Ulcerative Colitis

Aka: Ulcerative Colitis

1. Epidemiology
   1. Most common cause of chronic colitis
   2. Incidence: 2-7 cases per 100,000 per year
   3. Prevalence: 250,000 to 500,00 persons affected in United States
   4. Onset
      1. First peak onset at age 15-25 years (up to age 40 years)
      2. Second peak onset occurs after age 50 years
   5. Gender: Men and women affected equally
2. Risk Factors
   1. Less common in ongoing Tobacco abuse but risk is higher after Tobacco Cessation
      1. Boyko (1987) N Engl J Med 316:707-10 [PubMed]
   2. Specific Bacterial Gastroenteritis infections are associated with 10 fold risk of Ulcerative Colitis development
      1. Nontyphoid Salmonella
      2. Campylobacter
   3. Genetic predisposition
      1. Family History confers 10 fold risk
         1. Ashkenazi Jewish population afflicted more often
      2. Siblings with disease increase risk
         1. Sibling: 4.6 fold increased risk
         2. Monozygotic twin: 95 fold increased risk
   4. Dietary factors
      1. Higher risk with refined sugar intake
      2. Higher risk with increased meat and fat intake
      3. Decreased risk with increased vegetable intake
3. Pathophysiology
   1. Etiology unknown
   2. Inflammation localized to mucosa only
      1. Crohn's Disease involves all layers of bowel wall
   3. Always involves Rectum and extends proximally to contiguous sections of colon
      1. Ulcerative Proctitis
         1. Involves Distal 12 cm colonic mucosa
      2. Proctosigmoiditis
         1. Involves Rectum to splenic flexure
      3. Pancolitis
         1. Involves Rectum to cecum
4. Symptoms
   1. Typical presentation
      1. Hematochezia
      2. Diarrhea
      3. Abdominal Pain
   2. Classic Presentation
      1. Intermittent bloody Diarrhea
      2. Rectal urgency
      3. Tenesmus
5. Symptoms: General
   1. Abdominal Pain
   2. Rectal Bleeding (Hematochezia)
      1. Helps to differentiate from Crohn's Disease
   3. Diarrhea
   4. Tenesmus
   5. Fever
   6. Malaise
   7. Weight loss
6. Signs: Extraintestinal Manifestations
   1. Similar findings seen in Crohn's Disease
   2. Musculoskeletal
      1. Osteoporosis (15%)
      2. Colitic Arthritis or Arthralgias (5-21% of cases)
      3. Ankylosing Spondylitis (2%)
   3. Ocular
      1. Episcleritis (parallels Ulcerative Colitis course)
      2. Uveitis (occurs in up to 3-4% of cases)
         1. Variable course
         2. Associated with Enteropathic Arthritis
      3. Recurrent Iritis
   4. Dermatologic
      1. Digital Clubbing (presence increases likelihood of Ulcerative Colitis)
      2. Erythema Nodosum (3%)
         1. Parallels Ulcerative Colitis course
      3. Pyoderma Gangrenosum (up to 2% of cases)
      4. Lichen Planus
      5. Aphthous Stomatitis, Aphthous Ulcers or Canker Sores (4%)
      6. Psoriasis (1%)
   5. Hepatobiliary
      1. Hepatic Steatosis
      2. Primary Sclerosing Cholangitis (4-5% co-Incidence)
      3. Cholelithiasis
      4. Pericholangitis
   6. Miscellaneous
      1. Nephrolithiasis
      2. Hypercoagulable state
         1. Deep Vein Thrombosis or Pulmonary Embolism in 0.3% of cases
7. Labs: Distinguish from infectious causes of colitis
   1. Stool Culture
   2. Stool for Ova and Parasites
   3. Clostridium difficile Toxin and culture
8. Labs: Markers of inflammation and malabsorption
   1. C-Reactive Protein (C-RP) or Erythrocyte Sedimentation Rate (ESR)
      1. Mildly increased in moderate to severe cases
   2. Electrolyte abnormalities related to Chronic Diarrhea (e.g. Hypokalemia)
   3. Serum Albumin
      1. Decreased in moderate to severe cases
   4. Hemoglobin or Hematocrit
      1. Decreased in moderate to severe cases
9. Labs: Diagnosis
   1. Biopsy of colon wall (via Colonoscopy as described below)
      1. Diffuse, shallow, mucosa ulceration
      2. Crypt abscess and branching
      3. Muscularis mucosal thickening
      4. Inflammatory cell infiltration
10. Labs: Experimental markers
    1. pANCA with ASCA
       1. Combination is sensitive but not specific (pending further study)
       2. Labs
          1. Perinuclear antineutrophilic cytoplasmic antibodies (pANCA) and
          2. Anti-Saccharomyces cerevisiae antibodies (ASCA)
       3. References
          1. Reese (2006) Am J Gastroenterol 101:2410-22 [PubMed]
    2. Other markers increased in Ulcerative Colitis
       1. Fecal Calprotectin
       2. Lactoferrin
11. Diagnosis: Colonoscopy Findings (gold standard for diagnosis)
    1. General
       1. Mucosal inflammation begins at Rectum
       2. Inflammation extends without interruption
       3. Inflammation ends in a distinct proximal margin
    2. Mild disease
       1. Erythematous mucosa
       2. Decreased vascular pattern visualization
       3. Fine mucosal friability
    3. Moderate disease
       1. Diffuse edema and erythema
       2. Loss of vascular pattern
       3. Superficial erosions
       4. Mucosa bleeds with minimal Trauma
    4. Severe disease
       1. Frank Ulceration
       2. Spontaneous bleeding
12. Imaging
    1. Not recommended for diagnosis unless endoscopy not available
    2. Double contrast Barium Enema and Small Bowel follow-through
       1. Haustra loss
       2. Contiguous inflammation from Rectum proximally
          1. Contrast with non-contiguous and Small Bowel lesions of Crohn's Disease
    3. Abdominal XRay (long-standing disease signs)
       1. Bowel shortening
       2. Haustra loss
       3. Lumen narrowing and rigid appearance
13. Differential Diagnosis
    1. See Inflammatory Bowel Disease
    2. Crohn's Disease
    3. Ischemic Colitis
    4. Microscopic Colitis
    5. Diverticulitis
    6. Infectious colitis
       1. Amebic dysentary
       2. Clostridium difficile infection
       3. Bacterial colitis
       4. Parasitic colitis
       5. Viral colitis
14. Grading: Severity
    1. Mild Cases
       1. Stools: <4/day
       2. Bloody stool: Variable
       3. ESR: Normal (as are other lab and exam findings - see below)
       4. Systemic toxicity: Absent
    2. Moderate Cases
       1. Stools: 4-6/day
       2. Bloody stool: Variable
       3. ESR: Normal to elevated
       4. Systemic toxicity: Absent
    3. Severe Cases
       1. Stools: 7-10/day
       2. Bloody stool: Present
       3. ESR: Increased
       4. Systemic toxicity: Present
          1. Fever
          2. Tachycardia
          3. Leukocytosis
          4. Anemia
    4. Fulminant Cases
       1. Stools: >10/day
       2. Bloody stool: Present
       3. ESR: Increased
       4. Systemic toxicity: Present
          1. Severe symptoms above AND
          2. Abdominal tenderness or distention
          3. Continuous bleeding needing transfusion
15. Grading: Lab and Exam based
    1. Moderate to severe criteria
       1. Serum Albumin <3.5 mg/dl (Severe: <3.0 mg/dl)
       2. Body Temperature >99 F or 37.2 C (Severe: >100 F or 37.8 C)
       3. Bowel Movements >4 per day (Severe: >6 per day)
       4. ESR >20 mm/hour (Severe: >30 mm/hour)
       5. Hematocrit <40% (Severe: <30%)
       6. Heart Rate >90 beats per minute (Severe: >100 beats per minute)
       7. Weight loss >1% (Severe: >10%)
    2. References
       1. Chang (2004) Gastroenterol Clin North Am 33:236 [PubMed]
16. Management: Approach
    1. Mild to moderate distal colitis
       1. When remission occurs with any step, transition to maintenance dosing of current agent
       2. Step 1: Topical 5-ASA at active dose per Rectum for 4-6 weeks
          1. Suppository for isolated Proctitis
          2. Enema for more proximal, left-sided Ulcerative Colitis
       3. Step 2: Consider ADDing shortterm rectal Corticosteroids
          1. Hydrocortisone enema (Cortenema) or if enema not retained, then foam (Cortifoam, Uceris)
       4. Step 3: ADD oral 5-ASA at active dose for 4-6 weeks (while continuing rectal 5-ASA)
       5. Step 4: Go to step 2 under mild-moderate extensive colitis
    2. Mild to moderate extensive colitis
       1. Step 1: Oral 5-ASA at active dose for 4-6 weeks
          1. If remission occurs, continue oral 5-ASA at maintenance dosing
       2. Step 2: Oral Corticosteroids for 4-6 weeks
          1. If remission occurs, transition to Azathioprine (Imuran) at maintenance dosing
       3. Step 3: Infliximab (Remicade) for 4-6 weeks
          1. If remission occurs, continue Infliximab at maintenance dosing
       4. Step 4: Consider third-line medications
          1. Intravenous Corticosteroids
          2. Cyclosporine (Sandimmune)
       5. Step 5: Consider surgical intervention
          1. See Colectomy below
    3. Severe to fulminant colitis
       1. Hospital admission
       2. Step 1: Corticosteroids IV at active dose for 3-5 days
          1. If remission occurs, transition to Azathioprine (Imuran) at maintenance dosing
       3. Step 2: Consider third-line medications
          1. Cyclosporine (Sandimmune) for 3-5 days
             1. If remission occurs, transition to Azathioprine (Imuran) at maintenance dosing
          2. Infliximab (Remicade) for 3-5 days
             1. If remission occurs, continue Infliximab at maintenance dosing
       4. Step 3: Consider surgical intervention
          1. See Colectomy below
    4. References
       1. Adams (2013) Am Fam Physician 87(10): 699-705 [PubMed]
       2. Kornbluth (2010) Am J Gastroenterol 105(3): 501-23 [PubMed]
17. Management: Mild to Moderate disease
    1. Agents: 5-Aminosalicylic Acid Derivatives (5-ASA agents)
       1. No Sulfa Allergy: Sulfasalazine (Azulfidine)
          1. Often avoided in favor of 5-ASA agents
             1. Sulfasalazine is dosed four times daily, and is associated with Headache, Nausea, rash
          2. Active disease: Sulfasalazine 4-6 grams/day divided four times daily
          3. Maintenanance: Sulfasalazine 2-4 grams/day divided four times daily
       2. Sulfa Allergy: 5-Aminosalicylic acid (5-ASA, Mesalamine, Asacol, Pentasa)
          1. Oral (Asacol)
             1. Active disease: 2.4 to 4.8 grams/day divided 3 times daily
             2. Maintenance: 1.2 to 2.4 grams/day divided 3 times daily
          2. Suppository (Canasa)
             1. Active disease: 1000 mg once daily
             2. Maintenance: 500 mg once to twice daily
          3. Enema (Rowasa)
             1. Active disease: 1 to 4 grams daily
             2. Maintenance: 2-4 grams daily to every third day
       3. Other 5-ASA agents
          1. Olsalazine (Dipentum) 500 mg PO bid
          2. Lialda (Mesalamine) once daily
          3. Balsalazide (Colazal, Mesalamine) dosed three times daily
    2. Duration of medication use: 6-12 weeks
       1. Taper preparations to prevent rebound
    3. Route
       1. Rectal suppositories are preferred for Proctitis
       2. Use oral and rectal agents together for pancolitis
       3. Combined oral and rectal agents are more effective than either one alone
18. Management: Moderate to Severe disease
    1. Precaution
       1. Use only to stabilize active Ulcerative Colitis
       2. Avoid chronic use as these do not maintain remission and have serious longterm adverse effects
    2. Corticosteroids: Systemic
       1. Agents
          1. Prednisone 40-60 mg/day orally until improving, then decrease daily dose by 5-10 mg each week
          2. Methylprednisolone (Medrol) 40-60 mg/day orally
          3. Hydrocortisone (Cortef) 200-300 mg/day orally
          4. Methylprednisolone (Solu-Medrol) 40 mg IV daily
       2. Taper Corticosteroids gradually to prevent rebound
          1. Continue starting dose until clinical response (typically 10-14 days)
          2. After response, reduce dose by 5mg per week
       3. Efficacy
          1. Systemic Corticosteroids do not maintain remission and have serious side effects
    3. Coticosteroids: Uceris
       1. Uceris is a very expensive ($1200/month) oral budesonide tablet that primarily works locally in colon
       2. Contrast with Entocort EC that targets ileum and ascending colon in Crohn's Disease
       3. Contrast with Systemic Corticosteroids with their multitude of adverse effects
          1. Uceris Systemic Corticosteroid effects are increased with CYP3A4 Inhibitors
       4. Criscuoli (2013) Gastroenterology 144(3):e23 [PubMed]
    4. Corticosteroids: Rectal (for distal Ulcerative Colitis)
       1. Hydrocortisone Enema (Cortenema) 100 mg daily to twice daily
       2. Hydrocortisone Acetate 10% rectal foam (Cortifoam) 90 mg once to twice daily
    5. Disposition
       1. Hospitalization required when cases refractory to oral steroids and possibly outpatient Infliximab trial or
       2. Acute Abdomen or systemic toxicity
19. Management: Immunosuppressants for Refractory disease
    1. Indications:
       1. Poor control with Corticosteroids
       2. Serious Corticosteroid complications
       3. Steroid dependent to control symptoms
       4. May avert surgical resection
    2. Agents
       1. Infliximab (Remicade)
          1. Active Disease: 5-10 mg/kg on weeks 0, 2 and 6
          2. Maintenance: 5-10 mg/kg every 4-8 weeks
       2. Azathioprine (Imuran)
          1. Active Disease: Not indicated
          2. Maintenance: 50-100 mg/day
       3. Cyclosporine (Sandimmune)
          1. Active Disease: 2-4 mg/kg/day
             1. Consider in acute cases refractory to IV Corticosteroids
          2. Maintenance: Not indicated
       4. 6-Mercaptopurine (Purinethol)
       5. Xeljanz (tofacitinib)
          1. Oral Monoclonal Antibody available in 2019
    3. Duration
       1. For long term therapy only
       2. Ineffective for acute dx
       3. Onset of action: 2-6 months
    4. Complications
       1. Pancreatitis
       2. Infection risk
       3. Hepatitis
       4. Bone Marrow suppression (Follow Complete Blood Count)
20. Management: Surgery
    1. Surgical management of Ulcerative Colitis is curative
    2. Indications
       1. Medical failure
       2. Corticosteroid intolerance
       3. Growth retardation in children
       4. Dysplasia or malignancy
       5. Fulminant colitis with or without Megacolon
          1. Perforation
          2. Peritonitis
          3. Hemorrhage
    3. Procedures
       1. Total proctocolectomy (Brooke ileostomy)
          1. Completely cures Ulcerative Colitis
          2. Entire colorectal mucosa is excised
          3. Results in gas or Stool Incontinence
          4. Requires external collecting bag
          5. High rate of re-operation (>50%) due to post-surgical complication
       2. Ileal pouch anal anastomosis
          1. Patient maintains anal function and continence
          2. Pouchitis occurs in 30-50% of patients
    4. Complications
       1. Colonic stricture and increased risk of Bowel Obstruction
       2. Pouchitis or Pouch dysfunction
    5. References
       1. Cima (2005) Arch Surg 140:300-10 [PubMed]
21. Complications
    1. Colon Cancer (Adenocarcinoma)
       1. See monitoring below
       2. Colon Cancer risk is not increased in disease limited to Proctitis or proctosigmoiditis
       3. Risk increases with duration since diagnosis
          1. First 10 years: 2% risk
          2. First 20 years: 8% risk
          3. First 30 years: 18% risk
       4. References
          1. Eaden (2001) Gut 48:526-35 [PubMed]
    2. Toxic Megacolon
    3. Bowel Perforation
    4. Colonic Stricture
    5. Gastrointestinal Bleeding
22. Monitoring: Colon Cancer
    1. General Colonoscopy approach
       1. Biopsies taken from cecum to Rectum every 10 cm
    2. Pancolitis
       1. Colonoscopy every 1-2 years after 8-10 years of disease
    3. Left-sided Colitis
       1. Colonoscopy every 3 years after 12-15 years of disease (British use 15-20 years)
23. Course: Following initial attack of Ulcerative Colitis
    1. Continuous active Ulcerative Colitis: 75%
    2. Remission for 15 years: 10%
    3. Mortality within 1 year of initial attack: 5%
    4. Undergo total proctocolectomy within 5 years: 25%
24. Prevention: Probiotics for maintenance of remission
    1. Lactobacillus GG
       1. Zocco (2006) Aliment Pharmacol Ther 23(11): 1567-74 [PubMed]
    2. ProbioticE. coli Nissle 1917
       1. As effective as Mesalamine in relapse prevention
       2. Kruis (2004) Gut 53:1617-23 [PubMed]
25. References
    1. (2019) presc Lett 16(4): 22
    2. Adams (2013) Am Fam Physician 87(10): 699-705 [PubMed]
    3. Carter (2004) Gut 53:V1-16 [PubMed]
    4. Kornbluth (2004) Am J Gastroenterol 99:1371-85 [PubMed]
    5. Kornbluth (2010) Am J Gastroenterol 105(3): 501-23 [PubMed]
    6. Langan (2007) Am Fam Physician 76:1323-31 [PubMed]