Diet rich in saturated fats, and refined sugar has been associated with higher incidence of UC. Physical activity however, is not strongly associated to incidence of UC.^29–31 Smoking appears to have a protective effect for UC; conversely former smokers have an increased risk of UC compared to those who never smoked.^32–34 The apparent protective effect of smoking extends to some of the extraintestinal manifestations of UC, in particular primary sclerosing cholangitis (PSC) and occurrence of pouchitis.^35,36 Interestingly, an appendectomy also has a protective effect from developing UC, though the mechanism is essentially unknown. Large, retrospective studies have shown a protective effect of 55% to 70%,^37–41 especially if the findings at the operation were consistent with appendicitis or lymphadenitis.³⁹ The mechanistic theories proposed for this interesting finding include the notion that as the body’s immune system responds to the inflammatory process of appendicitis, it adapts such that the inappropriate inflammatory process that defines UC never occurs. The environmental risks for development of CD and UC have some similarities but the diseases are in essence distinct entities (Table 66-2).

CLINICAL FEATURES

UC symptoms parallel the degree of the disease. Typically, UC affects the rectum, extending proximally in a continuous fashion, and can involve the entire colon. Most commonly the distal colon is involved for various length, however, approximately 20% of the time, patients present with pancolitis.⁴² The classic symptoms of UC are diarrhea, and rectal bleeding. Additional symptoms include tenesmus, urgency, and colicky abdominal pain.⁴³ Persistent pain is uncommon, and often can represent severe disease with inflammation extending to the serosa.⁴⁴ The sensation of constipation and incomplete evacuation can occur if there is severe rectosigmoid inflammation and spasm. As the disease progresses, systemic symptoms of fever, anorexia, weight loss, and malaise ensue. Severity of disease can be calculated using the Mayo Severity Index Calculator (Table 66-3).⁴⁵ Other calculators exist.

Extraintestinal Disease

Hepatobiliary

Approximately 3% to 5% of UC patients develop PSC. Generally, the patients are asymptomatic, though as the disease progresses liver enzyme elevation, pruritus, fatigue, chills, and right upper quadrant pain can develop. The risk of acquiring PSC is independent of colonic UC activity, and the risk persists after proctocolectomy. In addition, PSC is an independent risk factor for developing dysplasia/cancer in patients with UC.⁴⁶

Ophthalmologic

Greater than 3% of patients with UC can develop iritis, episcleritis, or uveitis. Episcleritis severity can parallel GI symptoms, but uveitis does not match GI disease activity. Though uveitis is less common, the disease is more severe, and if not promptly treated can result in blindness. Topical steroids and infliximab have successfully been used in treating UC uveitis.⁴⁷

Cutaneous

Manifestations of UC can include erythema nodosum and pyoderma gangrenosum (Fig. 66-2). Erythema nodosum generally follows the disease progress of the GI symptoms, occurring in up to 4% of patients with UC.⁴⁸ These violet subcutaneous nodules can be treated with topical steroids, though most commonly, systemic treatment of GI symptoms will also help with erythema nodosum. While pyoderma gangrenosum occurs less frequently than erythema nodosum, its treatment is more difficult as the disease course of pyoderma gangrenosum does not always parallel UC activity. Infliximab has shown some promise in treating pyoderma gangrenosum.⁴⁹

Musculoskeletal

These conditions are responsible for the most frequent extraintestinal complaints. Sacroileitis and ankylosing spondylitis are associated with UC flairs, and remissions. Carriers of HLA-B27 are especially prone to ankylosing spondylitis. Successful treatment of sacroiliatis with NSAIDs does not preclude progression of spondylitis. Methotrexate has also been successfully used, and there are increasing data of successful use of anti-TNF agents.⁵⁰

DIAGNOSIS

Physical examination is often unrevealing, though generalized pain is often an indicator of severe disease. A triad of tachycardia, fever, and leukocytosis are indicators for systemic toxicity and should alert the clinician of impending need of surgical intervention. Vague discomfort, and perianal irritation are common findings due to bowel movement frequency.

Imaging

Conventional x-rays can be useful in the rare cases of obstruction and/or perforation. The use of contrast studies allow for the identification of signs of severe inflammation with loss of haustral markings, although they have largely been replaced by more modern imaging modalities. Figure 66-3 shows distended colon with loss of haustral markings, concerning for toxic megacolon.

Abdominal computed tomography with oral and/or rectal contrast and CT enterography protocols are the modern imaging techniques of choice and provide additional information regarding the severity of disease. The presence of fistulas, phlegmon, mass, or abscess is an indication of a disease process other than UC as these findings may in fact represent other diagnoses such as Crohn, diverticulitis, and cancer.

MRI has the advantage of limiting ionizing radiation exposure, benefiting the young especially, and those that potentially may require multiple imaging studies over the years. Additionally, MRI has the capability of improved soft tissue differentiation. Particularly in the last decade, developments in MRI hardware and software has made this imaging modality an especially valuable tool in diagnosing and following patients with UC (Fig. 66-4).⁵¹

Ultrasound and nuclear medicine may provide complementary information in addition to CT and MRI but are currently used less commonly and are utilized only for specific situations.

Endoscopy

Endoscopic evaluation is the most useful tool in diagnosing UC. Often the first step is a flexible sigmoidoscopy or rigid proctoscopy especially in cases of acute flare, when a full colonoscopy may pose a significant risk of perforation. The macroscopic appearance of the colon through the endoscopy can often differentiate between UC and CD. Biopsies are taken, in addition to stool samples to rule out bacterial pathogens and ova/parasites.

Pathology

Macroscopic Appearance

UC always starts in the rectum and progresses proximally (Fig. 66-5). Although UC is a mucosal and submucosal disease, in the acute setting of severe disease, the colon wall can be inflamed transmurally, mimicking CD.

The mucosa is involved in a confluent manner, and unlike CD, fibrosis and strictures are uncommon (Table 66-2). Most importantly, the presence of stricturing disease in UC represents the potential for malignancy, which must be excluded. Superficial fissures are common, as are pseudopolyps. On occasion, the rectum can appear to be spared, especially if topical medication has been used through enema or suppository.

Microscopic Appearance

UC is an inflammatory process, thus neutrophil infiltration is common, and crypt abscesses form, which then coalesce to form ulcers (Table 66-2). Goblet cell mucin depletion and crypt distortion are common in UC. In long-standing UC, special attention must be given to the presence of dysplastic lesions, though these can be difficult to identify in cases of acute inflammation.

Differential Diagnosis

Bloody diarrhea can be a symptom of an infectious process. It is important to rule out pathogenic bacteria, parasites, and viruses. Clostridium difficile should specifically be excluded. Other infectious agents include Salmonella, Escherichia coli (0157:H7 strain), Camphylobacter, and Entamoeba.

In nearly 10% of the cases, it is impossible to definitively classify the colitis. Over time, a portion of these indeterminate colitis cases will separate as either Crohn’s or UC. However some will remain as indeterminate, especially if the serology assessment is inconclusive (for both ASCA and p-ANCA).⁵²

MANAGEMENT

Medical Management

Corticosteroids

Corticosteroids are frequently used as the primary rescue medication in treatment of acute flares of UC. Corticosteroid efficacy in inducing remission approaches 70%.^53,54 Lack of improvement or disease progression with corticosteroid treatment is followed by biologic agent treatment (as a secondary rescue medication) or surgery.⁵⁵ Overall, the use of corticosteroids is decreasing, largely due to the increase in the number and treatment effectiveness of the biologic agents available. Corticosteroids should not be used for maintenance of remission due to their side-effect profile. Topical corticosteroids such as budesonide or rectal preparations can be effective and have a reduced side-effect profile. However, these medications are not typically used in the acute setting. The side-effect profile of systemic corticosteroids includes osteoporosis, diabetes, glaucoma, and infections, among others. Long-term use of corticosteroids is associated with an increase in mortality.⁵⁶

Aminosalicylic Acid Compounds (5-ASA)

These compounds are most commonly used as first line medications in treating mild UC, and can be used in maintenance of remission. Concomitant use of oral and rectal preparation is effective in maintenance of UC remission.⁵⁷ Noncompliance with 5-ASA maintenance therapy is associated with a fivefold increase in disease recurrence.^58,59 Cases of nephrotoxicity have been reported with use of 5-ASA, though these cases are rare. Folate must be supplemented with treatment of 5-ASA as its absorption is impaired by 5-ASA.

Immunomodulators (Nonbiologic)

Cyclosporine can be used as an effective first-line or second-line rescue medication (e.g., after failed corticosteroid treatment) and is currently used at a limited number of centers. It is most commonly used as first-line treatment, and serves as an option for those patients recalcitrant to corticosteroid treatment.⁶⁰ Close monitoring of cyclosporine levels is necessary. Cyclosporine toxicity profile includes hypertension, renal failure, and infections.⁶¹

Mercaptopurine (6-MP). 6-MP and its prodrug azathioprine are thiopurine analogs and have been used extensively in the treatment of UC. They are superior to 5-ASA treatment alone and are often clinically used in combination with either 5-ASA or anti-TNF drugs in treating IBD.⁶² Skin cancers and lymphoma have been reported with thiopurine.⁶³ Severe infections have been reported with use of these medications.⁶⁴ Liver enzyme elevations, pancreatitis, and cholestasis have also been seen, and the most commonly reported side effects are headaches, hypersensitivity, and abdominal pain.

Methotrexate. This medication is rarely used in UC, more commonly used in CD, although its side-effect profile makes its use difficult even in CD. Hepatotoxicity bone marrow suppression and central nervous system side effects limit the use of this medication.⁶⁵

Biologic Immunomodulator Agents

Infliximab is the first anti-TNF medication that was used in treatment of CD in 1988, then shortly after became FDA approved for use in UC. Infliximab is chimeric mouse–human monoclonal antibody. Infliximab has been found to successfully induce remission in over 60% of the UC patients treated in the ACT 1 and 2 trials.⁶⁶ Extended follow-up of the patients in the trial found that 15% of patients who initially responded to infliximab subsequently had to discontinue therapy due to side effects or loss of efficacy.⁶⁷ Approximately 9% of patients continued to be treated with infliximab for 3 years. Adalimumab, certolizumab, and golimumab were then added to the list of the anti-TNF agents, a list that is continually growing. Both infliximab and golimumab have been efficacious in inducing and maintaining remission in UC patients.^66,68,69 Among the biologic agents’ side-effect profile, infection remains a persistent concern.^70,71 The data regarding malignancy risk with anti-TNF agents are mixed; there appears to be an increased risk of lymphoma.⁷²

SURGERY

Indications of Surgical Intervention

2 Approximately 20% to 30% of patients that develop UC will ultimately need an operation.^73,74 Indications for surgery include fulminant colitis, toxic megacolon, uncontrolled bleeding, neoplasia, recalcitrance to medical management, unrelenting extraintestinal manifestations, and development of significant side effects of the treatment medications.

Toxic Megacolon

This is a life-threatening, surgical emergency. Toxic megacolon (Fig. 66-3) is not specific to UC; it can occur in cases of infectious collidities (C. difficile, Shigella, Salmonella, etc.), or ischemic colitis. Patients present with systemic toxicity, heralded by high fever, tachycardia, severe abdominal pain, leukocytosis or leukopenia, and a distended, thickened colon. Immediate, aggressive resuscitation and broad-spectrum antibiotics should be started, and all opiates, and antidiarrheal agents should be ceased. An infectious cause should immediately be ruled out as treatment for UC includes corticosteroids, treatment which would be detrimental to the management of infectious colidities. Toxic megacolon is seen most often in new cases of UC, but acute exacerbations of chronic UC can also lead to toxic megacolon. Nonoperative treatment can be attempted, however, any signs of instability, worsening of the clinical condition, or lack of improvement within 3 to 5 days should be followed by prompt operative treatment. In one study, nearly half of all patients with UC treated nonoperatively subsequently required surgery, most under urgent or emergent circumstances.⁷⁵ In the contemporary era of biologic options, failure can occur in up to 30% in the short term (within 30 days), and it is unclear in the long term how many of these patients will need a colectomy, and under what clinical circumstances.⁷⁶

Fulminant Colitis

Patients presenting with tachycardia, fever, and surgical tenderness need aggressive resuscitation. Intravenous steroids should be started promptly, and the patients should be offered surgical treatment immediately if their condition deteriorates. In general terms, patients should improve within 3 to 5 days on medical therapy. Early surgical intervention has shown a clear decrease in the mortality rate in patients failing medical therapy.^77,78

Uncontrolled Bleeding

Less than 5% of the patients affected with UC have life-threatening bleeding. In this rare circumstance an abdominal colectomy is necessary. These cases represent approximately 10% of the emergent colectomies performed in UC.⁷⁹

Carcinoma/Dysplasia

Stage for stage, cancer in the setting of UC has the same prognosis, however, cancer is often detected at a later stage in UC. Nearly 20% of the patients with colorectal carcinoma in the setting of UC are unresectable at the time of diagnosis.^80,81 The highest risk of colorectal cancer (CRC) is seen in those UC patients with a long history of pancolitis, a risk that accrues after 8 to 10 years of UC. The absolute risk of CRC development is less than 8% after 30 years of UC.⁸² Patients with over 8 years of UC, particularly with extensive colitis, should undergo colonoscopy yearly, or every 2 years.⁸³ It is often difficult to identify dysplasia in inflamed colon, and thus at the time of colonoscopy, random biopsies are obtained in addition to sampling any polyps, adenomas, or dysplasia-associated mass or lesions (DALM). Undetected synchronous cancer can coexist in areas of low- and high-grade dysplasia.⁸⁴ Thus, high-grade dysplasia, nonadenoma-like DALMs, and multifocal dysplasia are indications for proctocolectomy, though there is ongoing research in this area.

Recalcitrance to Medical Treatment

Some patients do not respond fully to medical treatment, and either have persistent symptoms despite maximal medical treatment, or respond only to corticosteroids, and are thus subject to the side effects of long-term corticosteroid treatment.

Extracolonic Manifestations

3 Proctocolectomy can help with some of the extracolonic manifestations, though PSC, pyoderma gangrenosum, and ankylosing spondylitis specifically do not respond to surgery. Proctocolectomy has shown to help with erythema nodosum, and small/large joints arthralgia, though the role of colectomy is not completely defined in the treatment of extraintestinal manifestations of UC.⁸⁵

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