First Decompensation Outweighs Portal Vein Thrombosis in Cacld: Molecular Profiling and Derivation of the VAIL Score

BACKGROUND & AIMS:The temporal relationship between hepatic decompensation and portal vein thrombosis (PVT) in compensated advanced chronic liver disease (cACLD) remains unclear. We investigated their temporal sequence, prognostic significance, and molecular signatures and developed a biologically grounded predictive model for decompensation. METHODS:In this prospective study, 367 rigorously defined patients with cACLD without previous decompensation or PVT were followed for up to 11 years. Baseline assessment included hepatic venous pressure gradient, liver stiffness, upper endoscopy, Doppler ultrasound, and serum measurement of 35 biomarkers spanning angiogenesis, inflammation, endothelial injury, hypoxia, and gut permeability. Temporal associations were analysed using Kaplan-Meier and time-dependent Cox models. Biomarkers independently associated with decompensation were integrated to derive the VAIL score, which was compared with established prognostic scores. RESULTS:During follow-up, 102/367 (27.7%) patients developed hepatic decompensation and 22/367 (6.0%) developed non-malignant PVT. Among patients experiencing both events, decompensation preceded PVT in 53.3% whereas PVT preceded decompensation in 33.3%. Time-dependent Cox analysis showed that hepatic decompensation was the strongest determinant of mortality (HR 11.86, 95% CI 5.68 to 24.78; p<0.001), whereas PVT was not independently associated with mortality (HR 0.56, 95% CI 0.12 to 2.46; p=0.443). Biomarker profiling showed a restricted signature for isolated PVT (Tie2, mesothelin) but broad multisystem dysregulation preceding decompensation. The VAIL score showed the most robust predictive performance (optimism-corrected coefficient 1.76, 95% CI 1.48-4.36; p<0.001) after bootstrap validation, outperforming all established prognostic scores. CONCLUSIONS:In cACLD, hepatic decompensation is an early, biologically active, and prognostically dominant event, whereas PVT is a late, biologically restricted complication. The VAIL score (VEGF-D, Angiopoietin-1, I-FABP, IL-6) provides superior mechanism-based risk stratification for predicting clinical deterioration.