Serum Autotaxin Activity Correlates with Pruritus in Pediatric Cholestatic Disorders

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 (BASD) [3beta-hydroxy-C27-steroid-oxidoreductase (n = 7) and Delta-3-oxosteroid-5beta-reductase deficiency (n = 2)] and of 22 healthy children were studied. Serum ATX activity and total serum bile salt (TBS) were determined enzymatically, ATX protein content was semi-quantified by western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor (FXR) agonists or vehicle. RESULTS: Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean +/- SD: 16.1 +/- 4.3 nmol mL min) compared to non-pruritic cholestatic children with BASD (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 TBS 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 FXR ligands. CONCLUSIONS: Serum ATX activity correlated with itch intensity in cholestatic children. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in paediatric cholestatic disorders.