pathophysiology Prof. Sina Aziz PhD (Paediatrics) KMDC/ASH - PowerPoint PPT Presentation

IBD (Inflammatory bowel disease) pathophysiology Prof. Sina´ Aziz PhD (Paediatrics) KMDC/ASH 6/30/2012 PNDS/sina aziz 1

Contents of this presentation • GI anatomy • Prevalence of IBD • IBD definition layman • IBS and IBD • Signs and symptoms of IBD • Pathophysiology IBD • Crohns disease- etiology/anatomy/pathogenesis/signs and symptoms • Ulcerative colitis- etiology/anatomy/pathogenesis/signs and symptoms • Comparison between UC and CD • Research material 6/30/2012 PNDS/sina aziz 2

Prevalence of IBD Up to 1 million Americans are thought to have IBD, which occurs most often in ages 15 to 30, but can affect younger kids and older people. Most cases are reported in western Europe and North America http://kidshealth.org/parent/medical/digestive/ibd.html 6/30/2012 PNDS/sina aziz 3

IBD definition Inflammatory bowel disease (which is not the same thing as irritable bowel syndrome, or IBS) refers to two chronic diseases that cause inflammation of the intestines: 1. ulcerative colitis and 2. Crohn's disease. Although the diseases have some features in common, there are some important differences 6/30/2012 PNDS/sina aziz 4

IBS • Irritable bowel syndrome (IBS) is a disorder that leads to abdominal pain and cramping, changes in bowel movements, and other symptoms. • IBS is not the same as inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. In IBS, the structure of the bowel is not abnormal. 6/30/2012 PNDS/sina aziz 5

Signs and symptoms-IBD • Common symptoms of both ulcerative colitis and Crohn's disease are diarrhea and abdominal pain. Diarrhea can range from mild to severe (as many as 20 or more trips to the bathroom a day). If the diarrhea is extreme, it can lead to dehydration, rapid heartbeat, and a drop in blood pressure. • And continued loss of small amounts of blood in the stool can lead to anemia. • The loss of fluid and nutrients from diarrhea and chronic inflammation of the bowel can also cause fever, fatigue, weight loss, and malnutrition. • . 6/30/2012 PNDS/sina aziz 6

Signs and symptoms • Pain is usually from the abdominal cramping, which is caused by irritation of the nerves and muscles that control intestinal contractions • At times, those with IBD may also be constipated. • Crohn's disease, this can happen as a result of a partial obstruction (called stricture) in the intestines. • Ulcerative colitis, constipation may be a symptom of inflammation of the rectum (known as proctitis). 6/30/2012 PNDS/sina aziz 7

Signs and symptoms • IBD can cause other health problems that occur outside the digestive system. • IBD can show signs of inflammation elsewhere in the body, including the joints, eyes, skin, and liver. • Skin tags that look like hemorrhoids or abscesses may also develop around the anus. • IBD might delay puberty or cause growth problems for some children because it can interfere with them getting nutrients from food. 6/30/2012 PNDS/sina aziz 8

Multifactorial etiopathogenesis of CD Triggering event infectious Genetic Gut microflora predisposition Cytokines Abnormal mucosal immune response Cytokines chemokines, adhesion molecules Eicosanoside nitrous oxide Reactive oxygen metabolites Acute phase reaction Neuropeptides intestinal permeability Growth factors Normal Intestinal inflammation immune down regulation homeostasis lack of immune down -regulation Chronic IBD 6/30/2012 PNDS/sina aziz 9

Environmental influences • Specific microbial trigger • Mycobacteria • Viruses • Role of enteric flora • Role of diet • Risk factors-early life exposures Other modulating factors • Smoking • Oral contraceptives Host environment interactions • Defective mucosal barrier • Immunoregulatory abnormalities • Defective innate immunity- NOD2/CARD15 • Adaptive immune response • control of mucosal immune response 6/30/2012 PNDS/sina aziz 10

Anatomy and frequency of area involved 6/30/2012 PNDS/sina aziz 11

CD-Pathology – anatomic distribution • Panenteric inflammatory process • Endoscopy with biopsy identifies histologic abnormalities GIT • CD is characteristically segmental, with spared areas in the intestinal tract • Terminal ileum is the most common affected area • Colonoscopy and small bowel radiography • Upper EGD with biopsy- microscopic involvement of esophagus/stomac and duodenum • Gastroduodenal disease-only rarely the sole or predominant site of crohns disease 6/30/2012 PNDS/sina aziz 12

Data of hospital for sick children Toronto 1990-1999 and Gastroenterol clin north am 2002;31:307-27 % Intestinal involvement ( by colonoscopy and small bowel radiography) 29% terminal ileum with or without cecal disease 38% Small intestine alone 9% More isolated proximal (ileal or jejunal) disease 42% Ileocolonic inflammation 38% In combination with colon 20% Colon involvement 20% Colon alone 6/30/2012 PNDS/sina aziz 13

Macroscopic appearance • Crohn's often involves the small intestine, the colon, or both. • Internal tissues may develop shallow, crater- like areas or deeper sores and a cobblestone pattern, as seen here. 6/30/2012 PNDS/sina aziz 14

Microscopic appearence- Endoscopic biopsy showing granulomatous inflammation of the colon in a case of Crohn's disease. H&E stain http://wikimediafoundation.org/wiki/Home 6/30/2012 PNDS/sina aziz 15

Prevalence of individual symptoms at the time of diagnosis of CD Mendeloff et al Clin. Gastroenterology 1980;9: 258 symptom Toronto pediatric IBD data UK and Ireland surveillance base N = 386 N = 379 Abdominal pain 86 72 Diarrhea 78 56 Blood in the stool 49 22 Weight loss 80 58 fevers 38 Not stated Perianal lesions 8 fistula or abscess, 19 tags, 7 fistula or abscess 22 fissures Arthralgias/arthritis 17 8 Mouth ulcers 28 Not stated Skin lesions 8 1 6/30/2012 PNDS/sina aziz 16

Modes of presentation of CD- The hospital for sick children, Toronto 1980-89 Mode N (%) Classic presentation (abdominal pain, diarrhea, weight loss ± extra 235 (78.6) intestinal manifestations) Growth failure predomination 10 (3.3) Extraintestinal manifestation predominating 25 (8.4) • Arthritis 13 • Recurrent fevers 8 • Recurrent oral ulcers 1 • Oral chelitis 1 • Pyoderma gangrenosum 1 • Recurrent acute pancreatitis 1 Anemia as the major complaint 8 (2.7) Perianal disease predominating 11 (3.7) Anorexia, weight loss predominating 6 (2) Laparotomy for acute abdominal pain 4 (1.3) Total 299 6/30/2012 PNDS/sina aziz 17

Crohns Disease complications - malnutrition and growth impairment Factor Reason Cytokines produced by Direct role of inflammatory cytokines in linear growth inhibition chronically inflamed intestine (IGF-I) inhibition: interference in kinetics of bone growth Insufficient caloric intake Food avoidance because of exacerbation of Gi symptoms by eating: cytokine mediated anorexia Stool losses Mucosal inflammation leading to protein loosing enteropathy; steatorrhoea if extensive Increased nutritional needs Fever, chronic deficits Cortico steroid treatment Inhibition of IGF-1 (insulin like growth factor) EXTRA INTESTINAL MANIFESTATIONS JOINTS SKIN EYE HEPATOBILIARY PANCREAS RENAL VASCULAR 6/30/2012 PNDS/sina aziz 18 BONE

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UC-Ulcerative colitis 6/30/2012 PNDS/sina aziz 20

Ulcerative colitis • Is an inflammatory disease of the large intestine, or colon. • Inner lining (mucosa) of the intestine becomes inflamed (red and swollen) and develops ulcers (open, painful wounds). • Severe in the rectal area, which can cause frequent diarrhea. Mucus and blood often appear in the stool (feces or poop) if the lining of the colon is damaged 6/30/2012 PNDS/sina aziz 21

Comparison of pathological features of UC & CD Feature Ulcerative colitis Crohns disease Gross/endoscopic Typically diffuse, continuous, Focal disease characterized by skip extending proximally from the lesions • Colonic involvement rectum Almost always involved Frequently spared • Rectal involvement Non- specific “backwash ileitis” Typically involved with ulceration • Ileal involvement and nodularity Broad and shallow Early aphthous lesions, ulcer knife- • ulceration like and fissuring, intervening areas of oedema may give cobblestone appearence Microscopic Depth of inflammation Mucosal, except in severe disease Typically transmural Absent except for occ. Giant cell reaction to damagedcrypts granulomas Non-caseating granulomas seen fibrosis unusual typical 6/30/2012 PNDS/sina aziz 22

Etiologic factors in the pathogenesis of UC • Genetic predispostion Frequent positive F/H (15-25%) Higher rates of concordance in monozygotic twins than in dizygotic twins Association with specific HLA class II genes Association with other genetic disorders e.g Turners syndrome • Environmental factors Early childhood events e.g diarrheal illness; may increase risk Appendectomy at an early age: may decrease risk Psychological stress; may cause exacerbations Smoking tobacco; decreases risk • Drugs NSAID may cause exacerbations Oral contraceptives; conflicting data • Microbial factors ; important in pathogenesis 6/30/2012 PNDS/sina aziz 23