HHMI investigators Gerald Shulman, Helen Hobbs, and Richard Flavell are each studying fatty liver disease from different perspectives and finding unique roads into the complex disease and its causes.

“Fatty liver disease is the number one liver disease in this country in both adults and children,” says HHMI investigator Gerald Shulman of the Yale School of Medicine. Rates of fatty liver disease have risen dramatically over the past two decades. “Furthermore, it is strongly linked to hepatic insulin resistance and type 2 diabetes,” he says. Understanding these triggers and how the disease progresses may stop the uptick in its occurrence.

Scientists know that fat buildup in the liver is more common in people who are overweight, have type 2 diabetes, or drink excessive amounts of alcohol. But beyond that, not much about fatty liver disease is well understood. Does the diabetes or fatty liver come first? Do certain genes predispose people to fatty liver disease? How can the disease be detected early and treated? Do other diseases contribute to fat in the liver? These are only some of the questions that Shulman and others are pondering as they study who gets fatty liver disease and why.

“This is a slowly progressing disease,” says hepatologist Rohit Loomba of the University of California, San Diego, School of Medicine. “If we want to prevent liver disease down the road, we need to act now.” According to a 2008 estimate, the disease will be the leading reason for liver transplants by 2020, overtaking hepatitis C.

With a sense of urgency, scientists are pushing forward with studies on the basic biochemistry behind fatty liver. They are coming at the problem from different disciplines—genetics, endocrinology, immunology, and biochemistry—and their findings show a complex, sometimes contradictory story of what pollutes the liver with fat.

From Food and Genes to Fat

Fatty liver disease is rarely detected because of symptoms. Most often, a patient gets a routine blood test and the doctor notices altered levels of proteins made by the liver. Even then, there’s no one test to give a definitive diagnosis of fatty liver disease. By ruling out other causes of abnormal liver proteins in the blood—such as a hepatitis infection or tumor—a doctor may conclude that the patient has fatty liver disease. If the patient is not a heavy drinker, then the diagnosis is nonalcoholic fatty liver disease (NAFLD). Today, more than three-quarters of fatty liver cases are NAFLD.

“It’s an incredibly broad diagnosis,” says HHMI investigator Helen Hobbs of the University of Texas Southwestern Medical Center. “It can mean anything from mild fatty liver to severe inflammation.”

Genes Versus Fast Foods: Eat, Drink and Be Wary
Helen Hobbs at the NIH Director’s Wednesday Afternoon Lecture on November 17, 2010.

As recently as a decade ago, not much more was known about the prevalence of NAFLD, says Hobbs. Clinicians had a poor grasp of the overall incidence, how it progressed, or how to identify patients at risk for developing it in the first place. So when Hobbs launched the Dallas Heart Study, tracking the health of 6,000 individuals in the Dallas area, she and her colleagues included questions about all aspects of cardiovascular and metabolic health. Among topics such as cholesterol and diabetes, they also homed in on NAFLD.

Photos: Shulman: Brian Park; Hobbs: David Gresham / UT Southwestern Medical Center; Flavell: Yale University

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