Kremer Andreas E, Gonzales Emmanuel, Schaap Frank G, Oude Elferink Ronald P J, Jacquemin Emmanuel, Beuers Ulrich
*Department of Medicine I, Friedrich-Alexander-University of Erlangen, Erlangen, Germany †Tytgat Institute for Liver and Intestinal Research and Department of Hepatology & Gastroenterology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ‡Pediatric Hepatology Unit and National Reference Centre for Biliary Atresia, DHU Hepatinov, CHU Bicêtre, Assistance Publique-Hôpitaux de Paris, University Paris-Sud, Paris, and Inserm UMR-S1174, Orsay, France §Department of Surgery, University of Maastricht, Maastricht, The Netherlands.
J Pediatr Gastroenterol Nutr. 2016 Apr;62(4):530-5. doi: 10.1097/MPG.0000000000001044.
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.
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 (3β-hydroxy-C27-steroid-oxidoreductase [n = 7] and Δ-3-oxosteroid-5β-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.
Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean ± standard deviation: 16.1 ± 4.3 nmol · mL · min) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 ± 4.7 nmol · mL · min; P < 0.01) and healthy controls (7.6 ± 2.3 nmol · mL · min; 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 < 0.001 and 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.
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.
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潜在病因的溶血磷脂酶，在有或无瘙痒症状的小儿胆汁淤积性疾病中的情况。
对45名儿童进行队列研究，其中包括14名有瘙痒症状的患者（阿拉吉耶综合征[n = 10]、完全性肝外胆道闭锁[n = 2]、新生儿硬化性胆管炎[n = 1]、2型进行性家族性肝内胆汁淤积症[n = 1]），9名胆汁酸合成缺陷患者（3β-羟基-C27-类固醇氧化还原酶[n = 7]和Δ-3-氧类固醇-5β-还原酶缺乏症[n = 2]），以及22名健康儿童。通过酶法测定血清ATX活性和总血清胆汁盐，通过蛋白质印迹法对ATX蛋白含量进行半定量分析。使用实时聚合酶链反应，研究法尼酯X受体激动剂或赋形剂处理的HepG2细胞中ATX mRNA的表达。
与患有胆汁酸合成缺陷的非瘙痒性胆汁淤积性疾病儿童（10.4±4.7 nmol·mL·min；P < 0.01）和健康对照儿童（7.6±2.3 nmol·mL·min；P < 0.001）相比，患有阿拉吉耶综合征和其他胆汁淤积性综合征的瘙痒儿童血清ATX活性升高（平均值±标准差：16.1±4.3 nmol·mL·min）。ATX蛋白水平与血清ATX活性密切相关。血清ATX活性和总血清胆汁盐与瘙痒强度呈线性相关（分别为r = 0.66，P < 0.001和r = 0.80，P < 0.001）。未观察到ATX活性与胆红素之间的相关性。法尼酯X受体配体未诱导HepG2细胞中ATX mRNA的表达。
胆汁淤积性疾病患儿血清ATX活性与瘙痒强度相关。胆汁盐在体外未增加ATX表达。ATX抑制剂可能是小儿胆汁淤积性疾病中有用的止痒药物。
