The Obesity-MASLD-Myopenia Cascade: A Dynamic Loop within Metabolic Metamorphosis in Liver Disease

Background & AimsThe metabolic interplay between obesity and myopenia (MP) in chronic liver disease (CLD) remains poorly understood. We investigated whether progressive liver dysfunction mediates an obesity-MASLD (metabolic dysfunction{square}associated steatotic liver disease)-MP cascade and assessed the prognostic impact of MP and myopenic obesity (MO) in advanced CLD (ACLD). MethodsWe analyzed 859 CLD patients cross{square}sectionally and 169 obese patients longitudinally (median 38{square}months), using multimodal MRI to measure liver stiffness (LS), proton{square}density fat fraction (PDFF), and body composition. Temporal relationships between changes ({Delta}) in adiposity, muscle mass, and liver injury markers were assessed. Prognosis in ACLD (n=328) was evaluated using Cox regression. ResultsMP and MO were present in 29% and 8% of patients, respectively. In the longitudinal cohort, MO prevalence increased significantly from 15% to 23% (P{square}<{square}0.01). In fibrosis stages F0-2, {Delta}visceral adipose tissue significantly correlated with {Delta}PDFF, {Delta}ALT, and {Delta}LS (all P{square}<{square}0.01), whereas {Delta}muscle mass decreased, likely from weight loss. In F3-4, {Delta}ALBI score and {Delta}PDFF (hepatic fat "burning{square}out") independently correlated with {Delta}muscle mass (both P{square}<{square}0.01). In ACLD, MP--but not obesity itself--was an independent predictor of liver{square}related death (HR{square}2.27, 95%{square}CI{square}1.08-4.78, P{square}={square}0.025). ConclusionsOur findings suggest an obesity-MASLD-MP cascade driven by a liver-centered metabolic paradox: preserved hepatic function promotes harmful fat accumulation, whereas hepatic dysfunction leads to fat depletion (energy deficiency) and muscle loss. Recognition of this dynamic loop highlights the need for stage-specific strategies: fat reduction initially, followed by aggressive muscle preservation and energy repletion in ACLD.