Characteristics and long-term mortality of patients with non-MAFLD hepatic steatosis

A cluster of hepatic steatosis without metabolic abnormalities has been excluded by the MAFLD definition, referred to as non-MAFLD steatosis. We aimed to characterize the non-MAFLD steatosis.

We included 16,308 individuals from the UK Biobank who had magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) to describe the clinical and genetic features of non-MAFLD steatosis in a cross-sectional design, and 14,797 individuals of the NHANES III who underwent abdominal ultrasonography at baseline to assess the long-term mortality of non-MAFLD steatosis in a prospective cohort design.

Of 16,308 individuals in the UK Biobank, 2747 fatty liver disease (FLD) cases (2604 MAFLD and 143 non-MAFLD) and 3007 healthy controls (without metabolic dysfunctions) were identified. The mean PDFF (10.65 vs. 9.00) and the proportion of advanced fibrosis (fibrosis-4 index > 2.67, 1.27% vs. 1.40%) were comparable between MAFLD and non-MAFLD steatosis. Non-MAFLD steatosis has the highest minor allele frequency of PNPLA3 rs738409, TM6SF2 rs58542926, and GCKR rs1260326 in contrast to the other two groups. The genetic risk score calculated by PNPLA3, TM6SF2, and GCKR has a certain predictive ability for non-MAFLD steatosis (AUROC = 0.69). NHANES III population showed that compared to healthy individuals, the adjusted hazard ratio of non-MAFLD steatosis increased by 1.52 (95% confidence interval: 1.21-1.91) and 1.78 (95% confidence interval: 1.03-3.07) for all-cause and heart disease-related mortality, respectively.

Non-MAFLD steatosis has comparable degrees of hepatic steatosis and fibrosis to MAFLD and increases the risk of mortality. Genetic predisposition highly contributes to the risk of non-MAFLD steatosis.