Abstract

Background: Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how family history may be used to identify first-degree relatives with advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of probands who have undergone assessment of liver fibrosis who are at higher risk of NAFLD with advanced fibrosis.

Methods: This prospective, cross-sectional, familial study consisted of a derivation cohort from San Diego,USA, and a validation cohort from Helsinki, Finland. This study included consecutive adult probands (n=242) with NAFLD and advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least one of their first-degree relatives. All included probands and first-degree relatives underwent evaluation of liver fibrosis, the majority by magnetic resonance elastography.Models were derived utilizing the UCSD (derivation) cohort to detect the presence of NAFLD with advanced fibrosis. Univariable and multivariable logistic regression analyses were performed in the UCSD (derivation) cohort for factors associated with NAFLD and advanced fibrosis. To develop a simple risk score based on a points system, regression coefficients from the logistic regression model were transformed into scores by rounding to an integer. The score was then externally validated in the Helsinki (validation) cohort.

Results:

A total of 396 first-degree relatives (64% male) were included. The median (IQR) age and BMI were 47 (32-62) years and 27.6 (24.1-32.5) kg/m², respectively. Age (1-point), type 2 diabetes (1-point), obesity (2-points) and proband with NAFLD and advanced fibrosis (2-points) were predictors of advanced fibrosis among first-degree relatives in the derivation cohort (n=220) and formed the NAFLD Familial Risk score. The area under the receiver operator characteristic curve (AUC) of the NAFLD Familial Risk score for detecting advanced fibrosis was 0.94 in the validation cohort (n=176). The NAFLD Familial Risk score outperformed the Fibrosis-4 index in the validation cohort (AUC 0.94 versus 0.70, p=0.02).

Conclusion:

The NAFLD Familial Risk Score accurately identifies NAFLD with advanced fibrosis in first-degree relatives of probands who have undergone an assessment of liver fibrosis. It is simple, does not require a calculator or extensive laboratory investigations, and may be a helpful alternative to FIB-4 for screening first-degree relatives. These data may have implications for surveillance in NAFLD.