Alcohol abuse is the leading cause of liver disease and associated mortality in the United States and other western nations. Yet according to Mayo Clinic hepatologist Vijay Shah, M.D., the lack of research and funding for alcoholic liver disease is striking.
"If you look at the ratio of the estimated death rate of different liver diseases compared with the number of trials focused on these diseases — what you might call the death-to-trial ratio — you can see that alcoholic liver disease is clinically understudied," he says.
Hepatitis B, for example, which accounts for roughly 1,100 out of every 100,000 deaths, has 850 registered clinical trials compared with 34 trials for alcoholic liver disease, which claims nearly 12 times as many lives.
Whatever the reason for the disparity — socioeconomic bias, a lack of committed researchers, disincentivized drug companies — the National Institutes of Health hopes to overcome it by specifically funding translational research in alcoholic hepatitis (AH).
To that end, Indiana University, Mayo Clinic and Virginia Commonwealth University have formed the Translational Research and Evolving Alcoholic-hepatitis Treatment (TREAT) consortium, which aims to increase understanding of the mechanisms of AH and develop and test novel therapies for the disease. Another goal is to establish a multicenter registry of patients with severe AH and matched controls — heavy drinkers with no obvious liver disease — and to develop a robust biorepository of their tissue and serum samples for future research.
The consortium will soon start enrolling patients for three multicenter clinical trials that will begin this summer and continue for four years.
One proof-of-concept trial will evaluate the use of Imm 124-E — bovine colostrum enriched with IgG anti-lipopolysaccharide (LPS) — in people with severe AH. Lipopolysaccharide endotoxin has been shown to play a major role in the disease, and reducing LPS may potentially improve symptoms. The study will also look at the role of microbiome-derived metabolites in the genesis and severity of AH.
A second multicenter placebo-controlled randomized controlled trial will look at bile salt metabolism in AH to determine whether the farnesoid X receptor (FXR) agonist obeticholic acid can reverse liver abnormalities by activating FXR signaling.
The third trial, centered at Mayo Clinic, will evaluate the ability of the caspase inhibitor emricasan to improve clinical outcomes in people with severe AH. In this randomized, double-blind, placebo-controlled study, 60 patients with severe AH who are not candidates for corticosteroid therapy will receive emricasan or a placebo for one month. At present, people unable to tolerate steroids have few treatment options. This study will also determine how cell death pathways contribute to AH and whether eliminating them through caspase inhibition can prevent liver inflammation and injury.
People with severe AH are at high risk of early death — at a rate of 50 percent within 30 days — and progression to cirrhosis. Recently, AH has also been linked to metabolic syndrome and viral hepatitis, both risk factors for hepatocellular cancer, making an even stronger case for the vital importance of AH research.
Dr. Shah stresses that the goal of the current trials is to advance understanding of AH. "Alcoholic liver disease is so common, yet our treatments are so few," he says. "We have to move the bar forward here."