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

Background & Aims: Excessive alcohol consumption accelerates fibrosis progression in steatotic liver disease. Disease activity can be described by fibrogenic activity, of which collagen formation is a central process. Type III collagen formation (PRO-C3) is a biomarker of fibrosis activity. We aimed to evaluate whether PRO-C3 predicts clinical outcomes in alcohol-related liver disease (ALD) independent of fibrosis stage. Methods: We conducted a prospective cohort study including 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, liver biopsies, clinical investigations, and non-invasive blood tests were performed. During follow-up, patients’ electronic healthcare records were manually reviewed for decompensation events and all-cause mortality. Decompensation was defined according to 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). At baseline, fibrosis stages were F0–1 (n = 260), F2 (n = 107), and F3-4 (n = 91). During follow-up, 67 patients experienced decompensation and 100 died. PRO-C3 provided prognostic value beyond fibrosis stage as a predictor of decompensation, both in patients with no to moderate fibrosis (F0-2; subhazard ratio per unit increase in PRO-C3 1.05; 95% CI 1.03–1.07; p <0.001) and in patients with cirrhosis (F4; subhazard ratio 1.01; 95% CI 1.00–1.03; p = 0.048). Conclusions: In ALD, prognosis is determined by both baseline fibrosis stage and markers of fibrosis activity. PRO-C3, a biomarker of fibrosis activity, was more strongly associated with the risk of decompensation 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.