Primary sclerosing cholangitis (PSC) is an uncommon chronic cholestatic liver disease characterized by an obliterating inflammatory fibrosis of the intrahepatic and extrahepatic bile ducts.1 It usually progresses to biliary cirrhosis, portal hypertension, and eventually hepatic failure, although PSC is often complicated by the development of cholangiocarcinoma, which develops in 10%–30% of patients.1 PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodeoxycholic acid. Effective medical management of PSC has been hindered by uncertainty regarding the pathogenesis of the disease and the factors responsible for its progression. Treatments which are efficacious in other cholestatic liver diseases have been tested in PSC with a limited degree of success. Ursodeoxycholic acid (UDCA) is a hydrophilic, dihydroxy bile acid which is increasingly accepted as an effective treatment of primary biliary cirrhosis (PBC). UDCA exerts a number of effects, all of which may be beneficial in chronic cholestasis: a choleretic effect by increasing bile flow; a direct cytoprotective effect; an indirect cytoprotective effect by displacement of the more hepatotoxic endogenous hydrophobic bile acids from the bile acid pool; an immunomodulatory effect; and finally an inhibitory effect on apoptosis.2 The relative importance of these different actions in alleviating cholestasis remains unclear. In addition, UDCA has been shown to inhibit growth stimulated in vitro by deoxycholic acid in several tumor cell lines including colon cancer.3 This has led to the suggestion that UDCA may reduce the risk of dysplasia and cancer in the biliary tree and/or the colon. UDCA has, therefore, also been investigated as a potential candidate for the treatment of PSC (Table 1). Small pilot trials of UDCA in the early 1990s demonstrated biochemical, and in some cases histological, improvement in patients with PSC, using doses of 10–15 mg/kg body weight/day.4-7 A more substantial trial was published by Lindor et al. in 1997,8 recruiting 105 patients in a double-blind placebo-controlled trial of 13–15 mg/kg of UDCA for 2 years. The initial results indicated improvement in serum liver tests but not in symptoms, and no improvement in liver histology as evaluated by disease stage.6 However, a recent reassessment showed a trend toward improved survival free of transplant in the treated group.9 Higher doses of UDCA were then studied on the grounds that larger doses might be necessary to provide sufficient enrichment of the bile acid pool in the context of cholestasis, and that these doses might also enhance a potential immunomodulatory effect of the drug.10 The Scandinavian UDCA trial in a group of 219 patients with PSC using a dose of 17–23 mg/kg/day for 5 years demonstrated a trend toward increased survival in the UDCA-treated group when compared with placebo.11 However, despite the relatively large number of patients recruited, the number of significant endpoints (liver transplantation or death) were fewer than expected, and the study proved to be insufficiently powered to produce a statistically significant result. In comparison to other studies, the biochemical response was unexpectedly poor in this trial, which prompted questions about adequate compliance in a part of the study population. Subsequently, two pilot studies of higher doses of UDCA of 25–30 mg/kg/day with small patient groups were performed.10, 11 Both studies, using the surrogate endpoint of Mayo Risk Score, suggested that the higher dose might improve survival and that high-dose UDCA was well tolerated.10, 11 In the light of these promising reports, a multicenter, long-term, double-blind controlled study enrolled 150 North American patients with PSC who were treated using high doses (28–30 mg/kg/day) of UDCA; the results are presented in this issue of HEPATOLOGY.9 Surprisingly, after 6 years, the study had to be terminated because of an enhanced risk in the UDCA treatment group for death or liver transplantation and serious adverse events, particularly in patients with advanced disease despite the fact that serum biochemical features improved in the whole UDCA group.7 As the authors point out, the worse outcome in the high-dose UDCA group was completely unanticipated, because all the previous studies in PSC and PBC had demonstrated UDCA to be safe. The study recruited a number of patients to both groups with established cirrhosis and varices, i.e., advanced liver disease, and primary endpoints were predictably higher in these patients. How can the apparent deleterious effect of the higher dose of UDCA, namely 28–30 mg/kg/day, in patients with PSC be explained? As the authors speculate, it may reflect a direct toxic effect of high-dose UDCA that causes hepatocyte necrosis in patients with advanced PSC who have downstream biliary obstruction due to strictures.14 Alternatively, increased levels of toxic bile acids produced from high levels of UDCA in the right colon may be an alternative explanation.15 Further analysis of the serum bile acid profile in the UDCA group should help clarify this important issue. Thus, the role for UDCA in slowing the progression of PSC-related liver disease is as-yet unclear and indeed, high-dose UDCA (28–30 mg/kg/day) may be harmful. However, on current evidence it would be premature to exclude bile acids as therapy for PSC. The novel bile acid 24-norursodeoxycholic acid has unique effects on biliary physiology which are potentially beneficial in PSC, involving the stimulation of bicarbonate-rich bile flow and concomitant flushing of injured bile ducts and by the induction of detoxification and elimination routes for toxic bile acids.16 Subsequently, 24-norursodeoxycholic acid, unlike UDCA, has been shown to have antifibrotic, anti-inflammatory, and antiproliferative effects in the multidrug resistance protein 2–null (Mdr2−/−) mouse model of cholangitis and biliary fibrosis.17 Human studies in cholestatic liver disease are currently in progress, and they offer hope for the future treatment of PSC. Recent retrospective studies have suggested that low-dose UDCA (10–15 mg/kg/day) may have a chemoprotective role in the prevention of the increased colonic neoplasia in patients with inflammatory bowel disease associated with underlying PSC. A cross-sectional study of 59 patients with PSC with ulcerative colitis (UC) who underwent colonoscopic surveillance found a significantly reduced risk of colonic dysplasia in patients taking UDCA, although in comparison to an exceptionally high rate of dysplasia in the control group.18 A historical cohort study compared 28 patients with PSC under UDCA treatment with UC to 92 patients with PSC with UC who were not treated with UDCA and found a trend toward a lower risk of colonic dysplasia and neoplasia under UDCA treatment and a significantly lower mortality.19 A third study followed 52 patients with PSC and UC for 355 patient-years who participated in a randomized, placebo-controlled UDCA trial that showed a significant reduction in the relative risk for UDCA-treated patients to develop colorectal dysplasia or carcinoma.20 The evidence for a beneficial effect of UDCA on the risk to develop cholangiocarcinoma is limited and comes from observational studies.21, 22 How then to proceed in the future? Multicenter randomized controlled trials remain mandatory to evaluate survival in patients with PSC. There are two ways to assess survival in patients who have a slowly progressive disease: either a large sample size and/or a long duration of therapy. In light of the difficulties in carrying out these trials in an uncommon disease such as PSC, pilot studies remain crucial. These need to be improved by the careful selection of phenotypically pure patients, excluding for example patients with immunoglobulin G4–associated cholangiopathy, who may follow a different natural history. In the past, surrogate markers such as standard liver function tests and liver histology have proved to be inadequate in pilot studies in PSC. In the light of this failure, new surrogate markers of efficacy need to be assessed and should include serum markers of fibrosis, and possibly prospective magnetic resonance cholangiopancreatography studies. Prognostic models such as the Mayo Risk Score may provide a surrogate measure of survival, but in general have been less reliable in PSC than in PBC. Clearly, despite the difficulties, there is a need to reevaluate old therapies such as UDCA in low to moderate doses and to assess new therapies such as the novel bile acid 24-norursodeoxycholic acid to prevent the progression of hepatobiliary disease and provide chemoprotection against biliary and colonic malignancy.
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