2.5.1 HOSPITALIZATION

Hospitalization is indicated for the following reasons:
1. Failure of mild disease to improve significantly within four weeks of the start of outpatient treatment. Hospitalization removes the patient from an aggravating environment and provides the physician with the opportunity to initiate more effective and intensive therapeutic measures.
2. Severe illness with anorexia, nausea, vomiting, fever and uncontrollable bloody diarrhea (severe ulcerative colitis). Early hospitalization is critical for such patients so that they may be provided with therapy to control the disease and prevent complications, especially toxic megacolon.
3. Development of local or systemic complications including massive hemorrhage, persistent anemia, severe hypoalbuminemia, and/or cancer. Hospitalization at this time provides for assessment of the need for surgical therapy.

Supportive therapy consists of medications that improve the patient’s general state of health or alleviate symptoms. Chronic losses of potassium, sodium and water must be replaced with oral and/or intravenous fluids, since uncorrected fluid and electrolyte deficits have been implicated in the development of toxic megacolon and renal calculi. Blood loss due to severe disease should be replaced with transfusions. With mild disease, oral iron replacement is indicated. The use of antidiarrheal agents – e.g., diphenoxylate (Lomotil¨) or loperamide (Imodium¨) – for patients with ulcerative colitis is generally contraindicated. In severe disease where the colonic mucosa is severely damaged, antidiarrheal agents are generally ineffective, since there is a loss of absorbing capacity. Furthermore, they may contribute to the development of toxic megacolon. Similarly, anticholinergics can also precipitate toxic megacolon and thus should not be prescribed for patients with ulcerative colitis.

Neither total parenteral nutrition nor enteral nutrition has yet been shown to have any beneficial effect in inducing remission of ulcerative colitis.

2.5.4 DRUG THERAPY

Corticosteroids should be used to treat active ulcerative colitis. They have no role in maintenance treatment to prevent relapse. The dosage and routes of administration vary with the severity and location of ulcerative colitis.

These are available in enema formulations as hydrocortisone 100 mg in a 60 mL aqueous suspension (Cortenema¨) and as budenoside (a first-pass metabolized steroid) 2 mg in 100 mL aqueous suspension (Entocort¨), in foam formulation as hydrocortisone acetate 80 mg in a propylene glycol gel (Cortifoam¨), and in ointment formulation as hydrocortisone acetate 10 mg or 40 mg in an ointment base (Cortiment¨). In general, enema preparations will cover a larger surface area of the colon, while the effect of foam and ointment preparations is generally limited to the rectum. With mild disease, especially that of the distal colon, rectal instillation of steroids will induce or maintain remission for a high percentage of patients. With mild to moderately severe ulcerative proctitis, twice-daily rectal steroids combined with systemic therapy will promote remission and more quickly return the rectum to its normal functional reservoir capacity. Patients should instill the solution while in the left lateral decubitus position and then change their position to right decubitus followed by prone for at least 20 minutes after each position, to allow for maximal topical coverage. Studies indicate that up to one-half of rectally administered steroids is absorbed. Even though systemic absorption does occur, adrenal cortical responsiveness is not adversely affected.

In active pancolonic disease of mild to moderate severity, prednisone should be started in a dose of 40 mg/ day. A single daily dose of prednisone is most convenient; however, such a dose does produce adrenal suppression. No significant difference in healing between groups given single daily doses or divided daily doses of oral steroids has been detected. For patients whose disease responds promptly to oral steroids, withdrawal should be undertaken at 5 mg/week until a dose of 20 mg/ day is reached; then the drug should be tapered by 2.5 mg/week to off. In the case of severe ulcerative colitis, the patient requires hospitalization, and intravenous steroids (prednisone 40 mg equivalent/day) should be started. The tapering off protocol is as outlined above.

Once the disease is in remission, further steroid treatment should be avoided until a subsequent exacerbation occurs. Treatment is then reinstituted at a level appropriate to the severity of exacerbation (steroid enemas for mild to moderate exacerbations of proctosigmoiditis, oral or intravenous steroids for moderate to severe pancolonic relapses). If, however, symptoms recur with the attempted withdrawal of steroids, then long-term steroid therapy may be necessary until the patient experiences remission. The use of high doses of steroids to maintain the patient relatively symptom-free is not recommended, however, in view of the potential side effects of steroid therapy. If a patient requires more than 15 mg of oral prednisone daily for many months in order to keep the colitis in control, elective colectomy should be considered as an alternative means of treatment.

Steroids, particularly steroids in the high doses necessary for severe cases, may “mask” a perforation of the colon and lead to peritoneal soiling and death; therefore, careful monitoring of the patient on such high doses is vitally important.

Mesalamine (5-aminosalicylic acid mesalazine, or 5-ASA) has been shown to be the active part of sulfasalazine and is effective in the treatment of active disease and in maintenance therapy to prevent relapse.

During the past decade mesalamine has been developed in the form of rectal enemas and suppositories. Mesalamine enemas have an overall efficacy of about 80% in patients with active left-sided colitis. Side effects occur in less than 2% of ulcerative colitis patients, many of whom would have had previous allergic reactions to sulfasalazine. In comparison studies, mesalamine enemas are as effective as corticosteroid enemas in the treatment of proctitis and proctosigmoiditis (15). In patients with distal proctitis, mesalamine suppositories (500 mg b.i.d.) are rapidly effective without side effects (16).

5-ASA is available as sulfasalazine (Salazopyrin¨) or as second-generation 5-ASA products that deliver the active ingredient (5-ASA) to the colon without the toxic sulfapyridine moiety (Asacol^®, Dipentum^®, Mesasal^TM, Pentasa^®, Salofalk^®) (Table 7).

Sulfasalazine is metabolized by colonic flora, thus releasing sulfapyridine, an absorbable antibiotic, and 5-aminosalicylic acid (5-ASA), the active ingredient. The sulfapyridine acts only to carry the 5-ASA to the colon and, when released by bacterial metabolism, it is absorbed and is responsible for the dose-related side effects of sulfasalazine. The acetylation rate of sulfapyridine is genetically determined; slow acetylators develop side effects at lower dose levels of sulfasalazine than fast acetylators. The most common dose-related symptoms are anorexia, nausea, dyspepsia and diarrhea. Common hematological complications include impairment of folate absorption (thus supplemental folate therapy is a requirement for all patients on sulfasalazine) and Heinz- body hemolytic anemia. Hypospermia may occur and is reversible through withdrawal of the drug. Hypersensitivity reactions are rare; symptoms include fever, rash, bone marrow suppression, infiltrative lung disease, a lupus-like syndrome, pancreatitis and hepatic toxicity. Sulfasalazine is inferior to corticosteroids in the treatment of acute, moderately severe colitis. For this reason, sulfasalazine is used as an adjunctive to steroid therapy and not as the first line of therapy for acute attacks of ulcerative colitis. Therefore, once steroids have been started and the patient is tolerating oral fluids well, sulfasalazine can be started at a dose of 1 g/day and gradually increased to 4–6 g/day within 7 days. The second-generation site-specific compounds capable of delivering mesalamine to the colon appear to have less systemic toxicity than sulfasalazine. Patients doing well on sulfasalazine are usually not changed to mesalamine product. Nevertheless, new patients presenting with ulcerative colitis are often started on second-generation mesalamine product rather than sulfasalazine.

The two main pharmacological approaches of the second-generation mesalamine compounds adopted are (1) the creation of azo-derivative compounds similar to sulfasalazine but linked with mesalamine through a diazo- bond with another mesalamine molecule (olsalazine, as in Dipentum¨); and (2) the incorporation of mesalamine either into pH-dependent delivery capsules such as Asacol^® (pH 7.0) or Mesasal^TM and Salofalk^® (pH 6.0), or into a mixed slow-release pH-dependent polymer (Pentasa^®). These second-generation compounds have shown comparable efficacy to sulfasalazine, with generally fewer side effects (17). Comparative studies assessing which compound might favor a higher mesalamine release into the colon and thus would be more suitable for patients with colonic inflammation are yet to be finalized. Comparison of mesalamine product dose and cost is presented in Table 7.

Once remission has been induced by either corticosteriod or mesalamine therapy, the risk of ulcerative colitis relapse can be reduced from 60% to approximately 20% with maintenance mesalamine therapy in approximately one-half the active treatment dose.

In general, the use of immunosuppresive agents (azathioprine, 6-mercaptopurine) has been disappointing in ulcerative colitis. Encouraging preliminary results with methotrexate in severe ulcerative colitis have been published; however, larger trials to confirm these results are yet to be completed (18). High doses of intravenous cyclosporine (10-15 mg/kg/day) have been shown effective in improving severe ulcerative colitis that might otherwise have gone to surgery. However, once the cyclosporine is stopped, the vast majority of these patients relapse and end up requiring surgical therapy (colectomy). In this regard, cyclosporine may be useful in patients who are not psychologically ready for a total colectomy. Since ulcerative colitis is curable with a colectomy, the majority of experts would not use immunosuppresive agents in the treatment of ulcerative colitis over the long term because of their significant side effects.

Unlike Crohn’s disease, ulcerative colitis does not respond to metronidazole.

Twenty to 25% of patients with extensive ulcerative colitis eventually undergo colectomy, usually because their disease has not responded to medical therapy. The decision between surgery and continued medical therapy is often not clear-cut, and in many cases arguments can be made for either course. In ulcerative colitis, colectomy is a “curative” procedure, in contrast to Crohn’s disease, in which there is a significant likelihood of recurrence some time after the colectomy. The development of the ileoanal anastomosis, eliminating the need for an ileostomy, has made the thought of colectomy more tolerable for many. In general, patients who require continuous high-dose cortico-steroids and/or immunosuppressants to keep their disease under control should be strongly advised to consider colectomy. Those at high risk for colonic carcinoma (pancolitis of greater than 10 to 15 years duration) should also be considering colectomy or alternatively entry into a colonoscopic surveillance program.

Ulcerative colitis may be complicated by a variety of associated conditions. These are (1) local complications arising in and around the colon, and (2) systemic complications arising at sites distant from the colon (Table 12).

Minor local complications in ulcerative colitis, unlike those in Crohn’s colitis, are infrequent and generally heal with conservative management. Enteroenteric perianal fistulas develop in a very small number of patients with ulcerative colitis. In these instances the physician must be certain that he or she is not dealing with Crohn’s colitis, in which enteroenteric fistulas are common.

2.6.2 MAJOR LOCAL COMPLICATIONS

Toxic megacolon is characterized by an acute dilation of all or part of the colon to a diameter greater than 6 cm (measured in the mid-transverse colon) and is associated with severe systemic toxicity. Toxic megacolon occurs in 1– 2% of patients with ulcerative colitis. Histological examination reveals extensive deep ulcerations and acute inflammation that involves all muscle layers of the colon and often extends to the serosa. This widespread inflammation accounts for toxic megacolon’s systemic toxicity (fever, tachycardia, localized abdominal pain and leukocytosis). The loss of colonic muscular tone results in the dilation of the colon.

Though the association between a barium enema and toxic megacolon has not been experimentally proven, there are many reports of toxic megacolon developing after the patient has undergone a barium enema. Thus, a barium enema should not be performed on patients who are acutely ill with ulcerative colitis.

Clinically, the patient with toxic megacolon presents as severely ill with a fever, tachycardia, dehydration, abdominal pain and distention (Table 13). Examination reveals absent bowel sounds, tympany and rebound tenderness. Leukocytosis (greater than 10,000), anemia and hypoalbuminemia are often present. A plain x-ray of the abdomen will reveal dilation of a colonic segment or of the entire colon. On plain supine x-ray, dilation of the transverse colon is most often seen. This distention of the transverse colon does not indicate severity of disease in this segment of the colon; rather, the distention is determined by the anterior position of the transverse colon. Repositioning the patient to a prone position will redistribute the gas to the more posterior descending colon and will dramatically decrease gaseous tension in the transverse colon.

If toxic megacolon is the presenting symptom of ulcerative colitis, diagnosis may be difficult, since a history of rectal bleeding and diarrhea is sometimes obscured by toxic megacolon. Most often, toxic megacolon complicates chronic intermittent ulcerative colitis and the diagnosis is not difficult. Occasionally, however, a patient seriously ill with ulcerative colitis and the resultant profuse bloody diarrhea will experience a sudden decrease in the frequency of bowel motions upon development of toxic megacolon. This decrease in stool frequency represents diminished colonic evacuation rather than improvement in the patient’s status. In this instance, a delay in diagnosis could result in perforation and death.

Treatment of toxic megacolon consists of general supportive measures, including replacement of fluid and electrolyte deficits, correction of hypokalemia, transfusions and nasogastric suction. Intravenous steroids (prednisone equivalent 60–80 mg/day) should be utilized for 48 to 72 hours. If there is insufficient response, surgery should be seriously considered. If the systemic symptoms subside and the abdominal signs improve, high-dose steroids should be continued for 10 to 14 days, after which the dose should be gradually tapered off.

Patients whose disease does not respond to appropriate intensive medical therapy within three days have a risk of colonic perforation of 50%. Mortality in the face of recognized or unrecognized perforation is approximately 85%; thus, surgery should be considered at an early stage rather than at a later.

Carcinoma of the colon afflicts patients with ulcerative colitis 7 to 30 times more frequently than it does the general population. The risk of colon cancer in ulcerative colitis is related to two factors: (1) duration of the colitis, and (2) extent of colonic involvement. The risk of colon cancer for patients who have had the disease less than 10 years is low, but this risk steadily increases. The cancer risk for patients who have had disease activity for 10 to 20 years is 23 times that of the general population, while a disease duration of more than 20 years is associated with a cancer risk 32 times greater than that of the general population. The extent of colonic involvement in colitis also influences the risk of cancer. The incidence of cancer when ulcerative colitis is limited to the rectum or to the left side of the colon is much lower than when ulcerative colitis involves the entire colon.

The colonic malignancy associated with ulcerative colitis is generally an adenocarcinoma evenly scattered throughout the colon. The adenocarcinoma is often flatter than cancers in the general population and has fewer overhanging margins. It is generally considered extremely aggressive.

Because of this high cumulative risk of cancer, prophylactic diagnostic procedures have been employed in an attempt to detect early malignant changes in the colon of patients with ulcerative colitis. Colonoscopy and biopsy have revealed that colorectal dysplasia is associated with colonic malignancy. However, areas of dysplasia can be missed at the time of biopsy, and the interpretation of dysplasia in the presence of active inflammatory disease is difficult, since regenerative epithelium may exhibit many of the features of dysplasia.

In summary, no test or group of diagnostic tests (not even frequent colonoscopies and biopsies) can absolutely guarantee that the patient with long-term ulcerative colitis is free of focal malignancy.

Patients with ulcerative colitis should have a colonoscopy and multiple biopsies performed after 5 years of disease. If no dysplasia is revealed by multiple colonic biopsies, repeat colonoscopy can be performed every 2 years thereafter. For patients with moderate or severe dysplasia on colonoscopic biopsies, repeat colonoscopy every 6 months to 1 year is recommended. Until more diagnostic tools are available to identify those patients at risk for cancer, colectomy at 10 years to cure the ulcerative colitis and prevent colonic cancer is highly recommended.

Colonic stricture occurs infrequently but may mimic colonic adenocarcinoma clinically and radiologically. If there is any question regarding the diagnosis, surgical removal is advocated.

Although rectal bleeding is universal in cases of ulcerative colitis, massive, life-threatening colonic hemorrhage is rare. For most patients, massive colonic hemorrhage can be medically managed with blood transfusions, steroids and 5-ASA products. Hemorrhage usually resolves spontaneously.

2.6.3 Systemic complications

Pericholangitis is seen in 30% of patients with ulcerative colitis. It tends to occur more often in patients with pancolitis than in those with ulcerative colitis limited to the distal colon. This liver lesion is characterized by periportal inflammatory infiltrates, degenerative changes in bile ductules, and varying degrees of periportal edema and fibrosis. The lesion of pericholangitis is patchy; therefore, sampling error on needle biopsy of the liver often occurs. Clinical manifestations of pericholangitis or its progression to cirrhosis are exceedingly rare, and many patients have only minor abnormalities in serum alkaline phosphatase.

Sclerosing cholangitis develops in less than 1% of patients with ulcerative colitis. In this disorder, the bile duct becomes severely narrowed and resultant recurrent attacks of jaundice, right upper quadrant pain, fever and leukocytosis occur. This lesion must be distinguished from other causes of obstruction of the common bile duct. Sclerosing cholangitis does not respond to any therapy.

Fatty infiltration of the liver is seen in 30% of patients with ulcerative colitis. The etiology of the fat deposition is unknown, but it may be due to malnutrition and protein depletion resulting from diarrhea and protein-losing enteropathy. Liver function studies are normal or only mildly abnormal in patients with fatty infiltration.

The most common hematologic abnormality in ulcerative colitis is iron deficiency anemia secondary to gastrointestinal blood loss. Most often this can be treated with oral ferrous sulfate (300 mg t.i.d.). However, for some patients, gastrointestinal intolerance of ferrous sulfate will necessitate parenteral iron injections (Imferon¨).

Heinz-body hemolytic anemia can be seen in patients receiving sulfasalazine. This type of hemolytic anemia is directly related to the sulfasalazine and resolves when the offending agent is withdrawn. Additionally, autoimmune hemolytic anemia and microangiopathic hemolytic anemia, with or without disseminated intravascular coagulation, can occur.

Secondary thrombocytosis may appear. It is not associated with coagulation defects. However, in addition to thrombocytosis, increased levels of factor V and fibrinogen can be seen, together with reductions in levels of antithrombin III. In rare instances, pulmonary embolism and thrombosis of mesenteric or cranial vessels due to thromboembolic disease can occur. Repeated pulmonary embolisms in spite of adequate anticoagulation therapy or massive colonic hemorrhage during anticoagulation therapy will necessitate a vena cava ligation with colectomy.

The arthritis of ulcerative colitis may antedate the colonic symptoms. It tends to be migratory and affect the larger joints, is associated with a synovitis and swollen painful joints, and is nondeforming with no involvement of adjacent cartilage or bone. Rheumatoid factors are negative in these patients. Arthritis usually subsides with control of the colitis.

There is a high incidence of ankylosing spondylitis and sacroiliitis in patients with ulcerative colitis. Unlike peripheral arthritis, the ankylosing spondylitis in ulcerative colitis is chronic, progressive, deforming and generalized. It does not respond to corticosteroids and will progress in the face of quiescent colitis. The incidence of sacroiliitis is higher than that of ankylosing spondylitis in patients with ulcerative colitis. However, the sacroiliitis is often asymptomatic and can be identified only through appropriate x-rays of the pelvis.

Erythema nodosum with raised tender erythematous swellings on the extensor surfaces of the legs and arms is less frequent with ulcerative colitis than with Crohn’s disease.

Pyoderma gangrenosum complicates severe ulcerative colitis but is rarely seen with mild disease. This skin lesion begins as a small, elevated nodule, which gradually becomes gangrenous, thus resulting in progressive necrosis of the surrounding skin. It tends to ulcerate deeply, involving underlying soft tissue and sometimes bone.

Usually both erythema nodosum and pyoderma gangrenosum will respond to control of the colitis. Occasionally, despite control of the colonic disease, the pyoderma gangrenosum will progress. Persistent severe pyoderma gangrenosum is thus an indication for colectomy.

Iritis occurs in 5% of patients with ulcerative colitis and presents as blurred vision, eye pain and photophobia. The attack may be followed by atrophy of the iris, anterior and posterior synechiae, and pigment deposits on the lens. Episcleritis and other ocular lesions are only rarely seen with ulcerative colitis.

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