Lysophosphatidic acid is a potential mediator of cholestatic pruritus.
OBJECTIVE
Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons.


METHODS
Cytosolic free calcium ([Ca(2+)](i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)](i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device.


RESULTS
Transient increases in neuronal [Ca(2+)](i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)](i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or mu-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal.


CONCLUSIONS
We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.
Kremer
Andreas E
AE
Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Amsterdam, The Netherlands. a.e.kremer@amc.uva.nl
Martens
Job J W W
JJ
Kulik
Wim
W
Ruëff
Franziska
F
Kuiper
Edith M M
EM
van Buuren
Henk R
HR
van Erpecum
Karel J
KJ
Kondrackiene
Jurate
J
Prieto
Jesus
J
Rust
Christian
C
Geenes
Victoria L
VL
Williamson
Catherine
C
Moolenaar
Wouter H
WH
Beuers
Ulrich
U
Oude Elferink
Ronald P J
RP
D000328:Adult; D000368:Aged; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002780:Cholestasis, Intrahepatic / Q000097:blood* / Q000150:complications / Q000628:therapy; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004322:Drainage; D005260:Female; D005470:Fluorometry; D006801:Humans; D007271:Injections, Intradermal; D008105:Liver Cirrhosis, Biliary / Q000097:blood* / Q000150:complications / Q000628:therapy; D008246:Lysophospholipids / Q000008:administration & dosage / Q000097:blood*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000097:blood; D009474:Neurons / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000097:blood; D010727:Phosphoric Diester Hydrolases; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood* / Q000628:therapy; D011537:Pruritus / Q000097:blood / Q000139:chemically induced / Q000209:etiology*; D011755:Pyrophosphatases / Q000097:blood; D012720:Severity of Illness Index; D013997:Time Factors; D015854:Up-Regulation; D000099189:Lysophospholipase D
D002118:Calcium; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid