Biomarkers of Extracellular Matrix Remodelling Are Linked to Severity and Outcome of Advanced Chronic Liver Disease

Abstract

Background: Extracellular matrix (ECM) remodelling in advanced chronic liver disease (ACLD) is characterised by hepatic fibrosis and (sinusoidal) basement membrane development contributing to portal hypertension (PH) and clinical complications. Methods: Patients with stable ACLD (n = 232) undergoing hepatic venous pressure gradient (HVPG) measurement were included. Blood biomarkers reflecting fibrosis formation (PRO-C3, PRO-C6, PRO-C4 and PRO-C18L) and degradation (C3M, C4M and C6Ma3), as well as the Enhanced Liver Fibrosis (ELF) score were measured. Associations with disease severity and liver-related events (LRE: decompensation, acute-on-chronic liver failure, or liver-related death) were analysed. Results: The cohort included 131 (57%) patients with decompensated ACLD (dACLD), median HVPG 18 (13–21) mmHg and MELD 11 (9–14). ECM remodelling biomarkers increased in patients with dACLD and with PH severity (HVPG 6–9: n = 28, 10–19: n = 124, ≥ 20 mmHg: n = 80; all p < 0.05), except PRO-C18L (p = 0.231). Collagen degradation markers C3M and C4M—but not C6Ma3—also increased with HVPG (p < 0.01). Median follow-up was 28.9 (IQR 12.0–43.6) months. Fibrogenesis biomarkers (ELF, PRO-C3/-C4/-C6) were predictive of first decompensation in cACLD, while no clinically meaningful association with LRE was observed in dACLD. In multivariate Cox regression models adjusted for HVPG, MELD, albumin, and decompensation state, PRO-C4 (aHR per 100 ng/mL: 1.22, p < 0.001), C3M (aHR per ng/mL: 0.98, p = 0.044), and C4M (aHR per ng/mL: 0.98, p = 0.084) displayed independent prognostic value for LRE. The predictive value of fibrogenesis biomarkers for first decompensation (ELF, PRO-C3, PRO-C6) was validated in an independent cACLD cohort (n = 185). Conclusion: ECM remodelling biomarkers reflect PH and disease severity in ACLD. Their prognostic value for disease progression is largely restricted to cACLD. Future studies should investigate whether repeated measurements improve risk stratification. Trial Registration: NCT03267615.