Role of cholestatic liver disease-related genes in intrahepatic cholestasis of pregnancy
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摘要: 妊娠期肝内胆汁淤积症(ICP)是妊娠期最常见的特异性肝病。通常出现在妊娠晚期,主要表现为皮肤瘙痒、黄疸,实验室检查血清总胆汁酸及转氨酶升高,对胎儿影响较大,可导致早产、死胎、畸形。其病因复杂,研究发现遗传、代谢、免疫、激素等多种因素均可导致其发病。与胆汁淤积相关的基因,如ABCB11、ABCB4、ATP8B1、FXR等与ICP的遗传易感性有关。综述了胆汁淤积相关基因及其与ICP的关系。Abstract: Intrahepatic cholestasis of pregnancy ( ICP) is the most common liver disease during pregnancy. ICP usually occurs in late pregnancy, with main manifestations of pruritus, jaundice, and increases in serum levels of total bile acid and aminotransferases found by laboratory examination. ICP has great impact on the fetus and may lead to preterm birth, stillbirth, and deformity. ICP has complex etiologies, and studies have shown that genetic, metabolic, immunological, and hormonal factors may contribute to the onset of ICP. The genes associated with cholestasis, such as ABCB11, ABCB4, ATP8 B1, and FXR, are associated with the genetic susceptibility of ICP. This article reviews the association between cholestasis-related genes and ICP.
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Key words:
- cholestasis /
- pregnancy complications /
- genes /
- genetic variation
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[1] BICOCCA MJ, SPERLING JD, CHAUHAN SP. Intrahepatic cholestasis of pregnancy:Review of six national and regional guidelines[J]. Eur J Obstet Gynecol Reprod Biol, 2018, 231:180-187. [2] BROUWERS L, KOSTER MP, PAGE-CHRISTIAENS GC, et al. Intrahepatic cholestasis of pregnancy:Maternal and fetal outcomes associated with elevated bile acid levels[J]. Am J Obstet Gynecol, 2015, 212 (1) :100. e1-e7. [3] TAKATSU H, TANAKA G, SEGAWA K, et al. Phospholipid flippase activities and substrate specificities of human type IV P-type ATPases localized to the plasma membrane[J]. J Biol Chem, 2014, 289 (48) :33543-33556. [4] KLINDT C, BONUS M, BAUMANN U, et al. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants[J].J Hepatol, 2017, 67 (6) :1253-1264. [5] WANG L, SOROKA CJ, BOYER JL. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II[J]. J Clin Invest, 2002, 110 (7) :965-972. [6] BULL LN, THOMPSON RJ. Progressive familial intrahepatic cholestasis[J]. Clin Liver Dis, 2018, 22 (4) :657-669. [7] DROGE C, BONUS M, BAUMANN U, et al. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants[J].J Hepatol, 2017, 67 (6) :1253-1264. [8] SAMBROTTA M, STRAUTNIEKS S, PAPOULI E, et al. Mutations in TJP2 cause progressive cholestatic liver disease[J].Nature Genetics, 2014, 46 (4) :326-328. [9] GISSEN P, ARIAS IM. Structural and functional hepatocyte polarity and liver disease[J]. J Hepatol, 2015, 63 (4) :1023-1037. [10] CARIELLO M, PICCININ E, GARCIA-IRIGOYEN O, et al. Nuclear receptor FXR, bile acids and liver damage:Introducing the progressive familial intrahepatic cholestasis with FXR mutations[J]. Biochim Biophys Acta, 2018, 1864 (4) :1308-1318. [11] MASSAFRA V, van MIL SWC. Farnesoid X receptor:A"homeostat"for hepatic nutrient metabolism[J]. Biochim Biophys Acta, 2018, 1864 (1) :45-59. [12] GOMEZ-OSPINA N, POTTER CJ, XIAO R, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis[J]. Nat Commun, 2016, 7:107-113. [13] KNOWLES BC, ROLAND JT, KRISHNAN M, et al. Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease[J]. J Clin Invest, 2014, 124 (7) :2947-2962. [14] GONZALES E, TAYLOR SA, DAVIT-SPRAUL A, et al. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease[J]. Hepatology, 2017, 65 (1) :164-173. [15] QIU YL, GONG JY, WANG JS, et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed lowγ-glutamyl transferase cholestasis[J]. Hepatology, 2017, 65 (5) :1655-1699. [16] THOMPSON RJ, BULL LN. Treating genetic disease:Expanding the options[J]. Hepatology, 2015, 62 (2) :349-351. [17] DIXON PH, WILLIAMSON C. The molecular genetics of intrahepatic cholestasis of pregnancy[J]. Obstet Med, 2008, 1 (2) :65-71. [18] GERMAIN AM, KATO S, CARVAJAL JA, et al. Bile acids increase response and expression of human myometrial oxytocin receptor[J]. Am J Obstet Gynecol, 2003, 189 (2) :577-582. [19] JACQUEMIN E, CRESTEIL D, MANOUVRIER S, et al. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy[J]. Lancet, 1999, 353 (9148) :210-211. [20] DIXON PH, WILLIAMSON C. The pathophysiology of intrahepatic cholestasis of pregnancy[J]. Clin Res Hepatol Gastroenterol, 2016, 40 (2) :141-153. [21] PHDIXON N, WEERASEKERA KJ, LINTON O, et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy:Evidence for a defection protein trafficking[J]. Hum Mol Genet, 2000, 9 (8) :1209-1217. [22] ELORANTA ME, HAKLI T, HIHUNEN M, et al. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy[J]. Seand J Gastroenterol, 2003, 38 (6) :648-652. [23] GEENES V, CHAMBERS J, KHURANA R, et al. Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy[J]. Eur J Obstet Gynecol Reprod Biol, 2015, 189:59-63. [24] STRAUTNIEKS SS, BYRNE JA, PAWLIKOWSKA L, et al. Severe bile salt export pump deficiency:82 different ABCB11mutations in 109 families[J]. Gastroenterology, 2008, 134 (4) :1203-1214. [25] LANG T, HABERL M, JUNG D, et al. Genetie variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11) [J].Drug Metab Dispos, 2006, 34 (9) :1582-1599. [26] KEITEL V, VOGT C, HFIUSSINGER D, et al. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy[J]. Gastroenterology, 2006, 131 (2) :624-629. [27] DENG R, YANG D, RADKE A, et al. The hypolipidemic agent gugguls terone regulates the expression of burn bile salt export pump:Dominance of transactivation over farsenoid X receptor-mediated antagonism[J]. J Pharmacol ExpTher, 2007, 320 (3) :1153-1162. [28] VALLEJO M, BFIZ O, SERRANO MA, et al. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic eholestasis of pregnancy[J]. J Hepatol, 2006, 44 (6) :150-1157. [29] MULLENBAEH R, BENNETT A, TETLOW N, et al. ATP8B1mutations in British cases with intrahepatic cholestasis of pregnancy[J]. Gut, 2005, 54 (6) :829. [30] PAINTER JN, SAVANDER M, ROPPONEN A, et al. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy[J]. Eur J Hum Genet, 2005, 13 (4) :435-439. [31] DIXON PH, SAMBROTTA M, CHAMBERS J, et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy[J]. Sci Rep, 2017, 7 (1) :11823. [32] van MIL SW, MILONA A, DIXON PH, et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy[J]. Gastroenterology, 2007, 133 (2) :507-516. [33] SOOKOIAN S, CASTANO G, BURGUENO A, et al. Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy[J]. J Hepatol, 2008, 48 (1) :125-132. [34] GEENES V, CHAPPELL LC, SEED PT, et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes:A prospective population-based case control study[J]. Hepatology, 2014, 59 (4) :1482-1491. [35] YEAP SP, HARLEY H, THOM R, et al. Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy:Diagnostic and management implications[J]. J Gastroenterol Hepatol, 2019, 34 (2) :425-435.
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