Zhang Yan, Tan Wenting, Wang Xianbo, Zheng Xin, Huang Yan, Li Beiling, Meng Zhongji, Gao Yanhang, Qian Zhiping, Liu Feng, Lu Xiaobo, Shi Yu, Shang Jia, Yan Huadong, Zheng Yubao, Zhang Weituo, Gu Wenyi, Qiao Liang, Deng Guohong, Zhou Yi, Hou Yixin, Zhang Qun, Xiong Shue, Liu Jing, Duan Lihua, Chen Ruochan, Chen Jinjun, Jiang Xiuhua, Luo Sen, Chen Yuanyuan, Jiang Chang, Zhao Jinming, Ji Liujuan, Mei Xue, Li Jing, Li Tao, Zheng Rongjiong, Zhou Xinyi, Ren Haotang, Cheng Xiaoliang, Guo Lining, Li Hai
Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Shanghai, China.
Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
J Hepatol. 2023 Nov;79(5):1159-1171. doi: 10.1016/j.jhep.2023.07.011. Epub 2023 Jul 29.
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with 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 patients with ACLF, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognostication.
We performed a metabolomics profiling of 1,024 plasma samples collected from patients with HBV-related chronic liver disease 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 plasma 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 90-day mortality in patients with ACLF (area under the curve 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (area under the curve 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.
Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods.
NCT02457637 and NCT03641872.
Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality affecting 25% of patients hospitalized with cirrhosis. Chronic hepatitis B is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognostication are critical for improving clinical outcomes in patients with ACLF. Based on novel metabolite biomarkers, we developed liquid chromatography-mass spectrometry tests with improved accuracy for the early diagnosis and prognostication of HBV-related ACLF. The liquid chromatography-mass spectrometry tests can be implemented in clinical labs and used by physicians to triage patients with HBV-related ACLF to ensure optimized clinical management.
慢加急性肝衰竭（ACLF）是一种与慢性肝病患者短期高死亡率相关的临床综合征。慢性乙型肝炎是中国和其他亚洲国家ACLF（HBV-ACLF）的主要病因。为改善ACLF患者的疾病管理和生存率，我们旨在发现新的生物标志物以加强HBV-ACLF的诊断和预后评估。
在一项多年多中心前瞻性研究中，我们对1024份入院时患有急性加重的HBV相关慢性肝病患者的血浆样本进行了代谢组学分析（367例ACLF患者和657例非ACLF患者）。样本被随机等分为发现集和验证集。我们使用统计分析和机器学习确定了与ACLF组90天死亡率以及非ACLF组（ACLF前期）28天内进展为ACLF相关的代谢物。我们在发现集中开发了诊断算法，并使用这些算法评估验证集中的结果。
ACLF显著改变了血浆代谢组，特别是在膜脂代谢、类固醇激素、氧化应激途径和能量代谢方面。许多代谢物与ACLF组的90天死亡率和/或非ACLF组的ACLF前期显著相关。我们开发了用于预测ACLF患者90天死亡率的算法（发现集和验证集的曲线下面积分别为0.87和0.83）以及ACLF前期诊断的算法（发现集和验证集的曲线下面积分别为0.94和0.88）。为将我们的发现转化为实际临床检测，我们使用液相色谱-质谱法开发了靶向检测方法。
基于新的代谢物生物标志物，我们建立了用于HBV相关ACLF的检测方法，其准确性高于现有方法。
NCT02457637和NCT03641872。
慢加急性肝衰竭（ACLF）是一种与短期高死亡率相关的临床综合征，影响25%的肝硬化住院患者。慢性乙型肝炎是中国和其他亚洲国家ACLF的主要病因。目前尚无有效治疗方法。早期诊断和准确的预后评估对于改善ACLF患者的临床结局至关重要。基于新的代谢物生物标志物，我们开发了液相色谱-质谱检测方法，提高了HBV相关ACLF早期诊断和预后评估的准确性。液相色谱-质谱检测方法可在临床实验室实施，供医生用于对HBV相关ACLF患者进行分类，以确保优化临床管理。
