妊娠肝内胆汁淤积症患者MDR3基因突变的研究

妊娠肝内胆汁淤积症（intrahepatic cholestasis of pregnancy, ICP）是妊娠期特发性疾病,患者可出现全身瘙痒、肝功能异常,部分伴有黄疸、血清总胆汁酸（TBA）水平升高.尽管ICP患者预后良好，但可发生胎儿早产、胎心率异常、羊水粪染、围产儿死亡率增加。近年来的研究证实，MDR3基因存在多个位点突变。且与ICP的发病有关。本研究采用PCR-单链构象多态性分析（PCR-SSCP）技术，检测ICP患者MDR3基因外显子的突变情况。现报道如下。     

妊娠期肝内胆汁淤积症中MDR3基因表达的研究

目的:探讨MDR3基因mRNA的表达与妊娠期肝内胆汁淤积症(ICP)发病的关系.方法:从36例ICP患者和38例正常孕妇外周血标本中抽提总RNA,反转录.聚合酶链反应(RTPCR)技术扩增MDR3基因和β-Actin基因,采用凝胶分析软件对RT-PCR产物进行半定量分析,比较两组间差异.结果:MDR3基因mRNA的表达在ICP患者和正常孕妇组间差异无统计学意义(P＞0.05).结论:MDR3基因mRNA的表达异常可能与中国皖南地区ICP发生无关或关联很小,中国人ICP的发生可能存在其他的发病机制.     

妊娠期肝内胆汁淤积症相关基因的研究

妊娠期肝内胆汁淤积症(intrahepatic chlestasis of pregnancy,ICP)是两种获得性胆汁淤积性肝脏疾病之一,是严重威胁围生儿健康的妊娠期并发症,可导致早产、羊水胎粪污染及胎死宫内.ICP发病机制至今仍未明确,可能与激素、遗传变异、免疫因素及环境因素相关.近年有关ICP的发病与基因突变关系...     

妊娠期肝内胆汁淤积症

妊娠期肝内胆汁淤积症徐先明综述庄依亮审校（上海医科大学妇产科医院）妊娠期肝内胆汁淤积症（Ｉｎｔｒａｈｅｐａｔｉｃｃｈｏｌｅｓｔａｓｉｓｏｆｐｒｅｇｎａｎｃｙ，ＩＣＰ）易引起早产和胎儿窘迫、死胎、死产，近年来受到产科医生的重视，被列为高危妊娠之一，目前...     

妊娠期肝内胆汁淤积症

妊娠期肝内胆汁淤积症患者由于有较高的围产儿患病率和死亡率,已被列为高危妊娠受到学者们的日益关注.本文就近几年有关其病因、病理变化、临床表现、实验室检查以及诊断和治疗方面研究进展进行综述.     

妊娠期肝内胆汁淤积症患者多药耐药3基因外显子8和12突变的研究

目的:研究多药耐药3(MDR3)基因外显子8和12突变与妊娠期肝内胆汁淤积症(ICP)的关系,探讨ICP的发生机制。方法:从29例ICP患者及32例正常孕妇的外周血中提取DNA,聚合酶链反应(PCR)扩增MDR3基因外显子8和12,对PCR产物进行DNA测序分析。结果:ICP患者和对照组PCR均扩增出目的片段,且存在多态性位点G711A及A1260G,两组的8号外显子基因型频率和12号外显子基因型频率比较,差异均有统计学意义(P<0.05,P<0.01)。结论:云南临沧地区ICP的发生可能与MDR3外显子8和12的突变有关。     

妊娠期肝内胆汁淤积症

妊娠期肝内胆汁淤积症患者由于有较高的围产儿患病率和死亡率,已被列为高危妊娠受到学者们的日益关注,本文就近几年有关其病因,病理变化。临床表现,实验室检查以及诊断和治疗方面研究进展进行综述。     

妊娠期肝内胆汁淤积症61例临床分析

妊娠期肝内胆汁淤积症cy,ICP)是妊娠期重要的并发症,以妊娠期出现皮肤瘙痒、黄疸和胆汁淤积为特征,早产率及围产儿死亡率高.1999年4月至2000年3月我院收治ICP61例,占此期间分娩总数1985例的3.02%.现分析如下.1 资料与方法1.1 临床资料 1999年4月至2000年3月我院产前检查筛查出ICP孕妇61例,24～34岁,平均26.7岁,于妊娠早、中、晚期分别测定肝功能.随机分为A、B两组,A组30例,按常规以葡萄糖醛酸内酯(肝泰乐)、维生素B6、天门冬氨酸钾镁,支链氨基酸针剂保肝治疗,B组31例以腺苷蛋氨酸(思美泰)1000mg/d、还原型谷胱甘肽(古拉定)1200mg/d保肝治疗,两组所用的其他常规对症药物及处理均相同,观察用药2周后肝功能变化.所有数据采用t检验.     

妊娠期肝内胆汁淤积症病因学研究进展

妊娠期肝内胆汁淤积症(ICP)为高危妊娠,是妊娠期特有疾病.临床上以妊娠中晚期母体皮肤瘙痒和血清胆汁酸升高为特征,与围生儿不良结局密切相关,ICP已逐步引起产科医师的重视.然而,ICP的病因学复杂,至今尚不完全清楚,有可能是遗传易感妇女体内生殖激素及其代谢产物造成胆汁淤积,环境因素及其他因素也有可能参与其发病,其发病原...     

胎盘MDR3的表达及其与妊娠期肝内胆汁淤积症关系的研究

目的探讨妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)胎盘中胆盐载体磷脂输出泵(multidrug resistance p-plycoprotein,MDR3)的表达,以及母、胎血中总胆汁酸(total bile acids,TBA)和甘胆酸(cholylglycine,CG)水平的变化;进一步分析胎盘胆盐载体对胆汁酸水平的调节作用及其与ICP的关系。方法ICP(ICP组)及正常妊娠(对照组)孕妇各20例。母血、胎儿脐静脉血中TBA、CG水平的测定分别采用放射免疫法和速率法;胎盘组织中胆盐载体MDR3 mRNA的表达采用荧光定量PCR法。结果(1)ICP组母血、脐血中的TBA、CG水平均高于对照组(P<0.05)。ICP组母血TBA水平高于脐血(25.8±16.6和8.6±5.5)μmol/L,CG水平高于脐血(3416.1±1986.0和821.8±673.2)μg/dL(P<0.05);对照组母血和脐血TBA水平(3.4±2.5和4.4±3.3)μmol/L,CG水平(342.7±234.9和309.3±145.2)μg/dL比较,差异无统计学意义(P>0.05)。(2)ICP和正常妊娠各期胎盘组织中均有MDR3 mRNA的表达。ICP组MDR3 mRNA表达量低于对照组(0.80±0.67和162.63±334.33)拷贝/ng(P<0.05)。(3)ICP组、对照组胎盘中MDR3 mRNA表达量与母血、脐血中TBA和CG水平均无相关性(r=-0.60~0.165,P>0.05)。结论ICP胎盘胆盐载体MDR3 mRNA表达降低,可能引起ICP胎盘对胆汁酸的转运障碍、胎儿体内胆汁淤积,可能是引起ICP胎儿窘迫的原因。     

雌激素受体基因多态性与妊娠期肝内胆汁淤积症关系的研究

目的研究雌激素受体α（estrogen receptor α，ERα）基因多态性表达，探讨ER基因多态性与江西籍汉族人群妊娠期肝内胆汁淤积症（intrahepatic cholestasis of pregnancy，ICP）的相关关系。方法应用聚合酶链反应、限制性片段长度多态性分析方法分析ERα基因多态性在ICP人群中的分布规律以及ERα基因型、等位基因与ICP的相关关系。结果（1）ERα基因XbaI位点多态性在ICP组和对照组的之间有统计学意义。（2）ERα基因PvuII位点多态性在ICP组和对照组的比较中无统计学意义。（3）ICP组中，突变杂合子基因型Xx的OR值为3．429（95％CI：1．509-7．791），XX、Xx联合分析OR值为3．143（95％CI：1．431-6．905）ICP组和对照组ERα XbaI等位基因频率比较发现X等位基因的相对危险度是x等位基因的2．071倍。（4）PvuII和XbaI联合基因型分布在ICP组和对照组间有统计学差异，杂合子联合基因型PpXx与野生型ppxx之间的差异在ICP组和对照组中有统计学意义，OR值为3．956（95％CI：1．287-12．157）。结论ERα基因XbaI酶切位点限制性片段长度多态性与江西籍汉族人群ICP的发生之间存在相关性。而PvuII酶切位点限制性片段长度多态性与该病无关。X等位基因是ICP发病的易感基因，Xx基因型为易感基因型，单倍体PpXx可能使ICP发病风险升高。     

克拉玛依地区妊娠肝内胆汁淤积症流行病学调查结果分析

目的　了解本地区妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy, ICP)的发病率及发病特点。　方法　从妊娠20~24周开始普查,动态观察至36周以上,以总胆汁酸酶循环法测定血清总胆汁酸(total bile acid,TBA),TBA>28.5μmol /L为异常,同时复查肝功能加以确诊。　结果　共普查1275例,确诊为ICP 的患者102 例,发病率为8.00%。妊娠33~36 周ICP的发病率(66/351,18.80%)明显高于其他不同孕龄组(P<0.01)。少数民族孕妇ICP的发病率(47/328,14.33%)高于汉族孕妇(55/947, 5. 81%) (P< 0. 01)。有ICP 高危因素的患者ICP 发病(10/67,14.93%)高于无高危因素组(92/208,7.62%)(P<0.01)。　结论　克拉玛依地区ICP的发病率为8 00%,为ICP的高发地区。少数民族孕妇ICP的发病率明显高于汉族发病率。ICP的发病与孕周、孕妇年龄、家族、服药史等有一定的相关性。TAB在整个孕期的波动范围较大。     

妊娠期肝内胆汁淤积症发生死胎的临床因素分析

目的 探讨妊娠期肝内胆汁淤积症(ICP)孕妇发生胎儿死亡的临床特点、实验室指标及胎儿监护手段.方法 对1999年1月至2010年12月浙江大学医学院附属妇产科医院收治的发生死胎的21例ICP孕妇的临床资料进行回顾性分析.结果 (1)21例ICP孕妇的平均年龄(30.2±4.6)岁,其中＞35岁者4例;经产妇6例,1例2年前因ICP发生死胎而引产1次;20例单胎妊娠,1例双胎妊娠.(2)21例ICP孕妇的死胎均发生在孕晚期,胎儿死亡的孕周为29～41周,平均(33.8±4.2)周.12例发生在孕29～37周,9例发生在孕37周后.9例为门诊B超检查时确诊胎死宫内;9例因诊断ICP入院治疗期间发生胎心消失;2例临产后胎心消失;1例胎心监护提示V型减速,拟行急诊刮宫产术于麻醉期间胎心消失.在所有ICP孕妇中围产儿死亡率为0.148%(21/14 184).(3)21例ICP孕妇均有皮肤瘙痒,其中11例有全身皮肤瘙痒.10例在发生死胎前自觉胎动减少或消失.21例ICP孕妇血清甘胆酸水平均升高,其中21.49～64.48 μmol/L 11例,t≥64.48 μmol/L 10例.血清总胆汁酸水平升高16例(另5例未检查),最高达270μmoL/L.血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平升高14例,总胆红素＞21μmol/L 7例,直接胆红素升高12例.21例ICP孕妇中,重度15例,轻度6例.(4)9例孕妇门诊即确诊宫内死胎未做胎心监护,其余12例住院检查结果 为:胎心监护结果 可疑2例,无应激试验(NST)提示胎心轻度V型减速1例,B超提示脐动脉舒张期血流缺如3例,胎儿生物物理指标评分低值1例.(5)21例ICP孕妇均经阴道分娩.6例为自然宫缩娩出死胎,其余15例予米非司酮配合依沙吖啶羊膜腔注射或缩宫素引产,14例在48 h内成功娩出死胎,仅1例追加地诺前列酮栓后引产成功.所有死胎外观无异常,脐带长度均在正常范围,有4例脐带绕颈或绕体.胎盘胎膜外观无异常,18例羊水Ⅲ度胎粪污染,2例合并羊水过少.10例行死胎及胎盘病理检查,其中1例合并多发畸形,其余死胎病理检查未见明显异常,10例胎盘病理检查均有绒毛膜周围或底蜕膜、大血管周围的纤维蛋白沉积,同时伴有钙化、退行性变、红色梗死及局灶性合体细胞结节增多.结论 ICP孕妇发生死胎的孕周常在孕晚期,时间常在正常宫缩后,ICP重度可能是发生死胎的关键因素;尚无有效的胎儿监护指标可预测死胎的发生.因此,应综合评估病情,加强胎儿监护,适时终止妊娠.

Abstract：

Objective To investigate the clinical features,critical laboratory parameters,and fetal monitoring methods in intrahepatic cholestasis of pregnancy(ICP).Methods A retrospective analysis of 21 cases of ICP suffered with fetal death in Women's hospital.School of Medicine.Zhejiang University from January 1999 to December 2010 were discussed.Results(1)The average age of ICP patients suffered with fetal death were(30.2±4.6)years old.Among them,4 cases were older than 35 years,six cases were multipara.oneo of them suffered stillbirth 2 year before.Twenty cases were singleton pregnancies and 1 cage was twin pregnancy.(2)All 21 cases of fetal death occurred in the third trimester,12 cases occurred before 37 weeks,9 cases after 37 weeks.Nine cases were diagnosed by ultrasound in outpatient clinics,fetal heart beat disappeared in 9 patients after admission because of ICP, two disappeared after labor, one during anesthesia before emergent surgery. Perinatal mortality rate of ICP was 0. 148% (21/14 184), and fetal death occurred from 29 to 41 weeks with an average gestational age of ( 33.8 ± 4. 2 ) weeks, ( 3 ) Puritus occurred in all 21 cases while 11 of them had pruritus all over the body. Ten pregnant women felt the fetal movement decreased or disappeared before diagnosis of fetal death. The glycocholic acid levels increased in all of the 21 cases. Among them, glycocholic acid levels in 11 cases were (21.49 -64. 48) μmol/L, while in 10 cases were ≥64. 48 μmol/L Serum bile acid levels elevated in 16 cases which had been analyzed ( the other 5 cases had not been checked ), and the highest level reached 270 μmol/L Serum alanine aminotransferase and aspartate aminotransferase were increased in 14 cases. Seven cases had their total bilirubin ＞21 μmoL/L, and 12 cases had their direct bilirubin levels significantly elevated. Among the 21 cases of ICP, 15 cases were in severe status, while the other 6 cases were mild. (4) Nine patients had no antepartum surveillance since fetal death were diagnosed before admission. The results of antepartum surveillance were as follows: 2 cases had nonreassuring nonstress test (NST), one had mild "V" type deceleration. Absence of diastolic flow in umbilical artery were found in 3 cases, and low fetal biophysical score was got in one case. ( 5 ) All 21 patients had vaginal delivery. Six of them delivered after natural contraction, and the remaining 14 cases delivered after oral intake of mifepristone and amniotic injection of ethacridine, or oxytocin induced labor within 48 hours, only one case delivered after additional dinoprostone suppositories. The appearance of fetus, placentas and membranes were normal, the lengths of umbilical cord were average. Four cases were found with cords binding the necks or the bodies. Eighteen cases had grade Ⅲ amniotic fluid with meconium-stained, and 2 cases complicated by oligohydramnios. Ten cases had their fetuses and placentas examined by pathologist. Among them, one case had multiple malformations, no more obvious pathological abnormalities were found in other fetuses. Pathologic examination showed that fibrin deposited around chorion and deciduas basalis, large vessels accompanied by calcification, degeneration,hemorrhagic infarction, and increased focal syncytial nodules could be seen in all of the ten placentas. Conclusions Fetal death in pregnant women with ICP of ten occurs after the contractions, Severe ICP may be a key factor that involved in the occurrence of fetal death. Up to now, there is no valid indicators in fetal monitoring, which can predict fetal death. Extensive assessment of the severity and careful antepartum surveillance should be achieved before timely termination of pregnancy.     

妊娠肝内胆汁淤积症患者血清甘胆酸水平变化与胎盘细胞凋亡调节基因表达的关系

目的　探讨妊娠肝内胆汁淤积症 (ICP)患者血清甘胆酸水平变化与胎盘细胞凋亡的关系 ,进一步分析ICP患者胎盘功能减退的可能机制。方法　应用放射免疫方法 ,测定 30例ICP患者(ICP组 )及 2 7例正常孕妇 (对照组 )分娩前血清甘胆酸水平 ,应用免疫组化方法测定两组孕妇胎盘细胞凋亡调节基因bax和bcl 2的表达。结果　 (1)ICP组甘胆酸水平为 (5 1 8± 5 9) μmol/L ,对照组为(9 4± 5 6 ) μmol/L ,两组比较 ,差异有显著性 (P <0 0 5 )。 (2 )ICP组胎盘合体滋养细胞bax阴性 2例 ,弱阳性 9例 ,中等阳性 11例 ,强阳性 8例 ;bcl 2弱阳性 12例 ,中等阳性 12例 ,强阳性 6例。对照组bax阴性 9例 ,弱阳性 13例 ,中等阳性 4例 ,强阳性 1例 ;bcl 2弱阳性 3例 ,中等阳性 4例 ,强阳性 2 0例。两组比较 ,ICP组bax表达阳性率显著高于对照组 (P <0 0 0 0 5 ) ,而bcl 2的表达阳性率又显著低于对照组 (P <0 0 0 0 5 )。 (3)孕妇血甘胆酸水平与胎盘bax表达阳性率呈线性正相关 (P <0 0 0 5 ) ,与胎盘bcl 2表达呈线性负相关 (P <0 0 0 5 )。结论　ICP患者血中高水平的甘胆酸使胎盘合体滋养细胞bax基因过度表达 ,这可能是ICP患者胎盘功能减退的机制之一。     

妊娠期肝内胆汁瘀积症红细胞膜ATP酶及离子变化

测定２４例正常未孕妇女，３８例正常孕妇及３４例妊娠期肝内胆汁瘀积症患者细胞膜ＡＴＰ酶活力和红细胞内离子浓度。结果ＩＣＰ患者红细胞膜Ｎａ＾＋－Ｋ＾＋ＡＴＰ酶、Ｃａ＾＋＋ＡＴＰ酶及Ｍｇ＾＋＋ＡＴＰ酶活力明显低于正常组（Ｐ＜０．０１），ＩＣＰ患者红细胞内Ｎａ＾＋，Ｃａ＋＋明显高于正常组（Ｐ＜０．０１）。     

1340例妊娠期肝内胆汁淤积症的回顾性分析

目的 回顾分析1340例妊娠期肝内胆汁淤积症(intrahepatic eholestasis of pregnancy,ICP)患者的临床资料,探讨ICP分型对诊断和处理的临床意义. 方法 对我院2000年1月至2007年12月的8年中收治的1340例ICP患者病例资料进行回顾性分析.比较不同ICP分型患者的临床表现、生化结果、分娩方式、围产儿结局等指标. 结果 ICP患者占同期产科住院孕妇总数的8.58 oA(1340/15 625),院内分娩孕妇的早产发生率为11.72 %(124/1058).新生儿窒息率为2.07%(23/1110),围产儿死亡率为1.08%(12/1110).75.97%(1018/1340)的ICP孕妇以皮肤瘙痒为主要症状,轻、重型ICP患者皮肤瘙痒症状出现的比例差异无统计学意义[74.89%(522/697)和77.14%(496/643),X~2=0.94,P>±.05].ICP患者有、无皮肤瘙痒时的围产儿死亡率(1.02%和1.46%)、新生儿窒息率(2.30%和1.82%)和早产发生率(11.61%和12.04%)差异均无统计学意义(P均>0.05).甘胆酸(glycocholic,acid,CG)≥64.43/μmol/L与CG＜64.43μmol/L、AST和(或)ALT≥250U/L与AST和ALT均<250U/L、TBA>40/μmol/L与TBA<40μmol/L的患者比较,前者的围产儿死亡率、新生儿窒息率和早产的发生率均低于后者(P均d0.05).轻型ICP患者平均分娩孕周晚于重型ICP患者[(38.3±1.9)周和(36.1±1.7)周,P<0.05],而剖宫产率(73.73%和97.33%)、早产率(6.13%和18.28%)、新生儿窒息率(1.05%和3.49%)和围产儿死亡率(0.18%和2.26%)均低于重型ICP患者(P均<0.05). 结论 ICP分型对终止妊娠时问、分娩方式选择有指导意义,重型ICP宜剖宫产,轻型ICP可在密切监护下阴道试产.     

妊娠期肝内胆汁淤积症患者母胎混合淋巴细胞培养的研究

目的　通过观察母胎间混合淋巴细胞反应 ,探讨母胎组织相容性与妊娠期肝内胆汁淤积症 (ICP)发病的关系。方法　采用淋巴细胞转化法对 2 2例ICP患者 [ICP组 ,其中 5例合并妊娠高血压综合征 (妊高征 ) ]和 2 1例正常孕妇 (对照组 )进行母胎淋巴细胞混合培养 ,计算淋巴细胞转化率 ;比较两组间淋巴细胞转化率的差异。通过检测ICP组孕妇的血清甘胆酸盐水平 ,分析淋巴细胞转化率与血清甘胆酸盐水平的相关性。结果　ICP组淋巴细胞转化率为 ( 2 4± 5 ) % ,对照组为 ( 3 6± 9) % ,两组比较 ,差异有极显著性 (P <0 0 0 1)。ICP组合并与不合并妊高征者的淋巴细胞转化率无显著性差异 (P >0 0 5 )。ICP组淋巴细胞转化率与血清甘胆酸盐水平无显著相关性 [相关系数 (r) =0 40 3 ,P>0 0 5 ]。结论　ICP患者母胎混合淋巴细胞培养反应性降低 ,提示母胎间组织相容性增高、免疫识别与反应性降低。这一变化可能与ICP的发生有关     

Increased levels of the novel hepatokine fetuin B in patients with intrahepatic cholestasis of pregnancy

Objectives: To investigate liver-derived plasma protein fetuin B levels in healthy pregnant women and pregnant women with intrahepatic cholestasis of pregnancy (ICP).

Materials and methods: Forty women with ICP and 40 healthy pregnant women were included in this cross-sectional study. The serum fetuin B levels of these patients were analyzed. The patients were followed up to delivery.

Results: Maternal age, gravida, parity, BMI at assessment, and gestational age at blood sampling were similar between the ICP and control groups (p?>?.05). However, the gestational age at delivery and the birth weight were significantly lower in the ICP group (p?p?p?Conclusions: Serum fetuin B was higher in patients with ICP compared to healthy pregnant women and might be a new biomarker.