Liver and Bile
J Hepatol. 2022;77(6):1554–63
Plasma ammonia levels predict hospitalization with liver-related complications and mortality in clinically stable outpatients with cirrhosis
Background and aims: Hyperammonemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis.
Methods: 754 clinically stable outpatients with cirrhosis from 3 independent liver units were studied. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary end point was hospitalization with liver-related complications (a composite end point of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver center.
Results: Overall, 260 patients (35%) were hospitalized with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio [HR] = 2.13; 95% confidence interval [CI]: 1.89–2.40; p < 0.001) and mortality (HR = 1.45; 95% CI: 1.20–1.76; p < 0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p < 0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation.
Conclusion: Ammonia is an independent predictor of hospitalization with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications.