Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis

Abstract

Background: The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis.

Methods: This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE).

Results: The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8-126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1-146.1, P = 0.0438).

Conclusion: Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients.

Ucsd irb: 140084.

Funding: National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

Figure 1. Prevalence of advanced fibrosis in first-degree relatives of patients with NAFLD-cirrhosis and NAFLD without advanced fibrosis and non-NAFLD controls.

The prevalence of advanced fibrosis assessed by MRE (>3.63 kPa), expressed as percentage of individuals with advanced fibrosis among the first-degree relatives of probands with non-NAFLD (total n = 69; blue bar), NAFLD without advanced fibrosis (total n = 25; green bar), and NAFLD with cirrhosis (total n = 39; pink bar), was 1.4%, 12%, and 18%, respectively, which was both clinically and statistically significant (*P < 0.003 by Cochran-Armitage test for trend).

Figure 2. Distribution of factors associated with NAFLD and fibrosis in first-degree relatives of patients with NAFLD-cirrhosis.

The prevalence of each factor is expressed as percentage of first-degree relatives of patients with NAFLD-cirrhosis and without advanced fibrosis (blue bars; total n = 32) and percentage of first-degree relatives of patients with NAFLD-cirrhosis and advanced fibrosis (pink bars; total n = 7). DM, diabetes mellitus; HTN, hypertension. *P < 0.05 by χ² test.

Figure 3. Risk of advanced fibrosis in first-degree relatives of NAFLD-cirrhosis patients.

Compared with non-NAFLD controls (n = 69), the OR of cirrhosis in first-degree relatives of NAFLD-cirrhosis patients (n = 39) was 14.9 (95% CI, 1.8–126.0, P = 0.0133). The cirrhosis risk remained statistically and clinically significant after adjustment for age, sex, Hispanic ethnicity (no/yes), BMI, and diabetes, with a multivariable-adjusted OR of 12.5 (95% CI, 1.1–146.1, P = 0.0438). ORs were assessed by unadjusted and multivariable-adjusted logistic regression analyses.

Figure 4. Representative MRE in a proband with NAFLD-cirrhosis and her first-degree relatives.

Representative MRE map of (A) a 73-year-old female with cirrhosis diagnosed with MRE of 4.36 kPa, (B) her 69-year-old brother with cirrhosis diagnosed with MRE of 4.3 kPa, and (C) her 66-year-old sister without cirrhosis excluded with MRE of 1.82.

Figure 5. PNPLA3 p.I148M minor G allele frequencies.

The allele frequency of PNPLA3 p.I148M minor variant G is expressed as percentage of minor allele G in probands with NAFLD-cirrhosis (pink bar; total n = 12 alleles) compared with non-NAFLD controls (blue bar; total n = 92 alleles) and percentage of first-degree relatives of patients with NAFLD-cirrhosis (pink bar; total n = 46 alleles) compared with first-degree relatives of controls (blue bar; total n = 88 alleles). P value was determined using a Fisher exact test or a χ² test when appropriate.