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Primary sclerosing cholangitis: Inflammatory bowel disease and colorectal cancer

Primary sclerosing cholangitis: Inflammatory bowel disease and colorectal cancer
Author:
Kris V Kowdley, MD, FAASLD, FACP, FACG, FASGE, AGAF
Section Editor:
J Thomas Lamont, MD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Dec 2022. | This topic last updated: Oct 04, 2022.

INTRODUCTION — Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. The majority of patients with PSC have underlying inflammatory bowel disease (IBD). Patients with concurrent PSC and IBD have an increased risk of colorectal cancer (CRC) [1-6]. This topic review will focus on the epidemiology, pathogenesis, clinical features, diagnosis, and management of IBD in patients with PSC in addition to the risk of CRC and guidelines for CRC surveillance. CRC surveillance in patients with IBD is presented separately. (See "Surveillance and management of dysplasia in patients with inflammatory bowel disease".)

INFLAMMATORY BOWEL DISEASE

Epidemiology — The prevalence of inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) approaches 90 percent [7,8]. Ulcerative colitis (UC), Crohn disease (CD), and indeterminate colitis of the colon account for 80, 10, and 10 percent, respectively [9]. In a study of patients with UC who underwent proctocolectomy with ileal pouch-anal anastomosis (IPAA), patients who developed pouchitis were more likely have a history of PSC [10] (See "Primary sclerosing cholangitis: Epidemiology and pathogenesis", section on 'PSC and inflammatory bowel disease'.)

Clinical manifestations

Clinical features — Colitis in patients with PSC often presents at an earlier age as compared with patients with IBD alone [11]. The colitis usually has a mild or quiescent course. Patients are often asymptomatic but in rare cases present with rectal bleeding. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Colitis' and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults", section on 'Clinical features'.)

Following colectomy, patients can present with stomal and peristomal variceal bleeding secondary to portal hypertension associated with PSC. Patients with proctocolectomy with ileal pouch anal anastomosis also have an increased risk of pouchitis [9,12,13]. Symptoms of pouchitis include increased stool frequency, urgency, abdominal cramps, pelvic pressure, tenesmus, and night-time fecal seepage to incontinence. (See "Ileostomy or colostomy care and complications", section on 'Stomal bleeding' and "Pouchitis: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

The course of colitis following liver transplantation for PSC is variable. Although the colitis may remain quiescent in some patients, other patients may have severe symptoms (10 or more stools per day with severe cramps and continuous bleeding) despite the immunosuppression used for the transplant [14-16]. (See "Primary sclerosing cholangitis in adults: Management", section on 'Inflammatory bowel disease' and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Colitis'.)

Endoscopic features — IBD in patients with PSC often involves the entire colon. Less often the colitis is right-sided with relative sparing of the rectum or there is terminal ileal involvement [9]. Endoscopic features of colitis are non-specific and include erythema, granularity of the mucosa, petechiae, exudates, edema, and erosions. The endoscopic appearance of the colon may be normal even in the presence of active underlying colonic inflammation [17].

Diagnosis — Given the high prevalence of IBD in patients with PSC, colonoscopy is recommended at the time of initial diagnosis of PSC regardless of the presence of symptoms of colitis (eg, rectal bleeding, diarrhea). IBD in PSC does not have any characteristic, endoscopic, or histologic features. As with all cases of IBD, the diagnosis requires evidence of colonic inflammation and chronic changes on biopsy. Since these features are not specific for UC or CD, establishing the diagnosis also requires the exclusion of other causes of colitis by history, laboratory studies, and by biopsies of the colon obtained on colonoscopy [18]. Random biopsies of the colon should be obtained even if the mucosa appears endoscopically normal as a significant number of patients may not have symptoms or endoscopic evidence of colitis [8]. The evaluation to exclude other causes of colitis is discussed in detail separately. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Evaluation'.)

Differential diagnosis — The differential diagnosis of IBD includes other causes of colitis. This includes infectious, radiation, diversion, medication-induced colitis, and diverticular colitis. These can be differentiated from IBD by history, laboratory studies, and biopsies of the colon obtained on colonoscopy. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Differential diagnosis' and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Evaluation'.)

Management — The management of IBD in patients with concurrent PSC is the same as in patients with IBD alone and is discussed in detail, separately. However, patients undergoing colectomy should be informed of surgery-related complications including a higher risk of pouchitis and peristomal varices, and patients should be monitored closely for hepatic decompensation following surgery. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis" and "Management of the hospitalized adult patient with severe ulcerative colitis" and "Management of moderate to severe ulcerative colitis in adults" and "Overview of the medical management of mild (low risk) Crohn disease in adults" and "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)

COLORECTAL CANCER

Epidemiology — Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC) and colonic dysplasia [19,20]. Among patients with IBD, an increased risk of CRC in patients with ulcerative colitis (UC) complicated by PSC has been observed in a number of studies. In one case-control study, the cumulative absolute risk of CRC or dysplasia after 10, 20, and 25 years of colitis in patients with PSC and UC was significantly higher as compared with patients with UC alone (9, 31, and 50 percent versus 2, 5, and 10 percent, respectively) [2]. However, the CRC risk in patients with concomitant Crohn disease (CD) and PSC is unclear and results have been conflicting [1-3,21-24]. This was illustrated in a 2016 meta-analysis that included 16 observational studies. The meta-analysis concluded that the CRC risk was increased by approximately threefold in patients with PSC and IBD as compared with those with IBD alone (odds ratio [OR] 3.24; 95% CI 2.14-4.9) [25]. When the results were stratified by IBD subtype, the presence of PSC in patients with UC but not CD was associated with an increased risk of colorectal neoplasia and CRC. However, only three studies in the meta-analysis included patients with CD and PSC. Additional studies are needed to confirm these findings.

Several studies have suggested that the risk of CRC is increased following liver transplantation, however, the CRC risk may be related to the duration of IBD and not the transplant itself [26]. In a meta-analysis of 16 cohort studies that included 1017 patients, the incidence of CRC in patients with PSC-IBD and an intact colon at the time of liver transplantation was 13.5 per 1000 person-years. A long duration of IBD and extensive colitis were identified as risk factors for CRC [14,27].(See "Primary sclerosing cholangitis in adults: Management", section on 'Liver transplantation'.)

Pathogenesis — The mechanism by which concomitant PSC increases the risk of colonic neoplasia in patients with IBD is unknown. It has been hypothesized that this is due to the increased concentration of secondary bile acids in the proximal colon [3]. Secondary bile acids (eg, deoxycholic acid and lithocholic) are cytotoxic to colonic epithelial cells, induce hyperproliferation, and may also influence the development of sporadic colonic adenomas and CRC [28-32]. In support of this hypothesis is the observation that patients with UC, colonic dysplasia, or CRChave higher fecal bile acid concentrations than those without colonic neoplasia [33]. Furthermore, IBD in PSC tends to be characterized by rectal sparing and backwash ileitis, suggesting that epithelial injury may be relatively more severe in the proximal colon [9]. PSC patients also have a disproportionately higher likelihood of developing CRC proximal to the splenic flexure [3,21].

Chronic inflammatory activity may be the driver of carcinogenesis. Colitis in patients with PSC can have low endoscopic activity, which may mask an active histologic inflammation that possibly contributes to an increased risk of malignancy [17]. (See 'Endoscopic features' above.)

Clinical features — CRC in patients with concomitant PSC and IBD is more often right-sided and is diagnosed earlier as compared with sporadic CRC with a median age at diagnosis of 49 years [22]. Most patients are asymptomatic and are diagnosed as a result of CRC screening. Less often patients present with symptoms of CRC, including hematochezia or melena and abdominal pain, otherwise unexplained iron deficiency anemia, and/or a change in bowel habits. (See 'Diagnosis' above and 'Colorectal cancer screening' below.)

Diagnosis — The diagnosis of CRC should be suspected in PSC patients with IBD and symptoms of hematochezia, melena, abdominal pain, otherwise unexplained iron deficiency anemia, and/or a change in bowel habits. However, most patients are asymptomatic and are detected on CRC screening. The diagnosis of CRC is established by examination of tissue biopsies obtained on colonoscopy. The diagnosis, differential diagnosis, and staging of CRC are discussed in detail, separately. (See "Clinical presentation, diagnosis, and staging of colorectal cancer".)

Management — The management of CRC in PSC associated with IBD does not differ from other patients with CRC. However, patients undergoing colectomy should be informed of surgery-related complications, including a higher risk of pouchitis and peristomal varices, and patients should be monitored closely for hepatic decompensation following surgery. (See "Overview of the management of primary colon cancer" and "Primary sclerosing cholangitis in adults: Management", section on 'Proctocolectomy'.)

Prevention

Colorectal cancer screening — The goal of CRC screening is to detect IBD early and to detect colorectal neoplasia at an earlier stage in those with established IBD. Evidence to guide screening intervals is lacking and guidelines are largely based on consensus opinion. Our approach is largely consistent with recommendations of the American Gastroenterological Association [34], the American College of Gastroenterology [35], and the British Society of Gastroenterology [36].

PSC and IBD — Due to the high risk of colonic dysplasia in PSC patients with IBD and right-sided predominance of CRCs, surveillance with colonoscopy should be performed annually [18,37]. The management of colonic dysplasia in PSC patients with IBD does not differ from other patients with IBD and is discussed in detail, separately. (See "Surveillance and management of dysplasia in patients with inflammatory bowel disease", section on 'Patient selection and timing'.)

PSC without IBD — In patients with PSC without IBD, we perform surveillance colonoscopy every five years [38].

Chemoprevention — Although several agents have been evaluated for prevention of CRC in PSC patients with IBD, none have conclusively been demonstrated to decrease the risk of CRC. (See "Surveillance and management of dysplasia in patients with inflammatory bowel disease", section on 'Chemoprevention'.)

Ursodeoxycholic acid — Ursodeoxycholic acid (UDCA) is not recommended for chemoprevention of CRC in patients with PSC [18]. It was hypothesized that UDCA, a hydrophilic bile acid, may have a chemoprotective effect on CRC by reducing the colonic concentration of toxic secondary bile acids [28,31,33,39-41]. UDCA also inhibits proliferation of colon cancer cell lines in animal models [29,39,40,42]. UDCA slows intestinal cell proliferation by sustained hyperphosphorylation of extracellular signal–regulated 1 kinase, which in turn slows down the cell cycle and reduces expression of insulin receptor substrate 1 protein [43]. However, results from clinical studies have been conflicting and high-dose UDCA is associated with significant adverse effects [44]. (See "Primary sclerosing cholangitis in adults: Management", section on 'Ursodeoxycholic acid'.)

A placebo-controlled trial included 52 patients with PSC and UC who had previously participated in a controlled trial of UDCA (13 to 15 mg/kg body weight per day in divided doses) for PSC [45,46]. The average age of participants was 43, the majority had pancolitis, and the median duration of ulcerative colitis was 15 years. During follow-up, colorectal neoplasia developed in three patients who had received UDCA compared with eight initially assigned to placebo (10 versus 35 percent, relative risk 0.26, 95% CI 0.06-0.92).

Conflicting results were obtained in a nested cohort study using data from a double-blind, placebo-controlled trial of high-dose UDCA (28 to 30 mg/kg/day) in which 56 patients were followed for a total of 235 patient-years [47]. In this study, patients who received high doses of UDCA had a significantly increased risk of developing colorectal neoplasia (dysplasia or cancer) compared to placebo (hazard ratio 4.4, 95% CI 1.3-20.1).

Folate — Few studies have evaluated the effect of folate/folic acid supplementation on the development of colonic neoplasia in PSC patients with IBD and their role in the prevention of CRC is unclear [3,48]. In one observational study that included 98 patients with UC, of whom 30 percent developed colorectal neoplasia, the relative risk of developing colonic dysplasia or cancer was not significantly lower in patients who received folate supplementation (0.47, 95% CI 0.18-1.20) [48].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer" and "Society guideline links: Primary sclerosing cholangitis".)

SUMMARY AND RECOMMENDATIONS

The prevalence of inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) approaches 90 percent. Ulcerative colitis (UC), Crohn disease (CD), and indeterminate colitis account for 80, 10, and 10 percent, respectively. (See 'Inflammatory bowel disease' above and 'Epidemiology' above.)

Colitis in patients with PSC presents earlier in life as compared with patients with IBD alone. IBD in PSC patients usually has a mild or quiescent course. Patients are often asymptomatic, but in rare cases, present with rectal bleeding. (See 'Clinical features' above.)

PSC patients with IBD often have a pancolitis. Less often, the colitis is right sided with relative sparing of the rectum or there is terminal ileal involvement. The colon may also be normal in endoscopic appearance even in the presence of active underlying inflammation. (See 'Endoscopic features' above.)

Given the high prevalence of IBD in patients with PSC, colonoscopy should be performed at the time of initial diagnosis of PSC regardless of the presence of symptoms of colitis (eg, rectal bleeding, diarrhea). IBD in PSC does not have any characteristic endoscopic or histologic features. The diagnosis requires evidence of colonic inflammation and chronic changes on biopsy and exclusion of other causes of colitis. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Patients with PSC and IBD have an approximately threefold increase in risk of CRC as compared with patients with IBD alone. Among patients with IBD, an increased risk of CRC in PSC patients with concomitant UC has been demonstrated in multiple studies, however, the CRC risk in patients with concomitant CD is unclear. (See 'Epidemiology' above.)

CRC in patients with concomitant PSC and IBD is more often right sided and is diagnosed earlier as compared with sporadic CRC with a median age at diagnosis of 49 years. Most patients are asymptomatic and CRCs are detected on screening. (See 'Clinical features' above.)

The management of CRC in PSC associated with IBD does not differ from other patients with CRC. However, patients undergoing colectomy should be informed of surgery-related complications including a higher risk of pouchitis and peristomal varices, and patients should be monitored closely for hepatic decompensation following proctocolectomy. (See 'Management' above.)

Although several agents have been evaluated for prevention of CRC in patients with concomitant PSC and IBD, none have conclusively been demonstrated to decrease the risk of CRC. (See 'Chemoprevention' above.)

ACKNOWLEDGMENT — We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.

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