Bob Roehr

November 04, 2010

November 4, 2010 (Boston, Massachusetts) — The first randomized controlled trial to use histology as a measure for treating nonalcoholic fatty liver disease (NAFLD) in children has found that neither metformin nor vitamin E provide a statistically significant sustained reduction in alanine transaminase (ALT) levels, the primary end point of the study, compared with placebo.

Results of the TONIC study by the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network, presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, by Joel Lavine, MD, from the Department of Gastroenterology, Hepatology, and Nutrition at Columbia University in New York City, "reinforce the PIVENS [trial] findings in adults with NASH."

The rise of childhood obesity has helped make NAFLD the most common cause of chronic liver disease in American children. "NASH-related cirrhosis has been described in children as early as 7 years," and it is also a risk factor for metabolic syndrome, Dr. Lavine said. There is no established pharmacologic treatment for NAFLD or NASH in children, in part because no pediatric study of liver disease has ever used histology as an end point.

The researchers enrolled 173 children 8 to 17 years of age with biopsy-confirmed NAFLD and elevated serum alanine aminotransferase (ALT > 60 U/L). Diabetes, cirrhosis, significant alcohol use, ALT above 400 U/L, and a recent pharmaceutical course of therapy for fatty liver disease were exclusionary factors. Most of the 229 children screened but not enrolled had insufficiently high ALT levels to meet the entry criteria.

Patients were randomized in a 1:1:1 manner to receive 400 IU of the natural form of vitamin E twice a day (58 subjects), 500 mg of metformin in gel capsules twice a day (57 subjects), or placebo (58 subjects) for 96 weeks, with 24 weeks of follow-up to ascertain durability. They also were counseled on diet and lifestyle changes to improve their health.

The primary end point was a sustained reduction in ALT to either below 40 IU/L or below 50% from baseline ALT from weeks 48 to 96. In light of the 2 separate interventions being evaluated in the study, the floor for statistical significance was established as P < .025.

Dr. Lavine said that "ALT [levels] decreased in all 3 groups," primarily because of changes in diet and exercise. The vitamin E group showed an early (week 24) statistically significant sharp decline in ALT levels, "but by the time 96 weeks came around, they all converged, to a decline of about 40 IU/L."

There was a sustained 25.9% reduction in serum ALT levels in the vitamin E group, a 15.8% reduction in the metformin group, and a 17.2% reduction in the placebo group. The decline seen with vitamin E, compared with placebo, was just shy of significance (P = .26); with metformin, the significance was more distant (P = .83).

There were statistically significant improvements in hepatocellular ballooning: 44%, 44%, and 21% in the vitamin E, metformin, and placebo groups, respectively. Improvement was also seen in patients with NASH or borderline NASH at baseline: 58% in the vitamin E group and 28% in the placebo group (P = .006). There was no significant impact on fibrosis or inflammation with either intervention.

"There also was no change in insulin resistance, which was somewhat surprising in light of the fact that metformin is used to treat type 2 diabetes in children," said Dr. Lavine.

Diet and activity questionnaires were administered at baseline and at weeks 48 and 96. Analysis of the way changes in these parameters affected metabolic responses will be published in the future.

One audience member noted the significant improvement on all measures in the placebo group, and wondered if that might not mask some of the contributions of vitamin E and metformin.

Dr. Lavine would not speculate on that. He added: "I think that lifestyle advice works in the context of having frequent follow-up and the amount of attention these children received, and the investment by their families in making considerable changes in terms of the type of foods they were eating and activities they pursued." But such an intense intervention probably is not possible to implement on a broader population basis.

Ronald J. Sokol, MD, from the University of Colorado in Aurora, praised the study for its completeness. He was surprised by the ALT data that showed a convergence of all 3 groups at the end of the study. He wondered if there are follow-on data.

Dr. Lavine responded that "this is not a durable response. ALT will rise again once vitamin E and placebo are discontinued, but it doesn't rise back to its baseline. That is probably because of the adoption and maintenance of lifestyle changes."

The study was totally supported by the National Institutes of Health. Dr. Lavine has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 110. Presented November 1, 2010.

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