胃肠外营养相关性胆汁淤积症早产儿血MDR3基因mRNA表达
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摘要
目的研究MDR3基因表达与早产儿胃肠外营养相关性胆汁淤积症(PNAC)发病的相关性。方法将2011年6月至2017年11月收治的行胃肠外营养超过14 d且未合并PNAC的早产儿80例为非PNAC组,患有PNAC的早产儿76例为PNAC组,所有研究对象均分别于生后1、14、30、60、90 d动态观察血清肝胆生化(丙氨酸氨基转移酶、总胆红素、直接胆红素、总胆汁酸和γ-谷氨酰转肽酶)及纤维化指标(透明质酸、层黏连蛋白、Ⅲ型前胶原N端肽、Ⅳ型胶原)变化,以及临床表现;采用实时荧光定量PCR法检测两组MDR3 mRNA水平的相对表达量;分析MDR3 mRNA表达水平与血清肝胆生化指标的相关性。结果 PNAC组早产儿血清肝胆生化及纤维化指标水平在生后14 d上升,至生后30 d达最高峰,生后60 d下降,且PNAC组生后第14、30、60、90天的血清肝胆生化及纤维化指标均高于非PNAC组(P<0.05)。PNAC组早产儿外周血细胞MDR3 mRNA的相对表达水平高于非PNAC组(P<0.05)。PNAC组患儿外周血细胞MDR3 mRNA的相对表达量与血清肝胆生化指标水平(丙氨酸氨基转移酶、总胆红素、直接胆红素、总胆汁酸和γ-谷氨酰转肽酶)均呈负相关(P<0.001)。结论 MDR3 mRNA高表达可能与早产儿PNAC发病有关,但具体机制仍需进一步研究探讨。
Objective To study the association between the expression of the MDR3 gene and the pathogenesis of parenteral nutrition-associated cholestasis(PNAC) in preterm infants. Methods Among the preterm infants who were admitted to the hospital from June 2011 to November 2017 and received parenteral nutrition for more than 14 days, 80 who did not develop PNAC were enrolled as non-PNAC group, and 76 who developed PNAC were enrolled as PNAC group. On days 1, 14, 30, 60 and 90 after birth, serum hepatobiliary biochemical parameters [alanine aminotransferase(ALT), total bilirubin(TBil), direct bilirubin(DBil), total bile acid(TBA) and gamma-glutamyl transpeptidase(γ-GT)], fibrosis indices [hyaluronic acid, laminin, procollagen Ⅲ N-terminal peptide and type IV collagen] and clinical manifestations were observed. Real-time quantitative PCR was used to measure the mRNA expression of MDR3 in both groups, and the correlation between the mRNA expression of MDR3 and serum hepatobiliary biochemical parameters was analyzed. Results In the PNAC group, serum levels of hepatobiliary biochemical parameters and fibrosis indices increased on day 14 after birth and reached the peak on day 30 after birth, followed by a reduction on day 60 after birth. On days 14, 30, 60 and 90 after birth, the PNAC group had significantly higher serum levels of hepatobiliary biochemical parameters and fibrosis indices than the non-PNAC group(P<0.05). The PNAC group had higher relative mRNA expression of MDR3 in peripheral blood cells than the non-PNAC group(P<0.05). In the PNAC group, the relative m RNA expression of MDR3 in peripheral blood cells was negatively correlated with serum levels of hepatobiliary biochemical parameters(ALT, TBil, DBil, TBA and γ-GT)(P<0.001). Conclusions High m RNA expression of MDR3 in preterm infants may be associated with the development of PNAC, and further studies are needed to identify the mechanism.
Objective To study the association between the expression of the MDR3 gene and the pathogenesis of parenteral nutrition-associated cholestasis(PNAC) in preterm infants. Methods Among the preterm infants who were admitted to the hospital from June 2011 to November 2017 and received parenteral nutrition for more than 14 days, 80 who did not develop PNAC were enrolled as non-PNAC group, and 76 who developed PNAC were enrolled as PNAC group. On days 1, 14, 30, 60 and 90 after birth, serum hepatobiliary biochemical parameters [alanine aminotransferase(ALT), total bilirubin(TBil), direct bilirubin(DBil), total bile acid(TBA) and gamma-glutamyl transpeptidase(γ-GT)], fibrosis indices [hyaluronic acid, laminin, procollagen Ⅲ N-terminal peptide and type IV collagen] and clinical manifestations were observed. Real-time quantitative PCR was used to measure the mRNA expression of MDR3 in both groups, and the correlation between the mRNA expression of MDR3 and serum hepatobiliary biochemical parameters was analyzed. Results In the PNAC group, serum levels of hepatobiliary biochemical parameters and fibrosis indices increased on day 14 after birth and reached the peak on day 30 after birth, followed by a reduction on day 60 after birth. On days 14, 30, 60 and 90 after birth, the PNAC group had significantly higher serum levels of hepatobiliary biochemical parameters and fibrosis indices than the non-PNAC group(P<0.05). The PNAC group had higher relative mRNA expression of MDR3 in peripheral blood cells than the non-PNAC group(P<0.05). In the PNAC group, the relative m RNA expression of MDR3 in peripheral blood cells was negatively correlated with serum levels of hepatobiliary biochemical parameters(ALT, TBil, DBil, TBA and γ-GT)(P<0.001). Conclusions High m RNA expression of MDR3 in preterm infants may be associated with the development of PNAC, and further studies are needed to identify the mechanism.
引文
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[25]张韶明,陈茂琼,陈晓霞.早产儿胃肠外营养相关性胆汁淤积症研究进展[J].世界最新医学信息文摘,2017,17(26):52-53.
[26]唐清,王琳琳,单庆文,等.熊去氧胆酸对婴儿胆汁淤积性肝炎多药耐药蛋白3及法尼醇受体基因表达的影响和意义[J].中国当代儿科杂志,2013,15(9):756-758.
[2]Aamann L,?rntoft N,Vogel I,et al.Unexplained cholestasis in adults and adolescents:diagnostic benefit of genetic examination[J].Scand J Gastroenterol,2018,53(3):305-311.
[3]Gordo-Gilart R,Hierro L,Andueza S,et al.Heterozygous ABCB4 mutations in children with cholestatic liver disease[J].Liver Int,2016,36(2):258-267.
[4]Degiorgio D,Crosignani A,Colombo C,et al.ABCB4mutations in adult patients with cholestatic liver disease:impact and phenotypic expression[J].J Gastroenterol,2016,51(3):271-280.
[5]李静,谭彩虹.血浆micro RNA实时荧光定量PCR检测方法的建立[J].国际检验医学杂志,2015,36(1):57-59.
[6]夏世文.早产儿胃肠外营养相关性胆汁淤积[J].中国新生儿科杂志,2011,26(5):289-292.
[7]Carey AN,Zhang W,Setchell KDR,et al.Hepatic MDR3expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates[J].Pediatric Res,2017,82(1):122-132.
[8]Zhao G,Xu D,Yuan Z,et al.8-Methoxypsoralen disrupts MDR3-mediated phospholipids efflux and bile acid homeostasis and its relevance to hepatotoxicity[J].Toxicology,2017,386:40-48.
[9]Zollner G,Thueringer A,Lackner C,et al.Alterations of canalicular ATP-binding cassette transporter expression in druginduced liver injury[J].Digestion,2014,90(2):81-88.
[10]Khabou B,Durand-Schneider AM,Delaunay JL,et al.Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases[J].Int J Biochem Cell Biol,2017,89:101-109.
[11]Morita SY,Terada T.Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts[J].Biomed Res Int,2014,2014:954781.
[12]Chen HL,Liu YJ,Chen HL,et al.Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia[J].Pediatr Res,2008,63(6):667-673.
[13]赵国翠.妊娠肝内胆汁淤积症患者MDR3基因突变的研究[J].中国卫生产业,2013,32(11):124-125.
[14]曾慧.胎盘中转运蛋白表达水平对胆汁酸排泌的影响[J].东南大学学报(医学版),2016,35(6):913-917.
[15]Anselmo DM,Ghobrial RM,Jung LC,et al.New era of liver transplantation for hepatitis B:a 17-year single-center experience[J].Ann Surg,2002,235(5):611-619.
[16]Trauner M,Fickert P,Wagner M.MDR3(ABCB4)defects:a paradigm for the genetics of adult cholestatic syndromes[J].Semin Liver Dis,2007,27(1):77-98.
[17]苏亚非,宋敏,周蓉蓉,等.Mucin-3和MDR3在胆固醇结石形成中的作用[J].齐鲁医学杂志,2011,26(1):46-48.
[18]Park HJ,Kim TH,Kim SW,et al.Functional characterization of ABCB4 mutations found in progressive familial intrahepatic cholestasis type 3[J].Sci Rep,2016,6:26872.
[19]Delaunay JL,Durand-Schneider AM,Dossier C,et al.A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3[J].Hepatology,2016,63(5):1620-1631.
[20]Schatz SB,Jüngst C,Keitel-Anselmo V,et al.Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset[J].Hepatol Commun,2018,2(5):504-514.
[21]Cardoso MF,E Branco JC,Anapaz V,et al.A complex case of cholestasis in a patient with ABCB4 and ABCB11 mutations[J].GE Port J Gastroenterol,2018,25(4):189-194.
[22]Fuchs CD,Paumgartner G,Mlitz V,et al.Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2-/-mice by modulating composition,signalling and excretion of faecal bile acids[J].Gut,2018,67(9):1683-1691.
[23]Lammert F,Matern S.The genetic background of cholesterol gallstone formation:an inventory of human lithogenic genes[J].Curr Drug Targets Immune Endocr Metabol Disord,2005,5(2):163-170.
[24]宋诗蓉,吴捷.早产儿胃肠外营养相关性胆汁淤积症临床研究[J].国际儿科学杂志,2017,44(4):286-290.
[25]张韶明,陈茂琼,陈晓霞.早产儿胃肠外营养相关性胆汁淤积症研究进展[J].世界最新医学信息文摘,2017,17(26):52-53.
[26]唐清,王琳琳,单庆文,等.熊去氧胆酸对婴儿胆汁淤积性肝炎多药耐药蛋白3及法尼醇受体基因表达的影响和意义[J].中国当代儿科杂志,2013,15(9):756-758.