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Pathogenesis of Diseases of the Large Intestine

Pathogenesis of Diseases of the Large Intestine. Dr Paul L. Crotty Department of Pathology AMNCH, Tallaght October 2008. Large intestine: by aetiology. Congenital : Anal anomalies, atresia, stenosis, Hirshsprung’s disease Acquired

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Pathogenesis of Diseases of the Large Intestine

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  1. Pathogenesis ofDiseases of theLarge Intestine Dr Paul L. Crotty Department of Pathology AMNCH, Tallaght October 2008

  2. Large intestine: by aetiology • Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease • Acquired • Infection:Infective enterocolitis (viral, bacterial, protozoal) • Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse • Chemical/Toxic: NSAIDs • Circulatory disturbances: Ischaemic bowel disease • Immunological disturbance: • Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis • Idiopathic:: Crohn’s disease, ulcerative colitis • Psychosomatic: : • Pre-neoplastic/ Neoplastic: • Adenoma -> adenocarcinoma • CIBD -> dysplasia -> adenocarcinoma

  3. Fluid dynamics Food intake: ~2 litres/d Saliva: ~1 litre/d Gastric secretions: ~2 litres/d Bile: ~1 litre/d Pancreas: ~2-3 litres/d Small intestinal secretions: ~1 litre/d Total 9-10 litres/d

  4. Fluid dynamics Re-absorption: Small intestine: ~6 litres/d Large intestine: normally ~2-3 litres/d but with capacity to increase up to ~6 litres/d Average stool weight 200-250g/d of which 65-85% is water

  5. Mechanisms of Diarrhoea Secretory: increased secretions: persists after fasting. Examples: cholera, some viral infections Osmotic: some solute present: osmotic retention of fluid in stool, resolves on fasting. Examples: disaccharidase deficiency; some viral infections Exudative: pus present: ulceration in bowel. Examples: invasive bacterial infection: idiopathic chronic inflammatory bowel disease Dysmotility-associated: Examples: Irritable bowel syndrome, hyperthyroidism Malabsorption: Steatorrhoea

  6. Chronic Inflammatory Bowel Disease Most (but not all) can be separated into 1 of 2 patterns: (1) Crohn’s disease (2) Ulcerative colitis based on clinical, endoscopic and pathological features

  7. Features of both Crohn’s disease and ulcerative colitis Idiopathic chronic inflammatory diseases Both have acute exacerbations and remissions Typically onset 15-40 y: (small second peak ~ 65-70y) - Active inflammation during acute exacerbation - Neutrophils in crypts (cryptitis, crypt abscesses) - Over time: destruction of mucosal architecture

  8. Crohn’s disease - Granulomatous inflammation - May involve any part of bowel - Typically small intestine and/or colon (one third each) - Discontinuous: ‘skip lesions’ typically with rectal sparing - Aphthous ulcers early: linear ulcers later - Transmural inflammation - Wall thickening/strictures with luminal narrowing - Deep fissures/fistulas - Extra-intestinal disease - Probable small increased risk of colorectal carcinoma

  9. Ulcerative colitis - NOT granulomatous - Colon only involved (no small bowel involvement) - Extends variable distance in continuity from rectum - Rectum always involved - Has well-defined proximal limit - No skip lesions - Broad-based ulcers with pseudo-polyps - Mucosal-based inflammation: NOT transmural - No wall thickening, no strictures, - No fissures , no fistulas - Extra-intestinal disease: also P.S.C. - Significant risk of dysplasia and carcinoma

  10. Normal colonic mucosa

  11. Crypt abscesses

  12. Transmural inflammation, serosal granulomas Crohn’s colitis

  13. Granulomas in Crohn’s disease

  14. Fissure in Crohn’s disease

  15. Normal

  16. Crohn’s disease

  17. Crohn’s disease Crohn: 1932 [Morgagni: 1761: “ileal passion”] initially termed terminal/regional ileitis - later identified could also have colonic involvement - later still recognised colonic-only pattern of disease “Idiopathic”: but what do we know about its causes?

  18. Crohn’s disease Genetic predisposition: Sibling risk: 15-40x risk of general population MZ twin concordance: 40-50% DZ twin concordance: 3-7% Linkage to loci on 16 (IBD1) also chromosome 3, 12

  19. Crohn’s disease linkage to locus on chromosome 16: high LOD score ~ 5.8 2001: NOD2 (nucleotide-binding oligomerisation domain) - normal function as signalling protein in macrophages - activates NFkB in response to bacterial LPS - 40% of Crohn’s disease patients: NOD2 polymorphism - but polymorphism also in ~15% of general population - heterozygous 2-4x risk/ homozygous 40x risk

  20. Crohn’s disease Smoking: 2-3X increased risk of Crohn’s disease counterbalanced by decrease in risk of ulcerative colitis Urban > Rural “Good” hygiene > Poor ? Theory: Delayed exposure to antigens/bacteria

  21. Crohn’s disease Is there an infectious agent? Animal models do not develop disease if kept in a strict germ-free environment Candidates ??Atypical mycobacteria ??Measles virus

  22. Crohn’s disease Is there immune dys-regulation? Is there a defect in the normal mechanisms of suppression of the inflammatory response to normal gut flora? New NOD2 data supportive of this theory

  23. Crohn’s disease Present with pain, variable diarrhoea, fever Diagnosis: Clinical, endoscopy, mucosal biopsies, barium Complications: Strictures: obstruction Fissures: abscesses Fistulas: bladder, vagina, skin, entero-enteric Peri-anal disease Malabsorption (terminal ileal disease, blind loops) Slight increased risk of cancer

  24. Ulcerative colitis

  25. Pseudopolyps in ulcerative colitis

  26. Mucosal-based inflammation and ulceration Ulcerative colitis

  27. Dysplasia in ulcerative colitis

  28. Ulcerative colitis

  29. Ulcerative colitis Wilks: 1859 claim on first distinction from dysentery 1888: RSM in London debate on aetiology of the disease ? Diet ? Infection ? Psychosocial Genetic: MZ concordance HLA association ? Infection ? Allergy ? Immune dys-regulation

  30. Ulcerative colitis Mucosal inflammation leading to ulceration Chronicity leads to mucosal destruction, regeneration 40% rectum/ recto-sigmoid only 40% extends from rectum to point x 20% pan-colonic Presents with diarrhoea, pain, weight loss Diagnosis: Clinical, endoscopy, biopsy

  31. Ulcerative colitis Complications: Fulminant colitis: Toxic megacolon Extra-intestinal manifestations Including primary sclerosing cholangitis Significant risk of dysplasia and malignancy especially with pan-colitis, long duration

  32. Large intestine: by aetiology • Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease • Acquired • Infection:Infective enterocolitis (viral, bacterial, protozoal) • Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse • Chemical/Toxic: NSAIDs • Circulatory disturbances: Ischaemic bowel disease • Immunological disturbance: • Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis • Idiopathic:: Crohn’s disease, ulcerative colitis • Psychosomatic: : • Pre-neoplastic/ Neoplastic: • Adenoma -> adenocarcinoma • CIBD -> dysplasia -> adenocarcinoma

  33. Infective organisms causing diarrhoea World-wide: mortality 5 million /year, most children Mechanisms by which infectious agents cause diarrhoea: (1) Pre-formed toxin in food no live organisms ingested e.g. C botulinum, some S. aureus (2) Live organisms: Non-invasive: (a) organisms colonise gut and produces toxin e.g. V. cholerae, C. difficile, some E. coli (b) organisms bind to brush border e.g. Cryptosporidium Invasive: (a) mucosal e.g. Shigella, most Salmonella, some E. coli (b) deeper layers e.g. S. typhi, Yersinia

  34. Viral enterocolitis Rotavirus infects enterocytes lining villi in small intestine near-normal/minimal shortening of villi main effect is absence of lactase => osmotic diarrhoea Norwalk virus Adenovirus Astrovirus

  35. Vibrio cholerae Toxin production includes binding units, catalytic unit => binds to glycolipid on surface of enterocyte => catalytic unit taken up into enterocyte => activated intracellularly => stimulates G-protein => increases intracellular cAMP => actively stimulates secretion of Na, Cl, water

  36. Shigella => stimulates its own endocytosis => proliferates within cell => rapid cell death, lysis => infects adjacent cells

  37. Large intestine: by aetiology • Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease • Acquired • Infection:Infective enterocolitis (viral, bacterial, protozoal) • Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse • Chemical/Toxic: NSAIDs • Circulatory disturbances: Ischaemic bowel disease • Immunological disturbance: • Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis • Idiopathic:: Crohn’s disease, ulcerative colitis • Psychosomatic: : • Pre-neoplastic/ Neoplastic: • Adenoma -> adenocarcinoma • CIBD -> dysplasia -> adenocarcinoma

  38. Antibiotic-associated (pseudomembranous) colitis • Clostridium difficile in normal flora • When other bacteria eradicated by antibiotics, C. difficile proliferates • Selection of toxin-producing forms • Enterotoxin (A) and cytotoxin (B) • Disrupt cytoskeleton, inflammation • Cell death, confluent ulceration

  39. Antibiotic-associated (pseudomembranous) colitis

  40. Large intestine: by aetiology • Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease • Acquired • Infection:Infective enterocolitis (viral, bacterial, protozoal) • Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse • Chemical/Toxic: NSAIDs • Circulatory disturbances: Ischaemic bowel disease • Immunological disturbance: • Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis • Idiopathic:: Crohn’s disease, ulcerative colitis • Psychosomatic: : • Pre-neoplastic/ Neoplastic: • Adenoma -> adenocarcinoma • CIBD -> dysplasia -> adenocarcinoma

  41. Ischaemic bowel disease • SMA, IMA -> mesenteric arcades • collateral supply • watershed areas: splenic flexure • venous drainage • acute, subacute, chronic

  42. Ischaemic bowel disease • Arterial thrombosis • atherosclerosis, dissection, hypercoagulation • Arterial embolism • atherosclerosis, arrhythmias, SBE • Venous thrombosis • hypercoagulation • Generalised hypoperfusion • hypotensive shock, CCF

  43. Ischaemic bowel disease • Transmural infarction • acute occlusion (arterial or venous, thrombotic or embolic) -> acute abdomen • perforation/gangrene if untreated • Mucosal/submucosal infarction • acute/subacute hypoperfusion • can mimic acute colitis • Fibrosis and mucosal atrophy • chronic, strictures: can mimic Crohn’s

  44. Large intestine: by aetiology • Congenital: Anal anomalies, atresia, stenosis, Hirshsprung’s disease • Acquired • Infection:Infective enterocolitis (viral, bacterial, protozoal) • Physical: Obstruction, Diverticular disease, Rectal mucosal prolapse • Chemical/Toxic: NSAIDs • Circulatory disturbances: Ischaemic bowel disease • Immunological disturbance: • Iatrogenic: (NSAIDs) Antibiotic-associated pseudomembranous colitis • Idiopathic:: Crohn’s disease, ulcerative colitis • Psychosomatic: : • Pre-neoplastic/ Neoplastic: • Adenoma -> adenocarcinoma • CIBD -> dysplasia -> adenocarcinoma

  45. Diverticular disease • Diverticulum: blind pouch off GI tract • Incidence: 40-50% in >60 years in West • Diet low in fibre -> decreased stool volume • Chronic increased intraluminal preseeure • Acquired ‘blow-out’ diverticuli • at points of focal weakness in wall of colon where vessels cross muscle layer

  46. Diverticular disease • Complications • Inflammation • Abscess formation • Perforation • Bleeding

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