Characterization of multi-stage metabolic alterations in hepatitis B virus-related acute-on-chronic liver failure using high-coverage metabolomics

INTRODUCTION: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a serious condition characterized by acute liver decompensation and multiple organ failure, which leads to high short-term mortality rates. OBJECTIVES: This study aims to understand the metabolic changes across different stages-normal, chronic hepatitis B (CHB), and HBV-ACLF-to provide important insights into disease progression and potential diagnostic markers. METHODS: This retrospective study analyzed serum samples from 125 HBV-ACLF patients (49 at ACLF-1, 47 at ACLF-2, and 29 at ACLF-3) classified according to the COSSH criteria, along with 34 patients with CHB and 32 healthy controls (HCs). High-sensitivity untargeted metabolomic profiling was performed using chemical isotope labeling (CIL) techniques. RESULTS: A total of 2053 amine/phenol-containing metabolites were detected. Significant metabolic alterations were identified, including 32 positively identified metabolites exhibiting persistent changes initiating at the CHB stage. This number increased to 91 in ACLF-1, decreased to 51 in ACLF-2, and further decreased to 38 in ACLF-3. Specifically, we observed increased levels of γ-glutamyl dipeptides and metabolites from the tryptophan-kynurenine pathway, while levels of metabolites from the tryptophan-serotonin pathway decreased. Additionally, metabolic pathways involving cysteine, methionine, and taurine displayed activation, indicating a compensatory response to oxidative stress and liver dysfunction. CONCLUSION: This study identifies distinct metabolic trajectories from normal liver function to CHB and ultimately to HBV-ACLF, contributing to understand the relationship between liver dysfunction and systemic inflammation. Our findings may facilitate the development of diagnostic biomarkers and tailored therapeutic strategies. Further research is needed to explore the mechanisms behind these metabolic changes and their relevance to managing patients with HBV-ACLF.