1. Malabsorption

2. Case 32 year old man previously well: 3 months loose, soft foul-smelling bowel movement 6 kg weight loss Tired, weak Abdominal distension Bleeding tendency Back pain

3. Case Thin, pale, bruises on skin Ankle edema Hemoglobin 11.2 g/dL, MCV 105 Albumin 3.1 g/dL (N >3.4) PT-INR 1.9 (N <1.2) Serum calcium 6.9 (N 8.5-10.2 mg/dL) Stool fecal fat excretion 19 g/day

4. Malabsorption Clinical syndrome: Due to defects occurring during the digestion and absorption of food nutrients by the gastrointestinal tract Result of many different disease processes: –Luminal –Absorptive –Post-abortive phases

5. Symptoms 3 months loose, soft foul-smelling bowel movement Diarrhea –Most common symptomatic complaint –Frequently watery –Cause Osmotic load received by the intestine Bacteria produce hydroxy fatty acids from undigested fat increases net fluid secretion from the intestine

6. Symptoms 3 months loose, soft foul-smelling bowel movement - Stool fecal fat excretion 19 g/day Steatorrhea >7g fat/day –Steatorrhea - fat malabsorption –Pale, bulky, and malodorous stools Float on top of the toilet water Difficult to flush Oil droplets in the toilet following defecation

7. Symptoms 6 kg weight loss Tired Weight loss and fatigue –Weight loss is common –Compensate by increasing caloric consumption, –Most noticeable in diffuse diseases Celiac disease and Whipple disease

8. Symptoms Abdominal distension Flatulence and abdominal distention –Bacterial fermentation of unabsorbed food hydrogen and methane Causes abdominal distention and cramps

9. Symptoms Bleeding tendency, bruises on skin, PT-INR 1.9 (N <1.2) Bleeding disorders –Vitamin K malabsorption and subsequent hypoprothrombinemia. –Easy bruising –Rarely melena and hematuria

10. Symptoms Ankle edema, albumin 3.1 g/dL (N >3.4) Edema (also ascites) Hypoalbuminemia –Protein malabsorption –Loss of protein into lumen Intestinal lymphangiectasia –Obstruction of the lymphatic system, Lymphoma

11. Symptoms Back pain, serum calcium 6.9 (N 8.5-10.2 mg/dL) Metabolic defects of bones –Vitamin D deficiency Osteopenia or osteomalacia. –Bone pain and pathological fractures Malabsorption of calcium can lead to secondary hyperparathyroidism.

12. Symptoms Weakness Neurological manifestations –Vitamin malabsorption Generalized motor weakness Peripheral neuropathy

13. Digestion and Absorption Carbohydrate (CHO) Protein Fat Vitamins and minerals Water and electrolytes

14. Malabsoption - Mechanisms Luminal phase –Impaired nutrient hydrolysis –Impaired micelle formation –Luminal processing Mucosal phase –Impaired brush-border hydrolase activity –Impaired nutrient absorption Post absorptive phase

15. Malabsorption Luminal Phase

16. Luminal Phase Pancreas Exocrine –Enzymes (acini) –Bicarbonate (ducts)

17. Luminal Malabsortion or Maldigestion Impaired Nutrient Hydrolysis Pancreatic insufficiency –Chronic pancreatitis, pancreatic resection, pancreatic cancer, or cystic fibrosis –Lipase, protease, carbhydrase deficiency leads to lipid,protein, carbohydrate malabsorption, respectively

18. Malabsorption - Pancreas Methods to assess dysfunction 1.Anatomic - damage 2.Physiology - assessement of function

19. Anatomical – Chronic Pancreatitis Calcified Pancreas

20. Anatomical – ERCP Chronic Pancreatitis and Carcinoma Carcinoma

21. Anatomical – Chronic Pancreatitis - EUS

22. Malabsorption – Pancreatic Function Secretory Function Non-invasive –Low fecal Chymotrypsin and Elastase 1 –Bentiromide Test Invasive –Collect pancreatic juice –Before and after hormonal stimulation Secretin, CCK –Analyze volume, enzyme activity and bicarbonate

23. Function - Bentiromide Test PABA is cleaved off by pancreatic chymotrypsin Free PABA is absorbed, conjugated by the liver, and excreted in urine and measured Decreased PABA excretion pancreatic insufficiency Highly sensitive and specific for advanced pancreatic failure Not very sensitive in mild pancreatic insufficiency

24. Luminal Malabsortion or Maldigestion Impaired Micelle Formation – Bacterial Overgrowth Bile salt deconjugation: Stasis of intestinal content caused by a motor abnormality (eg, scleroderma, diabetic neuropathy, intestinal obstruction), Anatomic abnormality (eg, small bowel diverticula, stricture, blind loops Small bowel contamination from enterocolonic fistulas

25. Malabsorption - Bacterial Overgrowth Small Bowel Series DiverticulosisScleroderma

26. Malabsorption – Bacterial Overgrowth Breath Tests Hydrogen breath test –Glucose Bile acid breath test –C 13 -glycocholate breath test Xylose breath test –C 13 -xylose

27. Malabsorption - Bacterial Overgrowth Culture Quantitative culture of an aspirate of luminal fluid –The gold standard –Positive culture > 10 6 organisms/mL –Aerobic or anaerobic culture

28. Luminal Malabsortion or Maldigestion Impaired Micelle Formation Impaired fat solubilization – Decreased bile salt synthesis from severe parenchymal liver disease –impaired bile secretion from biliary obstruction or cholestatic jaundice X

29. Luminal Malabsortion or Maldigestion Impaired Micelle Formation –Impaired enterohepatic bile circulation small bowel resection or regional enteritis X

30. Luminal Malabsortion or Maldigestion Impaired Nutrient Hydrolysis Inadequate mixing of nutrients, bile, and pancreatic enzymes –Rapid transit –Gastrojejunostomy

31. Malabsorption Mucosal phase

32. Malabsorption Mucosal phase Reduced brush-border hydrolase Primary lactase deficiency –Genetic factors Secondary lactase deficiency –Acute gastroenteritis, chronic alcoholism, celiac sprue, radiation enteritis, regional enteritis, or AIDS enteropathy.

33. Malabsorption - Mucosal phase Impaired nutrient absorption Acquired disorders Damaged absorbing surface: –Celiac sprue, tropical sprue, giardiasis, Crohn disease, AIDS enteropathy, chemotherapy, or radiation therapy Decreased absorptive surface area: –intestinal resection or intestinal bypass –Infiltrating disease of the intestinal wall: lymphoma and amyloidosis.

34. Malabsorption Postabsorptive Phase

35. Malabsorption Postabsorptive Phase Obstruction of the lymphatic system Congenital : –Intestinal lymphangiectasia Acquired –Whipple disease, neoplasm [ie.g. lymphoma], tuberculosis –Impaired absorption of chylomicrons and lipoproteins –fat malabsorption and/or protein-losing enteropathy

36. Investigation of Malabsorption Confusion Jungle

37. Malabsorption - Investigation Does the patient have malabsorption? –History –Physical –Initial blood tests Deficiencies of vitamins and minerals –Stool examination 3-Day Fecal Fat >6g/day or > 7% of fat intake

38. Suspected malabsorption

39. Malabsorption Major Categories and Causes Intraluminal - maldigestion –Pancreatic insufficiency –Bacterial overgrowth –Defective bile secretion Mucosal - malabsorption –Celiac disease –Tropical sprue –Infection – bacteria, parasites –Whipple’s disease –Intestinal resection –short gut –Abetalipoproteinemia –Crohn’s disease

40. Malabsorption Luminal, Mucosal or Postabsorptive? D-Xylose test –Oral dose 25 g D-xylose in 250 – 500 mL water over 10 min to fasting subject –D-xylose measurement in blood hourly upto 5 h and in 5 h-urine –Normal blood D-xylose rises upto 30 – 35 mg/dL –at least 25 % of the dose should be excreted in 5 h-urine Diabetes mellitus Liver disease (20% of cirrhosis patients, chronical hepatitis, fat liver) Hypoglycemia Malnutrition Overdose antidiabetic drug Pancreas cancer Chronical alcohol abuse Hyperglycemia Reference range for OGTT: Fasting 60 min 120 min normal <100 mg/dL 160 mg/dL 120 mg/dL impaired 100-130 mg/dL 160-220 mg/dL 120-150 mg/dL Assessment of Malabsorption Carbohydrate I – oral dose 25 g D-xylose in 250 – 500 mL water over 10 min to fasting subject – D-xylose measurement in blood hourly upto 5 h – Normal blood D-xylose rises upto 30 – 35 mg/dL at least 25 % of the dose should be excreated in 5 h-urine D-Xylose test in patient with bowel resection after treatment with TPN and EN

41. Malabsorption - Investigation Xylose Normal Suspect pancreatic disease

42. Malabsorption- Pancreatic Failure Trial of Treatment Pancreatic enzyme replacement –Provides sufficient lipase, trypsin, and amylase to abolish maldigestion of fat, protein, and carbohydrate – Arrives intact in appropriate amounts in the duodenum –Liberates active enzyme in the duodenum –Has a long shelf life. –Palatable, cheap and reliable.

43. Malabsorption - Bacterial Overgrowth Trial of treatment –Antibiotics

44. Malabsorption Mucosal/Postmucosal Disease

45. Mucosal Malabsorption – Small Bowel Series Small bowel barium studies –An abnormal small bowel pattern –The mucosa pattern associated with celiac disease often becomes obliterated or coarsened –Flocculation of the barium occurs in the gut lumen –Regional enteritis of the small intestine can lead to stricture, ulceration, and fistula formation

46. Mucosal Malabsorption Biopsy Endoscopically obtained Definitive diagnosis of malabsorption of the mucosal/post absorptive phase Examples –Celiac sprue, giardiasis, Crohn disease, Whipple disease, amyloidosis, abetalipoproteinemia, and lymphoma.

47. Jejunal biopsy-Whipple's disease

48. Eosinophilic Gastroenteritis

49. Lymphangiectasia Dilated Submucosal Lacteals

50. Celiac disease

51. Celiac Disease Genetically-determined Chronic inflammatory intestinal disease Environmental precipitant- gluten. Mainly non-gastrointestinal symptoms Patients present to various medical practitioners

52. Celiac Disease - Genetics Multigenic disorder Associated with HLA-DQ2 (DQA1*05/DQB1*02) or HLA-DQ8 (DQA1*0301/DQB1*0302). HLA-DQ2 >90% of people with coeliac disease. HLA-DQ2 or HLA-DQ8 necessary, but not sufficient, to develop the disease. Identical twins 70% concordance

53. Epidemiological studies 1/100 people Any age Mortality excess - 1·9–3·8 Reduction in excess mortality after 1–5 years on gluten free diet

54. Celiac Disease – The Old Picture

55. Celiac disease – The Usual Picture

56. What we see is the tip of the iceberg

57. Celiac Disease Most cases undiagnosed

58. Celiac Disease - Clinical Classification Symptomatic, active, or classic celiac disease –diarrhoea, with or without malabsorption; Asymptomatic –Gastrointestinal symptoms are absent or not prominent Latent celiac disease –May develop celiac disease in the future –At time of investigation has normal mucosa while ingesting gluten

59. Celiac – Spectrum of Disease

61. Celiac Disease – Toxic Proteins Gliadin - most studied All gluten containing proteins Barley - hordeins Rye - secalins Dose-dependent response

62. Celiac Disease - Clinical Symptomatic –weight loss, metabolic bone disease, anaemia, and general weakness Trigger Pregnancy Traveler's diarrhea Gastroenteritis Gastrointestinal surgery

63. Celiac Disease – Atypical Presentations Osteoporosis Infertility Autoimmune diseases Malignant disease, especially lymphomas

64. Celiac Disease – Atypical Presentations Aphthous stomatitis Arthritis Dental enamel defects Abnormal liver transminases

65. Celiac Disease – Atypical Presentations Villous atrophy in patients undergoing endoscopy Assessment of iron concentrations and bone density Dermatitis herpetiformis Neurological symptoms –peripheral neuropathy –ataxia –epilepsy

66. Celiac Disease - Screening First-degree relatives Type 1 diabetes Down's syndrome Chronic liver disease –primary biliary cirrhosis

67. Celiac Disease - Diagnosis Small intestinal biopsy – gold standard Improvements in clinical symptoms or histological tests on a gluten-free diet Positive serological tests

68. Celiac Disease - Endoscopy NormalCeliac Disease

69. Celiac Disease - Biopsies Loss of crypts Increased mitotic activity Loss of brush border Infiltration with lymphocytes and plasma cells (B-cells sensitized to gliaden) Lesion more severe in proximal small intestine than distal NormalCeliac Disease

70. Celiac Disease - Serological Testing Anti-gliadin antibodies Anti-endomysium almost 100% Anti- tissue transglutaminase (Anti-tTG)

71. Celiac Disease – Pitfalls in Diagnosis Serological tests Selective IgA deficiency 1·7%–2·6% 10 to 16-fold higher - general population Check total serum IgA Test for IgG endomysial antibodies, IgG anti-tTG

72. Celiac Disease – Serological Testing Titres of anti-endomysial antibodies correlate with: –Degree of villous atrophy –Presentation with symptoms Patients with partial villous atrophy –May not have antibodies against endomysium or tTG –Usually have antibodies against gliadin Anti endomysium only – miss 20% Up to 33% - one antibody absent Titres of endomysial antibodies are usually undetectable after 6–12 months on diet

73. Celic Disease – Role of Serological Testing Screening patients or populations at risk Confirming diagnosis when biopsy questionable Follow-up for compliance Diagnosis? – biopsy still required

74. Celiac Disease - Treatment Dietician - gluten-free diet for life Avoid trial of gluten restriction without a biopsy Avoid wheat, barley, and rye Oats are not toxic Support groups Correct deficiencies Active follow-up - compliance

75. Celiac Disease - Response Rapid – most patients Extremely ill – admission –repletion of fluids and electrolytes, –intravenous alimentation – steroids. Iron or folate supplements if deficiency documented

76. Celiac Disease Before treatment 3 months treatment

77. Poorly or Non-responsive Celiac Disease Review original biopsy, Continued gluten ingestion Lactose or fructose intolerance Intolerance to other foods is rare Microscopic colitis Collagenous colitis Inflammatory bowel disease Lymphoma, Ulcerative jejunitis, Collagenous sprue

78. Refractory Sprue. Intractable diarrhoea Severe villous atrophy Failure to respond to a gluten-free diet. Response to steroids, azathioprine or cyclosporin

79. Celiac Disease – Special Considerations Malignant disease – increased –Small bowel adenocarcinoma, –Esophageal and oropharyngeal squamous carcinoma –non-Hodgkin lymphoma A gluten-free diet is protective

80. Celiac Disease - Autoimmune Disorders Autoimmune disorders RR x10arise –Insulin dependent diabetes –Thyroid disease –Sjögren's syndrome –Addison's disease –Autoimmune liver disease –Cardiomyopathy –Neurological disorders. Can improve on diet

81. Celiac Disease – Other Complications Osteoporosis –Measurement of bone mineral density Fertility –Delayed menarche, –Premature menopause, –Amenorrhoea, –Recurrent abortions Postnatal –Low birthweight –Increased perinatal mortality –shorter duration of breast feeding Gluten-free diet improves

83. Digestion and Absorption GENERAL PRINCIPLES Breakdown of complex molecules – Enzymes (pH) Absorption into gut cells – Intestinal epithelium – Lymphatics

84. SECRETIONS OF THE GUT

85. Bulk flow of liquid in gut Input –Ingestion ~ 2 litres per day –Secretion (gut) ~ 7 litres/day Output –Faeces ~100 ml/day Conclude ~ 9 litres/day absorbed

86. Carbohydrate Digestion

87. Carbohydrate Absorption

88. Protein Digestion Proteins to peptides –Gastric pepsinogen –Activated by HCl AND pepsin –Pancreatic proteases (trypsin, chymotrypsin etc.)

89. Protein Absorption Peptides to amino acids (brush border) Absorbed by secondary active transport –Depends on Na + transport

90. Fat Digestion Fat to triglycerides (pancreatic lipase) Bile salts emulsify (surface area) Bile salts — micelles containing monoglycerides and free fatty acids (FFA) Enter passively Triglyceride synthesis — chylomicrons Exocytosis and thence to lacteals

91. Fat Absorption Monoglycerides and FFA enter cells by diffusion Triglyceride synthesis Add protein Chylomicrons To lacteal (lymph)