Stage-Specific Drivers of Clinical Progression in Advanced Chronic Liver Disease

Different pathophysiological mechanisms contribute to the progression of advanced chronic liver disease. This study investigated the clinical trajectory of advanced chronic liver disease in a contemporary cohort and evaluated biomarkers reflecting key pathophysiological mechanisms for their stage-specific prognostic value.

Patients with advanced chronic liver disease (n = 464) were prospectively recruited at hepatic venous pressure gradient measurement between 2017 and 2021 (VICIS; NCT03267615). Clinical states at baseline and follow-up were defined as compensated advanced chronic liver disease, first decompensation, further decompensation/acute-on-chronic liver failure (combined), liver-related death, and recompensation. Multistate modeling was used to investigate the risk of stage transitions during follow-up (median 35 months). The association of biomarkers for portal hypertension (hepatic venous pressure gradient), endothelial dysfunction (von Willebrand factor), liver fibrogenesis (Enhanced Liver Fibrosis score), liver function (Model for End-stage Liver Disease/albumin/bile acids), systemic inflammation (C-reactive protein/interleukin-6/procalcitonin), and circulatory dysfunction (N-terminal prohormone of brain natriuretic peptide/copeptin) with stage transitions was evaluated.

In patients with compensated advanced chronic liver disease (n = 179), 13% developed first decompensation at 24 months, 2.8% developed further decompensation/acute-on-chronic liver failure, 1.9% experienced liver-related death; and 0.9% developed recompensation after decompensation. In decompensated cirrhosis (n = 168), 19% developed further decompensation/acute-on-chronic liver failure and 6.1% experienced liver-related death, whereas 8.0% achieved recompensation. Among patients with further decompensation at baseline (n = 117), 33% experienced liver-related death and 3.0% recompensation at 12 months. Portal hypertension, endothelial dysfunction, fibrogenesis, and impaired liver function were indicative of progression in compensated advanced chronic liver disease, shifting towards systemic inflammation and liver function in decompensated cirrhosis, with the additional contribution of circulatory dysfunction in further decompensation. Hepatic venous pressure gradient and albumin provided independent prognostic information in compensated advanced chronic liver disease, C-reactive protein in decompensated cirrhosis, and copeptin in further decompensation.

Targeting portal hypertension should be prioritized in compensated advanced chronic liver disease, whereas modulating systemic inflammation and circulatory dysfunction is crucial for preventing disease progression in decompensated cirrhosis. Precision medicine based on individual biomarker profiles could optimize patient outcomes in future clinical trials.

gov, Number: NCT03267615.