雌激素和血脂代谢异常与妊娠期肝内胆汁淤积症的关联性研究
摘要
目的：探讨妊娠期肝内胆汁淤积症（ICP）患者雌激素的变化规律以及雌激素受体β基因多态性与ICP的相关性；ICP患者血脂和氧化低密度脂蛋白（oxLDL）水平变化的特点，以及胎盘氧化低密度脂蛋白受体（LOX-1）表达与ICP的关系；雌激素受体β基因多态性与孕妇血脂和肝脏功能的关系。方法：运用病例-对照研究分三部分逐步展开：（第一部分） ICP患者血脂、肝功能、雌激素水平变化的临床研究；2008年4月-2009年4月在新疆医科大学第一附属医院住院分娩确诊为ICP，符合研究要求的共72例患者，其中轻度49例（49／72），重度23例（23／72），选择同期剖宫产分娩的正常孕妇72例作为对照组。空腹采血行血脂、肝功能、雌二醇（E2）、雌三醇（E3）测定，三组比较采用方差分析；血脂与雌激素和肝功能关系的分析采用多元线性回归；各项检测指标作为自变量，胎儿窘迫发生率作为结果变量进行Logistic回归，分析预测胎儿窘迫的影响因素。（第二部分）氧化低密度脂蛋白及其受体与ICP的关系；2008年4月-2009年9月在新疆医科大学第一附属医院住院分娩符合标准的ICP患者94名（包括第一部分患者），随机选择同期住院分娩的正常孕妇94名（包括第一部分孕妇）作为对照组，抽取两组孕妇空腹肘静脉血5ml，采用双抗体夹心酶联免疫吸附测定法测定血浆中oxLDL的浓度，另各组受试对象的胎盘娩出后30分钟内，立即在无菌状态下取两块胎盘组织约1cm×1cm×lcm大小，无菌生理盐水冲洗后存入冻存管中，液氮保存后存入-80℃冰箱保存，应用Westernblot法检测胎盘LOX-1的表达，病例组与对照组oxLDL、LOX-1比较采用t检验，方差不齐时，采用t’检验。（第三部分）雌激素β受体基因多态性与血脂、肝功能指标及ICP的关系；2008年4月至2011年4月于新疆医科大学第一附属医院分娩的ICP患者210例，其中维吾尔族105例，汉族105例，取同期维吾尔族、汉族正常孕妇各105例为对照组（包括第一、第二部分受试对象）。应用PCR扩增、酶切等分子生物学方法检测ERβ基因Rsa I、Alu I多态性的分布情况。应用2检验、Fisher确切概率法对检测结果进行统计学分析，并比较其与血脂和肝功能的关系。结果：1）轻度、重度ICP患者和正常对照组E2水平两两比较，差异均有统计学意义（P＜0.01）；但是轻度与重度ICP组E3水平差异无统计学意义（P＞0.05）；总胆红素（T-BIL）、天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）水平在轻度ICP组与对照组之间差异无统计学意义（P＞0.05），但与重度ICP组比较有差异（P＜0.05），总胆汁酸（TBA）水平三组比较均有统计学意义（P＜0.05）；甘油三酯（TG）水平三组两两比较，差异均有统计学意义（P＜0.01）；总胆固醇（CHOL）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）对照组与轻度ICP组比较，差异无统计学意义（P＞0.05），与重度ICP组比较有差异（P＜0.05）；血脂与雌激素、肝功能的关系经多元线性回归分析：TG、CHOL、LDL的回归方程式有意义，偏回归系数的t检验可知T-BIL的回归系数有统计学意义；通过预测胎儿窘迫的多因素Logistic回归分析发现，E2、TBA和ALT的系数有统计学意义；2）ICP患者胎盘LOX-1蛋白高表达，两组比较有统计学意义（P＜0.05），ICP患者oxLDL均数略高，但两组比较无统计学意义（P＞0.05）；3）维吾尔族和汉族正常孕妇ERβ基因Rsa I、Alu I多态性分布无差异（P＞0.05）；汉族病例组和对照组两组之间Rsa I、Alu I多态性分布差异无统计学意义（P＞0.05），而维吾尔族两组之间基因型分布则不同（P＜0.05），Rsa I和Alu I在两组中均呈多态性分布，ICP组R等位基因频率为35.71%，对照组为50.95%，OR值0.535（95%可信区间为0.3619～0.7910），P＜0.01；ICP组A等位基因频率为21.43%，对照组为10.95%，OR=2.2174，95%可信区间为1.2866～3.8215，P＜0.05。维吾尔族病例组RRaa型频率（4.76%，5例）低于对照组（13.33%，14名），rrAa型频率（14.29%，15例）高于对照组（2.86%，3名）（P值均＜0.05）。维吾尔族各基因型正常孕妇的血脂、T-BIL、AST比较无统计学差异，但ALT、TBA有统计学差异，AA+Aa基因型组均高于其它组。维吾尔族各基因型ICP患者TG、CHOL、LDL、T-BIL、AST、ALT、TBA比较均有差异，AA+Aa基因型各项指标均数均大于其它各组。各基因型患者HDL比较差别无统计学意义。结论：1）E2、ALT、CHOL、LDL均可考虑作为疾病分度的指标，ICP患者血脂升高主要与胆红素水平有关，血脂的改变可能是胆汁淤积的直接结果，与肝功能变化是并列关系而不是因果关系；血脂变化对胎儿窘迫的预测不敏感，TBA、E2、ALT是预测胎儿窘迫较好的指标；2）尽管ICP患者血浆LDL浓度高，但是oxLDL水平却没有相应升高，可能与抗氧化物质-胆红素升高有关。ICP患者胎盘中高表达的LOX-1可能通过Bcl-2途径诱导胎盘滋养细胞凋亡，从而参与ICP的病理生理过程。因此，LOX-1可以考虑作为治疗ICP潜在的靶点，具有进一步研究的价值；3）ERβ基因多态性在乌鲁木齐地区维吾尔族和汉族孕妇中分布无差异，与维吾尔族ICP发病有关，R等位基因可能是其保护因素，A等位基因可能是其危险因素，且rrAa可能是维吾尔族ICP患者的易感基因型。维吾尔族ERβ各基因型正常孕妇和ICP患者肝功能比较均有差异，说明ERβ基因多态性可能是控制孕妇肝脏代谢的一个基本因素。AA+Aa基因型位点变异并未改变所编码的氨基酸序列，但是可通过增强与雌激素β受体结合，强化雌激素生物作用，使肝脏代谢功能受损，在ICP的发生中可能具有一定的作用，并与病情严重程度有关。
Objective: To investigate estrogen change in intrahepatic cholestasis of pregnancy(ICP) and the distribution of estrogen receptorβ (ERβ) gene polymorphisms between theUygurs and the Hans in Urumqi and the association of the polymorphisms with ICP in theUygurs and the Hans. To explore the role of lipid, oxidized low-density lipoprotein(oxLDL) and lectin-like oxidized low-density lipoprotein receptor-1(LOX-1) in ICP. Toanalysis the relationship between the estrogen and lipid in ICP. Methods: The first part72patients of ICP from obstetric department of First Affiliated Hospital in XinJingMedical University were recruited from April2008to April2009and were divided intotwo groups according to the glycocholic acid (CG), severe group23cases, mild group49cases, and control group72cases. CG was analyzed by RIA, liver function and lipid weretest by enzymic mothods, Estradiol (E2), Esrtriol (E3) were analyzed by ELISA. Thesecond part The plasma oxLDL level and placenta LOX-1expression were detected in94patients (ICP group) and94healthy pregnant women (control group) from obstetricdepartment of First Affiliated Hospital in XinJing Medical University were recruited fromApril2008to September2009. The placentas LOX-1expression detected by Westernblotting; the plasma oxLDL measured by enzymelinked immunosorbent assay. The thirdpart ICP patients and controls from obstetric department of First Affiliated Hospital inXinJing Medical University were recruited from April2008to April2011, a total of105ICP patients of Uygurs as a Uygurs Case group,105ICP patients were selected by arandom number table from total Hans ICP patients as a Hans Case group,105Uygurs and105Hans healthy pregnant women were recruited as control groups. The distribution ofRsa I and Alu I of ERβ gene polymorphism were analyzed by PCR amplification andrestriction and other molecular biology approaches. Statistic analysis by χ2and Fisherexact propability. Results:1) There were significant difference among three groups aboutE2and total bile acid (TBA) and triglyeride (TG),(P＜0.01). The value of E3were nostatistics difference between severe and mild group (P＞0.05). The total bilirubin (T-BIL)and aspartate aminotransferas (AST) and alanine aminotransferase (ALT) and cholesterol (CHOL) and high density lipoprotein (HDL) and low-density lipoprotein (LDL) were nostatistics difference between control group and mild group (P＞0.05). The result of therelationship between blood-fat and estrogen and the relationship between blood-fat andliver function were analyzed by multiple factor line regression analysis, it shows that theregression equation of TG、CHOL、LDLwere statistics difference and the regressioncoefficient T-BIL is available. The coefficient of E2, CG and ALT are statisticalsignificant by multiple factor regression analysis for evaluating fetal distress.2) Theplacentas LOX-1expression in ICP group were higher than those in control group (P＜0.05), whereas the plasma oxLDL did not differ significantly between the patients withICP and healthy pregnant women (P＞0.05).3) The genotype frequency of rr、Rr、RR、aa、Aa、AA were no statistically significant between the two case groups (P＞0.05) andbetween the two control groups (P＞0.05) and between two Hans groups (P＞0.05),while it was significant different between two Uygur groups (P＜0.05). Rallelicfrequency was35.71%and50.95%in ICP patients and in control group, respectively,odds ratio (OR) was0.535[95%confidence intervals (CI)=0.3619～0.7910], P＜0.01. Aallelic frequency was21.43%and10.95%in ICP patients and in control group,respectively, OR was2.2174[95%CI=1.2866～3.8215], P＜0.05. Gene frequency ofRsaI and AluI in the two groups was distributed with polymorphism, P＜0.01. Thefrequency of RRaa in the Uygur case group was lower (4.76%,5cases) than controlgroup (13.33%,14cases)(P＜0.05), while the frequency of rrAa in the Uygur case groupwas significantly higher (14.29%,15cases) than control group (2.86%,3cases)(P＜0.05).The level of TG、CHOL、LDL、T-BIL、AST、ALT、TBA of every gene type in Uygurcase group were statistically significant, especially the lever of them in AA+Aa groupwere higher than others. Conclusions:1) E2, ALT, CHOL, LDLwere considered to be theindex of graduating the ICP, the elevated of blood-fat lever are relative to the increasingof bilirubin, it is supposed that the change of blood-fat were caused by the cholestasis, therelation between blood-fat and liver function was juxtaposed instead of causality.Blood-fat was not sensitive to predict the fetal distress, CG, E2and ALT were availableindex for evaluating fetal distress.2) LOX-1may play crucial roles in thepathophysiological processes of ICP via mediation over-apoptosis of trophoblast.Moreover, LOX-1could be a potential target for therapeutic intervention.3) Thedistribution difference of ERβgene polymorphism is no significant between the Uygursand Hans，ERβgene polymorphism may correlate with Uygurs instead of Hans, R allelemay be the guard factor, and A allele may be its risk factor．Uygurs and Hans have different genetic predisposing factors to the Development of ICP, and rrAa might be oneof risk factors for ICP in the Uygurs. ER β genetic polymorphism may control the hepaticmetabolism of pregnant women. AA+Aa genetype are factors of hepatic functiondamaged by change the encoded amino acid sequence and enhance express of estrogen βreceptors. It related to the severity of ICP.
Objective: To investigate estrogen change in intrahepatic cholestasis of pregnancy(ICP) and the distribution of estrogen receptorβ (ERβ) gene polymorphisms between theUygurs and the Hans in Urumqi and the association of the polymorphisms with ICP in theUygurs and the Hans. To explore the role of lipid, oxidized low-density lipoprotein(oxLDL) and lectin-like oxidized low-density lipoprotein receptor-1(LOX-1) in ICP. Toanalysis the relationship between the estrogen and lipid in ICP. Methods: The first part72patients of ICP from obstetric department of First Affiliated Hospital in XinJingMedical University were recruited from April2008to April2009and were divided intotwo groups according to the glycocholic acid (CG), severe group23cases, mild group49cases, and control group72cases. CG was analyzed by RIA, liver function and lipid weretest by enzymic mothods, Estradiol (E2), Esrtriol (E3) were analyzed by ELISA. Thesecond part The plasma oxLDL level and placenta LOX-1expression were detected in94patients (ICP group) and94healthy pregnant women (control group) from obstetricdepartment of First Affiliated Hospital in XinJing Medical University were recruited fromApril2008to September2009. The placentas LOX-1expression detected by Westernblotting; the plasma oxLDL measured by enzymelinked immunosorbent assay. The thirdpart ICP patients and controls from obstetric department of First Affiliated Hospital inXinJing Medical University were recruited from April2008to April2011, a total of105ICP patients of Uygurs as a Uygurs Case group,105ICP patients were selected by arandom number table from total Hans ICP patients as a Hans Case group,105Uygurs and105Hans healthy pregnant women were recruited as control groups. The distribution ofRsa I and Alu I of ERβ gene polymorphism were analyzed by PCR amplification andrestriction and other molecular biology approaches. Statistic analysis by χ2and Fisherexact propability. Results:1) There were significant difference among three groups aboutE2and total bile acid (TBA) and triglyeride (TG),(P＜0.01). The value of E3were nostatistics difference between severe and mild group (P＞0.05). The total bilirubin (T-BIL)and aspartate aminotransferas (AST) and alanine aminotransferase (ALT) and cholesterol (CHOL) and high density lipoprotein (HDL) and low-density lipoprotein (LDL) were nostatistics difference between control group and mild group (P＞0.05). The result of therelationship between blood-fat and estrogen and the relationship between blood-fat andliver function were analyzed by multiple factor line regression analysis, it shows that theregression equation of TG、CHOL、LDLwere statistics difference and the regressioncoefficient T-BIL is available. The coefficient of E2, CG and ALT are statisticalsignificant by multiple factor regression analysis for evaluating fetal distress.2) Theplacentas LOX-1expression in ICP group were higher than those in control group (P＜0.05), whereas the plasma oxLDL did not differ significantly between the patients withICP and healthy pregnant women (P＞0.05).3) The genotype frequency of rr、Rr、RR、aa、Aa、AA were no statistically significant between the two case groups (P＞0.05) andbetween the two control groups (P＞0.05) and between two Hans groups (P＞0.05),while it was significant different between two Uygur groups (P＜0.05). Rallelicfrequency was35.71%and50.95%in ICP patients and in control group, respectively,odds ratio (OR) was0.535[95%confidence intervals (CI)=0.3619～0.7910], P＜0.01. Aallelic frequency was21.43%and10.95%in ICP patients and in control group,respectively, OR was2.2174[95%CI=1.2866～3.8215], P＜0.05. Gene frequency ofRsaI and AluI in the two groups was distributed with polymorphism, P＜0.01. Thefrequency of RRaa in the Uygur case group was lower (4.76%,5cases) than controlgroup (13.33%,14cases)(P＜0.05), while the frequency of rrAa in the Uygur case groupwas significantly higher (14.29%,15cases) than control group (2.86%,3cases)(P＜0.05).The level of TG、CHOL、LDL、T-BIL、AST、ALT、TBA of every gene type in Uygurcase group were statistically significant, especially the lever of them in AA+Aa groupwere higher than others. Conclusions:1) E2, ALT, CHOL, LDLwere considered to be theindex of graduating the ICP, the elevated of blood-fat lever are relative to the increasingof bilirubin, it is supposed that the change of blood-fat were caused by the cholestasis, therelation between blood-fat and liver function was juxtaposed instead of causality.Blood-fat was not sensitive to predict the fetal distress, CG, E2and ALT were availableindex for evaluating fetal distress.2) LOX-1may play crucial roles in thepathophysiological processes of ICP via mediation over-apoptosis of trophoblast.Moreover, LOX-1could be a potential target for therapeutic intervention.3) Thedistribution difference of ERβgene polymorphism is no significant between the Uygursand Hans，ERβgene polymorphism may correlate with Uygurs instead of Hans, R allelemay be the guard factor, and A allele may be its risk factor．Uygurs and Hans have different genetic predisposing factors to the Development of ICP, and rrAa might be oneof risk factors for ICP in the Uygurs. ER β genetic polymorphism may control the hepaticmetabolism of pregnant women. AA+Aa genetype are factors of hepatic functiondamaged by change the encoded amino acid sequence and enhance express of estrogen βreceptors. It related to the severity of ICP.
引文
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