Original article
Randomized Placebo-Controlled Trial of Ursodeoxycholic Acid With Vitamin E in Nonalcoholic Steatohepatitis

https://doi.org/10.1016/j.cgh.2006.09.025Get rights and content

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a frequent liver disease that can progress to cirrhosis and for which there is no recognized therapy. UDCA and vitamin E have been considered separately as therapeutic options and have not been shown to be effective. This study tested their combination. Methods: Patients with elevated aminotransferase levels and drinking less than 40 g alcohol/week with biopsy-proven NASH were randomly assigned to receive UDCA 12–15 mg · kg−1 · day−1 with vitamin E 400 IU twice a day (UDCA/Vit E), UDCA with placebo (UDCA/P), or placebo/placebo (P/P). After 2 years, they underwent a second liver biopsy. Biopsy specimens were collected, blinded, and scored by a single liver pathologist. Results: Forty eight patients were included, 15 in the UDCA/Vit E group, 18 in the UDCA/P group, and 15 in the P/P group; 8 patients dropped out, none because of side effects. Baseline parameters were not significantly different between the 3 groups. Body mass index remained unchanged during the study. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels diminished significantly in the UDCA/Vit E group. Neither the AST nor the ALT levels improved in the P/P group and only the ALT levels in the UDCA/P group. Histologically, the activity index was unchanged at the end of the study in the P/P and UDCA/P groups, but it was significantly better in the UDCA/Vit E group, mostly as a result of regression of steatosis. Conclusions: Two years of treatment with UDCA in combination with vitamin E improved laboratory values and hepatic steatosis of patients with NASH. Larger trials are warranted.

Section snippets

Study Design

Patients 18–75 years of age with a persistent elevation of serum ALT levels of at least 1.5 times the upper limit of normal for at least 6 months and a weekly alcohol consumption of less than 40 g confirmed by the patient and eventually by someone close to the patient were eligible if they had a liver biopsy performed no more than 6 months before inclusion showing macrovesicular steatosis of more than 10% of the hepatocytes, hepatocellular injury (ballooning, dropout), and lobular inflammation.

Results

Between January 1, 1999 and December 31, 2002, 48 patients from 7 different Swiss centers were included in the study. The demographic characteristics (age, gender, body mass index [BMI], ongoing therapy for arterial hypertension, and diabetes mellitus) were not significantly different between the 3 groups (Table 1). The mean serum levels of ALT and AST were elevated in the 3 groups at baseline and not significantly different. None of the 6 histologic parameters was significantly different among

Discussion

This double-blind, randomized, placebo-controlled study found that UDCA 12–15 mg · kg−1 · day−1 in combination with vitamin E 400 IU twice daily improves serum aminotransferase levels and liver histology of patients with NASH. This combination had beneficial effects, which could not be reached with UDCA monotherapy. With this therapeutic association the average of the serum AST and ALT levels reached normal range, and their decrease was significant. This was not the case in the P/P group or in the

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