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

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。

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 decompo‐sition during cirrhosis. Five biomarkers were found to exhibit effective diagnosis value(AUC > 0.6), including phosphatidylcholine, lysoPC(18:1(9 Z)), creatine, taurochenodeoxycholic acid and taurocholic acid. Furthermore,we found that the relative content ratio between phosphatidylcholine and lysoPC(18: 1(9 Z)) had a better distin‐guishing 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.