Lower circulating angiotensinogen levels across ACLD stages are associated with hepatic dysfunction and mortality.

INTRODUCTION

The liver produces angiotensinogen (AGT), the key upstream precursor of the renin-angiotensin system (RAS). We measured AGT levels in patients across distinct advanced chronic liver disease (ACLD) stages and investigated the impact of AGT levels on clinical outcomes.

METHODS

We included clinically stable ACLD outpatients undergoing hepatic venous pressure gradient (HVPG) measurement between May 2018 and October 2023, as well as healthy controls (HCs) recruited in the prospective Vienna Cirrhosis Study (VICIS; NCT03267615). AGT was assessed by converting it to angiotensin I (Ang I) through incubation with excess recombinant human renin. RAS parameters were measured by liquid chromatography-tandem mass spectrometry. Patients were stratified as compensated (cACLD), single decompensated (sdACLD), or further decompensated ACLD (fdACLD).

RESULTS

Overall, 60 individuals (cACLD: n=16; sdACLD: n=22; fdACLD: n=12; HC: n=10) were included. AGT levels decreased significantly compared with HC and with increasing ACLD severity (HC: 943.2 vs. cACLD: 550.4 vs. sdACLD: 476.9 vs. fdACLD: 439.8 nmol/L; p<0.001). In contrast, plasma concentrations of Ang II (cACLD: 23.1 vs. sdACLD: 156.0 vs. fdACLD: 162.4 pmol/L; p=0.002) and Ang 1-7 (cACLD: 3.0 vs. sdACLD: 3.2 vs. fdACLD: 8.5 pmol/L; p=0.022) increased significantly with ACLD severity. AGT did not correlate with Ang II (ρ=-0.23; p=0.101), but with Ang 1-7 (ρ=0.32; p=0.022) and MELD-Na (ρ=-0.29; p=0.042). Exploratory survival analyses, limited by the small sample size, showed that lower AGT was associated with all-cause mortality (adjusted for age and MELD-Na: asHR: 1.59; 95% CI: 1.09-2.27; p=0.012/adjusted for age and albumin: asHR: 1.52; 95% CI: 1.05-2.21; p=0.026).

CONCLUSIONS

AGT levels decreased in ACLD, correlated with hepatic dysfunction, and were linked to all-cause mortality in exploratory survival analyses. Still, classical and alternative RAS parameters increased in parallel to ACLD severity.