title: Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions.
abstract: Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values.
  
  
  CONCLUSIONS
  Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kremer
authors.forename: Remco
authors.initials: R
authors.lastname: van Dijk
authors.forename: Pamela
authors.initials: P
authors.lastname: Leckie
authors.forename: Frank G
authors.initials: FG
authors.lastname: Schaap
authors.forename: Edith M M
authors.initials: EM
authors.lastname: Kuiper
authors.forename: Thomas
authors.initials: T
authors.lastname: Mettang
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Reiners
authors.forename: Ulrike
authors.initials: U
authors.lastname: Raap
authors.forename: Henk R
authors.initials: HR
authors.lastname: van Buuren
authors.forename: Karel J
authors.initials: KJ
authors.lastname: van Erpecum
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.forename: Christian
authors.initials: C
authors.lastname: Rust
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000704:Analysis of Variance; D000982:Antipruritics / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000150:complications; D016022:Case-Control Studies; D002779:Cholestasis / Q000097:blood* / Q000150:complications; D015331:Cohort Studies; D000069472:Colesevelam Hydrochloride; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D056945:Hep G2 Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000150:complications; D008245:Lysophospholipase / Q000097:blood; D008297:Male; D015999:Multivariate Analysis; D010727:Phosphoric Diester Hydrolases / Q000097:blood* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011537:Pruritus / Q000097:blood* / Q000188:drug therapy* / Q000209:etiology; D012372:ROC Curve; D012293:Rifampin / Q000627:therapeutic use; D016896:Treatment Outcome; D000099189:Lysophospholipase D
chemical_list: D000499:Allylamine; D000982:Antipruritics; D015415:Biomarkers; D000069472:Colesevelam Hydrochloride; D005346:Fibroblast Growth Factors; D008245:Lysophospholipase; D010727:Phosphoric Diester Hydrolases; D012293:Rifampin; D000099189:Lysophospholipase D