Intrahepatic cholestasis of pregnancy can increase the risk of metabolic disorders: A Meta-Analysis focusing on Pregnancy Population

LeiYing Zhang; Chen Tang; ChenLian Ye; LuRen Huang; Yan Wu

doi:10.5937/jomb0-33222

LeiYing Zhang Department of Gynecology and Obstetrics, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China
Chen Tang Department of Gynecology and Obstetrics, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China
ChenLian Ye Department of Gynecology and Obstetrics, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China
LuRen Huang Department of Gynecology and Obstetrics, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China
Yan Wu Department of Gynecology and Obstetrics, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China

DOI: https://doi.org/10.5937/jomb0-33222

Keywords: intrahepatic cholestasis of pregnancy, preeclampsia, gestational diabetes mellitus

Abstract

Background: Gestational diabetes mellitus (GDM) and preeclampsia (PE) as one of the common complications during pregnancy, Studies indicated that abnormal bile acid metabolism is related to its pathogenesis. Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease,which classic symptoms include generalized pruritus that commonly, and biochemical evidence of elevated bile acids.Our study aimed to explore the correlation between the ICP presence and risk of GDM,PE incident in pregnant women.

Methods: A meta-analysis, which included 10 eligible studies including 17,688 ICP cases and 1,386,771 controls, is performed to assess the correlation of ICP with preeclampsia (PE) and gestational diabetes mellitus (GDM). There are 7 studies to investigate the relationship between ICP and PE, and 9 studies for evaluating the relationship between ICP and GDM. All eligible studies are screened from Pubmed, Web of science and EBSCO database.

Results: The results of this meta-analysis indicate that ICP significantly increase the risk for both PE (pooled odds ratio [OR]: 2.56 [95%CI: 2.27~2.88], I²_{heterogeneity}= 35%, p _{heterogeneity}= 0.16) and GDM (pooled OR: 2.28 [95%CI: 1.69~3.07], I² _{heterogeneity} = 81%, p _{heterogeneity} < 0.001). In the sensitivity analysis of GDM, excluding the largest heterogeneity study can not change the result (pooled OR: 2.86 [95%CI: 2.59~3.16], I²_{heterogeneity}= 0%, p _{heterogeneity}= 0.56).

Conclusions: This meta-analysis shows that ICP is closely associated with ICP inceased risk of PE and GDM) during pregnancy.

References

[1] Jim B, Karumanchi SA. Preeclampsia: Pathogenesis, Prevention, and Long-Term Complications[J]. Seminars in Nephrology, 2017; 37(4):386-397.
[2] Blumer I, Hadar E, Hadden DR, Jovanovič L, Mestman JH, Murad MH, Yogev Y . Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2013; 98:4227-4249.
[3] Saraid McIlvride, Peter H Dixon, Catherine Williamson. Bile acids and gestation. Molecular Aspects of Medicine.2017; 56: 90-100.
[4] Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man[J]. N Engl J Med, 1977; 296(24):1365-1371.
[5] Herrema H, Meissner M, van Dijk, TH Brufau G, Boverhof R, Oosterveer MH, Reijngoud DJ, Muller M, Stellaard F, Groen AK, Kuipers F. Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptor alpha-controlled metabolic pathways in mice. Hepatology, 2010; 51 (3): 806-816.
[6] Dann AT, Kenyon AP, Seed PT, Poston L, Shennan AH, Tribe RM. Glutathione S-transferase and liver function in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology,2004; 40 (6):1406-1414.
[7] Kalaany NY, Mangelsdorf DJ. LXRS AND FXR: The Yin and Yang of Cholesterol and Fat Metabolism[J]. Annual Review of Physiology, 2006, 68(68):159-191.
[8] Kumar DP, Rajagopal S, Mahavadi S, Mirshahi F, Grider JR, Murthy KS,
Sanyal AJ. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic beta cells[J]. Biochemical & Biophysical Research Communications, 2012; 427(3):600-605.
[9] Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest,2006, 116 (4): 1102-1109.
[10] Dixon P H, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy.[J]. Clinics & Research in Hepatology & Gastroenterology, 2016;40(2):141.
[11] Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy[J]. Orphanet Journal of Rare Diseases, 2007; 2(1):26.
[12] Goulis D G, Walker I A L, Swiet M D, Redman CWG， Williamson C. Preeclampsia with Abnormal Liver Function Tests Is Associated with Cholestasis in a Subgroup of Cases[J]. Hypertension in Pregnancy, 2009; 23(1):19.
[13] Martineau MG, Raker C, Dixon PH, Chambers J, Machirori M, King NM, Hooks ML, Manoharan R, Chen K, Powrie R, Williamson C. The metabolic profile of intrahepatic cholestasis of pregnancy is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. Diabetes Care, 2015;38 (2): 243-248.
[14] Martineau M, Raker C, Powrie R, Williamson C. Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes. European Journal of Obstetrics Gynecology & Reproductive Biology, 2014; 176(1):80-85.
[15] Glantz A， Marschall HU， Mattsson LA. Intrahepatic Cholestasis of Pregnancy: Relationships Between Bile Acid Levels and Fetal Complication Rates. HEPATOLOGY, 2004;(2):464–474.
[16] Wood AM，Livingston EG， Hughes BL， Kuller JA. Intrahepatic Cholestasis of Pregnancy: A Review of Diagnosis and Management. OBSTETRICAL AND GYNECOLOGICAL SURVEY,2018;(73):103–109.
[17] Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol, 2009; 15: 2049–2066.
[18] 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.
[19] Ben W J Mol, Claire T Roberts, Shakila Thangaratinam, Laura A Magee, Christianne J M de Groot, G Justus Hofmeyr. Pre-eclampsia. Lancet,2015;(15):1-13.
[20] Chen S, Yang J, Xiang H, Chen W, Zhong H, Yang G, Fang T. Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction. Int J Mol Med, 2015 Apr;35(4):1103-8.
[21] Liu H, Peng H, Chen S, Liu Y, Xiang H, Chen R, Chen W, Zhao S, Chen P, Lu H. S1PR2 antagonist protects endothelial cells against high glucose-induced mitochondrial apoptosis through the Akt/GSK-3β signaling pathway. Biochem Biophys Res Commun, 2017 Aug 26;490(3):1119-1124.
[22] Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol, 2007 Jun;27(6):1312-8.
[23] Sanchez T, Thangada S, Wu MT, Kontos CD, Wu D, Wu H, Hla T. PTEN as an effector in the signaling of antimigratory G protein-coupled receptor. Proc Natl Acad Sci U S A,2005 Mar 22;102(12):4312-7.
[24] Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa WC. Akt
down-regulation of p38 signaling provides a novel mechanism of vascular
endothelial growth factor-mediated cytoprotection in endothelial cells. J Biol
Chem, 2001;276:30359-30365.
[25] Nagahashi M, Takabe K, Liu R, Peng K, Wang X, Wang Y, Hait NC, Wang X, Allegood JC, Yamada A. Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology, 2015 Apr;61(4):1216-26.
[26] Adada M, Canals D, Hannun YA, Obeid LM. Sphingosine-1-phosphate receptor 2. FEBS J, 2013 Dec;280(24):6354-66.
[27] Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol,1991; 165:1667-1672.
[28] Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, CatalanoPM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes, Diabetes Care 2007; 30 (Suppl 2): S112-S119.
[29] Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk, TH, Grefhorst A, Abdelkarim M, Caron S, Torpier G, Fruchart JC, Gonzalez FJ, Kuipers F, Staels B, The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice[J]. Journal of Biological Chemistry, 2006; 281(16):11039-11049.
[30] Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, Edwards PA. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2006; 103(4):1006-1011.
[31] Lin BC, Wang M, Blackmore C, Desnoyers LR. Liver-specific activities of FGF19 require Klotho beta[J]. Journal of Biological Chemistry, 2007;282(37):27277-84.
[32] Carter J. Serum bile acids in normal pregnancy.[J]. Bjog An International Journal of Obstetrics & Gynaecology, 2010; 98(6):540-543.
[33] Fulton IC, Douglas JG, Hutchon DJ, Beckett GJ. Is normal pregnancy cholestatic?[J]. Clinica Chimica Acta, 1983; 130(2):171-176.
[34] Lucangioli SE, Castano G, Contin MD, Tripodi VP. Lithocholic acid as a biomarker of intrahepatic cholestasis of pregnancy during ursodeoxycholic acid treatment.[J]. Annals of Clinical Biochemistry, 2009; 46(Pt 1):44-49.
[35] 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[J]. European Journal of Obstetrics Gynecology & Reproductive Biology, 1998; 80(1):31-38.
[36] Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann SH, Gores GJ. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas[J]. Journal of Clinical Investigation, 1999; 103(1):137-145.