Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Amsterdam, The Netherlands.
Gastroenterology (Impact Factor: 16.72). 09/2010; 139(3):1008-18, 1018.e1. DOI: 10.1053/j.gastro.2010.05.009
Source: PubMed


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.
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.
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.
We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.

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Available from: Ulrich Beuers, Sep 29, 2015
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    • "The parents of the patients noted an improvement in sleep disturbance during the night and in their child’s skin condition. In contrast to the relief of the itching, the serum levels of bile acids and ATX and of ATX activity, all of which have been proposed as potential pruritogens in cholestasis [24], were not decreased by 4PB therapy in any of the patients (Figures  2B, 3A, B). The itch remained unchanged for 6, 4, and 6 weeks after cessation of 4PB therapy in patients 1, 2, and 3, respectively, but then gradually exacerbated, resulting in regeneration of erosion and hemorrhage again because of intense scratching. "
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    ABSTRACT: Background Progressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) that increases the expression and function of BSEP. Here, we tested 4PB therapy in three patients with PFIC1. Methods The therapeutic potency of 4PB in these patients was tested by oral administration of this drug with gradually increasing dosage (200, 350, and 500 mg/kg/day) for 6 months. Biochemical, histological, and clinical data were collected. Results 4PB therapy had no beneficial effect on the patients’ liver functions, as assessed by biochemical and histological analyses, despite an increase in hepatic BSEP expression. However, therapy with 4PB at a dosage of 350 or 500 mg/kg/day significantly relieved the intractable itch. Serum levels of potential pruritogens in cholestasis were much higher than the reference ranges during the 4PB therapy. Conclusions 4PB therapy may be a new medication for patients with intractable cholestatic pruritus and may improve quality of life for patients and their families.
    Orphanet Journal of Rare Diseases 07/2014; 9(1):89. DOI:10.1186/1750-1172-9-89 · 3.36 Impact Factor
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    • "Similarly, symptoms of nerve injury-induced neuropathic pains are attenuated in mice with heterozygous ATX/ENPP2 gene mutations, suggesting an involvement of ATX/ENPP2 in pain generation [20]. Serum ATX/ENPP2 levels are increased in patients with follicular lymphoma [21] and in patients with intrahepatic cholestasis of pregnancy (ICP) [22], suggesting that the LPA produced by ATX/ENPP2 may affect the pathology of these diseases. Moreover, plasma LPA levels were increased in patients with acute coronary syndrome (ACS), suggesting a possible involvement of ATX/ENPP2 in this disease [17]. "
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    ABSTRACT: Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation. The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4–19 nM for recombinant autotaxin/ENPP2 proteins and 4.7–11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration. Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.
    PLoS ONE 04/2014; 9(4):e93230. DOI:10.1371/journal.pone.0093230 · 3.23 Impact Factor
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    • "Besides bile acids, which apparently seem to play a major role as pruritogens, elevated levels of endogenous opioids and amphiphilic lysophosphatidic acid (LPA) were also found in patients with cholestatic pruritus [16]. In contrast to bile acids, LPA and autotaxin (the enzyme responsible for the transformation of lysophosphatidylcholine into LPA) plasma levels were demonstrated to correlate significantly with the severity of patients’ pruritus [19]. This indicates a crucial role of LPA and autotaxin in the pathophysiology of pruritus. "
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    ABSTRACT: Summerskill-Walshe-Tygstrup syndrome is a rare benign chronic liver disease characterized by recurring cholestasis with jaundice and severe pruritus. Due to insufficient conservative treatment, liver dialysis by Prometheus(®) was applied to a 45-year-old female patient with resistant pruritus. Initially, other possible liver diseases were excluded and the patient was treated symptomatically since the diagnosis of Summerskill-Walshe-Tygstrup was stated in 1998. As conservative and endoscopic methods progressively failed to relieve the patient's suffering, Prometheus(®) liver dialysis was performed regularly since 2006 at 3-month intervals and successfully led to a decrease in the patient's symptoms. Cholestatic liver enzymes and also serum bile acids could be lowered significantly from an average of 22.5 ± 2.7 to 7.3 ± 1.7 µmol/l. Consequently, Prometheus(®) liver dialysis may be a beneficial option for patients with benign recurrent intrahepatic cholestasis suffering from therapy-resistant symptoms and may be used as well as other extracorporeal liver support devices which have already been reported to improve cholestatic pruritus.
    Case Reports in Gastroenterology 05/2012; 6(2):550-6. DOI:10.1159/000342348
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