Jirsa Milan, Bronský Jiří, Dvořáková Lenka, Šperl Jan, Šmajstrla Vít, Horák Jiří, Nevoral Jiří, Hřebíček Martin
Milan Jirsa, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic.
World J Gastroenterol. 2014 May 21;20(19):5867-74. doi: 10.3748/wjg.v20.i19.5867.
To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency.
Mutational analysis of ABCB4, screening for copy number variations by multiplex ligation-dependent probe amplification, genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome (LPAC, OMIM #600803) and in 5 young females with suspected LPAC and their families (5 probands, 15 additional family members). The probands came to medical attention for contraceptive-associated intrahepatic cholestasis.
A possibly pathogenic variant of ABCB4 was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4. Among these 16, however, none developed gallstones in childhood. In 5 index patients, all young females carrying at least one pathogenic mutation in one allele of ABCB4, manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives. Variants ABCB11 c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC.
Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied to pediatric patients with idiopathic gallstones. Sexual immaturity even prevents manifestation of LPAC.
探讨ABCB4突变对小儿特发性胆结石疾病的影响，以及激素避孕药引发多药耐药蛋白3缺乏临床表现的可能性。
对35例符合低磷脂相关胆石症综合征（LPAC，OMIM #600803）临床标准的小儿特发性胆结石患者，以及5例疑似LPAC的年轻女性及其家属（5名先证者，15名其他家庭成员）进行ABCB4突变分析、多重连接依赖探针扩增法筛查拷贝数变异、ABCB11低表达等位基因c.1331T>C基因分型，以及成人中先前与胆固醇胆结石相关的ABCG8基因变异c.55G>C基因分型。这些先证者因避孕药相关性肝内胆汁淤积前来就医。
在35例小儿特发性胆固醇胆结石患者中仅1例发现ABCB4可能致病变异，而在研究的5个LPAC家族的15名成员中证实存在该变异，另有1名高度怀疑携带ABCB4可预测的致病突变。然而，在这16人中，无人在儿童期患胆结石。在5例索引患者中，所有ABCB4一个等位基因至少携带一个致病突变的年轻女性，激素避孕药均诱发了LPAC表现为肝内胆汁淤积伴γ-谷氨酰转移酶血清活性升高。ABCB11 c.1331T>C和ABCG8 c.55G>C变异在35例疑似LPAC的受检患者中未显著富集。
ABCB4突变导致的LPAC综合征临床标准不适用于小儿特发性胆结石患者。性不成熟甚至会阻止LPAC的表现。
