The TONIC trial: a step forward in treating pediatric nonalcoholic fatty liver disease

Abstract

Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659–1668. (Reprinted with permission).

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established.

OBJECTIVE: To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin.

DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8–17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks.

MAIN OUTCOME MEASURES: The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures.

RESULTS: Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was −35.2 U/L (95% CI, −56.9 to −13.5) with placebo vs −48.3 U/L (95% CI, −66.8 to −29.8) with vitamin E (P = .07) and −41.7 U/L (95% CI, −62.9 to −20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, −0.2 to 0.3) vs −0.5 with vitamin E (95% CI, −0.8 to −0.3; P = .006) and −0.3 with metformin (95% CI, −0.6 to −0.0; P = .04); and in NAFLD activity score, −0.7 with placebo (95% CI, −1.3 to −0.2) vs −1.8 with vitamin E (95% CI, −2.4 to −1.2; P = .02) and −1.1 with metformin (95% CI, −1.7 to −0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features.

CONCLUSION: Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063635.

Figure 1. The role of insulin resistance and oxidative stress in the development and progression of nonalcoholic fatty liver and the potential mechanism of action for metformin and vitamin E

Systemic and hepatic Insulin resistance are now recognized as a critical event for development of hepatic steatosis; the “first-hit” of NAFLD development. Metformin – a biguanide – inhibits gluconeogenesis and increases glucose uptake by peripheral tissues, resulting in reduced insulin resistance. Early in the disease process the liver adapts to excess FFA; however, over time these adaptive mechanisms fail resulting to lipotoxicity. Lipotoxicity can trigger ER stress, lysosomal permeability, and mitochondrial dysfunction. As a consequence, there is increased production of a wide variety of reactive oxygen species (ROS). ROS can react with a range of molecules in the cell, leading to impaired nucleotide and protein synthesis, which in turn injure organelles such as mitochondria. The ensuing disruption of mitochondrial function triggers cell death; key “second-hits” in NASH pathobiology. In conjunction, release of ROS from hepatocytes can trigger activation of immune cells and convert the normally quiescent stellate cells to a fibrosis-inducing cell. Vitamin E is a highly effective antioxidant, by readily donating a hydrogen to free radicals, and rendering them inactive. Abbreviations :FFA, free fatty acids; ROS, reactive oxygen species.