S2328 Phenotyping MASLD Using Unsupervised Clustering of Liver and Metabolic Traits in NHANES (2017–2018)

Introduction: The redefinition of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes its connection to cardiometabolic risk and replaces the term NAFLD to reduce stigma and simplify diagnosis. However, this simplification may overlook heterogeneity among affected individuals. Identifying patient sub-populations may guide more specific management. To address this gap, we applied unsupervised clustering to identify distinct MASLD phenotypes and examine how they differ in metabolic, hepatic, and demographic traits. Methods: We analyzed U.S. adults (≥18 years) from NHANES 2017–2018 with complete transient elastography, laboratory, and anthropometric data. K-means clustering was performed on scaled variables: liver stiffness (LSM), steatosis (CAP), body mass index (BMI), waist circumference, glucose, triglycerides (TG), HDL, and blood pressure. MASLD was defined as alanine aminotransferase (ALT) ≥40 U/L with ≥2 metabolic risk factors (BMI ≥25 kg/m2, TG ≥150 mg/dL, glucose ≥100 mg/dL, or low sex-specific HDL). Clusters were compared by liver traits, MASLD prevalence, fibrosis-4 (FIB-4) score, age, sex, and race/ethnicity. Results: Among 3,415 participants, 4 distinct clusters emerged. Cluster 1, “Young Men with Advanced Fibrosis” (n = 165): Most fibrotic (LSM 15.6 kPa), highest ALT and FIB-4, with 42.4% MASLD prevalence. Predominantly younger men, and Hispanic and non-Hispanic Black individuals. Cluster 2, “Metabolically Obese with Severe Steatosis” (n = 1,110): Metabolically obese (BMI 35.9, glucose 113.2, CAP 311.5), highest MASLD prevalence (45.9%). Balanced by age and sex; 38% non-Hispanic White. Cluster 3, “Overweight Individuals with Moderate Steatosis” (n = 727): Overweight with moderate steatosis (CAP 258.5), relatively preserved HDL; MASLD in 40.3%. Slight man predominance; 35% non-Hispanic Black. Cluster 4, “Lean, Low-Risk, Metabolically Healthy” (n = 1,413): Leanest profile (BMI 24.1, CAP 222.7, LSM 4.8), highest HDL, and lowest MASLD prevalence (22.8%). Skewed woman and younger. Despite differing metabolic profiles, MASLD prevalence remained substantial (23–46%), and ALT/FIB-4 tracked with liver stiffness. Conclusion: This clustering approach identified 4 distinct MASLD phenotypes, revealing important metabolic and demographic differences. These findings highlight MASLD as a spectrum, not a single disease state. Data-driven phenotyping may enable more precise screening, risk stratification, and personalized interventions, critical next steps in improving care for this common and often stigmatized condition.