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

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.

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.

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.

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