MASLD Beyond the Liver: A Systemic Driver of Cardiovascular, Renal, and Oncologic Risk

Abstract Purpose of Review This review aims to synthesize current evidence on metabolic dysfunction-associated steatotic liver disease (MASLD) as a systemic driver of extrahepatic complications beyond its hepatic manifestations. We sought to answer two key questions: (1) Which multisystemic diseases show independent associations with MASLD after adjustment for traditional cardiometabolic risk factors? (2) What shared pathophysiological mechanisms link hepatic steatosis to distant organ dysfunction? Recent Findings Large cohort studies and meta-analyses demonstrate MASLD independently increases cardiovascular, renal, gastrointestinal, and oncologic risks, independently from traditional cardiometabolic risk factors. Key mechanisms include systemic inflammation, insulin resistance with hyperinsulinemia, endothelial dysfunction, visceral adipose tissue dysregulation, gut dysbiosis with metabolic endotoxemia, atherogenic dyslipidemia, PNPLA3 genetic variants, and oxidative stress. Hepatic fibrosis consistently amplifies multisystemic risk across organ systems. Summary MASLD represents a multisystem metabolic disorder requiring integrated risk assessment. Systematic fibrosis staging emerges as the strongest disease-specific prognostic factor. Future research must develop risk prediction models and liver-directed interventions targeting the gut-liver axis to mitigate MASLD's growing population-level burden