NIH-funded, NEJM study is largest ever to look at nonalcoholic steatohepatitis, an obesity-related condition
NEW YORK (April 29, 2010) — Vitamin E has been shown effective in treating nonalcoholic steatohepatitis (NASH), an obesity-associated chronic liver disease that can lead to cirrhosis, liver cancer and death. NASH also is related to or a part of type 2 diabetes, lipid disorders and cardiovascular disease.
The often asymptomatic condition affects 2 to 5 percent of Americans, although an additional 10 to 20 percent of the population has fat in their liver, but no inflammation or liver damage, a condition called “fatty liver” that is a precursor to NASH. There is no established treatment.
The government-funded multicenter study was organized by the Nonalcoholic Steatohepatitis Clinical Research Network of the National Institute of Diabetes and Digestive and Kidney Diseases, and is the largest ever placebo-controlled randomized trial of treatment for NASH. Results are published in the April 28 online edition of the New England Journal of Medicine.
Beginning in the late 1990s, study of vitamin E for NASH was pioneered in pilot trials by Dr. Joel Lavine, now a faculty member in the Department of Pediatrics at Columbia University College of Physicians and Surgeons and chief of gastroenterology, hepatology and nutrition at NewYork-Presbyterian/Morgan Stanley Children’s Hospital. Researchers followed patients at nine centers, including the University of California, San Diego, where Lavine was previously on faculty.
“There is an increasing prevalence of nonalcoholic steatohepatitis in this country, something that is directly related to the obesity epidemic,” says Lavine, co-chair of the Network’s steering committee and a co-author of the study. “The good news is that this study showed that cheap and readily available vitamin E can help many of those with the condition. We also looked at the drug pioglitazone, which showed some benefits, although not as dramatic as with vitamin E.”
Lavine cautions that there are risks with any therapy, even vitamin E, and all treatment should be done under medical supervision. “Individuals who are overweight or have a family history of liver disease should ask their doctor to be tested for the condition. In addition, physicians should be aware that liver enzyme levels considered normal are actually elevated. Healthy levels are <30 U/L for a man and <20 for a woman.”
In the Pioglitazone or vitamin E for NASH Study (PIVENS), investigators randomly assigned 247 nondiabetic adults with biopsy-confirmed NASH to receive vitamin E, pioglitazone or placebo. Vitamin E functions as an antioxidant while pioglitazone improves the sensitivity of cells to insulin, a hormone that controls both sugar and fat metabolism.
After 96 weeks of treatment, vitamin E improved all features of NASH with the exception of the amount of scar tissue in the liver; 43 percent of those treated with vitamin E met the primary endpoint of the trial, which was a composite of the scores for several features of NASH indicative of disease activity, compared with only 19 percent of those who received a placebo. Pioglitazone also improved many features of NASH and met the primary endpoint in 34 percent of individuals who received it but fell short of statistical significance. Pioglitazone treatment led to an average weight gain of 10 pounds over the 96-week duration of this study. Liver enzyme tests, which are commonly used to assess liver injury, also improved in those who received either pioglitazone or vitamin E. However, upon stopping the medications, the liver enzymes worsened again suggesting the need for long-term treatment.
The study was conducted in those with NASH who did not have diabetes, and the benefits of either drug for those with NASH who also have diabetes remain unknown. Also, the study lasted for two years only and the potential long-term benefits and risks of taking vitamin E or pioglitazone in these doses are uncertain.
Lead author of the study and the other NASH Clinical Research Network co-chair is Dr. Arun Sanyal, professor of medicine and chairman of the Division of Gastroenterology at Virginia Commonwealth University in Richmond.
Pioglitazone (trade name Actos) was provided by Takeda Pharmaceuticals North America, and vitamin E was provided by Pharmavite. Both also supplied placebos.
Lavine joined NewYork-Presbyterian/Columbia from the University of California San Diego in February and brought his NIH grant for the study of fatty liver to NewYork-Presbyterian/Columbia. He is currently preparing a report on a multicenter study he led of vitamin E and the diabetes drug metformin for NASH in children.