This article is more than 5 years old. Information may no longer be current.

Genetic steatosis linked to hepatic fibrosis in twins

Individuals with genetic susceptibility to hepatic steatosis also have genetic susceptibility to hepatic fibrosis, according to results of a cross-sectional analysis of twin pairs.

“Our lab had previously shown that liver fat and liver fibrosis are heritable traits. This study shows that liver fat and fibrosis are not only heritable among themselves, but also with one another,” Jeffrey Y. Cui, MD, of the NAFLD Research Center, University of California San Diego, told Healio.com/Hepatology. “Therefore, the same genes involved with liver fat development may also be involved with liver fibrosis development.”

Jeffrey Y. Cui

Cui and colleagues, including Rohit Loomba, MD, MHSc, from the NAFLD Translational Research Unit, University of California San Diego, sought to determine whether individuals with genetic susceptibilities to hepatic steatosis had the same susceptibilities to hepatic fibrosis. Therefore, they conducted an analysis of a prospective cohort of community-dwelling monozygotic (n = 45) and dizygotic (n = 20) twin pairs living in southern California. Each individual underwent clinical research assessment at the NAFLD Research Center where researchers measured hepatic steatosis via MRI-proton density fat fraction (MRI-PDFF) and hepatic fibrosis with magnetic resonance elastography (MRE).

Rohit Loomba

A standard bivariate twin model was used to assess the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects, according to the research.

Twenty percent of the cohort had hepatic steatosis determine by an MRI-PDFF of 5% or greater (26/130) and 8.2% had hepatic fibrosis measured by MRE 3 Kpa or greater (10/122). Twins with NAFLD had higher hepatic steatosis via MRI-PDFF (10.7 ± 5.1 vs. 2.4 ± 0.9; P < .0001) and hepatic fibrosis via MRE (3 ± 1.2 vs. 2.2 ± 0.4; P < .0001) compared with twins without NAFLD.

The following metabolic risk factors had shared genetic effects with hepatic steatosis: diastolic blood pressure (0.444; 95% CI, 0.444-0.742), systolic blood pressure (0.36; 95% CI, 0.052-0.636), triglycerides (0.678; 95% CI, 0.585-0.83), glucose (0.716; 95% CI, 0.716-1), homeostatic model assessment of insulin resistance (HOMA-IR; 0.49; 95% CI, 0.212-0.739), insulin (0.289; 95% CI, 0.017-0.531), hemoglobin A1c (HbA1c; 0.588; 95% CI, 0.588-1) and low high-density lipoprotein (HDL; –0.451; 95% CI, –0.643 to 0.216).

The following metabolic risk factors shared genetic effects with hepatic fibrosis: triglycerides (0.657; 95% CI, 0.657-1), glucose (0.746; 95% CI, 0.746-1), HOMA-IR (0.61; 95% CI, 0.218-1), insulin (0.429; 95% CI, 0.167-0.735), HbA1c (0.566; 95% CI, 0.566-1) and low HDL (–0.614; 95% CI, –0.890 to –0.614).

Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% CI, 0.716-1; P < .0001).

“Currently, most liver experts believe that the presence of liver fat alone is a benign trait, and only liver fibrosis can result in adverse outcomes such as increased mortality and liver transplantation. Our results provide a shift from this paradigm, and suggest that fatty liver alone, without fibrosis, is enough to portend a worse outcome in NAFLD patients, even if these adverse outcomes will take many years to develop,” Cui said.

The bivariate twin model showed a significant shared environmental effect between hepatic steatosis and ferritin at 0.307 (95% CI, 0.019-0.544). No environmental effect between hepatic fibrosis and metabolic risk factors were observed.

“These findings provide a new paradigm linking liver fat with liver fibrosis. It was earlier believed that fat has nothing to do with fibrosis and both of these were regulated by independent mechanisms,” Loomba told Healio.com/Hepatology.

The researchers concluded: “Additional studies with larger sample sizes will be needed to identify individual genes or pathways that may be implicated in hepatic steatogenesis and/or fibrogenesis. The identification of these genes may allow for further individualized, targeted therapy that may prevent and even reverse hepatic steatosis and fibrosis.” – by Melinda Stevens

Disclosure: Cui reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.