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pathogenesis of Crohn's disease presented on KMC,kol july, 2013
 

pathogenesis of Crohn's disease presented on KMC,kol july, 2013

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    pathogenesis of Crohn's disease presented on KMC,kol july, 2013 pathogenesis of Crohn's disease presented on KMC,kol july, 2013 Presentation Transcript

    • Pathophysiology of intestinal manifestations of Crohn’s disease Speaker: Dr. Dibbendhu Khanra Chairperson: Dr. K. D. Biswas
    • Part I Pathology 19001950 Part II Immunology 19501990 Part III Genetics 19902010 Part IV Future & beyond 21st century Discourse along history
    • 1900: Sorrow of Prince Albert Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve ?
    • Terminal ileitis Regional ileitis Granulomatous entreocolitis Crohn’s disease
    • M=F Sedentary life style Developed nations OCP Smoking Appediculectomy Use of refrigerator
    • Part I: Pathology
    • Macroscopic appearance Aphthous ulcer  Mycobacterium paratuberculosis  E. coli  Yersinia  Listeria  Measles ‘Cobblestone’ Perianal disease  Inflammatory symptoms Small Bowel : 70 - 80 % Small And Large Bowel : 50 % Large Bowel Only : 15 - 20 %  Obstructive symptoms  Fistulous symptoms  Perianal diseases
    • Microscopic appearance Transmural ulcer Crypt abscess Non-caseating granuloma Aphthoid ulcer in Peyer’s patch
    • Microscopic appearance: CD vs UC
    • Radiological appearance String sign Fat halo sign Comb sign
    • Sorrow of Prince Charming Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve Crohn’s disease antimicrobials Surgery
    • What kind of disease is Crohn’s disease? Is it infective disease?
    • 1950: Sorrow of Miss America Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve Crohn’s disease
    • Part II: Immune dysregulations Power struggle & sensitivity issues
    • POWER V/S INJUSTICE JUSTICE Blood vessels Gut Innate Innate Immunity Immunity Organized Disorganized war Microbial Invasion Immune response Adaptive Adaptive Immunity Immunity Inflammation Barrier function Epithelial damage Increased small intestinal permeability Malabsorption & deficiency
    • Adaptive immunity inadequate inadequate Genetic innate microbial predisposition immunity elimination Adaptive immunity Neutrophil IL12 Th0 IL4, 23 Th1 CAMIntegrin Extraintestinal manifestations Macrophage Lymphocyte Th2 IFN gamma IL4, 5 13 Granulomatous inflammation Superficial ulceration IL6, TGFb Th17 IL17, 21 Neutrophilic recruitment TNFa, IL1, IL6 Extraintestinal manifestations
    • Abdominal pain 1. Stretch receptors stimulated as a food bolus passes through stenotic bowel 2. ganglia of the myenteric plexuses increased in size and number 3. Substance P receptors have increased around lymphoid follicles, microvasculature, and enteric neurons Diarrhea Fever & weight loss: TNF-alpha 1. Increased mucosal permeability 2. Cytokines, PG, ROS 3. imbalance in the luminal concentration of bile salts relative to dietary fat 4. Bacterial overgrowth 5. Disordered colonic motility
    • Antibodies in Crohn’s disease ASCA is present in ITB (50%) and CD (50%) both
    • 1950: Sorrow of Miss America Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve 1950 1960 Steroid Immuno modulators Surgery
    • What kind of disease is Crohn’s disease? Is it immunologic disease?
    • 2000: Sorrow of a Rock diva Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve Crohn’s disease
    • Part III: Genetics & Innate Immunity - Days of glory
    • Immune dysregulations 2 L/O oral tolerance L/O autophagy L/O NODing
    • L/O Oral Oral tolerance T reg cells depleted Fox P3 transcription factor IL10 TGF-b Inflammation Antiinflammation
    • L/O Autophagy ATG16L1 protein inadequate microbial elimination
    • Role of NOD inadequate microbial elimination
    • NOD2/ CARD15 Chr 16 Genetic determinism ATG16L1 Chr 2 TLR4 LPS signaling defect Microbial invasion Innate Immunity Adaptive Immunity TNFSF15 IL23R CTLA4 Mucosal integrity DLG 5 Chr 10 OCTN 1 Chr 15
    • Crohn’s victim to Crohn’s survivor Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve Crohn’s disease 2000 Biologics
    • What kind of disease is Crohn’s disease? Is it genetic disease?
    • 2010: a magician in trouble Chronic diarrhea Abdominal cramps Weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve Crohn’s disease
    • Part IV: What lies ahead Theory of everything
    • NODophagy meets Autophagy
    • Endoplasmic reticulum stress and unfolded protein response
    • miRNA inadequate microbial elimination
    • A magic trick Chronic diarrhea Abdominal cramps weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve 2013 Rapamycin
    • What kind of disease is Crohn’s disease? What we have learned today?
    • Summary 1
    • Summary 2
    • Summary 3 Abdominal pain Diarrhea fistula Weight loss Mal nutrition Stricture Mass
    • Crohn’s disease Defective GUT Genetic determinism Immune injustice Thank you