Chronic alcohol abuse can damage the liver, leading to fat accumulation, inflammation, fibrosis (as healthy tissue is replaced with scar tissue) and, eventually, cirrhosis, a late-stage disease in which fibrosis is extensive and irreversible. Not all cases of liver disease progress to cirrhosis, however. Findings of a new study suggest that specific genetic mutations might predispose some people to developing cirrhosis. The presence of these mutations could potentially be used to identify those individuals at greater risk. Chandrashekhar R. Gandhi (University of Cincinnati and Cincinnati Children's Hospital Medical Center, OH) led the team that carried out the study. “It will be a major breakthrough if there are reliable diagnostic markers and a known genetic disposition that puts some alcoholics at increased risk to develop irreversible cirrhosis,” he said in a press release.

A lack of suitable animal models has limited study of liver cirrhosis. Gandhi's team developed a mouse model in which a protein called augmenter of liver regeneration (ALR) was depleted. ALR is required for survival of liver cells, and depletion of ALR led to the development of liver disease, including fatty liver, inflammation and fibrosis, in mice. The researchers hypothesized that deficiency of ALR might accelerate liver damage in response to stress such as alcohol abuse. To test that hypothesis, they provided ALR-deficient and wild-type mice with alcohol for a period of 4 weeks and then examined their livers. ALR-deficient mice had extensive liver fibrosis that resembled cirrhosis in people, whereas wild-type mice had accumulation of fat in the liver but did not develop fibrosis.

The researchers next investigated whether ALR was compromised in people. They searched for mutations in the gene encoding ALR and identified several single-nucleotide polymorphisms (SNPs) that had not been previously identified. Gandhi explained, “We postulate that some of these SNPs could be responsible for the predisposition to develop cirrhosis.” To test this idea, the team intends to compare the frequency of the ALR SNPs in people with and without alcoholic liver disease. Should the SNPs turn out to occur more frequently in people with liver disease, they could be used to identify those at greater risk of developing cirrhosis, allowing earlier intervention to stop or slow the progression of disease.

The results were presented by Sudhir Kumar, a member of Gandhi's team, at the American Society for Investigative Pathology Annual Meeting, part of Experimental Biology 2015 (28 March 2015; Boston, MA).