Is Ursodeoxycholic Acid Effective for the Treatment of Primary Sclerosing Cholangitis?
Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease characterized by inflammation and obliterative fibrosis of the intrahepatic and extrahepatic biliary tree. The causes for the initial bile duct injury remain largely unknown. Proposed mechanisms include genetic predisposition, immunologic abnormalities, bacterial proteins from the enterohepatic circulation, chronic viral infections, and ischemia. Progressive disease, however, is thought to be due to the development of cholestasis and retention of hydrophobic bile salts within the liver. Bile salt–mediated injury to cholangiocytes and hepatocytes in turn results in the development of fibrosis, cirrhosis, and, ultimately, end-stage liver disease. The course of PSC in any one individual is unpredictable—bacterial infections and development of a dominant stricture can accelerate disease progression—but worldwide the median survival of patients with PSC has been documented to be 10 to 12 years.1
There is no commonly accepted medical treatment for PSC. The interest in ursodeoxycholic acid (UDCA) as therapy of PSC stems from its successful use in other cholestatic diseases, specifically primary biliary cirrhosis (PBC). The rationale for UDCA use in PSC is the same as in PBC (see Question 31 for discussion). Both PBC and PSC are cholestatic disorders in which hydrophobic bile acids retained within the liver are responsible for progressive disease. As a hydrophilic bile acid, UDCA is the least effective detergent and therefore the least toxic constituent of the bile acid pool. When given in pharmacologic doses, UDCA becomes proportionately the most common bile acid in the enterohepatic circulation, thus decreasing the overall toxicity of the bile acid pool. By stimulating bile flow it also increases the clearance of toxic hydrophobic bile acids from the liver. Finally, UDCA has been shown to modulate both the proapoptotic and antiapoptotic intracellular pathways, thus decreasing the bile acid–induced hepatocyte and cholangiocyte injury.
The first study to evaluate the effectiveness of UDCA in PSC was an open label trial in which 12 subjects received UDCA 10 mg/kg/d for 30 months.1 Published in 1991, it reported improvements in both liver enzymes and symptoms (histology was not evaluated) and encouraged initiation of larger randomized controlled trials. The results from 6 such trials (total of 261 subjects) using varying amounts of UDCA (10 mg/kg/d, 13 to 15 mg/kg/d, and fixed doses of 600 and 750 mg/d) were published during the 1990s. Although these trials confirmed the beneficial effect of UDCA on biochemical liver tests, none showed improvements in symptoms or (more importantly) histology.2 Further, even the largest trial (105 subjects randomized) was insufficiently powered to adequately measure UDCA effect on survival. The same disappointing results were obtained by a meta-analysis of 5 of the studies (183 subjects): when compared to placebo or no treatment, UDCA significantly improved biochemical liver tests including bilirubin and transaminases, but not albumin; however, UDCA however was not shown to significantly reduce the risk of death, frequency of treatment failure (liver transplantation, varices, ascites, encephalopathy), liver histologic deterioration, or cholangiographic deterioration.3
The meta-analysis as well as some of the individual studies was criticized because a significant proportion of the subjects received UDCA at doses 10 mg/kg/d. As indicated previously (see Question 31 for discussion) the optimal dose of UDCA in PBC is thought to be 13 to 15 mg/kg/d. Experience in other cholestatic diseases, eg, cystic fibrosis associated cholestasis, suggests that even higher doses may be required for UDCA to be effective.1 The rationale for use of higher doses of UDCA is based on an observation that with worsening cholestasis the UDCA enrichment of the bile acid pool declined and that higher doses of UDCA were required to achieve the same level of enrichment.4 A recent study of the biliary bile acid composition of 56 patients with PSC, however, showed that biliary enrichment with UDCA increases with increasing dose but that the effect may plateau at 22 to 25 mg/kg/d with enrichment of 58.6%.1 Thus, the optimal dose of UDCA in PSC has yet to be determined.
Three studies have explored the use of UDCA at doses as high as 30 mg/kg/d. In a pilot study, 30 subjects with PSC were treated with UDCA 25 to 30 mg/kg/d for 1 year. Liver biochemistries improved significantly and when these were used to determine the subject prognosis (the Mayo Natural History Model for PSC can be found at http://www.mayoclinic.org/gi-rst/models.html), the expected mortality at 4 years would have declined from 17% to 11%.1 The second trial randomized 26 subjects to UDCA 20 mg/kg/d or placebo. After 2 years there was significant improvement in liver biochemistries, cholangiographic appearance of the biliary tree, and liver fibrosis as assessed by disease staging.4 The largest recent trial compared UDCA 17 to 23 mg/kg/d and placebo in 219 subjects for up to 5 years. While there were fewer deaths, liver transplantations, and cholangiocarcinomas in the UDCA-treated group, the differences when compared to placebo were not statistically significant.5 Thus, in spite of the relatively large number of subjects recruited, the study remained underpowered. The trend toward survival benefit in the UDCA-treated group, however, is encouraging, especially if, as seems likely from previous discussion, the dose of UDCA was too low to adequately enrich the bile acid pool. Currently, a National Institutes of Health–sponsored, multicenter placebo-controlled trial of UDCA 25 to 30 mg/kg/d is underway and by 2010 should answer the question of whether UDCA should be used in PSC.
In summary, UDCA has been shown to improve biochemical abnormalities in patients with PSC. Since this effect is irrespective of the dose, I usually start all my patients with PSC on 13 to 15 mg/kg/d (the dose most frequently used in controlled trials). To date, however, there is no evidence that UDCA, whatever the dose, improves survival or delays time to liver transplantation. While higher doses of UDCA ultimately may be shown to improve histology and cholangiographic appearance of bile ducts (20 mg/kg/d), improve prognosis as calculated by Mayo PSC model (25 to 30 g/kg/d), or decrease the frequency of death, transplantation, and cholangiocarcinoma (17 to 23 mg/kg/d), the study proving that has not yet been completed. Thus, at this time I cannot recommend the routine use of high-dose UDCA in patients with PSC.
1. Sandhu BS, Luketic VA. Management of primary sclerosing cholangitis. Gastroneterol Hepatol. 2006;2:843-849.
2. Cullen SN, Chapman RW. The medical management of primary sclerosing cholangitis. Semin Liver Dis. 2006;26:52-61.
3. Chen W, Gluud C. Bile acids for primary sclerosing cholangitis (review). Cochrane Database Syst Rev. 2004;3:CD004036.
4. Mitchell SA, Bansi DS, Hunt N, et al. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology. 2001;121:900-907.
5. Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129:1464-1472.