Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial

Approximately 60 million adults in the United States have nonalcoholic fatty liver disease (NAFLD)1. The histologic spectrum of NAFLD spans from simple steatosis to nonalcoholic steatohepatitis (NASH), characterized by hepatocellular injury, inflammation, and fibrosis that can eventually progress to cirrhosis2,3.. Until recently, no therapy had been definitely proven beneficial for patients with NASH. A recent study showed some benefits of therapy with vitamin E in a proportion of patients with NASH4, however, there is still a need for additional and more effective therapies for patients with NASH. Multiple factors and pathways are involved in the pathogenesis and progression of NAFLD and NASH. Imbalances in inflammatory cytokines, oxidative stress, and insulin resistance are some of the proposed mechanisms involved in NASH pathogenesis and progression5–8. Cytokines including tumor necrosis factor alpha (TNF-alpha)9,10, a pro-inflammatory cytokine, and adiponectin, an anti-inflammatory cytokine9, are believed to play an important role in hepatocellular damage, inflammation and fibrogenesis in NASH11. In mice, fatty liver disease is improved by inhibition of hepatic TNF-alpha production12 and by infusion of anti-TNF-alpha neutralizing antibody13,14. Pentoxifylline (PTX) is a methylxanthine derivative known to increase red blood cell flexibility, reduce blood viscosity, and decrease platelet aggregation15,16. There is evidence supportive of a potential role for PTX in NASH. PTX inhibits a number of pro-inflammatory cytokines including TNF alpha17–19. In addition, PTX may have hepatoprotective effects17,20. It increases hepatic glutathione levels in mice with steatohepatitis induced by a methionine choline deficient diet17 and reduces the production of oxygen radicals induced by prolonged ischemia time in rat livers21. Potential antifibrogenic effects of PTX have been suggested by in vitro studies on hepatic stellate cells22,23, and in a rat model of biliary duct occlusion24. Therefore, PTX has a number of mechanisms that may provide therapeutic benefit to NASH patients. Pilot studies of PTX in patients with NASH have been conducted and their results have suggested possible benefits of PTX in NASH25,26. However, to date, published studies have had significant limitations, predominantly uncontrolled design, small sample sizes, and lack of histological follow up evaluation. The primary aim of this study was to compare the effectiveness of PTX over one year with placebo in patients with NASH. The primary outcome measure was defined as an improvement of 2 or more points in the NAFLD activity score (NAS)27. Other aims were to compare the effects of PTX compared to placebo on serum transaminases; to assess the effect of PTX on insulin sensitivity; to assess the effect of PTX on hepatocyte apoptosis; and to assess the effect of therapy with PTX on serum levels of TNF alpha and adiponectin. We also aimed to compare the rate of adverse events in patients with NASH receiving PTX compared with placebo.