ABCB11缺陷病同胞共患基因型与表型分析并文献复习

Relationship between phenotype and genotype of ABCB11 deficiency in siblings and literature review

目的探讨ABCB11缺陷病基因型和表型关系。方法回顾性分析2010年2月—2017年5月复旦大学附属儿科医院传染科、复旦大学附属金山医院儿科收治的一对共患ABCB11缺陷病姐弟的临床资料，并以＂ABCB11 gene/BSEP;cholestasis;child＂＂ABCB11基因或胆盐输出泵；胆汁淤积，肝内；儿童＂为关键词，检索PubMed数据库、中国知网和万方数据库建库至2017年8月的相关文献，发现经过基因确证的共患同胞，探讨其临床表型与基因型的关系。结果一对同胞姐弟患儿，均于生后3 d起病，临床表现为黄疸、瘙痒、肝脾肿大，例1初诊时2月13日龄，血清胆红素总量170 μmol/L，直接胆红素115.8 μmol/L，丙氨酸转氨酶168 U/L，胆汁酸总量186.3 μmol/L；例2初诊时1月13日龄，血清胆红素总量148.8 μmol/L，直接胆红素96.3 μmol/L，丙氨酸转氨酶232.8 U/L，胆汁酸总量226 μmol/L。谷氨酰转肽酶水平均正常，均接受口服熊去氧胆酸和补充脂溶性维生素治疗。姐弟二人基因检测结果均为ABCB11基因c.145C〉T（p.Q49X）、c.1510G〉A（p.E504K）复合杂合变异。姐姐于生后3月余黄疸消退，口服熊去氧胆酸至5岁，瘙痒减退，现9岁2月龄，随访肝功能正常。弟弟持续黄疸，组织病理提示肝细胞气球样变，部分多核巨细胞转化，可见灶性坏死，肝细胞内胆汁淤积，8月龄肛周脓肿术后出现肝衰竭，9月20日龄行肝移植（母亲供肝），现1岁5月龄，随访肝功能正常。2例患儿远期预后仍在随访中。文献报道来自7个家庭、同胞之间ABCB11基因变异均相同的18例患儿的预后，7例口服熊去氧胆酸和（或）行胆汁转流术病情缓解，5例行肝移植术，2例发生肝细胞性肝癌，4例儿童期死亡。结论相同基因型的ABCB11缺陷病患儿临床表型可有较大区别，治疗方法及预后可能有较大差异。

ObjectiveTo explore the relationship between genotype and phenotype of ABCB11 deficiency.MethodsClinical data of two siblings with ABCB11 deficiency were retrospectively analyzed. Related literature from PubMed, CNKI and Wangfang databases was reviewed to date （up to August 2017） with ＇ABCB11 gene’ or ＇bile salt export pump’, ＇cholestasis’ and ＇child’ as key words.ResultsThe patients were siblings. Both of them presented as jaundice, pruritus and hepatosplenomegaly since 3 days after birth. Significant laboratory findings on admission of the older sister included high total bilirubin, 170 μmol/L;conjugated bilirubin, 115.8 μmol/L;alanine aminotransferase, 168 U/L;total bile acid 186.3 μmol/L and normal gamma-glutamyl transpeptidase. While routine laboratory data of the younger brother were as follows： total bilirubin, 148.8 μmol/L;conjugated bilirubin, 96.3 μmol/L;alanine aminotransferase, 232.8 U/L;total bile acid 226 μmol/L, and normal gamma-glutamyl transpeptidase.Both received ursodeoxycholic acid and fat-soluble vitamins. Liver pathology of the younger brother showed giant hepatocytes with ballooning degeneration, focal necrosis and intrahepatic cholestasis. Both the patients harbor the same compound heterozygous mutations in ABCB11 gene, c.145C〉T （p.Q49X） and c.1510G〉A （p.E504K）. The sister is 9 years old now, with normal liver function. Jaundice faded around 3 months after birth, pruritus relieved at age 5, and medications was stopped since then. The brother progressed to liver failure after an operation on perianal abscess when he was 8-month-old, and received living-related liver transplantation when he was 9 month and 20 days old （from his mother）. Now he is 1 year and 5 months old, with normal liver function. Both are under our follow-up. Literature review revealed 18 ABCB11 deficiency patients from 7 families who had apparent different prognoses, within each family the siblings had the same ABCB11 gene mutation. Seven cases relieved after ursodeoxycholic acid therapy and/or partial external biliary diversion, 5 received orthotopic liver transplantation, 2 developed hepatocellular carcinoma and 4 cases died in childhood.ConclusionsThe clinical manifestations of ABCB11 deficiency may vary greatly in patients carrying the same genotype, even in siblings. Patients should be managed in individualized maner.