Crohn's Disease

Aka: Crohn's Disease, Terminal Ileitis, Regional Enteritis, Crohn's Colitis

1. See Also
   1. Inflammatory Bowel Disease
   2. Gynecologic Manifestations of Crohn's Disease
2. Epidemiology
   1. Prevalence: 201 per 100,00 in U.S.
   2. Peak onset: 15-30 years (onset up to age 40)
   3. Women more often affected than men
   4. Familial aggregation
      1. First degree relative confers 2-4 fold risk
      2. Second degree relative confers less increased risk
3. Pathophysiology
   1. Etiology unknown
   2. Related genetic mutation: NOD2 (Chromosome 16 in IBD1)
      1. Associated with increased Crohn's relative risk
         1. One NOD 2 mutation: 2 fold relative risk
         2. Two NOD 2 mutations: 15-35 fold relative risk
      2. Proposed mechanism
         1. Related to defective bacterial sensing by Monocytes
         2. Results in hyper-immune response to bacterial LPS
      3. References
         1. Ahmad (2002) Gastroenterology 122:854
   3. Chronic granulomatous inflammation
      1. Transmural extension to entire bowel wall
      2. Ulcerative Colitis only affects mucosa
   4. Effects entire Gastrointestinal tract, mouth to anus
      1. Distal ileum and proximal colon most often involved
      2. Isolated colonic involvement in 25% of cases
   5. Irregular involvement ("Skip lesions")
4. Symptoms
   1. Fever
   2. Weight loss
   3. Fatigue
   4. Nausea
   5. Anorexia
   6. Abdominal Pain (Low abdominal ache or cramp)
   7. Diarrhea (85%)
   8. Rectal bleeding
      1. Much less prominent than in Ulcerative Colitis
      2. Non-bloody Diarrhea is typical for Crohn's Disease
5. Symptoms: Based on location
   1. Ileum and colon (35%)
      1. Diarrhea
      2. Abdominal cramping or Abdominal Pain
      3. Weight loss
   2. Colon only (32%)
      1. Diarrhea
      2. Rectal bleeding
      3. Perirectal Abscess
      4. Fistula
      5. Perirectal ulcer
      6. Associated with skin lesions and arthralgias
   3. Small Bowel only (28%)
      1. Diarrhea
      2. Abdominal cramping or Abdominal Pain
      3. Weight loss
      4. Associated with fistulas and abscesses
   4. Gastroduodenal region (5%)
      1. Anorexia
      2. Weight loss
      3. Nausea and Vomiting
      4. Associated with Bowel Obstruction
6. Signs: Gastrointestinal
   1. Stool Occult Blood positive
   2. Anal Disease(20%)
      1. Perirectal fistula
      2. Anal Skin Tag
      3. Anal Ulceration or Anal Fissure
      4. Perirectal Abscess
   3. Right Lower Quadrant abdominal palpable mass (common)
7. Signs: Extra-abdominal manifestations
   1. See Gynecologic Manifestations of Crohn's Disease
   2. Similar to manifestations in Ulcerative Colitis
   3. Anemia (>9%)
   4. Anterior Uveitis (17%)
   5. Episcleritis (29%)
   6. Aphthous stomatitis (>4%)
   7. Cholelithiasis (>13%)
   8. Erythema Nodosum (>2%)
   9. Inflammatory arthropathy (>10%)
   10. Nephrolithiasis (>8%)
   11. Osteoporosis (>2%)
   12. Pyogenic gangrenosum (>0.5%)
   13. Scleritis (18%)
   14. Venous Thromboembolism (>10%)
8. Signs: Extra-abdominal Manifestations (10% Incidence)
   1. Similar findings in Ulcerative Colitis
      1. See Ulcerative Colitis extraintestinal manifestations
   2. Minimal increased Colon Cancer risk
9. Labs
   1. Complete Blood Count with platelet
      1. Mild Anemia: Chronic blood loss
      2. Mild Leukocytosis: Crohn's Disease exacerbation
      3. Marked Leukocytosis
         1. Severe colitis
         2. Toxic Megacolon
         3. Intra-abdominal abscess
   2. Comprehensive metabolic panel (Liver Function Tests, Renal Function tests)
   3. Acute phase reactants
      1. C-Reactive Protein (C-RP)
      2. Erythrocyte Sedimentation Rate (ESR)
   4. Stool studies
      1. Stool Culture
      2. Ova and Parasites
      3. Clostridium difficile Toxin
   5. Markers of nutritional status
      1. Serum Ferritin
      2. Serum Iron
      3. Total Iron Binding Capacity
      4. Serum Vitamin B12
      5. Serum Folate
      6. Serum Albumin
      7. Serum Prealbumin
      8. Vitamin D
      9. Serum Calcium
   6. Diagnostic labs
      1. Fecal lactoferrin
         1. Sidhu (2010) Aliment Pharmacol Ther 31(12): 1365-70
      2. Fecal Calprotectin
         1. Kallel (2010) Eur J Gastroenterol Hepatol 22(3): 340-5
      3. Escherichia coli outer membrane porin Antibody
      4. Saccharomyces cerevisiae Antibody
      5. Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)
10. Differential Diagnosis
    1. See Inflammatory Bowel Disease
    2. Ulcerative Colitis
    3. Celiac Sprue
    4. Chronic Pancreatitis
    5. Colorectal Cancer
    6. Diverticulitis
    7. Yersinia infection
    8. Mycobacterium infection
    9. Irritable Bowel Syndrome
    10. Ischemic Colitis
    11. Small BowelLymphoma
    12. Sarcoidosis
    13. Cummings (2008) BMJ 336(7652): 1062-6
11. Diagnosis: Colonoscopy with Ileoscopy
    1. Focal Ulcerations: aphthous, stellate, or linear
    2. Skip areas
    3. Rectal sparing
    4. Cobblestone appearance
    5. Strictures
12. Imaging
    1. Newer studies
       1. CT Abdomen
       2. MRI Abdomen
       3. Capsular Endoscopy
    2. Older studies with lower Test Sensitivity and Test Specificity
       1. Small Bowel follow-through
       2. Barium Enema with retrograde terminal ileum filling
          1. May show classic thumbprinting
          2. Defect protrudes into lumen
13. Management: General Measures
    1. No immunosuppressants if infectious colitis possible
    2. Tobacco Cessation
    3. Update vaccinations
       1. Hepatitis B Vaccine
       2. Influenza Vaccine
       3. Pneumococal Vaccine
    4. Avoid exacerbating factors
       1. Pregnancy
       2. NSAIDs
       3. Oral Contraceptives
    5. Consider baseline DEXA Scan and Vitamin D level
    6. Consider concurrent vitamin supplementation
       1. Folic Acid
       2. Vitamin B12
       3. Vitamin D Supplementation
       4. Fat soluble vitamins
       5. Calcium Supplementation
    7. Prior to starting an anti-TNF agent
       1. Chest XRay
       2. Purified Protein Derivative (PPD) or Quantiferon
14. Management: Protocol based on severity
    1. Mild to Moderate (Weight loss <10%, tolerating P.O.)
       1. Step 1: Start Salicylate (5-ASA preparations)
          1. Mesalamine (Rowasa, Pentasa, Asacol) or
          2. Sulfasalazine (Azulfidine)
       2. Step 2: Anaerobic agent if Salicylate not effective
          1. Metronidazole 10-20 mg/kg/day or
          2. Ciprofloxacin 1 gram/day
       3. Step 3: Treat as moderate to severe if refractory
       4. Step 4: Maintenance therapy for remission
          1. Mesalamine (Rowasa) 3.2 to 4 grams per day
    2. Moderate to Severe (Significant systemic symptoms)
       1. Step 1: Systemic Corticosteroids
          1. Prednisone 40 mg PO qd for 8-12 weeks
             1. Consider Budesonide instead of Prednisone
          2. Budesonide (Entocort EC)
             1. Minimal absorption and may be preferred over Prednisone as first line agent
             2. Dose: 9 mg PO qAM for up to 8 weeks
          3. Methylprednisolone IV for severe fulminant disease
          4. Taper once control is achieved
             1. Initial: Taper by 5-10 mg weekly
             2. Below 20 mg: Taper by 2.5 to 5 mg weekly
       2. Step 2: Consider immunosuppresant for maintenance
          1. Start while tapering Corticosteroid off
          2. Azathioprine 50 mg orally daily (maximum 2-2.5 mg/kg/day) or
          3. 6-Mercaptopurine 60 mg orally daily (maximum 1.5 mg/kg/day)
       3. Step 3: Anti-tumor necrosis factors
          1. Indicated if refractory to Steps 1 and 2
          2. Agents
             1. Adalimumab (Humira) 160 mg SQ once initially, then 80 mg SQ once at week 2, then 40 mg every 2 weeks
             2. Certrolizumab pegol (Cimzia) 400 mg SQ once at weeks 0, 2, and 4, then 400 mg every 4 weeks
             3. Infliximab (Remicade) 5 mg/kg IV once at weeks 0, 2, and 6, then 5 mg/kg every 8 weeks
       4. Step 4: Consider other immunomodulator if refractory
          1. Methotrexate 25 mg weekly
          2. Tacrilimus and Cyclosporine have also been used
    3. References
       1. Knutson (2003) Am Fam Physician 68(4):707-14
       2. Wall (1999) Pharmacotherapy 19:1138-52
       3. Hanauer (2003) Gastroenterology 125:906-10
15. Management: Available preparations
    1. Similar to Ulcerative Colitis Management
    2. Antiinflammatory agents
       1. Corticosteroids
       2. Oral 5 ASA preparations
          1. Not effective for small bowel Crohn's Disease
          2. Sulfasalazine (Azulfidine)
             1. Inexpensive but significant side effects
          3. Olsalazine (Dipentum)
             1. Diarrhea commonly occurs
          4. Mesalamine (Asacol, Pentasa, Canasa, Rowasa)
          5. Balsalazide (Colazal)
       3. Immunosuppressive agents
          1. 6-Mercaptopurine
          2. Azathioprine
          3. Methotrexate
    3. Fish Oil (Enteric Coated)
       1. Dose: 2.7 g qd
       2. Marked reduction in relapse in 1 year (28% vs 69%)
       3. Serum markers of inflammation also reduced
       4. Reference
          1. Belluzzi (1996) N Engl J Med 334:1557-60
    4. Metronidazole (Flagyl)
       1. Effective for Crohn's Disease and perianal disease
    5. Monoclonal Antibody (anti-tumor necrosis factor agents)
       1. Adalimumab (Humira)
       2. Certrolizumab pegol (Cimzia)
       3. Infliximab (Remicade)
    6. Other agents currently being researched
       1. Thalidomide (not used in women who can conceive)
       2. Mycophenalate (Cellcept)
       3. Tacrolimus
       4. IL-10, 11 and 18
       5. Probiotics
16. Management: Intestinal resection (75% of patients)
    1. Efficacy
       1. Not Curative (unlike for Ulcerative Colitis)
       2. Symptoms nearly always recur after surgery
          1. Five years: 30% symptoms recur
          2. Ten years: 50% symptoms recur
          3. Fifteen years: 70% symptoms recur
       3. Surgery associated with improved quality of life
          1. Delaney (2003) J Am Coll Surg 196:714-21
    2. Indications
       1. Colon obstruction
       2. Intractable pain or other symptoms
17. Complications: Gastrointestinal
    1. Colon Cancer
       1. Much lower risk than with Ulcerative Colitis
    2. Rectal disease (50% of Crohn's Disease patients)
       1. Rectal Fissure
       2. Rectocutaneous fistula
       3. Perirectal Abscess
18. Prognosis: Risk for intestinal resection
    1. Poor prognostic indicators (relapse)
       1. Crohn's involving Small Intestine
       2. Perianal fistulas
    2. Favorable prognostic indicators
       1. Ileocecal disease
       2. Colorectal disease
       3. Relapse-free period of 10 years
    3. References
       1. Bernell (2000) Ann Surg 231:38-45
19. Monitoring
    1. Colon Cancer screening
       1. Periodic Colonoscopy after 15 years of disease (annual in some cases)
    2. Serum Alkaline Phosphatase annually for both Ulcerative Colitis or Crohn's Disease
       1. Evaluate for Primary Sclerosing Cholangitis
20. References
    1. Botoman (1998) Am Fam Physician 57(1):57-72
    2. Cummings (2008) BMJ 336(7652): 1062-6
    3. Moses (1998) Postgrad Med 103(5):77-84
    4. Sands (2000) Gastroenterology 118(2 Suppl 1):S68-82
    5. Stein (2001) Surg Clin North Am 81(1):71-101
    6. Wilkins (2011) Am Fam Physician 84(12):1365-75