Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study

Abstract

Background & aims: Little is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort.

Methods: We performed a cross-sectional analysis of a cohort of well-characterized twins residing in Southern California including 60 pairs of twins (42 monozygotic and 18 dizygotic; average age, 45.7 ± 22.1 y; average body mass index, 26.4 ± 5.7 kg/m(2)). We collected data on medical history, physical examinations, fasting laboratory test results, and liver health; all participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver from January 2012 through January 2015. Hepatic steatosis was quantified noninvasively by MRI and determined based on the proton-density fat fraction (MRI-PDFF); liver fibrosis was measured based on stiffness measured by magnetic resonance elastography.

Results: Twenty-six of the 120 subjects (21.7%) had nonalcoholic fatty liver disease (defined as MRI-PDFF ≥ 5% after exclusion of other causes of hepatic steatosis). The presence of hepatic steatosis correlated between monozygotic twins (r(2) = 0.70; P < .0001) but not between dizygotic twins (r(2) = 0.36; P = .2). The level of liver fibrosis also correlated between monozygotic twins (r(2) = 0.48; P < .002) but not between dizygotic twins (r(2) = 0.12; P = .7). In multivariable models adjusted for age, sex, and ethnicity, the heritability of hepatic steatosis (based on MRI-PDFF) was 0.52 (95% confidence interval, 0.31-0.73; P < 1.1 × 10(-11)) and the heritability of hepatic fibrosis (based on liver stiffness) was 0.5 (95% confidence interval, 0.28-0.72; P <6.1 × 10(-11)).

Conclusions: A study of twins provides evidence that hepatic steatosis and hepatic fibrosis are heritable traits.

Keywords: Fatty Liver; Genetic Factors; NAFLD; NASH.

Figure 1. Twin-ship correlation by hepatic steatosis assessed by MRI

The mono-zygotic twin-pairs showed a robust correlation in hepatic steatosis as quantified by MRI-PDFF (r2 of 0.70, p-value <0.0001) but not the di-zygotic twin-pairs (r2 of 0.36, p-value .2); demonstrating that hepatic steatosis is a heritable trait.

Figure 2. Twin-ship correlation by hepatic fibrosis assessed by MRE

The mono-zygotic twin-pairs showed a robust correlation in liver fibrosis as quantified by MRE-stiffness (r2 of 0.48, p-value <0.002) but not the di-zygotic twin-pairs (r2 of .12, p-value .7); demonstrating that hepatic fibrosis is a heritable trait.

Figure 3. Novel MRI-PDFF map and MRE-map demonstrating the detailed phenotyping of the twins based upon the presence (or absence) of hepatic steatosis

Footnote: A twin-pair that is concordant for presence of NAFLD and advanced fibrosis (figure 3A), a twin-pair that is concordant for the absence of NAFLD (figure 3B), and a twin-pair that is discordant for NAFLD (figure 3C)

Figure 3. Novel MRI-PDFF map and MRE-map demonstrating the detailed phenotyping of the twins based upon the presence (or absence) of hepatic steatosis

Footnote: A twin-pair that is concordant for presence of NAFLD and advanced fibrosis (figure 3A), a twin-pair that is concordant for the absence of NAFLD (figure 3B), and a twin-pair that is discordant for NAFLD (figure 3C)

Figure 3. Novel MRI-PDFF map and MRE-map demonstrating the detailed phenotyping of the twins based upon the presence (or absence) of hepatic steatosis

Footnote: A twin-pair that is concordant for presence of NAFLD and advanced fibrosis (figure 3A), a twin-pair that is concordant for the absence of NAFLD (figure 3B), and a twin-pair that is discordant for NAFLD (figure 3C)