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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

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aetiology and pathology of inflammatory bowel disease

Aetiology and Pathology of Inflammatory Bowel Disease.

Dr Bryan F Warren

Consultant Gastrointestinal Pathologist,

John Radcliffe Hospital, Oxford, UK

M62 Course 2004

slide2

Lecture planning!

Aetiology and Pathology in

15 minutes!

aetiology of ibd
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

Genetic predisposition?
complex trait genetics and environment
Complex trait – genetics and environment

Blood Group

Lung Cancer

IBD

Car crash

Eye Colour

Diabetes

Cystic Fibrosis

Malaria

100% Environment

(multiple factors)

100% Genetic

(multiple mutations)

slide7

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 mutationOR 20.5[11.9 – 35.4]

Economou 2004

slide8

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
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: knockout mouse
nod2 more questions than conclusions
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
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 ibd1
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
Potential pathogenesis of IBD
  • Cytokine imbalance
  • Intestinal mucus barrier function-structure/sulphationetc
  • Leucocyte endothelial interactions(integrins etc)
why differentiate cd colitis and uc
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
When is it difficult to differentiate CD colitis and UC?
  • Fulminant colitis
  • After treatment of UC
  • When rare variants of Uc are not recognised.
fulminant uc
Fulminant UC

Diffuse changes: when the mucosa is ulcerated away,

diffuse, deeper ulceration occurs.

Catch: mucin is often strikingly well preserved.

biopsy pathology uc
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

slide22

CMV in UC

Beware of superimposed infection

After immunosuppressive treatment.

quiescent uc
Quiescent UC

Polyp

Flat mucosa

May have only architectural distortion, =/-paneth cells,

may return to ‘normal’-review original biopsies ? Infection.

diversion in uc
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!
crohn s large bowel biopsy
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
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
Crohn’s colitis

Schiller KFR, Cockel R, Hunt RH, Warren BF. 2001

An atlas of gastrointestinal endoscopy and related pathology

crohn s colitis1
Crohn’s colitis

Focal erosions and

Focal inflammation

Aphthous ulcer

Perineural chronic inflammation

and granuloma.

crohn s colitis2
Crohn’s colitis

Transmural inflammation in the form of lymphoid aggregates

when does ulcerative colitis mimic crohn s colitis
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
skip lesions in uc
Skip lesions in UC

Acceptable ones:

  • Appendix –Davison and Dixon
  • Caecal patch – D‘Haens

Not contraindications to pouch surgery.

caecal patch in uc
Caecal patch in UC

Courtesy of Dr Axel von Herbay

ibd aetiology and pathology
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.

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