From Our 2010 Archives

Researchers Identify 2 Genes Linked to Fatty Liver Disease

By Ed Edelson
HealthDay Reporter

WEDNESDAY, March 24 (HealthDay News) -- Researchers have identified two gene variants that increase the risk of both the most common chronic liver disease in the United States as well as type 2 diabetes.

People who carry the variants of a gene for apolipoprotein C3 (APOC3), which produces an enzyme important in fat metabolism, have a higher incidence of nonalcoholic fatty liver disease and also insulin resistance, according to a report in the March 25 issue of the New England Journal of Medicine. The research group was led by Dr. Gerald I. Shulman, a professor of physiological chemistry, medicine and cellular and molecular physiology at Yale University.

Identification of the gene variants "might make it possible to screen individuals to see if they have a higher risk of fatty liver disease," Shulman said. "It also can provide an ideal drug target to prevent development of fatty liver disease and insulin resistance."

Fatty liver disease can be caused by excessive alcoholic consumption and obesity. Its incidence has increased in the United States, and more than 30% of Americans are estimated to have it, Shulman said.

In many cases, excess buildup of fat in the liver causes only minor problems. But it can progress to cause major, life-threatening deterioration of liver function. In the same way, insulin resistance can lead to type 2 diabetes, a major risk factor for heart attack, stroke and other cardiovascular problems.

Shulman and his colleagues first looked for the APOC3 gene variants in 95 lean Asian Indian men, an ethnic group in which the incidence of fatty liver disease is high, for unknown reasons. "Carriers of these gene variants had 5.5% fat in their liver, and were also markedly insulin-resistant," Shulman said.

The variants cause higher levels of APO3C, which inhibits an enzyme that breaks down fats, Shulman said. The excess fats are deposited in the liver. Thirty-eight percent of the men with the gene variants had fatty liver disease.

The Yale group then did the same genetic study in a mixed ethnic group of 163 men and found a similar incidence of fatty liver disease and insulin resistance among those with the gene variants.

The next step in the Yale program will be an effort to learn why the condition is more common in East Asian men, Shulman said. But a longer-term goal is to put the finding to use to detect high-risk individuals, he noted.

"If you have a test, you can make them careful about their weight," he said. "The good news is that we have shown that even modest weight reduction can reduce the risk. Dropping 15 pounds reverses fatty liver disease and insulin resistance."

Beyond that would be a treatment aimed at the gene variants, Shulman said. "It's even better if you have something you can do about it," he said. "You could screen people, test for fatty liver and insulin resistance and treat that with agents."

A screening test could help single out people whose fatty livers were not dangerous, said Dr. Anna Mae Diehl, chief of gastroenterology at Duke University, who wrote an accompanying editorial in the journal.

"Simply having extra fat in the liver is of unknown significance," Diehl said. "Many people who have it are fine. Some get more advanced forms of liver disease. We want to know if this polymorphism is associated not only with fat, but also with damage."

Such a determination now requires a biopsy to remove a segment of the liver for examination, Diehl said. "We still don't have a noninvasive blood test," she said. "That might help sort out who has more serious damage. We are hoping that in the next few years better tests become available."

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SOURCES: Gerald I. Shulman, M.D., Ph.D, professor, physiological chemistry, medicine, cellular and molecular physiology, Yale University, New Haven, Conn.; Anna Mae Diehl, M.D., professor, medicine, and chief, gastroenterology, Duke University, Durham, N.C.; March 25, 2010, New England Journal of Medicine