Trimming the Fat

by Matthew Greseth

Silence is not always golden

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers a wide spectrum of liver diseases that are serious and often difficult to diagnose. As the name suggests, this condition results in a build-up of extra fat in liver cells that is not caused by alcohol consumption. The diseases involved can range from a simple increase in fat in the liver tissue to fatty tissue accompanied by inflammation. The inflammation, in turn, can cause injury and eventually scarring or fibrosis; this more severe form of fatty liver disease, which includes the inflammatory type, is called nonalcoholic steatohepatitis (NASH) and is now known to lead to cirrhosis in many patients.

“What I think is important is the fibrosis and scarring,” says Wing-Kin Syn, M.D., Ph.D., associate professor and attending physician in the Department of Medicine at MUSC and the Ralph H. Johnson Veterans Affairs (VA) Medical Center. “These are fundamental things that define outcomes, not fat. The fat is just a sign that maybe you’ve been less physically active, maybe you ate too much, or maybe you have other risk factors such as diabetes or hypertension.”

It is normal for the liver to contain some fat, but NAFLD is the diagnosis when more than 5% of liver cells show fat accumulation. One of the most dangerous aspects of NAFLD is that it is a silent, indolent disease. Most people don’t recognize this disease and often associate it with alcohol consumption. Although NAFLD is the most common liver disease, the vast majority of patients with fatty liver can live years asymptomatically. According to The NASH Education Program, 34% of Americans have NAFLD and 12% have the more severe disease, NASH.

NAFLD is becoming increasingly more common, especially as the incidence of metabolic syndrome—type II diabetes, hypertension, centripetal obesity and hypercholesterolemia—is on the rise across the nation, and notably in South Carolina. Relatedly, having NAFLD may enhance the risk of cardiovascular death, developing chronic kidney disease or developing type II diabetes.

“Our westernized diet and lack of exercise are key contributors to the development of fatty liver disease, and we are now in the middle of an epidemic of fatty liver disease leading to inflammation, fibrosis and cirrhosis,” says Don C. Rockey, M.D., professor and chair of the Department of Medicine.

“This is extremely common. People need to really be aware of the risk factors of fatty liver,” adds Syn. “Patients need to be monitored for these diseases with a view to early treatment through lifestyle changes as well as antifibrotics if they have severe disease.” 

Pioneering novel therapy options at MUSC and the Ralph H. Johnson VA Medical Center

While there are currently no FDA-approved fatty liver treatments, some of the negative effects of NAFLD can be mitigated, and even possibly reversed, by implementing lifestyle changes like eating a healthy diet and exercising regularly.

“There is always a balance of input and output,” says Syn. “Nutritional diet ties in with physical activity. Exercise has been shown in clinical trials to lower liver fat, mitigating your risk of fibrosis and even reducing some of the symptoms.”

The next phase in fatty liver treatment aims to supplement lifestyle changes with pharmacotherapy. Currently, there are 55 different drugs in various stages of approval that target comorbid conditions, such as diabetes or cardiovascular disease, or aim to reduce liver fibrosis. However, there are only a few centers around the country that offer these clinical treatments.

“I’m delighted to say that here at MUSC, we have developed a portfolio of studies that will provide novel treatments to patients here that aren’t available anywhere else in South Carolina,” says Rockey. “This provides patients with opportunities that they don’t have at other places and have never had before.”

As one of the only sites offering these clinical trials in the Southeast, MUSC enrolls patients in trials that focus on the most promising therapeutic candidates. MUSC is currently running five active clinical trials, and additional studies should begin soon. Furthermore, the Ralph H. Johnson VA Medical Center, one of the largest centers in the country conducting clinical trials on NAFLD, has three active trials and five more in the pipeline. For more information on clinical trials at MUSC or the VA, please visit scresearch.org.

“We are one of the few centers nationally now recognized to have a framework built to noninvasively diagnose and treat patients with NAFLD,” says Syn, who is leading the effort at the VA. “We have state-of-the-art elastography machines that quantify the degree of liver fibrosis without the need for a liver biopsy. Eventually, once you develop progressive disease, you may need these new antifibrotic drugs to prevent further disease progression or induce disease regression.”

In addition to pioneering several encouraging clinical trials, researchers at MUSC are also studying the biology of these diseases to better understand them and to develop more targeted therapies.

“We’re also very interested in understanding how the liver responds to injury. In the laboratory, we have identified the key fibrogenic cell,” explains Rockey. “These cells respond to the injury process by producing abundant amounts of scar tissue. As far as we can tell, it doesn’t care too much about fat but does care a great deal about inflammation. By identifying this cell and manipulating its pathways, we believe that we may be able to modify fibrosis.”

The best way to predict the future is to create it

While diet and exercise can help curtail the pathogenesis of NAFLD, it is becoming clear that there is a need for sustained treatment of this silent class of diseases. Due to the Western diet and lifestyle, the affected population is skewing younger and younger.

Future work in this field will aim at developing noninvasive diagnostic technology and identifying new pharmacotherapeutic targets and treatments. Currently, the only definitive way to diagnose NAFLD is with a liver biopsy. It is very difficult to identify at-risk patients when the disease is silent. A collaborative research endeavor at MUSC hopes to provide the next step in early detection of NAFLD.

“We are using artificial intelligence to try and refine the way we identify individuals at risk for progressive disease as early as we can,” says Syn, who is developing this technology at the VA with Lewis J. Frey, Ph.D., associate professor in the Department of Public Health Sciences. “Then we can intervene with diet and lifestyle changes, and maybe even drugs.”