Navigating MASLD heterogeneity: from metabolic risk to precision stratification

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous multisystem condition characterized by hepatic steatosis occurring in the context of metabolic dysfunction, and its prevalence continues to rise globally in parallel with the epidemics of obesity, type 2 diabetes, and metabolic syndrome. The heterogeneity of MASLD spanning etiology, pathophysiology, clinical presentation, and therapeutic response, poses substantial challenges for clinical management and underscores the need for a stratified approach to diagnosis and treatment. This review provides a comprehensive overview of MASLD heterogeneity, tracing the evolution of its classification from the exclusion-based NAFLD/NASH paradigm to the current positive-diagnosis MASLD framework with four principal subtypes: isolated MASLD, MetALD, MASH, and MASLD with other liver diseases. The multifactorial etiology of MASLD is examined, encompassing hepatic lobular spatial heterogeneity, lipid overload and inflammatory pathways, genetic and epigenetic determinants, and modifiable environmental risk factors. The heterogeneous clinical manifestations, including the distinct phenotypes of lean vs. obese MASLD and variable natural disease trajectories, are discussed. Diagnostic strategies are evaluated across the spectrum of disease severity, from non-invasive screening tools (MRI-PDFF, CAP, FIB-4, elastography) to histological assessment of MASH. Therapeutic approaches, including lifestyle modification, pharmacological therapies, and surgical interventions, are reviewed. Recognizing and systematically addressing this heterogeneity is essential for advancing precision medicine in this field. Based on subtype classification, risk factor profiling, and stage-appropriate diagnostic and therapeutic strategies, this review presents a stratification framework that offers clinicians a practical roadmap for delivering more personalized and effective care across the diverse spectrum of MASLD patients. In contrast to recent comprehensive reviews that provide broad overviews of MASLD, this review specifically addresses how disease heterogeneity should drive clinical decision-making, bridging the gap between subtype classification and personalized therapeutic selection.