29 Inflammatory Bowel Diseases- Pathophysiology.docx

Inflammatory Bowel Disease: Pathophysiology Learning Objectives Explain the proposed etiologies underlying the development of inflammatory bowel disease (IBD). Describe the differences in disease distribution and major pathophysiologic findings between ulcerative colitis (UC) and Crohn’s disease (CD...

Inflammatory Bowel Disease: Pathophysiology Learning Objectives Explain the proposed etiologies underlying the development of inflammatory bowel disease (IBD). Describe the differences in disease distribution and major pathophysiologic findings between ulcerative colitis (UC) and Crohn’s disease (CD). Recognize the typical clinical presentation of UC and CD, including diagnosis and how to gauge disease severity. List relevant diagnostic tests for inflammatory bowel disease (IBD). Introduction Definition of Inflammatory Bowel Disease Immune-mediated, mucosal inflammatory condition of various regions of the gastrointestinal tract Chronic, idiopathic, refractory disease Types Ulcerative Colitis (UC) Crohn’s disease (CD) Intermediate colitis ***Note: IBD is NOT related to irritable bowel syndrome Epidemiology Age: bimodal distribution Gender: relatively equal Regional: Western countries North America, Northern Europe, UK Incidence CD: 6-15.5/100,000 UC: 1.2-20/100,000 Health system costs: 2 BILLION dollars annually Hospitalization rates: 27/100,000 and estimated length of stay = 9 days 38% of patients on chronic corticosteroids require surgery within 1 year HALF of hospitalizations require surgery Etiology Genetic Infectious Immunologic Psychological Lifestyle, dietary, medications Genetic etiology Predisposes patients to IBD, not causative alone First-degree relatives up to 20x risk of developing IBD Polymorphisms involved NOD2 – involved in pathogen recognition 1 copy = increased CD risk by 2-4x; 2 copies = increased risk by 20-40x System autophagy – enables cells to regulate and degrade diverse intracellular components, regulates secretion of IL-1B Organic cation transporter (OCTN1) Linked with CD in Caucasian populations Infectious etiology Dysbiosis: more bacteria that promote inflammation located in GI tract Higher mucus and epithelial bacteria burden Possibly leads GI tract to lose tolerance to normal GI flora Suspects? Bacteria, protozoans, viruses Immunologic etiology Everything is working well! Reduction in innate immune system Breakdown of the intestinal wall and epithelial barrier which ↑ susceptibility to microbiome Paneth cells ↓ defensin secretion and Goblet cells ↓ mucus ↑ permeability and mucus alterations ↑ translocation of microbiome into intestinal lining Resulting activation of inflammatory response Prolonged inflammation → epithelial injury Leads to: erosions, ulcerations, and ↓ in defensin production → amplifies inflammatory response Cytokine dysregulation T-helper (Th) = lymphocyte type Th1 induces cell-mediated immunity ↑ in Crohn’s Th2 induces humoral response ↑ in UC IBD: increased Th1 response Also, increased TNF-alpha In IBD, intestinal epithelium infiltrated with: Innate immune cells (neutrophils, macrophages, dendritic cells, NK T cells) Adaptive immune cells (B and T cells) Infiltrations will increase inflammatory response ↑ TNF-alpha ↑ IL-1B ↑ interferon-gamma ↑ cytokines Many of these are drug targets! Psychological etiology Stress correlates with IBD flares Stress reduction has not shown to alter progression of IBD Lifestyle, Diet, and Medication Etiologies Lifestyle Diet Medications Hygiene Hypothesis Refined Sugars NSAIDs Smoking Protein Antibiotics Accutane® Hormonal Contraception Pathophysiology Clinical Features Clinical Features Clinical Features UC CD Rectal bleeding ✓✓ ✓ Transmural Rare ✓ Cobblestone appearance Absent ✓ Systemic symptoms Uncommon ✓ Stricture/Fistula/ Abdominal Mass/ Granuloma Rare ✓ Extraintestinal Manifestations Anemia Dermatologic: erythema nodosum, psoriasis, pyoderma gangrenosum Hepatobiliary: fatty liver, autoimmune hepatitis, cirrhosis, cholelithiasis Ocular: iritis, uveitis, conjunctivitis Oral apthous lesions Osteoporosis Information to collect if suspecting IBD Signs/symptoms Abdominal pain, frequency of stool, presence of extraintestinal manifestations, hematochezia (+/-), weight loss Vital signs Temperature, blood pressure, heart rate Signs of bleeding Hematochezia, bloody stools/black, anemia (Hgb) Markers of inflammation: CRP/ESR Abdominal imaging CT abdomen, abdominal ultrasound, MRI Ulcerative Colitis Ulcerative Colitis Affects mucosal and submucosal layers Local complications: hemorrhoids, anal fissures, perirectal abscesses Severe complications Toxic megacolon Colonic perforation Colonic hemorrhage Colonic stricture Colorectal carcinoma ↑ risk – 5x Clinical presentation of UC Usually relapsing disease Typical presentation Abdominal pain Anemia Bloody diarrhea Rectal urgency/tenesmus Weight loss Diagnostic tests or procedures Stool examinations C. diff assay Stool cultures Lab testing ESR/CRP CBC, CMP Bacterial/parasitic infection- rule out Sigmoidoscopy/colonoscopy Biopsy Chronic inflammatory cells visible Ulcerative Colitis: Severity No standard measure of severity 4-5 scales available Based on clinical signs and symptoms of disease Distal vs. extensive disease Distal: limited to areas distal to the splenic flexure Extensive: Proximal to splenic flexure Mild: no systemic signs/symptoms, Hgb >11 g/dL Severe: systemic signs/symptoms (fever, tachycardia, anemia) UC Poor Prognostic Factors Age <40 at diagnosis Elevated CRP Extensive colitis Hospitalization for colitis Low serum albumin Severe endoscopic disease (Mayo Endoscopic subscore 3, UCEIS ≥ 7) *The greater number of factors, the higher likelihood of colectomy *Will dictate treatment Crohn’s Disease Crohn’s Disease Transmural Mouth to anus Most commonly at terminal ileum <5% of patients have gastroduodenal disease (may present like PUD) Discontinuous disease: “Cobblestone” appearance Deep and long ulcerations Clinical presentation of CD Diarrhea, abdominal pain, hematochezia (50% of patients with colonic involvement) Vitamin deficiencies are possible Risk of carcinoma increased but not as greatly as with UC Diagnosis and Presentation Diagnosis Shown as focal, asymmetric, transmural or granulomatous CD should be considered for Chronic/nocturnal diarrhea Abdominal pain/tenderness Bowel obstruction Weight loss, fever, night sweats Intestinal inflammation Fibrosis/fistula Diagnosis and Presentation Signs and symptoms Pallor Cachexia Abdominal mass/tenderness Perianal fissures, fistula or abscess Diagnostic Tests Diagnosis is based on a composite of endoscopy/ colonoscopy, radiographic, and pathological findings Rule out C. diff Test Findings and examples Endoscopy Visual examination of GI tract Anoscopy not sufficient Possibly therapeutic for strictures Video capsule endoscopy: superior for detecting small bowel pathology Radiographic CT scan MRI Pathologic Biopsy Fistula Crohn’s Disease: Severity Based upon Crohn’s Disease Activity Index (CDAI) Helps determine remission Scale from 0-600 Harvey Bradshaw Index Clinical response to treatment = reduction in total score by 3 points Clinical response is NOT necessarily absence of active disease Clinical remission is a Harvey Bradshaw Index <4 Remission = absence of active disease Crohn’s Disease Severity Severity Category CDAI Localized symptoms Weight loss Systemic toxicity Other Signs and Symptoms Treatment failure Mild- Moderate 150-220 - <10% None Tolerates PO, no dehydration - Moderate- Severe 221-450 + >10% + Intermittent nausea and vomiting, anemia + Severe- Fulminant >450 + >10% + Abscess, cachexia, persistent vomiting, intestinal obstruction + CDAI = Crohn’s Disease Activity Index + = positive - = negative PO = by mouth Localized symptoms = abdominal tenderness Systemic toxicity = fever, rigors Summary IBD is an autoimmune disorder characterized by consistent inflammation of the GI tract Multiple etiologies contribute to disease formation and progression Key features differentiate UC and CD Diagnosis and disease severity tools help assess patients and direct therapy