Aetiology and Pathology of Inflammatory Bowel Disease.

Dr Bryan F WarrenConsultant Gastrointestinal Pathologist,

John Radcliffe Hospital, Oxford, UKM62 Course 2004

Lecture planning!

Aetiology and Pathology in15 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 twinshigher 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 controlsNon-Jewish Caucasian

Single mutation OR 2.7 [2.3 – 3.3]

Double mutation OR 20.5 [11.9 – 35.4]

Economou 2004

1.0 4.02.0Odds ratio, Susceptibility for Crohn’s disease

Carriage of one or more NOD2 mutationPHENOTYPE

Familial

Stenosing

Small bowel

Small bowel disease (Oxford study)100% carriers of 2 mutations - ileal disease56% ileal disease - no NOD2 mutation Economou 2004

Lesage 2002Ahmad 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 inflammationand basal plasma cells

UC after treatment

CMV in UC

Beware of superimposed infectionAfter 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. 2001An atlas of gastrointestinal endoscopy and related pathology

Crohn’s colitis

Focal erosions and Focal inflammation

Perineural chronic inflammationand 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.

ConclusionsGenetics 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.