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 Monozygotic twins vs. Dizygotic twins higher disease concordance No simple mendelian inheritance pattern

Complex trait – genetics and environment 100% Genetic (multiple mutations) 100% Environment (multiple factors) Blood Group Eye Colour Cystic Fibrosis Car crash Lung Cancer IBD Malaria Diabetes

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 [2.3 – 3.3] Double mutation OR 20.5 [11.9 – 35.4] Economou 2004

Odds ratio, Susceptibility for Crohn’s disease Carriage of one or more NOD2 mutation PHENOTYPE Familial Stenosing Small bowel 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) Pauleau Mol Cell Biol 2003

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 UC- emergency 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. Early disease-diffuse Chronic inflammation and basal plasma cells UC after treatment

CMV in UC Beware of superimposed infection After immunosuppressive treatment.

Quiescent UC May have only architectural distortion, =/-paneth cells, may return to ‘normal’-review original biopsies ? Infection. Polyp Flat mucosa

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 An atlas of gastrointestinal endoscopy and related pathology

Crohn’s colitis Focal erosions and Focal inflammation Perineural chronic inflammation and granuloma. Aphthous ulcer

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.