HBV re-activation is associated with increased mortality and dysregulation of oxidative and polyamine metabolism in pre-acute-on-chronic liver failure
Abstract
Abstract 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).
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Authors: Mirco Glitscher, Keerthihan Thiyagarajah, Jianyi Wei, Jannik Sonnenberg, Pia Lembeck, Wenyi Gu, Georgios Grammatikos, Lining Guo, Jonel Trebicka, Guohong Deng, Xianbo Wang, Xin Zheng, Yan Huang, Jinjun Chen, 孟忠吉, Yanhang Gao, Zhiping Qian, Feng Liu, Xiaobo Lu, Yu Shi, Yubao Zheng, Yingli He, Hai Li, Eberhard Hildt, Kai‐Henrik Peiffer
Institutions: Shanghai Jiao Tong University, Sun Yat-sen University, Central South University, Dalian Medical University, University Hospital Münster, Zhejiang University, Chongqing Medical University, Army Medical University, Union Hospital, Huazhong University of Science and Technology, Second Affiliated Hospital of Chongqing Medical University, Third Affiliated Hospital of Sun Yat-sen University, Capital Medical University, Beijing Ditan Hospital, Goethe University Frankfurt, Jilin University, Shanghai Medical College of Fudan University, University Hospital Frankfurt, Nankai University, Xinjiang Medical University, First Affiliated Hospital of Xinjiang Medical University, Hasso Plattner Institute, Xiangya Hospital Central South University, Shanghai Public Health Clinical Center, Southwest Hospital, Hubei University of Medicine, Taihe Hospital, First Affiliated Hospital of Xi'an Jiaotong University, First Hospital of Jilin University, Paul Ehrlich Institut, State Key Laboratory of Diagnosis and Treatment of Infectious Diseases, Shanghai Institute of Hematology, St. Luke's Hospital