PDF(708 KB)
PDF(708 KB)
PDF(708 KB)
疑难病研究-钠牛磺胆酸共转运多肽缺陷病表现为婴儿早期胆汁淤积性黄疸
Sodium taurocholate cotransporting polypeptide deficiency manifesting as cholestatic jaundice in early infancy: a complicated case study
钠牛磺胆酸共转运多肽 （NTCP）缺陷病是由于SLC10A1基因突变，肝细胞基侧膜转运蛋白NTCP的胆汁酸盐摄取功能受损面形成的一种遗传代谢病。该文患儿因发现皮肤巩膜黄染5.5个月 （生后第2天出现黄疸）、肝功能异常4月余就诊。肝功能示总胆红素、直接胆红素、间接胆红素和总胆汁酸均明显上升。曾按胆汁淤积性肝病内科治疗，疗效欠佳，于2月龄时行剖腹探查+胆囊造瘘+胆道造影术，术中发现胆汁粘稠但胆道通畅。术后黄疸消退，但转氨酶和总胆汁酸水平逐渐升高。患儿母亲亦发现有轻微高胆汁酸血症。患儿未予特殊治疗，目前已门诊随访两年余，转氨酶逐渐恢复正常，总胆汁酸波动于23.3~277.7 μmol/L。患儿2岁9个月行SLC10A1基因分析，结果证实患儿及其母均为致病性变异c.800C > T （p.S267F）的纯合子，从而确诊NTCP缺陷病。该研究提示，NTCP缺陷病成人患者仅有轻微高胆汁酸血症，但儿科患者胆汁酸升高明显而且持续，且部分病例在婴儿早期可表现为胆汁淤积性黄疸。
Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is caused by SLC10A1 mutations impairing the NTCP function to uptake plasma bile salts into the hepatocyte. Thus far, patients with NTCP deficiency were rarely reported. The patient in this paper was a 5-month-19-day male infant with the complaint of jaundiced skin and sclera for 5.5 months as well as abnormal liver function revealed over 4 months. His jaundice was noticed on the second day after birth, and remained visible till his age of 1 month and 13 days, when a liver function test unveiled markedly elevated total, direct and indirect bilirubin as well as total bile acids (TBA). Cholestatic liver disease was thus diagnosed. Due to unsatisfactory response to medical treatment, the patient underwent exploratory laparotomy, cholecystostomy and cholangiography when aged 2 months. This revealed inspissated bile but unobstructed bile ducts. Thereafter, his jaundice subsided, but the aminotransferases and TBA levels gradually rose. Of note, his mother also had mildly elevated plasma TBA. Since the etiology was unclear, no specific medication was introduced. The infant has been followed up over 2 years. The aminotransferases recovered gradually, but TBA levels fluctuated within 23.3-277.7 μmol/L (reference range:0-10 μmol/L). On SLC10A1 genetic analysis at 2 years and 9 months, both the infant and his mother proved to be homozygous for a pathogenic variant c.800C > T (p.S267F), and NTCP deficiency was thus definitely diagnosed. The findings suggest that, although only mildly increased plasma TBA is presented in adults with NTCP deficiency, pediatric patients with this disorder exhibit persistent and remarkable hypercholanemia, and some patients might manifest as cholestatic jaundice in early infancy.
胆汁淤积症 / NTCP缺陷病 / SLC10A1基因 / 突变 / 儿童
Cholestasis / Sodium taurocholate cotransporting polypeptide deficiency / SLC10A1 gene / Mutation / Child
[1] Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter[J]. J Clin Invest, 1994, 93(3):1326-1331.
[2] Ho RH, Leake BF, Roberts RL, et al. Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition[J]. J Biol Chem, 2004, 279(8):7213-7222.
[3] Pan W, Song IS, Shin HJ, et al. Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations[J]. Xenobiotica, 2011,41(6):501-510.
[4] Hagenbuch B, Dawson P. The sodium bile salt cotransport family SLC10[J]. Pflugers Arch, 2004, 447(5):566-570.
[5] Anwer MS, Stieger B. Sodium-dependent bile salt transporters of the SLC10A transporter family:more than solute transporters[J]. Pflugers Arch, 2014, 466(1):77-89.
[6] Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife, 2012, 1:e00049.
[7] Vaz FM, Paulusma CC, Huidekoper H, et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency:conjugated hypercholanemia without a clear clinical phenotype[J]. Hepatology, 2015, 61(1):260-267.
[8] Deng M, Mao M, Guo L, et al. Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency[J]. Exp Ther Med, 2016, 12(5):3294-3300.
[9] Karpen SJ, Dawson PA. Not all (bile acids) who wander are lost:the first report of a patient with an isolated NTCP defect[J]. Hepatology, 2015, 61(1):24-27.
[10] Andrianov MG, Azzam RK. Cholestasis in infancy[J]. Pediatr Ann, 2016, 45(12):e414-e419.
[11] Yan H, Peng B, Liu Y, et al. Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide[J]. J Virol, 2014, 88(6):3273-3284.
[12] Hagenbuch B, Meier PJ. The superfamily of organic anion transporting polypeptides[J]. Biochim Biophys Acta, 2003, 1609(1):1-18.
[13] Ballatori N, Christian WV, Lee JY, et al. OST alpha-OST beta:a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia[J]. Hepatology, 2005, 42(6):1270-1279.
[14] Zhu QS, Xing W, Qian B, et al. Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia[J]. Biochim Biophys Acta, 2003, 1638(3):208-216.
[15] Peng L, Zhao Q, Li Q, et al. The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B[J]. Hepatology, 2015, 61(4):1251-1260.
国家自然科学基金（81270957，81570793）。
