Clinical outcomes of lean metabolic dysfunction-associated steatotic liver disease by phenotypic subtypes.

Abstract

Aims: Lean metabolic dysfunction-associated steatotic liver disease (MASLD) is often treated as a single entity despite substantial heterogeneity. We assessed whether body mass index (BMI) strata, cardio-metabolic risk factor (CMRF) phenotype, and CMRF burden stratify the risk of clinical outcomes.

Methods: Using the TriNetX Global Network, we identified adults with MASLD from 2005 to 2024. Lean MASLD was defined by BMI less than 25 kg/m² and stratified into underweight and normal-weight groups. Underweight and normal-weight MASLD were compared after 1:1 propensity score matching. Within normal-weight MASLD, phenotypes were defined as hypertension-only, type 2 diabetes (T2D)-only, dyslipidemia-only, and multi-factor burden, categorized as 2 CMRF or 3 CMRF. Outcomes were major adverse liver outcomes (MALO), major adverse cardiovascular events (MACE), extrahepatic cancer, and all-cause mortality.

Results: We identified 40,456 patients with lean MASLD, including 2121 underweight and 38,335 normal weight. After matching, 2115 patients remained in each group. Underweight MASLD had higher risks of all-cause mortality (HR 2.03; 95% CI 1.68-2.44) and MALO (HR 2.01; 95% CI 1.49-2.70). MACE risk was higher (HR 1.30; 95% CI 1.02-1.66), while extrahepatic cancer was not significantly different (HR, 1.14; 95% CI 0.85-1.52). Among normal-weight MASLD, multi-factor burden showed graded increases in mortality, MALO, and MACE compared with hypertension-only. T2D-only was associated with higher MALO, while dyslipidemia-only was associated with lower risks of mortality, MALO, and MACE.

Conclusions: Lean MASLD is prognostically heterogeneous. Underweight status and CMRF phenotype and burden identify clinically meaningful risk strata across hepatic and extrahepatic outcomes.