Malabsorption syndromes

Malabsorption syndromes

1. Malabsorption Syndrome Speaker : Dr. Saikat Mandal Moderator : Prof(Dr.) Sarbani Chattopadhyay

2. Malabsorption Syndrome Maldigestion: impaired breakdown of nutrients (carbohydrates, protein, fat) to absorbable split-products (mono-, di-, or oligosaccharides; amino acids; oligopeptides; fatty acids; monoglycerides) Malabsorption: defective mucosal uptake and transport of adequately digested nutrients including vitamins and trace elements .

3. Malabsorption Syndrome Malabsorption , which presents most commonly as chronic diarrhea, is characterized by defective absorption of fats, fat- and water-soluble vitamins, proteins, carbohydrates, electrolytes and minerals, and water Malabsorption Syndrome is a clinical term that encompasses defects occurring during the digestion and absorption of food nutrients by the gastrointestinal tract.

4. The digestion or absorption of a single nutrient component may be impaired, as in lactose intolerance due to lactase deficiency. However, when a diffusion disorder, such as celiac disease or Crohn's disease, affects the intestine, the absorption of almost all nutrients is impaired.

5. External Causes Diabetes mellitus Hyperthyroidism Hypothyroidism Addisons' disease Hyperparathyroidism Hypoparathyroidism Carcinoid syndrome Widespread skin disease Malnutrition. Collagen diseases. Eating disorders.

6. Pathophysiology Malabsorption results from disturbance in at least one of the four phases of nutrient absorption: Intraluminal digestion Terminal digestion Transepithelial transport Lymphatic transport

7. Defects in Malabosorptive and Diarrheal Disease Disease Intraluminal Digestion Terminal Digestion Terminal Digestion Lymphatic Transport Celiac disease + + Tropical sprue + + Chronic pancreatitis + Cystic fibrosis + Primary bile acid malabsorption + + Carcinoid syndrome + Autoimmune enteropathy + + Disaccharidase deficiency + Whipple disease + Abetalipoproteinemia + Viral gastroenteritis + + Bacterial gastroenteritis + + Inflammatory bowel disease + + +

8. Causes of Malabsorption Syndrome The best way to classify the numerous causes of malabsorption is to consider the aforesaid 4 phases of digestion and absorption.

9. The Luminal Phase Impaired nutrient hydrolysis The most common cause for impaired nutrient hydrolysis is pancreatic insufficiency. The resultant deficiencies in lipase and proteases lead to lipid and protein malabsorption, respectively. Inactivation of pancreatic enzymes by gastric hypersecretion

10. The Luminal Phase Inadequate mixing of nutrients, bile, and pancreatic enzymes, also causes impaired hydrolysis. Failure to convert a proenzyme to active form, cause protein maldigestion and malabsorption.

11. Impaired micelle formation Impaired micelle formation causes a problem in fat solubilization and subsequent fat malabsorption. D ecreased bile salt synthesis I mpaired bile secretion from biliary obstruction or cholestatic jaundice I mpaired enterohepatic bile circulation B ile salt deconjugation

12. Stasis of intestinal content caused by a motor abnormality ( eg , scleroderma, diabetic neuropathy, intestinal obstruction), an anatomic abnormality ( eg , small bowel syndrome, stricture, ischemia, blind loops), or small bowel contamination from enterocolonic fistulas can cause bacterial overgrowth.

13. Mucosal phase Disaccharidase deficiency can lead to disaccharide malabsorption . Lactase deficiency, either primary or secondary, is the most common form of disaccharidase deficiency. Secondary lactase deficiency can be due to acute gastroenteritis (rotavirus and giardia infection), chronic alcoholism, celiac sprue , radiation enteritis, regional enteritis, or AIDS enteropathy .

14. Mucosal phase Immunoglobulin A (IgA) deficiency (most common immunodeficiency) is due to decreased or absent serum and intestinal IgA, which clinically appears similar to celiac disease and is unresponsive to a gluten-free diet. Acrodermatitis enteropathica is an autosomal recessive disease with selective inability to absorb zinc, leading to villous atrophy and acral dermatitis.

15. Mucosal phase Impaired nutrient absorption Nutrient malabsorption is due to inherited or acquired defects. Inherited defects include glucose- galactose malabsorption, abetalipoproteinemia , cystinuria , and Hartnup disease.

16. Acquired disorders are far more common and are caused by the following: (1) Decreased absorptive surface area, (2) Damaged absorbing surface,; (3) Infiltrating disease of the intestinal wall, (4) Infections,

17. Post - absorptive Phase Obstruction of the lymphatic system, both congenital ( eg , intestinal lymphangiectasia , Milroy disease) and acquired ( eg , Whipple disease, neoplasm [including lymphoma], tuberculosis), impairs the absorption of chylomicrons and lipoproteins

18. Risk Factors Factors that may increase chance of having malabsorption include: Medical conditions affecting the intestine Use of laxatives Excessive use of antibiotics Intestinal surgery Excessive use of alcohol Travel to countries with high incidence of intestinal parasites.

19. Pathophysiology of Clinical Manifestations of Malabsorption Disorders Symptom or Sign Mechanism Weight loss/malnutrition Anorexia, malabsorption of nutrients Diarrhea Impaired absorption or secretion of water and electrolytes; colonic fluid secretion secondary to unabsorbed dihydroxy bile acids and fatty acids Flatus Bacterial fermentation of unabsorbed carbohydrate Glossitis , cheilosis , stomatitis Deficiency of iron, vitamin B12, folate , and vitamin A Abdominal pain Bowel distention or inflammation, pancreatitis Bone pain Calcium, vitamin D malabsorption , protein deficiency, osteoporosis Tetany , paresthesia Calcium and magnesium malabsorption Weakness Anemia, electrolyte depletion (particularly K + ) Azotemia, hypotension Fluid and electrolyte depletion Amenorrhea, decreased libido Protein depletion, decreased calories, secondary hypopituitarism Anemia Impaired absorption of iron, folate , vitamin B12 Bleeding Vitamin K malabsorption , hypoprothrombinemia Night blindness/ xerophthalmia Vitamin A malabsorption Peripheral neuropathy Vitamin B12 and thiamine deficiency Dermatitis Deficiency of vitamin A, zinc, and essential fatty acid

20. Diarrhea Diarrhea is the most common symptomatic complaint Diarrhea is defined as an increase in stool mass, frequency, or fluidity, typically greater than 200 g per day. In severe cases stool volume can exceed 14 L per day and, without fluid resuscitation, result in death. Painful, bloody, small-volume diarrhea is known as dysentery.

21. . Diarrhea can be classified according to four major categories: • Secretory diarrhea is characterized by isotonic stool and persists during fasting. • Osmotic diarrhea , due to the excessive osmotic forces exerted by unabsorbed luminal solutes. The diarrhea fluid is over 50 mOsm more concentrated than plasma and abates with fasting. • Malabsorptive diarrhea follows generalized failures of nutrient absorption and is associated with steatorrhea and is relieved by fasting. • Exudative diarrhea is due to inflammatory disease and characterized by purulent, bloody stools that continue during fasting.

22. Steatorrhea Steatorrhea is the result of fat malabsorption. The hallmark of steatorrhea is the passage of pale, bulky, and malodorous stools. Such stools often float on top of the toilet water and are difficult to flush. Also, patients find floating oil droplets in the toilet following defecation.

23. Weight loss and fatigue Weight loss is common and may be pronounced; however, patients may compensate by increasing their caloric consumption, masking weight loss from malabsorption. The chance of weight loss increases in diffuse diseases involving the intestine, such as celiac disease and Whipple disease.

24. Flatulence and abdominal distention Bacterial fermentation of unabsorbed food substances releases gaseous products, such as hydrogen and methane, causing flatulence. Flatulence often causes uncomfortable abdominal distention and cramps.

25. Edema Hypoalbuminemia from chronic protein malabsorption or from loss of protein into the intestinal lumen causes peripheral edema. Extensive obstruction of the lymphatic system, as seen in intestinal lymphangiectasia , can cause protein loss. With severe protein depletion, ascites may develop.

26. Anemia Depending on the cause, anemia resulting from malabsorption can be either microcytic (iron deficiency) or macrocytic (vitamin B-12 deficiency). Iron deficiency anemia often is a manifestation of celiac disease. Ileal involvement in Crohn disease or ileal resection can cause megaloblastic anemia due to vitamin B-12 deficiency.

27. Metabolic defects of bones Vitamin D deficiency can cause bone disorders, such as osteopenia or osteomalacia . Bone pain and pathologic fractures may be observed. Malabsorption of calcium can lead to secondary hyperparathyroidism.

28. Investigations

29. Tests for steatorrhea Quantitative test 72hr stool fat collection – gold standard > 6gm/day – pathologic P’ts with steatorrhea - >20gm/day Modest elevation in diarrheal disease (may not necessarily indicate Malabsorption ) Qualitative tests Sudan lll stain Detect clinically significant steatorrhea in >90% of cases Acid steatocrit – a gravimetric assay Sensitivity – 100%, specificity – 95% , PPV – 90% NIRA (near infra reflectance analysis) Equally accurate with 72hr stool fat test Allows simultaneous measurement of fecal fat, nitrogen, CHO

30. Schilling test To determine the cause of cobalamine (B 12 ) malabsorbtion Helps to asses the integrity of gastric, pancreatic and ileal functions. Abnormal cobalamine absorbtion in: pernicious anemia, ch. Pancreatitis, Achlorohydria , Bacterial overgrowth, ileal dysfunction The test Administering 58Co-labeled cobalamine Cobalamine 1mg i.m . 1hr after ingestion to saturate hepatic binding sites Collecting urine for 24 hr ( dependant on normal renal & bladder function) Abnormal - <10% excretion in 24 hrs

31. Schilling test cont …. 58Co-Cbl With Intrinsic factor With pancreatic enzyme 5 Days Of Ab Pernicious Anemia  N   Chronic Pancreatitis   N  Bacterial overgrowth    N Ileal disease    

32. D-xylose test D-xylose A Pentose monosacharide absorbed exclusively at the proximal SB Used to asses proximal SB mucosal function The test After overnight fast, 25gm D-xylose Urine collected for next 5 hrs Abnormal test - <4.5 gm excretion False + ve results: Renal dysfunction Inadequate urine sample Impaired gastric empyting , Ascitis Drugs( ASA,indometacin,Neomycin )

33. D-Xylose Test Helpful in Distinguishing Maldigestion from Malabsorption MALDIGESTION (pancreatic insufficiency) MALABSORPTION (celiac sprue ) Fecal Fat D-Xylose Excretion Normal Jejunal Biopsy Normal Abnormal “flat”

34. Barium studies A. Normal individual. B. Celiac sprue . C. Jejunal diverticulosis. D. Crohn's disease

35. Endoscopy Gross morphology – gives diagnostic clue Reduced duodenal folds and scalloping of duodenal mucosa – celiac disease Use of vital dyes to identify villous atrophy Biopsy – to establish Dx For p’ts with documented steatorrhea or ch. Diarrhea Lesions seen – classified in to three Diffuse, specific e.g. whippl’s Disease Patchy, specific – crohn’s D., lymphoma infectious causes Diffuse, non-specific – Celiac sprue , Tropical sprue autoimmune enteropathy Suspected distal pathology - push enteroscopy wireless capsule endoscopy

36. Cystic fibrosis ( MUCOVISCIDOSIS) is a disorder of ion transport in epithelial cells. It affects fluid secretion in Exocrine glands Respiratory , Gastrointestinal , and Reproductive tracts .

37. C ystic fibrosis transmembrane conductance regulator (CFTR )

38. Pathophysiology Gastrointestinal Pancreas Absence of CFTR limits function of chloride-bicarbonate exchanger to secrete bicarbonate Leads to retention of enzymes in the pancreas, destruction of pancreatic tissue. Intestine Decrease in water secretion leads to thickened mucus and dessicated intraluminal contents Obstruction of small and large intestines Biliary tree Retention of biliary secretion Focal biliary cirrhosis Bile duct proliferation Chronic cholecystitis , cholelithiasis

39. Gastrointestinal Exocrine pancreatic insufficiency Found in >90% of CF patients Protein and fat malabsorption Frequent bulky, foul-smelling stools Vitamin A, D, E, K malabsorption Sparing of pancreatic beta cells Beta cell function decreases with age Increased incidence of GI malignancy

40. Diagnosis DNA analysis not useful due to large variety of CF mutations Sweat chloride test >70 mEq /L 1-2% of patients with clinical manifestations of CF have a normal sweat chloride test Nasal transepithelial potential difference

41. Criteria One of the following Presence of typical clinical features History of CF in a sibling Positive newborn screening test Plus laboratory evidence for CFTR dysfunction Two elevated sweat chloride concentrations on two separate days Identification of two CF mutations Abnormal nasal potential difference measurement

42. Celiac Disease

43. History of Celiac Cereal grains were first domesticated from wild grasses in the Fertile Crescent about 10,000 years ago Simopoulos AP (ed): Evolutionary Aspects of Nutrition and Health. Diet, Exercise, Genetics and Chronic Disease. World Rev Nutr Diet. Basel, Karger, 1999, vol 84, pp 19–73

44. History of Celiac Aretaeus from Cappadochia (now Turkey) in the 2nd century AD described a chronic malabsorptive condition He named this disorder " koiliakos ” which is Greek for "suffering in the bowels.” Booth, CC. History of celiac disease. BMJ 1989; 298:527.

45. History of Celiac During World War II, celiac children improved during the food shortages when bread was unavailable. After the war, symptoms reoccurred when bread and cereals were reintroduced. Dutch pediatrician Willem K Dicke recognized and confirmed this association between cereal grains and malabsorption . Dicke, WK. Simple dietary treatment for the syndrome of GheeHerter. Ned Tijdschr Geneeskd 1941; 85:1715. DICKE, WK, WEIJERS, HA, VAN DE, KAMER JH. Coeliac disease. II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr 1953; 42:34.

46. Pathophysiology Celiac disease as an immune disorder that is triggered by an environmental agent (the gliadin component of gluten) in genetically predisposed individuals. Also known as- Celiac sprue Non - tropical sprue Gluten intolerance Gluten-sensitive enteropathy

47. Grain protein exists in four general storage forms which are categorized by their solubility characteristics: Prolamins (soluble in ethanol) Glutenins (partially soluble in dilute acid or alkali solutions) Globulins (soluble in 10 percent NaCl ) Minor albumins (soluble in water) Glutens specifically are the prolamins and the glutenins

48. Pathophysiology The pathophysiology of gliadin toxicity in celiac patients is poorly understood S imilarities between gliadin proteins and certain enteral pathogens may result in the immunologic response to antigens in gluten. The current hypotheses: Gliadin -sensitive T cells in genetically predisposed individuals recognize gluten-derived peptide epitopes and develop an inflammatory response which produces mucosal damage

49. Pathogenesis of Celiac Disease

50. Genetic factors play an important role- there is significantly increased risk of celiac among family members A close association with the HLA-DQ2 and/or DQ8 gene locus has been recognized HLA-DQ2 is found in 98 percent of celiac patients from Northern Europe. However, ~25% of “normal” individuals in this population will also demonstrate HLA-DQ2

51. HLA class II molecules are expressed on the surface of antigen-presenting cells They can bind to and subsequently present “foreign” peptides to populations of CD4 T cells that recognize the DQ2- or DQ8-peptide complex. Role of Tissue Transglutaminase - Tissue transglutaminase can deamidate glutamine, converting glutamine to negatively charged glutamic acid This renders these peptides better binders to the disease relevant DQ2 or DQ8 molecules Once bound to DQ2 or DQ8, the DQ-“gluten” peptide complexes activate DQ2 or DQ8 restricted T cells

52. Risk Factors for Celiac Disease People suffering from other immune diseases and certain genetic disorders are more likely to have celiac disease. Some disorders associated with celiac include: R heumatoid arthritis T ype 1 diabetes Thyroid disease A utoimmune liver disease Addison’s disease Sjogren’s disease L upus Down syndrome Turner syndrome L actose intolerance I ntestinal lymphoma

53. Malignant disease Malignant diseases are more frequent in patients with long-term untreated classical CD. Small-bowel adenocarcinoma , esophageal and oropharyngeal squamous -cell carcinoma, and non-Hodgkin’s lymphoma occur more often in CD patients than in healthy control individuals.

54. Diagnosis of Celiac: Serologic Testing Some of the serologic tests used to diagnose celiac: IgA and IgG antigliadin antibodies IgA endomysial antibodies IgA and IgG tissue transglutaminase antibodies Anti reticulin antibodies (no longer used )

55. 2. Histopathology : The only definitive test is small intestinal biopsy taken endoscopically (the proximal duodenum is maximally affected) or by Crosby capsule. It shows subtotal or total villous atrophy with intense inflammatory infiltration . 3. Genetic Testing : HLA‐DQ2 and HLA‐DQ8 markers in >90% CD patients

56. Normal Pathology

57. Diagnosis: Small Bowel Endoscopy Normal Celiac

58. Diagnosis of Celiac: Gluten Rechallenge Gluten Rechallenge - improvement in symptoms and histology with gluten avoidance with a documented return of these features upon gluten reintroduction. May be performed by consuming 10 g of gluten per day (an amount contained in four slices of regular bread) for four to six weeks. One hazard of rechallenge is development of fulminant diarrhea, with dehydration, acidosis, and other metabolic disturbances (" gliadin shock"). KRAINICK, HG, DEBATIN, F, GAUTIER, E, et al. [Additional research on the injurious effect of wheat flour in celiac disease.I . Acute gliadin reaction ( gliadin shock).]. Helv Paediatr Acta 1958; 13:432

59. Diagnosis of Celiac Disease Positive Negative Probability < 2 to 5 percent Obtain IgA endomysial or tTG Ab and serum IgA level Small bowel biopsy Diagnosis excluded

60. Probability > 2 to 5 percent IgA endomysial or tTG Ab + IgA AND Small bowel biopsy Family history Unexplained iron deficiency anemia Steatorrhea or other GI symptoms Failure to thrive Type 1 diabetes mellitus or other associated disorders Other symptoms { Both positive Histology - Serology + Histology + Serology - Both negative Review and/or repeat biopsy Diagnosis excluded Rule out other causes of villous atrophy - + + TREAT -

61. Lactose Intolerance

62. Lactose Intolerance Lactose intolerance is the inability to break down a type of natural sugar called lactose . Lactose is commonly found in dairy products, such as milk and yogurt.

63. Lactose Intolerance A person becomes lactose intolerant when his or her small intestine stops making enough of the enzyme lactase to digest and break down the lactose. When this happens, the undigested lactose moves into the large intestine. The bacteria that are normally present in the large intestine interacts with the undigested lactose. The condition may also be called lactase deficiency .

64. Etiology of lactose malabsorption Primary lactose malabsorption Racial or ethnic lactose malabsorption Developmental lactase deficiency Congenital lactase deficiency Secondary lactose malabsorption Bacterial overgrowth/stasis Mucosal injury of GIT that causes villus flattening

65. Racial or ethnic lactose malabsorption Genetically determined reduction of lactase activity Most common form of lactose malabsorption The great majority of the world’s population develop low intestinal lactase during mid-childhood (approximately at age 5 yrs ) This finding is most prominent in Asian and African populations; rare in Caucasians of Scandinavian background Molecular basis remains unknown

66. Developmental lactase deficiency Low lactase levels as a consequence of prematurity Lactase activity in the fetus increases late in gestation Premature infants born at 28-32 weeks of gestation have a reduced lactase activity

67. Congenital lactase deficiency Rare autosomal recessive disorder (Finnish population) Characterized by the absence of lactase activity in the small intestine, with normal histologic findings A gene located on the same chromosome of the lactase gene, is responsible for CLD Affected infants have diarrhea from birth, hypercalcemia and nephrocalcinosis

68. Secondary lactose malabsorption Bacterial overgrowth or stasis syndromes Increased fermentation of dietary lactose in the small bowel, leading to symptoms of lactose intolerance. Suspected from clinical history and from a very early peak of breath hydrogen during lactose challenge. Mucosal injury Villus flattening or damage to the intestinal epithelium Celiac disease Crohn’s disease Radiation enteritis, chemotherapy HIV enteropathy Whipple’s disease

69. The acidic and osmotic effects of undigested lactose may cause: Loose watery stool - with a degree of urgency an hour or two after ingestion of milk. Perianal itching due to acidic stools. Symptoms occur from one to several hours after ingestion of milk or dairy products. These symptoms are very nonspecific and occur with other disorders such as milk-protein sensitivity, allergic-type reactions to other substances in the meal, or intolerance of other saccharides .

70. Diagnosis Lactose tolerance test Oral administration of 50 gram lactose Blood glucose levels 0, 60 and 120 min Increase of blood glucose by less than 20mg/dl + symptoms – diagnostic False negative – diabetes, bacterial overgrowth, delayed gastric emptying Sensitivity of 75%, specificity of 96%

71. Lactose breath hydrogen test Oral lactose (2g/kg) Breath hydrogen sampled at baseline and at 30 min intervals for three hours Breath hydrogen value of 10ppm – normal, 10-20ppm – indeterminate unless symptomatic, >20ppm – diagnostic False positive – recent smoking , false negative – recent use of antibiotics, lung disorders, 1% non-hydrogen producers

72. Whipple Disease

73. Whipple’s Disease Whipple's disease is a rare bacterial infection that most often affects gastrointestinal system. Whipple's disease interferes with normal digestion by impairing the breakdown of foods, such as fats and carbohydrates Whipple's disease also can infect other organs, including brain, heart, joints and eyes. The cause of Whipple's disease is infection with the bacterium Tropheryma whipplei .

74. Tropheryma whippelli I solated in a cell culture from a patient with endocarditis aerobic , rod-shaped, gram-positive, non- acid fast , periodic acid-Schiff (PAS) positive bacillus member of the Actinomycetes ( placed between the genus Cellulomonas and the Actinomycetes clade ) It is found both intracellularly and extracellularly grow slowly in acidic vacuoles of cells

75. The bacteria will lead to the development of internal sores and cause body tissue to thicken. When the villi (finger-like tissues that absorb nutrients in the small intestine) begin to thicken, their natural shape begins to change. This damages the villi and prevents them from effectively absorbing nutrients. This, in turn, leads to many of the symptoms connected with Whipple’s.

76. Risk factors Because so little is known about the bacterium that causes Whipple's disease, risk factors for the disease haven't been clearly identified. Based on available reports, it appears more likely to affect: Middle-age and older individuals. Males more than females. Caucasian patients. Family clusters (suggesting an immunogenetic component). HLA-B27 antigen; HLA-DRB1*13 and DQB1*06 alleles. Sewage plant workers, farmers and agricultural workers.

77. Diagnosis Periodic acid schiff : PAS-positive, diastase-resistant inclusions on light microscopy Confirmed by characteristic trilaminar cell wall Polymerase Chain reaction: PCR-sequenced bacterial 16sRNA PCR can be applied to duodenal tissue, lymph node, pleural-fluid cells, and peripheral blood Abnormal Labs: ESR, CRP anaemia of chronic disease hypoalbuminaemia

78. The morphologic hallmark of Whipple disease is a dense accumulation of distended, foamy macrophages in the small intestinal lamina propria . The macrophages contain periodic acid–Schiff (PAS)-positive, diastase-resistant granules that represent lysosomes stuffed with partially digested bacteria. Intact rod-shaped bacilli can also be identified by electron microscopy

79. Whipple's Disease: showing macrophages in the small intestine

80. Whipple's Disease

81. Complications Whipple's disease is a progressive and potentially fatal disease. Although the infection is rare, associated deaths continue to be reported, due in large part to late diagnoses and delayed treatment. Death often is caused by the spread of the infection to the central nervous system, which can cause irreversible damage.

82. Tropical Sprue

83. Tropical Sprue Tropical sprue : is a malabsorption disease commonly found in the tropical regions, marked with abnormal flattening of the villi and inflammation of the small intestinal mucosa. Unrelated to gluten ingestion. People with tropical sprue do not absorb nutrients properly, especially vitamin B12 and folic acid.

84. Pathophysiology The exact pathogenesis poorly understood. An acute intestinal infection leads to jejunal and ileal mucosa injury; then intestinal bacterial overgrowth and increased plasma enteroglucagon results in retardation of small-intestinal transit. Central to this process is folate deficiency, which probably contributes to further mucosal injury.

85. Hormone enteroglucagon and motilin levels are elevated. Enteroglucagon causes intestinal stasis The upper small intestine is predominantly affected; Klebsiella , E coli and Enterobacter species , cyclospora are isolated and are the usual organisms associated with tropical sprue.

86. Bacterial over growth of small bowel Normal small intestine is bacterial sterile due to : Acid Int. peristalsis (major) Immunoglobulin Cause of bacterial growth. e.g. Small intestinal diverticuli Blind loop Strictures DM/ Scleroderma

87. Pathophysiology Bacterial over growth: Metabolize bile salt resulting in deconjugation of bile salt   Bile Salt  Impaired intraluminal micelle formation Malabsorption of fat. Intestinal mucosa is damaged by  Bacterial invasion  Toxin  Metabolic products  Damage villi  may cause total villous atrophy.

88. Clinically:  Steatorrhea  Anaemia  B12 def . Reversed of symptom after antibiotic treatment . Diagnosis:  Breath test  xylose test  Culture of aspiration (definitive) Treatment: Antibiotic  Tetracyclin  Ciprofl0xacin  Metronidazole  Amoxicillin

89. Autoimmune Enteropathy

90. X-linked disorder characterized by severe persistent diarrhea and autoimmune disease. O ccurs most often in young children. S evere familial form, termed IPEX I mmune dysregulation , P olyendocrinopathy , E nteropathy , X-linkage D ue to a germline mutation in the FOXP3 gene , which is located on the X chromosome .

91. FOXP3 is a transcription factor expressed in CD4+ regulatory T cells. I ndividuals with IPEX and FOXP3 mutations have defective T-regulatory function. Autoantibodies to enterocytes and goblet cells are common. A ntibodies to parietal or islet cells. Within the small intestine intraepithelial lymphocytes may be increased .

92. A rare autosomal recessive disease characterized by an inability to secrete triglyceride-rich lipoproteins. C aused by a mutation in the microsomal triglyceride transfer protein (MTP) that catalyzes transport of triglycerides , cholesterol esters, and phospholipids. MTP-deficient enterocytes are unable to export lipoproteins and free fatty acids .

93. The malabsorption of is therefore a failure of transepithelial transport . Lipid vacuolization of small intestinal epithelial cells is evident and can be highlighted by special stains, such as oil red-O, particularly after a fatty meal. P resents in infancy with failure to thrive, diarrhea, and steatorrhea . C omplete absence of all plasma lipoproteins containing apolipoprotein B. Acanthocytic red cells (burr cells) in peripheral blood smears.

94. Possible Complications Long-term malabsorption can result in: Anemia Gallstones Kidney stones Osteoporosis and bone disease Malnutrition and vitamin deficiencies

95. Take Home Message Wide spectrum of disorders Both local and systemic causes are there Various genetic, environmental & pathogenic organisms implicated History & HPE often diagnostic

96. Thank You