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Serum Autotaxin Activity Correlates With Pruritus in Pediatric Cholestatic Disorders
Andreas E Kremer1, Emmanuel Gonzales, Frank G Schaap
1*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.
Insights
Serum autotaxin (ATX) activity correlates with itch intensity in pediatric cholestatic diseases. ATX inhibitors show potential as antipruritic agents for children with these conditions.
Area of Science:
- Hepatology
- Pediatric Gastroenterology
- Biochemistry
Background:
- Pruritus (itching) is a frequent and distressing symptom in pediatric cholestatic liver disorders.
- Autotaxin (ATX), a lysophospholipase, has been implicated as a potential mediator of cholestatic pruritus.
Purpose of the Study:
- To evaluate autotaxin (ATX) levels and activity in children with cholestatic liver diseases, with or without pruritus.
- To investigate the correlation between ATX activity, bile salt levels, and itch intensity.
Main Methods:
- A cohort of 45 children, including those with Alagille syndrome, biliary atresia, neonatal sclerosing cholangitis, progressive familial intrahepatic cholestasis, and bile acid synthesis defects, alongside healthy controls.
- Enzymatic determination of serum ATX activity and total serum bile salt.
- Semi-quantification of ATX protein by Western blotting and mRNA expression analysis in HepG2 cells.
Main Results:
- Serum ATX activity was significantly elevated in children with pruritic cholestatic syndromes compared to those with non-pruritic conditions and healthy controls.
- Serum ATX activity and total serum bile salt levels showed a strong positive linear correlation with itch intensity.
- No correlation was found between ATX activity and bilirubin levels; ATX mRNA expression was not induced by FXR ligands in vitro.
Conclusions:
- Serum ATX activity is a potential biomarker for itch intensity in pediatric cholestatic disorders.
- Bile salts do not appear to directly increase ATX expression in vitro.
- Autotaxin (ATX) inhibitors represent a promising therapeutic strategy for managing pruritus in pediatric cholestatic diseases.
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 (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.
Results:
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.
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.
