Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies

Lee RH, Mara G, Metz TD, Pettker CM. Society for maternal-fetal medicine consult series #53: intrahepatic cholestasis of pregnancy: replaces consult #13, April 2011. Am J Obstet Gynecol. 2021;224:B2-b9

Article  CAS  PubMed  Google Scholar 

Wikström Shemer EA, Stephansson O, Thuresson M, Thorsell M, Ludvigsson JF, Marschall HU. Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study. J Hepatol. 2015;63:456–461

Article  PubMed  Google Scholar 

MacDorman MF, Reddy UM, Silver RM. Trends in stillbirth by gestational age in the United States, 2006–2012. Obstet Gynecol. 2015;126:1146–1150

Article  PubMed  PubMed Central  Google Scholar 

Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Ilio C, Chambers J, et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet. 2019;393:899–909

Article  PubMed  PubMed Central  Google Scholar 

Cheong-See F, Schuit E, Arroyo-Manzano D, Khalil A, Barrett J, Joseph KS, et al. Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis. BMJ. 2016;354: i4353

Article  PubMed  PubMed Central  Google Scholar 

Sepúlveda WH, González C, Cruz MA, Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol. 1991;42:211–215

Article  PubMed  Google Scholar 

Vasavan T, Deepak S, Jayawardane IA, Lucchini M, Martin C, Geenes V, et al. Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations. J Hepatol. 2021;74:1087–1096

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fan X, Zhou Q, Zeng S, Zhou J, Peng Q, Zhang M, et al. Impaired fetal myocardial deformation in intrahepatic cholestasis of pregnancy. J Ultrasound Med. 2014;33:1171–1177

Article  PubMed  Google Scholar 

Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40:467–474

Article  PubMed  Google Scholar 

Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology. 2014;59:1482–1491

Article  PubMed  Google Scholar 

Mei Y, Lin Y, Luo D, Gao L, He L. Perinatal outcomes in intrahepatic cholestasis of pregnancy with monochorionic diamniotic twin pregnancy. BMC Pregnancy Childbirth. 2018;18:291

Article  PubMed  PubMed Central  Google Scholar 

Song F, Chen Y, Chen L, Li H, Cheng X, Wu W. Association of elevated maternal serum total bile acids with low birth weight and intrauterine fetal growth restriction. JAMA Netw Open. 2021;4: e2117409

Article  PubMed  PubMed Central  Google Scholar 

Reyes H, Radrigan ME, Gonzalez MC, Latorre R, Ribalta J, Segovia N, et al. Steatorrhea in patients with intrahepatic cholestasis of pregnancy. Gastroenterology. 1987;93:584–590

Article  CAS  PubMed  Google Scholar 

Maldonado M, Alhousseini A, Awadalla M, Idler J, Welch R, Puder K, et al. Intrahepatic cholestasis of pregnancy leading to severe vitamin K deficiency and coagulopathy. Case Rep Obstet Gynecol. 2017;2017:5646247

PubMed  PubMed Central  Google Scholar 

Expert consensus on the diagnosis and treatment of intrahepatic cholestasis (2021 edition). Zhonghua Gan Zang Bing Za Zhi 2022;30:137–146.

de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab. 2013;17:657–669

Article  PubMed  PubMed Central  Google Scholar 

McIlvride S, Dixon PH, Williamson C. Bile acids and gestation. Mol Aspects Med. 2017;56:90–100

Article  CAS  PubMed  Google Scholar 

Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, et al. ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. Dig Liver Dis. 2013;45:226–232

Article  CAS  PubMed  Google Scholar 

Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet. 1999;353:210–211

Article  CAS  PubMed  Google Scholar 

Kawakita T, Parikh LI, Ramsey PS, Huang CC, Zeymo A, Fernandez M, et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol. 2015;213(570):e571-578

Google Scholar 

Meier Y, Zodan T, Lang C, Zimmermann R, Kullak-Ublick GA, Meier PJ, et al. Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump. World J Gastroenterol. 2008;14:38–45

Article  CAS  PubMed  PubMed Central  Google Scholar 

Halilbasic E, Claudel T, Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol. 2013;58:155–168

Article  CAS  PubMed  PubMed Central  Google Scholar 

Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular physiology of bile acid signaling in health, disease, and aging. Physiol Rev. 2021;101:683–731

Article  CAS  PubMed  Google Scholar 

Müllenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, et al. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut. 2005;54:829–834

Article  PubMed  PubMed Central  Google Scholar 

Song X, Vasilenko A, Chen Y, Valanejad L, Verma R, Yan B, et al. Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy. Hepatology. 2014;60:1993–2007

Article  CAS  PubMed  Google Scholar 

Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJ. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol. 2006;44:1150–1157

Article  CAS  PubMed  Google Scholar 

Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology. 2000;118:422–430

Article  CAS  PubMed  Google Scholar 

Trauner M, Arrese M, Soroka CJ, Ananthanarayanan M, Koeppel TA, Schlosser SF, et al. The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology. 1997;113:255–264

Article  CAS  PubMed  Google Scholar 

Abu-Hayyeh S, Martinez-Becerra P, Sheikh Abdul Kadir SH, Selden C, Romero MR, Rees M, et al. Inhibition of Na+-taurocholate Co-transporting polypeptide-mediated bile acid transport by cholestatic sulfated progesterone metabolites. J Biol Chem. 2010;285:16504–16512

Article  CAS  PubMed  PubMed Central  Google Scholar 

Raz Y, Lavie A, Vered Y, Goldiner I, Skornick-Rapaport A, Landsberg Asher Y, et al. Severe intrahepatic cholestasis of pregnancy is a risk factor for preeclampsia in singleton and twin pregnancies. Am J Obstet Gynecol. 2015;213(395):e391-398

Google Scholar 

Brites D, Rodrigues CM, van Zeller H, Brito A, Silva R. Relevance of serum bile acid profile in the diagnosis of intrahepatic cholestasis of pregnancy in an high incidence area: Portugal. Eur J Obstet Gynecol Reprod Biol. 1998;80:31–38

Article  CAS  PubMed  Google Scholar 

Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15:1677–1689

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lunzer M, Barnes P, Byth K, O’Halloran M. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis. Gastroenterology. 1986;91:825–829

Article  CAS  PubMed  Google Scholar 

Jendryczko A. Tomala J [Bile acids from blood serum of women during normal pregnancy]. Ginekol Pol. 1994;65:230–233

CAS  PubMed  Google Scholar 

Pascual MJ, Serrano MA, El-Mir MY, Macias RI, Jiménez F, Marin JJ. Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism. Clin Sci (Lond). 2002;102:587–593

Article  CAS  PubMed  Google Scholar 

Ontsouka E, Schroeder M, Ok L, Vaillancourt C, Stroka D, Albrecht C. The placenta-a new source of bile acids during healthy pregnancy? first results of a gene expression study in humans and mice. Int J Mol Sci. 2023;24:9511

Article  CAS  PubMed  PubMed Central  Google Scholar 

Colombo C, Roda A, Roda E, Buscaglia M, dell’Agnola CA, Filippetti P, et al. Correlation between fetal and maternal serum bile acid concentrations. Pediatr Res. 1985;19:227–231

Article  CAS  PubMed  Google Scholar 

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