Lean MAFLD: A Hepatocentric Phenotype with Systemic Manifestations

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) continues to increase worldwide, partly because of rising rates of obesity and metabolic syndrome. However, a substantial proportion of patients with MAFLD are neither overweight nor obese and are classified as having lean MAFLD. The increasingly recognized phenotype of lean MAFLD challenges the traditional paradigm linking obesity to metabolic risk. Despite a normal body mass index (BMI), lean MAFLD is associated with substantial metabolic dysfunction and a range of extrahepatic manifestations. Evidence from systematic reviews and meta-analyses including more than 10 million individuals indicates that patients with lean MAFLD have metabolic profiles comparable to those of overweight or obese patients with MAFLD, including insulin resistance, dyslipidemia, and hypertension. Importantly, although cardiovascular and cancer-related mortality appear broadly similar across BMI categories, liver-related mortality is consistently higher in lean individuals, suggesting distinct hepatocentric vulnerability. Variation in all-cause mortality estimates is influenced by disease severity, study design, and ethnicity. Important mechanistic factors include genetic susceptibility, sarcopenia, and visceral adiposity. These findings support comprehensive metabolic and hepatic assessment in lean MAFLD beyond BMI-based risk classification. This review examines lean MAFLD as a hepatocentric phenotype with systemic effects beyond BMI.