Non-neoplastic intestinal disease Malabsorption Paul L. Crotty Department of Pathology - PowerPoint PPT Presentation

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Non-neoplastic intestinal disease Malabsorption Paul L. Crotty Department of Pathology

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  1. Non-neoplastic intestinal disease Malabsorption Paul L. Crotty Department of Pathology Tallaght Hospital October 2007

  2. Outline of lecture • Review normal digestion/absorption • How diseases interfere with the process • Tests for malabsorption • Coeliac disease • Chronic pancreatitis • Bacterial overgrowth

  3. Malabsorption/Maldigestion • diverse disease processes • final common pathway of interference with normal digestion and absorption of nutrients • similar/overlapping clinical presentations • understanding normal digestion and absorption is central to understanding diseases that interfere with same

  4. Normal digestion and absorption • (1) Luminal phase • (2) Mucosal phase • (3) Removal phase

  5. As example: Triglycerides • Luminal phase: in small intestine • Pancreatic lipase: enzymatic hydrolysis into mono-acyl glycerol and free fatty acids • Solubilisation: incorporation into micelles with bile salts • Mucosal phase: in enterocyte cytoplasm • assembly into chylomicra with apoproteins • Removal phase: in lymphatics

  6. Normal process of fat digestion and absorption

  7. Diseases interfering with luminal phase • Pancreatic exocrine insufficiency • chronic pancreatitis • Bile salt deficiency • liver disease, especially cholestatic • bacterial overgrowth • terminal ileal disease • Other: post-gastrectomy, Zollinger-Ellison

  8. Diseases interfering with mucosal phase • Small bowel disease • Coeliac disease • Tropical sprue • Whipple’s disease • Crohn’s disease • Post-small bowel resection • Specific enzyme deficiency,transport protein defects, abetalipoproteinaemia

  9. Diseases interfering with removal phase • Lymphatic blockage • Primary lymphangiectasia • Obstruction

  10. Major disease entities • Coeliac disease • Chronic pancreatitis • Bacterial overgrowth

  11. Consequences of malabsorption • Effects of excess fat in stool • Steatorrhoea: bulky, pale, foul-smelling • Nutrient deficiencies: global/specific • Energy, Protein (failure to thrive, short stature, weight loss) • Specific deficiencies esp. fat soluble vitamins A, D, E and K, also iron

  12. Quantitation of fat in stool • Normal stool fat <6g/day (over range of dietary fat from 60 to 200g) • With diarrhoea of any cause: stool fat can rise up to 14g/day • With fat malabsorption: stool fat much higher: 50-100g/day range • Standard: 3-5 day collection

  13. D-xylose test • 5 carbon sugar: absorbed by passive diffusion • D-xylose test is a measure of functional surface area of small bowel • After overnight fast: 25g D-xylose given p.o • Measure serum level at 1h (normal >20mg/dl) • 5h urine collection (normal >4g) • FP: incomplete collection/dehydration/renal disease

  14. What do you expect the result of a D-xylose test will be in… • Chronic pancreatitis? • Coeliac disease? • Cholestatic liver disease? • Bacterial overgrowth?

  15. Key role of duodenal biopsy • Biopsy diagnosis of specific diseases • Giardia infestation, Whipple’s disease • abetalipoproteinaemia, lymphangiectasia • Significantly blunted villi or flat mucosa (partial or complete villous atrophy) • classically seen in untreated coeliac disease • but can also be seen in other food allergies, rarely in viral infection, Crohn’s disease, tropical sprue • Normal mucosa

  16. Patient with malabsorption with a normal duodenal biopsy • Any disease interfering with luminal phase of absorption • chronic pancreatitis • bile salt deficiency • ...but also in any primary small bowel disease with focal involvement

  17. 17 centuries later...

  18. 1950: Paulley identified villous abnormality Later shown that the histological abnormality normalised after gluten withdrawal and recurred after gluten challenge

  19. Alpha-Gliadin

  20. Alpha-GLIADIN PEPTIDES (SYNTHETIC) FOR WHICHTHERE IS IN VIVO EVIDENCE OF ACTIVITY

  21. Ingestion of gluten (or alpha-gliadin or even synthetic peptides) by a patient with coeliac disease causes symptoms in few hours and villous abnormality in 8-12 hours Why are gliadins toxic in some patients and not in others?

  22. Genetic factors • First degree relatives: 10% risk • MZ twin concordance: 70-90% • HLA-identical sibs: 30-50% concordance • In Europe: Coeliac patients >95% HLA-DQ2+ (vs. 25% in non-coeliacs) • >99% of DQ2+ individuals do not have coeliac disease • But significant component of genetic risk is accounted for by other non-HLA genes

  23. Immunological factors • Increased immunoglobulin production in small intestine • Most have circulating antibodies to alpha-gliadin • ...but is this cause or an effect of the disease ? • Antibodies to alpha-gliadin also seen in other intestinal diseases • Other circulating antibodies also found in coeliacs

  24. Current hypothesis • T-cell-mediated immunity of primary importance in pathogenesis • Increased intraepithelial CD8+ T lymphocytes • Increased CD4+ T lymphocytes in lamina propria • Evidence of T-cell activation

  25. Theory of pathogenesis • In a patient with a genetic predisposition... • Some initial trigger? • Adenoviral infection early in life?? • Immune response including presence of T cells with specific ability to respond to alpha-gliadin peptides

  26. Theory of pathogenesis • So later when any gluten-containing food is ingested…. • Rapid T cell activation with Th1 pattern of cytokine release causing enterocyte apoptosis • Enterocyte apoptosis leads to villous blunting/flattening • Loss of surface area for absorption of nutrients clinically reflected as malabsorption

  27. Antibodies SensitivitySpecificity AGA IgA 89% 95% IgG 99% 86% EMA >95% >95% tTG (IgA/IgG) >95% >95% IgA tests negative in the 2-3% of coeliacs with IgA deficiency

  28. Presentation • Any age: failure to thrive/short stature/wt loss • Steatorrhoea, fat-soluble vitamin deficiency • Diagnosis based on: • Clinical suspicion • Endoscopy with biopsy • Serology: circulating antibodies • Response to gluten withdrawal

  29. Complications • Long term effects of malabsorption: chronic vitamin deficiencies • Refractory sprue, ulcerative jejunoileitis, enteropathy-associated T cell lymphoma: all stages in a monoclonal lymphoid proliferation/lymphoma • Controversial whether there is a small increase in risk of carcinoma or not • dermatitis herpetiformis

  30. Dermatitis herpetiformis

  31. Chronic pancreatitis

  32. Exocrine pancreas • Pancreatic secretions: 2-3 litres/day • Secretion co-ordinated with presence of food in duodenum (via intestinal CCK) • Proteases (trypsin, chymotrypsin, aminpeptidase) • Pancreatic amylase • Pancreatic lipases

  33. How does pancreas protect itself from self-digestion? • Secreted as inactive pro-enzymes compartmentalised in granules • Activation of pro-enzymes requires presence of activated trypsin • Duodenal-derived enterokinase is required to activate trypsin • Pancreas also secretes trypsin inhibitors

  34. Pancreatitis • Acute (mild to severe necrotising/haemorrhagic) • Chronic (result of repeated episodes of mild acute pancreatitis) • Main causes: Alcohol, Gallstone disease • Other: medications, trauma, hypercalcaemia, hyperlipidaemia, post-instrumentation, blockage of duct by parasites or tumour

  35. Pathogenesis of pancreatitis • Gallstone disease: Duct obstruction • Alcohol: • ? Directly toxic to pancreas • ? Altered secretions: leads to plugging of duct • ? Sphincter of Oddi: alternate spasm/relaxation • In both: pancreatic self-destruction by enzymes • If chronic: scarring and loss of exocrine function

  36. Tests of pancreatic function • Direct measure of enzymes in duodenal aspirate • Indirect tests: • Bentiromide test: NBT-PABA bond cleaved by chymotrypsin: measure urinary PABA metabolites • Pancrealauryl test: Fluorescein dilaurate cleaved by pancreatic arylesterase: detect fluorescein in urine