【摘要】：目的基于血清膽汁酸代謝輪廓分析,篩選妊娠肝內(nèi)膽汁淤積癥(intrahepatic cholestasis of pregnancy,ICP)的診斷標(biāo)志物,探討熊去氧膽酸(ursodeoxycholic acid,UDCA)治療過(guò)程中ICP患者血清膽汁酸代謝輪廓的動(dòng)態(tài)變化特征,并獲得血清中各游離膽汁酸間的相互影響的代謝信息,為ICP的診斷與治療提供實(shí)驗(yàn)依據(jù)。方法1.以超高效液相色譜-三重四級(jí)桿飛行時(shí)間質(zhì)譜為技術(shù)平臺(tái),采用靶標(biāo)與非靶標(biāo)掃描技術(shù)聯(lián)合,實(shí)現(xiàn)孕婦血清膽汁酸的定性鑒定和定量分析;2.檢測(cè)ICP首診孕婦和正常孕婦的血清膽汁酸代謝輪廓,采用偏最小二乘判別分析(partial least squares-discriminant analysis,PLS-DA)對(duì)膽汁酸代謝輪廓進(jìn)行挖掘,結(jié)合受試者工作特征曲線和Logistic回歸分析篩選潛在的診斷ICP的生物標(biāo)志物;3.監(jiān)測(cè)ICP患者接受UDCA治療后的血清膽汁酸代謝輪廓,并對(duì)其治療過(guò)程的膽汁酸代謝輪廓進(jìn)行PLS-DA,獲得其代謝變化信息;4.對(duì)ICP首診孕婦和正常孕婦的血清游離膽汁酸代謝輪廓進(jìn)行路徑分析,探索各游離膽汁酸間的相互關(guān)系。結(jié)果1.本研究識(shí)別了28種商品化的膽汁酸,初步鑒定了33種膽汁酸(包括12種游離型膽汁酸,15種牛磺結(jié)合型膽汁酸,6種甘氨結(jié)合型膽汁酸)。與正常孕婦相比,icp孕婦的血清膽汁酸代謝輪廓發(fā)生了明顯變化;此外,總膽汁酸正常的icp患者的膽汁酸代謝輪廓,既不同于正常孕婦,也不同于總膽汁酸異常的icp孕婦;2.基于膽汁酸代謝輪廓分析,篩選出由�；悄懰�(taurocholicacid,tca)、α-鼠膽酸(α-muricholicacid,α-mca)和gtri-8(甘氨結(jié)合型三羥基膽汁酸,m/z464.3018,保留時(shí)間11.46min)組成的聯(lián)和診斷生物標(biāo)志物有較高的診斷效能,受試者工作特征曲線(receiveroperatingcharacteristiccurve,roc)分析顯示曲線下面積(areaundercurve,auc)為0.996,尤登指數(shù)為0.940;3.icp患者接受udca治療期間,其血清膽汁酸代謝逐漸恢復(fù),但直至產(chǎn)后才完全恢復(fù)正常;4.游離膽汁酸路徑分析顯示:在icp孕婦和正常孕婦中,鵝脫氧膽酸(chenodeoxycholicacid,cdca)對(duì)膽酸和udca的代謝均具有顯著性的影響,在正常孕婦中,cdca對(duì)udca具有正向的調(diào)節(jié)作用,而在icp孕婦中該作用轉(zhuǎn)變?yōu)榉聪蛘{(diào)節(jié)作用。在icp患者組,α-mca對(duì)udca的代謝影響具有顯著性意義,而β-mca對(duì)udca和ω-mca的代謝影響具有顯著性意義。結(jié)論icp患者有其特征的血清膽汁酸代謝輪廓。tca、α-mca和gtri-8可成為聯(lián)合診斷ICP的潛在生物標(biāo)志物。UDCA治療可在一定程度上改善ICP患者的血清膽汁酸代謝。游離膽汁酸的路徑分析為篩選更優(yōu)的ICP治療藥物提供實(shí)驗(yàn)證據(jù)。
[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), 偽 -murine cholic acid (偽 -muricholicacid, 偽 -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, 偽-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, 偽 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.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R714.255;R446.1

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