HBV re-activation is associated with increased mortality and dysregulation of oxidative and polyamine metabolism in pre-acute-on-chronic liver failure

Background/Aims Acute-on-chronic liver failure (ACLF) is one of the deadliest complications of chronic liver disease yet treatment options are sparse. In Asia, HBV-reactivation (HBVr) is one of the most common triggers. Recently, HBV-associated ACLF was associated with distinct changes in the metabolome. Here, metabolic impacts of HBVr were analysed in-depth in non-ACLF, pre-ACLF and ACLF. Methods Clinical and metabolic data of 1024 Chinese patients (CATCH-LIFE studies) with chronic HBV mono-infection were analyzed. ACLF was diagnosed according to COSSH criteria. Metabolites in plasma were quantified using LC-MS, compared to non-ACLF and subjected to enrichment and pathway analyses using the database SMPDB via MetaboAnalyst v6. Results In 1024 patients (611: non-ACLF, 72: pre-ACLF, 341: ACLF), HBVr was present in 20.2% (ACLF) or 33.3% (pre-ACLF) of patients. HBVr increased 28-day mortality in pre-ACLF patients (2.1% in HBVnr vs. 25% in HBVr). Energy metabolism generating reactive oxygen species (ROS) was highly induced in the absence of ROS-detoxifying pathways in pre-ACLF. Urea cycle, thus nitric oxide (NO) build-up, the polyamine metabolism and related pathways were highly increased in both HBVr pre-ACLF and ACLF, shifting pre-ACLF close to mature ACLF. Specific metabolites could be identified as putative markers and key-regulators herein. Conclusion HBV reactivation induces inflammation, hepatic injury and mortality especially in pre-ACLF patients. Metabolic disruption in the ROS/NO/polyamine axis favors stress and hinders liver regeneration. Findings help identifying and alleviating HBVr-driven progression towards ACLF via pharmacological or biopharmaceutical intervention. Trial registration Analyses were based on the CATCH-LIFE studies. The CATCH-LIFE studies were registered at Clinical.trials.gov (Clinical Trial Number: NCT02457637, first registered 2015-01-31 and NCT03641872, first registered 2018-08-14).