June 25, 2004 ROCHESTER, Minn. -- Obesity is the number one cause of chronic liver disease in the United States. Mayo Clinic researchers have discovered the mechanism that causes liver damage in many obese children and adults: excess fatty acids cause a protein reaction that kills liver cells, causing scarring and liver damage.
Known as Non-Alcoholic Fatty Liver Disease - NAFLD - the condition was first identified and named by a Mayo Clinic research team in 1980. It affects up to a quarter of the population in western countries. The latest Mayo Clinic discovery on NAFLD appears in today’s version of the journal Hepatology online.
"As a pediatrician, I feel we are dealing with a big epidemic — NAFLD is certainly surpassing Hepatitis C, in terms of potential damage to the liver," says Ariel Feldstein, M.D., Mayo Clinic pediatric gastroenterologist and principal investigator. "NAFLD is a growing worldwide problem related to affluence and the diet and lifestyle associated with it. It's as true in the U.S. as it is in Europe, Japan, and my native country Argentina." See how NAFLD occurs here.
Early signs of NAFLD consist of accumulation of fat in the liver, which can be found in almost two-thirds of obese people. Another indication is inflammation of the liver, sometimes with scarring. While simple fatty liver is usually a benign condition, about 10 percent of individuals can develop other liver abnormalities including inflammation and scarring that can lead to impaired function in a condition known as Nonalcoholic Steatohepatitis, or NASH. Both NAFLD and NASH are strongly associated with other components of the metabolic syndrome including diabetes, elevated cholesterol and triglyceride levels, and hypertension.
Significance of the Mayo Clinic Research
The discovery of how excess fatty acids poison livers is important because currently there is no treatment for obesity-associated liver disease. Knowing the cellular mechanisms behind NAFLD is the necessary first step to developing treatments for it. And while most cases of NAFLD do not progress to cirrhosis or require a liver transplant, physicians are nonetheless worried that this could change because they are seeing more symptoms of pediatric NAFLD earlier.
"Every week I have several patients in which the mean age is about 12 that come with symptoms of liver disease—and that’s very young for this to be happening," says Dr. Feldstein. "Perhaps 1 in 10 of my patients has signs of liver disease, and that group can be thought of as the first step toward NASH: nonalcoholic steatohepatitis."
Other symptoms include an enlarged liver or minor elevation of the liver enzyme in tests. Fatty liver disease can be suspected based on ultrasound or computerized tomography (CT) scan, but the diagnosis must be confirmed by liver biopsy.
The Experiment and Its Findings
By studying livers of both obese and lean mice, as well as liver samples from obese and lean human patients, the Mayo Clinic researchers discovered key points about how NAFLD works. The process starts when there’s so much dietary fat in the blood that it can no longer be contained in the usual storage places, such as fat cells. When this happens, the fatty acids are "free," roving around space inside cells known as cytosol.These freely circulating fatty acids inside the liver cells’ cytosol start the chain of events that the Mayo Clinic researchers discovered.
Understanding these processes gives researchers a basis for designing treatments to interrupt the chain of events, and thus, shut down injurious cellular processes. This could lead one day to new drugs for NAFLD. Drug-development approaches are important because the only treatment for early-stage NAFLD now is the same as that prescribed for the other symptoms of metabolic syndrome, such as insulin resistance, high blood pressure, high blood fats, and these measures- eat less and exercise more to lose weight- are difficult for certain patients to do.
In addition to Dr. Feldstein, the Mayo Clinic research paper was authored by Nathan W. Werneburg, Ali Canbay, M.D.; Maria Eugenia Guicciardi, Ph.D.; Steven F. Bronk, Robert Rydzewski, Laurence J. Burgart, M.D., and Gregory Gores, M.D., in whose laboratory the investigation was conducted. The work was supported by a grant from the National Institutes of Health to Dr. Gores, the American Gastroenterological Association Transition Award to Dr. Feldstein, and the Mayo Foundation.
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