Metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic fatty liver disease (NAFLD): distinct fatty liver entities with different clinical outcomes?

Abstract

In 2019, metabolic dysfunction-associated fatty liver disease (MAFLD) was introduced as a novel definition in order to represent the causal etiologies (i.e., overweight, type 2 diabetes, metabolic syndrome) of the majority of patients with fatty liver disease without discrimination for chronic alcohol consumption, as non-alcoholic fatty liver disease (NAFLD) became the leading cause of chronic injury in western societies (1). NAFLD diagnosis is based on the detection of hepatic steatosis with exclusion of any secondary causality, especially chronic harmful alcohol ingestion. Unlike NAFLD, MAFLD definition requires invasive or non-invasive hepatic steatosis assessment in addition to being overweight/obese, and/or type 2 diabetes and/or the presence of two metabolic dysfunction criteria without the exclusion of other liver diseases. Therefore, MAFLD and NAFLD do not reflect the same patient population. While MAFLD includes any patient with relevant metabolic risk factors and steatosis regardless of additional causes, NAFLD includes a significant number of patients without metabolic risk factors (lean NAFLD). However, to date there is little data available on the impact of the modified definition on clinical outcome and associated mortality, as previously discussed elsewhere (2). With great interest we read the original article by Kim et al. focusing on the differences between MAFLD and NAFLD regarding cardiovascular, cancer-related, and all-cause mortality (3). Unfortunately, the authors did not have access to liver-related mortality data nor differentiate into different cancer types (i.e., hepatic vs. extrahepatic). However, in a nested analysis of the NHANES III cohort, representing 7,761 individuals, Kim et al. clearly demonstrated that MAFLD was associated with significantly higher all-cause mortality (HR =1.17; 95% CI: 1.04-1.32). In contrast, individuals that were declared as NAFLD following ultrasound diagnosis of steatosis and exclusion of harmful alcohol intake and viral hepatitis B or C had no significant increase in all-cause mortality after multivariate analysis and adjustment for metabolic risk factors. Indeed, advanced fibrosis in MAFLD, as estimated by NAFLD fibrosis score, FIB-4 or APRI resulted in an even higher risk for all-cause mortality (HR =2.0; 95% CI: 1.49-2.69), while in NAFLD, individuals with advanced fibrosis remained at a non-significant level of all-cause mortality (HR =1.45; 95% CI: 0.95-2.21). Looking at specific causes, cancer-related mortality was associated with MAFLD (HR =1.95; 95% CI: 1.05-3.62), but not with NAFLD. A recent meta-analysis revealed that MAFLD and NAFLD overlapped at a rate of 81.59% (CI: 66.51-Editorial Comment on: Kim D, Konyn P, Sandhu KK, et al. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.