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

Abstract

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.