THE PAST DECADE HAS BEEN A ROCKY ONE FOR THE NATION’S LIVERS. New and acute infections with hepatitis C, which targets the body’s largest internal organ, have been steadily on the rise since 2010, and remain the leading cause of transplants. With the approval of a highly effective treatment for hepatitis C in 2013, however, physicians hope to finally bring that crisis under control. Now a new threat has appeared, one that affects a greater number of people and may be much harder to treat.

As many as 100 million Americans have some form of fatty liver disease, a buildup of fat that can cause inflammation and scarring of the liver, similar to the scars caused by chronic alcohol use, diminishing the organ’s ability to function. Fatty liver disease is closely tied to the obesity epidemic, and the number of people who have it has nearly doubled in the past two decades.

Up to one in five people with the condition will go on to develop a more serious complication called nonalcoholic steatohepatitis, or NASH. Experts predict NASH will eclipse hepatitis C as the leading indication for liver transplant in the United States by 2020.

A search for treatments is gaining pace but faces substantial obstacles. Where researchers looking to cure hepatitis C had to hit a single, viral target, the mechanisms behind NASH are still not well understood. And NASH is difficult to both diagnose and measure, requiring a liver biopsy for each.

In fact, the painful biopsy tends to dissuade patients from even enrolling in the research programs that are needed to find answers. “Patients are reluctant to enter clinical trials because they don’t want one biopsy, much less two or three,” says Michelle Lai, a gastroenterologist at Beth Israel Deaconess Medical Center in Boston. “We just don’t have a good biomarker to say that we can see the disease is improving.”

For now, the Food and Drug Administration has said that a successful drug for NASH is considered to be one that helps on at least one of two fronts. It must either resolve pathological evidence of steatohepatitis or improve liver scarring without making NASH worse.

Considering the lack of treatment options and the high cost of drug development, it makes sense that the FDA would set an achievable benchmark for what’s considered an approvable first generation of drug, says Paul Pockros, a hepatologist at Scripps Clinic and Scripps Translational Science Institute in La Jolla, Calif. Still, Pockros adds, “I think the bar is low.”

Physicians may have several options that hit those benchmarks in the coming years. Four candidates for treating NASH are nearing possible approval, and dozens more are working their way through Phase 1 and 2 trials. These drugs all work in different ways, some targeting metabolism and others targeting molecular pathways that regulate tissue inflammation and cell damage.

Eventually, NASH patients may require combinations of multiple drugs, or some sort of radiological or serum diagnostic biomarkers to identify which drug works best for which patient, says Zobair Younossi, a hepatologist at the Center for Liver Diseases at Inova Fairfax Hospital in Falls Church, Va. “I don’t think there’s going to be a single one drug that can cure this disease,” he says. “There is significant evidence suggesting that NASH is a phenotype. There are multiple pathways to this disease, so to make a difference you have to address a number of these pathways.”

Such treatments will likely not come cheaply. Obeticholic acid, a drug manufactured by Intercept Pharmaceuticals that is being studied as a potential NASH treatment, is already approved for a different chronic liver disease, primary biliary cholangitis. It was priced at $70,000 per year. And, unlike sofosbuvir for hepatitis C, these new NASH drugs are long-term treatments, not cures, and must be cost-effective.

“They’re not going to be a magic pill, honestly,” says Lai, “because NASH is part of the metabolic syndrome—diabetes, high blood presssure, high cholesterol.” Despite all of these concerns, the current standard of care—getting patients to diet and exercise—isn’t working, so physicians are looking forward to new options for their patients. “It is important to treat the liver, but also to get the whole patient healthier in general,” she says.

Still, Lai wishes insurance companies would reimburse for the time she spends counseling patients about weight loss, exercise and diet. “It’s appealing to say, ‘Look, we have a drug that can treat this disease,’” she says. But without a more holistic approach, she worries that NASH will be just another expensive symptom of the obesity epidemic, awaiting a smarter treatment of its root cause.