A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis† ‡

Abstract

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsyproven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study. (HEPATOLOGY 2004;39:188 -196.)

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

“…22,27 In the PIVENS trial the change in ballooning score was significantly higher with pioglitazone. 26 Intralobular inflammation improved in most 22,26,27,30 but not all 21 studies. Portal inflammation was either unchanged or worse in one study with rosiglitazone.…”

“…26 Fibrosis. No studies convincingly demonstrated improvement in fibrosis: despite an end-of-treatment reduction 22,27,30 there was no statistical difference with the comparator arm, or only a marginal level suggestive of type 1 error. 27 When measured by micromorphometry, a more sensitive and quantitative technique, there was still no significant improvement, even after prolonged treatment with rosiglitazone.…”

“…In nondiabetic patients, pioglitazone induced a significant improvement in IS by clamp studies 23 or surrogate markers (hyperinsulinemia or homeostasis model assessment [HOMA]). 26,30 In one study, impaired glucose tolerance was no longer present in half of the patients. 30 In diabetic patients, both glitazones induced a 30% reduction in serum insulin 21,22 and a significant reduction in serum glucose 21,22 and HOMA.…”

“…26,30 In one study, impaired glucose tolerance was no longer present in half of the patients. 30 In diabetic patients, both glitazones induced a 30% reduction in serum insulin 21,22 and a significant reduction in serum glucose 21,22 and HOMA. 21 A reduction in serum-free fatty acid and a 1.9-to 2.8-fold increase in serum adiponectin were also documented with both glitazones.…”

“…Response to glitazones is short-lived. 21,28,30 After drug discontinuation, aminotransferases rose rapidly, returning to baseline within 3 months. 21 Serum insulin and HOMA were still maintained at 3 months, 21 but rose above baseline 1 year after, whereas adiponectin declined.…”