Work

Fibrosis activity vs. disease stage: Complementary and independent predictors of outcomes in alcohol-related liver disease

Year: 2026

Type: article

Abstract: Background & Aims Excessive alcohol consumption accelerates fibrosis progression in steatotic liver disease. Disease activity may be described by fibroblast activity of which collagen formation is a central event and type III collagen formation (PRO-C3) is a biomarker of that. We aimed to evaluate if PRO-C3 predicts clinical outcomes in alcohol-related liver disease (ALD) independent of fibrosis stage. Methods Prospective cohort study of patients with prior or current excessive alcohol intake (men: ≥36 g/day, women: ≥24 g/day for >1 year) and no prior decompensation. At baseline, we performed liver biopsies, clinical investigations, and non-invasive blood tests. During follow up, we manually reviewed patients' electronic healthcare records for decompensations and all-cause mortality. Decompensation was defined per Baveno VII recommendations. Results We followed 458 patients with ALD (76% male, mean age 57±10 years) for a median of 5.9 years (IQR 4.5-7.8). Baseline fibrosis stages: F0-1 (n=260), F2 (n=107), F3-4 (n=91). During follow-up, 67 patients decompensated and 100 died. PRO-C3 added prognostic value on top of fibrosis stage as a predictor of decompensation, both for patients with no to moderate fibrosis, F0-2 (subhazard ratio, sHR PRO-C3 1.05; 95% CI 1.03-1.07, p<0.001), and cirrhosis, F4 (sHR PRO-C3 1.01; 95% CI 1.00-1.03, p=0.048). In head-to-head comparison, PRO-C3 (< 15.6 vs ≥ 15.6 ng/mL) was associated with higher risk of later decompensation than fibrosis stage (F0-2 vs F3-4), with sHR PRO-C3 7.97 (95% CI 3.17-20.03, p<0.001) versus sHR F-stage 4.99 (95% CI 2.79-8.95, p<0.001), respectively. Conclusions In ALD, patients' prognoses are predicted by both baseline markers of disease stage and fibrosis activity. PRO-C3, a marker of fibrosis activity, was associated with higher risk of outcomes than Kleiner fibrosis stage, and predicted decompensation across fibrosis stages. Impact and implications This study shows that fibrosis activity measured by PRO-C3 captures dynamic disease processes in alcohol-related liver disease that are not fully reflected by histological fibrosis stage. These findings are important for clinicians and patients because PRO-C3 independently predicts decompensation and supports stratifying risk by fibrosis activity in addition to stage. Practically, incorporating fibrosis-activity biomarkers could guide earlier monitoring and interventions aimed at modulating fibrogenic activity.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2026.101746