Ulcerative Colitis

Epidemiology

Most common cause of chronic colitis
Incidence: 2-7 cases per 100,000 per year
Prevalence: 250,000 to 500,00 persons affected in United States
Onset
1. First peak onset at age 15-25 years (up to age 40 years)
2. Second peak onset occurs after age 50 years
Gender: Men and women affected equally

Risk Factors

Less common in ongoing Tobacco Abuse but risk is higher after Tobacco Cessation
1. Boyko (1987) N Engl J Med 316:707-10 [PubMed]
Specific Bacterial Gastroenteritis infections are associated with 10 fold risk of Ulcerative Colitis development
1. Nontyphoid Salmonella
2. Campylobacter
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
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

Pathophysiology

Etiology unknown
Inflammation localized to mucosa only
1. Crohn's Disease involves all layers of bowel wall
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

Symptoms

Typical presentation
Classic Presentation
1. Intermittent bloody Diarrhea
2. Rectal urgency
3. Tenesmus

Symptoms
General

Abdominal Pain
Rectal Bleeding (Hematochezia)
1. Helps to differentiate from Crohn's Disease
Diarrhea
Tenesmus
Fever
Malaise
Weight loss

Signs
Extraintestinal Manifestations

Similar findings seen in Crohn's Disease
Musculoskeletal
1. Osteoporosis (15%)
2. Colitic Arthritis or Arthralgias (5-21% of cases)
3. Ankylosing Spondylitis (2%)
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
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%)
Hepatobiliary
1. Hepatic Steatosis
2. Primary Sclerosing Cholangitis (4-5% co-Incidence)
3. Cholelithiasis
4. Pericholangitis
Miscellaneous
1. Nephrolithiasis
2. Hypercoagulable state
  1. Deep Vein Thrombosis or Pulmonary Embolism in 0.3% of cases

Labs
Distinguish from infectious causes of colitis

Labs
Markers of inflammation and malabsorption

C-Reactive Protein (C-RP) or Erythrocyte Sedimentation Rate (ESR)
1. Mildly increased in moderate to severe cases
Electrolyte abnormalities related to Chronic Diarrhea (e.g. Hypokalemia)
Serum Albumin
1. Decreased in moderate to severe cases
Hemoglobin or Hematocrit
1. Decreased in moderate to severe cases

Labs
Diagnosis

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

Labs
Experimental markers

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]
Other markers increased in Ulcerative Colitis
1. Fecal Calprotectin
2. Lactoferrin

Diagnosis
Colonoscopy Findings (gold standard for diagnosis)

General
1. Mucosal inflammation begins at Rectum
2. Inflammation extends without interruption
3. Inflammation ends in a distinct proximal margin
Mild disease
1. Erythematous mucosa
2. Decreased vascular pattern visualization
3. Fine mucosal friability
Moderate disease
1. Diffuse edema and erythema
2. Loss of vascular pattern
3. Superficial erosions
4. Mucosa bleeds with minimal Trauma
Severe disease
1. Frank Ulceration
2. Spontaneous bleeding

Imaging

Not recommended for diagnosis unless endoscopy not available
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
Abdominal XRay (long-standing disease signs)
1. Bowel shortening
2. Haustra loss
3. Lumen narrowing and rigid appearance

Differential Diagnosis

See Inflammatory Bowel Disease
Crohn's Disease
Ischemic Colitis
Microscopic Colitis
Diverticulitis
Infectious colitis
1. Amebic dysentary
2. Clostridium difficile infection
3. Bacterial colitis
4. Parasitic colitis
5. Viral colitis

Grading
Severity

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
Moderate Cases
1. Stools: 4-6/day
2. Bloody stool: Variable
3. ESR: Normal to elevated
4. Systemic toxicity: Absent
Severe Cases
1. Stools: 7-10/day
2. Bloody stool: Present
3. ESR: Increased
4. Systemic toxicity: Present
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

Grading
Lab and Exam based

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%)
References
1. Chang (2004) Gastroenterol Clin North Am 33:236 [PubMed]

Management
Approach

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
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
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
References
1. Adams (2013) Am Fam Physician 87(10): 699-705 [PubMed]
2. Kornbluth (2010) Am J Gastroenterol 105(3): 501-23 [PubMed]

Management
Mild to Moderate disease

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
Duration of medication use: 6-12 weeks
1. Taper preparations to prevent rebound
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

Management
Moderate to Severe disease

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
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
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]
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
Disposition
1. Hospitalization required when cases refractory to oral steroids and possibly outpatient Infliximab trial or
2. Acute Abdomen or systemic toxicity

Management
Immunosuppressants for Refractory disease

Indications:
1. Poor control with Corticosteroids
2. Serious Corticosteroid complications
3. Steroid dependent to control symptoms
4. May avert surgical resection
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
Duration
1. For long term therapy only
2. Ineffective for acute dx
3. Onset of action: 2-6 months
Complications
1. Pancreatitis
2. Infection risk
3. Hepatitis
4. Bone Marrow suppression (Follow Complete Blood Count)

Management
Surgery

Surgical management of Ulcerative Colitis is curative
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
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
Complications
1. Colonic stricture and increased risk of Bowel Obstruction
2. Pouchitis or Pouch dysfunction
References
1. Cima (2005) Arch Surg 140:300-10 [PubMed]

Complications

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]
Toxic Megacolon
Bowel Perforation
Colonic Stricture
Gastrointestinal Bleeding

Monitoring
Colon Cancer

General Colonoscopy approach
1. Biopsies taken from cecum to Rectum every 10 cm
Pancolitis
1. Colonoscopy every 1-2 years after 8-10 years of disease
Left-sided Colitis
1. Colonoscopy every 3 years after 12-15 years of disease (British use 15-20 years)

Course
Following initial attack of Ulcerative Colitis

Continuous active Ulcerative Colitis: 75%
Remission for 15 years: 10%
Mortality within 1 year of initial attack: 5%
Undergo total proctocolectomy within 5 years: 25%

Prevention
Probiotics for maintenance of remission

Lactobacillus GG
1. Zocco (2006) Aliment Pharmacol Ther 23(11): 1567-74 [PubMed]
Probiotic E. coli Nissle 1917
1. As effective as Mesalamine in relapse prevention
2. Kruis (2004) Gut 53:1617-23 [PubMed]

References