1. Inflammatory bowel disease By: Elias S. Maruf A.

2. IBD  Idiopathic and chronic intestinal inflammation.  Two major types: Crohn’s disease(CD) Ulcerative colitis(UC)  CD 1 st seen by the German surgeon Wilhelm Fabry in 1623 1 st seen by the German surgeon Wilhelm Fabry in 1623 Later described and named after US physician Burril B. Crohn Later described and named after US physician Burril B. Crohn  UC 1 st described by the British physician Sir Samuel Wilks in 1958 1 st described by the British physician Sir Samuel Wilks in 1958

3. Epidemiology – CD, UC Highest incidence rates  North America, Northern Europe, UK Highest incidence rates  North America, Northern Europe, UK Low incidence Areas  Southern Europe, Asia, Most Developing countries Low incidence Areas  Southern Europe, Asia, Most Developing countries Age of onset: Two peaks  15-30yrs, 60-80y. Age of onset: Two peaks  15-30yrs, 60-80y. Sex: M:F  UC  1:1 CD  1.1-1.8:1 Sex: M:F  UC  1:1 CD  1.1-1.8:1 Race: CD (N.America) per 100,000 P. Race: CD (N.America) per 100,000 P. Whites > African A. > Asian A. > Hispanic A. 43.6 29.8 5.9 4.1Whites > African A. > Asian A. > Hispanic A. 43.6 29.8 5.9 4.1 Both more prevalent in Jewish people than any other ethnic groupBoth more prevalent in Jewish people than any other ethnic group

4. Genetics  Familial aggregation of IBD 1 st reported in 1930  +ve Family Hx – the largest independent risk Factor Prevalence in 1 st degree Relatives  Concordance b/n P’t and 1 st degree relative Disease type  75-80% Disease pattern  64% Extraintestinal manifestation  70% CD CD UC UC IBD in Gen. IBD in Gen. P’t with CD 2.2-16.2% 2.2-16.2% 5.2-22.5% 5.2-22.5% P’t with UC 5.7-15.7% 5.7-15.7% 6.6-15.8% 6.6-15.8%

5. Genetics Cont…  Twin study Pooled systematic concordance analysis Monozygotic twins: CD – 37%, UC – 10% Dizygotic twins: CD – 7%, UC – 3% Pooled systematic concordance analysis Monozygotic twins: CD – 37%, UC – 10% Dizygotic twins: CD – 7%, UC – 3% MT > DT, CD > UC MT > DT, CD > UC  IBD - Polygenic disease So far – 12 chromosomes identified 16,12,6,14,5,19,1,7,3 (IBD 1-9) So far – 12 chromosomes identified 16,12,6,14,5,19,1,7,3 (IBD 1-9) Some specific gene loci – mapped Some specific gene loci – mapped Ch.16 – NOD2(card15)  associated with CDCh.16 – NOD2(card15)  associated with CD Ch. 5 – OCTN1,OCTN2Ch. 5 – OCTN1,OCTN2 Ch. 6 – encodes for MHC mutations in HLA Alleles: HLA DRB*0103 / B27 / B35 / B44Ch. 6 – encodes for MHC mutations in HLA Alleles: HLA DRB*0103 / B27 / B35 / B44 Mutation in IL23R gene – protective against CDMutation in IL23R gene – protective against CD

7. Environmental & other factors Life style Life style Urban > RuralUrban > Rural Poor socioeconomic status -  RiskPoor socioeconomic status -  Risk Excessive sanitation -  RiskExcessive sanitation -  Risk Smoking : Aggravate the course of CD  Risk of UC Smoking : Aggravate the course of CD  Risk of UC Psychological stress Adverse life events/day to day stress  activity of IBD (worsening, Relapse) Psychological stress Adverse life events/day to day stress  activity of IBD (worsening, Relapse) Infectios agents  Normal flora  ?M.paratuberculosis, Paramyxovirus, Helicobactor H.  ?others – Salmonella,Shigella, Campylobactor Infectios agents  Normal flora  ?M.paratuberculosis, Paramyxovirus, Helicobactor H.  ?others – Salmonella,Shigella, Campylobactor Drugs: OCP – weak association with CD NSAID Drugs: OCP – weak association with CD NSAID Breast feeding – protective against IBD Breast feeding – protective against IBD Appendectomy : ?protective for UC, ?  complications of CD Appendectomy : ?protective for UC, ?  complications of CD

8. Immunopathology  GI mucosal surface A physical interface of immune system with outside world : rich in lymphoid tissue A physical interface of immune system with outside world : rich in lymphoid tissue Bombarded with high Ag load Bombarded with high Ag load Harbors >500 sp. of micro floraHarbors >500 sp. of micro flora Normal state - Immune tolerance Normal state - Immune tolerance Non-Responsiveness (inhibited immune function)Non-Responsiveness (inhibited immune function) Mechanism- not clearly understoodMechanism- not clearly understood Dysregulated immune function - IBD Dysregulated immune function - IBD

9. Healthy Gut A complex network of Lymphoid, non-Lymphoid cells, Humoral factors A complex network of Lymphoid, non-Lymphoid cells, Humoral factors Balanced differentiation of T-helper cells Effecter c.(Th1,Th2,Th17) Regulatory c. (Tr, Th3) Balanced differentiation of T-helper cells Effecter c.(Th1,Th2,Th17) Regulatory c. (Tr, Th3) Tightly regulated cytokine network Tightly regulated cytokine network Tightly regulated immunity Tightly regulated immunity

10. IBD – Dysregulated immune response Leaky barrier – luminal Ag gain access Leaky barrier – luminal Ag gain access Commensals recognized as pathogens Commensals recognized as pathogens Expression of different profile & pattern of receptors Expression of different profile & pattern of receptors Imbalanced T-helper cell differentiation  effector cells CD: Th0  Th1 (INF ∂,IL12) UC: Th0  Th2 (IL5) Imbalanced T-helper cell differentiation  effector cells CD: Th0  Th1 (INF ∂,IL12) UC: Th0  Th2 (IL5)  NK cells  NK cells Cyclic activation of macrophages Cyclic activation of macrophages Continious inappropriate inflammatory response Continious inappropriate inflammatory response

11. Ulcerative Colitis A mucosal disease (non-transmural) A mucosal disease (non-transmural) Relapsing Relapsing Involve rectum and colon Involve rectum and colon 40-45% - rectum & recto sigmoid40-45% - rectum & recto sigmoid 30-40% - extend beyond sigmoid30-40% - extend beyond sigmoid 20% - total colitis20% - total colitis 10-20% - backwash ileitis 10-20% - backwash ileitis continuous spread continuous spread Mild inflammation – Erythema with fine granular surfaceMild inflammation – Erythema with fine granular surface More sever disease – ulceration with hemmge and edemaMore sever disease – ulceration with hemmge and edema Long standing disease – inflammatory polypsLong standing disease – inflammatory polyps Major histologic feature Major histologic feature Distorted crypt architectureDistorted crypt architecture Cyptitis, crypt abscessCyptitis, crypt abscess

12. UC cont… Typical presentation Typical presentation Diarrhea,tenesmus,passage of pus,mucus crampy abdominal painDiarrhea,tenesmus,passage of pus,mucus crampy abdominal pain Site specific presentation Site specific presentation Distal disease (proctitis): Passage of fresh blood, constipation Abdominal pain – RareDistal disease (proctitis): Passage of fresh blood, constipation Abdominal pain – Rare Proximal disease (colon) gross bloody diarrhea, abd. Pain nausea, vomiting, W’t lossProximal disease (colon) gross bloody diarrhea, abd. Pain nausea, vomiting, W’t loss Imading studies Imading studies Plain abd. Film: colon thickning, dilatationPlain abd. Film: colon thickning, dilatation Barium: thickned mucosa with superficial ulcer Deep ulcer – “collar button” loss of haustrationBarium: thickned mucosa with superficial ulcer Deep ulcer – “collar button” loss of haustration CT – mild mural thickning (<1.5cm) with inhomogenous wall densityCT – mild mural thickning (<1.5cm) with inhomogenous wall density

13. UC cont…..  Natural course 50% of the P’ts – clinical remission at any given time 50% of the P’ts – clinical remission at any given time 90% - intermittent course 90% - intermittent course  Complications Massive hemorrhage (1%) Massive hemorrhage (1%) Toxic megacolon (5%) Toxic megacolon (5%) Perforation Perforation ?Rarely – colonic obstruction ?Rarely – colonic obstruction Long term - malignancy Long term - malignancy

14. Croh’ns disease Transmural, Relapsing Transmural, Relapsing Affect any part of GI – from mouth to anus Affect any part of GI – from mouth to anus Location: Terminal ileum – 47% colon – 28%, ileocolon – 21% upper GI – 3%Location: Terminal ileum – 47% colon – 28%, ileocolon – 21% upper GI – 3% Rectum- sparedRectum- spared Segmental involvement with skip areas Segmental involvement with skip areas Disease behaviour Disease behaviour Non-stricturing/non-penetrating – 70%Non-stricturing/non-penetrating – 70% Stricturing – 17%, Penetrating – 13%Stricturing – 17%, Penetrating – 13% Mild disease: aphtous ulcerations Mild disease: aphtous ulcerations More active disease: “cobble stone” appearance May involve liver & pancreas More active disease: “cobble stone” appearance May involve liver & pancreas Major histologic finding: noncaseating Granulomas Major histologic finding: noncaseating Granulomas

15. CD cont……  Clinical presentation – depends on the site Ileocolitis : common site - terminal ileum  RLQ pain, diarrhea, palpable mass low grade fever, w’t loss  edema / bowel wall thickening fibrosis  narrowing of the lumen ( radiographic “string” sign) Ileocolitis : common site - terminal ileum  RLQ pain, diarrhea, palpable mass low grade fever, w’t loss  edema / bowel wall thickening fibrosis  narrowing of the lumen ( radiographic “string” sign) Jejunoileitis : loss of digestive/absorptive surface  Malabsorption, steatorrhea Jejunoileitis : loss of digestive/absorptive surface  Malabsorption, steatorrhea Colitis :  Bloody diarrhea, abd cramp, tenesmus Massive bleeding (1-2%) Colitis :  Bloody diarrhea, abd cramp, tenesmus Massive bleeding (1-2%) Perianal disease (1/3 of p’ts) : incontinence, anal stricture, anorectal fistula, abscess Perianal disease (1/3 of p’ts) : incontinence, anal stricture, anorectal fistula, abscess Gastro duodenal : Nausea, vomiting, epigastric pain Gastro duodenal : Nausea, vomiting, epigastric pain

16. CD cont….  Natural course 67-73% - chronic intermittent course 67-73% - chronic intermittent course 10-13% - remain in remission for several yrs 10-13% - remain in remission for several yrs After 20 yrs – most require surgery After 20 yrs – most require surgery  Complication Strictures - Bowel obstruction (40% of cases) Strictures - Bowel obstruction (40% of cases) Fistula, Abscess Fistula, Abscess Malabsorbtion syndrome Malabsorbtion syndrome rarely – massive hemmorhage rarely – massive hemmorhage

17. UC CD

20. Extra intestinal manifestations In 25% of IBD cases In 25% of IBD cases Usually seen with colonic involvement Usually seen with colonic involvement Involve any organ system Involve any organ system Skin, joints, eyes, biliary tract commonly affected Skin, joints, eyes, biliary tract commonly affected Mainly immune mediated Mainly immune mediated Most respond to Rx of the underlying disease Most respond to Rx of the underlying disease

21. The common ones  Skin : Erythema nodosum, Pyoderma gangrenosum  Joints : Peripheral arthritis, Ankylosing spondylitis Sacroliitis  Ocular : conjunctivitis, anterior uveitis / iritis, episcleritis  Hepatobiliary : Hepatic steatosis, Cholelithiasis P. sclerosing cholangitis  Urologic : Nephrolithiasis, ureteral obstruction, Fistulas

22. THANK YOU