NIH-funded researchers gain ground in treatment
A specific form of vitamin E improved the most severe form of fatty liver disease in some children, according to a study funded by the National Institutes of Health. Results appear in the April 27 issue of the Journal of the American Medical Association. A previous study found vitamin E effective in some adults with the disease.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease among U.S. children. NAFLD ranges in severity from steatosis (fat in the liver without injury) to nonalcoholic steatohepatitis or NASH (fat, inflammation, and liver damage). Fatty liver increases a child's risk of developing heart disease and liver cirrhosis. The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy. Weight loss may reverse the disease in some children, but other than dietary advice, there are no specific treatments. Excess fat in the liver is believed to cause injury by increasing levels of oxidants, compounds that damage cells.
Most children with fatty liver disease are overweight and resistant to insulin, a critical hormone that regulates energy. Boys are more likely affected than girls, as are Hispanic children compared to African-Americans and whites.
Using liver biopsies, researchers found that after 96 weeks of treatment, 58 percent of the children on vitamin E no longer had NASH, compared to 41 percent of the children on metformin (a diabetes drug), and 28 percent on placebo. Vitamin E was better than placebo because it significantly reduced enlargement and death of liver cells.
"These results suggest that vitamin E improves or resolves NASH in at least half of children, which we previously showed to be true in adults," said Stephen P. James, M.D., director of the digestive diseases and nutrition division at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which funded the study. While the results are encouraging, patients using vitamin E for NASH should be under a doctor's care. "We hope to build on these results by looking for other therapies and reliable, non-invasive ways to monitor the disease and response to therapy."
The Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) trial studied whether vitamin E (an antioxidant) or metformin could improve fatty liver disease. The endpoint to measure success was either a sustained reduction in the liver enzyme alanine aminotransferase (ALT) or improvements in the liver as shown by biopsies. A total of 173 children, mostly whites and Hispanics ages 8 to 17, were recruited into three treatment groups. The children received either 500 milligrams of metformin or 400 international units of a natural form of vitamin E or placebo twice a day for two years.
Neither vitamin E nor metformin were significantly better than placebo in reducing ALT levels. Twenty-six percent of patients on vitamin E, 16 percent on metformin, and 17 percent of those on placebo had reduced liver enzyme levels. Interestingly, ALT levels improved more rapidly among patients on vitamin E (within six months) compared to those on placebo. The ALT levels among the children on placebo improved over the two years.
"We believe all children in the trial benefited from the frequent diet and exercise advice provided throughout the study," said Joel E. Lavine, M.D., Ph.D., a TONIC principal investigator and professor of pediatrics at Columbia University, New York. "Now we have information on the natural history of a placebo group over time, which will help us design future trials."
Using biopsies in children with liver disease is unique. "TONIC is ground-breaking on two fronts. It is the first study to use liver biopsy to evaluate potential treatments for any liver disease in children," said Patricia Robuck, Ph.D., M.P.H., the project scientist at NIDDK. "It is also the first multi-center, randomized, controlled trial to use a liver biopsy to evaluate a therapy for fatty liver in children, considered the most rigorous design for studies of liver disease."
TONIC was conducted by NASH Clinical Research Network investigators at:
Case Western Reserve University and the Cleveland Clinic, Cleveland
Children's National Medical Center, Washington, D.C.
Indiana University, Indianapolis
Johns Hopkins University, Baltimore (data coordinating center)
Saint Louis University and Washington University, St. Louis
Texas Children's Hospital, Houston
University of California, San Diego
University of San Francisco
Virginia Commonwealth University, Richmond
Virginia Mason Medical Center, teamed with the University of Washington, Seattle
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