2.  Two chronic inflammatory disorders of unknown etiology are Crohn ’ s disease (CD) and ulcerative colitis (UC).  CD is a granulomatous disease that may affect any portion of the gastrointestinal tract from mouth to anus but most often involves the small intestine and colon.  UC is a nongranulomatous disease limited to colonic involvement.

3.  Crohn disease and ulcerative colitis differ in many respects, including the natural history of the disease, pathological aspects, and in the types of therapies and responses to treatment.

4.  The normal intestine is in a steady state of "physiologic" inflammation, representing a dynamic balance between :  (1) factors that activate the host immune system, such as luminal microbes, dietary antigens, and endogenous inflammatory stimuli  (2) host defenses that down-regulate inflammation and maintain the integrity of the mucosa. The search for the causes of loss of this balance in Crohn disease and ulcerative colitis has revealed many parallels, but the origins of both diseases remain unexplained (thus their designation as idiopathic ).

5.  The pathogenesis of IBD involves genetic susceptibility, failure of immune regulation, and triggering by microbial flora

6. 1] Genetic predisposition. -Familial aggregations in IBD. -First-degree relatives are 3 to 20 times more likely to develop the disease, and 15% of persons with IBD have affected first-degree relatives -CD-HLA- -DR7 and DQ4 alleles are associated with approximately 30% of Crohn disease cases in North American white males -UC – HLA-DRB1 - IBD 1 locus on chromosome 16, NOD 2 gene (NFkB) -A gene in CD and UC is a mutant form of the IL-23 receptor ( IL-23R ) gene. IL-23 is a cytokine that promotes the production of IL-17 by T cells, and IL-17 has been implicated in inflammatory reactions in IBD

7. 2]Infectious causes. -Mycobacterium paratuberculosis and measles virus. 3]Abnormal host immunoreactivity: -Stimulated immune system. - In IBD: cytokine IL-17 a recently discovered subset of CD4+ T cells that is being called the "T H 17" subset is secreted - cytokine TNF may play an important pathogenic role in Crohn disease -Induction of cytotoxic antiepithelial AB or natural killer cells - ANCA are present in about 75% of persons with ulcerative colitis and only 11% of individuals with Crohn disease..

8.  To summarize, IBD is a heterogeneous group of diseases characterized by an exaggerated and destructive mucosal immune response. The tissue injury in IBD is likely to be initiated by diverse genetic and immunologic pathways that are modified by environmental influences, including microbes and their products  Inflammation is the final common pathway for the pathogenesis of IBD.

9. Idiopathic inflammatory bowel disease Etiology and Pathogenesis Factors that activate the host immune system Luminal microbes Dietary antigens Endogenous inflammatory stimuli Host defenses that down- regulate inflammation and maintain the integrity of the mucosa The normal intestine is in a steady state of physiologic Inflammation, representing a dynamic balance

10.  Crohn ’ s disease is a chronic inflammatory disorder that most commonly affects the ileum and colon but has the potential to involve any part of the gastrointestinal tract from the mouth to the anus.  Crohn disease must be viewed as a systemic inflammatory disease  Active cases of the disease are often accompanied by extra-intestinal complications of immune origin, such as uveitis, sacroiliitis, migratory polyarthritis, erythema nodosum, bile duct inflammatory disorders, and obstructive uropathy with attendant nephrolithiasis.

11.  CD is characterized by: a. Skip areas – regional entities. b. Non-caseating epitheliod cell granulomas. c. Transmural (full-thickness) inflammation of affected parts. d. Fissuring and fistula formation. e. Systemic manifestations

12.  Worldwide in distribution, Crohn disease is much more prevalent in the United States, Great Britain, and Scandinavia than in Central Europe, and is rare in Asia and Africa.  It occurs at any age, from young childhood to advanced age, but the peak incidence is between the second and third decades of life, with a minor peak in the sixth and seventh decades.  Females are affected slightly more often than males.  Whites appear to develop the disease two to five times more often than do nonwhites.  In the United States, Crohn disease occurs three to five times more often among Jews than among non-Jews.

13. Pathology  Combine ileal and colonic disease (30%). The ileum alone in 40% and the colon in 30%.  Perianal lesions such as abscesses, fistulas and skin tags – 75%.  Segmental with skip areas.  Acute phases: swollen and reddened with ulceration.  Chronic phase: thickened and rigid (lead pipe or garden hose appearance).  Mesenteric fat creeps from the mesentery to the bowel wall (creeping fat).  The mucosal surface: longitudinal serpiginous ulcers (cobblestone effect).  Fissures and fistulas.

14. Crohn ’ s Disease

16. Microscopic features  Distortion of mucosal crypt architecture.  Transmural inflammation.  Presence of epitheliod granulomas.  Fissure-ulcers.  Fibrosis.  The regional mesenteric lymph nodes are enlarged and may contain non-caseating granulomas.

17. Crohn ’ s Disease

19.  is highly variable and unpredictable.  The dominant manifestations are recurrent episodes of diarrhea, crampy abdominal pain, and fever lasting days to weeks.  These manifestations usually begin insidiously but may be acute  melena is present in about 50% of cases with colon involvement  In most patients, after an initial attack, the manifestations remit either spontaneously or with therapy, but characteristically they are followed by relapses, and intervals between successive attacks grow shorter.  malabsorption

20. (1) fistula formation to other loops of bowel, the urinary bladder, vagina, or perianal skin (2) abdominal abscesses or peritonitis (3) intestinal stricture (4) Bleeding (5) toxic dilation of the colon (6) carcinoma of the colon or small intestine

21.  Ulcerative colitis is an inflammatory disease of colon of uncertain cause.  Limited to the mucosa and submucosa  begins in the rectum and extends proximally in a continuous fashion, sometimes involving the entire colon  UC is a systemic disorder associated in some persons with migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, erythema nodosum, and hepatic involvement (pericholangitis and primary sclerosing cholangitis

22.  In USA, incidence = 4-12/100,000.  the incidence of this condition has risen in recent decades  Age: 20-25 years, any age.  Slightly higher in females than in males.  Whites are more often affected than blacks.  Jews more often than non-Jews.  Prevalent in North America and Western Europe and less prevalent in Asia, Africa and South America.  about 20% of persons with the disorder have affected relatives  Individuals with ulcerative colitis and ankylosing spondylitis have an increased frequency of the HLA-B27 allele

23. Pathology  UC is a disease of the rectum.  The disease extends proximally from the rectum in a continuous manner without skip areas.  The appendix is involved in about 30% of cases.  UC involves mainly the mucosa.  The mucosal surface shows diffuse hyperemia with numerous superficial ulcerations in the acute phase.  Chronic: mucosa flat, atrophic, inflammatory pseudopolyp.

24.  Well-formed granulomas are absent.  There are no skip lesions.  The mucosal ulcers rarely extend below the submucosa, and there is surprisingly little fibrosis.  Mural thickening does not occur, and the serosal surface is usually completely normal.  There appears to be a high risk of carcinoma development.

25. Microscopic appearance Acute phase :  Mucous marked inflammation with neutrophils, lymphocytes, and plasma cells.  Crypt abscesses and active cryptitis. Chronic phase:  Crypt atrophy, distorted architecture and chronic inflammatory cells in the lamina propria.  Active inflammation correlates well with the severity of symptoms.  The inflammation is usually restricted to the mucosa.  Dysplasia and high grade adenocarcinoma.

29.  UC is chronic relapsing and remitting disorder  Attacks of bloody mucoid diarrhea  Abdominal cramps and colicky pain relieved by defecation  Extra-intestinal manifestations particularly migratory polyarthritis.

30.  Sever diarrhea  Rupture  Massive hemorrhage  perforation  Toxic megacolon  colon carcinoma: Two factors govern the risk: 1. duration of the disease, at 20 years the risk is on the order of 2%. 2. With pancolitis, the risk of carcinoma is 10% at 20 years and 15% to 25% by 30 years.

31. Toxic megacolon