卫璐戈, 王肖辉, 牛明, 刘晓熠, 涂灿, 周元园, 胡黄婉茵, 张雅铭, 李会芳, 邹正升, 肖小河, 王伽伯. 慢性药物性肝损伤相关肝硬化的代谢组学诊断标志物研究J. 药学学报, 2019,54(8): 1449-1456. doi: 10.16438/j.0513-4870.2018-1059
引用本文: 卫璐戈, 王肖辉, 牛明, 刘晓熠, 涂灿, 周元园, 胡黄婉茵, 张雅铭, 李会芳, 邹正升, 肖小河, 王伽伯. 慢性药物性肝损伤相关肝硬化的代谢组学诊断标志物研究J. 药学学报, 2019,54(8): 1449-1456. doi: 10.16438/j.0513-4870.2018-1059
WEI Lu-ge, WANG Xiao-hui, NIU Ming, LIU Xiao-yi, TU Can, ZHOU Yuan-yuan, HU Huangwan-yin, ZHANG Ya-ming, LI Hui-fang, ZOU Zheng-sheng, XIAO Xiao-he, WANG Jia-bo. Metabolomic screening for diagnostic biomarkers of drug-induced chronic liver injury related cirrhosisJ. Acta Pharmaceutica Sinica, 2019,54(8): 1449-1456. doi: 10.16438/j.0513-4870.2018-1059
Citation: WEI Lu-ge, WANG Xiao-hui, NIU Ming, LIU Xiao-yi, TU Can, ZHOU Yuan-yuan, HU Huangwan-yin, ZHANG Ya-ming, LI Hui-fang, ZOU Zheng-sheng, XIAO Xiao-he, WANG Jia-bo. Metabolomic screening for diagnostic biomarkers of drug-induced chronic liver injury related cirrhosisJ. Acta Pharmaceutica Sinica, 2019,54(8): 1449-1456. doi: 10.16438/j.0513-4870.2018-1059

慢性药物性肝损伤相关肝硬化的代谢组学诊断标志物研究

Metabolomic screening for diagnostic biomarkers of drug-induced chronic liver injury related cirrhosis

  • 摘要: 药物性肝损伤(drug-induced liver injury,DILI)约有15%~20%可进展为慢性化,进而较快发展为肝硬化,临床预后差。因此,筛选发现非侵入性诊断生物标志物对早期发现慢性DILI肝硬化患者具有重要临床意义。本研究通过血清代谢组学研究发现,慢性DILI无肝硬化组(34例)与慢性DILI肝硬化组(15例)在代谢谱存在显著差异,通过主成分分析(PCA)及正交校正偏最小二乘法-判别分析(OPLS-DA),筛选出慢性DILI肝硬化组区别于未肝硬化组的特征差异代谢物35个。经代谢物鉴定及代谢通路富集分析,发现慢性DILI肝硬化组较无肝硬化组血清中胆汁酸、糖类代谢等代谢通路水平上调,溶血卵磷脂代谢水平下调,这些变化反映出肝硬化阶段肝脏的胆汁酸、脂质合成分解等功能性损伤更严重。进一步从差异代谢物中筛选到具有区分诊断能力的生物标志物5个:磷脂酰胆碱(phosphatidylcholine)、lysoPC(18:1(9Z))、肌酸(creatine)、牛磺鹅去氧胆酸(taurochenodeoxycholic acid)和牛磺胆酸(taurocholic acid),ROC曲线下面积均大于0.6。其中磷脂酰胆碱与lysoPC(18:1(9Z))的峰面积比值具有更好的区分诊断效果,ROC曲线下面积达0.867,且比值法有利于降低样本处理与检测仪器等系统误差,具有较好的临床应用潜力。

     

    Abstract: About 15%-20% of drug-induced liver injury (DILI) will progress to chronic manifestation (CH-DILI), which sometimes advances rapidly to liver cirrhosis (LC-DILI) within 0.5-1 year with deteriorative clinical prognosis. Therefore, it is important to find a non-invasive diagnosis for early detection of liver cirrhosis. In this study, the metabolomic profiles revealed significant differences in the metabolites from the plasma of LC-DILI versus CH-DILI. We found 35 differential metabolites through principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Through pathway enrichment analysis, some up-regulated metabolic pathways reflected impaired liver functions such as bile acid, lipid synthesis and decomposition during cirrhosis. Five biomarkers were found to exhibit effective diagnosis value (AUC > 0.6), including phosphatidylcholine, lysoPC (18:1 (9Z)), creatine, taurochenodeoxycholic acid and taurocholic acid. Furthermore, we found that the relative content ratio between phosphatidylcholine and lysoPC (18:1 (9Z)) had a better distinguishing ability (AUC=0.867). The relative content ratio also had the feature to reduce systematic errors of sample processing and instrument detection, therefore having a greater value for clinical application.

     

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