药学学报, 2019, 54(8): 1449-1456
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.
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 cirrhosis[J]. Acta Pharmaceutica Sinica, 2019, 54(8): 1449-1456.

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
卫璐戈1,2, 王肖辉2, 牛明2, 刘晓熠2, 涂灿2, 周元园2, 胡黄婉茵2, 张雅铭2, 李会芳1, 邹正升3, 肖小河4, 王伽伯2
1. 山西中医药大学, 山西 晋中 030619;
2. 解放军302医院全军中医药研究所, 北京 100039;
3. 解放军302医院非感染性肝病诊疗与研究中心, 北京 100039;
4. 解放军302医院中西医结合诊疗与研究中心, 北京 100039
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。
关键词:    药物性肝损伤      慢性化      肝硬化      代谢组学      诊断      生物标志物     
Metabolomic screening for diagnostic biomarkers of drug-induced chronic liver injury related cirrhosis
WEI Lu-ge1,2, WANG Xiao-hui2, NIU Ming2, LIU Xiao-yi2, TU Can2, ZHOU Yuan-yuan2, HU Huangwan-yin2, ZHANG Ya-ming2, LI Hui-fang1, ZOU Zheng-sheng3, XIAO Xiao-he4, WANG Jia-bo2
1. Shanxi University of Traditional Chinese Medicine, Jinzhong 030619, China;
2. China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China;
3. Treatment and Research Center for Non-infectious Liver Diseases, 302 Military Hospital, Beijing 100039, China;
4. Integrative Medicine Center, 302 Military Hospital, Beijing 100039, China
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.
Key words:    drug-induced liver injury    chronicity    liver cirrhosis    metabolomics    diagnosis    biomarker   
收稿日期: 2019-04-26
DOI: 10.16438/j.0513-4870.2018-1059
基金项目: 国家重大新药创制专项课题(2015ZX09501-004-001-008);国家自然科学基金青年基金资助项目(81503247);北京市科技新星计划项目(Z16111000490000);国家公益性行业专项课题(201507004-04);国家中药标准化项目(ZYBZH-Y-BJ-07).
通讯作者: 邹正升,Tel:86-10-66933424,E-mail:zszou302@163.com;肖小河,Tel:86-10-66933322,E-mail:pharmacy302@126.com;王伽伯,Tel:86-10-66933323,E-mail:wjb0128@126.com
Email: zszou302@163.com;pharmacy302@126.com;wjb0128@126.com
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