Ulcerative Colitis

See Also

Definitions

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

Epidemiology

Most common cause of chronic colitis
Incidence: 2-7 cases per 100,000 per year in U.S.
Prevalence: 250,000 to 500,00 persons affected in United States
1. More common in industrialized countries
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
Gender
1. 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
3. Clostridioides difficile
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 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

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
Presentations

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

Symptoms
General

Abdominal Pain
Rectal Bleeding (Hematochezia)
1. Helps to differentiate from Crohn's Disease
2. Bloody Diarrhea is the most common presenting complaint
Diarrhea
Tenesmus
Fever
Malaise
Weight loss

Signs
Extraintestinal Manifestations

Similar findings seen in Crohn's Disease
1. However extraintestinal findings are more common with 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

Fecal Calprotectin (see below)
1. Useful in both diagnosis and in predicting relapse versus remission
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
Complete Blood Count
1. Hemoglobin or Hematocrit decreased in moderate to severe cases

Labs
Diagnosis

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]
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. Lactoferrin

Diagnosis
Colonoscopy

Indications
1. Colonoscopy should be performed in all patients suspected of Ulcerative Colitis
2. Colonoscopy is the gold standard for Ulcerative Colitis diagnosis
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)
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
Radiation Colitis
Diverticulitis
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

Grading
Severity

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

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

Management
5-Aminosalicylic Acid Derivatives in Mild to Moderate disease

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
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
Corticosteroids for 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 (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]
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
Biologic Agents and 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
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
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
Selective Adhesion Molecule Inhibitors
1. Vedolizumab (Entyvio)
  1. Start: 300 mg at week 0, 2 and 6
  2. Next: 300 mg every 8 weeks
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
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)
Duration
1. For long term therapy only
2. Ineffective for acute dx
3. Onset of action: 2-6 months
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)

Management
Surgery

Surgical management of Ulcerative Colitis is curative
Colectomy Prevalence 15% in Ulcerative Colitis
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
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
  1. Increased risk of Bowel Obstruction
2. Pouchitis (50%)
  1. Postoperative, autoimmune inflammation of residual rectal tissue
3. 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%
1. Fecal Calprotectin elevation predicts relapse (while negative serial values predict remission)
2. Heida (2017) Inflamm Bowel Dis 23(6): 894-902 [PubMed]
Remission for 15 years: 10%
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]
Undergo total proctocolectomy within 5 years: 25%

Prognosis
Predictors of Aggressive Disease

Age <40 years old
Pancolitis
Severe disease on endoscopy
Extraintestinal manifestations
Increased inflammatory markers
Early need for Corticosteroids

Prevention
Probiotics, Herbals, General Measures for maintenance of remission

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]
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
Other medications
1. Curcumin
  1. Dosed 2 to 3 g daily, adjunctive in mild Ulcerative Colitis
  2. Coeiho (2020) Nutrients 12(8): 2296 [PubMed]
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

References