妊娠肝内胆汁淤积症发生的分子机制研究进展

妊娠肝内胆汁淤积症(Intrahepatic cholestasis of pregnancy,ICP)是发生在妊娠中晚期,以皮肤瘙痒、黄疸、血清胆汁酸升高,伴轻度肝功能损害为特征的妊娠并发症,严重影响母儿健康。ICP的发病机制尚未完全阐明,但有研究表明在遗传易感性妇女中,性激素及其代谢产物导致胆汁酸代谢异常与本病的发生密切相关。现就目前国内外有关ICP发病机制的研究进展做一综述,一方面为探寻更深层次的机制提供理论基础,另一方面为临床治疗ICP提供思路和方法。     

妊娠肝内胆汁淤积症发生的分子机制研究进展

妊娠肝内胆汁淤积症（Intrahepatic cholestasis of pregnancy, ICP）是发生在妊娠中晚期,以皮肤瘙瘁、黄疸、血清胆汁酸升高,伴轻度肝功能损害为特征的妊娠并发症,严重影响母儿健康。ICP的发病机制尚未完全阐明,但有研究表明在遗传易感性妇女中,性激素及其代谢产物导致胆汁酸代谢异常与本病的发生密切相关。现就目前国内外有关ICP发病机制的研究进展做一综述,一方面为探寻更深层次的机制提供理论基础,另一方面为临床治疗ICP提供思路和方法。     

Biochemical Characterization of P4-ATPase Mutations Identified in Patients with Progressive Familial Intrahepatic Cholestasis

Mutations in the P4-ATPase ATP8B1 cause the inherited liver disease progressive familial intrahepatic cholestasis. Several of these mutations are located in conserved regions of the transmembrane domain associated with substrate binding and transport. Assays for P4-ATPase-mediated transport in living yeast cells were developed and used to characterize the specificity and kinetic parameters of this transport. Progressive familial intrahepatic cholestasis mutations were introduced into the yeast plasma membrane P4-ATPase Dnf2p, and the effect of these mutations on its catalysis of phospholipid transport were determined. The results of these measurements have implications for the basis of the disease and for the mechanism of phospholipid transit through the enzyme during the reaction cycle.     

Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center

Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5’UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission.     

Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update

Biochemical Genetics - Familial combined hyperlipidemia (FCHL) is one of the most common familial lipoprotein disorders of the lipoproteins, with a prevalence of 0.5% to 2% in different...     

妊娠期肝内胆汁淤积症的处理与预防护理研究

目的:研究妊娠期肝内胆汁淤积综合症(ICP)的产科处理及预防护理,探讨治疗对母婴预后的影响。方法:选取2009年1月至2010年1月第四军医大学西京医院妇产科收治ICP患者共67例,分为治疗组49例,经过丁烷二磺酸腺苷蛋氨酸(思美泰),对照组18例服用熊去氧胆酸治疗的孕妇。对孕妇症状、生化指标、母婴结局进行比较分析。结果:治疗组临床症状、生化指标较治疗前明显下降较对照组明显好转(p0.01),直接胆红素下降两组间无显著差异(p0.01)。将治疗组和对照组胎儿宫内窘迫率存在显著性差异(p0.01)。结论:应用丁烷二磺酸腺苷蛋氨酸(思美泰)积极正确处理ICP,可明显减轻孕妇瘙痒症状及肝功异常,同时明显降低胎儿宫内窘迫率,提高围生儿的生存质量。     

Molecular characterization of exons 6, 8 and 9 of ABCB4 gene in children with Progressive Familial Intrahepatic Cholestasis type 3

Aim of work: To estimate the frequency of mutations involving exons 6, 8 and 9 of Adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene among children with progressive intrahepatic cholestasis with high γ-GT activity (PFIC3).

Subjects and methods: Cross sectional study was conducted on 30 children with PFIC3. Genotyping was performed by sequencing analysis of exons 6, 8 and exon 9 of ABCB4 gene.

Results: Heterozygous synonymous polymorphic variant was detected in exon 6 (rs 1202283) and in exon 8 (rs 2109505). No mutations in studied exons were detected.

Conclusion: Exons 6, 8 and 9 mutations of ABCB4 gene are not common among Egyptian children with PFIC3.     

妊娠期肝内胆汁淤积症256例临床分析

目的:探讨改善妊娠期肝内胆汁淤积症患者围生结局及围生儿预后的方法。方法:对2006年3月-2011年3月在我院住院分娩的256例ICP患者及从我院住院无并发症正常分娩的10112个患者中随机抽取的256例患者的产检情况、分娩方式、围生儿结局进行回顾性分析。结果:ICP组与对照组在分娩方式、产后出血、早产、新生儿窒息、羊水粪染、围产儿死亡等方面比较差异均具有统计学意义(P<0.05);产检组与未检组在产后出血、早产、新生儿窒息、羊水粪染、围产儿死亡等方面比较差异有统计学意义(P<0.05)。结论:妊娠期肝内胆汁淤积症可增加早产、胎儿宫内窘迫、新生儿窒息、产后出血发生率,重视产前检查和孕期保健,对ICP患者做到早发现、早诊断、早治疗,选择适当分娩方式、适时终止妊娠,对改善围生结局及围生儿预后有积极的意义。     

Comparative Proteomics Analysis of Placenta from Pregnant Women with Intrahepatic Cholestasis of Pregnancy

Introduction

Intrahepatic cholestasis of pregnancy (ICP) usually occurs in the third trimester and associated with increased risks in fetal complications. Currently, the exact cause of this disease is unknown. In this study we aim to investigate the potential proteins in placenta, which may participate in the molecular mechanisms of ICP-related fetal complications using iTRAQ-based proteomics approach.

Methods

The iTRAQ analysis combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to separate differentially expressed placental proteins from 4 pregnant women with ICP and 4 healthy pregnant women. Bioinformatics analysis was used to find the relative processes that these differentially expressed proteins were involved in. Three apoptosis related proteins ERp29, PRDX6 and MPO that resulted from iTRAQ-based proteomics were further verified in placenta by Western blotting and immunohistochemistry. Placental apoptosis was also detected by TUNEL assay.

Results

Proteomics results showed there were 38 differentially expressed proteins from pregnant women with ICP and healthy pregnant women, 29 were upregulated and 9 were downregulated in placenta from pregnant women with ICP. Bioinformatics analysis showed most of the identified proteins was functionally related to specific cell processes, including apoptosis, oxidative stress, lipid metabolism. The expression levels of ERp29, PRDX6 and MPO were consistent with the proteomics data. The apoptosis index in placenta from ICP patients was significantly increased.

Conclusion

This preliminary work provides a better understanding of the proteomic alterations of placenta from pregnant women with ICP and may provide us some new insights into the pathophysiology and potential novel treatment targets for ICP.     

妊娠期肝内胆汁淤积症患者血管内皮祖细胞生物学变化

目的:研究妊娠期肝内胆汁淤积症(Intrahepatic Cholestasis of Pregnancy,ICP)患者血管内皮祖细胞(Endothelial Progenitor Cells,EPC)的生物学变化并探讨其意义.方法:40例28-40周孕妇分为ICP组(n=20)、正常组(n=20).用酶联免疫吸附试验法测定两组血胆汁酸浓度;用密度梯度离心法从外周血分离两组单个核细胞培养后进行EPC数量、增殖率、黏附及迁移能力测定并对胆汁酸与EPC相关性进行分析.结果:ICP组孕妇的EPC黏附、增殖和迁移能力明显受损;数量较正常组减少(P=0.00).结论:ICP患者血管内皮祖细胞功能受损,可能与高胆汁酸造成的细胞膜损伤有关.     

Coccidioidomycosis: An Update

Coccidioidomycosis is the oldest of the major mycoses. In recent years the incidence of the disease has increased in California and Arizona, which may be partially due to the massive migration to the endemic region. The endemic region for the disease lays exclusively in the Western Hemisphere, between the 40° latitudes north and south. The disease manifests in one of four clinical syndromes: acute pulmonary, chronic pulmonary and acute or chronic disseminated coccidioidomycosis. Serologic tests identifying anticoccidioidal antibodies are the most frequently employed assays for diagnosis. Primary coccidioidomycosis is usually self-limited; therapy of primary disease is recommended when symptoms persist for more than 6 weeks, for severe acute cases and for patients with impaired cellular immunity. Chronic pulmonary coccidioidomycosis and all forms of disseminated coccidioidomycosis require antifungal therapy. The drugs of choice are either fluconazole or itraconazole.     

96例妊娠期肝内胆汁淤积症患者的妊娠结局分析及护理对策

目的:探讨妊娠合并肝内胆汁淤积症(ICP)对妊娠结局的影响,并探索相对应的护理策略.方法:选取在我院治疗的ICP患者96例,根据ICP分度标准分为轻度与重度型,分别观察其妊娠.结果:重型组患者新生儿窒息、羊水污染、剖宫产的发生率都明显高于轻型组患者(P＜0.05);而两组围产儿死亡率和产后出血率相比,差异无显著性意义(P＞0.05).结论:ICP对孕妇妊娠结局具有重要的不良影响作用,针对其可能导致的不良妊娠结局采取针对性的护理策略具有重要的临床意义.     

妊娠期肝内胆汁淤积导致新生儿肺损伤的高危因素及干预对策

目的:探讨妊娠期肝内胆汁淤积症综合症所致新生儿肺损伤的危险因素,并采取相应的措施以提高临床治疗水平。方法:选取2010年1月-2013年1月我院收治的70例妊娠肝内胆汁淤积症综合症患者作为观察组,另选取同期接受体检的65例正常晚期妊娠妇女为对照组。分析新生儿肺损伤的相关因素。结果:妊娠肝内胆汁淤积症综合症所致新生儿肺损伤高危险因素有高雌激素水平、机体免疫失衡、高微量元素硒、高总胆汁酸、高甘胆酸(p均0.05)。结论:妊娠肝内胆汁淤积症综合症所致新生儿肺损伤的高危因素较多,临床上要积极采取措施,避免产后母婴并发症的发生。     

347例妊娠期肝内胆汁淤积症羊水性状与妊娠结局的分析

目的:探讨妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy ICP)羊水性状与妊娠结局的关系。方法:对我院2005年1月～2009年12月住院分娩的患者资料进行回顾分析,统计羊水污染率、新生儿窒息发生率、围产儿死亡率及剖宫产率等。结果:347例ICP中轻度278例,重度69例。羊水污染89例(Ⅰ级19例,Ⅱ级14例,Ⅲ级56例),羊水污染率为25.6%。重度ICP中羊水污染46例,发生率为66.7%。89例ICP羊水Ⅱ级及Ⅲ级病例中出现3例新生儿窒息。结论:ICP的羊水性状与病情程度基本一致,羊水污染预示着不良的妊娠结局,适时终止妊娠可降低围生儿病率。     

Elevated Plasma Levels of Hypermethylated RASSF1A Gene Sequences in Pregnant Women with Intrahepatic Cholestasis

Intrahepatic cholestasis of pregnancy (ICP) is associated with increased perinatal mortality and morbidity. Circulating cell-free fetal DNA has been a useful parameter for monitoring of pregnancy-associated diseases. The purpose of this study was to determine the concentrations of hypermethylated RAS-association domain family 1, isoform A (RASSF1A) gene sequences in the plasma of pregnant women with intrahepatic cholestasis. This study included 56 women in their third trimester of pregnancy, of whom 26 had ICP (study group) and 30 were healthy (control group). Real time PCR was performed to detect RASSF1A concentrations after methylation-sensitive restriction digestion with HinpII and HhaI to measure cell-free fetal DNA. Beta-actin was detected as an internal control to confirm complete enzyme digestion. The data show a significant increase in the circulating hypermethylated RASSF1A levels regarding the pregnancies complicated with ICP as compared with normal pregnancies. Circulating hypermethylated RASSF1A levels in maternal plasma related to total bile acid. Based on these observations, we suggest that the circulating hypermethylated RASSF1A levels in maternal plasma may be used as a diagnostic marker for ICP.     

347例妊娠期肝内胆汁淤积症羊水性状与妊娠结局的分析

目的:探讨妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy ICP)羊水性状与妊娠结局的关系.方法:对我院2005年1月～2009年12月住院分娩的患者资料进行回顾分析,统计羊水污染率、新生儿窒息发生率、围产儿死亡率及剖宫产率等.结果:347例ICP中轻度278例,重度69例.羊水污染89例(Ⅰ级19例,Ⅱ级14例,Ⅲ级56例),羊水污染率为25.6％.重度ICP中羊水污染46例,发生率为66.7％.89例ICP羊水Ⅱ级及Ⅲ级病例中出现3例新生儿窒息.结论:ICP的羊水性状与病情程度基本一致,羊水污染预示着不良的妊娠结局,适时终止妊娠可降低围生儿病率.     

The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy Is Corrected by Ursodeoxycholic Acid

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.     

熊脱氧酸治疗妊娠期肝内胆汁淤积症的临床效果分析

目的:探讨熊脱氧酸治疗妊娠期肝内胆汁淤积症(ICP)的临床效果及其可能机制。方法:选择2013年8月到2018年2月在我院诊治的ICP患者105例作为研究对象,根据治疗方法分为对照组50例和研究组55例,对照组给予腺苷蛋氨酸治疗,研究组给予腺苷蛋氨酸联合熊脱氧酸治疗,检测和比较两组的临床总有效率,治疗前后的血清肿瘤坏死因子α(TNF-α)、白细胞介素12(IL-12)、甘胆酸(CG)和总胆汁酸(TBA)水平的变化及妊娠结局。结果:所有患者都顺利分娩,无死亡产妇与胎儿。研究组的总有效率为98.2%,显著高于对照组(88.0%),差异有统计学意义(P0.05)。两组治疗后的血清CG、TBA、IL-12及TNF-α水平均显著低于治疗前(P0.05),且研究组以上指标均明显低于对照组(P0.05)。研究组的剖宫产、早产、新生儿窒息、产后出血、羊水粪染等发生率显著低于对照组(P0.05)。结论:熊脱氧酸治疗ICP能有效提高治疗效果,改善妊娠结局,这可能与其降低血清患者TNF-α、IL-12、CG、TBA水平有关。     

重度妊娠期肝内胆汁淤积症对母婴结局影响的临床分析

目的：分析重度妊娠期肝内胆汁淤积症（intrahepatic cholestasis of pregnancy,ICP）对母婴结局的影响,以提高对ICP的认识与治疗水平。方法：选择ICP产妇58例,根据ICP分度标准分为轻度组（n=26例）和重度组（n=32例）,比较两组产妇的母婴结局。结果：与轻度组相比,重度组产妇剖宫产率、产后出血与平均产后出血量显著升高或增加,阴道分娩率显著降低,组间比较差异均具有统计学意义（P〈0.05）;重度组新生儿早产、胎儿窘迫、羊水污染和新生儿窒息的发生率均显著上升,新生儿平均出生体重显著降低,组间比较差异均具有统计学意义（P〈0.05）。结论：ICP对产妇及新生儿均有不良影响,对ICP严重程度进行划分,有利于临床处理。对于重度ICP产妇,应尽早采取剖宫产分娩的方式终止妊娠。