Ulcerative Colitis

Debra Ford, MD, FACS
Associate Professor and Head Section of Colon and Rectal Surgery
Howard University College of Medicine
Washington, DC

Ulcerative colitis, an idiopathic inflammatory bowel disease, is a chronic disease characterized by diffuse mucosal and submucosal inflammation limited to the colon and rectum. It extends proximally in a symmetrical, circumferential pattern to involve parts or all of the large intestine. The dominant symptom in ulcerative colitis is diarrhea, which is usually, but not always, associated with blood in the stool. The diarrhea is often associated with rectal urgency and tenesmus.¹ The clinical course is characterized by exacerbations and remissions that may occur spontaneously or in response to medical management. Medical management is not curative; however, surgical removal of the colon and rectum cures the intestinal manifestations of the disease and markedly reduces or eliminates the risk of malignancy. Therefore, management of patients with ulcerative colitis requires a multidisciplinary approach between gastroenterologist and surgeons. The goal of this review is to discuss the etiology, pathogenesis, clinical evaluation, and medical management of the intestinal manifestations of ulcerative colitis. A brief discussion of the indications for surgical intervention will also be discussed.

Ulcerative colitis affects approximately 35-100/100,000 individuals in North America and Northern Europe with an incidence of 2-10/100,000 population per year. The incidence has remained relatively constant over the last five decades but varies greatly within different geographic locations. These rates refer to the Caucasian population.¹ In the United States, the incidence of ulcerative colitis in the African-American population is one-fifth to one-half of the Caucasian population, but in recent years the gap has become smaller. ¹ Ulcerative colitis accounts for a quarter million physician visits annually and 20,000 hospitalizations per year. The annual financial costs are substantial.²

The peak age of onset of ulcerative colitis is between 15 and 25 years with another lesser peak of incidence occurring between 55 and 65 years. Most series show an equal incidence between males and females.¹

Theories about what causes ulcerative colitis abound, but none have been proven. The most popular theory is that the body’s immune system responds to an antigenic trigger that activates the immune response in ulcerative colitis. Over the years, an intensive search has been ongoing to identify the antigen(s) that trigger the immune response in inflammatory bowel disease. Immune activation in ulcerative colitis is largely confined to the gastrointestinal tract. The search for the antigenic trigger has focused on antigens in the intestinal lumen which are most likely microbial or dietary. Three major hypotheses have been proposed: 1) the antigenic triggers are microbial pathogens, 2) the antigenic trigger is a common dietary antigen and 3) the antigenic trigger is one that is expressed on the patient’s own cells.¹

The most established risk factor for the development of ulcerative colitis is a positive family history. This provides some evidence for a genetic basis for the disease. Several environmental influences have been identified that impact pathogenesis.³ There is no dispute that there is a strong association between non- smokers and ulcerative colitis; specifically, ex-smokers and ulcerative colitis. Among patients with ulcerative colitis, the incidence of smoking is less than the general population. This association has initiated studies looking at the use of nicotine as treatment for acute colitis.⁴

Another epidemiological factor is a history of appendectomy. Appendectomy strongly protects against the development of ulcerative colitis. This effect in ulcerative colitis is noted particularly when an appendectomy has been performed for an inflammatory problem such as appendicitis or mesenteric adenitis and if done before the age of 21.⁵

Clinical Features

The most common presenting symptoms in ulcerative colitis patients are diarrhea and rectal bleeding. Other symptoms include tenesmus, fever, pain, weight loss and symptoms associated with extraintestinal manifestations. The patient’s clinical picture is, in part, a function of the extent of the disease. Systemic symptoms (fever, malaise, weight loss) are more common if all or most of the colon is involved. If the disease is confined to the rectum, the patient may complain of urgency and tenesmus with or without blood or diarrhea.¹

The extent of disease is the single most important determinant of both prognosis and response to medical treatment.⁶ In a series of 1116 patients, 46% had proctosigmoiditis, 17% had left-sided disease (to the splenic flexure) and 37% had pancolitis.⁷ Patients with pancolitis are more likely to develop toxic megacolon, refractory symptoms, malignancies, extraintestinal manifestations and the need for surgery.

Assessment of disease severity in ulcerative colitis is important for clinical management. Truelove and Witts⁸ devised a system to categorize disease activity into mild, moderate and severe colitis (Table 1). This system incorporates the frequency of bowel movements and evidence of systemic toxicity. There are newer indices that use biochemical or molecular markers or endoscopic appearance of the colon, but the criteria described by Truelove and Witts are the easiest to apply clinically for selection of medical or surgical therapies.¹

Table 1*

*Modified from Truelove and Witts⁸

Patients with fulminant or toxic colitis are characterized by > 10 bowel movements per day, continuous bleeding, increased transfusion requirements, hypoalbuminemia, abdominal distention, and signs of systemic sepsis.⁶

Extraintestinal manifestations associated with ulcerative colitis include peripheral arthritis, axial arthritis, erythema nodosum, pyoderma gangrenosum, ocular conditions, and cholestatic disease.

Diagnosis and Assessment

In a patient presenting with persistent bloody diarrhea, rectal urgency or tenesmus, stool examination and sigmoidoscopy with biopsy should be performed to confirm the presence of colitis and exclude any infectious etiologies. Characteristic endoscopic and histologic findings with negative evaluation for infectious causes will suggest the diagnosis of ulcerative colitis. The typical endoscopic features are superficial ulcerations, granularity and distorted mucosal vascular patterns extending from the rectum proximally.¹ The differential diagnoses of ulcerative colitis include, but is not limited to, Crohn’s colitis, infectious colitis, antibiotic-associated colitis, ischemic colitis and diverticulitis.

Treatment

The goals of treatment should be directed at inducing and maintaining remission of symptoms and mucosal inflammation in order to provide an improved quality of life. Once the diagnosis of ulcerative colitis is confirmed, the anatomic extent of disease is assessed endoscopically. The proximal margin of inflammation is important to determine because the mode of treatment will depend upon this information. The anatomic extent and clinical severity of an acute attack determines the approach to treatment.¹

The medical therapies for ulcerative colitis are divided into three categories: aminosalicylates (sulfasalazine, olsalazine, mesalamine, balsalazide), corticosteroids and immunosuppresives (mercaptopurine, azathioprine, cyclosporine).⁹ Biologic agents are under investigation. There are also several alternative therapies currently under evaluation, such as nicotine and heparin.² Surgical therapy is indicated for patients with medically refractory disease, fulminant diseases or its complications, dysplasia or malignancy.

Management of Mild/Moderate Distal Colitis

Patients with mild-to-moderate distal colitis may be treated with oral aminosalicylates, topical mesalamine, or topical steroids. Topical mesalamine agents are superior to topical steroids or oral aminosalicylates. The combination of oral and topical aminosalicylates are more effective than either alone. This combination can be used if single agent therapy is not effective. These drugs act within 2 to 4 weeks and are effective in 40-80% of patients. Side effects are common with sulfasalazine; they include nausea, vomiting, dyspepsia, anorexia and headache. Those patients that cannot tolerate sulfasalazine can usually be changed to one of the other aminosalicylates. An alternative to oral aminosalicylates is topical therapy with either mesalamine suppositories or enemas. Mesalamine is not only capable of treating the acute disease but also will maintain remission. Advantages of topical therapy include a generally quicker response time and a less frequent dosing schedule than oral therapy.²

Management of Mild/Moderate Extensive Active Colitis

Patients with mild-to moderate extensive colitis should begin therapy with oral sulfasalazine in doses up to 4-6grams per day, or an alternate aminosalicylate. Approximately 80% of patients will respond to this regimen with complete clinical remission or significant clinical improvement within 4 weeks. If these patients do not respond to the aminosalicylates then oral steroids may be started. The recommended dose is 40-60 mg of prednisone per day until significant clinical improvement occurs and then a weekly dose taper. In those patients that do not respond to oral prednisone but do not require admission and IV medication then 6-mercaptopurine (6-MP) or azathioprine are effective. Aminosalicylates should be used in conjunction to maintain remission. Azathioprine or 6-MP may be used for maintenance of remission if aminosalicylates are ineffective.²

Management of Severe Colitis

Patients that present with severe ulcerative colitis often require hospitalization. These patients will usually require IV corticosteroids as aminosalicylates are not effective with severe acute colitis. In addition to steroids, these patients should be hydrated and transfused as needed. Nasogastric decompression may be required. If there are systemic signs of sepsis then broad-spectrum antibiotics are warranted. Patients with severe colitis who do not improve significantly after 7-10 days of maximal medical therapy should either be referred for surgery or offered treatment with intravenous cyclosporine. It has been reported that starting cyclosporine at a dose of 4 mg per kilogram per day in patients with steroid-refractory severe colitis avoided emergent colectomy during the acute stage of disease. These patients can then be switched to oral cyclosporine with the addition of 6-MP or azathioprine. It must be stressed that a patient’s cholesterol level must be normal prior to starting cyclosporine. Care must be taken when using these agents because of the many serious side effects such as nephrotoxicity, infection and seizures.^1,2,6

Patients with fulminant colitis or toxic megacolon should be treated with IV corticosteroids, hydration, NPO, nasogastric decompression if an ileus is present, and instructed to rotate frequently to assist in the redistribution of colonic gas. Broad-spectrum antibiotics are used. There is controversy regarding duration of treatment of these severe conditions. Most experts recommend surgery after 72 hours if the patient does not respond to maximal medical management. However, any clinical, laboratory or radiologic deterioration on medical therapy mandates immediate colectomy.²

Indications for Surgical Intervention

Indications for surgical intervention in ulcerative colitis can be divided into two categories: emergent and elective. Situations that require emergent intervention are fulminant disease activity unresponsive to maximal medical therapy, toxic megacolon, colonic perforation and massive hemorrhage. The goal of therapy in this setting is to treat the emergency and restore the patient to good health so that a restorative procedure can be performed in the future. Elective surgical procedures may be performed for failure of medical management (the most common indication), intolerable side effects of medical treatment, development of mucosal dysplasia, diagnosis of carcinoma, colonic stricture and growth retardation in children. Rarely, the extraintestinal manifestations of ulcerative colitis may require elective surgical intervention.⁹ What ever the indication for surgery, patients should be informed of the different operations available and be educated as to the risks and benefits of the chosen operative procedure. Emergency procedures usually include subtotal colectomy with ileostomy; however, in rare instances the surgeon may have to perform a proctocolectomy with end ileostomy. The elective procedures include the commonly performed proctocolectomy with ileal pouch-anal anastomosis. Other procedures include: subtotal colectomy with ileorectal anastomosis, proctocolectomy with Kock continent ileostomy and proctocolecolectomy with end ileostomy.⁹ The reader is directed to numerous textbooks regarding the details of the listed procedures.

Colorectal Cancer, Dysplasia, and Colonoscopic Surveillance

The risk of colorectal cancer in ulcerative colitis is higher than that of the general population. This excess risk appears to be a result of chronic colonic inflammation. In addition, the severity, anatomical extent, and duration of inflammation are independent risk factors for the development of colorectal cancer. Additional risk factors include: a family history of colorectal cancer and primary sclerosing cholangitis.¹⁰ After 10 years of pancolitis, the risk of cancer is in the range of 0.5-1% per year. Patients with disease limited to the left side of the colon have a cumulative cancer risk after 3 to 4 decades of disease.²

Compared with sporadic colorectal cancers, colitis-associated cancers are more often multiple, broadly infiltrating, anaplastic, and uniformly distributed throughout the colon. The colitis-associated cancers often occur in a younger patient population and seem to arise from flat mucosa.² Genomic instability is an early step in cancer associated with ulcerative colitis. These cancers do not seem to follow the usual adenoma-carcinoma sequence described for sporadic cancers.¹⁰

The association of colon cancer and dysplasia in ulcerative colitis is firmly established, but the benefits of surveillance for dysplasia are not as clear.^1,11 The current recommendations are as follows: after 8-10 years of pancolitis, annual or biannual surveillance colonoscopy with multiple random biopsies at regular intervals should be performed. The finding of high-grade dysplasia in flat mucosa or associated with a lesion confirmed by expert pathologists’ review, is an indication for colectomy.² Current recommendations for surveillance are widely practiced, but the recommendations are not evidence-based. Some patients develop advanced cancers despite compliance with surveillance recommendations. One limitation of the current surveillance strategy is sampling error. However, reports are promising regarding chromoendoscopy in the early detection of dysplasia and cancer.¹¹ The present system of surveillance is not ideal, but no definitive or useful alternative markers of malignancy in ulcerative colitis have been identified.

References

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7. Farmer RG, Easley KA, Rankin GB: Clinical patterns, natural history, and progression of ulcerative colitis: A long-term follow-up of 1,116 patients. Dig Dis Sci 1993;38:1137-1146.
8. Truelove SC, Witts LJ: Cortisone in ulcerative colitis: final report on a therapeutic trial. BMJ, 1955;2:1041-1048.
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10. Rutter M, Forbes A: Colorectal cancer in inflammatory bowel disease. IBD Monitor 2004;6:2-7.
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