S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial

Abstract

Background: S-adenosyl-L-methionine (SAM) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione, the main cellular antioxidant. Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases (ALDs). The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24-week trial. The primary endpoints were changes in serum aminotransferase levels and liver histopathology scores, and the secondary endpoints were changes in serum levels of methionine metabolites.

Methods: We randomized 37 patients with ALD to receive 1.2 g of SAM by mouth or placebo daily. Subjects were required to remain abstinent from alcohol drinking. A baseline liver biopsy was performed in 24 subjects, and a posttreatment liver biopsy was performed in 14 subjects.

Results: Fasting serum SAM levels were increased over timed intervals in the SAM treatment group. The entire cohort showed an overall improvement of AST, ALT, and bilirubin levels after 24 weeks of treatment, but there were no differences between the treatment groups in any clinical or biochemical parameters nor any intra- or intergroup differences or changes in liver histopathology scores for steatosis, inflammation, fibrosis, and Mallory-Denk hyaline bodies.

Conclusions: Whereas abstinence improved liver function, 24 weeks of therapy with SAM was no more effective than placebo in the treatment for ALD.

Copyright © 2011 by the Research Society on Alcoholism.

Figures

Figure 1. Methionine metabolism

Methionine is converted by methionine adenosyltransferase (MAT1A) to S-adenosylmethionine (SAM), which is subsequently metabolized to S-adenosylhomocysteine (SAH) by donating its methyl moiety to DNA methyltransferases (DNMTs) or to other methyltransferases that include glycine N-methyltransferase (GNMT). SAH hydrolase (SAHH) regulates the bi-directional reaction that leads to the synthesis of homocysteine from SAH or vice versa. Completing the cycle, homocysteine is converted to methionine by methionine synthase (MS), but is also reduced through the transsulfuration pathway, which leads to the synthesis of glutathione (GSH). This pathway is regulated by the vitamin B6-dependent enzymes cystathionine β synthase (CβS) and γ-cystathionase. Alpha-aminobutyric acid (ABU) is the collateral product of the reaction catalyzed by cystathionase.

Figure 2. Adjusted serum SAM levels

SAM treatment group presented overall higher serum SAM levels over time than placebo group during the 24 weeks of the trial. All serum SAM levels were obtained after 12-hour fasting.