Ulcerative Colitis

Aka: Ulcerative Colitis, Idiopathic Proctocolitis

1. See Also
   1. Crohn's Disease
   2. Inflammatory Bowel Disease
2. Definitions
   1. Ulcerative Colitis
      1. Inflammatory Bowel Disease affecting the mucosa of the Large Intestine and Rectum
      2. Presents with Abdominal Pain, bloody Diarrhea, fever and weight loss
3. Epidemiology
   1. Most common cause of chronic colitis
   2. Incidence: 2-7 cases per 100,000 per year in U.S.
   3. Prevalence: 250,000 to 500,00 persons affected in United States
      1. More common in industrialized countries
   4. Onset
      1. First peak onset at age 15 to 25 years (up to age 40 years)
      2. Second peak onset occurs after age 50 years
   5. Gender
      1. Men and women affected equally
4. 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. Clostridioides difficile
   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 and soda intake
      2. Higher risk with increased meat and fat intake
      3. Decreased risk with increased vegetable intake
      4. Decreased with tea intake
      5. Decreased in infants who were Breast fed
5. 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
6. Symptoms: Presentations
   1. Typical presentation
      1. Hematochezia
      2. Diarrhea
      3. Abdominal Pain
   2. Classic Presentation
      1. Intermittent bloody Diarrhea
      2. Rectal or fecal urgency
      3. Tenesmus
7. Symptoms: General
   1. Abdominal Pain
   2. Rectal Bleeding (Hematochezia)
      1. Helps to differentiate from Crohn's Disease
      2. Bloody Diarrhea is the most common presenting complaint
   3. Diarrhea
   4. Tenesmus
   5. Fever
   6. Malaise
   7. Weight loss
8. Signs: Extraintestinal Manifestations
   1. Similar findings seen in Crohn's Disease
      1. However extraintestinal findings are more common with 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
9. Labs: Distinguish from infectious causes of colitis
   1. Stool Culture or NAAT
   2. Stool for Ova and Parasites
   3. Clostridium difficile Toxin and culture
10. Labs: Markers of inflammation and malabsorption
    1. Fecal Calprotectin (see below)
       1. Useful in both diagnosis and in predicting relapse versus remission
    2. C-Reactive Protein (C-RP) or Erythrocyte Sedimentation Rate (ESR)
       1. Mildly increased in moderate to severe cases
    3. Electrolyte abnormalities related to Chronic Diarrhea (e.g. Hypokalemia)
    4. Serum Albumin
       1. Decreased in moderate to severe cases
    5. Complete Blood Count
       1. Hemoglobin or Hematocrit decreased in moderate to severe cases
11. Labs: Diagnosis
    1. Fecal Calprotectin
       1. No serum biomarker completely excludes diagnosis in ongoing symptoms, or in adults
       2. Normal Fecal Calprotectin <100 mcg/g in CHILDREN nearly excludes Ulcerative Colitis
          1. Walker (2020) Arch Dis Child 105(10): 957-63 [PubMed]
    2. 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
12. 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. Lactoferrin
13. Diagnosis: Colonoscopy
    1. Indications
       1. Colonoscopy should be performed in all patients suspected of Ulcerative Colitis
       2. Colonoscopy is the gold standard for Ulcerative Colitis diagnosis
    2. Distribution
       1. Mucosal inflammation begins at Rectum
       2. Inflammation extends without interruption
       3. Inflammation ends in a distinct proximal margin
       4. Regions
          1. Proctitis (anal verge to 18 cm proximally)
          2. Left-sided Colitis (anal verge to splenic flexure)
          3. Pancolitis (anal verge to regions proximal to the splenic flexure)
    3. Mild disease
       1. Erythematous mucosa
       2. Decreased vascular pattern visualization
       3. Fine mucosal friability
    4. Moderate disease
       1. Diffuse edema and erythema
       2. Loss of vascular pattern
       3. Superficial erosions
       4. Mucosa bleeds with minimal Trauma
    5. Severe disease
       1. Frank Ulceration
       2. Spontaneous bleeding
14. 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
15. Differential Diagnosis
    1. See Inflammatory Bowel Disease
    2. Crohn's Disease
    3. Ischemic Colitis
    4. Microscopic Colitis
    5. Radiation Colitis
    6. Diverticulitis
    7. Infectious Colitis
       1. Amebic Dysentery
          1. Travel history to endemic regions
       2. Clostridium difficile infection
       3. Bacterial Acute Inflammatory Diarrhea (e.g. Salmonella, Shigella, E. coli, Yersinia, Campylobacter)
       4. Parasitic colitis
       5. Viral colitis
          1. Cytomegalovirus (CMV) in Immunocompromised patients
16. Grading: Severity
    1. Mild Cases
       1. Stools: <4/day
       2. Bloody stool: Variable
       3. ESR or CRP: 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 or CRP: Normal to elevated
       4. Systemic toxicity: Absent
    3. Severe Cases
       1. Stools: 7-10/day
       2. Bloody stool: Present
       3. ESR or CRP: 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 or CRP: Increased
       4. Systemic toxicity: Present
          1. Severe symptoms above AND
          2. Abdominal tenderness or distention
          3. Continuous bleeding needing transfusion
17. 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]
18. 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 biologic agents (see below) at maintenance dosing
       3. Step 3: Biologic Agents (see below)
          1. If remission occurs, continue biologic agent (see below) at maintenance dosing
    3. Severe to fulminant colitis
       1. Hospital admission (up to 25% of Ulcerative Colitis acute presentations)
       2. Step 1: Corticosteroids IV at active dose for 3-5 days
          1. If remission occurs, transition to biologic agents at maintenance dosing
       3. Step 2: Biologic agents are considered first-line therapy
          1. Consider Cyclosporine or Infliximab for failed response to Corticosteroids
       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]
19. Management: 5-Aminosalicylic Acid Derivatives in 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 non-sulfa 5-ASA agents
             1. Sulfasalazine is dosed four times daily, and is associated with Headache, Nausea, rash
             2. Mesalamine and other non-sulfa agents have higher efficacy in inducing remission
          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
20. Management: Corticosteroids for 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 (extended release Budesonide)
       1. Uceris (extended release Budesonide) 9 mg orally daily for up to 8 weeks
       2. Uceris cost is an oral budesonide tablet that primarily works locally in colon
       3. Contrast with Entocort EC that targets ileum and ascending colon in Crohn's Disease
       4. Contrast with Systemic Corticosteroids with their multitude of adverse effects
          1. Uceris Systemic Corticosteroid effects are increased with CYP3A4 Inhibitors
       5. 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
21. Management: Biologic Agents and 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. Interleukin Inhibitors (IL-12, IL-23)
       1. Ustekinumab (Stelera)
          1. Start: 260 to 520 mg injection (weight based)
          2. Next: 90 mg every 8 weeks
    3. Janus Kinase Inhibitors
       1. Tofacitinib (Xeljanz)
          1. Start: 10 mg orally twice daily for 8 weeks
          2. Next: 5 to 10 mg orally twice daily
    4. Selective Adhesion Molecule Inhibitors
       1. Vedolizumab (Entyvio)
          1. Start: 300 mg at week 0, 2 and 6
          2. Next: 300 mg every 8 weeks
    5. Tumor Necrosis Factor Inhibitors (TNF-alpha)
       1. Adalimumab (Humira)
          1. Start: 160 mg at week 0
          2. Next: 80 mg at week 2
          3. Next: 40 mg every other week
       2. Golimumab (Simponi)
          1. Start: 200 mg at week 0
          2. Next: 100 mg at week 2
          3. Next: 100 mg every 4 weeks
       3. 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
    6. Older Agents
       1. Azathioprine (Imuran)
          1. Active Disease: Not indicated
          2. Maintenance: 50-100 mg/day
       2. Cyclosporine (Sandimmune)
          1. Active Disease: 2-4 mg/kg/day
             1. Consider in acute cases refractory to IV Corticosteroids
          2. Maintenance: Not indicated
       3. 6-Mercaptopurine (Purinethol)
    7. Duration
       1. For long term therapy only
       2. Ineffective for acute dx
       3. Onset of action: 2-6 months
    8. Complications
       1. Bancruptcy (most of these agents are >$5000 per month)
       2. Pancreatitis
       3. Infection risk
       4. Hepatitis
       5. Bone Marrow suppression (Follow Complete Blood Count)
22. Management: Surgery
    1. Surgical management of Ulcerative Colitis is curative
    2. Colectomy Prevalence 15% in Ulcerative Colitis
    3. Indications
       1. Medical failure (e.g. 3 days of IV Corticosteroids)
       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
    4. 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
    5. Complications
       1. Colonic stricture
          1. Increased risk of Bowel Obstruction
       2. Pouchitis (50%)
          1. Postoperative, autoimmune inflammation of residual rectal tissue
       3. Pouch dysfunction
    6. References
       1. Cima (2005) Arch Surg 140:300-10 [PubMed]
23. 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
24. 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)
25. Course: Following initial attack of Ulcerative Colitis
    1. Continuous active Ulcerative Colitis: 75%
       1. Fecal Calprotectin elevation predicts relapse (while negative serial values predict remission)
       2. Heida (2017) Inflamm Bowel Dis 23(6): 894-902 [PubMed]
    2. Remission for 15 years: 10%
    3. Mortality within 1 year of initial attack was previously estimated at 5%
       1. Later studies show no increased mortality
       2. Fumery (2018) Clin Gastroenterol Hepatol 16(3): 343-56 [PubMed]
    4. Undergo total proctocolectomy within 5 years: 25%
26. Prognosis: Predictors of Aggressive Disease
    1. Age <40 years old
    2. Pancolitis
    3. Severe disease on endoscopy
    4. Extraintestinal manifestations
    5. Increased inflammatory markers
    6. Early need for Corticosteroids
27. Prevention: Probiotics, Herbals, General Measures for maintenance of remission
    1. Probiotics
       1. VSL #3
          1. Probiotic that improves symptoms and reduces pouchitis
          2. Tursi (2010) Am J Gastroenterol 105(10):2218-27 [PubMed]
       2. Lactobacillus GG
          1. Zocco (2006) Aliment Pharmacol Ther 23(11): 1567-74 [PubMed]
       3. ProbioticE. coli Nissle 1917
          1. As effective as Mesalamine in relapse prevention
          2. Kruis (2004) Gut 53:1617-23 [PubMed]
    2. Lifestyle
       1. Regular Exercise
          1. Eckert (2019) BMC Gastroenterol 19(1): 115 [PubMed]
       2. Avoid FODMAPS
       3. Avoid NSAIDs, Opioids and Anticholinergic Agents during acute exacerbations as musch as possible
    3. Other medications
       1. Curcumin
          1. Dosed 2 to 3 g daily, adjunctive in mild Ulcerative Colitis
          2. Coeiho (2020) Nutrients 12(8): 2296 [PubMed]
    4. Complication Evaluation and prevention
       1. Periodic DEXA Scan (esp. with regular Corticosteroid)
       2. Vaccination (manage as Immunocompromised state)
       3. Skin cancer screening
       4. Annual Cervical Cytology (Pap Smear)
       5. See Colon Cancer screening above
28. References
    1. (2019) presc Lett 16(4): 22
    2. Adams (2013) Am Fam Physician 87(10): 699-705 [PubMed]
    3. Adams (2022) Am Fam Physician 105(4): 406-11 [PubMed]
    4. Carter (2004) Gut 53:V1-16 [PubMed]
    5. Kornbluth (2004) Am J Gastroenterol 99:1371-85 [PubMed]
    6. Kornbluth (2010) Am J Gastroenterol 105(3): 501-23 [PubMed]
    7. Langan (2007) Am Fam Physician 76:1323-31 [PubMed]