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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.