血清胆汁酸代谢轮廓在妊娠肝内胆汁淤积症中的研究
发布时间：2018-12-27 14:44
【摘要】：目的基于血清胆汁酸代谢轮廓分析,筛选妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的诊断标志物,探讨熊去氧胆酸(ursodeoxycholic acid,UDCA)治疗过程中ICP患者血清胆汁酸代谢轮廓的动态变化特征,并获得血清中各游离胆汁酸间的相互影响的代谢信息,为ICP的诊断与治疗提供实验依据。方法1.以超高效液相色谱-三重四级杆飞行时间质谱为技术平台,采用靶标与非靶标扫描技术联合,实现孕妇血清胆汁酸的定性鉴定和定量分析;2.检测ICP首诊孕妇和正常孕妇的血清胆汁酸代谢轮廓,采用偏最小二乘判别分析(partial least squares-discriminant analysis,PLS-DA)对胆汁酸代谢轮廓进行挖掘,结合受试者工作特征曲线和Logistic回归分析筛选潜在的诊断ICP的生物标志物;3.监测ICP患者接受UDCA治疗后的血清胆汁酸代谢轮廓,并对其治疗过程的胆汁酸代谢轮廓进行PLS-DA,获得其代谢变化信息;4.对ICP首诊孕妇和正常孕妇的血清游离胆汁酸代谢轮廓进行路径分析,探索各游离胆汁酸间的相互关系。结果1.本研究识别了28种商品化的胆汁酸,初步鉴定了33种胆汁酸(包括12种游离型胆汁酸,15种牛磺结合型胆汁酸,6种甘氨结合型胆汁酸)。与正常孕妇相比,icp孕妇的血清胆汁酸代谢轮廓发生了明显变化;此外,总胆汁酸正常的icp患者的胆汁酸代谢轮廓,既不同于正常孕妇,也不同于总胆汁酸异常的icp孕妇;2.基于胆汁酸代谢轮廓分析,筛选出由牛磺胆酸(taurocholicacid,tca)、α-鼠胆酸(α-muricholicacid,α-mca)和gtri-8(甘氨结合型三羟基胆汁酸,m/z464.3018,保留时间11.46min)组成的联和诊断生物标志物有较高的诊断效能,受试者工作特征曲线(receiveroperatingcharacteristiccurve,roc)分析显示曲线下面积(areaundercurve,auc)为0.996,尤登指数为0.940;3.icp患者接受udca治疗期间,其血清胆汁酸代谢逐渐恢复,但直至产后才完全恢复正常;4.游离胆汁酸路径分析显示:在icp孕妇和正常孕妇中,鹅脱氧胆酸(chenodeoxycholicacid,cdca)对胆酸和udca的代谢均具有显著性的影响,在正常孕妇中,cdca对udca具有正向的调节作用,而在icp孕妇中该作用转变为反向调节作用。在icp患者组,α-mca对udca的代谢影响具有显著性意义,而β-mca对udca和ω-mca的代谢影响具有显著性意义。结论icp患者有其特征的血清胆汁酸代谢轮廓。tca、α-mca和gtri-8可成为联合诊断ICP的潜在生物标志物。UDCA治疗可在一定程度上改善ICP患者的血清胆汁酸代谢。游离胆汁酸的路径分析为筛选更优的ICP治疗药物提供实验证据。
[Abstract]:Objective to screen the diagnostic markers of intrahepatic cholestasis of pregnancy (intrahepatic cholestasis of pregnancy,ICP) based on the analysis of serum bile acid metabolism profile and to explore ursodeoxycholic acid (ursodeoxycholic acid,). UDCA) the dynamic changes of serum bile acid metabolism profile in patients with ICP, and the metabolic information of the interaction between free bile acids in serum were obtained, which provided experimental basis for the diagnosis and treatment of ICP. Method 1. The qualitative identification and quantitative analysis of serum bile acids of pregnant women were realized by means of the combination of target and non-target scanning technique on the platform of ultra-high performance liquid chromatography-quadruple four-pole time-of-flight mass spectrometry. 2. The profile of serum bile acid metabolism in first-visit pregnant women with ICP and normal pregnant women was detected. Partial least squares discriminant analysis (partial least squares-discriminant analysis,PLS-DA) was used to mine the profile of bile acid metabolism. Combined with the operating characteristic curve and Logistic regression analysis, potential biomarkers for the diagnosis of ICP were screened. 3. Monitoring the profile of serum bile acid metabolism after UDCA treatment in patients with ICP, and obtaining the metabolic information of bile acid metabolism by PLS-DA,. 4. The profile of free bile acid metabolism in serum of first visit pregnant women and normal pregnant women with ICP was analyzed in order to explore the relationship between free bile acids and free bile acids. Result 1. In this study, 28 commercial bile acids were identified, and 33 bile acids (including 12 free bile acids, 15 taurosulfonated bile acids and 6 glycosamino-bound bile acids) were identified. Compared with normal pregnant women, the serum bile acid metabolism profile of icp pregnant women changed obviously, in addition, the bile acid metabolism profile of icp patients with normal total bile acids was different from that of normal pregnant women and icp pregnant women with abnormal total bile acids. 2. Based on the profile analysis of bile acid metabolism, Taurocholic acid (taurocholicacid,tca), 伪 -murine cholic acid (伪 -muricholicacid, 伪 -mca) and gtri-8 (glycosamino-binding trihydroxycholic acid, m / z464.3018) were selected. The combined diagnostic biomarkers composed of retention time (11.46min) had higher diagnostic efficacy. The area under the curve (areaundercurve,auc) was 0.996 and the Uden index was 0.940 by the analysis of the operating characteristic curve (receiveroperatingcharacteristiccurve,roc) of the subjects. The serum bile acid metabolism of 3.icp patients recovered gradually during udca treatment, but did not return to normal until postpartum. 4. Free bile acid pathway analysis showed that chenodeoxycholic acid (chenodeoxycholicacid,cdca) had a significant effect on the metabolism of cholic acid and udca in icp and normal pregnant women, and cdca had a positive effect on udca in normal pregnant women. In pregnant women with icp, this role changes to reverse regulation. In the icp group, 伪-mca had a significant effect on the metabolism of udca, while 尾-mca had a significant effect on the metabolism of udca and 蠅-mca. Conclusion the profile of serum bile acid metabolism in patients with icp has its own characteristics. Tca, 伪 mca and gtri-8 may be potential biomarkers for combined diagnosis of ICP. UDCA treatment can improve serum bile acid metabolism in ICP patients to some extent. Path analysis of free bile acids provides experimental evidence for screening better ICP drugs.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R714.255;R446.1
本文编号：2393230
[Abstract]:Objective to screen the diagnostic markers of intrahepatic cholestasis of pregnancy (intrahepatic cholestasis of pregnancy,ICP) based on the analysis of serum bile acid metabolism profile and to explore ursodeoxycholic acid (ursodeoxycholic acid,). UDCA) the dynamic changes of serum bile acid metabolism profile in patients with ICP, and the metabolic information of the interaction between free bile acids in serum were obtained, which provided experimental basis for the diagnosis and treatment of ICP. Method 1. The qualitative identification and quantitative analysis of serum bile acids of pregnant women were realized by means of the combination of target and non-target scanning technique on the platform of ultra-high performance liquid chromatography-quadruple four-pole time-of-flight mass spectrometry. 2. The profile of serum bile acid metabolism in first-visit pregnant women with ICP and normal pregnant women was detected. Partial least squares discriminant analysis (partial least squares-discriminant analysis,PLS-DA) was used to mine the profile of bile acid metabolism. Combined with the operating characteristic curve and Logistic regression analysis, potential biomarkers for the diagnosis of ICP were screened. 3. Monitoring the profile of serum bile acid metabolism after UDCA treatment in patients with ICP, and obtaining the metabolic information of bile acid metabolism by PLS-DA,. 4. The profile of free bile acid metabolism in serum of first visit pregnant women and normal pregnant women with ICP was analyzed in order to explore the relationship between free bile acids and free bile acids. Result 1. In this study, 28 commercial bile acids were identified, and 33 bile acids (including 12 free bile acids, 15 taurosulfonated bile acids and 6 glycosamino-bound bile acids) were identified. Compared with normal pregnant women, the serum bile acid metabolism profile of icp pregnant women changed obviously, in addition, the bile acid metabolism profile of icp patients with normal total bile acids was different from that of normal pregnant women and icp pregnant women with abnormal total bile acids. 2. Based on the profile analysis of bile acid metabolism, Taurocholic acid (taurocholicacid,tca), 伪 -murine cholic acid (伪 -muricholicacid, 伪 -mca) and gtri-8 (glycosamino-binding trihydroxycholic acid, m / z464.3018) were selected. The combined diagnostic biomarkers composed of retention time (11.46min) had higher diagnostic efficacy. The area under the curve (areaundercurve,auc) was 0.996 and the Uden index was 0.940 by the analysis of the operating characteristic curve (receiveroperatingcharacteristiccurve,roc) of the subjects. The serum bile acid metabolism of 3.icp patients recovered gradually during udca treatment, but did not return to normal until postpartum. 4. Free bile acid pathway analysis showed that chenodeoxycholic acid (chenodeoxycholicacid,cdca) had a significant effect on the metabolism of cholic acid and udca in icp and normal pregnant women, and cdca had a positive effect on udca in normal pregnant women. In pregnant women with icp, this role changes to reverse regulation. In the icp group, 伪-mca had a significant effect on the metabolism of udca, while 尾-mca had a significant effect on the metabolism of udca and 蠅-mca. Conclusion the profile of serum bile acid metabolism in patients with icp has its own characteristics. Tca, 伪 mca and gtri-8 may be potential biomarkers for combined diagnosis of ICP. UDCA treatment can improve serum bile acid metabolism in ICP patients to some extent. Path analysis of free bile acids provides experimental evidence for screening better ICP drugs.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R714.255;R446.1
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