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  • The diagnosis of ICP is currently based on the

    2022-11-07

    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 etiology that differs from women with ICP. Furthermore, the management of these conditions is different from that of ICP. Autotaxin (ATX) is a lysophospholipase D 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 Linezolid (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].
    Materials and methods
    Results
    Discussion The lysophospholipase D autotaxin represents the secreted form of ectonucleotide pyrophosphatase (ENPP2) and plays a critical role in diverse physiological conditions, such as vascular and neuronal development, during pregnancy or lymphocyte migration [24]. The present study provides new insights into the role of ATX in normal pregnancy and pregnancy-related liver disease. Conditions that raise female steroid hormones, such as intake of oral contraceptives or uncomplicated pregnancy, are associated with increased circulating ATX levels in healthy controls. In contrast, neither the regular menstrual cycle nor oral food intake or day-night rhythm affect serum ATX activity. In intrahepatic cholestasis of pregnancy (ICP), elevated serum ATX represents an accurate biomarker to differentiate ICP from other pregnancy-related disorders. Unexpectedly, the marked rise of ATX observed during ICP is derived from other sources than placental tissue. The importance of ATX in fetal development is underlined by the fact that ATX-deficient mice are embryonically lethal due to vascular malformation and neuronal abnormalities [15], [22]. During pregnancy, ATX serum levels have been shown to increase [17] and correlate positively with gestation. Placental trophoblasts and syncytiotrophoblast were assumed to be the source of the increased ATX levels [25]. However, we were unable to identify the increased serum ATX activities in fetal blood stream, even in newborn babies of women suffering from ICP (Fig. 2E), despite the high levels in the maternal circulation. Thus, ATX secretion from trophoblasts may represent a unidirectional process towards the maternal, but not the fetal circulation. Alternatively, the marked increase in serum ATX activities during ICP may be derived from other tissue than placenta as no differences in mRNA and protein level could be observed in placental tissue from patients with ICP and healthy mothers. Thus, a yet to be defined source is responsible for increased ATX levels during ICP. As ATX levels are also increased in serum of patients with other cholestatic disorders, particularly in those suffering from pruritus [18], [26], we hypothesize that a factor capable of increasing ATX expression (or reducing its clearance) accumulates in cholestatic patients. Further studies are warranted to identify this factor and the source of circulating ATX levels.