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Aetiology and Pathology of Inflammatory Bowel Disease. Dr Bryan F Warren Consultant Gastrointestinal Pathologist, John Radcliffe Hospital, Oxford, UK M62 Course 2004 Lecture planning! Aetiology and Pathology in 15 minutes! Aetiology of IBD • Genetics vs environment • Liverpool family studies Genetic predisposition? Crohn’s disease 8-12% patients have affected 1º relative Sibling risk of disease: s 15-35 Monozygotic twins vs. Dizygotic twins higher disease concordance No simple mendelian inheritance pattern Complex trait – genetics and environment Blood Group Lung Cancer IBD Car crash Diabetes Eye Colour Cystic Fibrosis Malaria 100% Environment (multiple factors) 100% Genetic (multiple mutations) Discovery of the NOD2/CARD15 gene Nature 2001 Risk of developing Crohn’s disease 11 studies, 3616 Crohn’s / 3055 controls Non-Jewish Caucasian Single mutation OR 2.7 Double mutation OR 20.5 Economou 2004 [2.3 – 3.3] [11.9 – 35.4] Carriage of one or more NOD2 mutation PHENOTYPE Familial Small bowel Stenosing 1.0 2.0 4.0 Odds ratio, Susceptibility for Crohn’s disease Small bowel disease (Oxford study) 100% carriers of 2 mutations - ileal disease 56% ileal disease - no NOD2 mutation Economou 2004 Lesage 2002 Ahmad 2002 NOD2 : Crohn’s phenotype Weak association • earlier age at diagnosis No association with • Disease severity, need for surgery • Extraintestinal manifestations • Drug response (inc. infliximab) NOD2: knockout mouse • Doesn’t get Crohn’s disease… • Protected against endotoxin challenge (iv) NOD2: more questions than conclusions • What is the physiological function of NOD2 in vivo? • intracellular recognition of bacteria? • Why do mutations in NOD2 cause Crohn’s disease? • Which bacteria are important? • a quarter of UK Crohn’s disease • tends toward stenotic small bowel phenotype Potential environmental factors in the pathogenesis of IBD Early environmental factors: • Maternal infection • Measles • Mumps • Whooping cough • Birth order • Breast feeding (protects) • Early weaning • Poor household amentities Potential environmental factors in the pathogenesis of IBD At all ages • Luminal bacteria (normal/abnormal) • Diet • Smoking • Tonsillectomy • Appendicectomy • NSAIDs (Jersey) Potential pathogenesis of IBD • Cytokine imbalance • Intestinal mucus barrier function-structure/sulphationetc • Leucocyte endothelial interactions(integrins etc) Why differentiate CD colitis and UC? • Previously good to know for prognosis. • Now - crucial for selection for pouch surgery. When is it difficult to differentiate CD colitis and UC? • Fulminant colitis • After treatment of UC • When rare variants of Uc are not recognised. 1/9/2003 Colectomy-quiescent UC – restorative proctocolectomy for intermittent but severe symptoms Fulminant UCemergency colectomy. Fulminant UC Diffuse changes: when the mucosa is ulcerated away, diffuse, deeper ulceration occurs. Catch: mucin is often strikingly well preserved. Biopsy pathology UC • Crypt architectural distortion takes 6 weeks • Diffuse changes• Architecture, mucin depletion, chronic inflammation, acute inflammation • Rectum most severe • Distribution of changes in a biopsy and in a biopsy series. • Catch-patchiness-post treatment or at junction of diseased and normal, or in caecal patch. UC after treatment Early disease-diffuse Chronic inflammation and basal plasma cells CMV in UC Beware of superimposed infection After immunosuppressive treatment. Quiescent UC Polyp Flat mucosa May have only architectural distortion, =/-paneth cells, may return to ‘normal’-review original biopsies ? Infection. Diversion in UC • Transmural inflammation • Granulomas • PMC like change • Mimics Crohn’s • It is UC and not a contraindication to pouch surgery. • Seen as part of the three stage pouch procedure. • Comforting if this occurs-helps confirm pouch has been made in UC! UC DALMs Crohn’s disease Crohn’s large bowel biopsy. • May be normal • May mimic UC • Patchiness is most reproducible feature • Mucosal granulomas – may mislead Definition of a granuloma 2 • “>/= 5 epithelioid macrophages in aggregation” Guidelines for initial biopsy diagnosis of suspected chronic inflammatory bowel disease. Jenkins D et al BSG group. J Clin Pathol 1997; February Crohn’s colitis Schiller KFR, Cockel R, Hunt RH, Warren BF. 2001 An atlas of gastrointestinal endoscopy and related pathology Crohn’s colitis Focal erosions and Focal inflammation Aphthous ulcer Perineural chronic inflammation and granuloma. Crohn’s colitis Transmural inflammation in the form of lymphoid aggregates Ileal Crohn’s disease – fat wrapping Crohn’s colitis-terminal ileal disease. When does ulcerative colitis mimic Crohn’s colitis? • Granulomas in response to crypt damage • Patchiness of disease after treatment • Resolution of histological changes after treatment • Fulminant colitis • Diversion proctitis in UC • SKIP LESIONS • Caecal patch • Appendix Granuloma in response to crypt damage-neutrophils and mucin. Skip lesions in UC Acceptable ones: • Appendix –Davison and Dixon • Caecal patch – D‘Haens Not contraindications to pouch surgery. Caecal patch in UC Courtesy of Dr Axel von Herbay Diverted Crohn’s colitis IBD: aetiology and pathology. Conclusions Genetics of IBD now providing more information about phenotype and risk. Clear diagnosis needed: UC, CD, indeterminate There are pathological’catches’. Help your pathologist-tell him what you have done.