Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease

Abstract

Background & aims: Ammonia levels predicted hospitalisation in a recent landmark study not accounting for portal hypertension and systemic inflammation severity. We investigated (i) the prognostic value of venous ammonia levels (outcome cohort) for liver-related outcomes while accounting for these factors and (ii) its correlation with key disease-driving mechanisms (biomarker cohort).

Methods: (i) The outcome cohort included 549 clinically stable outpatients with evidence of advanced chronic liver disease. (ii) The partly overlapping biomarker cohort comprised 193 individuals, recruited from the prospective Vienna Cirrhosis Study (VICIS: NCT03267615).

Results: (i) In the outcome cohort, ammonia increased across clinical stages as well as hepatic venous pressure gradient and United Network for Organ Sharing model for end-stage liver disease (2016) strata and were independently linked with diabetes. Ammonia was associated with liver-related death, even after multivariable adjustment (adjusted hazard ratio [aHR]: 1.05 [95% CI: 1.00-1.10]; p = 0.044). The recently proposed cut-off (≥1.4 × upper limit of normal) was independently predictive of hepatic decompensation (aHR: 2.08 [95% CI: 1.35-3.22]; p <0.001), non-elective liver-related hospitalisation (aHR: 1.86 [95% CI: 1.17-2.95]; p = 0.008), and - in those with decompensated advanced chronic liver disease - acute-on-chronic liver failure (aHR: 1.71 [95% CI: 1.05-2.80]; p = 0.031). (ii) Besides hepatic venous pressure gradient, venous ammonia was correlated with markers of endothelial dysfunction and liver fibrogenesis/matrix remodelling in the biomarker cohort.

Conclusions: Venous ammonia predicts hepatic decompensation, non-elective liver-related hospitalisation, acute-on-chronic liver failure, and liver-related death, independently of established prognostic indicators including C-reactive protein and hepatic venous pressure gradient. Although venous ammonia is linked with several key disease-driving mechanisms, its prognostic value is not explained by associated hepatic dysfunction, systemic inflammation, or portal hypertension severity, suggesting direct toxicity.

Impact and implications: A recent landmark study linked ammonia levels (a simple blood test) with hospitalisation/death in individuals with clinically stable cirrhosis. Our study extends the prognostic value of venous ammonia to other important liver-related complications. Although venous ammonia is linked with several key disease-driving mechanisms, they do not fully explain its prognostic value. This supports the concept of direct ammonia toxicity and ammonia-lowering drugs as disease-modifying treatment.

Keywords: ACLD, advanced chronic liver disease; ACLF, acute-on-chronic liver failure; ARLD, alcohol-related liver disease; AUROC, area under the receiver operating characteristic curve; Acute-on-chronic liver failure; BAs, Bile acids; CRP, C-reactive protein; CTP, Child–Turcotte–Pugh score; Cirrhosis; Death; Decompensation; ELF®-test, enhanced liver fibrosis-test; HE, hepatic encephalopathy; HSC, hepatic stellate cell; HVPG, hepatic venous pressure gradient; Hepatic encephalopathy; MAFLD, metabolic-associated fatty liver disease; MAP, mean arterial pressure; NAFLD, non-alcoholic fatty liver disease; NH3-ULN, ammonia-adjusted for the upper limit of normal; PCT, procalcitonin; SHR, subdistribution hazard ratio; UNOS MELD (2016), United Network for Organ Sharing model for end-stage liver disease (2016); aHR, adjusted hazard ratio; vWF, von Willebrand factor.