Aetiology and Pathology of Inflammatory Bowel Disease.

1
Aetiology and Pathology of Inflammatory Bowel
Disease.

• Dr Bryan F Warren
• Consultant Gastrointestinal Pathologist,
• John Radcliffe Hospital, Oxford, UK
• M62 Course 2004

2
Lecture planning!
Aetiology and Pathology in 15 minutes!
3
Aetiology of IBD

• Genetics vs environment
• Liverpool family studies

4
Genetic predisposition?

• Crohns 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

5
Complex trait genetics and environment
Blood Group
Lung Cancer
IBD
Car crash
Eye Colour
Cystic Fibrosis
Diabetes
Malaria
100 Environment (multiple factors)
100 Genetic (multiple mutations)
6
Discovery of the NOD2/CARD15 gene

• Nature 2001

7
Risk of developing Crohns disease 11 studies,
3616 Crohns / 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
8
Carriage of one or more NOD2 mutation PHENOTYPE
Familial
Small bowel
Stenosing
1.0
4.0
2.0
Odds ratio, Susceptibility for Crohns 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
9
NOD2 Crohns phenotype

• Weak association
• earlier age at diagnosis
• No association with
• Disease severity, need for surgery
• Extraintestinal manifestations
• Drug response (inc. infliximab)

10
NOD2 knockout mouse

• Doesnt get Crohns disease

• Protected against endotoxin challenge (iv)
• Pauleau Mol Cell Biol 2003

11
NOD2 more questions than conclusions

• What is the physiological function of NOD2 in
  vivo?
• intracellular recognition of bacteria?
• Why do mutations in NOD2 cause Crohns disease?
• Which bacteria are important?
• a quarter of UK Crohns disease
• tends toward stenotic small bowel phenotype

12
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

13
Potential environmental factors in the
pathogenesis of IBD

• At all ages
• Luminal bacteria (normal/abnormal)
• Diet
• Smoking
• Tonsillectomy
• Appendicectomy
• NSAIDs (Jersey)

14
Potential pathogenesis of IBD

• Cytokine imbalance
• Intestinal mucus barrier function-structure/sulpha
  tionetc
• Leucocyte endothelial interactions(integrins etc)

15
Why differentiate CD colitis and UC?

• Previously - good to know for prognosis.
• Now - crucial for selection for pouch surgery.

16
When is it difficult to differentiate CD colitis
and UC?

• Fulminant colitis
• After treatment of UC
• When rare variants of Uc are not recognised.

17
1/9/2003
18
Colectomy-quiescent UC restorative
proctocolectomy for intermittent but severe
symptoms
19
Fulminant UC- emergency colectomy.
20
Fulminant UC
Diffuse changes when the mucosa is ulcerated
away, diffuse, deeper ulceration occurs. Catch
mucin is often strikingly well preserved.
21
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
22
CMV in UC
Beware of superimposed infection After
immunosuppressive treatment.
23
Quiescent UC
Polyp
Flat mucosa
May have only architectural distortion, /-paneth
cells, may return to normal-review original
biopsies ? Infection.
24
Diversion in UC

• Transmural inflammation
• Granulomas
• PMC like change
• Mimics Crohns
• 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!

25
UC DALMs
26
Crohns disease
27
Crohns large bowel biopsy.

• May be normal
• May mimic UC
• Patchiness is most reproducible feature
• Mucosal granulomas may mislead

28
Definition of a granuloma 2

• gt/ 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

29
Crohns colitis
Schiller KFR, Cockel R, Hunt RH, Warren BF.
2001 An atlas of gastrointestinal endoscopy and
related pathology
30
Crohns colitis
Focal erosions and Focal inflammation
Aphthous ulcer
Perineural chronic inflammation and granuloma.
31
Crohns colitis
Transmural inflammation in the form of lymphoid
aggregates
32
Ileal Crohns disease fat wrapping
33
Crohns colitis-terminal ileal disease.
34
When does ulcerative colitis mimic Crohns
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

35
Granuloma in response to crypt damage-neutrophils
and mucin.
36
Skip lesions in UC

• Acceptable ones
• Appendix Davison and Dixon
• Caecal patch DHaens
• Not contraindications to pouch surgery.

37
Caecal patch in UC
Courtesy of Dr Axel von Herbay
38
Diverted Crohns colitis
39
IBD aetiology and pathology.

• Conclusions
• Genetics of IBD now providing more information
  about phenotype and risk.
• Clear diagnosis needed UC, CD, indeterminate
• There are pathologicalcatches. Help your
  pathologist-tell him what you have done.