No effective medical therapy is available for all patients with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) has been suggested to be of benefit based on open label clinical studies. We randomized 166 patients with liver biopsy-proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years. End points included changes in liver test results and liver histology at 2 years of therapy. The treatment groups were comparable at entry with regard to age, gender, risk factors for NASH, serum liver biochemistries, and baseline liver histology. A total of 126 patients completed 2 years of therapy. Pre-and posttreatment liver biopsies were available in 107 patients for review at the end of the study. UDCA was well tolerated and body weight was stable during the study duration. Serum liver biochemistries were stable or improved in both the UDCA and placebo-treated groups. Changes in the degree of steatosis, necroinflammation, or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups. In conclusion, 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d, although safe and well tolerated, is not better than placebo for patients with NASH. (HEPATOLOGY 2004; 39:770 -778.) N onalcoholic steatohepatitis (NASH), an increasingly recognized cause of chronic liver disease, is histologically indistinguishable from alcoholinduced liver injury but occurs in patients who deny alcohol abuse. 1 NASH represents only one stage within the spectrum of nonalcoholic fatty liver disease, 2 which may be the most common cause of chronic liver disease in the United States 3,4 and other countries. 5,6 Most patients with NASH have some degree of liver fibrosis 7 ; in a subset of patients the disease progresses to cirrhosis 8 and liver cancer, 9 and in some patients it may lead to liver trans-plantation. 10 There are no proven treatments for NASH. Treatment of associated conditions such as obesity, diabetes mellitus, and dyslipidemia is frequently attempted but seldom effective in reversing NASH. 11 Pharmacologic therapy with insulin-sensitizing medications 12-14 and antioxidants 15,16 holds promise, but only small pilot studies lasting 1 year or less have been reported to date.
Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with multiple hepatoprotective activities, improves liver condition in patients with a wide range of chronic liver diseases. 17 In an open-label pilot study, 18 we previously reported that in patients with NASH, 1 year of treatment with UDCA (13-15 mg/kg/d) improves liver enzymes and degree of steatosis evaluated by way of liver biopsy. Based on those results, we conducted a large-scale, placebo-controlled trial aimed at determining the efficacy of UDCA for the treatment of patients with NASH.
Methods
Study Design. Between 1994 and 2000, a total of 174 patients with liver biopsy-proven NASH were entered into this prospective, randomized, double-blind, placebocontrolled trial. Patients were enrolled from 13 medical centers in the United States and Canada. The study was conducted in compliance with the Declaration of Hel-