Zinc deficiency and sarcopenia define a metabolic frailty phenotype predicting hepatic encephalopathy and early mortality in cirrhosis.

Cirrhosis is characterized by progressive metabolic vulnerability, yet early indicators of clinical decompensation remain limited. Zinc, a key cofactor in ammonia detoxification and protein metabolism, may reflect and contribute to metabolic frailty when deficient. We aimed to determine whether zinc deficiency and sarcopenia jointly define a metabolic frailty phenotype that predicts overt hepatic encephalopathy (OHE) and mortality in cirrhosis. In this 12-month prospective cohort, 109 adults with cirrhosis were followed to evaluate OHE incidence and survival. Serum zinc, dietary intake, and nutritional parameters were assessed at baseline and 3, 6, and 12 months. Sarcopenia was defined by dual-energy X-ray absorptiometry and handgrip strength. Logistic regression identified independent predictors of OHE, and Kaplan-Meier analysis evaluated survival. OHE occurred in 27.5% of patients and was associated with lower zinc levels (50.3 ± 13.2 vs. 62.8 ± 18.9 µg/dL; p = 0.002) and higher sarcopenia prevalence (53.3% vs. 16.5%; p = 0.001). Zinc deficiency was associated with increased OHE risk (OR 3.9; 95% CI 1.5-10.1; p = 0.005), while multivariable analysis identified sarcopenia, age, and Child-Pugh class as independent predictors. The coexistence of zinc deficiency and sarcopenia identified a subgroup with the highest 1-year mortality (log-rank p = 0.001). Zinc deficiency and sarcopenia were associated with adverse clinical outcomes in cirrhosis and may reflect a broader state of metabolic vulnerability. Their coexistence defines a metabolic frailty phenotype in cirrhosis, associated with reduced metabolic reserve, OHE, and poor survival. Recognition of this phenotype provides a framework for targeted nutritional and metabolic interventions aimed at restoring functional reserve.