Liver Fibrosis Risk Equal Parts Genes and Environment

Pam Harrison

October 21, 2015

Genes contribute to at least half of the risk of developing not only hepatic steatosis but also hepatic fibrosis, results from a twin study suggest. Identification of new genetic targets that contribute to fibrosis could open the door to new therapeutic approaches for this serious liver disease.

"I had anticipated that the heritability of hepatic steatosis (fat in the liver) would be somewhere between 30% to 50%, and it was 50%, but I did not expect to find that hepatic fibrosis would have 50% heritability as well, even after adjustment for age, sex, and ethnicity," Rohit Loomba, MD, from the University of California, San Diego, in La Jolla, told Medscape Medical News.

"This means that we can now look for relevant genes as potential therapeutic targets for the treatment of hepatic fibrosis."

The study, published online August 20 in Gastroenterology, was a cross-sectional analysis of a prospective cohort study of 60 pairs of twins residing in southern California, 42 of whom were monozygotic and 18 dizygotic. The average age of the cohort was 45.7 years, and the average body mass index was 26.4 kg/m2.

Participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver, and hepatic steatosis or fatty liver was quantified noninvasively by MRI-determined proton-density-fat-fraction (MRI-PDFF). The researchers estimated liver fibrosis based on stiffness measured by magnetic resonance elastography.

Nonalcoholic fatty liver disease was defined as the presence of hepatic steatosis on MRI-PDFF of 5% or more without any secondary causes of hepatic steatosis such as significant alcohol intake.

"Twenty-six of the 120 subjects (21.7%) had non-alcoholic fatty liver disease," Dr Loomba and colleagues write.

The monozygotic twin-pairs showed a robust correlation in hepatic steatosis, as quantified by MRI-PDFF (P < .0001), but the dizygotic twin-pairs did not. Similarly, the monozygotic twin-pairs showed a robust correlation in liver fibrosis, as quantified by magnetic resonance elastography-stiffness (P < .002), but the dizygotic twin-pairs did not.

"[T]his study provides evidence that both hepatic steatosis and hepatic fibrosis are heritable traits," the investigators observe.

The data also confirm that hepatic steatosis is closely linked to metabolic traits and, for the first time, that genes and the environment each contribute equally to the trait of hepatic fibrosis.

"Currently, people are looking into some potential genetic targets," Dr Loomba said. For example, as a next step, Dr Loomba and colleagues have expanded their study to extended family members and relatives with nonalcoholic steatohepatitis cirrhosis.

"I think we will be able to find genes for [nonalcoholic steatohepatitis] cirrhosis running in these families," Dr Loomba said. "And once we find some of those genes, we can look for perturbations in those pathways and directly target them."

Heritability of Fatty Liver

Asked by Medscape Medical News to comment on the study, Chris Day, FmedSci, pro-vice-chancellor and professor of liver medicine, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom, said it was not a big surprise that the heritability of fatty liver is 50%.

"The surprise is that 50% of fibrosis was heritable as well, and I don't think anybody's really looked at this before in as detailed a way," Dr Day said.

In his own research, Dr Day noted that they have identified several genes that are associated with the risk of developing fibrosis, "so there is no doubt that there is a heritable component to fibrosis," he noted.

"What this study has done is verify that fibrosis is equally genetic as fatty liver, and the fact that fibrosis is 50% genetic really gives strength to those of us in the field to continue to try and isolate fibrosis genes."

Support for this study was provided by Atlantic Philanthropies Inc, the John A. Hartford Foundation, the Association of Specialty Professors, and the American Gastroenterological Association. The authors and Dr Day have disclosed no relevant financial relationships.

Gastroenterology. Published online August 20, 2015. Abstract

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