Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes

Abstract

Acute-on-chronic liver failure (ACLF) is a clinical syndrome of high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for ACLF patients, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognosis. We performed a metabolomics profiling of 1,024 plasma samples collected from HBV-related chronic liver disease patients with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. ACLF significantly altered the serum metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of ACLF 90-day mortality (area under curve, AUC: 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (AUC: 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography mass spectrometry (LCMS). Based on novel metabolite biomarkers, we established HBV-ACLF tests with higher accuracy than existing methods. Acute-on-chronic liver failure (ACLF) is a clinical syndrome of high short-term mortality affecting 25% of hospitalized cirrhosis patients. Chronic hepatitis B (HBV) is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognosis for disease management are critical for improving clinical outcomes for ACLF patients. Based on novel metabolite biomarkers, we developed liquid chromatography mass spectrometry (LCMS) tests with improved accuracy for the early diagnosis and prognosis of HBV-ACLF. The LCMS tests can be implemented in clinical labs and used by physicians to triage HBV-ACLF patients for treatment options and proactive disease management. NCT02457637 and NCT03641872.