Abstract: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 mRNA 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 mRNA expression of MDR3 in preterm infants may be associated with the development of PNAC, and further studies are needed to identify the mechanism.
YANG Xiu-Fang,LIU Guo-Sheng,CHEN Yu-Lan et al. mRNA expression of MDR3 gene in the blood of preterm infants with parenteral nutrition-associated cholestasis[J]. CJCP, 2019, 21(2): 125-130.
Fujikura K, Yamasaki T, Otani K, et al. BSEP and MDR3:useful immunohistochemical markers to discriminate hepatocellular carcinomas from intrahepatic cholangiocarcinomas and hepatoid carcinomas[J]. Am J Surg Pathol, 2016, 40(5):689-696.
[2]
Aamann L, Ørntoft 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. ABCB4 mutations in adult patients with cholestatic liver disease:impact and phenotypic expression[J]. J Gastroenterol, 2016, 51(3):271-280.
Carey AN, Zhang W, Setchell KDR, et al. Hepatic MDR3 expression 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.
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.
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.