Session V THERAPEUTIC OPTIONS FOR NASH Clofibrate and Other Fat Lowering Agents for Treatment of NASH

The pathogenesis of NASH is unknown but may relate to excessive accumulation of lipids in the liver. Steatotic livers secondary to alcohol abuse or associated with type Il diabetes mellitus contain predominantly triglycerides and to a lesser extent cholesterol esters. Elevated hepatic free fatty acids, products of triglyceride hydrolysis, have been identified in fatty liver of pregnancy, alcohol-induced hepatitis, and morbid obesity and have been shown to cause cellular injury. There is no proven treatment for NASH. Few studies have been performed examining the role of lipid lowering agents in the treatment of NASH. Clofibrate has been demonstrated to decrease the amount of hepatic triglycerides in animal studies. In a pilot study, sixteen patients with hypertriglyceridemia and NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound were placed on clofibrate, 2glday for 12 months. (Laurin J et al. Hepatology 1996;23:1464-7). All obese patients were strongly encouraged to lose weight. The group comprised 11 women and 5 men with a mean age of 50 years. Obesity was present in 10 of 16 (62%) patients. Six patients were taking oral hypoglycemic agents or had a fasting glucose ~ 150 mgldL. No patients required insulin or had diabetes that was difficult to control. Among these patients, there was no significant change from baseline in mean ALT, AST, Vglutamyl transpeptidase (GGT), total serum bilirubin, cholesterol, or triglyceride level, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase decreased 8igniflcanuy from baseline. The change in alkaline phosphatase did not correlate with weight loss. This group did not have significant weight loss after 12 month8 of therapy. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this one-year pilot study.