Chinese Children With Chronic Intrahepatic Cholestasis and High γ-Glutamyl Transpeptidase: Clinical Features and Association With ABCB4 Mutations
Chinese Children With Chronic Intrahepatic Cholestasis and High γ-Glutamyl Transpeptidase: Clinical Features and Association With ABCB4 Mutations
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DOI：
10.1097/mpg.0b013e31824ef36f
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发表时间：
2012-08-01
影响因子：
2.9
通讯作者：
Wang, Jian-She
中科院分区：
文献类型：
--
作者：
Fang, Ling-Juan;Wang, Xiao-Hong;Wang, Jian-She
目的：本研究的目的是研究ABCB 4基因突变在中国大陆儿童慢性肝内胆汁淤积症的意义，并与临床特征和响应熊去氧胆酸（UDCA）therapeutic.Methods：13例慢性肝内胆汁淤积症和血清γ-谷氨酰转肽酶活性升高的原因不明的患者在一个单一的儿科中心。对ABCB 4的所有编码外显子和侧翼区进行测序。可用的肝活检标本进行多药耐药蛋白3免疫染色。结果：在3例患者中发现6种不同的ABCB 4突变，每例患者均为复合杂合子。除了C。139 C>T（p.R47X），均为新发现，包括c. 344+2_+3insT，c.1376A>G（p.D459G），c.1745G>A（p.R582Q），c.2077_2078delC（p.P693HfsX698），c.3825_3826delA（p.M1276WfsX1308）。ABCB 4突变患者多药耐药蛋白3小管免疫染色缺失或减少。ABCB 4突变患者的血清总胆汁酸水平高于无ABCB 4突变患者（352.5 +/- 97.0 vs 55.9 +/- 50.4 μ mol/L，P = 7.32E-05）。其他生化指标在ABCB 4突变患者和非ABCB 4突变患者之间无差异。3例ABCB 4突变患者口服UDCA后，瘙痒消失，生长改善，脾脏缩小，血小板计数增加。在10例没有ABCB 4突变，UDCA治疗的反应不一致observed.Conclusions：在中国大陆的儿童，一些情况下，慢性肝内胆汁淤积症高γ-谷氨酰转肽酶可归因于ABCB 4突变。UDCA给药部分改善了临床症状和肝功能。
Objective: The aims of the present study was to study the significance of ABCB4 mutations in mainland Chinese children with chronic intrahepatic cholestasis and to correlate genetic findings with clinical features and response to ursodeoxycholic acid (UDCA) therapy.Methods: Thirteen patients with chronic intrahepatic cholestasis and elevated serum gamma-glutamyl transpeptidase activity of unknown cause were enrolled in a single pediatric center. All of the encoding exons and flanking areas of ABCB4 were sequenced. Available liver biopsy specimens were immunostained for multidrug resistance protein 3. The clinical features, biochemical parameters, and responses to therapy were compared with patients with or without ABCB4 mutation(s).Results: Six different ABCB4 mutations were identified in 3 patients; each patient was a compound heterozygote. Apart from c. 139C>T (p.R47X), all were novel, including c. 344+2_+3insT, c.1376A>G (p.D459G), c.1745G>A (p.R582Q), c.2077_2078delC (p.P693HfsX698), and c.3825_3826delA (p.M1276WfsX1308). Absent or reduced multidrug resistance protein 3 canalicular immunostaining was demonstrated in patients with ABCB4 mutations. Serum total bile acid levels were higher in patients with ABCB4 mutations than in patients without ABCB4 mutations (352.5 +/- 97.0 vs 55.9 +/- 50.4 mu mol/L, P = 7.32E-05). There was no difference in other biochemical parameters between patients with and without ABCB4 mutations. After oral UDCA administration in 3 patients with ABCB4 mutations, pruritus disappeared, growth improved, spleen size decreased, and platelet counts increased. In the 10 patients without ABCB4 mutations, an inconsistent response to UDCA therapy was observed.Conclusions: In mainland Chinese children, some cases of chronic intrahepatic cholestasis with high gamma-glutamyl transpeptidase could be attributed to ABCB4 mutations. UDCA administration partially improved clinical symptoms and liver function.