UvA-DARE ( Digital Academic Repository ) The role of autotaxin in cholestatic pruritus

Background & aims: Intrahepatic cholestasis of pregnancy (ICP) is defined by pruritus, elevated total fasting serum bile salts (TBS) and transaminases, and an increased risk of adverse fetal outcome. An accurate diagnostic marker is needed. Increased serum autotaxin correlates with cholestasis-associated pruritus. We aimed to unravel the diagnostic accuracy of autotaxin in ICP. Methods: Serum samples and placental tissue were collected from 44 women with uncomplicated pregnancies and 105 with pruritus and/or elevated serum transaminases. Autotaxin serum levels were quantified enzymatically and by western blotting, autotaxin gene expression by quantitative PCR. Results: Serum autotaxin was increased in ICP (mean ± SD: 43.5 ± 18.2nmol·mL-1·min-1, n=55, p<0.0001) compared to other pruritic disorders of pregnancy (16.8 ± 6.7nmol·mL-1·min-1, n=33), pre-eclampsia complicated by HELLP-syndrome (16.8 ± 8.9nmol·mL-1·min-1, n=17), and pregnant controls (19.6 ± 5.7nmol·mL-1·min-1, n=44). Longitudinal analysis during pregnancy revealed a marked rise in serum autotaxin with onset of ICP-related pruritus. Serum autotaxin was increased in women taking oral contraceptives. Increased serum autotaxin during ICP was not associated with increased autotaxin mRNA in placenta. With a cut-off value of 27.0nmol·mL-1 ·min-1, autotaxin had an excellent sensitivity and specificity in distinguishing ICP from other pruritic disorders or pre-eclampsia/HELLP-syndrome. Serum autotaxin displayed no circadian rhythm and was not influenced by food intake. Conclusions: Increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP. INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a pregnancyspecific liver disorder with onset mainly in the third trimester of pregnancy. ICP is characterized by pruritus, elevated serum fasting bile salts and transaminases and an increased risk of adverse fetal outcomes.1-3 This disorder typically affects 0.2–2% of all pregnant women. The incidence of ICP, however, varies considerably with ethnicity and geographical location with the highest rates observed in Northern Europe and Southern America.2,4 Pruritus is the defining symptom of ICP, which progressively worsens as the pregnancy advances. Pruritus may considerably reduce quality of life, lead to sleep deprivation, depressed mood, and even suicidal ideation in more severe cases. In contrast to other more commonly observed pruritic dermatoses of pregnancy,5 a concern in ICP is the increased risk of adverse fetal outcomes.1,2 ICP increases the risk of fetal distress, cardiotocography abnormalities, preterm labor and sudden intrauterine death particularly in those women with total serum fasting bile salt (TBS) levels exceeding 40μmol/L.3,4,6,7 Therefore a proper diagnosis is essential to enable pharmacological treatment with ursodeoxycholic acid (UDCA), close antenatal monitoring and potentially the induction of labor after 37 weeks with the aim of reducing fetal distress and intrauterine death.8,9 The diagnosis of ICP is currently based on the presence of pruritus, raised fasting serum TBS levels above 10μmol/L, and/or elevated serum transaminases (in the absence of diseases that cause cholestasis or pruritus) as well as spontaneous relief of signs and symptoms within four to six weeks after delivery.1,10 However, diagnosis of ICP may be difficult when considering other pregnancy-associated dermatoses, liver diseases and their possible co-existence. The most sensitive marker for ICP is a raised fasting level of TBS while serum transaminases may be normal in up to 30% of cases.6,11 However, an asymptomatic elevation of TBS levels, hypercholanaemia, is observed in approximately 10% of pregnant women,12 and has been reported to affect up to 40% of Argentinean pregnancies.13 In addition, serum TBS increase upon food intake, thereby increasing variation unless serum is collected upon fasting. Elevated serum transaminases during the 3rd trimester of pregnancy are seen in women with HELLP-syndrome (hemolysis, elevated liver enzymes and low platelet count), pre-eclampsia, acute fatty liver of pregnancy and other non pregnancy-related liver disorders including obesity.1,2,6 These women also hold an increased risk for fetal adverse outcomes, but have an aetiology that differs from women with ICP. Furthermore, the management of these conditions is different from that of ICP. Autotaxin (ATX) is a lysophospholipase D which is essential for angiogenesis and neuronal development during embryogenesis.14 Other physiological functions attributed to ATX include cellular motility, proliferation, and lymphocyte homing.15 The effects of ATX are largely mediated by the enzymatic formation of lysophosphatidic acid (LPA) which may act via one of at least six different LPA receptors.14,16 ATX levels have been reported to be increased during pregnancy and correlate positively with gestational age.17 To identify the pruritogens of cholestasis we recently screened sera from ICP women for activation of neuronal cells and identified LPA as a potent neuronal activator.18 LPA and ATX levels were significantly increased in ICP women compared to gestation-matched pregnant controls. LPA could be related to pruritus during ICP as intradermal injection of LPA in mice caused a dose-dependent scratch response.18 AUTOTAXIN ACTIVITY HAS A HIGH ACCURACY TO DIAGNOSE ICP