RESEARCH FOCUSES ON GENETIC DIAGNOSTIC AND THERAPEUTIC APPROACHES TO NAFLD

Nonalcoholic fatty liver disease (NAFLD), now esti­mated to be the most common form of liver disease in the United States and worldwide, is expected to be the primary cause for liver transplantation by the end of the decade.

Dr. Speliotes examines human liver cell lines through a microscopy.

However, regardless of its pervasiveness, there are many unknowns surrounding the disease. Elevations in liver enzymes may indicate NAFLD; however, the accuracy of such tests is poor, and the standard procedure for diagnosis, liver biopsy, is aggressive. Further, the condi­tion can manifest from a plethora of factors, and initial symptoms, including abdominal pain and fatigue, are indis­tinct, if expressed at all.

As a result, many individuals with NAFLD are initially oblivious to even having it, until it advances to something much more serious, such as cirrhosis or liver failure. Additionally, there are inadequate treatments for the disease, so patients are frequently left without viable options, even if diagnosed early and accurately.

Because of these difficulties, Elizabeth K. Speliotes, MD, PhD, MPH, assistant professor of internal medicine, compu­tational medicine and bioinformatics at the University of Michigan Health System, hopes to uncover the disease’s actual pervasiveness and risk, in addi­tion to identifying effective treatments through genetic research.

NAFLD AND OBESITY GENES DIFFER

In working with the Genetics of Obesity- Related Liver Disease Consortium, Dr. Speliotes’ team has identified five genetic loci associated with NAFLD. Using a group of approximately 7,000 people, the investigators calculated liver fat based on CT scans and carried out related genome-wide associa­tion analyses to recognize genetic patterns related to fatty liver. They then performed genetic analyses of people with NAFLD.

One noteworthy finding was that genes related to NAFLD are different from those associated with obesity.

Dr. Speliotes and Alissa Wall, medical student, open a liquid nitrogen tank containing human liver cell lines, which are used to model human disease.

“Obesity was one of my first interests and, in part, what drove me to study fatty liver disease,” Dr. Speliotes said. “Ultimately, I do think they are linked. But in terms of genetics, it looks like the main drivers of obesity are more neurologically based, whereas the drivers that seem to be causing fatty liver disease are more lipid-and glucose-based. That changes how we think about these diseases.”

Dr. Speliotes’ team also is exploring the relationship between NAFLD-related genes and environmental factors.

“Our studies suggest that approximately 25 to 30 percent of how much fat is in your liver is due to genetics, and the rest is probably environmental,” Dr. Speliotes said. “Some of my patients are the epitome of health. They tell me they work out every day. But it doesn’t matter. They still have a lot of fat in their liver.

“We’ve identified genetic variants that put some individuals at much higher risk for developing fat in the liver, even without being overweight. For example, we’ve identified one variant that confers a sixfold higher risk for developing scar­ring and cirrhosis, and another variant that is associated with a twelvefold higher risk for developing liver cancer.”

Future studies will be designed to identify new genes related to NAFLD in order to better inform people who are at risk for the disease and to develop more effective treatments.

“Currently, we can make specific recom­mendations for people who are at risk for developing some types of cancer, for example,” Dr. Speliotes said. “But it’s only through this kind of research that we’re going to be able to make similar recommendations for people with meta­bolic diseases.”

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