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Rare inheritable form of NAFLD driven by gene mutation

Researchers identified monoallelic ABHD5 mutations as a driver of inheritable nonalcoholic fatty liver disease that manifests after age 40 years, according to data published in Journal of Hepatology.

“The existence of inherited forms of NAFLD has been suspected, but neither a specific causal gene or a susceptibility locus has been identified,” Leila Youssefian, MSc, from Thomas Jefferson University in Philadelphia, Pennsylvania, and colleagues wrote. “The specific metabolic and cellular mechanism(s) leading to NAFLD are still under investigation, but there is strong evidence that increased hepatic deposition of triglycerides resulting from an imbalance in lipid storage ... plays an important role in the establishment and progression of NAFLD to [nonalcoholic steatohepatitis].”

According to Youssefian and colleagues, biallelic mutations in the same gene encoding for the lipid droplet-binding protein CGI-58 have been reported in patients with Chanarin-Dorfman syndrome (CDS). CGI-58, the protein encoded by ABHD5, is a highly conserved regulator of adipose triglyceride lipase and is involved in lipid metabolism, tumor progression, viral replication, and skin barrier formation.

To explore the potential presence of NAFLD in heterozygous carriers of ABHD5 mutations, the researchers analyzed six independent, highly consanguineous Iranian families with confirmed CDS along with a control group of family members without CDS.

Thirty-seven of 39 participants with ABHD5 mutations showed evidence of NAFLD, dyslipidemia, or both. All individuals aged 40 years or older with monoallelic mutations showed evidence of liver involvement, dyslipidemia, or both. The youngest ABHD5 carrier was aged 21 years and showed initial signs of NAFLD, “suggesting an age-dependent development of this inherited form of NAFLD, with complete clinical expression after the fourth decade of life,” the researchers wrote.

“Our findings disclose the existence of a rare heritable form of NAFLD associated with monoallelic mutations in ABHD5 involved in neutral lipid metabolism and highlight the importance of further studies on the role of [lipid droplet] disorders in the liver pathology,” Youssefian and colleagues concluded. – by Talitha Bennett

Disclosure: The researchers report no relevant financial disclosures.