Pathophysiology of Inflammatory Bowel Disease PDF

Undiagnosed or untreated CD may lead to complications ○ GASTROINTESTINAL COMPLICATIONS: pharyngeal or esophageal cancer, lymphoma or cancer of the small intestine, refractory CD (symptoms persisting despite adherence to a GFD) > Gluten Free Diet...

Undiagnosed or untreated CD may lead to complications ○ GASTROINTESTINAL COMPLICATIONS: pharyngeal or esophageal cancer, lymphoma or cancer of the small intestine, refractory CD (symptoms persisting despite adherence to a GFD) > Gluten Free Diet - ○ HEMATOPOIETIC: Non-Hodgkin lymphoma ○ UROGENITAL: infertility, recurrent miscarriage, premature birth, premature menopause ○ MUSCULOSKELETAL: osteoporosis and increased risk of bone fractures Treatment of Celiac Disease: only current available treatment is adherence to a strict gluten-free diet (GFD) Even very small amounts of gluten (50mg or a breadcrumb) can induce inflammatory changes in the small intestine and triggering symptoms in patients with CD Inflammatory bowel disease (IBD): Chronic condition resulting from complex interactions between intestinal microbiota and host immunity in genetically predisposed individuals Leads to inappropriate mucosal immune activation Comprises two disorders: ○ Ulcerative colitis ○ Crohn disease The distinction between UC and Crohn’s disease is primarily based on the distribution of affected sites and the morphologic expression of disease: ○ Ulcerative colitis involves only the colon and rectum and is generally limited to the mucosa and submucosa ↑ ○ Crohn disease (regional enteritis- frequent ileal involvement) may involve any area of the GI tract and is typically transmural and granulomatous in character. (mouth to anus) Epidemiology: ○ Exact causes are unknown despite progress in understanding its pathogenesis: Hygiene hypothesis: increasing incidence is related to improved food storage conditions, decreased food contamination, and changes in gut microbiome composition that result in inadequate development of regulatory processes that limit mucosal immune responses. => overactive immune ○ Some mucosa-associated microbes trigger persistent and chronic inflammation in response susceptible hosts. ○ Other potential explanations for increased IBD prevalence include the idea that preservatives and other materials added to processed foods induce low-grade mucosal damage that predisposes to IBD. IBD: Pathogenesis: ○ Results from combination of genetic risk and environmental factors: Genetic risk: Evaluation of single nucleotide polymorphisms (SNPs) in patients with IBD and in people without the disease found abnormalities in several categories of susceptibility genes:  ○ Immune regulation ○ Host-microbiome interactions ○ Epithelial barrier functions The relative risk of moth of these susceptibility genes is low (20-30% increase in relative risk of developing disease) Many of the genes linked to IBD are also associated with other autoimmune diseases including diabetes mellitus, rheumatoid arthritis, and psoriasis Environmental factors Pathogenic microorganisms (bacteria and viruses) The repertoire of indigenous intestinal microbes (the microbiota) Dietary factors Smoking Defective immune responses Psychosocial factors In Crohn disease, the modulation of inflammatory responses to dietary and microbial antigens may be defective which results in uncontrolled inflammation Mice lacking the TH1-inhibiting cytokine interleukin-10 have a TH1 cytokine profile and develop spontaneous intestinal inflammation Monoclonal antibodies to tumor necrosis factor alpha (TNFa) reduce inflammation in these animals and patients Similar factors may contribute to the pathogenesis of ulcerative colitis, including infections, allergies to dietary components, immune responses to bacteria and self-antigens, and psychosocial factors. In mice, targeted disruption of the genes for the T-cell receptor and the cytokine IL-2 results in GI tract disease resembling ulcerative colitis Neonatal period ○ Recent studies suggest that patterning activity of certain aspects of the immune system during the neonatal period strongly influence immune responses in the adult. ○ Early exposure to intestinal microbiota may be an important component of the pathogenesis of IBD ○ Maternal effects are thought to be a contributing factor to GI disease, because composition of the intestinal microbiota is in large part transmitted by the mother Crohn’s disease: Clinical manifestation: ○ In most patients, disease begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain ○ Approximately 20% of patients present acutely with RLQ pain, fever, and bloody diarrhea that may mimic acute appendicitis or bowel perforation ○ Periods of active disease are typically interrupted by asymptomatic periods that last for weeks to many months ↳ no observable symptoms  ○ Disease reactivation can be associated with a variety of external triggers, including physical or emotional stress, specific dietary items, and cigarette smoking. ○ In some cases, disease onset is associated with initiation of smoking, but smoking cessation does not result in disease remission. dissapearance > - ○ Individuals with colonic disease may develop iron deficiency anemia due to blood loss. ○ Extensive small bowel disease may result in protein loss sufficient to cause hypoalbuminemia and malabsorption of nutrients, vitamin B12, and bile salts. ○ Most typically occurs in the distal ileum ○ The distribution of the disease can also involve the colon or less commonly any other region of the GI tract (including the oral cavity, esophagus, stomach, and proximal small intestine) ○ Areas of ulceration and inflammation occur in a discontinuous fashion and involve the entire thickness of the bowel wall ○ Recurrence of disease can occur in previously uninvolved regions of the intestine and can even involve adjacent mesentery and lymph nodes. ○ The combination of deep mucosal ulceration and submucosal thickening gives the involved mucosa a characteristic “cobblestone” appearance Frequent complications: ○ Perforation ○ Fistula formation ○ Abscess formation ○ Small intestinal obstruction Fibrosing strictures, particularly of the terminal ileum, are common and require surgical resection Fistulae develop between loops of bowel and may also involve the urinary bladder, vagina, and abdominal or perianal skin Extraintestinal manifestations (may develop before intestinal disease is recognized): ○ Cutaneous nodules formed by granulomas ○ Uveitis, iritis ○ Migratory polyarthritis, sacroileitis, ankylosing spondylitis ○ Erythema nodosum, cutaneous granulomas ○ Autoimmune chronic active hepatitis, sclerosing cholangitis ○ Clubbing of the fingertips ○ Renal disorders, especially nephrolithiasis ○ Amyloidosis Therapies include: ○ Anti-inflammatory agents (e.g. salicylates) ○ Immunosuppressive drugs (e.g. corticosteroids) ○ Biologic therapies (e.g anti-TNF antibodies, antibodies against other cytokines (IL23) and cell trafficking (integrins and adhesions molecules), Targeted kinase inhibitors Janus kinase [JAK])