Serum Autotaxin Activity Correlates With Pruritus in Pediatric Cholestatic Disorders
Serum Autotaxin Activity Correlates With Pruritus in Pediatric Cholestatic Disorders
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DOI：
10.1097/mpg.0000000000001044
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发表时间：
2016-04-01
影响因子：
2.9
通讯作者：
Beuers, Ulrich
中科院分区：
文献类型：
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作者：
Kremer, Andreas E.;Gonzales, Emmanuel;Beuers, Ulrich
目的：瘙痒是胆汁淤积性肝病的常见症状。本研究旨在评估自分泌运动因子 (ATX)，一种最近被确定为胆汁淤积性瘙痒的潜在原因的溶血磷脂酶，在伴有或不伴有瘙痒的儿科胆汁淤积性疾病中进行评估。方法：由 45 名儿童组成的队列，其中 14 名经历瘙痒的患者（Alagille 综合征 [n = 10]、完全性肝外胆道闭锁 [n = 2]、新生儿硬化性胆管炎 (n = 1)、研究人员对进行性家族性肝内胆汁淤积 2 型 [n = 1]）、9 名胆汁酸合成缺陷患者（3 β-羟基-C27-类固醇氧化还原酶 [n = 7] 和 Delta(4)-3-oxosteroid-5 β-还原酶缺乏症 [n = 2]）和 22 名健康儿童进行了研究。通过酶法测定血清ATX活性和血清总胆汁盐，通过Western blotting半定量ATX蛋白含量。使用实时聚合酶链反应，研究了法尼醇 X 受体激动剂或媒介物处理的 HepG2 细胞中 ATX mRNA 的表达。结果：与胆汁酸治疗的非瘙痒性胆汁淤积性疾病儿童相比，患有 Alagille 和其他胆汁淤积综合征的瘙痒儿童的血清 ATX 活性升高（平均值 +/- 标准差：16.1 +/- 4.3 nmol 中心点 mL(-1) 中心点 min(-1)）合成缺陷（10.4 +/- 4.7 nmol 中心点 mL(-1) 中心点 min(-1)；P < 0.01）和健康对照（7.6 +/- 2.3 nmol 中心点 mL(-1) 中心点 min(-1)；P < 0.001）。 ATX蛋白水平与血清ATX活性密切相关。血清ATX活性和血清总胆盐与瘙痒强度呈线性相关（分别为r = 0.66，P r = 0.80，P < 0.001）。未观察到 ATX 活性与胆红素之间存在相关性。法尼醇X受体配体不诱导HepG2细胞中ATX mRNA的表达。结论：胆汁淤积性疾病儿童血清ATX活性与瘙痒强度相关。胆汁盐在体外不会增加 ATX 表达。 ATX 抑制剂可能是治疗小儿胆汁淤积性疾病的有效止痒剂。
Objective:Pruritus is a common symptom of cholestatic liver disorders. The present study aimed at evaluating autotaxin (ATX), a lysophospholipase recently identified as potential cause for cholestatic pruritus, in pediatric cholestatic diseases presenting with or without itching.Methods:A cohort of 45 children consisting of 14 patients experiencing itching (Alagille syndrome [n = 10], complete extrahepatic biliary atresia [n = 2], neonatal sclerosing cholangitis (n = 1), progressive familial intrahepatic cholestasis type 2 [n = 1]), 9 patients with bile acid synthesis defects (3 beta-hydroxy-C27-steroid-oxidoreductase [n = 7] and Delta(4)-3-oxosteroid-5 beta-reductase deficiency [n = 2]), and 22 healthy children were studied. Serum ATX activity and total serum bile salt were determined enzymatically, ATX protein content was semiquantified by Western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor agonists or vehicle.Results:Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean +/- standard deviation: 16.1 +/- 4.3 nmol center dot mL(-1) center dot min(-1)) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 +/- 4.7 nmol center dot mL(-1) center dot min(-1); P < 0.01) and healthy controls (7.6 +/- 2.3 nmol center dot mL(-1) center dot min(-1); P < 0.001). ATX protein levels closely correlated with serum ATX activity. Serum ATX activity and total serum bile salt showed a linear correlation with itch intensity (r = 0.66, P r = 0.80, P < 0.001, respectively). No correlation was observed between ATX activity and bilirubin. ATX mRNA expression in HepG2 cells was not induced by farnesoid-X-receptor ligands.Conclusions:Serum ATX activity correlated with itch intensity in children with cholestatic diseases. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in pediatric cholestatic disorders.