Treatment of Nonalcoholic Fatty Liver Disease in Children

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological diagnosis in which more than 5% of hepatocytes demonstrate macrovesicular steatosis in an individual without significant history of alcohol intake. NAFLD has become the most common cause of chronic liver disease in children in the United States, and encompasses a range of severity from bland steatosis to nonalcoholic steatohepatitis (NASH) that may ultimately result in advanced fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD was selected as the histologic entry criterion for this study because of a lack of knowledge about the natural history in the pediatric subset.<br><br>Treatment approaches to NAFLD in adults and children target reduction in insulin resistance and oxidative stress. Based on pediatric pilot data demonstrating potential efficacy of metformin or vitamin E, the NASH Clinical Research Network (NASH CRN), initiated a phase 3, multicenter, randomized, double-blinded, placebo-controlled trial evaluating vitamin E or metformin for the Treatment of NAFLD in Children (TONIC). The purpose of this study was to determine if therapeutic modification of insulin resistance or oxidative stress leads to improvement in serum or histologic indicators of liver injury or quality of life.<br><br>173 eligible patients were randomized in permuted blocks of treatments stratified by clinical center. Patients were assigned in a 1:1:1 ratio to 1 of 3 groups for 96 weeks of treatment, either (1) oral metformin (500 mg twice daily) and vitamin E placebo twice daily, (2) vitamin E (400 IU twice daily) and metformin placebo twice daily, or (3) vitamin E placebo and metformin placebo, each twice daily.

The complete TONIC data is now available.