高效液相色谱法检测ICP脐血胆汁酸谱及妊娠结局
|
摘要
目的探讨妊娠期肝内胆汁淤积症(ICP)不同分度标准孕妇肝功能指标异常,脐血胆汁酸谱和妊娠结局。
方法高效液相色谱法检测ICP脐血胆汁酸谱,包括牛磺熊脱氧胆酸(TUDCA)、牛磺胆酸(TCA)、甘氨胆酸(GCA)、甘氨石胆酸(GLCA)、牛磺鹅脱氧胆酸(TCDCA)、牛磺脱氧胆酸(TDCA)、甘氨鹅脱氧胆酸(GCDCA)、甘氨脱氧胆酸(GDCA)。应用四种ICP分度方法比较ICP孕妇肝功能指标、脐血胆汁酸谱及妊娠结局。
结果(1)正常妊娠组和轻度ICP组比较,标准三、标准四ALT、AST、TBIL、DBIL差异均有统计学意义(P<0.05),四种分度标准脐血TCA、GCA差异均有统计学意义(P<0.05),标准一和标准二脐血GLCA差异有统计学意义(P<0.05),标准四脐血GCDCA差异有统计学意义(P<0.05),标准三早产儿差异有统计学意义(P<0.05)。(2)正常妊娠组和重度ICP组比较,四种分度标准ALT、AST、TBIL、DBIL差异均有统计学意义(P<0.05),四种标准脐血TCA、GCA、GLCA、TCDCA差异均有统计学意义(P<0.05),标准一、标准二、标准四脐血GCDCA差异有统计学意义(P<0.05),标准一、标准二、标准四早产儿和羊水粪染差异有统计学意义(P<0.05)。(3)轻度ICP组和重度ICP组比较,标准一、标准二ALT、AST、TBIL、DBIL差异均有统计学意义(P<0.05),四种分度标准脐血TCA、TCDCA差异均有统计学意义(P<0.05),标准一脐血GCDCA差异有统计学意义(P<0.05),标准四脐血GLCA差异有统计学意义(P<0.05),标准一早产儿差异有统计学意义(P<0.05)。
结论ICP分度反映了ICP孕妇肝功能异常的程度不同;ICP脐血胆汁酸谱的主要成分是牛磺结合型胆汁酸和甘氨结合型胆汁酸,牛磺结合型胆汁酸比甘氨结合型胆汁酸浓度高,重度ICP的脐血TCA、TCDCA和GLCA均明显高于轻度ICP和正常妊娠;重度ICP羊水粪染、早产儿发生率明显高于轻度ICP及正常妊娠。
Objective To investigate the differences of liver function of pregnant women, the bile acids profile of umbilical cord blood and pregnant outcome under different grading standards of intrahepatic cholestasis of pregnancy (ICP).
Methods Bile acids profiles of umbilical cord blood of intrahepatic cholestasis of pregnancy were analyzed by high performance liquid chromatography. Eight kinds of bile acids including tauroursodeoxycholic acid (TUDCA), taurocholic acid (TCA), glycocholic acid(GCA), glycolithocholic acid(GLCA), taurochenodeoxycholic acid(TCDCA), taurodeoxycholic acid(TDCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholicacid (GDCA) were involved in the study. Maternal liver function, bile acids profiles of umbilical cord blood and pregnant outcomes were analyzed under four kinds of ICP grading standard.
Results (1) When compared with normal pregnancy group and mild ICP group, there were statistically significant differences of ALT, AST, TBIL, DBIL under the third ICP grading standard and the fourth standard (P <0.05), there were statistically significant differences of TCA, GCA under the four standards (P <0.05), there were significant difference of GLCA under the first standard and the second standard (P <0.05), there were significantly differences of GCDCA under the fourth standard (P <0.05), there was significantly difference of the morbidity of premature infant under the third standard (P <0.05).
(2) When compared with normal pregnancy group and severe ICP group, there were significant differences of ALT, AST, TBIL, DBIL with under four standards (P <0.05), there were significant differences of TCA, GCA, GLCA, TCDCA under four standards (P <0.05), there were significant differences of GCDCA under the first standard ,the second standard and the fourth standard (P<0.05), there were significant differences of the morbidity of premature infant and meconium staining of amniotic fluid under the first standard, the second standard and the fourth standard (P <0.05).
(3) When compared with mild ICP group and severe ICP group, there were significant differences of ALT, AST, TBIL, DBIL under the first standard and the second standard (P <0.05), there were significant differences of TCA, TCDCA under four standards (P <0.05), there were significantly difference of GCDCA under the first standard(P <0.05), there were significantly difference of GLCA under the fourth standard(P <0.05), there were significant difference of the morbidity of pr emature infant under the first standard (P <0.05).
Conclusion The ICP grading standard reflects the differences of liver function of pregnant women with ICP. Tauro-conjugated and glyco-conjugated bile acids are the predominant increase in serum bile acids of cord blood,and the concentration of tauro-conjugated bile acid are higher than that of glyco-conjugated. TCA, TCDCA and GLCA are significant higher in the severe ICP group than the mild ICP group. The morbidity of premature infant and meconium staining of amniotic fluid are significant higher in the severe ICP group than the mild ICP group.
方法高效液相色谱法检测ICP脐血胆汁酸谱,包括牛磺熊脱氧胆酸(TUDCA)、牛磺胆酸(TCA)、甘氨胆酸(GCA)、甘氨石胆酸(GLCA)、牛磺鹅脱氧胆酸(TCDCA)、牛磺脱氧胆酸(TDCA)、甘氨鹅脱氧胆酸(GCDCA)、甘氨脱氧胆酸(GDCA)。应用四种ICP分度方法比较ICP孕妇肝功能指标、脐血胆汁酸谱及妊娠结局。
结果(1)正常妊娠组和轻度ICP组比较,标准三、标准四ALT、AST、TBIL、DBIL差异均有统计学意义(P<0.05),四种分度标准脐血TCA、GCA差异均有统计学意义(P<0.05),标准一和标准二脐血GLCA差异有统计学意义(P<0.05),标准四脐血GCDCA差异有统计学意义(P<0.05),标准三早产儿差异有统计学意义(P<0.05)。(2)正常妊娠组和重度ICP组比较,四种分度标准ALT、AST、TBIL、DBIL差异均有统计学意义(P<0.05),四种标准脐血TCA、GCA、GLCA、TCDCA差异均有统计学意义(P<0.05),标准一、标准二、标准四脐血GCDCA差异有统计学意义(P<0.05),标准一、标准二、标准四早产儿和羊水粪染差异有统计学意义(P<0.05)。(3)轻度ICP组和重度ICP组比较,标准一、标准二ALT、AST、TBIL、DBIL差异均有统计学意义(P<0.05),四种分度标准脐血TCA、TCDCA差异均有统计学意义(P<0.05),标准一脐血GCDCA差异有统计学意义(P<0.05),标准四脐血GLCA差异有统计学意义(P<0.05),标准一早产儿差异有统计学意义(P<0.05)。
结论ICP分度反映了ICP孕妇肝功能异常的程度不同;ICP脐血胆汁酸谱的主要成分是牛磺结合型胆汁酸和甘氨结合型胆汁酸,牛磺结合型胆汁酸比甘氨结合型胆汁酸浓度高,重度ICP的脐血TCA、TCDCA和GLCA均明显高于轻度ICP和正常妊娠;重度ICP羊水粪染、早产儿发生率明显高于轻度ICP及正常妊娠。
Objective To investigate the differences of liver function of pregnant women, the bile acids profile of umbilical cord blood and pregnant outcome under different grading standards of intrahepatic cholestasis of pregnancy (ICP).
Methods Bile acids profiles of umbilical cord blood of intrahepatic cholestasis of pregnancy were analyzed by high performance liquid chromatography. Eight kinds of bile acids including tauroursodeoxycholic acid (TUDCA), taurocholic acid (TCA), glycocholic acid(GCA), glycolithocholic acid(GLCA), taurochenodeoxycholic acid(TCDCA), taurodeoxycholic acid(TDCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholicacid (GDCA) were involved in the study. Maternal liver function, bile acids profiles of umbilical cord blood and pregnant outcomes were analyzed under four kinds of ICP grading standard.
Results (1) When compared with normal pregnancy group and mild ICP group, there were statistically significant differences of ALT, AST, TBIL, DBIL under the third ICP grading standard and the fourth standard (P <0.05), there were statistically significant differences of TCA, GCA under the four standards (P <0.05), there were significant difference of GLCA under the first standard and the second standard (P <0.05), there were significantly differences of GCDCA under the fourth standard (P <0.05), there was significantly difference of the morbidity of premature infant under the third standard (P <0.05).
(2) When compared with normal pregnancy group and severe ICP group, there were significant differences of ALT, AST, TBIL, DBIL with under four standards (P <0.05), there were significant differences of TCA, GCA, GLCA, TCDCA under four standards (P <0.05), there were significant differences of GCDCA under the first standard ,the second standard and the fourth standard (P<0.05), there were significant differences of the morbidity of premature infant and meconium staining of amniotic fluid under the first standard, the second standard and the fourth standard (P <0.05).
(3) When compared with mild ICP group and severe ICP group, there were significant differences of ALT, AST, TBIL, DBIL under the first standard and the second standard (P <0.05), there were significant differences of TCA, TCDCA under four standards (P <0.05), there were significantly difference of GCDCA under the first standard(P <0.05), there were significantly difference of GLCA under the fourth standard(P <0.05), there were significant difference of the morbidity of pr emature infant under the first standard (P <0.05).
Conclusion The ICP grading standard reflects the differences of liver function of pregnant women with ICP. Tauro-conjugated and glyco-conjugated bile acids are the predominant increase in serum bile acids of cord blood,and the concentration of tauro-conjugated bile acid are higher than that of glyco-conjugated. TCA, TCDCA and GLCA are significant higher in the severe ICP group than the mild ICP group. The morbidity of premature infant and meconium staining of amniotic fluid are significant higher in the severe ICP group than the mild ICP group.
引文
[1] Casta?o G, Lucangioli S, Sookoian S ,et al. Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy[J]. Clin Sci (Lond). 2006 ,110(4):459～65
[2] Rodrigues CM, Marín JJ, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment[J]. Gut. 1999 ,45(3):446～52
[3] Itoh S, Onishi S, Isobe K, et al. Foetomaternal relationships of bile acid pattern estimated by high-pressure liquid chromatography[J]. Biochem. 1982, 204(1):141～145
[4] Méndez-Sánchez N, Chavez-Tapia NC, Uribe M. New molecular features of cholestatic diseases of the liver[J]. Rev Invest Clin. 2003, 55(5):546～56
[5] Mazzella G,Nicola R,Francesco A,et a1.Ursodexycholic acid administration in patients with cholestasis of pregnancy:effects on primary bile acids in babies and mothers[J].Hepatology. 2001,33(3):504～508
[6]曹泽毅.中华妇产科学[M].第2版.北京:人民卫生出版社,1999:468-474
[7]赵纯全,邵勇,吴味辛.妊娠期肝内胆汁郁积症的临床分型研究(附-501例分析) [J].实用妇产科杂志. 1999,15(4):199～200
[8]漆洪波,邵勇,吴味辛等.妊娠肝内胆汁淤积症分度诊断和处理的临床意义[J].中华妇产科杂志.2004, 39(1):14～17
[9] Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:relationships between bile acid levels and fetal complication rates[J]. Hepatology . 2004,40(2):467～74
[10]张惜阴.实用妇产科学[M].第2版.北京:人民卫生出版社,2003:181,253,259,454
[11]黄延风,朱朝敏.胆汁酸的毒性作用[J] .国际检验医学杂志,2006,27(2):152-153,157
[12] Macias RI, Marin JJ, Serrano MA.Excretion of biliary compounds during intrauterine life [J]. World J Gastroenterol. 2009 Feb 21;15(7):817～28
[13] Howard PJ, Murphy GM.Bile acid stress in the mother and baby unit[J]. EurJ Gastroenterol Hepatol.2003,15(3):317～21
[14] Zimber A, Zusman I, Bentor R, et a1.Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats[J].Teratology . 1991, 43(4): 355～61
[15] Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: a potential link between the placenta and poor pregnancy outcome[J].Obstet Gynecol. 1992,79 (5 Pt 1): 760–6
[16]林安平,卢春冬,王琳等.1340例妊娠期肝内胆汁淤积症的回顾性分析[J] .中华围产医学杂志.2010,13(2):102～106
[17] Brites D.Rodrigues CM ,van—Zeller H,et a1.Relevance of serum bile acid profile in the diagnosis of intrahepatic cholestasis of pregnancy in an highincidence area:Portuga1[J].Eur J Obstet Gynecol Reprod Biol. 1998,80(1):31～38
[18]张艳,朱瑞建.妊娠妇女血清CG与TBA水平值相关性分析[J].放射免疫杂志.1999,13:133
[19] Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems[J].World J Gastroenterol,2008,14 (38):5781–5788
[20] Setchell KD,Dumaswala R,Colombo C,et a1.Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile[J].J Biol Chem .l988,263(32):16637～16644
[21] Nakagawa M,Setehell KDR.Bile acid metabolism in early life:studies of amniotic fluid [J].J Lipid Res. 1990,31(6):1089～1098
[22] Nichols AA.Cholestasis of pregnancy: a review of the evidence[J].J Perinat Neonatal Nurs,2005, 19 (3):217–225
[1]黄延风,朱朝敏.胆汁酸的毒性作用[J].国际检验医学杂志.2006,27(2):152～153,157
[2] Méndez-Sánchez N, Chavez-Tapia NC, Uribe M. New molecular features of cholestatic diseases of the liver[J].Rev Invest Clin. 2003, 55(5):546～56
[3] Sj?vall K, Sj?vall J. Serum bile acid levels in pregnancy with pruritus (bile acids and steroids 158) [J]. Clin Chim Acta. 1966, 13(2):207～11
[4] Bacq Y, Myara A, Brechot MC, et a1. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy[J].J Hepatol. 1995,22(1):66～70
[5] Brites D.Rodrigues CM ,van-Zeller H,et a1.Relevance of serum bile acidprofile in the diagnosis of intrahepatic cholestasis of pregnancy in an high incidence area:Portuga1[J].Eur J Obstet Gynecol Reprod Biol. 1998,80(1):31～38
[6] Yannick Bacqa, Anne Myarab, Marie-Claude Brechotc, et a1. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy[J].Journal of Hepatology. 1995, 22( 1): 66～70
[7] J. Heikkinen . Serum bile acids in the early diagnosis of intrahepatic cholestasis of pregnancy[J].Obstet Gynecol. 1983,61(5):581～587
[8] J. Heikkinen, P. Yl?stalo, O. M?entausta, et a1. Bile acids in maternal serum, umbilical cord serum and amniotic fluid of healthy women, women with pruritus and patients with intrahepatic cholestasis of pregnancy [J].Journal of Obstetrics and Gynaecology. 1983, 4(1) :17～20
[9] Itoh S, Onishi S, Isobe K, et a1.Foetomaternal relationships of serum bile acid pattern estimated by high-pressure liquid chromatography[J].Biochem J. 1982, 204(1):141～145
[10]刘春芳,丁敏,何俊,等.应用高效液相色谱法建立妊娠肝内胆汁淤积症的胆汁酸谱[J].中华检验医学杂志.2005,28(7):713～715
[11] .Lian Ye , Suya Liu , Meng Wang, et a1 . High-performance liquid chromatography–tandem mass spectrometry for the analysis of bile acid profiles in serum of women with intrahepatic cholestasis of pregnancy[J].Journal of Chromatography B.2007, 860(1):10～17
[12] Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:relationships between bile acid levels and fetal complication rates[J].Hepatology. 2004,40(2):467～74
[13] Colombo C,Zuliani G ,Ronchi M,et a1.Biliary bile acid composition of the human fetus in early gestation[J].Pediatr Res. l987,2l(2):l97～200
[14] Zhang LJ, Xiang H, Ding YL.Influence of total bile acid in maternal serum and cord blood on neonatal cardiac function from intrahepatic cholestasis of pregnancy [J].Zhonghua Fu Chan Ke Za Zhi. 2009,44(3):188～90
[15] Mazzella G,Nicola R,Francesco A,et a1.Ursodexycholic acid administration inpatients with cholestasis of pregnancy:effects on primary bile acids in babies and mothers[J].Hepatology. 2001,33(3):504～508
[16] Setchell KD,Dumaswala R,Colombo C,et a1.Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile[J].J Biol Chem.l988,263(32):16637～16644
[17] Nakagawa M,Setehell KDR.Bile acid metabolism in early life:studies of amniotic fluid[J].J Lipid Res. 1990,31(6):1089～1098
[18] Norberg S,Powell TI ,Jansson T.Intrauterine growth restriction is associated with a reduced activity of placental taurine transporters[J].Pediatr Res.1998,44(2):233～238
[19] Itoh S, Onishi S. Hepatic taurine,glycine and individual bile acids in early human fetus[J].Early Hum Dev. 2000,57(1):71～77
[20] Macias RI, Marin JJ, Serrano MA.Excretion of biliary compounds during intrauterine life[J].World J Gastroenterol. 2009, 15(7):817～28
[21] Howard PJ, Murphy GM.Bile acid stress in the mother and baby unit[J]. EurJ Gastroenterol Hepatol.2003,15(3):317～21
[22] Zimber A, Zusman I, Bentor R, et a1.Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats [J].Teratology. 1991, 43(4): 355～61
[23] Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: a potential link between the placenta andpoor pregnancy outcome[J].Obstet Gynecol. 1992,79 (5 Pt 1): 760–6
[24]徐洲,曹幼红,邢爱耘.妊娠肝内胆汁淤积症胎儿胆汁酸代谢与围生儿结局的关系[J].中华妇幼临床医学杂志(电子版).2006,2(3):169～171
[25] Casta?o G, Lucangioli S, Sookoian S ,et al. Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy[J].Clin Sci (Lond). 2006,110(4):459～65
[26] Reyes H, Sjovall J. Bile acids and progesterone metabolitesin intrahepatic cholestasis of pregnancy[J].Ann Med. 2000, 32(2):94～106
[27] Lunzer M, Barnes P, Byth K , et al. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis[J].Gastroenterology.1986,91(4): 825～829
[28] Pascual MJ, Serrano MA, El-Mir MY , et al. Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism[J].Clin Sci(Lond). 2002,102(5):587-93
[29] Brites, D. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bileacid balance and improvement by ursodeoxycholic acid[J].Ann. Hepatol. 2002,1(1):20～28
[30] Fulton IC, Douglas JG, Hutchon DJ, et a1. Is normal pregnancy cholestatic[J].Clin Chim Acta.1983,130(2):171～6
[31] Tribe RM, Dann AT, Kenyon AP, et a1. Longitudinal profiles of 15 serum bile acids in patients with intrahepatic cholestasis of pregnancy[J].Am J Gastroenterol. 2010,105(3):585～95
[32] Brites D, Oliveira N, van-Zeller H, et al. Correction of fetal cord serum bileacid profile by maternal ursodeoxycholic acid therapy in cholestasis of pregnancy[J].J Hepatol. 1997,26:163A
[33] Serrano MA, Brites D, Larena MG, et a1. Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta[J]. Hepatol. 1998,28(5):829-39
[34] Glantz A, Marschall HU, Lammert F, et a1. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid[J].Hepatology. 2005 ,42(6):1399-405
[35] Mela M, Mancuso A, Burroughs AK. Review article: pruritus in cholestatic and other liver diseases[J].Aliment Pharmacol Ther. 2003;17(7):857～870
[36] Brites D, Rodrigues CM, Oliveira N, et al. Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy[J].J Hepatol . 1998,28(1): 91～8
[37] Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment ofcholestasis of pregnancy: a randomized, double-blind study controlled with placebo[J].J Hepatol . 1997;27(6):1022～8
[38] Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy[J].Gastroenterology. 2005,129(3):894～901
[39] Laifer SA,StillerR J,SiddiquiD S,et a1.Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy[J].2001, 10(2):131～5
[40] Brites D, Rodrigues CMP. Elevated levels of bile acids in colostrum in patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy[J].J Hepatol . 1998,29(5):743～51
[41] Brites D, El-Mir MY, Oliveira N, et al. Amniotic fluid bile acid changes inthe course of ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy[J].Hepatol. 1997,26:164A
[42] Poupon RE, Chrétien Y, Poupon RV, et al. Serum bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid therapy[J].Hepatology. 1993,17(4):599～604
[43] Guldutuna S,Zimmer G,Imbef M,et a1.Molecular aspects of membrane stabilization by ursodexyeholate[J].Gasm~enterology. 1993,104(6):1736～1744
[44] Crosignani A, Podda M, Battezzati PM, et al. Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acidadministration[J].Hepatology. 1991,14(6):1000～7
[45] Lucangioli SE, Casta?o G, Contin MD, et al.Lithocholic acid as a biomarkerof intrahepatic cholestasis of pregnancy during ursodeoxycholic acid treatment[J].Ann Clin Biochem. 2009,46(Pt 1):44～9
[46] Rodrigues CM, Marín JJ, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment[J].Gut. 1999,45(3):446～52
[2] Rodrigues CM, Marín JJ, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment[J]. Gut. 1999 ,45(3):446～52
[3] Itoh S, Onishi S, Isobe K, et al. Foetomaternal relationships of bile acid pattern estimated by high-pressure liquid chromatography[J]. Biochem. 1982, 204(1):141～145
[4] Méndez-Sánchez N, Chavez-Tapia NC, Uribe M. New molecular features of cholestatic diseases of the liver[J]. Rev Invest Clin. 2003, 55(5):546～56
[5] Mazzella G,Nicola R,Francesco A,et a1.Ursodexycholic acid administration in patients with cholestasis of pregnancy:effects on primary bile acids in babies and mothers[J].Hepatology. 2001,33(3):504～508
[6]曹泽毅.中华妇产科学[M].第2版.北京:人民卫生出版社,1999:468-474
[7]赵纯全,邵勇,吴味辛.妊娠期肝内胆汁郁积症的临床分型研究(附-501例分析) [J].实用妇产科杂志. 1999,15(4):199～200
[8]漆洪波,邵勇,吴味辛等.妊娠肝内胆汁淤积症分度诊断和处理的临床意义[J].中华妇产科杂志.2004, 39(1):14～17
[9] Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:relationships between bile acid levels and fetal complication rates[J]. Hepatology . 2004,40(2):467～74
[10]张惜阴.实用妇产科学[M].第2版.北京:人民卫生出版社,2003:181,253,259,454
[11]黄延风,朱朝敏.胆汁酸的毒性作用[J] .国际检验医学杂志,2006,27(2):152-153,157
[12] Macias RI, Marin JJ, Serrano MA.Excretion of biliary compounds during intrauterine life [J]. World J Gastroenterol. 2009 Feb 21;15(7):817～28
[13] Howard PJ, Murphy GM.Bile acid stress in the mother and baby unit[J]. EurJ Gastroenterol Hepatol.2003,15(3):317～21
[14] Zimber A, Zusman I, Bentor R, et a1.Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats[J].Teratology . 1991, 43(4): 355～61
[15] Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: a potential link between the placenta and poor pregnancy outcome[J].Obstet Gynecol. 1992,79 (5 Pt 1): 760–6
[16]林安平,卢春冬,王琳等.1340例妊娠期肝内胆汁淤积症的回顾性分析[J] .中华围产医学杂志.2010,13(2):102～106
[17] Brites D.Rodrigues CM ,van—Zeller H,et a1.Relevance of serum bile acid profile in the diagnosis of intrahepatic cholestasis of pregnancy in an highincidence area:Portuga1[J].Eur J Obstet Gynecol Reprod Biol. 1998,80(1):31～38
[18]张艳,朱瑞建.妊娠妇女血清CG与TBA水平值相关性分析[J].放射免疫杂志.1999,13:133
[19] Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems[J].World J Gastroenterol,2008,14 (38):5781–5788
[20] Setchell KD,Dumaswala R,Colombo C,et a1.Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile[J].J Biol Chem .l988,263(32):16637～16644
[21] Nakagawa M,Setehell KDR.Bile acid metabolism in early life:studies of amniotic fluid [J].J Lipid Res. 1990,31(6):1089～1098
[22] Nichols AA.Cholestasis of pregnancy: a review of the evidence[J].J Perinat Neonatal Nurs,2005, 19 (3):217–225
[1]黄延风,朱朝敏.胆汁酸的毒性作用[J].国际检验医学杂志.2006,27(2):152～153,157
[2] Méndez-Sánchez N, Chavez-Tapia NC, Uribe M. New molecular features of cholestatic diseases of the liver[J].Rev Invest Clin. 2003, 55(5):546～56
[3] Sj?vall K, Sj?vall J. Serum bile acid levels in pregnancy with pruritus (bile acids and steroids 158) [J]. Clin Chim Acta. 1966, 13(2):207～11
[4] Bacq Y, Myara A, Brechot MC, et a1. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy[J].J Hepatol. 1995,22(1):66～70
[5] Brites D.Rodrigues CM ,van-Zeller H,et a1.Relevance of serum bile acidprofile in the diagnosis of intrahepatic cholestasis of pregnancy in an high incidence area:Portuga1[J].Eur J Obstet Gynecol Reprod Biol. 1998,80(1):31～38
[6] Yannick Bacqa, Anne Myarab, Marie-Claude Brechotc, et a1. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy[J].Journal of Hepatology. 1995, 22( 1): 66～70
[7] J. Heikkinen . Serum bile acids in the early diagnosis of intrahepatic cholestasis of pregnancy[J].Obstet Gynecol. 1983,61(5):581～587
[8] J. Heikkinen, P. Yl?stalo, O. M?entausta, et a1. Bile acids in maternal serum, umbilical cord serum and amniotic fluid of healthy women, women with pruritus and patients with intrahepatic cholestasis of pregnancy [J].Journal of Obstetrics and Gynaecology. 1983, 4(1) :17～20
[9] Itoh S, Onishi S, Isobe K, et a1.Foetomaternal relationships of serum bile acid pattern estimated by high-pressure liquid chromatography[J].Biochem J. 1982, 204(1):141～145
[10]刘春芳,丁敏,何俊,等.应用高效液相色谱法建立妊娠肝内胆汁淤积症的胆汁酸谱[J].中华检验医学杂志.2005,28(7):713～715
[11] .Lian Ye , Suya Liu , Meng Wang, et a1 . High-performance liquid chromatography–tandem mass spectrometry for the analysis of bile acid profiles in serum of women with intrahepatic cholestasis of pregnancy[J].Journal of Chromatography B.2007, 860(1):10～17
[12] Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:relationships between bile acid levels and fetal complication rates[J].Hepatology. 2004,40(2):467～74
[13] Colombo C,Zuliani G ,Ronchi M,et a1.Biliary bile acid composition of the human fetus in early gestation[J].Pediatr Res. l987,2l(2):l97～200
[14] Zhang LJ, Xiang H, Ding YL.Influence of total bile acid in maternal serum and cord blood on neonatal cardiac function from intrahepatic cholestasis of pregnancy [J].Zhonghua Fu Chan Ke Za Zhi. 2009,44(3):188～90
[15] Mazzella G,Nicola R,Francesco A,et a1.Ursodexycholic acid administration inpatients with cholestasis of pregnancy:effects on primary bile acids in babies and mothers[J].Hepatology. 2001,33(3):504～508
[16] Setchell KD,Dumaswala R,Colombo C,et a1.Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile[J].J Biol Chem.l988,263(32):16637～16644
[17] Nakagawa M,Setehell KDR.Bile acid metabolism in early life:studies of amniotic fluid[J].J Lipid Res. 1990,31(6):1089～1098
[18] Norberg S,Powell TI ,Jansson T.Intrauterine growth restriction is associated with a reduced activity of placental taurine transporters[J].Pediatr Res.1998,44(2):233～238
[19] Itoh S, Onishi S. Hepatic taurine,glycine and individual bile acids in early human fetus[J].Early Hum Dev. 2000,57(1):71～77
[20] Macias RI, Marin JJ, Serrano MA.Excretion of biliary compounds during intrauterine life[J].World J Gastroenterol. 2009, 15(7):817～28
[21] Howard PJ, Murphy GM.Bile acid stress in the mother and baby unit[J]. EurJ Gastroenterol Hepatol.2003,15(3):317～21
[22] Zimber A, Zusman I, Bentor R, et a1.Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats [J].Teratology. 1991, 43(4): 355～61
[23] Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: a potential link between the placenta andpoor pregnancy outcome[J].Obstet Gynecol. 1992,79 (5 Pt 1): 760–6
[24]徐洲,曹幼红,邢爱耘.妊娠肝内胆汁淤积症胎儿胆汁酸代谢与围生儿结局的关系[J].中华妇幼临床医学杂志(电子版).2006,2(3):169～171
[25] Casta?o G, Lucangioli S, Sookoian S ,et al. Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy[J].Clin Sci (Lond). 2006,110(4):459～65
[26] Reyes H, Sjovall J. Bile acids and progesterone metabolitesin intrahepatic cholestasis of pregnancy[J].Ann Med. 2000, 32(2):94～106
[27] Lunzer M, Barnes P, Byth K , et al. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis[J].Gastroenterology.1986,91(4): 825～829
[28] Pascual MJ, Serrano MA, El-Mir MY , et al. Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism[J].Clin Sci(Lond). 2002,102(5):587-93
[29] Brites, D. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bileacid balance and improvement by ursodeoxycholic acid[J].Ann. Hepatol. 2002,1(1):20～28
[30] Fulton IC, Douglas JG, Hutchon DJ, et a1. Is normal pregnancy cholestatic[J].Clin Chim Acta.1983,130(2):171～6
[31] Tribe RM, Dann AT, Kenyon AP, et a1. Longitudinal profiles of 15 serum bile acids in patients with intrahepatic cholestasis of pregnancy[J].Am J Gastroenterol. 2010,105(3):585～95
[32] Brites D, Oliveira N, van-Zeller H, et al. Correction of fetal cord serum bileacid profile by maternal ursodeoxycholic acid therapy in cholestasis of pregnancy[J].J Hepatol. 1997,26:163A
[33] Serrano MA, Brites D, Larena MG, et a1. Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta[J]. Hepatol. 1998,28(5):829-39
[34] Glantz A, Marschall HU, Lammert F, et a1. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid[J].Hepatology. 2005 ,42(6):1399-405
[35] Mela M, Mancuso A, Burroughs AK. Review article: pruritus in cholestatic and other liver diseases[J].Aliment Pharmacol Ther. 2003;17(7):857～870
[36] Brites D, Rodrigues CM, Oliveira N, et al. Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy[J].J Hepatol . 1998,28(1): 91～8
[37] Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment ofcholestasis of pregnancy: a randomized, double-blind study controlled with placebo[J].J Hepatol . 1997;27(6):1022～8
[38] Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy[J].Gastroenterology. 2005,129(3):894～901
[39] Laifer SA,StillerR J,SiddiquiD S,et a1.Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy[J].2001, 10(2):131～5
[40] Brites D, Rodrigues CMP. Elevated levels of bile acids in colostrum in patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy[J].J Hepatol . 1998,29(5):743～51
[41] Brites D, El-Mir MY, Oliveira N, et al. Amniotic fluid bile acid changes inthe course of ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy[J].Hepatol. 1997,26:164A
[42] Poupon RE, Chrétien Y, Poupon RV, et al. Serum bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid therapy[J].Hepatology. 1993,17(4):599～604
[43] Guldutuna S,Zimmer G,Imbef M,et a1.Molecular aspects of membrane stabilization by ursodexyeholate[J].Gasm~enterology. 1993,104(6):1736～1744
[44] Crosignani A, Podda M, Battezzati PM, et al. Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acidadministration[J].Hepatology. 1991,14(6):1000～7
[45] Lucangioli SE, Casta?o G, Contin MD, et al.Lithocholic acid as a biomarkerof intrahepatic cholestasis of pregnancy during ursodeoxycholic acid treatment[J].Ann Clin Biochem. 2009,46(Pt 1):44～9
[46] Rodrigues CM, Marín JJ, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment[J].Gut. 1999,45(3):446～52