Clinical

High-dose ursodeoxycholic acid may worsen outcome of cholangitis

Last Updated: 2009-08-26 9:03:21 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Long-term, high-dose ursodeoxycholic acid (UDCA) should not be used for treatment of primary sclerosing cholangitis because of the increased risk of severe adverse effects, including death.

Primary sclerosing cholangitis is a rare, chronic disease that usually progresses to biliary cirrhosis, portal hypertension, and liver failure over a 10- to 15-year period. There is no approved treatment, but studies of UDCA at doses of 13 to 23 mg/kg/day have indicated some benefit that often did not achieve statistical significance, lead author Dr. Keith D. Lindor and associates note in the their paper in the September issue of Hepatology.

Dr. Lindor from the Mayo Clinic in Rochester, Minnesota, and his team conducted a double-blind, randomized trial in 150 adults with primary sclerosing cholangitis. Seventy-six patients were assigned to high dose UDCA (28-30 mg/kg/day) and 74 were assigned to placebo.

The plan was to follow the patients for 5 years and then perform liver biopsy and cholangiography. The trial was stopped after 6 years due to futility, however.

Even though liver enzyme levels declined with treatment, other primary clinical endpoints - development of cirrhosis, esophageal and/or gastric varices, cholangiocarcinoma, liver transplantation, or death - tended to worsen, the authors report.

By the close of the trial, the intent-to-treat analysis revealed that 39% of the UDCA group and 26% of the placebo group had reached at least one of the endpoints. Serious adverse events were also more common in the active treatment group (63% vs 37%, p < 0.01)

After adjusting for confounding variables, patients treated with UDCA were at nearly triple the risk of reaching a primary endpoint (hazard ratio 2.73, p = 0.004).

It's possible, Dr. Lindor and associates suggest, that the higher doses allowed unabsorbed UDCA to enter the colon, where it was modified into hepatotoxic bile acids. Another possibility is that the drug may prevent apoptosis, thereby contributing to fibrogenesis and advanced liver disease.

"UDCA at a dose of 25 to 30 mg/kg/day for patients with of primary sclerosing cholangitis should not be used," the authors warn, adding, "There is no treatment that can be recommended at this time, and only therapy in the context of prospective trials should be considered."

Hepatology 2009.