Perspectives in clinical gastroenterology and hepatology
Primary Sclerosing Cholangitis: Diagnosis, Prognosis, and Management

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Primary sclerosing cholangitis (PSC) is a chronic immune-mediated disease of the liver of unclear etiology, characterized by chronic inflammation and fibrosis of bile ducts. It primarily affects middle-aged men and is associated with 4-fold increased mortality as compared with an age- and sex-matched population. Progressive biliary and hepatic damage results in portal hypertension and hepatic failure in a significant majority of patients over a 10- to 15-year period from the initial diagnosis. In addition, PSC confers a markedly increased risk of hepatobiliary cancer, including cholangiocarcinoma and gallbladder cancer, as compared with the general population, and cancer is the leading cause of mortality in patients with PSC. It is associated with inflammatory bowel disease in 70% of patients and increases the risk of colorectal cancer almost 10-fold. Despite significant research efforts in this field, the pathogenic mechanisms of PSC are still incompletely understood, although growing evidence supports the role of genetic and immunologic factors. There are no proven medical therapies that alter the natural course of the disease. Thus, liver transplantation is the only available treatment for patients with advanced PSC, with excellent outcomes in this population.

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Epidemiology and Risk Factors

The incidence of PSC is estimated at 1 per 100,000 population, with evidence that the incidence is increasing over time based on a recent meta-analysis of population-based studies from Northern Europe, the United Kingdom, the United States, and Canada.9 The highest annual incidence is reported in Norway (1.3 per 100,000), with a prevalence of 8.5 per 100,000,10 and in this population PSC is the leading indication for LT.11 In the United States, the overall age- and sex-adjusted incidence of PSC

Pathogenesis

The pathogenesis of PSC continues to be elusive, and is reviewed in detail elsewhere.16 It is believed to be a complex immune-mediated disease rather than a true autoimmune disease given the lack of classic features (male rather than female predisposition, lack of response to immunosuppressive medications, and lack of highly selective and pathogenic auto-antibodies).16 The most commonly accepted theory is that in a genetically predisposed individual, an initial insult to cholangiocytes through

Clinical Manifestations

The majority of patients (44%–56%) are asymptomatic at the time of diagnosis,1, 6 and the discovery of PSC increasingly is based on the investigation of abnormal serum liver tests and/or the incidental discovery of intrahepatic bile duct dilatation on cross-sectional imaging. Notably, up to 17% of asymptomatic patients may have cirrhosis on liver biopsy at the time of diagnosis.27 In asymptomatic patients, the estimated survival without decompensated cirrhosis at 7 years is 75% in comparison

Small-Duct Primary Sclerosing Cholangitis

Small-duct PSC is diagnosed when patients have clinical, biochemical, and histologic features of PSC in the setting of a normal cholangiogram (Figure 2B). This represents approximately 11% to 17% of patients with PSC based on population-based studies.1, 12 The diagnosis is difficult to confirm in the absence of IBD. Long-term follow-up studies have shown that approximately 25% of subjects progress to large-duct PSC over time. These patients have significantly longer transplantation-free

Complications and Associated Conditions

Because of the markedly increased risk of cancer in patients with PSC, it should be considered a premalignant condition that warrants close surveillance.

Medical Management

To date, there are no medical therapies that have been proven to alter the natural course of PSC. The most comprehensively studied agent is ursodeoxycholic acid (UDCA), 7-β-epimer of chenodeoxycholic acid that improves hepatobiliary secretion, is hepatoprotective, has immunomodulatory properties, and is very effective in the management of primary biliary cirrhosis.84 An initial placebo-controlled, randomized, controlled trial showed that standard-dose UDCA (13–15 mg/kg/d) was no superior to

Prognosis

PSC is an insidious and slowly progressive disease without effective medical therapy. Although the median time from diagnosis to death or LT is 12 years,105 there is significant interpatient variability in prognosis depending on the stage of disease at diagnosis as well as inherent differences in the phenotype of PSC (small duct vs large duct). Several prognostic models for PSC have been described to determine risk factors for disease progression and the best time for LT.2, 3, 7, 45, 106, 107

Conclusions

PSC is a chronic cholestatic liver disease that impacts survival and quality of life of affected patients. Complications related to chronic cholestasis and portal hypertension from progressive disease as well as hepatobiliary and colorectal cancer occur in a significant number of patients. To date, no medical therapies have been shown to modify the natural course of PSC except for LT.

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    Conflicts of interest The authors disclose no conflicts.

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