Abstract：
OBJECTIVE: Biallelic variants in the adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease.
METHODS: The clinical and genotypic data on pediatric patients seen at King\'s College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed.
RESULTS: Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease.
CONCLUSIONS: Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.
METHODS: The clinical and genotypic data on pediatric patients seen at King\'s College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed.
RESULTS: Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease.
CONCLUSIONS: Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.
摘要：
目的：编码多药耐药3蛋白（MDR3）的三磷酸腺苷结合盒亚家族B成员4（ABCB4）基因的双等位基因变异导致3型肝内胆汁淤积。然而,单等位基因变异体越来越被认为是导致成人肝病的原因.我们的目的是描述大量胆汁淤积性肝病婴儿和儿童中MDR3杂合变异的临床特征。
方法：在国王学院医院看到的儿科患者的临床和基因型数据，伦敦,回顾了2004年至2022年之间，发现ABCB4中具有杂合变体的情况。
结果：在1568名患者中，有92名患者被鉴定为单等位基因变体（5.9％）。最常见的问题是共轭高胆红素血症（n=46；50％），其次是胆石症（n=12；13％）和胆汁淤积性肝炎（n=10；11％）。介绍时肝脏生物化学的中值为：GGT105IU/L和总胆红素86µmol/L。鉴定出32种遗传变异，包括22种错义（69％），4个缺失（13%），5个剪接位点(16%)和1个终止位点(3%)。在1年的中位随访中，肝脏疾病的消退。
结论：在患有胆汁淤积性肝病的婴儿和儿童中发现了罕见的ABCB4变异。出现的问题是可变的，异常随着时间的推移趋于正常化。那些具有严重突变的人可能会在以后的生活中发展为肝脏疾病，当暴露于进一步的侮辱时，应该得到适当的建议。
方法：在国王学院医院看到的儿科患者的临床和基因型数据，伦敦,回顾了2004年至2022年之间，发现ABCB4中具有杂合变体的情况。
结果：在1568名患者中，有92名患者被鉴定为单等位基因变体（5.9％）。最常见的问题是共轭高胆红素血症（n=46；50％），其次是胆石症（n=12；13％）和胆汁淤积性肝炎（n=10；11％）。介绍时肝脏生物化学的中值为：GGT105IU/L和总胆红素86µmol/L。鉴定出32种遗传变异，包括22种错义（69％），4个缺失（13%），5个剪接位点(16%)和1个终止位点(3%)。在1年的中位随访中，肝脏疾病的消退。
结论：在患有胆汁淤积性肝病的婴儿和儿童中发现了罕见的ABCB4变异。出现的问题是可变的，异常随着时间的推移趋于正常化。那些具有严重突变的人可能会在以后的生活中发展为肝脏疾病，当暴露于进一步的侮辱时，应该得到适当的建议。
