MASH Cirrhosis: A Stage-Specific Framework for Care and Clinical Trial Design

Metabolic dysfunction-associated steatohepatitis (MASH) is an increasingly important cause of cirrhosis, yet no pharmacological therapy is approved specifically for MASH cirrhosis. Completed trials indicate that this therapeutic gap reflects limitations in biological targeting, population definition, treatment duration, and endpoint selection rather than evidence that established disease is immutable. Most agents evaluated in compensated MASH cirrhosis did not meet their prespecified primary endpoints; aldafermin met an enhanced liver fibrosis endpoint without establishing histological benefit, and later assessment of efruxifermin suggested that structural change may require longer exposure. MASH cirrhosis should therefore not be investigated as a simple extension of precirrhotic MASH. Disease stage, clinically significant portal hypertension, metabolic comorbidity, and frailty influence both prognosis and treatment tolerance. Selected invasive and cross-sectional studies suggest heterogeneity in the relationship between hepatic venous pressure gradient and clinical events in advanced MASLD or MASH, but prospective data confirm that hepatic venous pressure gradient remains prognostic; these observations do not establish a universally distinct hemodynamic phenotype. Mechanistic findings involving sinusoidal endothelium, bile handling, and canalicular architecture are translational leads rather than validated clinical markers. We propose a stage-specific framework that separates current care from trial design; prioritizes clinical outcome endpoints in compensated disease with portal hypertension and in decompensated disease; and treats biopsy, liver stiffness, enhanced liver fibrosis, hemodynamic, and frailty measures according to their context and level of validation. Prospective MASH-cirrhosis cohorts and competing-risk-aware trials are now required.