Researchers have discovered genetic factors that could help identify patients most at risk of developing nonalcoholic fatty liver disease and who may be more likely to progress to severe forms of the disease.

To definitively assess mild fibrosis, a critical juncture on the way to severe fibrotic disease, doctors now use a painful and expensive liver biopsy. This early research, built on the first large-scale genome-wide association study in overweight patients with diabetes, suggests another potential option.

“The work is exciting because it will help us understand the disease process better. There’s no treatment, you can’t cure it once it develops,” says investigator Johanna DiStefano, director of Translational Genomics Research Institute’s Diabetes, Cardiovascular and Metabolic Diseases division, where the sequencing and analysis were performed.

“This is first stage. We can’t say it’s predictive, for that we’ll need a longitudinal study,” says DiStefano. “But this is the first step to differentiate among stages of the disease, and the first study using genomics, as opposed to imaging.” Imaging such as CT scans and MRI are usefully only in detecting advanced disease, and while a laboratory panel of blood biomarkers can identify moderate to severe nonalcoholic fatty liver disease, it cannot predict who is at risk for developing advanced disease.

“We discovered genes that may help identify those patients most at risk for the types of liver disease so severe that they could require transplants,” says Glenn S. Gerhard, co-investigator of the study, who was part of Geisinger Health System’s Weis Center for Research at the time the work was done. Until now, there was currently no way to determine which patients will be on the pathway to that.

Taking advantage of stored liver biopsy specimens from extremely obese patients that had undergone gastric by-pass surgery as a treatment for obesity in Geisinger’s bariatric program, the team conducted large scale sequencing and genome-wide association studies on samples from more than 2,000 patients and looked at what genes affected the development of non-alcoholic fatty liver disease. Several previously implicated genes were identified as well as one new gene that encodes a structural protein present in most tissues.

While most people have a bit of excess fat in their liver, it’s typically not a concern. But those who are overweight, and in particular those who are obese, have more than five to ten percent of their liver weight made up of fat, and that can ultimately lead to fibrosis and even liver cancer.

Catching nonalcoholic fatty liver disease early, with time enough to change behaviors and modify a patient’s overall health before inflammation and tissue damage sets in, is critical. The disease spans a spectrum of conditions, from inconsequential to chronic cirrhosis, depending on the amount of fat deposits in the liver, and is now the most common cause of chronic liver disease in the United States.

Geisinger Health Systems, concerned about the cost of treating chronic disease, is hoping the new results will ultimately identify which patients will benefit from early behavior modification efforts. Weight loss of 9 percent over a period of months can help reverse the disease, and even less weight loss than that can help lessen buildup of fat in the liver, slowing disease progression.