DISEASES OF THE SMALL INTESTINE

1. DISEASES OF THE SMALL INTESTINE Disorders causing malabsorption

2. Coeliac disease

3. Coeliac disease is an immunologically mediated inflammatory disorder of the small bowel occurring in genetically susceptible individuals and resulting from intolerance to wheat gluten and similar proteins found in rye, barley and, to a lesser extent, oats. It is more common in northern Europe

4. Celiac disease does not develop unless a person has alleles that encode for HLA-DQ2 or HLA-DQ8 proteins.

5. Clinical features Coeliac disease can present at any age. In infancy it occurs after weaning on to cereals and typically presents with diarrhoea, malabsorption and failure to thrive. In older children it may present with non-specific features such as delayed growth.. Affected children have both growth and pubertal delay, leading to short stature in adulthood.

6. In adults peak onset is in the third or fourth decade and females are affected twice as often as males. The presentation is highly variable, depending on the severity and extent of small bowel involvement. Some patients have florid malabsorption while others develop non-specific symptoms such as tiredness, weight loss, folate deficiency or iron deficiency anaemia.

7. Classification of CD: Clinically overt (active, symptomatic) CD: Typical gastrointestinal symptoms and signs of malabsorption, histological changes with villous atrophy and hypertrophic crypts. The severity of the coeliac intestinal lesion does not necessarily correlate with the severity of clinical symptoms. Although there is a gradient of decreasing severity from the proximal to the distal small intestine, correlating with the higher proximal concentration of dietary gluten, sampling error can occur due to some inhomogeneity of mucosal inflammation.

8. Latent CD: subjects with genetic predisposition who have initially normal histology with no atrophy or crypt hyperplasia. Immunological abnormalities such as increased count of intra epithelial lymphocyts and positive anti-endomysial antibody or Tissue transglutaminase antibody test are sometimes present. These subjects may develop clinically overt CD later in life.

9. Silent CD: Asymptomatic patients with typical histological changes. Refractory CD: patients who do not respond to a gluten free diet or who previously respond but later become non responsive to a gluten free diet. Intestinal lymphoma may have developed.

10. Disease associations of coeliac disease Insulin-dependent diabetes mellitus (2-8%) Thyroid disease (5%) Primary biliary cirrhosis (3%) Sjögren's syndrome (3%) IgA deficiency (2%) Pernicious anaemia Inflammatory bowel disease Myasthenia gravis Dermatitis herpetiformis Down's syndrome Enteropathy-associated T-cell lymphoma Small bowel carcinoma Squamous carcinoma of oesophagus Ulcerative jejunitis Pancreatic insufficiency Microscopic colitis & Splenic atrophy

11. Investigations Antibodies: IgA anti-endomysial antibodies are detectable by immunofluorescence in most untreated cases. They are sensitive (85-95%) and specific (approximately 99%) for the diagnosis. IgG antibodies, however, must be analysed in patients with coexisting IgA deficiency. TheTissue transglutaminase (tTG assay) has replaced other blood tests in many countries as it is easier to perform, semi-quantitative and more accurate in patients with IgA deficiency. These antibody tests constitute a valuable screening tool in patients with diarrhoea but are not a substitute for small bowel biopsy; they usually become negative with successful treatment.

12. Duodenal biopsy Endoscopic small bowel biopsy is the gold standard. The histological features are usually characteristic but other causes of villous atrophy should also be considered. Sometimes the villi appear normal but there are excess numbers of intra-epithelial lymphocytes present.

14. Management The aims are to correct existing deficiencies of iron, folate, calcium and/or vitamin D, and to commence a life-long gluten-free diet. This requires the exclusion of wheat, rye, barley and initially oats Initially, frequent dietary counselling is required to make sure the diet is being observed, as the most common reason for failure to improve with dietary treatment is accidental or unrecognised gluten ingestion. Rarely, patients are 'refractory' and require treatment with corticosteroids or immunosuppressive drugs to induce remission.

15. Complications A twofold increased risk of malignancy, particularly of enteropathy-associated T-cell lymphoma, small bowel carcinoma and squamous carcinoma of the oesophagus, has been reported. A few patients develop ulcerative jejuno-ileitis; fever, pain, obstruction or perforation may then supervene. Osteoporosis and osteomalacia may occur in patients with long-standing, poorly controlled coeliac disease.

16. Dermatitis herpetiformis This is characterised by crops of intensely itchy blisters over the elbows, knees, back and buttocks. Immunofluorescence shows granular or linear IgA deposition at the dermo-epidermal junction. Almost all patients have partial villous atrophy on duodenal biopsy identical to that seen in coeliac disease, even though they usually have no gastrointestinal symptoms. In contrast, fewer than 10% of coeliac patients have evidence of dermatitis herpetiformis.

17. Treatment The rash usually responds to a gluten-free diet but some patients require additional treatment with dapsone (100-150 mg daily).

19. Tropical sprue Tropical sprue is defined as chronic, progressive malabsorption in a patient in or from the tropics, associated with abnormalities of small intestinal structure and function.

20. Pathophysiology: The epidemiological pattern and occasional epidemics suggest that an infective agent may be involved. Although no single bacterium has been isolated, the condition often begins after an acute diarrhoeal illness. Small bowel bacterial overgrowth with Escherichia coli, Enterobacter and Klebsiella is frequently seen. The changes closely resemble those of coeliac disease.

21. Clinical features There is diarrhoea, abdominal distension, anorexia, fatigue and weight loss. When the disorder becomes chronic, the features of megaloblastic anaemia (folic acid malabsorption) and other deficiencies, including ankle oedema, glossitis and stomatitis, are common.

22. Treatment Tetracycline 250 mg 6-hourly for 28 days is the treatment of choice and brings about long-term remission or cure. In most patients folic acid (5 mg daily) improve symptoms and jejunal morphology.

23. Small bowel bacterial overgrowth ('blind loop syndrome') The normal duodenum and jejunum contain less than 104/mL organisms which are usually derived from saliva. In bacterial overgrowth there may be 108-1010/mL organisms, most of which are normally found only in the colon.

25. Clinical features The patient presents with watery diarrhoea and/or steatorrhoea with anaemia due to B12 deficiency. These arise because of deconjugation of bile acids, which impairs micelle formation, and because of bacterial utilisation of vitamin B12.

26. Investigations Serum vitamin B12 concentration is low, whilst folate levels are normal or elevated because the bacteria produce folic acid. The diagnosis can often be made non-invasively using the glucose hydrogen or 14C-glycocholic acid breath tests. In these tests breath samples are serially measured after oral ingestion of the test material. Bacteria within the small bowel rapidly metabolise the glucose causing an early rise in breath hydrogen from glucose or 14C from 14C-glycocholate. which normally resulting from metabolism by colonic flora.

28. Management The underlying cause of small bowel bacterial overgrowth should be addressed. Tetracycline 250 mg 6-hourly for 7 days is the treatment of choice. Metronidazole 400 mg 8-hourly or ciprofloxacin 250 mg 12-hourly is an alternative. Some patients require up to 4 weeks of treatment and, in a few, continuous rotating courses of antibiotics are necessary.

29. Whipple's disease This rare condition is characterised by infiltration of small intestinal mucosa by 'foamy' macrophages which stain positive with periodic acid-Schiff (PAS) reagent. The disease is a multisystem one and almost any organ can be affected, sometimes long before gastrointestinal involvement becomes apparent.

30. Pathophysiology The disease is caused by infection with the Gram-positive bacillus Tropheryma whipplei which becomes resident within the macrophages in the bowel mucosa. Villi are widened and flattened containing densely packed macrophages in the lamina propria , which may obstruct lymphatic drainage, causing fat malabsorption.

31. Clinical features Middle-aged men are most commonly affected and the presentation depends on the pattern of organ involvement.

33. Whipple's disease is often fatal if untreated but responds well, at least initially, to intravenous ceftriaxone 2 g daily for 2 weeks, followed by oral co-trimoxazole for at least 1 year. Symptoms usually resolve quickly. Long-term follow-up is essential, as relapse occurs in up to one-third of patients.

34. Protein-losing enteropathy This term is used when there is excessive loss of protein into the gut lumen, sufficient to cause hypoproteinaemia. Protein-losing enteropathy occurs in many gut disorders but is most common in those where ulceration occurs . In other disorders protein loss results from increased mucosal permeability or obstruction of intestinal lymphatic vessels.

36. Patients present with peripheral oedema and hypoproteinaemia in the presence of normal liver function and without proteinuria. The diagnosis is confirmed by measurement of faecal clearance of α1-antitrypsin or 51Cr-labelled albumin after intravenous injection. Other investigations are performed to determine the underlying cause. Treatment is that of the underlying disorder, with nutritional support and measures to control peripheral oedema.

37. Lactose intolerance Human milk contains around 200 mmol/L (68 g/L) of lactose which is normally digested to glucose and galactose by the brush border enzyme lactase prior to absorption. In most populations enterocyte lactase activity declines throughout childhood. The enzyme is deficient in up to 90% of adult Africans, Asians and South Americans, but only 5% of northern Europeans.

38. In cases of genetically determined (primary) lactase deficiency, jejunal morphology is normal. 'Secondary' lactase deficiency occurs as a consequence of disorders which damage the jejunal mucosa, such as coeliac disease and viral gastroenteritis. Unhydrolysed lactose enters the colon, where bacterial fermentation produces volatile short-chain fatty acids, hydrogen and carbon dioxide.

39. Clinical features In most people lactase deficiency is completely asymptomatic. However, some complain of colicky pain, abdominal distension, increased flatus, borborygmi and diarrhoea after ingesting milk or milk products. Irritable bowel syndrome is often suspected but the diagnosis is suggested by clinical improvement on lactose withdrawal. The lactose hydrogen breath test is a useful non-invasive confirmatory investigation. Dietary exclusion of lactose is recommended, although most sufferers are able to tolerate small amounts of milk without symptoms. Addition of commercial lactase preparations to milk has been effective in some studies but is costly.

40. Carcinoid tumours These are derived from enterochromaffin cells and are most common in the appendix. Localised spread and the potential for metastasis to the liver increase with primary lesions over 2 cm in diameter. Overall, these tumours are less aggressive than carcinomas and their growth is usually slow.

41. The term 'carcinoid syndrome' refers to the systemic symptoms produced when secretory products of the neoplastic enterochromaffin cells reach the systemic circulation. When produced by the primary tumour they are usually metabolised in the liver and do not reach the systemic circulation. The syndrome is therefore only seen when 5-HT, bradykinin and other peptide hormones are released by hepatic metastases.

42. Clinical features of carcinoid tumours Small-bowel obstruction due to the tumour mass Intestinal ischaemia (due to mesenteric infiltration or vasospasm) Hepatic metastases causing pain, hepatomegaly and jaundice Flushing and wheezing Diarrhoea Cardiac involvement (tricuspid regurgitation, pulmonary stenosis, right ventricular endocardial plaques) leading to heart failure Facial telangiectasia

43. Management The treatment of a carcinoid tumour is surgical resection. The treatment of carcinoid syndrome is palliative because hepatic metastases have occurred, although prolonged survival is common. Hepatic artery embolisation retards growth of hepatic deposits. Octreotide 200 μg 8-hourly by subcutaneous injection is used to reduce tumour release of 5-HT, bradykinin and peptide hormones. Cytotoxic chemotherapy has only a minor role.