Dual‐aetiology MAFLD and metabolic dysfunction

We thank Dr. Ma et al.1 for their interest and comments on our work.2 Consistent with our findings, the authors elegantly demonstrated that metabolic dysfunction-associated fatty liver disease (MAFLD) has a stronger independent association with a high risk of atherosclerotic cardiovascular disease (ASCVD) than does metabolic dysfunction-associated steatotic liver disease (MASLD) in a 10 365-person Chinese population via the 10-year ASCVD risk prediction model. Notably, the dual aetiology of MAFLD with either excessive alcohol intake or viral infection further augments the risk of ASCVD. This study demonstrated that the application of appropriate diagnostic criteria for MAFLD may reveal novel at-risk populations. The interplay between MAFLD and other causes of liver disease, such as alcohol intake and viral hepatitis, is complex. There are differences in how the current definitions of fatty liver disease caused by metabolic dysfunction—MAFLD and MASLD—address this issue. Multiple recent studies and viewpoints have raised various concerns and cast doubts on the ‘MetALD’ concept, which was introduced in the MASLD definition to describe patients with MASLD and excessive alcohol intake.3 No other terms to describe MASLD coexist with any other causes. In contrast, the definition of MAFLD opted not to create a new term, and instead put forth the concept of dual aetiologies, which encompasses the presence of MAFLD alongside any other cause, including excessive alcohol consumption. Additionally, although the MASLD is an adapted version of the MAFLD term and its diagnostic criteria, the MASLD criteria allow for ‘liberalized’ requirements for evidence of metabolic dysfunction to a single criterion instead of two for lean individuals, with some alterations in the metabolic risk factor cut-offs used. There is robust evidence that the risk of ASCVD increases with the number of metabolic risk factors that patients have.4, 5 The concept of dual aetiologies within the MAFLD framework could have several implications, including (1) the distinction of diagnostic criteria from inclusion criteria for research studies; (2) the enabling of the appreciation of distinct, polygenic diseases contributing to hepatic steatosis or liver injury with clinical practical expansion to include patients with MAFLD and alcohol use or other aetiologies; and (3) the identification of specific patient populations according to disease pathology and risk factors, leading to efficient disease management, such as single-aetiology versus dual-aetiology MAFLD—the latter emerging as an important condition for study owing to its potentially higher risk profile,4 as highlighted by the current study.1 In conclusion, we acknowledge the complexity of MAFLD and other coexisting aetiologies, as highlighted by Dr. Ma et al.1 The introduction of the dual aetiology framework within the MAFLD definition and the distinction of MAFLD subtypes provide an opportunity to identify specific patient populations at higher risk for hepatic and extrahepatic outcomes, thus enabling effective disease management. ME is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). The authors do not have any disclosures to report. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.