Gastroenterology Hepatology

Ulcerative colitis

How can I be sure that the patient has ulcerative colitis?

Ulcerative colitis (UC), one of main subgroups of the inflammatory bowel diseases, most commonly presents with diarrhea, abdominal discomfort, and fatigue, overlapping with symptoms of Crohn's disease.

Bloody diarrhea, the hallmark of ulcerative colitis, is usually a presenting symptom and can be accompanied by campy abdominal pain and urgency that dissipates after a bowel movement.

Patients can present with a variety of extraintestinal manifestations, including arthritis or arthralgias, primary sclerosing cholangitis, and ocular findings (i.e., iritis, episcleritis, and skin disease).

Ulcerative colitis can involve inflammation in the colon to any extent: the rectum alone (proctitis), the rectosigmoid (proctosigmoiditis), left side (up to the splenic flexure), or pancolitis, but it virtually always involves the rectum, is confluent to the proximal limit of disease, and does not extend into the ileum. One uncommon occurrence is what is termed “backwash ileitis,” occurring in about 10% of cases of pancolitis in which generally mild ileal inflammation can be seen.

The chief set of diseases that may mimic UC include infections, irritable bowel and Crohn’s disease. The differentiation of ulcerative colitis from Crohn’s disease can be readily made in cases of ileal Crohn’s disease, but cases of Crohn’s that involve only the colon can be more difficult.

UC and irritable bowel syndrome (IBS) should not present a major dilemma, as IBS should not have bloody diarrhea, and the presence of inflammation evident endoscopically and histologically would confirm a diagnosis of UC. Ischemic colitis, although usually an acute process that resolves spontaneously, can become a chronic disease in as much as 10% of individuals, and is at times overlooked as a diagnosis.

A tabular or chart listing of features and signs and symptoms

What are the common features of ulcerative colitis?

Symptoms of UC can range from only mild diarrhea, consisting of some blood and/or mucus with several episodes a day to the severe end of the spectrum, with more than 15 stools in a day; fevers; marked fatigue; and abdominal pain.

The arthritis that can accompany UC most typically is peripheral and nondeforming, involving the larger joints, more commonly the hips and knees and parallel colonic disease activity, although joints can herald the onset of a flare. Central arthritis or spine disease does not necessarily follow the colitis activity and HLA-B27-associated disease should be considered.

No pathognomonic features exist for UC, but bloody diarrhea is the most frequent presenting sign. Crohn's disease and UC can present similarly and can be difficult to distinguish in some cases.

Extraintestinal manifestations, such as primary sclerosing cholangitis, can occur, particularly in younger men and should be screened for with liver function blood tests done at initial presentation in all patients.

A distinction between irritable bowel and inflammatory bowel disease should be determined by the presence of inflammation at colonoscopy. Infectious diarrhea should be excluded and could be confused early in the disease. In patients with more severe symptoms, other less common infections should be considered, as well such as cytomegalovirus (CMV) colitis. Amoebic dysentery could mimic UC.

How can I confirm the diagnosis?

An initial evaluation should include common laboratory tests such as a CBC, ESR, and CRP, although those could be normal. If early in the disease course, stool tests should be performed for routine pathogens. A colonoscopy is the crucial test to confirm a diagnosis.

If UC is suspected and stool tests are negative, a colonoscopy is indicated to assess a diagnosis, as well as the extent of disease.

Although a sigmoidoscopy can be adequate as well to confirm a diagnosis, colonoscopy would be preferable to permit a more complete assessment of the extent of disease and severity of inflammation and to help eliminate Crohn's disease as a potential diagnosis.

The endoscopic appearance in mild disease can consist of a subtle blurring of the vascular pattern and some congestion. Friability, or bleeding on gentle rubbing against the mucosa, can be seen in mild disease as well. Ulcerations, although suggested by the name of ulcerative colitis, more commonly is seen with more severe disease and can be seen with edema, a mucopus exudate, and spontaneous hemorrhage.

Endoscopy can help in distinguishing UC from Crohn's disease, although it can confuse the picture as well. While a confluent picture of inflammation, starting in the rectum and extending more proximally, is anticipated in UC, the extent to which UC can occasionally have patchy inflammation is underappreciated. In addition, a cecal patch, or a focal area of inflammation in the cecum, or a periappendiceal area of inflammation is consistent with UC and does not constitute a skip lesion, suggesting a diagnosis of Crohn's disease.

A review of histology should help confirm the diagnosis, although there no pathognomonic histologic features with acute and chronic inflammation as the nonspecific findings. Serologic diagnoses such as pANCA may help distinguish between Crohn’s disease and UC but rarely contribute significantly to a diagnosis and more often confirm what has been already assessed and determined. Other serologic measures of inflammation, such as ESR or CRP, can frequently be normal even with significantly active disease. Stool calprotectin or lactoferrin can help monitor disease activity but would not play a central role in the primary diagnosis of UC.

Indirect measures of colonic disease or inflammation, whether radiologic evidence by computed tomography, magnetic resonance, or other techniques, should not be relied on to identify UC; however, colonoscopy is the clear gold standard.

What is the epidemiology of UC?

The epidemiology of UC remains incompletely determined. The disease can occur at a young age but is not seen predominantly in this age group and is diagnosed as new-onset disease at any age. Smokers are relatively protected against the development of UC, but former smokers have a higher risk than nonsmokers. Nonsteroidal anti-inflammatory drug (NSAID) use may increase an individual's risk of developing the disease and patients should avoid NSAIDs as these may provoke flares.

More common diseases associated with UC include primary sclerosing cholangitis (PSC), which occurs particularly in younger males with UC. PSC can be present in as many as 5% of patients with UC. A number of extraintestinal complications include arthralgias, ocular findings (iritis, episcleritis, etc.), skin manifestations (erythema nodosum or pyoderma gangrenosum), or aphthous stomatitis.

Patients with PSC, most commonly occurring in young men, may have mild disease, although typically will present with pancolitis. All patients with PSC should undergo a colonoscopy even if asymptomatic, as 70% of patients with PSC have UC. All patients with UC should have liver tests, including alkaline phosphatase tested, as 5% of UC patients may have PSC.

Patients with UC are at a higher risk of colon cancer, which is particularly associated with duration of disease (more than 8-10 years) and ongoing active inflammation (see below).

What other diseases, conditions, or complications should I look for in patients with ulcerative colitis?

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What is the right therapy for the patient with ulcerative colitis?

Treatment is tailored to disease severity. For mild to moderate disease, sulfasalazine or mesalamine can be highly effective, both for flares as well as for maintenance of disease in up to 70% of patients.

Glucocorticosteroids are effective to treat flares but are not used for long term maintenance both because of side effects as well as lack of efficacy as a maintenance medication. If a patient repeatedly flares despite one or more rounds of steroids, alternative strategies should be considered with an immunosuppressant therapy such as azathioprine or 6-mercaptopurine. Biologic agents (anti-TNF agents such as infliximab) have been proven effective for those on the more severe end of the spectrum. Many patients, particularly younger patients and those above 60 with a good functional status are candidates for an ileal pouch with anal anastomosis (IPAA or J-pouch), which permits a high quality of life on most patients.

There are few clear lifestyle directives for patients with UC. NSAIDs can cause flares in some patients and so should be avoided. Smoking, while a risk for Crohn's disease, can be protective of the development of UC, although patients who quit smoking have a higher risk than those who have never smoked tobacco. While conventional wisdom suggests that diet is irrelevant, some data suggests that it plays an important role, although the evidence is not strong enough to suggest a particular diet. A low roughage diet can be helpful for a subgroup but is not necessary or beneficial consistently.

What is the most effective initial therapy?

Mesalamine or sulfasalazine can be highly effective (50-70% remission or response) in patients with mild to moderate symptoms (i.e., fewer than 10 stools per day). Numerous formulations of mesalamine are commercially available (Asacol, Colazal, Lialda, Apriso) for oral delivery, and for topical/rectal delivery, an enema or suppository of mesalamine can be utilized as well.

The oral formulations appear all therapeutically equivalent. Higher doses than the FDA approved doses are widely used with some data to suggest that higher doses provide greater response rates, although this may be applicable only to those with moderate (rather than mild) disease activity. Frequency of oral dosing has been reduced so that studies have suggested an equal benefit for the treatment of active disease or maintenance of remission, depending on the formulation, at once a day to be equivalent to more frequent dosing.

While sulfasalazine may be poorly tolerated by 20% to 30% of individuals (headache and rash being most common), such problems are not encountered by most patients on mesalamine and can be well tolerated by as many as 95% of UC patients. A rare but important adverse event associated with these medications can be worsening of UC symptoms of diarrhea. This complication is important to recognize so that patients do not go on for more aggressive therapy on this basis as discontinuation can result in significant improvement in a few days.

For those patients with moderate to severe disease or those not responding to mesalamine, glucocorticoids can be utilized but not for more than several months at a time. A strategy should be considered early on during therapy to avoid steroid dependency. Alternative or substitute therapy for which steroids may provide a bridge would include azathioprine or 6-mercaptopurine and/or an anti-TNF agents, of which only infliximab is FDA-approved for the treatment of UC. For more severe hospitalized patients, in addition to these therapies, cyclosporine may offer a benefit as a bridge to azathioprine/6-mercatpurine as well.

Azathioprine/6-mercaptopurine can be an effective medication, with up to 60% response, although it is not effective for treatment of an acute flare as patients will take about 2 to 3 months – some may take up to 6 months – to experience a benefit . A strategy is required to make a transition from management of the acute flare to maintenance of remission with one of these immune suppressants.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

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A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

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Listing of these, including any guidelines for monitoring side effects.

Although mesalamine is a very well-tolerated medication, still some monitoring is suggested, even if minor, including a CBC, BUN/creatinine, and liver tests within 3 months of initiation and annually.

Sulfasalazine requires more frequent testing, particularly to assess renal function as well as LFTs and CBC monitoring within 4 weeks of initiation and every 3 to 4 months as well.

Azathioprine/6-mercaptopurine require more extensive monitoring, with thiopurine methyltransferase (TPMT) activity or genotype-testing recommended before the start of the medication. Azathioprine and 6 mercaptopurine are dosed by weight with a target of 2.5 mg/kg for azathioprine and 1.5 mg/kg for 6-mercaptopurine. About 20% of patients who started on azathioprine or 6-mercaptopurine are unable to continue on it. Pancreatitis (2-4%) or hepatitis (<1%) can happen acutely, most often within the first 8 weeks. Infection is another principle concern in the setting of neutropenia as well as a normal white blood cell count.

Subsequently, monitoring should be throughout for neutropenia, as well as an elevation of liver tests, and dose may need to be reduced. The genotype assessment for TPMT will identify a subgroup at risk for neutropenia but that is likely only a subgroup of 25% of patients; neutropenia will occur in others even after they have been on medication for long durations.

Metabolite measurement for 6-thioguanine levels to guide dosing are supported by some data but cannot be uniformly endorsed for all patients. Only a subgroup that is not responding may benefit from such monitoring to determine if further dosing is futile or if an increased dose may be beneficial. Once initiated, CBC and LFTs should be checked as frequently as every 2 wks for the first 6 wks, then monthly for 3 months, followed by testing every 2 to 3 months, although such guidelines have not been consistently supported by data or consensus.

Prior to initiating infliximab, a screen for tuberculosis should be performed with a PPD or a QuantiFERON Gold assay done. Appropriate blood monitoring for infliximab once initiated is uncertain, although rare events have been reported, such as hepatitis and neutropenia.

How should I monitor the patient with ulcerative colitis?

A prime concern for patients with UC is the increased risk for colorectal cancer, which is increased with duration of disease, particularly after 8 to 10 years of disease.

Established risk factors for cancer include a younger age of onset of the disease, extent of disease, and ongoing histologic inflammation. Surveillance should begin after 8 to 10 years of disease and is currently recommended every other year until 20 years of disease, after which annual surveillance should be performed.

Patients should undergo routine screening with biopsies, even with normal appearing mucosa, and more than 32 biopsies throughout the colon should be taken for a higher than 90% chance of identifying dysplasia. Individuals with PSC are at a significantly increased risk as well and should undergo annual screening, independent of duration of disease.

These recommendations have been revised in the British guidelines to decreased surveillance intervals in those patients without histologic evidence of inflammation. The role of chromoendoscopy is evolving in that it appears to improve the yield of these procedures, and would be recommended in higher-risk individuals, where possible at various practices or institutions.

If high- or low-grade dysplasia is identified on biopsy, initial steps should be taken to have that diagnosis confirmed on review by a second expert pathologist. High-grade dysplasia indicates a high likelihood of concurrent cancer and warrants a colectomy. The management of low-grade dysplasia remains controversial and, at the very least, necessitates close follow-up with a repeat colonoscopy within 3 to 6 months, although some data would support colectomy.

What's the evidence?

Kamm, MA, Sandborn, WJ, Gassull, M. "Once-daily, high-concentration MMX mesalamine in active ulcerative colitis". Gastroenterology. vol. 132. 2007. pp. 66-75.

Sandborn, WJ, Korzenik, J, Lashner, B. "Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis". Gastroenterology. vol. 138. 2010. pp. 1286-96, 1296.

Rutgeerts, P, Sandborn, WJ, Feagan, BG. "Erratum". N Engl J Med. vol. 354. 2006 May. pp. 2200-76.

Sandborn, WJ, Rutgeerts, P, Feagan, BG. "Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab". Gastroenterology. vol. 137. 2009. pp. 1250-60.

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