I. What every physician needs to know.

Ulcerative colitis, a disease of the mucosal surface of the colon, almost always involves the rectum and may extend proximally in a continuous fashion to involve the entire colon. The extent of the disease varies and in rare cases may involve the ileum, termed “backwash ileitis.” Cases that involve the rectum only are termed “ulcerative proctitis.”

Pathogenesis is not completely understood, but pathogenesis is believed to be multifactorial, with genetic and environmental factors, immune dysregulation, and alteration in the barrier of the gastrointestinal lumen. Having a family member with inflammatory bowel disease is a risk factor. Worldwide, ulcerative colitis is the most common form of inflammatory bowel disease. It may be cured by colectomy.

II. Diagnostic Confirmation: Are you sure your patient has ulcerative colitis?

A relapsing and remitting course is typical; episodes of active disease may be followed by periods of remission. The rectum, which is almost always involved, will be uniformly inflamed. A colonoscopy or flexible sigmoidoscopy may reveal a grossly erythematous mucosa that lacks normal vascular pattern. The mucosa may appear friable and have petechiae on appearance.

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Hemorrhage, continuous ulceration and exudates may be observed in more severe disease. Biopsy specimens may show gland atrophy of the mucosa, crypt abscesses, and goblet cells that do not contain mucin. With pancolitis, disease stops at the ileocecal valve, and if disease involves the terminal ileum, it may be termed “backwash ileitis.” Infiltrates in the mucosal layer consist of plasma cells, granulocytes, and lymphocytes.

A. History Part I: Pattern Recognition:

The primary symptom in ulcerative colitis is bloody diarrhea that may be accompanied by mucous. The course of the disease is usually relapsing and remitting, with periods of active disease interspersed with symptom-free periods. Mucosal inflammation usually occurs in the rectum, spreads proximally, and may involve the entire colon. The symptoms of proctitis, disease that affects primarily the rectum, include constipation, fresh blood from the rectum, and fecal urgency.

Pancolitis may cause diarrhea, abdominal pain, fever, tenesmus, weight loss, and fatigue. Extraintestinal manifestations may occur and can be multisystemic. Skin lesions may include erythema nodosum and pyoderma gangrenosum. Ocular manifestations, such as uveitis and episcleritis, may be seen. Rheumatologic symptoms, such as migratory polyarthritis, sacroiliitis, and ankylosing spondylitis, may occur, primarily involving large joints. Primary sclerosing cholangitis and venous and arterial thromboembolism may also occur.

Severity of disease based on the model by Truelove and Witts:

Mild disease may be characterized by fewer than four bloody bowel movements per day, erythrocyte sedimentation rate (ESR) less than 20 mm/h, normal c-reactive protein (CRP), heart rate less than 90 bpm, hemoglobin greater than 11.5 g/dl, and temperature less than 37.5 degrees Celsius. Hallmarks of moderate disease include an ESR of 30 mm/h or less, hemoglobin greater than or equal to 10.5 g/dL and CRP of 30 mg/L or less. Severe disease is characterized by six or more bloody bowel movements per day, hemoglobin less than 10.5 g/dL, heart rate greater than 90, ESR greater than 30 mm/h, and CRP greater than 30 mg/L.

B. History Part 2: Prevalence:

The incidence of ulcerative colitis is 1–20 per 100,000 persons per year. Prevalence is 7–246 cases per 100,000 persons per year. Ulcerative colitis has a higher incidence in European countries, Canada, Australia, New Zealand, and the United States, linking it to a Westernized lifestyle. Peak incidence occurs at three age ranges, 20–24, 40–44, and 60–64. Smoking is associated with milder disease.

C. History Part 3: Competing diagnoses that can mimic ulcerative colitis.

Ischemic colitis, radiation colitis, diverticulitis, parasitic infection, Clostridium difficile diarrhea, graft versus host disease, solitary rectal ulcer syndrome, and medication-induced colitis are competing diagnoses. Culprit medications that produce colitis that may mimic ulcerative colitis include oral contraceptives, NSAIDS, retinoic acid, ipilimumab, mycophenolate, and gold.

Infectious causes of colitis—bacterial causes such as Salmonella, Aeromonas, Shigella, Campylobacter, and especially E. coli 0157:H7—can resemble ulcerative colitis, manifested by hematochezia, abdominal pain, and diarrhea, but the course should be self-limited and not episodic in nature, as with ulcerative colitis. Travel history and food outbreaks may be historical clues that can point toward infectious colitis. Parasitic infections may cause recurrent diarrhea following travel to endemic areas.

Microscopic colitis, such as lymphocytic colitis, will present with watery diarrhea and will typically require a biopsy to diagnose. Frequent enemas may also induce colitis that may mimic ulcerative colitis.

D. Physical Examination Findings.

Evidence of volume depletion from diarrhea, such as orthostatic blood pressure and tachycardia, may be present. Abdominal exam will be unremarkable for peritoneal signs, such as rebound tenderness and guarding.

E. What diagnostic tests should be performed?

Colonoscopy with biopsy is the gold standard in diagnosis.

The biopsy features suggestive of ulcerative colitis include crypt abscesses, crypt branching, shortening and disarray, and crypt atrophy. Basal plasmacytosis may also be a predictor of relapse in patients with seemingly well-controlled UC with complete mucosal healing.

In acute colitis, colonoscopy should be avoided because of risk of bowel perforation. Sigmoidoscopy may be performed in an acute flare, and biopsy may be necessary to exclude CMV colitis in patients who are steroid refractory. Antibody testing not part of diagnostic evaluation of patients with suspected IBD as accuracy is uncertain including for pANCA.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

CBC, serum albumin, erythrocyte sedimentation rate, and C-reactive protein should be performed, as should evaluation of stool, such as examination for ova, parasites, and fecal leukocytes. Stool studies should look for C. difficile toxin, routine cultures (Salmonella, Shigella, Campylobacter, Yersinia), specific testing for E. coli O157:H7, Giardia stool antigen (if travel history suggests along with test for amebiasis), test for N. gonorrhoeae, HSV and Treponema pallidum if sexual history is suggestive or having severe urgency or tenesmus.

It is important to exclude infection as a cause of colitis, and a sigmoidoscopy with biopsy may be necessary if the patient fails to respond to steroids in an acute flare in order to look for CMV colitis with immunoperoxidase staining (especially if the patient is immunocompromised).

Patients with ulcerative colitis and primary sclerosing cholangitis may have an elevation in serum alkaline phosphatase.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Abdominal radiograph should be performed to evaluate for toxic megacolon. Plain abdominal radiographs should be repeated if there is clinical deterioration to determine if there is colonic dilatation >5.5 cm or toxic megacolon (diameter >6 cm or cecum >9 cm and systemic toxicity). Patient with transverse colon diameter >5.5 cm should receive decompression with a nasoenteric tube.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Fecal calprotectin, which may be an indicator of inflammation within the intestines, is nonspecific. The gold standard of diagnosis relies on an appropriate history coupled with a flexible sigmoidoscopy with biopsy. Barium enema, which is often normal in patients with mild disease severity, is not commonly used in the diagnosis of ulcerative colitis. In fulminant UC, a barium enema may lead to toxic megacolon.

III. Default Management.

Pharmacologic treatment is aimed at reducing inflammation and inducing remission of symptoms. Steroid-sparing regimens are usually preferred long-term in order to reduce systemic side effects.

For mild to moderate disease, topical (rectal) and oral aminosalicylates, such as sulfasalazine and 5-aminosalicylates, should be used first. Oral and rectal forms (suppositories and enemas), which may be used in combination, can induce remission in roughly half of patients. Sulfasalazine dosing is usually in divided doses; for example, 1g may be given orally three to four times daily. Mild to moderate proctitis should be managed topically with mesalamine suppositories (1 gram per day) or enemas (2–4 grams per day). If remission is not achieved in two weeks, 5-aminosalycilate enemas (2–4 grams per day) or hydrocortisone/budesonide enemas may be tried.

To induce remission in a first flare or a flare requiring steroids annually, patient should be given an oral prednisone equivalent of 0.75–1 mg/kg for two to four weeks and tapered. After successful tapering, maintenance therapy with 5-ASA may be used. If remission cannot be maintained, the next course of oral steroids should be combined with azathioprine at 2–2.5mg/kg or mercaptopurine at 1–1.5 mg/kg.

A. Immediate management.

For severe disease requiring hospitalization, a coagulation profile and type and screen may be indicated if blood products are required. Fulminant ulcerative colitis requires inpatient treatment. Steroids, such as methylprednisolone 60mg or hydrocortisone 400 mg intravenously daily, are the first-line therapy. If the AZA-naïve patient does not respond (sustained fever, bloody diarrhea more than four times daily or continued elevated CRP) on days 3–7, IV cyclosporine or infliximab should be started. Cyclosporine is given at a dose of 2 mg/kg after exclusion of hypomagnesemia. Cyclosporine trough levels must be checked on day 3. If there is clinical improvement, AZA at 2–2.5 mg/kg or 6-MP at 1–1.5 mg/kg should be started before discharge, and oral cyclosporin should be continued for at least three months as a bridging therapy. If no improvement is achieved within 5–7 days, infliximab may be tried, or colectomy must be considered. If there is clinical improvement, infliximab should be continued at 5 mg/kg every 8 weeks.

B. Physical Examination Tips to Guide Management.

Rectal exam is important to note presence of blood in the rectal vault. As described above, dermatologic, ocular, and rheumatologic manifestations, which can be easily identified with a visual inspection of the eyes and skin, may be associated with ulcerative colitis.

Arthritis is the most common extra intestinal manifestation and is both a nondestructive peripheral arthritis, which primarily involves large joints and ankylosing spondylitis. Eye involvement includes uveitis, episcleritis, scleritis, iritis, or conjunctivitis with presentation ranging from asymptomatic to burning, itching, or redness of eyes. Skin involvement includes erythema nodosum and pyoderma gangrenosum. Patients also are at increased risk of venous and arterial thromboembolism.

C. Laboratory Tests to Monitor Response to and Adjustments in Management.

Monitor the number of bloody bowel movements, hemoglobin, and hematocrit.

D. Long-term management.

Steroid-dependent ulcerative colitis occurs if a patient relapses within twelve weeks after corticosteroid discontinuation or if corticosteroids cannot be tapered within sixteen weeks. Compliance with 5-ASA therapy must be assessed in patients deemed steroid-refractory. Surgical treatment may be considered when the patient has failed medical therapy or cannot tolerate medical therapy, or in the presence of toxic megacolon, severe bleeding, high-grade or multifocal dysplasia, colorectal cancer, or stunted growth in children.

E. Common Pitfalls and Side-Effects of Management

Antibiotics have no role in the treatment of ulcerative colitis. Clinicians should avoid long-term use of corticosteroids in order to prevent systemic side effects. Common pitfalls include suboptimal dosing of medications, specifically immunosuppressants, or changing to biologic agents prematurely. Another common pitfall is the long-term use of glucocorticoids, which pose significant systemic side effects.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Mercaptopurine dosing must be adjusted for creatinine clearance less than 50 and should be dosed every 48 hours. No supplement in HD or PD is required.

Azathioprine requires a dose adjustment for renal insufficiency as well. For CrCl of 10–50, dose should be decreased by 25 percent; for CrCl less than 10, dose reduction of 50 percent is recommended. With hemodialysis, a 0.25 mg/kg supplement should be prescribed. Nephrotoxicity may occur with the use of sulfasalazine.

B. Liver Insufficiency.

Mercaptopurine may be associated with jaundice, hepatotoxicity, hepatic encephalopathy, ascites and pancreatitis. Azathioprine has also been associated with hepatotoxicity, pancreatitis, and hepatic veno-occlusive disease.

C. Systolic and Diastolic Heart Failure

If blood products are being transfused, consideration of administration of a loop diuretic may be of utility to avoid volume overload and exacerbation of heart failure symptoms.

D. Coronary Artery Disease or Peripheral Vascular Disease

If patients have severe anemia and a history of coronary artery disease, transfusion parameters may be higher (i.e., hemoglobin/hematocrit of 10 mg/dL and 30 mg/dL, respectively).

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

Azathioprine carries a black box warning for risk of malignancy that is due to chronic immunosuppression, which includes post-transplant lymphoma and hepatosplenic T-cell lymphoma when used to treat inflammatory bowel disease. Infliximab treatment carries an increased risk of lymphoma and other malignancies. Cases of fatal hepatosplenic T cell lymphomas have been reported with infliximab in combination with azathioprine or 6-mercaptopurine.

Patients with UC have increased risk of colorectal cancer with the two most important risk factors being the extent of colitis and duration of the disease. The risk for colorectal cancer is highest in patients with pancolitis, and risk starts to increase 8 to 10 years following onset of symptoms.

Strictures in UC should be considered malignant until proven otherwise by endoscopic evaluation with biopsy.

G. Immunosuppression (HIV, chronic steroids, etc.)

Azathioprine acts as an immunosuppressive agent and may increase the risk of infection. Infliximab carries a black box warning for serious infection risk, including a risk of pulmonary and extrapulmonary tuberculosis, invasive fungal infections, and other opportunistic infections. Patients should be screened carefully for risk factors for tuberculosis and evidence of latent TB infection.

H. Primary Lung Disease (COPD, Asthma, ILD)

Sulfasalazine may be associated with interstitial lung disease and hypersensitivity pneumonitis.

I. Gastrointestinal or Nutrition Issues

Sulfasalazine can cause anorexia, nausea/vomiting, dyspepsia, and pancreatitis.

J. Hematologic or Coagulation Issues

Mercaptopurine may cause myelosuppression, manifested as anemia, leukopenia, or thrombocytopenia. Azathioprine can also cause myelosuppression, with side effects of anemia, thrombocytopenia, or leukopenia. Sulfasalazine may be associated with adverse reactions of hemolytic anemia, blood dyscrasias, agranulocytosis, and aplastic anemia.

Anemia can be secondary to blood loss, anemia of chronic disease, or autoimmune hemolytic anemia.

K. Dementia or Psychiatric Illness/Treatment

No change in Standard Management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Follow CBC.

B. Anticipated Length of Stay.

Goal length of stay should be about one week.

C. When is the Patient Ready for Discharge?

Readiness for discharge should be assessed when bloody bowel movements have resolved and the patient is afebrile and no longer requires blood product transfusion. The patient should be tolerating at least a bland diet at the time of release.

D. Arranging for Clinic Follow-up

Patients may be advised to follow up with a gastroenterologist. Patients with ulcerative colitis in whom total colectomy has not been performed, will need surveillance screening for malignant neoplasm of the colon.

1. When should clinic follow up be arranged and with whom?

Patient should follow up with a gastroenterologist within two weeks of discharge from the hospital, but sooner if symptoms of bloody diarrhea, fever, or abdominal pain return.

2. What tests should be conducted prior to discharge to enable the best clinic first visit?


3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?


E. Placement Considerations.


F. Prognosis and Patient Counseling.

The prognosis in ulcerative colitis is good during the first decade, and only few will require colectomy. Remission is often achieved.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

In an acute flare of ulcerative colitis, where bloody bowel movements may be present, refrain from administering pharmacologic DVT prophylaxis until symptoms have stabilized.

VII. What’s the Evidence?

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Bernstein, CN, Blanchard, JF, Houston, DS, Wajda, A. “The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study”. Thromb Haemost. vol. 85. 2001. pp. 430

Solem, CA, Loftus, EV, Tremaine, WJ, Sandborn, WJ. “Venous thromboembolism in inflammatory bowel disease”. Am J Gastroenterol. vol. 99. 2004. pp. 97

Irving, PM, Pasi, KJ, Rampton, DS. “Thrombosis and inflammatory bowel disease”. Clin Gastroenterol Hepatol. vol. 3. 2005. pp. 617

Spina, L, Saibeni, S, Battaglioli, T. “Thrombosis in inflammatory bowel diseases: role of inherited thrombophilia”. Am J Gastroenterol. vol. 100. 2005. pp. 2036

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Novacek, G, Weltermann, A, Sobala, A. “Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism”. Gastroenterology. vol. 139. 2010. pp. 779

Murthy, SK, Nguyen, GC. “Venous thromboembolism in inflammatory bowel disease: an epidemiological review”. Am J Gastroenterol. vol. 106. 2011. pp. 713

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Sandborn, WJ, Loftus, EV, Colombel, JF. “Utility of perinuclear anti-neutrophil cytoplasmic antibodies (PANCA), anti-saccharomyces cerevesiae (ASCA), and anti-pancreatic antibodies (APA) as serologic markers in a population based cohort of patients with Crohn’s disease (CD) and ulcerative colitis (UC) (abstract)”. Gastroenterology. vol. 118. 2000. pp. A106

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Sandborn, WJ, Loftus, EV, Colombel, JF. “Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn’s disease”. Inflamm Bowel Dis. vol. 7. 2001. pp. 192

De Dombal, FT, Watts, JM, Watkinson, G, Goligher, JC. “Local complications of ulcerative colitis: stricture, pseudopolyposis, and carcinoma of colon and rectum”. Br Med J. vol. 1. 1966. pp. 1442

Lutgens, MW, van Oijen, MG, van der Heijden, GJ. “Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies”. Inflamm Bowel Dis. vol. 19. 2013. pp. 789

Levin, B. “Inflammatory bowel disease and colon cancer”. Cancer. vol. 70. 1992. pp. 1313

Gyde, SN, Prior, P, Allan, RN. “Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres”. Gut. vol. 29. 1988. pp. 206

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Collins, RH, Feldman, M, Fordtran, JS. “Colon cancer, dysplasia, and surveillance in patients with ulcerative colitis. A critical review”. N Engl J Med. vol. 316. 1987. pp. 1654

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Nugent, FW, Haggitt, RC, Gilpin, PA. “Cancer surveillance in ulcerative colitis”. Gastroenterology. vol. 100. 1991. pp. 1241

Greenstein, AJ, Sachar, DB, Smith, H. “Cancer in universal and left-sided ulcerative colitis: factors determining risk”. Gastroenterology. vol. 77. 1979. pp. 290

Present, DH, Wolfson, D, Gelernt, IM. “Medical decompression of toxic megacolon by “rolling”. A new technique of decompression with favorable long-term follow-up”. J Clin Gastroenterol. vol. 10. 1988. pp. 485

Panos, MZ, Wood, MJ, Asquith, P. “Toxic megacolon: the knee-elbow position relieves bowel distension”. Gut. vol. 34. 1993. pp. 1726

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