Lean MAFLD and MASLD represent an underrecognized high risk phenotype beyond body mass index
TL;DR
Clinicians should consider screening lean individuals with metabolic risk factors even when BMI is within the normal range even when BMI is within the normal range, as a pragmatic and clinically reasonable first step can be used for the early identification and prevention of complications.
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) and the more recently proposed metabolic dysfunction-associated steatotic liver disease (MASLD) represent diagnostic frameworks evolving from non-alcoholic fatty liver disease (NAFLD), highlighting a greater emphasis on underlying metabolic dysfunction. Both frameworks improve recognition of hepatic steatosis in lean individuals. This perspective focuses primarily on lean MAFLD, acknowledging where relevant evidence derives from lean NAFLD or MASLD cohorts. In Asia, the prevalence of lean MAFLD disproportionately exceeds global estimates, partly due to the inadequacy of standard body mass index (BMI) thresholds. Lean MAFLD patients exhibit distinct clinical and histological features, including elevated serum alanine transaminase (ALT), hepatocyte ballooning and steatosis. Mechanisms such as genetic predisposition, particularly Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and Transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms, mitochondrial dysfunction, endotoxemia-induced epigenetic reprogramming, and impaired bile acid signalling appear to drive disease severity independent of BMI. Observational studies, some with residual confounding by age, diabetes, sarcopenia, and study design, have reported associations between lean MAFLD and cardiovascular risk, fibrosis, and mortality that are comparable to or, in selected cohorts, exceed those observed in obese MAFLD. BMI alone is an insufficient predictor of MAFLD severity. Clinicians should consider screening lean individuals with metabolic risk factors even when BMI is within the normal range. This pragmatic and clinically reasonable first step can be used for the early identification and prevention of complications. Incorporating waist circumference, family history, routine biochemical evaluation, and hepatic ultrasonography into clinical assessment is feasible in resource-limited settings. This framework is an author-proposed approach and has not been validated in prospective trials or endorsed by clinical guidelines.