NAFLD May Be Easier to Prevent than Treat

Expert Critique

FROM THE ASCO Reading Room

Melinda Engevik, PhD Postdoctoral Fellow Baylor College of Medicine

Nonalcoholic fatty liver disease (NAFLD) occurs when liver cells accumulate excess fat. This condition can be divided into fatty liver, in which there is only fat accumulation, and nonalcoholic steatohepatitis (NASH), in which there is an accumulation of fat, liver inflammation, and cell damage. NASH can progress to liver scarring, cirrhosis, and irreversible damage. NAFLD is closely associated with metabolic syndromes such as obesity and diabetes and appears to parallel an increasingly sedentary lifestyle. NAFLD has become increasingly prevalent, especially in Western countries. In the United States, NAFLD is now the most common form of chronic liver disease. Although several pharmacologic agents exist to treat the metabolic disorders that coexist with NAFLD, treatments specifically for NAFLD are lacking. As a result, new research has begun to examine potential methods for NAFLD prevention. A possible preventive measure and first-line treatment for NAFLD is lifestyle intervention. These changes include diet and exercise. It has been speculated that physical inactivity contributes to reduced insulin sensitivity, increased fat deposition, and increased free fatty acid uptake by the liver. Exercise may modulate or possibly prevent many aspects of NAFLD, including insulin resistance, metabolic syndrome, hepatic steatosis, and cardiovascular disease. In the diabetic populations, a population with a similar physiology to NAFLD, a combination of aerobic and resistance exercise achieves the greatest improvement in metabolic parameters. Further studies are needed to define the most beneficial form and duration of exercise for the prevention of NAFLD, but in general weekly exercise and diet changes can reduce the likelihood of NAFLD and improve overall quality of life.

Full Critique

Fatty liver disease is a leading -- and growing -- cause of liver-related morbidity and mortality worldwide, but effective treatments are still on the horizon, experts say.

However, lifestyle changes can prevent the development of non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH), and may lead to improvements in those with existing disease.

"Weight loss, accomplished through diet and exercise, as well as harm reduction, including curbing alcohol, are the most important interventions possible for NAFLD, even more impactful than medications," Raymond Chung, MD, chief of hepatology at Massachusetts General Hospital in Boston, told MedPage Today. "The issue is that they are also the most challenging to accomplish."

NAFLD and NASH refer to chronic liver disease resulting from the accumulation of fat in the liver, or steatosis. Fatty liver disease is closely associated with the metabolic syndrome and obesity. Traditionally, experts have distinguished between fatty liver disease in individuals who drink heavily and those who do not, but alcoholic and non-alcoholic manifestations fall along a spectrum and share some pathological features and clinical outcomes.

Fatty liver disease is typically asymptomatic in its early stages and may go undiagnosed for years or decades. Over time, however, steatosis can result in hepatocyte damage (known as ballooning), and the associated inflammation and fibrosis can interfere with normal liver function and lead to hepatocellular carcinoma. People with NAFLD have a shorter life expectancy compared with the general population, and they often die of cardiovascular disease rather than liver-related causes.

The prevalence of fatty liver disease is increasing along with the epidemic of obesity in the U.S. and worldwide. It is expected to account for a growing proportion of advanced liver disease, liver cancer, and liver transplantation as vaccination reduces the incidence of hepatitis B virus infection and new direct-acting antivirals cure hepatitis C before it can cause serious liver damage.

An estimated 65 million Americans have NAFLD, and nearly 17 million have NASH, Scott Friedman, MD, of the Icahn School of Medicine at Mount Sinai in New York City, said during a press briefing on the topic at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting this past November. He predicted that these numbers could reach 100 million and 27 million, respectively, by 2030.

Friedman and other speakers at the meeting emphasized that, unlike the situation with viral hepatitis, the general public is largely unaware of fatty liver disease, and even many medical professionals do not appreciate the extent of the problem.

"An epidemic is upon us that we have not fully recognized," Friedman told reporters.

Experimental Therapies

To date there are no approved therapies for NAFLD and NASH, but several approaches are under study.

"There are many trials of agents ranging from phase 1 to phase 3, encompassing several mechanisms that may be important to the pathogenesis of NAFLD," Chung said. "Some promising approaches include FXR [farnesoid X receptor] agonists, PPAR [peroxisome proliferator-activated receptor] agonists, ASK1 [apoptosis signal-regulating kinase 1] inhibitors, ACC1 [acetyl-CoA carboxylase 1] inhibitors, and CCR2/CCR5 inhibitors."

Rohit Loomba, MD, director of the NAFLD Research Center at the University of California at San Diego, told MedPage Today that several drugs are currently in phase 3 trials, including obeticholic acid, selonsertib, elafibrinor, and cenicriviroc, and that there are more than 50 drugs in the pipeline. These include:

• Obeticholic acid (Ocaliva), a synthetic bile acid that acts as an FXR agonist, is approved for the treatment of primary biliary cholangitis; it has shown promise for primary sclerosing cholangitis, and is being studied as a treatment for NASH. Obeticholic acid can cause severe adverse events in people with decompensated liver disease, however, prompting the FDA to require a "Black Box" warning

• Selonsertib (GS-4997), an ASK1 inhibitor that interferes with a signaling pathway that promotes inflammation and fibrosis. Loomba presented Phase 2 data at the 2016 Liver Meeting showing that the drug was safe and effective for patients with NASH and moderate to advanced fibrosis

• Elafibranor (GFT505), a PPAR alpha and delta agonist that improves insulin sensitivity and lipid metabolism and reduces inflammation. The drug did not meet its primary endpoint of reversing NASH without worsening fibrosis in the GOLDEN trial, but did improve steatosis and fibrosis in a subset of patients with moderate or severe NASH

• Cenicriviroc, a dual CCR5 and CCR2 receptor inhibitor that was previously evaluated as a treatment for HIV and is now under study for NASH. Friedman presented results from the Phase 2 CENTAUR study at the 2017 Liver Meeting, showing that although cenicriviroc did not reduce the severity of steatosis or liver inflammation more than placebo, it did lead to a significant reduction in fibrosis. Cenicriviroc is now being tested further in the Phase 3 AURORA trial

• GS-0976 is an ACC inhibitor that interferes with de novo lipogenesis, or conversion of carbohydrates into fatty acids in the liver. In another presentation at last year's Liver Meeting, Loomba reported that the drug led to significant reductions in liver fat accumulation and fibrosis in NASH patients in a Phase 2 study

• BMS-986036 is a recombinant fibroblast growth factor 21 analog that improved steatosis, hepatocyte ballooning, and liver inflammation in preclinical studies. Arun Sanyal, MD, of Virginia Commonwealth University in Richmond, reported Phase 2 study results at the Liver Meeting, showing that the drug significantly decreased liver fat and led to improved biomarkers of fibrosis and inflammation in people with NASH

Lifestyle Changes

As these and other therapy candidates make their way through the development pipeline, experts emphasize that changes in lifestyle can help improve fatty liver disease -- and better yet, prevent it from developing in the first place.

One recently published study showed that people who exercise for at least 2 and a half hours per week were 25% less likely to develop hepatic steatosis than those who were inactive, and patients with existing steatosis were more likely to see improvements.

"I advise patients to lose weight if they are overweight or obese," Loomba told MedPage Today. "I recommend losing 5% to 10% of body weight gradually, with a one pound weight loss a week."

He also recommends exercising for 30 minutes three to five times per week, avoiding sugar -- including sugar-containing beverages -- and limiting alcohol consumption to no more than one drink per day.

These lifestyle measures not only can reduce the likelihood of complications related to fatty liver disease, but they can also lower cardiovascular disease risk and improve overall quality of life.