Prevalence and Determinants of Liver Disease in Relatives of Italian Patients With Advanced MASLD

Abstract

Background and aimsMetabolic dysfunction associated steatotic liver disease (MASLD) has strong genetic components. The aim of this study was to examine non-invasively the prevalence of MASLD and of advanced fibrosis in relatives of patients with advanced MASLD and the risk factors for liver involvement, with a focus on the contribution of common genetic risk variants. MethodsWe prospectively enrolled 98 consecutive probands with advanced fibrosis and/or HCC due to MASLD and 160 non-twin first-degree relatives noninvasively screened for MASLD and advanced fibrosis at four Italian centers. We evaluated common genetic determinants and polygenic risk scores (PRS) of liver disease. ResultsAmong relatives, prevalence of MASLD was 56.8% overall, whereas advanced fibrosis was observed in 14.4%. At multivariable analysis in relatives, MASLD was associated with BMI (OR 1.31, 1.18-1.46) and tended to be associated with diabetes (OR 5.21, 0.97-28.10), alcohol intake (OR 1.32, 0.98-1.78) and with female sex (OR 0.54, 0.23-1.15), whereas advanced fibrosis was associated with diabetes (OR 3.13, 1.16-8.45) and nearly with BMI (OR 1.09, 1.00-1.19). Despite that the PNPLA3 risk variant was enriched in probands (p=0.003) and over-transmitted to relatives with MASLD (p=0.045), evaluation of genetic risk variants and PRS was not useful to guide noninvasive screening of advanced fibrosis in relatives. ConclusionsWe confirmed that about one in seven relatives of patients with advanced MASLD has advanced fibrosis, supporting clinical recommendations to perform family screening in this setting. Genetic risk variants contributed to liver disease within families but did not meaningfully improve fibrosis risk stratification.