MALABSORPTION SYNDROME

2. MALABSORPTION SYNDROME

3. The term maldigestion refers to defective hydrolysis of nutrients, whereas malabsorption refers to impaired mucosal absorption. • The major part of digestion occurs in the duodenum and most proximal jejunum.

4. The complete process of absorption consists of a luminal phase, in which various nutrients are hydrolyzed and solubilized; a mucosal phase, in which further processing takes place at the brush border of the epithelial cell with subsequent transfer into the cell; and a transport phase, in which nutrients are moved from the epithelium to the portal venous or lymphatic circulation.

5. LUMINAL PHASE • pancreatic enzymes, particularly lipase, colipase, and trypsin; • gastric digestive enzymes

6. Mucosal Phase • Extensive mucosal loss (resection or infarction) • Diffuse mucosal disease (celiac sprue;Crohn's disease; irradiation; infection; infiltrations; drugs: alcohol, colchicine, neomycin, iron salts) • Brush border hydrolase deficiency (lactase deficiency) • Transport defects (vitamin B12 and folate uptake)

7. TRANSPORT PHASE • After absorption, nutrients leave the cells through venous or lymphatic channels. Consequently, malabsorption may occur after mesenteric venous obstruction, lymphangiectasia, or lymphatic obstruction from malignancy or infiltrative processes (such as Whipple's disease.)

8. Tests of absorption These are required only in complicated cases. • Fat malabsorption. The confirmation of the presence of steatorrhoea is only occasionally necessary. Three-day faecal fat analysis, breath tests and serum β carotene are now rarely performed. In the rare cases when it is really necessary to confirm steatorrhoea, Sudan III staining of a faecal sample can be used. • Lactose tolerance test. This involves the oral ingestion of 50 g of lactose and the measurement of blood glucose. The test is of little use in adults as lactose intolerance is not a clinical problem since these patients avoid milk by choice.

9. Other tests • Hydrogen breath test. This is frequently used as a screening test to detect bacterial overgrowth. Oral lactulose or glucose is metabolized by bacteria with the production of hydrogen. • An early rise in the breath hydrogen will indicate bacterial breakdown in the small intestine.

10. Rapid transit of the lactulose to the large intestine will also produce a rise in breath hydrogen. As bacteria are present in the oral cavity, the mouth should be rinsed out with an antiseptic mouthwash prior to the test being performed. • This test is simple to perform and it does not involve radioisotopes. However, interpretation is often difficult with a low sensitivity and specificity.

11. 14C-glycocholic acid breath test.This was performed to look for bacterial overgrowth. Bacteria deconjugate the bile salts, releasing [14C]-glycine, which is metabolized and appears in the breath as 14CO2. It has largely been replaced by the hydrogen breath test. • Direct intubation.Aspiration of intestinal juices is another method by which bacterial contamination can be detected, but is seldom used. Bacterial counts are performed on aerobic and anaerobic cultures. Chromatography of bile salts can also be performed on the aspirate to detect evidence of deconjugation by bacteria.

12. Pancreatic tests.these are used in the differential diagnosis of steatorrhoea. • Other blood tests.Serum immunoglobulins are measured to exclude immune deficiencies. Gut peptides (e.g. vasoactive intestinal peptide - VIP) are measured in high-volume secretory diarrhoea, and chromogranins A and B are raised in endocrine tumours.

13. MALABSORPTION • In many small bowel diseases, malabsorption of specific substances occurs, but these deficiencies do not dominate the clinical picture. • An example is Crohn's disease, in which malabsorption of vitamin B12 can be demonstrated, but this is not usually a problem and diarrhoea and general ill-health are the major features.

14. Disorders of the small intestine causing malabsorption

15. Coeliac disease(gluten-sensitive enteropathy) • Coeliac disease is a condition in which there is an inflammation of the jejunal mucosa that improves when the patient is treated with a gluten-free diet and relapses when gluten is reintroduced. Gluten is contained in the cereals wheat, rye and barley.. • It is closely related to dermatitis herpetiformis, a skin disorder that has an associated gluten-sensitive enteropathy (see below).

16. Incidence • Coeliac disease is common in Northern Europe and epidemiological studies have shown a prevalence of 1 in 100 to 1 in 6500 in different temperate countries. It occurs throughout the world, but is rare in the black African. • There is an increased incidence of coeliac disease within families but the exact mode of inheritance is unknown; 10-15% of first-degree relatives will have the condition, although it may be asymptomatic.

17. DQ2 (DQA*0501, DQB1*0201) and DQ8 (DQA1*0301, DQB1*0302) are associated with coeliac disease. Over 90% of patients will have DQ2, compared with 20-30% of the general population. • Non-HLA regions linked to coeliac disease are chromosome 5q31-33, possibly 11q, and others are being identified. However, the fact that not all patients have these haplotypes, and that as many as 30% of identical twins are discordant for the condition, suggests an additional factor, e.g. environmental.

18. Aetiology • Gluten is a high - molecular - weight, heterogeneous compound that can be fractionated to produce α-, β-, γ- and ω-gliadin peptides. α-Gliadin is the main damaging peptide to the small intestinal mucosa although the other smaller peptides are also 'toxic'. • T cells play a central role in the aetiopathogenesis and react with the enzyme tissue transglutaminase (the main antigen of the endomysial antibody).

19. Pathology • The mucosa of the proximal small bowel is predominantly affected, the mucosal damage decreasing in severity towards the ileum as the gluten is digested into smaller 'non-toxic' fragments. • There is an absence of villi, making the mucosal surface flat. Histological examination shows crypt hyperplasia with chronic inflammatory cells in the lamina propria and villous atrophy (Marsh type III).

20. Clinical features • Coeliac disease can present at any age. In infancy it appears after weaning on to gluten-containing foods. The peak incidence in adults is in the fifth decade, with a female preponderance. • The symptoms are very variable and often non-specific with tiredness and malaise often associated with an anaemia. Many patients are asymptomatic (silent) and picked up on incidental findings, e.g. a raised MCV. • Common GI symptoms include diarrhoea or steatorrhoea, abdominal discomfort, bloating or pain and weight loss.

21. Mouth ulcers and angular stomatitis are frequent and can be intermittent. Infertility and neuropsychiatric symptoms of anxiety and depression occur. Osteoporosis is common and occurs even in patients on long-term gluten-free diets. • Rare complications include tetany, osteomalacia, or gross malnutrition with peripheral oedema. Neurological symptoms such as paraesthesia, ataxia (due to cerebellar calcification), muscle weakness or a polyneuropathy occur; the prognosis for these symptoms is variable.

22. There is an increased incidence of atopy and autoimmune disease, including thyroid disease, insulin-dependent diabetes, primary biliary cirrhosis and Sjögren's syndrome. • Other associated diseases include inflammatory bowel disease, chronic liver disease, fibrosing allergic alveolitis and epilepsy. IgA deficiency is more common than in the general population. • Physical signs are usually few and non-specific and are related to anaemia and malnutrition.

23. Investigations Endomysial (EMA) and tissue transglutaminase (tTG) antibodies (IgA). • These antibodies have a high sensitivity and specificity for the diagnosis of untreated coeliac disease and can also be used as screening tests. • They are the investigation of first choice. An immunofluorescent test for endomysial antibodies (EMA) can be performed on umbilical cord tissue or monkey oesophagus and the antigen for EMA is tissue transglutaminase.

24. Anti-tissue transglutaminase antibodies are measured using an ELISA. In the presence of a typical clinical picture and the presence of these antibodies, a confirmatory small bowel biopsy may not always be required although most doctors prefer to have one performed. • Anti-reticulin antibodies (ARA) are also very sensitive but not so specific, as they are seen in other gastrointestinal conditions (e.g. Crohn's disease). Anti-gliadin antibodies (AGA) are less sensitive and are not used.

25. Duodenal/jejunal biopsy. The mucosal appearance of a small bowel biopsy specimen is diagnostic and regarded as the 'gold standard' although errors occur, particularly with poorly orientated specimens. Other causes of a flat mucosa in adults are rare and are shown in. • At endoscopy, the duodenal folds look effaced and a dye can be sprayed on to the duodenal mucosa to accentuate the smoothness of the mucosa (positive dye test) before the biopsy is taken.

26. Haematology. A mild or moderate anaemia is present in 50% of cases. Folate deficiency is almost invariably present in coeliac disease, giving rise in most instances to a high MCV. B12 deficiency is rare but iron deficiency due to malabsorption of iron and increased loss of desquamated cells is common. • A blood film may therefore show microcytes and macrocytes as well as hypersegmented polymorphonuclear leucocytes and Howell-Jolly bodies due to splenic atrophy found in most patients.

27. Absorption tests are often abnormal but are seldom performed. • Radiology. A small bowel follow-through may show dilatation of the small bowel with a change in fold pattern. Folds become thicker and in the severer forms total effacement is seen. Radiology is now mainly used when a complication, e.g. lymphoma, is suspected.

28. Wireless capsule endoscopy. is used to look for gut abnormalities when a complication is suspected. • Bone densitometry. (DXA) should be performed on all patients because of the risk of osteoporosis. • Biochemistry. In the severely ill patient, biochemical abnormalities, e.g. hypoalbuminaemia, low calcium and high phosphate (osteomalacia) are seen.

29. Treatment and management • Treatment with a gluten-free diet usually produces a rapid clinical and morphological improvement. • Replacement haematinics, e.g. iron, folic acid, calcium, are given initially to replace body stores. • The usual cause for failure to respond to the diet is poor compliance. Dietary adherence can be monitored by serial tests for EMA and tTG. If clinical progress is suboptimal then a repeat intestinal biopsy should be taken.

30. If the diagnosis is equivocal a gluten challenge, i.e. reintroduction of gluten with evidence of jejunal morphological change, confirms the diagnosis, but is only performed if the diagnosis is equivocal. • A transient glutenintolerance can occur in early childhood.

31. Despite advice, many patients do not keep to a strict diet but nevertheless maintain good health. The long-term effects of this low gluten intake are uncertain but osteoporosis is seen even in the treated case. • Patients should have pneumococcal vaccinations (because of splenic atrophy) once every 5 years

32. Complications • A few patients do not improve on a strict diet (unresponsive 'coeliac disease'). Often no cause for this is found, but intestinal lymphoma, ulcerative jejunitis or carcinoma are sometimes responsible. The incidence of enteropathy-associated T-cell lymphoma (EATCL) is increased in coeliac disease. • Ulcerative jejunitis may present with fever, abdominal pain, perforation and bleeding.

33. Diagnosis for these conditions is with barium studies but laparotomy with full-thickness biopsies is often required. • Steroids and immunosuppressive agents, e.g. azathioprine, are used. • Carcinoma of the small bowel and oesophagus as well as extragastrointestinal cancers are also seen. Malignancy seems to be unrelated to the duration of the disease but the incidence is reduced by a gluten-free diet.

34. Dermatitis herpetiformis • This is an uncommon blistering subepidermal eruption of the skin associated with a gluten-sensitive enteropathy. • Rarely there may be gross malabsorption, but usually the jejunal morphological abnormalities are not as severe as in coeliac disease. • The inheritance and immunological abnormalities are the same as for coeliac disease. The skin condition responds to dapsone but both the gut and the skin will improve on a gluten-free diet.

35. Tropical sprue • This is a condition presenting with malabsorption that occurs in residents or visitors to a tropical area where the disease is endemic. • Malabsorption of a mild degree, sometimes following an enteric infection, is quite common and is usually asymptomatic. This is sometimes called tropical malabsorption.

36. The term tropical sprue is reserved for severe malabsorption (of two or more substances) that is usually accompanied by diarrhoea and malnutrition. Tropical sprue is endemic in most of Asia, some Caribbean islands, Puerto Rico and parts of South America. • Epidemics occur, lasting up to 2 years, and in some areas repeated epidemics occur at varying intervals of up to 10 years.

37. Aetiology • The aetiology is unknown, but is likely to be infective because the disease occurs in epidemics and patients improve on antibiotics. • A number of agents have been suggested but none has been shown to be unequivocally responsible. Different agents could be involved in different parts of the world.

38. Clinical features • These vary in intensity and consist of diarrhoea, anorexia, abdominal distension and weight loss. The onset is sometimes acute and occurs either a few days or many years after being in the tropics. Epidemics can break out in villages, affecting thousands of people at the same time. The onset can also be insidious, with chronic diarrhoea and evidence of nutritional deficiency. • The clinical features of tropical sprue vary in different parts of the world, particularly as different criteria are used for diagnosis.

39. Diagnosis • Acute infective causes of diarrhoea must be excluded , particularly Giardia, which can produce a syndrome very similar to tropical sprue. • Malabsorption should be demonstrated, particularly of fat and B12. • The jejunal mucosa is abnormal, showing some villous atrophy (partial villous atrophy). In most cases the lesion is less severe than that found in coeliac disease, although it affects the whole small bowel. Mild changes can be seen in asymptomatic individuals in the tropics, so jejunal mucosal changes must be interpreted carefully.

40. Treatment and prognosis • Many patients improve when they leave the sprue area and take folic acid (5 mg daily). Most patients also require an antibiotic (usually tetracycline 1 g daily) to ensure a complete recovery; it may be necessary to give this for up to 6 months. • The severely ill patient requires resuscitation with fluids and electrolytes for dehydration; any nutritional deficiencies should be corrected. Vitamin B12 (1000 μg) is also given to all acute cases. • The prognosis is excellent. Mortality is usually associated with water and electrolyte depletion, particularly in epidemics.

41. Bacterial overgrowth • The gut contains many resident bacteria with anaerobic bacteria, e.g. Bacteroides, bifidobacteria, being 100-1000 times more abundant than aerobic (facultative anaerobes), e.g. Escherichia, Enterobacter, Enterococcus. • This gut microflora has major functions including metabolic, e.g. fermentation of non-digestible dietary residues into short chain fatty acids as an energy source in the colon. Bacteria also initiate vitamin K production.

42. They control epithelial cell proliferation and are involved in the development and maintenance of the immune system. They protect the gut mucosa from colonization by pathogenic bacteria. • The upper part of the small intestine is almost sterile, containing only a few organisms derived fromthe mouth. Gastric acid kills most organisms and intestinal motility keeps the jejunum empty. The normal terminal ileum contains faecal-type organisms, mainly Escherichia coli and anaerobes and the colon has abundant bacteria.

43. Bacterial overgrowth is normally only found associated with a structural abnormality of the small intestine, although it can occur occasionally in the elderly without such abnormality. E. coli and/or Bacteroides, both in concentrations greater than 106/mL are found as part of a mixed flora. • These bacteria are capable of deconjugating and dehydroxylating bile salts, so that unconjugated and dehydroxylated bile salts can be detected in aspirates by chromatography. The clinical features are chiefly diarrhoea and steatorrhoea. Steatorrhoea occurs as a result of conjugated bile salt deficiency.

44. The bacteria are able to metabolize vitamin B12 and interfere with its binding to intrinsic factor, thereby leading to B12 deficiency. Conversely some bacteria produce folic acid giving a high serum folate. • Bacterial overgrowth has only minimal effects on other substances absorbed from the small intestine. The vitamin B12 deficiency is not so severe as to produce a neurological deficit. Confirmation of bacterial overgrowth is with the hydrogen breath test ; aspiration studies are not routinely performed.

45. Treatment • If possible, the underlying lesion should be corrected (e.g. a stricture should be resected). With multiple diverticula, grossly dilated bowel, or in Crohn's disease, this may not be possible and rotating courses of antibiotics are necessary, such as metronidazole, a tetracycline, or ciprofloxacin.

46. Intestinal resection • Intestinal resection is usually well tolerated, but massive resection is followed by the short-bowel syndrome. • The effects of resection depend on the extent and the areas involved. Because the gut is long, a 30-50% resection can usually be tolerated without undue problems. Residual jejunum shows less capacity for structural and functional adaptation than residual ileum.

47. Ileal resection • The ileum has specific receptors for the absorption of bile salts and vitamin B12, so that relatively small resections will lead to malabsorption of these substances. Removal of the ileocaecal valve increases the incidence of diarrhoea. • The following occur in ileal resection:Bile salts and fatty acids enter the colon and cause malabsorption of water and electrolytes leading to diarrhoea .

48. Increased bile salt synthesis can compensate for loss of approximately one-third of the bile salts in the faeces. • Greater loss than this results in decreased micellar formation and steatorrhoea, and lithogenic bile and gallstone formation.

49. Increased oxalate absorption is caused by the presence of bile salts in the colon. This gives rise to renal oxalate stones. • There is a low serum B12 and macrocytosis. • Glucagon-like peptide 2 (GLP-2) is low following ileal resection. GLP-2 is a specific growth hormone for the enterocyte and this deficiency may explain the lack of adaptation with an ileal resection.

50. Investigations include a small bowel follow-through, measurement of B12, bile salts and occasionally fat absorption. A hydrogen breath test will show rapid transit . • Many patients require B12 replacement and some need a low-fat diet if there is steatorrhoea. • If diarrhoea is a problem, colestyramine, which binds bile salts, often helps.