones (CTZs) in the floor of the fourth ventricle, and also by vagal afferents from the gut. These zones are directly stimulated by drugs, motion sickness and metabolic causes.
There are usually three phases:
■ nausea – a feeling of wanting to vomit, often associated with autonomic effects including salivation, pallor and sweating
■ retching – a strong involuntary unproductive effort to vomit associated with abdominal muscle contraction
■ vomiting – the expulsion of gastric contents through the mouth.
Many gastrointestinal (and non-gastrointestinal) conditions are associated with vomiting.
Large volumes of vomit and sometimes projectile vomiting suggest gastric outlet or upper intestinal obstruction. Faeculent vomit suggests low intestinal obstruction or the presence of a gastrocolic fistula. Nausea and frequent regurgitation of small amounts of gastric contents without other abdominal symptoms are frequently psychogenic.
Haematemesis is vomiting fresh or altered blood (‘coffeegrounds’)
Early-morning nausea and vomiting is seen in pregnancy, alcohol dependence and some metabolic disorders (e.g.uraemia).
Flatulence
This term describes excessive wind. It is used to indicate belching, abdominal distension, gurgling and the passage of flatus per rectum. Swallowing air is aerophagia. Some of the swallowed air passes into the intestine where most of it is absorbed, but some remains to be passed rectally. Intestinal bacterial breakdown of food also produces a small amount of gas. Rectal flatus thus consists of nitrogen, carbon dioxide, hydrogen and methane.
It is normal to pass rectal flatus up to 20 times per day.
Diarrhoea and constipation
These are common complaints and in the community are not usually due to serious disease. Some simple rules are useful; for example, a single episode of diarrhoea is commonly due to dietary indiscretion or anxiety; watery stools of large volume are always due to organic disease; bloody diarrhoea usually implies colonic disease; acute diarrhoea lasting 2–5 days is most often due to an infective cause. Stool cultures can be useful but not always possible. Patients often consider themselves constipated if their bowels are not open on most days, though normal stool frequency is very variable, from 3 times daily to 3 times a week.
The difficult passage of hard stool is also regarded as constipation, irrespective of stool frequency. True constipation with hard stools is rarely due to organic colonic disease.
Abdominal pain
Pain is stimulated mainly by the stretching of smooth muscle or organ capsules. Severe acute abdominal pain can be due to a large number of gastrointestinal conditions, and normally presents as an emergency. An apparent ‘acute abdomen’ can occasionally be due to referred pain from the chest, as in pneumonia, or to metabolic causes, such as diabetic ketoacidosis or porphyria.
Clinical enquiry in patients with abdominal pain should include:
■ site, intensity, character, duration and frequency of the pain
■ aggravating and relieving factors
■ associated symptoms, including non-gastrointestinal symptoms.
Upper abdominal pain
Epigastric pain is very common; it is often a dull ache, but sometimes sharp and severe and may be related to food intake. Although functional dyspepsia is the commonest diagnosis, the symptoms of peptic ulcer disease can be identical. Heartburn – a burning pain behind the sternum – is a common symptom of reflux.
Right hypochondrial pain may originate from the gall bladder or biliary tract. Biliary pain can also be epigastric. Biliary pain is typically intermittent, lasts a few hours and remits spontaneously to recur weeks or months later. Hepatic congestion (e.g. in hepatitis or cardiac failure) and sometimes peptic ulcer can present with pain in the right hypochondrium. Chronic, persistent or constant pain in the right (or left) hypochondrium in a well-looking patient is a frequent functional symptom; this chronic pain is not due to gall bladder disease.
Lower abdominal pain
Acute pain in the left iliac fossa is usually colonic in origin (e.g. acute diverticulitis). Chronic pain is most commonly associated with functional bowel disorders. Lower abdominal pain in women occurs in a number of gynaecological disorders and the differentiation from GI disease may be difficult. Persistent pain in the right iliac fossa over a long period is not due to chronic appendicitis and is most commonly functional.
Abdominal wall pain
Persistent abdominal pain with localized tenderness which is not relieved by tensing the abdominal muscles appears to arise from the abdominal wall itself. Causes are thought to include nerve entrapment, external hernias and entrapment of internal viscera (commonly omentum) within traumatic ruptures of abdominal wall musculature.
Anorexia and weight loss
Anorexia describes reduced appetite. It is common in systemic disease and may be seen in psychiatric disorders, particularly anorexia nervosa. Anorexia often accompanies cancer but is usually a late symptom and not of diagnostic help. Weight loss is almost always due to reduced food intake and is a frequent accompaniment of gastrointestinal diseases. Weight loss in malabsorption is primarily due to anorexia. Weight loss with a normal or increased dietary intake occurs with hyperthyroidism and other catabolic states. Weight loss should always be assessed objectively as patients’ impressions are unreliable.
Symptoms of oesophageal disorders
Major oesophageal symptoms are:
■ Dysphagia. This term means a sensation of obstruction during the passage of liquid or solid through the pharynx or oesophagus, i.e. within 15 seconds of food leaving the mouth. The characteristics of the progression of dysphagia to solids can be helpful, e.g. intermittent slow progression with a history of heartburn suggests a benign peptic stricture; relentless progression over a few weeks suggests a malignant stricture. The slow onset of dysphagia for solids and liquids at the same time suggests a motility disorder, e.g. achalasia.
■ Odynophagia is pain during the act of swallowing and is suggestive of oesophagitis. Causes include reflux, infection, chemical oesophagitis due to drugs such as bisphosphonates or slow-release potassium, or associated with oesophageal stenosis.
■ Substernal discomfort, heartburn. This is a common symptom of reflux of gastric contents into the oesophagus. It is usually a retrosternal burning pain that can spread to the neck, across the chest, and when severe can be difficult to distinguish from the pain of ischaemic heart disease. It is often worst lying down at night when gravity promotes reflux, or on bending or stooping.
■ Regurgitation is the effortless reflux of oesophageal contents into the mouth and pharynx. Uncommon iormal subjects, it occurs frequently in patients with gastro-oesophageal reflux disease or organic stenosis.
Signs of oesophageal disorders
The main sign of oesophageal disease is weight loss due to reduced food intake. Cervical lymphadenopathy with cancer is uncommon. Rarely a pharyngeal pouch may be seen to swell the neck during drinking.
GASTRO-OESOPHAGEAL REFLUX DISEASE (GORD)
Small amounts of gastro-oesophageal reflux are normal. The lower oesophageal sphincter (LOS) in the distal oesophagus is in a state of tonic contraction and relaxes transiently to allow the passage of a food bolus. Sphincter pressure also increases in response to rises in intra-abdominal and intragastric pressures. Other antireflux mechanisms involve the intra-abdominal segment of the oesophagus which acts as a flap valve. In addition, the mucosal rosette formed by folds of the gastric mucosa and the contraction of the crural diaphragm at the LOS acting like a pinchcock, prevent acid reflux. A large hiatus hernia can impair this mechanism. The oesophagus is also normally rapidly ‘cleared’ of refluxate by secondary peristalsis, gravity and salivary bicarbonate. The clinical features of reflux occur when the antireflux mechanisms fail, allowing acidic gastric contents to make prolonged contact with the lower oesophageal mucosa. The sphincter relaxes transiently independently of a swallow (Transient Lower oEsophageal Sphincter Relaxation, TLESR) after meals and this is the cause of almost all reflux in normals and about two-thirds in GORD patients.
Oesophageal mucosal defence mechanisms
■ Surface. Mucus and the unstirred water layer trap bicarbonate. This mechanism is a weak buffering mechanism compared to that in the stomach and duodenum.
■ Epithelium. The apical cell membranes and the junctional complexes between cells act to limit diffusion of H+ into the cells. In oesophagitis, the junctional complexes are damaged leading to increased H+ diffusion and cellular damage.
■ Postepithelium. Bicarbonate normally buffers acid in the cells and intracellular spaces. Hydrogen ions impair the growth and replication of damaged cells.
■ Sensory mechanisms. Acid stimulates primary sensory neurones in the oesophagus by activating the vanilloid receptor-1 (VR1). This can initiate inflammation and release of proinflammatory substances from the tissue and produce pain. Pain can also be due to contraction of longitudinal oesophageal muscle.
Clinical features
Heartburn is the major feature. The burning is aggravated by bending, stooping or lying down which promote acid exposure, and may be relieved by oral antacids. The patient complains of pain on drinking hot liquids or alcohol. The correlation between heartburn and oesophagitis is poor. Some patients have mild oesophagitis but severe heartburn; others have severe oesophagitis without symptoms, and may present with a haematemesis or iron deficiency anaemia from chronic blood loss. Psychosocial factors are often determinants of symptom severity. Many patients erroneously ascribe their symptoms to their hiatus hernia but the symptoms are due to reflux.
Differentiation of cardiac and oesophageal pain can be difficult; 20% of cases admitted to a coronary care unit have GORD. In addition to the clinical features, a trial of a PPI is always worthwhile and if symptoms persist, ambulatory pH and impedence monitoring should be performed. Regurgitation of food and acid into the mouth occurs, particularly on bending or lying flat. Aspiration pneumonia is unusual without an accompanying stricture, but cough and asthma can occur and respond slowly (1–4 months) to PPI.
Diagnosis and investigations
The clinical diagnosis can usually be made without investigation.
Unless there are alarm signs, especially dysphagia, patients under the age of 45 years can safely be treated initially without investigations. If investigation is required, there are two aims:
■ Assess oesophagitis and hiatal hernia by endoscopy. If there is oesophagitis or Barrett’s oesophagus, reflux is confirmed.
■ Document reflux by intraluminal monitoring. 24-hour intraluminal pH monitoring or impedance combined with manometry is helpful if the PPI test is negative and should always be performed to confirm reflux before surgery. Excessive reflux is defined as a pH < 4 for more than 4% of the time. There should also be a good correlation between reflux (pH < 4.0) and symptoms. It is also helpful to assess oesophageal dysmotility as a potential cause of the symptoms.
Treatment
Approximately half of patients with reflux symptoms in primary care can be treated successfully with simple antacids, loss of weight and raising the head of the bed at night. Precipitating factors should be avoided, with dietary measures, reduction in alcohol consumption and cessation of smoking. These measures are simple to say and difficult to carry out, but useful in mild disease in compliant patients. Helicobacter pylori eradication in GORD has little effect on the symptoms but is usually advised.
Drugs
Alginate-containing antacids (10 mL three times daily) are the most frequently used agents for GORD. They form a gel or ‘foam raft’ with gastric contents to reduce reflux. Available over the counter, they are often used by the patient before consultation. Common proprietary antacids contain sodium which may exacerbate fluid retention; aluminium hydroxide has less sodium than magnesium trisilicate. Magnesiumcontaining antacids tend to cause diarrhoea whilst aluminium-containing compounds cause constipation.
The dopamine antagonist prokinetic agents metoclopramide and domperidone are occasionally helpful as they enhance peristalsis and speed gastric emptying. H2-receptor antagonists (e.g. cimetidine, ranitidine, famotidine and nizatidine) are frequently used for acid suppression if antacids fail as they can often be obtained over the counter.
Proton pump inhibitors (PPIs: omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole) inhibit gastric hydrogen/potassium-ATPase. PPIs reduce gastric acid secretion by up to 90% and are the drugs of choice for all but mild cases.
Most patients with GORD will respond well but this is only 20–30% of patients presenting with heartburn. Patients with severe symptoms may need twice-daily PPIs and prolonged treatment, often for years. Once oesophageal sensitivity has normalized, a lower dose, e.g. omeprazole 10 mg, may be sufficient for maintenance. The patients who do not respond to a PPI are sometimes described as having non-erosive reflux disease (NERD) , when the endoscopy is normal. These patients are usually female and often the symptoms are functional, although a small group have a hypersensitive oesophagus, giving discomfort with only slight changes in pH.
Complications
Peptic stricture
Peptic stricture usually occurs in patients over the age of 60. The symptoms are those of intermittent dysphagia for solids which worsen gradually over a long period. Mild cases may respond to PPI alone. More severe cases need endoscopic dilatation and long-term PPI therapy. Surgery is required if medical treatment fails.
Barrett’s oesophagus
Barrett’s oesophagus is a condition in which part of the normal esophageal squamous epithelium is replaced by metaplastic columnar mucosa to form a segment of ‘columnar- lined oesophagus’ (CLO). It is a complication of severe gastro-oesophageal reflux disease due to severe LOS hypotension and there is almost always a hiatus hernia. The diagnosis is made by endoscopy showing proximal displacement of the squamocolumnar mucosal junction and biopsies demonstrating intestinal metaplasia. It may be seen as a continual sheet, or finger-like projections extending upwards from the squamocolumnar junction or as islands of columnar mucosa interspersed in areas of residual squamous mucosa. Recent guidelines suggest recording the length of circumferential CLO (C measurement) as well as the maximum length (M measurement) to aid assessment of progression or regression.
Central obesity increases the risk of Barrett’s by 4.3 times. Long segment (3 cm) and short segment (3 cm) Barrett’s is found respectively in 5% and 15% of patients, undergoing endoscopy for reflux symptoms. It is also often found incidentally in endoscoped patients without reflux symptoms. Barrett’s is commonest in middle-aged men. The major concern is that 0.5–1.0% of Barrett’s patients develop oesophageal adenocarcinoma per year. Barrett’s increases the chance of developing adenocarcinoma 30- to 50-fold. Progression of Barrett’s to cancer occurs through increasingly worse grades of dysplasia. The dysplasia is patchy, and biopsies from all four quadrants (every
Screening and surveillance in Barrett’s oesophagus. There is little consensus about screening or surveillance, though many have strong opinions. Screening does not identify those at risk for cancer (40% of patients with oesophageal adenocarcinoma (OA) have no history of reflux symptoms); survival for mainly elderly patients with Barrett’s oesophagus is not significantly different from that for control subjects in the general population; no study has shown that surveillance is reliable in detecting curable dysplasia, as interval cancers occur during surveillance schemes; and treatment of the dysplasia has not been shown to prolong survival and/or improve quality of life, specifically by preventing oesophageal cancer. The estimated cost varies between $24 700 and $98 000 per life-year saved.
A consensus would be that patients without dysplasia do not require surveillance. Low-grade dysplasia requires extensive rebiopsy after 8–12 weeks of a PPI, rebiopsy 6 monthly if persistent and then 2–3 yearly if negative for dysplasia. For high-grade dysplasia – see treatment.
Treatment of Barrett’s oesophagus. There is no evidence that treatment with PPIs or antireflux surgery leads to Barrett’s regression, but symptomatic response does not correlate well with abolition of reflux. Ablation of high grade dysplastic Barrett’s is under evaluation using photodynamic therapy, laser, endoscopic mucosal resection, argon plasma coagulation and wide-field diathermy, particularly in patients ineligible for surgery, but there is currently little long-term evidence of benefit. Because of the low rate of progression to cancer, ablation of non-dysplastic CLO seems unlikely to be of benefit.
MOTILITY DISORDERS
Achalasia
Achalasia is characterized by oesophageal aperistalsis and impaired relaxation of the lower oesophageal sphincter.
Clinical features
Achalasia incidence is 1 : 100 000 equally in males and females. It occurs at all ages but is rare in childhood. Patients usually have a long history of intermittent dysphagia, characteristically for both liquids and solids from the onset.
Regurgitation of food from the dilated oesophagus occurs, particularly at night, and aspiration pneumonia is a complication. Spontaneous chest pain occurs, said to be due to oesophageal ‘spasm’. Dysphagia may be mild and accepted by the patient as normal. The pain may be misdiagnosed as cardiac. Weight loss is usually not marked.
Pathogenesis
The aetiology is unknown. Autoimmune, neurodegenerative and viral aetiologies have been implicated. A similar clinical picture is seen in chronic Chagas’ disease where there is damage to the neural plexus of the gut.
Histopathology shows inflammation of the myenteric plexus of the oesophagus with reduction of ganglion cell numbers. Cholinergic innervation appears to be preserved. Reduction iitric oxide synthase-containing neurones has been shown by immunohistochemical staining. Pharmacologic studies in patients with achalasia support the selective loss of inhibitory, nitrergic neurones. Genetically engineered animals with targeted disruption of the gene encoding for the neuronal form of nitric oxide synthase and pharmacologic administration of NO donors substantiate the role of nitrergic denervation in achalasia. Thus the relaxation of the sphincter is impaired in the absence of nitric oxide. Some patients have autoantibodies to a dopamine-carrying protein on the surface of the cells in the myenteric plexus. Degenerative lesions are also found in the vagus. The differential diagnosis of achalasia world-wide includes genetic syndromes, infectious diseases, neoplasms and chronic inflammatory conditions.
Investigations
■ Chest X-ray shows a dilated oesophagus, sometimes with a fluid level seen behind the heart. The fundal gas shadow is absent.
■ Barium swallow shows lack of peristalsis and often synchronous contractions in the body of the oesophagus, sometimes with dilatation. The lower end shows a ‘swaeck deformity’ due to failure of the sphincter to relax.
■ Oesophagoscopy is performed to exclude a carcinoma at the lower end of the oesophagus which can produce a similar X-ray appearance. When there is marked dilatation, a 24-hour liquid-only diet and a washout prior to endoscopy is useful to remove food debris. In true achalasia the endoscope passes through the lower oesophageal sphincter with little resistance.
■ CT scan excludes distal oesophageal cancer.
■ Manometry shows aperistalsis of the oesophagus and failure of relaxation of the lower oesophageal sphincter
Treatment
All current forms of treatment for achalasia are palliative. Drug therapy rarely produces satisfactory or durable relief; nifedipine (20 mg sublingually) or sildenafil can be tried initially.
The treatment of choice is endoscopic dilatation of the LOS using a hydrostatic balloon under X-ray control. This weakens the sphincter and is successful initially in 80% of cases. About 50% of patients require a second or third dilatation in the first 5 years. There is a low but significant risk of perforation. Intrasphincteric injection of botulinum toxin A produces satisfactory initial results but the effects wear off within months. Further injections can be given. It is safer and simpler than dilatation, so may be valuable in patients at risk of death if a perforation occurs. Neither pneumatic dilatatioor botulinum toxin work as well in younger patients. If these measures fail, surgical division of the LOS (cardiomyotomy, or Heller’s operation) is performed. Reflux oesophagitis complicates all procedures and the aperistalsis of the oesophagus remains.
Complications
There is a slight increase in the incidence of squamous carcinoma of the oesophagus in both treated and untreated cases (7% after 25 years).
Systemic sclerosis
The oesophagus is involved in almost all patients with this disease. Diminished peristalsis and oesophageal clearance, detected manometrically or by barium swallow, is due to replacement of the smooth muscle by fibrous tissue. LOS pressure is decreased, allowing reflux with consequent mucosal damage. Strictures may develop. Initially there are no symptoms, but dysphagia and heartburn occur as the oesophagus becomes more severely involved. Similar motility abnormalities may be found in other connective tissue disorders, particularly if Raynaud’s phenomenon is present. Treatment is as for reflux and benign stricture.
Diffuse oesophageal spasm
This is a severe form of oesophageal dysmotility that can sometimes produce retrosternal chest pain and dysphagia. It can accompany GORD. Swallowing is accompanied by bizarre and marked contractions of the oesophagus without normal peristalsis. On barium swallow the appearance may be that of a ‘corkscrew’ oesophagus. However, asymptomatic oesophageal ‘dysmotility’ is not infrequent, particularly in patients over the age of 60 years. A variant of diffuse oesophageal spasm is the ‘nutcracker’ oesophagus, which is characterized by very high-amplitude peristalsis (pressures 200 mmHg) within the oesophagus. Chest pain is commoner than dysphagia.
Treatment
True oesophageal spasm producing severe symptoms is uncommon and treatment is often difficult. PPIs may be successful if reflux is a factor. Antispasmodics, nitrates or calcium-channel blockers – such as sublingual nifedipine 10 mg three times daily – may be tried. Occasionally, balloon dilatation or even longitudinal oesophageal myotomy is necessary.
Miscellaneous motility disorders
Abnormalities of motility that occasionally produce dysphagia are found in the elderly, in diabetes mellitus, myotonic dystrophy, oculopharyngeal muscular dystrophy and myasthenia gravis, as well as neurological disorders involving the brainstem.
OTHER OESOPHAGEAL DISORDERS
Oesophageal diverticulum
Diverticula occur:
■ immediately above the upper oesophageal sphincter (pharyngeal pouch – Zenker’s diverticulum).
■ near the middle of the oesophagus (traction diverticulum due to inflammation, or associated with diffuse oesophageal spasm or mediastinal fibrosis)
■ just above the lower oesophageal sphincter (epiphrenic diverticulum – associated with achalasia). Usually detected incidentally on a barium swallow performed for other reasons, these are often asymptomatic. Dysphagia and regurgitation can occur with a pharyngeal pouch.
Cancer of the oesophagus
This is the sixth most common cancer world-wide. Squamous tumours occurring in the middle third account for 40% of tumours, and in the upper third, 15%. Adenocarcinomas occur in the lower third of the oesophagus and at the cardia and represent approximately 45%. Primary small cell cancer is extremely rare.
Clinical features
Carcinoma of the oesophagus occurs mainly in those aged 60–70 years. Dysphagia is progressive and unrelenting. Initially there is difficulty in swallowing solids, but typically dysphagia for liquids follows within weeks. Impaction of food causes pain, but more persistent pain implies infiltration of adjacent structures.
The lesion may be ulcerative, proliferative or scirrhous, extending variably around the wall of the oesophagus to produce a stricture. Direct invasion of the surrounding structures and metastases to lymph nodes are commoner than disseminated metastases. Weight loss, due to the dysphagia as well as to anorexia, is frequent. Oesophageal obstruction eventually causes difficulty in swallowing saliva, and coughing and aspiration into the lungs is common.
Weight loss, anorexia and lymphadenopathy are the commonest physical signs.
Investigation
Diagnostic
■ Endoscopy provides histological or cytological proof of the carcinoma; 90% of oesophageal carcinomas can be confirmed with this technique.
■ Barium swallow can be useful where the differential diagnosis of dysphagia includes a motility disorder such as achalasia.
THE STOMACH AND DUODENUM
Structure
The stomach consists of a small area immediately distal to the oesophagus (the cardia), the upper region (the fundus, under the left diaphragm), the mid-region or body, and the antrum, which extends to the pylorus.
The smooth muscle of the wall of the stomach has three layers – outer longitudinal, inner circular and innermost oblique layers. There are two sphincters, the gastro-oesophageal sphincter and the pyloric sphincter. The latter is largely made up of a thickening of the circular muscle layer and controls the exit of gastric contents into the duodenum. The duodenum has outer longitudinal and inner smooth muscle layers. It is C-shaped and the pancreas sits in the concavity. It terminates at the duodenojejunal flexure where it joins the jejunum.
■ The mucosal lining of the stomach can stretch in size with feeding. The greater curvature of the undistended stomach has thick folds or rugae. The mucosa of the upper two-thirds of the stomach contains parietal cells that secrete hydrochloric acid, and chief cells that secrete pepsinogen (which initiates proteolysis). There is often a colour change at the junction between the body and the antrum of the stomach that can be seen macroscopically, and confirmed by measuring surface pH.
■ The antral mucosa secretes bicarbonate and contains mucus-secreting cells and G cells, which secrete gastrin. There are two major forms of gastrin, G17 and G34, depending on the number of amino-acid residues. G17 is the major form found in the antrum. Somatostatin is also produced by specialized antral cells (D cells).
■ Mucus-secreting cells are present throughout the stomach and secrete mucus and bicarbonate. The mucus is made of glycoproteins called mucins.
■ The ‘mucosal barrier’, made up of the plasma membranes of mucosal cells and the mucus layer, protects the gastric epithelium from damage by acid and, for example, alcohol, aspirin, NSAIDs and bile salts. Prostaglandins stimulate secretion of mucus, and their synthesis is inhibited by aspirin and NSAIDs, which inhibit cyclo-oxygenase.
■ The duodenal mucosa has villi like the rest of the small bowel, and also contains Brunner’s glands that secrete alkaline mucus. This, along with the pancreatic and biliary secretions, helps to neutralize the acid secretion from the stomach when it reaches the duodenum.
Function
Acid is not essential for digestion but does prevent some food-borne infections. Acid secretion is under neural and hormonal control. Both stimulate acid secretion through the direct action of histamine on the parietal cell. Acetylcholine and gastrin also release histamine via the enterochromaffin cells. Somatostatin inhibits both histamine and gastrin release and therefore acid secretion.
Other major gastric functions are:
■ reservoir for food
■ emulsification of fat and mixing of gastric contents
■ secretion of intrinsic factor
■ absorption (of only minimal importance).
Gastric emptying depends on many factors. There are osmoreceptors in the duodenal mucosa that control gastric emptying by local reflexes and the release of gut hormones. In particular, intraduodenal fat delays gastric emptying by
negative feedback through duodenal receptors.
H. pylori is a slow-growing spiral Gram-negative flagellate urease-producing bacterium which plays a major role in gastritis and peptic ulcer disease. Its complete genomic sequence is known. It colonizes the mucous layer in the gastric antrum but is found in the duodenum only in areas of gastric metaplasia. H. pylori is found in greatest numbers under the mucous layer in gastric pits, where it adheres specifically to gastric epithelial cells. It is protected from gastric acid by the juxtamucosal mucous layer which traps bicarbonate secreted by antral cells, and ammonia produced by bacterial urease.
Epidemiology of Helicobacter infection
The prevalence of H. pylori is high in developing countries (80–90% of the population), and much lower (20–50%) in developed countries. Infection rates are highest in lower income groups. Infection is usually acquired in childhood; although the exact route is uncertain, it may be faecal–oral or oral–oral, either by kissing or ingestion of contaminated vomit. Once acquired, the infection persists for life unless treated. The incidence increases with age, probably due to acquisition in childhood when hygiene was poorer (cohort effect) and not due to infection in adult life which is probably far less than 1% per year in developed countries.
Pathogenesis of Helicobacter infection
The pathogenetic mechanisms are not fully understood. H. pylori adheres by BabA adhesin to Lewis antigen expressed on the surface of gastric mucosal cells and causes gastritis in all infected subjects. Ulcers are commonest when the infecting strain expresses CagA (cytotoxic-associated protein) and VacA (vacuolating toxin) genes. CagA is a marker for a section of the bacterial DNA that contains genes responsible for a secretion system (Cag pathogenicity island, PaI) which injects CagA product into epithelial cells via a pilus. This causes alterations in cell morphology, replication and apoptosis. VacA is a pore-forming protein which increases host cell permeability, induces apoptosis and suppresses local immune mechanisms. Genetic variations in the host are also thought to be involved; for example, polymorphisms polymorphisms leading to increased levels of IL-1 are associated with atrophic gastritis and cancer.
Results of infection
■ Antral gastritis
■ peptic ulcers (duodenal and gastric)
■ gastric cancer.
Antral gastritis is the usual effect of H. pylori infection. It is usually asymptomatic, although occasionally patients without ulcers claim relief of dyspeptic symptoms after Helicobacter eradication. Antral gastritis causes hypergastrinaemia due to gastrin release from antral G cells. The subsequent increase in acid output is usually asymptomatic.
Duodenal ulcer (DU). H. pylori is causally associated with DU disease because in patients with DU:
■ 95% are infected with H. pylori in the antrum (antral gastritis).
■ Cure of the infection heals the ulcer and stops duodenal ulcer recurrence.
The precise mechanism of duodenal ulceration is unclear, as only 15% of patients infected with H. pylori (50–60% of the adult population world-wide) develop duodenal ulcers.
Factors that have been implicated include:
■ Increased acid secretion because of:
– increased parietal cell mass
– increased gastrin secretion.
■ Smoking impairing mucosal healing.
■ Virulence factors such as Vac A (vacuolating toxin) and CagA (cytotoxic-associated protein) as well as urease and adherence factors (see above).
■ Decreased inhibition of acid secretion; H. pylori-induced gastritis reduces somatostatin production in the antrum with loss of the negative feedback on gastrin secretion.
■ Genetic susceptibility: duodenal ulcers are more common in patients who have blood group O and are non-secretors of blood group substances in saliva.
■ Duodenal bicarbonate secretion is decreased by H.pylori inflammation and the damage and repair leads to gastric metaplasia which H. pylori colonizes, causing local release of cytokines and further damage.
Gastric ulcer (GU). Gastric ulcers are associated with a gastritis affecting the body as well as the antrum of the stomach (pangastritis) causing parietal cell loss and reduced acid production. The ulcers are thought to occur because of reduction of gastric mucosal resistance due to cytokine production by the infection or perhaps to alterations in gastric mucus.
Epidemiology of peptic ulcer disease
Duodenal ulcers affect 10–15% of the adult population and are two to three times more common than gastric ulcers. Ulcer rates are declining rapidly for younger men and increasing for older individuals, particularly women. Both DUs and GUs are common in the elderly. There is considerable geographical variation, with peptic ulcer disease being more prevalent in developing countries related to the high H. pylori infection.
Pathology of peptic ulcer disease
A peptic ulcer consists of a break in the superficial epithelial cells penetrating down to the muscularis mucosa; there is a fibrous base and an increase in inflammatory cells. Erosions, by contrast, are superficial breaks in the mucosa alone. Most DUs are found in the duodenal cap; the surrounding mucosa appears inflamed, haemorrhagic or friable (duodenitis). Gus are most commonly seen on the lesser curve near the incisura, but can be found in any part of the stomach. Peptic ulcers are seen without H. pylori, e.g. in patients on NSAIDs and in Zollinger–Ellison syndrome.
Clinical features of peptic ulcer disease
The characteristic feature of peptic ulcer is burning epigastric pain. It has been shown that if a patient points with a single finger to the epigastrium as the site of the pain this is strongly suggestive of peptic ulcer disease. The relationship of the pain to food is variable and on the whole not helpful in diagnosis. The pain of a DU classically occurs at night (as well as during the day) and is worse when the patient is hungry, but this is not reliable. The pain of both gastric and duodenal ulcers may be relieved by antacids.
Nausea may accompany the pain; vomiting is infrequent but often relieves pain. Anorexia and weight loss may occur, particularly with GUs. Persistent and severe pain suggests complications such as penetration into other organs. Back pain suggests a penetrating posterior ulcer. Severe ulceration can occasionally be symptomless, as many who present with acute ulcer bleeding or perforation have no preceding ulcer symptoms.
Untreated, the symptoms of a DU relapse and remit spontaneously. The natural history is for the disease to remit over many years due to the onset of atrophic gastritis and a decrease in acid secretion.
Examination is usually unhelpful; epigastric tenderness is quite common ion-ulcer dyspepsia.
Diagnosis of Helicobacter pylori infection
Non-invasive methods
■ Serological tests detect IgG antibodies and are reasonably sensitive (90%) and specific (83%). They have been used in diagnosis and in epidemiological studies. IgG titres may take up to 1 year to fall by 50% after eradication therapy and therefore are not useful for confirming eradication or the presence of a current infection. Antibodies can also be found in the saliva, but tests are not as sensitive or specific as serology.
■ 13C-Urea breath test. This is a quick and reliable test for H. pylori and can be used as a screening test. The measurement of 13CO2 in the breath after ingestion of
■ Stool antigen test. A specific immunoassay using monoclonal antibodies for the qualitative detection of H. pylori antigen is widely available. The overall sensitivity is 97.6% with a specificity of 96%. It is useful in the diagnosis of H. pylori infection and for monitoring efficacy of eradication therapy. (Patients should be off PPIs for 1 week but can continue with H2 blockers.)
Eradication therapy
Current recommendations are that all patients with duodenal and gastric ulcers should have H. pylori eradication therapy. Many patients have incidental H. pylori infection with no gastric or duodenal ulcer. Whether all such patients should have eradication therapy is controversial (Functional dyspepsia). However, eradication therapy is advised in the hope that symptoms will be reduced and because of the link between H. pylori and gastric cancer. The increase in the prevalence of GORD and adenocarcinoma of the lower oesophagus in the last few years is currently unexplained, but has been postulated to be linked to eradication of H. pylori. This seems unlikely but is not disproven.
Standard eradication therapies are successful in approximately 90% of patients.
Reinfection is very uncommon (1%) in developed countries. In developing countries reinfection is more common, compliance with treatment may be poor and metronidazole resistance is high (50%) (as it is frequently used for parasitic infections) so failure of eradication is common. There are many regimens for eradication, but all must take into account that:
■ good compliance is essential
■ there is a high incidence of resistance to metronidazole, particularly in some populations
■ oral metronidazole has frequent side-effects
■ bismuth chelate is unpleasant to take, even as tablets.
Metronidazole, clarithromycin, amoxicillin, tetracycline and bismuth are the most widely used agents. Resistance to amoxicillin (1–2%) and tetracycline (1%) is low except in countries where they are available without prescription where resistance may exceed 50%. Quinolones such as ciprofloxacin, furazolidone and rifabutin are also used when standard regimens have failed (‘rescue therapy’). Bismuth suppresses H. pylori effectively. None of these drugs is effective alone; eradication regimens therefore usually comprise two antibiotics given with powerful acid suppression in the form of a PPI, all given for 7 days.
Example regimes are:
■ omeprazole 20 mg clarithromycin 500 mg and amoxicillin
■ omeprazole 20 mg metronidazole 400 mg and clarithromycin 500 mg – all twice daily.
In some regimens, H2-receptor antagonists, e.g. ranitidine or ranitidine bismuth citrate, are included instead of a PPI.
Bismuth chelate is not usually given in initial regimens because of the more complex dosing regimen and side effects. In eradication failures bismuth chelate (120 mg 4 daily), metronidazole (400 mg 3daily), tetracycline (500 mg 4daily) and a PPI 20–40 mg 2daily) for 14 days is used. Sequential courses of therapy are being used in areas where resistance is high.
Prolonged therapy with a PPI after a course of PPI-based 7-day triple therapy is not necessary for ulcer healing in most H. pylori-infected patients. The effectiveness of treatment for uncomplicated duodenal ulcer should be assessed symptomatically.
If symptoms persist, breath or stool testing should be performed to check eradication.
Patients with a risk of bleeding or those with complications, i.e. haemorrhage or perforation, should always have a
Long-term PPIs may be necessary if a rebleed would be likely to be fatal.
General measures
Stopping smoking should be strongly encouraged as smoking slows mucosal healing. Patients with gastric ulcers should be routinely reendoscoped at 6 weeks to exclude a malignant tumour by confirming healing with biopsy if necessary.
Complications of peptic ulcer
Haemorrhage
Perforation .
The frequency of perforation of peptic ulceration is decreas– ing, partly attributable to medical therapy. DUs perforate more commonly than GUs, usually into the peritoneal cavity; perforation into the lesser sac also occurs. Surgery is usually performed to close the perforation and drain the abdomen. Conservative management using nasogastric suction, intravenous fluids and antibiotics is occasionally used in elderly and very sick patients.
Gastric outlet obstruction
The obstruction may be prepyloric, pyloric or duodenal. The obstruction occurs either because of an active ulcer with surrounding oedema or because the healing of an ulcer has been followed by scarring. However, obstruction due to peptic ulcer disease and gastric malignancy are now uncommon; Crohn’s disease or external compression from a pancreatic carcinoma are more common causes. Adult hypertrophic pyloric stenosis is a rare cause. The stomach becomes full of gastric juice and ingested fluid and food, giving rise to the main symptom of vomiting, usually without pain as the characteristic ulcer pain has abated owing to healing.
Vomiting is infrequent, projectile, large in volume, and the vomitus contains particles of previous meals. On examination of the abdomen there may be a succussion splash. The diagnosis is made by endoscopy but can be suspected by the nature of the vomiting; by contrast, psychogenic vomiting is frequent, small volume and usually noisy.
Severe or persistent vomiting causes loss of acid from the stomach and a metabolic alkalosis. Vomiting will often settle with intravenous fluid and electrolyte replacement, gastric drainage via a nasogastric tube and potent acid suppression therapy. Endoscopic dilatation of the pyloric region is useful and, overall, 70% of patients can be managed without surgery.
MANAGEMENT OF DYSPEPSIA IN THE COMMUNITY
Meal-related upper abdominal symptoms (commonly known by the unhelpful term ‘dyspepsia’) are very common. Overthe-counter antacids and H2-receptor antagonists (H2RAs) are available and are widely used. A history suggestive of gastro-oesophageal reflux disease (GORD) should be treated with antacids, lifestyle measures, and H2RAs or PPIs if necessary. Treatment may be ondemand or continuous, and may need to be long-term. In people under 45 years, gastric cancer or any pathology is very rare. Initial investigation with endoscopy is therefore not recommended. Blind Helicobacter eradication or ‘test and treat’ strategies are both used; their effectiveness depends on the prevalence of Helicobacter and local resistance patterns. Neither endoscopy nor ‘test and treat’ are cost effective. Further investigation may be necessary to reassure those H. pylori-negative subjects and those who remain symptomatic after successful H. pylori eradication, though organic disease is uncommon.
Older people (over 45 years) with new-onset dyspepsia and patients with alarm symptoms are traditionally investigated with endoscopy to exclude cancer and ulcers. Much investigation in this group is driven by the fear of missing a treatable cancer, though functional dyspepsia is by far the commonest diagnosis.
Treatments used for dyspepsia (often over-the-counter) include:
■ Antacids.
■ H2-receptor antagonists. These have molecular structures that fit the H2-receptors on the parietal cells. They can produce up to 80% reduction iocturnal acid production but are less effective by day. There is little difference between the several second-generation H2RAs such as ranitidine and famotidine, but they have fewer side-effects and cross-reactivity with other medication, e.g. warfarin.
■ Proton pump inhibitors are very effective for reflux symptoms, ulcer pain and healing but do not cure ulcer disease alone. They are also used empirically in
functional dyspepsia, despite their cost.
The small intestine extends from the duodenum to the ileocaecal valve. It is approximately
Each villus consists of a core containing blood vessels,
lacteals (lymphatics) and cells (e.g. plasma cells and lymphocytes). The lamina propria contains plasma cells, lymphocytes, macrophages, eosinophils and mast cells. The crypts of Lieberkьhn are the spaces between the bases of the villi.
In the small bowel digestion and absorption of nutrients and ions takes place, as does the regulation of fluid absorption and secretion. The epithelial cells of the small bowel form a physical barrier that is selectively permeable to ions, small molecules and macromolecules. Digestive enzymes such as proteases and disaccharidases are produced by intestinal cells and expressed on the surface of microvilli; others such as lipases produced by the pancreas are associated with the glycocalyx. Some nutrients are absorbed most actively in specific parts of the small intestine; iron and folate in the duodenum and jejunum, vitamin B12 and bile salts in the terminal ileum where they have specific receptors.
Presenting features of small bowel disease
Regardless of the cause, the common presenting features of small bowel disease are:
■ Diarrhoea. Although a common feature of small bowel disease, 10–20% of patients will have no diarrhoea or any other gastrointestinal symptoms. Steatorrhoea occurs when the stool fat is 17 mmol/day (or 6 g/day). The stools are pale, bulky, offensive, float (because of their increased air content), leave a fatty film on the water in the pan and are difficult to flush away.
■ Abdominal pain and discomfort. Abdominal distension can cause discomfort and flatulence. The pain has no specific character or periodicity and is not usually
severe.
■ Weight loss. Weight loss is largely due to the anorexia that invariably accompanies small bowel disease. The calorie deficit due to malabsorption is small relative to the reduction in intake.
■ Nutritional deficiencies. Deficiencies of iron, B12, folate or all of these, leading to anaemia, are the only common deficiencies. Occasionally malabsorption of other vitamins or minerals occurs, causing bruising (vitamin K deficiency), tetany (calcium deficiency), osteomalacia (vitamin D deficiency), or stomatitis, sore tongue and aphthous ulceration (multiple vitamin deficiencies). Ankle oedema due to hypoproteinamia is due to low intake and intestinal loss of albumin (protein-losing enteropathy).
Physical signs are few and non-specific. If present, they are usually associated with anaemia and the nutritional deficiencies described above. Abdominal examination is often normal, but sometimes distension and, rarely, hepatomegaly or an abdominal mass are found. Gross weight loss, oedema and muscle wasting is seen only in severe cases. A neuropathy, not always due to B12 deficiency, can be present.
Investigation of small bowel disease
The emphasis in the investigation of malabsorption is on the structural features of the underlying disorder, rather than on the documentation of malabsorption itself.
Blood tests
■ Full blood count and film. Anaemia can be microcytic, macrocytic or normocytic and the blood film may be dimorphic. Other abnormal cells (e.g. Howell–Jolly bodies) may be seen in splenic atrophy associated with coeliac disease.
– If the MCV is low, serum ferritin and the serum soluble transferrin receptor should be measured to differentiate iron deficiency from anaemia of chronic disorder.
– If the MCV is high, serum B12, and serum and red cell folate should be measured.
– However, with mixed deficiencies, the MCV may be normal. The red cell folate is a good indicator of the presence of small bowel disease. It is frequently low in both coeliac disease and Crohn’s disease, which are the two most common causes of small bowel disease in developed countries.
■ Serum albumin gives some indication of the nutritional status and the presence of intestinal protein loss. Always check urine protein loss to ensure that albumin
is not being lost from the kidneys.
■ Low serum calcium and raised alkaline phosphatase may indicate the presence of osteomalacia due to vitamin D deficiency.
■ Immunological tests. Measurement of serum antibodies to endomysium and tissue transglutaminase are useful for the diagnosis of coeliac disease.
■ HLA testing is useful in coeliac disease.
Small bowel anatomy
■ Small bowel follow-through. This detects gross anatomical defects such as diverticula, strictures and Crohn’s disease. Dilatation of the bowel and a changed fold pattern may suggest malabsorption but these are non-specific findings. Gross dilatation is seen in myopathic pseudo-obstruction.
INFLAMMATORY BOWEL DISEASE (IBD)
Two major forms of non-specific inflammatory bowel disease are recognized: Crohn’s disease (CD), which can affect any part of the GI tract, and ulcerative colitis (UC), which affects only the large bowel.
There is overlap between these two conditions in their clinical features, histological and radiological abnormalities; in 10% of cases of colitis a definitive diagnosis of either UC or CD is not possible. Currently it is necessary to distinguish between these two conditions because of certain differences in their management. It is possible that these conditions represent two aspects of the same disease.
Three additional forms of inflammatory bowel disease are also recognized, namely microscopic ulcerative, microscopic lymphocytic and microscopic collagenous colitis
Epidemiology
The incidence of CD varies from country to country but is approximately 4–10 per 100 000 annually, with a prevalence of 27–106 per 100 000. The incidence of UC is stable at 6–15 per 100 000 annually, with a prevalence of 80–150 per 100 000. Although both conditions have a world-wide distribution, the highest incidence rates and prevalence have been reported from northern Europe, the
Crohn’s disease is slightly commoner in females (M : F 1 : 1.2) and occurs at a younger age (mean 26 years) than UC (M : F 1.2 : 1; mean 34 years).
Aetiopathogenesis
Although the aetiology of IBD is unknown, it is becoming clear that IBD represents the outcome of three essential interactive co-factors: genetic susceptibility, the environment and host immune response, with the environmental factors representing both the local microenvironment (enteric microflora) and also the nutritional environment.
■ Familial. A positive family history is the largest independent risk factor for the disease. Thus up to
■ Genetic. There is increased concordance for the disease (CD more than UC) in monozygotic twins in comparison with dizygotic twins who demonstrated familial aggregation. UC and CD are polygenic diseases. There is no single locus but susceptibility loci have been identified on chromosomes 16 (IBD1), 12, 6, 14, 5, 19, 1, 16 (IBD8) and 3, and these have been renamed IBD1–9 respectively. Significant loci have also been found on chromosome 13q and in Jewish families on 1p and 3q. Linkage mutations have been found on Card 15 (NOD 2), the underlying gene on chromosome 16 (IBD1), and also genes underlying the IBD5 and IBD3 loci. The Card 15 (NOD 2) gene is associated with CD in white populations, and has been associated with structuring small bowel CD. Recent SNP (single nucleotide polymorphism) scans have identified a locus for UC and CD at ECM1 (extracellular matrix protein 1). Several other risk loci for both diseases have been found on IL23R, IL12B, NKX2-3 and MST1. The autophagy genes ATG16L1 and IRGM, which control an intracellular degradation process (along with CARD15), are specific for CD.
■ Environmental factors. Good domestic hygiene has been shown to be a risk factor for CD but not for UC. Thus poor and large families living in crowded conditions with no tap or hot water and consuming contaminated food have a lower risk of developing CD. H. pylori sero-prevalence is high in developing countries but low in patients with CD. A ‘clean’ environment may not expose the intestinal immune system to pathogenic or non-pathogenic microorganisms, particularly helminthic parasites, and therefore be ‘untrained’ to confront minor infections. Helminth infections are associated with a type 2 helper T cell response (Th2), which would counterbalance the type-1 helper T cell response (Th1) that is characteristic of CD. If such a mechanism is operative, it would explain why there is a frequent association of a recent intestinal infection with the first presentation and subsequent flare-ups of CD.
■ Lifestyle. Breast feeding may provide protection against inflammatory bowel disease developing in offspring. Breast feeding per se does not contribute to disease exacerbation.
– Nutritional factors. Many foods and food components have been suggested to play a role in the aetiopathogenesis of IBD (e.g. high sugar and fat intake) but unfortunately the results of numerous studies have been equivocal.
– Smoking. Patients with CD are more likely to be smokers, and smoking has been shown to exacerbate CD. By contrast, there is an increased risk of UC ion- or ex-smokers and nicotine has been shown to be an effective treatment of UC.
– Adverse life events and psychological factors such as chronic stress and depression seem to increase relapses in patients with quiescent disease.
■ Appendicectomy is ‘protective’ for the development of UC, particularly if performed for appendicitis or for mesenteric lymphadenitis before the age of 20. It also influences the clinical course of UC, with a lower incidence of colectomy and need for immunosuppressive therapy. By contrast, appendicectomy may increase the risk of development of CD and may result in more aggressive disease.
■ Intestinal microflora. The gut is colonized by 10 times more bacterial organisms than there are host cells, there being 300–400 distinct bacterial species. Evidence supports a hypothesis that IBD is characterized by an overaggressive immune response to luminal bacterial antigens and other products, occurring against a background of genetic susceptibility .
– Bacterial flora. There is an alteration in the bacterial flora, with an increase in anaerobic bacteria in CD and an increase in aerobic bacteria in UC.
– Bacterial antigens. Bacteria may exert their proinflammatory influence by producing toll-like receptor ligands such as peptidoglycan-polysaccharides (PGPS), lipopolysaccharides (LPS), which interact in the normal intestine with surface toll-like receptors (TLR).
The disruption in TLR signalling could prevent the mucosa withstanding bacterial insult.
– Intestinal mucosal invasion. The intestinal wall in IBD patients is contaminated by adherent and invading bacteria. Recently it has been shown that there is increased E. coli adherence to the ileal-epithelial cells in CD. This occurs via E. coli’s type 1 pilli to a protein called carcinoma embryonic antigen-related cell adhesion molecule 6 (CEACAM 6). The latter may become a marker for inflammation.
– Defective chemical barrier or intestinal defensins. Evidence suggests a decrease in human defensin-1 (HD-1) in both CD and UC and lack of induction of HD-2 and HD-3, HD-
– Impaired mucosal barrier function may explain the presence of unusual and potentially pathogenic bacteria, e.g. Mycobacterium paratuberculosis (MAP), Listeria and mucosal adherent E. coli. Their presence does not necessarily imply causation of the disease. However, MAP has recently been found in the blood of patients with CD and further studies are awaited.
– Butyrate. Sulphate-producing bacteria increase luminal levels of hydrogen sulphide (H2S), which leads to a reduction of butyrate oxidation in colonic mucosa, producing an energy-deficient state and leading to mucosal inflammation. H2S and methaneethiol may produce the malodorous flatus that some patients complain of prior to a flare-up.
■ Pathogenesis. IBD results from a defective mucosal immune system producing an inappropriate response to luminal antigens, such as bacteria which enter the intestine via a leaky epithelium. Bacterial ligands interact with toll-like receptors expressed on the epithelial cell membrane via co-stimulatory molecules which enable the epithelial cells to act as antigen presenting cells to myeloid dendritic cells. There then follows a stimulation of naпve Th 0 cells into effector T cells (Th1 (IL-12, INF), Th2 (IL-5) and Th17 (IL-17)), which predominate over the regulatory T cells (T reg). The pro-inflammatory cytokines released by these activated T cells stimulate macrophages to secret tumour necrosis factor (TNF-), IL-1 and IL-
Macrophages are also stimulated by plasmacytoid dendritic cells via natural killer cells which themselves can cause direct cytotoxic effects on cells and secrete inflammatory cytokines. These mechanisms all result in leucocytes leaving the circulation to enter the tissue and release chemokines (lymphokines, arachidonic acid metabolites, neuropeptides and free oxygen radicals), all of which lead to tissue damage and also attract more inflammatory cells like a vicious circle.
Pathology
■ Crohn’s disease is a chronic inflammatory condition that may affect any part of the gastrointestinal tract from the mouth to the anus but has a particular tendency to affect the terminal ileum and ascending colon (ileocolonic disease). The disease can involve one small area of the gut such as the terminal ileum, or multiple areas with relatively normal bowel in between (skip lesions). It may also involve the whole of the colon (total colitis) sometimes without small bowel involvement.
■ Ulcerative colitis can affect the rectum alone (proctitis), can extend proximally to involve the sigmoid and descending colon (left-sided colitis), or may involve the whole colon (total colitis). In a few of these patients there is also inflammation of the distal terminal ileum (backwash ileitis).
Macroscopic changes
In Crohn’s disease the involved small bowel is usually thickened and narrowed. There are deep ulcers and fissures in the mucosa, producing a cobblestone appearance. Fistulae and abscesses may be seen in the colon. An early feature is aphthoid ulceration, usually seen at colonoscopy;later, larger and deeper ulcers appear in a patchy distribution, again producing a cobblestone appearance.
I n ulcerative colitis the mucosa looks reddened, inflamed and bleeds easily. In severe disease there is extensive ulceration with the adjacent mucosa appearing as inflammatory polyps.
In fulminant colonic disease of either type, most of the mucosa is lost, leaving a few islands of oedematous mucosa (mucosal islands), and toxic dilatation occurs. On healing, the mucosa can return to normal, although there is usually some residual glandular distortion. Extragastrointestinal manifestations These occur with both diseases. Joint complications are commonest, and the peripheral arthropathies are classified as type 1 (pauci-articular) and type 2 (polyarticular). Type 1 attacks are acute, self-limiting (< 10 weeks) and occur with IBD relapses; they are associated with other extraintestinal manifestations of IBD activity.
Type 2 arthropathy lasts longer (months to years), is independent of IBD activity and usually associated with uveitis. There is an association of HLA DRB1*0103 with pauci-articular large joint arthritis in UC and CD and small joint symmetrical arthritis with HLA-B44. HLA B27 is associated with sacroileitis.
Crohn’s disease
Clinical features
The major symptoms are diarrhoea, abdominal pain and weight loss. Constitutional symptoms of malaise, lethargy, anorexia, nausea, vomiting and low-grade fever may be present and in 15% of these patients there are no gastrointestinal symptoms. Despite the recurrent nature of this condition, many patients remain well and have an almost normal lifestyle. However, patients with extensive disease often have frequent recurrences, necessitating multiple hospital admissions.
The clinical features are very variable and depend partly on the region of the bowel that is affected. The disease may present insidiously or acutely. The abdominal pain can be colicky, suggesting obstruction, but it usually has no special characteristics and sometimes in colonic disease only minimal discomfort is present. Diarrhoea is present in 80% of all cases and in colonic disease it usually contains blood, making it difficult to differentiate from UC. Steatorrhoea can be present in small bowel disease. Diarrhoea can also be due to bile acid malabsorption occurring as a consequence of the effects of old and presently inactive disease rather than to active disease.
Crohn’s disease can present as an emergency with acute right iliac fossa pain mimicking appendicitis. If laparotomy is undertaken, an oedematous reddened terminal ileum is found. There are other causes of an acute ileitis (e.g. infections such as Yersinia).
Up to 30% of patients presenting with acute ileitis turn out eventually to have CD. Crohn’s disease can be complicated by anal and perianal disease and this is the presenting feature in 25% of cases, often preceding colonic and small intestinal symptoms by many years. Enteric fistulae, e.g. to bladder or vagina, occur in 20–40% of cases, equally divided between internal and external fistulae; the latter usually occurring after surgery.
The large intestine starts at the caecum, on the posterior medial wall of which is the appendix. The colon is made up of ascending, transverse, descending and sigmoid parts, which join the rectum at the rectosigmoid junction. The muscle wall consists of an inner circular layer and an outer longitudinal layer. The outer layer is incomplete, coming together to form the taenia coli, which produce the haustral pattern seen in the normal colon.
The mucosa of the colon is lined with epithelial cells with crypts but no villi, so that the surface is flat. The mucosa is full of goblet cells. A variety of cells, mainly lymphocytes and macrophages, are found in the lamina propria. The blood supply to the colon is from the superior and inferior mesenteric vessels. Generally there are good anastomotic channels, but the caecum and splenic flexure are areas where ischaemia can occur. The colon is innervated mainly by the enteric nervous system with input from the parasympathetic and sympathetic pathways. Spinal afferent neurones from the dorsal root ganglia innervate the entire colon.
The rectum is about
Physiology of the colon
The main roles of the colon are the absorption of water and electrolytes) and the propulsion of contents from the caecum to the anorectal region. Approximately 1.5–2 L of fluid pass the ileocaecal valve each day. Absorption is stimulated by short-chain fatty acids which are produced predominantly in the right colon by the anaerobic metabolism of dietary fibre by bacterial polysaccharidase enzyme systems. Colonic contents are mixed, aiding absorption by non-propagative segmenting muscular contractions. Highamplitude propagative colonic contractions cause propulsion. Peristalsis is induced by the release of serotonin (5-HT) from neuroendocrine cells in response to luminal distension. Serotonin activates the HT4 receptors, which in turn results in the activation of sensory (calcitonin gene-related peptide (CGRP)) neurones. Normal colonic transit time is 24–48 hours with normal stool weights of up to 250 g/day.
Physiology of defecation
The role of the rectum and anus in defecation is complex. The rectum is normally empty. Stool is propelled into the rectum by propagated colonic contractions. Sensation of fullness, a desire to defecate and urgency to defecate are experienced with increasing volumes of rectal content (threshold 100 mL). The sensations are associated with rectal contraction and a relaxation of the internal anal sphincter, both of which serve to push the stool down into the proximal anal canal. This increases the defecatory urge, which can only be suppressed by vigorous contraction of the external sphincter and puborectalis. If conditions are appropriate for defecation the subject sits or squats, contracts the diaphragm and abdominal muscles and relaxes the pelvic floor muscles, including the puborectalis, and the anal sphincter muscles with the result that stool is expelled.
CONSTIPATION
‘Constipation’ is a very common symptom, particularly in women and the elderly. It is often more of a perception than a real entity. A consensus definition used in research (The Rome III criteria) defines constipation as having two or more of the following for at least 12 weeks: infrequent passage of stools (3/week), straining 25% of time, passage of hard stools, incomplete evacuation and sensation of anorectal blockage. According to these definitions ‘constipation’ affects more than
Many symptoms are attributed by patients to constipation and include headaches, malaise, nausea and a bad taste in the mouth. Other symptoms include abdominal bloating and/ or discomfort (undistinguishable from the irritable bowel syndrome) as well as local and perianal pain.
Assessment of constipation
This relies on the history. When there has been a recent change in bowel habit in association with other symptoms (e.g. rectal bleeding) a barium enema or colonoscopy is indicated.
A barium enema should always be preceded by a rectal examination and rigid sigmoidoscopy to exclude anorectal lesions that can otherwise be missed. By these means, gastrointestinal causes such as colorectal cancer and narrowed segments due to diverticular disease can be excluded.
Constipation can be classified into three broad categories but there is much overlap:
■ normal transit through the colon (59%)
■ defecatory disorders (25%)
■ slow transit (13%).
Defecatory disorders with slow transit can occur together (3%).
Normal-transit constipation
In normal-transit constipation, stool traverses the colon at a normal rate, the stool frequency is normal and yet patients believe they are constipated. This is likely to be due to perceived difficulties of evacuation or the passage of hard stools. Patients may complain of abdominal pain or bloating.
Normal-transit constipation can be distinguished from slow-transit constipation by undertaking marker studies of colonic transit. Capsules containing 20 radio-opaque shapes are swallowed on days 1, 2 and 3 and an abdominal X-ray obtained 120 hours after ingestion of the first capsule. Each capsule contains shapes of different configuration and the presence of more than 4 shapes from the first capsule, 6 from the second and 12 from the third denotes moderate to severe slow transit.
Slow-transit constipation
Slow-transit constipation occurs predominantly in young women who have infrequent bowel movements (usually less than once a week). The condition often starts at puberty and the symptoms are usually an infrequent urge to defecate, bloating, abdominal pain and discomfort, which can make the condition difficult to distinguish from constipationpredominant irritable bowel syndrome. Some patients with severe slow-transit constipation have delayed emptying of the proximal colon and others a failure of ‘meal-stimulated’ colonic motility. Histopathological abnormalities have been demonstrated in the colons of some patients with severe slow-transit constipation, and some patients have coexisting disorders of small intestinal motility, consistent with a diagnosis of chronic idiopathic intestinal pseudo-obstruction.
Defecatory disorders
A ‘paradoxical’ contraction rather than the normal relaxation of the puborectalis and external anal sphincter and associated muscles during straining may prevent evacuation (pelvic floor dyssynergia, anismus). These are mainly due to dysfunction of the anal sphincter and pelvic floor. An anterior rectocele is a common problem where there is a weakness of the rectovaginal septum, resulting in protuberance of the anterior wall of the rectum with trapping of stool if the diameter is 3 cm. In some patients the mucosa of the anterior rectal wall prolapses downwards during straining impeding the passage of stool, whilst in others there may be a higher mucosal intussusception.
In some patients the rectum can become unduly sensitive to the presence of small volumes of stool, resulting in the urge to pass frequent amounts of small-volume stool and the sensation of incomplete evacuation.
The defecatory disorders can often be characterized by performing evacuation proctography and tests of anorectal physiology.
Treatment
Any underlying cause should be treated. In patients with normal and slow-transit constipation the main focus should be directed to increasing the fibre content of the diet in conjunction with increasing fluid intake. Fibre intake should be increased by dietary means rather than by prescribing commercially available fibre sources in order to avoid substrate inducibility of colonic bacterial polysaccharidase enzyme systems which can lead in turn to excessive flatus production. These patients should therefore be referred to a dietician.
The use of laxatives should be restricted to severe cases. Types of laxatives available are listed in Box. Osmotic laxatives act by increasing colonic inflow of fluid and electrolytes; this acts not only to soften the stool but to stimulate colonic contractility. Magnesium sulphate 5–10 g dissolved in a glass of hot water should be taken before breakfast; it works in 2–4 hours. The polyethylene glycols (Macrogols) have the advantage over the synthetic disaccharide lactulose in that they are not fermented anaerobically in the colon to gas which can distend the colon to cause pain. The osmotic laxatives are preferred to the stimulatory laxatives, which act by stimulating colonic contractility and by causing intestinal secretion. The use of irritant suppositories can be helpful in some patients with defecatory disorders. The use of enemas should be restricted to the management of elderly, infirm and immobile patients and those with neurological disorders. Patients with defecatory disorders should be referred to a specialist centre as surgery may be indicated, for example, for anterior rectocele or internal anal mucosal intussusception.
Anterior mucosal prolapse can be treated by injection, and those with pelvic floor dyssynergia (anismus) can benefit from biofeedback therapy.
Laxatives
Laxative, or cathartic, drugs are used in several ways to speed the passage of the intestinal contents through the GI tract. Laxatives may be either chemical stimulants, which chemically irritate the lining of the GI tract; bulk stimulants (also called mechanical stimulants), which cause the fecal matter to increase in bulk; or lubricants, which help the intestinal contents move more smoothly
Chemical Stimulants
Drugs that act as chemical stimulants directly stimulate the nerve plexus in the intestinal wall, causing increased movement and the stimulation of local reflexes. Such laxatives include the following agents:
Cascara (generic), a reliable agent that leads to intestinal evacuation, may have a slow, steady effect or may cause severe cramping and rapid evacuation of the contents of the large intestine.
Senna (Senokot), another reliable drug with effects similar to cascara, is found in many over-the-counter (OTC) preparations.
Castor oil (Neoloid), an old standby, is used when a thorough evacuation of the intestine is desirable. This agent begins working at the beginning of the small intestine and increases motility throughout the rest of the GI tract. Because castor oil blocks absorption of fats (including fat-soluble vitamins) and may lead to constipation from GI tract exhaustion when there is no stimulus to movement, its frequent use is not desirable.
Bisacodyl (Dulcolax), chemically related to phenolphthalein (the acid-base chemical indicator), is often the drug of choice to empty the bowel before some surgeries or diagnostic tests, such as barium enema. It may be administered orally or rectally.
Laxatives and Antidiarrheal Agents
Children
Laxatives should not be used in children routinely. Proper diet including roughage, plenty of fluids, and exercise should be tried first if a child has a tendency to become constipated. If a laxative is needed, glycerin suppositories are the best choice for infants and young children.
Stool softeners can be used in older children; harsh stimulants should be avoided. Children with encopresis, however, are often given senna preparations or mineral oil to help them evacuate the massive stool.
Children receiving these agents should use them for only a short period and should be evaluated for potential underlying medical or nutritional problems if they are not able to return to normal function.
Loperamide may be the antidiarrheal of choice in children >2 years of age if such a drug is needed. Special precautions need to be taken to monitor for electrolyte and fluid disturbances and supportive measures taken as needed.
Adults
Adults who use laxatives need to be cautioned not to become dependent. Proper diet, exercise, and adequate intake of fluids should keep the gastrointestinal tract functioning normally. If an antidiarrheal is needed, adults should be carefully instructed in the proper dosing of the drug and monitoring of their total use to avoid excessive dosage.
The safety for the use of these drugs during pregnancy and lactation has not been established. Use should be reserved for those situations in which the benefit to the mother outweighs the potential risk to the fetus. A mild stool softener is often used after delivery. The drugs may enter breast milk and also may affect gastrointestinal activity in the neonate. It is advised that caution be used if one of these drugs is prescribed during lactation.
Older Adults
Older adults are more likely to develop adverse effects associated with the use of these drugs, including sedation, confusion, dizziness, electrolyte disturbances, fluid imbalance, and cardiovascular effects. Safety measures may be needed if these effects occur and interfere with the patient’s mobility and balance.
Older patients also may be taking other drugs that are associated with constipation and may need help to prevent severe problems from developing.
Older adults are more likely to have renal and/or hepatic impairment related to underlying medical conditions, which could interfere with the metabolism and excretion of these drugs.
The dosage for older adults should be started at a lower level than recommended for younger adults. The patient should be monitored very closely and dosage adjustment should be made based on patient response.
These patients also need to be alerted to the potential for toxic effects when using over-the-counter (OTC) preparations and should be advised to check with their health care provider before beginning any OTC drug regimen.
A psyllium product is the agent of choice with older adults because there is less risk of adverse reactions. The patient needs to be cautioned to drink plenty of fluid after taking one of these agents, to prevent problems that can occur if the drug starts to pull in fluid while stillin the esophagus.
The older adult should be encouraged to drink plenty of fluids, to exercise every day, and to get plenty of roughage in the diet. Many older adults have established routines, such as drinking warm water or prune juice at the same time each morning, that are disrupted with illness or hospitalization. These patients should be encouraged and helped to try to maintain their usual protocol as much as possible.
Bulk Stimulants
Bulk stimulants are rapid-acting, aggressive laxatives that increase the motility of the GI tract by increasing the fluid in the intestinal contents, which enlarges bulk, stimulates local stretch receptors, and activates local activity. Available bulk stimulants include the following agents:
Magnesium sulfate (Epsom Salts), a very potent laxative, is used when total evacuation of the GI tract is needed rapidly, as in cases of GI poisoning. This agent acts by exerting a hypertonic pull against the mucosal wall, drawing fluid into the intestinal contents.
Magnesium citrate (Citrate of Magnesia), found in a citrus-flavored base, is often used to stimulate bowel evacuation before many GI tests and examinations.
Magnesium hydroxide (Milk of Magnesia) is used to stimulate bulk and is a milder and slower-acting laxative. It also works by a saline pull, bringing fluids into the lumen of the GI tract. Lactulose (Chronulac) is the alternative choice for patients with cardiovascular problems.
This saltless osmotic laxative pulls fluid out of the venous system and into the lumen of the small intestine.
Polycarbophil (FiberCon) is a natural substance that forms a gelatin-like bulk out of the intestinal contents. This agent stimulates local activity. It is considered milder and less irritating than many other bulk stimulants. Patients must use caution and take polycarbophil with plenty of water. If only a little water is used, it may absorb enough fluid in the esophagus to swell into a gelatin-like mass that can obstruct the esophagus and cause severe problems.
Psyllium (Metamucil), another gelatin-like bulk stimulant, is similar to polycarbophil in action and effect.
Polyethylene glycol-electrolyte solution (GoLYTELY) is a bulk laxative used when a thorough bowel evacuation is needed. This is often used prior to colonoscopy, sigmoidoscopy, or other diagnostic procedures.
Lubricating Laxatives
Sometimes it is desirable to make defecation easier without stimulating the movement of the GI tract; this is done using lubricants. Patients with hemorrhoids and those who have recently had rectal surgery may need lubrication of the stool.
Some patients who could be harmed by straining might also benefit from this type of laxative. The type of laxative recommended depends on the condition of the patient, the speed of relief needed, and the possible implication of various adverse effects. Lubricating laxatives include the following:
Docusate (Colace) has a detergent action on the surface of the intestinal bolus, increasingthe admixture of fat and water and making a softer stool. This drug is frequently used as prophylaxis for patients who should not strain (such as after surgery, myocardial infarction, or obstetrical delivery).
Glycerin (Sani-Supp) is a hyperosmolar laxative that is used in suppository form to gently evacuate the rectum without systemic effects higher in the GI tract.
Mineral oil (Agoral Plain) is the oldest of these laxatives. It is not absorbed and forms a slippery coat on the contents of the intestinal tract. When the intestinal bolus is coated with mineral oil, less water is absorbed out of the bolus and the bolus is less likely to become hard or impacted. Frequent use of mineral oil can interfere with absorption of thefat-soluble vitamins A, D, E, and K. In addition, leakage and staining may be a problem when mineral oil is used and the stool cannot be retained by the external sphincter.
Therapeutic Actions and Indications
Laxatives work in three ways:
· by direct chemical stimulation of the GI tract
· by production of bulk or increased fluid in the lumen of the GI tract, leading to stimulation of local nerve receptors
· by lubrication of the intestinal bolus to promote passage through the GI tract.
Laxatives are indicated for the short-term relief of constipation; to prevent straining when it is clinically undesirable (such as after surgery, myocardial infarction, or obstetrical delivery); to evacuate the bowel for diagnostic procedures; to remove ingested poisons from the lower GI tract; and as an adjunct in anthelmintic therapy when it is desirable to flush helminths from the GI tract.
Measures, such as proper diet and exercise, and taking advantage of the actions of the intestinal reflexes, have eliminated the need for laxatives in many situations; therefore, these agents are used less frequently than they once were in clinical practice.
Most laxatives are available in OTC preparations, and they are often abused by people who then become dependent on them for stimulation of GI movement. Such individuals may develop chronic intestinal disorders as a result.
Pharmacokinetics
Most of these agents are only minimally absorbed and exert their therapeutic effect directly in the GI tract. Changes in absorption, water balance, and electrolytes resulting from GI changes can have adverse effects on patients with underlying medical conditions that are affected by volume and electrolyte changes. Use with caution during pregnancy and lactation because of the lack ofstudies regarding the effects of these drugs. Castor oil should not be used during pregnancy because its irritant effect has been associated with induction of premature labor. Magnesium laxatives can cause diarrhea in the neonate.
Contraindications and Cautions
Laxatives are contraindicated in acute abdominal disorders, including appendicitis, diverticulitis, and ulcerative colitis, when increased motility could lead to rupture or further exacerbation of theinflammation. Laxatives should be used with great caution during pregnancy and lactation. In some cases, stimulation of the GI tract can precipitate labor, and many of these agents cross the placenta and are excreted in breast milk.
Adverse Effects
The adverse effects most commonly associated with laxatives are GI effects such as diarrhea, abdominal cramping, and nausea. CNS effects, including dizziness, headache, and weakness, are not uncommon and may relate to loss of fluid and electrolyte imbalances that may accompany laxative use. Sweating, palpitations, flushing, and even fainting have been reported after laxative use. These effects may be related to a sympathetic stress reaction to intense neurostimulation of the GI tract or to the loss of fluid and electrolyte imbalance. A very common adverse effect that is seen with frequent laxative use or laxative abuse is cathartic dependence. This reaction occurs when patients use laxatives over a long period and the GI tract becomes dependent on the vigorous stimulation of the laxative. Without this stimulation, the GI tract does not move for a period of time (i.e., several days), which could lead to constipation and drying of the stool and ultimately to impaction.
DIARRHOEA
Diarrhoea is a common clinical problem and there is no uniformly accepted definition of diarrhoea. Organic causes (stool weights >
Mechanisms
Osmotic diarrhoea
The gut mucosa acts as a semi-permeable membrane and fluid enters the bowel if there are large quantities of nonabsorbed hypertonic substances in the lumen. This occurs because:
■ the patient has ingested a non-absorbable substance (e.g. a purgative such as magnesium sulphate or magnesium-containing antacid)
■ the patient has generalized malabsorption so that high concentrations of solute (e.g. glucose) remain in the lumen
■ the patient has a specific absorptive defect (e.g. disaccharidase deficiency or glucose–galactose malabsorption).
The volume of diarrhoea produced by these mechanisms is reduced by the absorption of fluid by the ileum and colon. The diarrhoea stops when the patient stops eating or the malabsorptive substance is discontinued.
Secretory diarrhoea
In this disorder, there is both active intestinal secretion of fluid and electrolytes as well as decreased absorption.
Common causes of secretory diarrhoea are:
■ enterotoxins (e.g. cholera, E. coli – thermolabile or thermostable toxin, C. difficile)
■ hormones (e.g. vasoactive intestinal peptide in the Verner–Morrison syndrome)
■ bile salts (in the colon) following ileal resection
■ fatty acids (in the colon) following ileal resection
■ some laxatives (e.g. docusate sodium).
Inflammatory diarrhoea (mucosal destruction)
Diarrhoea occurs because of damage to the intestinal mucosal cell so that there is a loss of fluid and blood. In addition, there is defective absorption of fluid and electrolytes. Common causes are infective conditions (e.g.dysentery due to Shigella), and inflammatory conditions (e.g. ulcerative colitis and Crohn’s disease).
Abnormal motility
Diabetic, post-vagotomy and hyperthyroid diarrhoea are all due to abnormal motility of the upper gut. In many of these cases the volume and weight of the stool is not all that high, but frequency of defecation occurs; this therefore may not be true diarrhoea.
It should be noted that the irritable bowel syndrome, colorectal cancer, diverticular disease and faecal impaction with overflow in the elderly do not cause ‘true’ organic diarrhoea (i.e. > 250 g/ day), even though the patients may complain of diarrhoea.
Acute diarrhoea (excluding cholera)
Diarrhoea of sudden onset is very common, often short-lived and requires no investigation or treatment. This type of diarrhoea is seen after dietary indiscretions, but diarrhoea due to viral agents also lasts 24–48 hours. Travellers’ diarrhoea, which affects people travelling outside their own countries, particularly to developing countries, usually lasts 2–5 days. Clinical features associated with the acute diarrhoeas include fever, abdominal pain and vomiting. If the diarrhoea is particularly severe, dehydration can be a problem; the very young and very old are at special risk from this. Investigations are necessary if the diarrhoea has lasted more than 1 week. Stools (up to three) should be sent immediately to the laboratory for culture and examination for ova, cysts and parasites. If the diagnosis has still not been made, a sigmoidoscopy and rectal biopsy should be performed and imaging should be considered.
Oral fluid and electrolyte replacement is ofteecessary. Special oral rehydration solutions (e.g. sodium chloride and glucose powder) are available for use in severe episodes of diarrhoea, particularly in infants. Antidiarrhoeal drugs are thought to impair the clearance of any pathogen from the bowel but may be necessary for short-term relief (e.g. codeine phosphate 30 mg four times daily, or loperamide 2 mg three times daily). Antibiotics are sometimes given) depending on the organism.
Chronic diarrhoea
This always needs investigation. All patients should have a sigmoidoscopy and rectal biopsy. When difficulties exist in distinguishing between functional and organic causes of diarrhoea, hospital admission for a formal 72-hour assessment of stool weights is helpful and will also assist in the diagnosis of factitious causes of
diarrhoea.
Antibiotic-associated diarrhoea (pseudomembranous colitis)
Pseudomembranous colitis may develop following the use of any antibiotic. Diarrhoea occurs in the first few days after taking the antibiotic or even up to 6 weeks after stopping the drug. The causative agent is Clostridium difficile
Bile acid malabsorption
Bile acid malabsorption is an underdiagnosed cause of chronic diarrhoea and many patients with this disorder are assumed to have irritable bowel syndrome. Bile acid diarrhoea occurs when the terminal ileum fails to reabsorb bile acids. Bile acids (particularly the dihydroxy bile acids –deoxycholate and chenodeoxycholate) when present in increased concentrations in the colon lead to diarrhoea by reducing absorption of water and electrolytes and, at higher concentrations, inducing secretion as well as increasing colonic motility. A variety of causes of bile acid malabsorption are recognized.
Bile acid malabsorption should be considered not only in patients with chronic diarrhoea of unknown cause but also in patients with diarrhoea and associated disease who are not responding to standard therapy (e.g. patients with
terminal ileal Crohn’s disease, microscopic inflammatory colitis).
Diagnosis is made using the SeHCAT test in which a radiolabelled bile acid analogue is administered and percentage retention at 7 days calculated (< 19% retention abnormal).
Treatment is with colestyramine, a resin which binds and inactivates the action of bile acids in the colon. The best results of treatment are obtained in patients with a SeHCAT retention of < 5%.
Factitious diarrhoea
Factitious diarrhoea accounts for up to 4% of new patients with diarrhoea attending gastroenterology clinics.
Purgative abuse
This is most commonly seen in females who surreptitiously take high-dose purgatives and are often extensively investigated for chronic diarrhoea. The diarrhoea is usually of high volume (>
In advanced cases a barium enema may show a dilated colon and loss of haustral pattern. Phenolphthalein laxatives can be detected by pouring an alkali (e.g. sodium hydroxide) on the stools, which then turn pink; a magnesium-containing purgative will give a high faecal magnesium content. Anthraquinones can also be measured in the urine. If the diagnosis is suspected, a locker or bed search (while the patient is out of the ward) is occasionally necessary. Management is difficult as most patients deny purgative ingestion. Purgative abuse often occurs in association with eating disorders and all patients needs psychiatric help. It is sometimes safer not to confront the patient with their diagnosis.
Dilutional diarrhoea
In this condition raised stool weights occur as a consequence of patients deliberately diluting their stool with urine or tap water. The diagnosis is made by measuring stool osmolality and electrolyte concentrations in order to calculate the faecal osmolar gap. Measurement of stool creatinine content is helpful in excluding dilution of stools with urine, and early admission to hospital for formal assessment of stool weights may avoid unnecessary invasive investigations being carried out.
Diarrhoea in patients with HIV infection
Chronic diarrhoea is a common symptom in HIV infection, but HIV’s role in the pathogenesis of diarrhoea is unclear. Cryptosporidium is the pathogen most commonly isolated. Isospora belli and microsporidia have also been found.
The cause of the diarrhoea is ofteot found and treatment is symptomatic.
Antidiarrheal Drugs
Antidiarrheal drugs that block stimulation of the GI tract are used for symptomatic relief from diarrhea. Available agents include the following:
Bismuth subsalicylate (Pepto-Bismol) acts locally to coat the lining of the GI tract and soothe any irritation that might be stimulating local reflexes to cause excessive GI activity and diarrhea. This agent has been found to be very helpful in treating traveler’s diarrhea and in preventing cramping and distention associated with dietary excess and some viral infections. Bismuth subsalicylate is absorbed from the GI tract, metabolized in the liver, and excreted in urine. It crosses the placenta and should be used in pregnancy only if the benefit to the mother outweighs any potential risk to the fetus. It is not known whether it enters breast milk.
Loperamide (Imodium) has a direct effect on the muscle layers of the GI tract to slow peristalsis and allow increased time for absorption of fluid and electrolytes. Loperamide is slowly absorbed, metabolized in the liver, and excreted in urine and feces. It may cross the placenta and enter breast milk.
It should be used in pregnancy or lactation only if the benefits clearly outweigh any potential risks to the fetus or neonate.
Opium derivatives (paregoric) block nerve impulses within the GI tract, stopping peristalsis and diarrhea and associated discomfort. A category C-III controlled substance, opium is readily absorbed, metabolized in the liver, and excreted in urine. It crosses the placenta and enters breast milk and can have adverse effects on the fetus or neonate.
In 2004, rifaximin (Xifaxan) was approved by the FDA specifically for treating traveler’s diarrhea. A new antibiotic, rifaximin acts locally in the GI tract against noninvasive strains of Escherichia coli, the most common cause of traveler’s diarrhea. About 80%–90 % of the drug is delivered to the intestines without being absorbed through the GI tract. Rifaximin acts locally in the GI tract to destroy the E. coli that causes the signs and symptoms associated with traveler’s diarrhea. The drug is taken in 200-mg tablets, three times a day for 3 days once the signs and symptoms of the disorder occur. It should not be used if the patient has bloody diarrhea or if diarrhea persists more than 48 hours or worsens during treatment with the drug. Destroying the causative agent will relieve the GI symptoms of diarrhea, nausea, and anorexia. Prevention remains the best intervention for traveler’s diarrhea.
FUNCTIONAL GASTROINTESTINAL DISORDERS
There is a large group of gastrointestinal disorders that are termed ‘functional’ because symptoms occur in the absence of any demonstrable abnormalities in the digestion and absorption of nutrients, fluid and electrolytes and no structural abnormality can be identified in the gastrointestinal tract.
Modern classification systems are based on the premise that for each disorder there is a symptom cluster that ‘breeds true’ across clinical and population groups. There is inevitably overlap, with some symptoms being common to more than one disorder.
These conditions are extremely common world-wide, making up to 80% of patients seen in the gastroenterology clinic.
FUNCTIONAL OESOPHAGEAL DISORDERS
The criteria for diagnosis rest mainly on compatible symptoms.
However, pathological gastro-oesophageal reflux and other causes may need full investigation, particularly in the elderly with a short history.
Globus
This presents as:
■ Persistent or intermittent sensation of a lump or foreign body in the throat.
■ Occurrence of the sensation between meals.
■ The absence of dysphagia and pain on swallowing (odynophagia).
Treatment is with explanation and reassurance and a trial of antireflux therapy. Antidepressants may be tried.
Laxatives
Chemical Stimulants
Bisacodyl
Cascara
castor oil
senna
Bulk Laxatives
lactulose
magnesium citrate
magnesium hydroxide
magnesium sulfate
polycarbophil
polyethylene glycol-electrolyte solution
psyllium
Lubricants
Docusate
glycerin
mineral oil
Gastrointestinal Stimulants
Dexpanthenol
metoclopramide
Antidiarrheal Drugs
bismuth subsalicylate
loperamide
opium derivatives
References
1. Drug facts and comparisons. (2006).
2. Gilman, A., Hardman, J.G., & Limbird, L.E. (Eds.). (2006). Goodman and Gilman’s the pharmacological basis of therapeutics (11th ed.).
3. Karch, A.M. (2006). 2007 Lippincott’s nursing drug guide.
4. The medical letter on drugs and therapeutics. (2006).
5. Porth, C.M. (2005). Pathophysiology: Concepts of altered health states (7th ed.).
6. Philadelphia: Lippincott Williams & Wilkins.
7. http://www.nlm.nih.gov/medlineplus/constipation.html
