Liver Disease Moving in Silence


Today, the field has a packed pipeline of drugs, mostly small molecules, that offer multiple approaches to tackling the three hallmarks of NASH: fat accumulation, inflammation, and fibrosis on the liver. Reversing the course of the disease will take a combination of drugs, liver specialists believe. The disease progresses slowly over years or even decades and researchers have yet to figure out when someone with a fatty liver is at risk for developing the inflammation and fibrosis that define NASH. That subtle, slow-moving process begins with the build-up of fat in the liver, a condition called nonalcoholic fatty liver disease, or NAFLD because it is not driven by alcohol consumption.

According to the U.S. Centers for Disease Control & Prevention, up to 20% of the American population has NAFLD, which occurs when fat makes up more than 5% of the liver. As Abdelmalek notes, “If you have isolated fat, you may live and die with your fatty liver and never know it.” But a portion of that population a number pegged at roughly 16 million people will go on to develop NASH’s telltale inflammation and scarring.

Anywhere from 1 million to 3 million people with NASH will go on to develop cirrhosis, where scarring has stiffened the liver so much that it can no longer function properly. From there, the outcomes can be grim: liver failure, liver transplant, or liver cancer. Studies have shown again and again that people are unable to stick to a healthier regime, and liver specialists would like to be able to offer treatments.

The need for drugs is made more urgent by the fact that obese, diabetic people are often low on the liver transplant list. Researchers still don’t know the speed at which NAFLD progresses, why some people with a fatty liver develop inflammation and scarring, and if particular groups of people are more at risk for developing cirrhosis.

“The challenge with fatty liver disease is that the targets are still not well characterized, the disease is very heterogeneous, the pathways are complex, and the animal models don’t characterize the human phenotype well,” Duke’s Abdelmalek says.

Of the 110 people given obeticholic acid, 45% saw a marked improvement in their “NAFLD score”-a measure of fat, inflammation, and swelling of liver cells-without their liver scarring getting worse. Because of the NASH population’s heterogeneity, the trial will be huge: The goal is to enroll 2,500 people, the majority of whom have Stage 2 or Stage 3 liver fibrosis, meaning they have significant scarring but are not yet considered cirrhotic.

FXR has become an attractive target because it has a hand in regulating multiple contributors to the complex disease: the synthesis and transport of bile acids, the breakdown of lipids in the liver and intestine, and the maintenance of glucose levels. Two side effects have emerged in studies of obeticholic acid, which has already been approved to treat another kind of liver disease.


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