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IBD: clinics and pathogenesis
Prof. Dr. Frank SeiboldGastroenterologie
Spital Netz Bern Tiefenau undInselspital Bern
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IBD: heterogeneous diseases
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Befallsmuster bei M. Crohn
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Intestinal involvement in CD
• Everywhere in the GIT
• Transmural• Segmental• Luminal, stenosing,
fistulizing
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IBD Clinics
• Ulcerative colitis– continuous– Inflammation starts in
the rectum– blood– mucosa– No fistula– Extraintestinal
manifestations
• Crohn‘s– segmental– ileocoecal– Not frequently blood– Transmural– Fistula– Extraintestinal
manifestations
– stenosing
In 10-30% differential diagnosis CD - UC not possible:Colitis indeterminata.
Both diseases: Fatique, fever, abdominal pain, cramps, diarrhea. From first symptoms till diagnosis >2 years
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Granuloma in Crohn‘s disease
• Found in max. 50% of pts with CD• Frequency: Small intestine 1: colon 6:
rectum 18: anus 36• Patients with multiple
granuloma in colon withmild course of diseaseChambers, Gut 1979
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Diagnostic relevance of antibodies to differentiate CD - UC (105 patients)
Marker status Serological diagnosis
Clinical diagnosis
Positive pre-dictive value
ASCA+, PAB+N=25
CD CD =25 100%
ASCA +N=30
CD CD=29UC=1
96%
PAB+N=6
CD CD=6 100%
pANCA+, ASCA+N=8
CD CD= 7UC=1
87%
pANCA+N=36
UC UC=32CD=4
89%
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Extraintestinal manifestations in IBD
• Indicates that IBD is a systemic disease• Arthritis (15%), Spondylitis, • hepatic: PSC• ocular: Episkleritis/Iridozyklitis• dermal: Erythema nodosum, Pyoderma
gangrenosum• Pankreas• lung, kidney, heart??
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Complications in IBD• bleeding• Stenosis• Ileus• Kachexia• Folic acid and Vit. B 12 deficiency• Short bowel• Stoma• Abszess • Fistula• Extraintestinal Manifestations• Colon carzinoma
10Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
240228216204192180168156144132120108968472604836241200
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20
30
40
50
60
70
80
90
100
PatientenMonate
2002 552 229 95 37N =
Penetrating
Stenosinginflammatory
Kum
ulat
ive
Häu
figke
it (%
)
Natural course in Crohn‘s
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Pathogenesis of IBD• Questions:
– tasks of the intestine?– challenges of the intestinal immune system?
• Epidemiology• Environmental factors• Genetics• immunology
Postsurgical Recurrence of CD
McLeod RS, et al. Gastroenterology. 1997;113:1823-1827.
Rising Incidence of CD
Courtesy of S. Schreiber.
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Nord-Süd-Gefälle in EuropaAktuell: Zunahme der Inzidenz in Nordafrika
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Epidemiologie IBD
• CH: IBD ca.: 2/1000 inhabitants• More frequently in agglomerations compared to
country• North-south gradient• Danmark: Incidence of pediatric Crohn-cases
1998-2000 in comparison to 1996 10-fold elevated
• Arabs are less diagnozed with CD than Jews
» UEGW 2003
Impact of Smoking Cessationon Crohn’s Disease Outcome
Gastroenterology 2001
p<0.001
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1435
21
37
0 12 24 36 48
Months after inclusion
20
40
60
80
100
Prob
abili
ty o
f Fla
re-u
p (%
)
6
0
QuittersContinuous smokersNon-smokers
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Further environmental factors
• No proven relationship to food intake• Appendectomy: AE protects from UC• Role of infection: association between
acute gastroenteritis and the development of IBD
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IBD Genetics• First-degree relatives of IBD: 3-20x risk to
develop disease• Twin studies• Concordance in the location and type of CD• Mouse studies• More than 40 mutations detected that are
involved in human IBD• Gen variants lead to a disturbed innate
immunity: autophagy, phagocytosis
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Genetic Complexity in IBD
‘Significant' Linkage
‘'Suggestive’ Linkage*
Replicated
Non=replicated
Non-replicated
Replicated
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16
IL-4 rec
CD10
CD11
E-cadherin
α 1-integrin
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VDR
NRAMP2
STAT6
MMP 18
α5-integrin
Interferon γ
β7-integrin
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TCR α and δ
Proteosome cluster
Leukotriene B4 rec 19
ICAM1
C3
TBXA2
LTB4H
IL 3-5,13
CSF 2
13 4
5 6
HLA Class I-III
MICA
NFκB
IFN-γR
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MUC 3
EGFR
HGF
CCR5
GNAI2
Cytokine cluster
hMLH1IL-2 gene
TGF-β2
TGF-β4
E2G
TNF-R family
HSPG2
UBE1L
IL12A
Satsangi et al. Best Pract Res Gastro 2003:17;3.
IBD1-locusIBD1-locus
NOD2/CARD15
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IBD 1: mutations in NOD2
• Susceptibility of ileal CD• NOD2 protein activates NFkB in response
to a fragment of bacterial peptidoglycan (muramyl dipeptid)
• Mutations found in 10-30% of patients with CD, mutation not found in Asia
• NOD2 gene found in macrophages
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IBD genetics• NOD2• IBD5• Il23 R• ATG16L1• Chr 5p13.1• Chr5q33.1• Chr10q21.1• NCF4• TNFSF15
Figure 2. Pathogenesis of Inflammatory Bowel Disease: Induction of Inflammatory Cascade Bacterial antigens inappropriately leak across the intestinal epithelial cell barrier.
Blumberg, R. S. et al. JAMA 2001;285:643-647
Copyright restrictions may apply.
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Mouse models in IBD
• MDR1 -/- altered epithelial barrier• IL10-/- Lack of T reg• SAMP1/YIT epithelial cell defect, expanded B cells• CD4 CD45RBhi decreased T reg• TCRa-/- lack of regulatory B cells• WASP-/- regulatory B cells• CD40L tg increased activated T cells• DSS direct damage to epithelial barrier• TNBS hapten• Muc 2-/- mucus defect• N-cadherin mutant barrier function• IL2-/- decreased CD4 CD25+ cells• NFkB-/- increased IL2 production
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IBD and flora• T cell and humoral response towards the
resident intestinal flora• Special E coli eg LF 82 that adheres to
epithelial cells of the ileum• In animal models specific germs eg
Bacteroides vulgatus were able to induce colitis in IL10-/- mice
• What is the „normal flora“?• IBD: flora is different
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Early lesions of recurrent CD caused by infusion of intestinal contents in excluded ileum
D‘Haens, Gastroenterology 1998, 114: 262
3 patientsInfusions of luminal contentsIn excluded ileum for 8daysFocal infiltration with Mononuclear cellsEosinophils in lamina propria, Vessels, and epithelium
Intestinal contents trigger postoperative recurrence of CD
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Unterschied DarmfloraAfrika vs Europa
• Darmflora durch Ernähung beeinflusst
• Aufbau normaler Darmflora nicht ausreichend bekannt
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Enteric flora in IBD
Arumungam Nature 2012
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Dysbiosis as a predictive factor for relapse in Crohn‘s
disease• 31 Kontrollen und 37 Patienten mit CD zum
Zeitpunkt IFX Stopp• Stuhlproben Monat 0,2,6• 18 Pat. Schub, 19 Remission• PCR Analyse der Bakteriengruppen • Dysbiose Monat 0 mit wenig Firmicutes, F.
prausnitzii• Patienten mit Rezidiv: Dysbiose mehr
ausgeprägt» Rajca, ECCO 2011
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Epithelial barrier
• Mucus• MUC2-/- mice develop colitis• Paneth cell deficiency increases the risk
for CD
Pathogenesis of IBD
Immune systeme
T-cell
Genetic predisposition, NOD2
Exogenous factors
Intestinal flora
Th17
Th2
IL4,IL13, IL10
IL2,γIFN, TNFa
IL1, IL6, IL8, Radicals, Leukotriens, NO Proteases, acute phase proteins
IL12IL4
HomingICAM
Inflammation
TNFa anti-TNFaThalidomid
T reg
Innate immunesystem
Th1
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Treatment of IBD
• Anti-inflammatory: eg. Mesalamin=5-ASA (UC)
• Antibiotics (CD), Probiotics (UC)• Prednisone/ prednisolone• Immunosuppressants: Azathioprin, 6-
mercaptopurine, metothrexate• TNF blocker
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Summary• IBD are heterogeneous diseases• IBD can be treated but not cured• CD: transmural, frequently patchy disease• UC: mucosal disease, always continuous
involvement• Incidence increasing• Pathogenesis: genetic, environmental and
immunologic reasons.• Defects in innate immunity of major importance