The present study indicates elevated ATX

The present study indicates elevated ATX activity as a highly sensitive and specific biomarker to differentiate ICP from other pregnancy-related liver disorders or pruritic dermatoses. In (-)-Bicuculline methobromide to the current gold standard for diagnosis, total fasting serum bile salt levels, ATX appeared as a very robust biomarker not being influenced by food intake or circadian rhythm. Thus, a serum ATX activity assay represents a potentially powerful test to reliably diagnose ICP, a disease that is associated with increased risk of adverse fetal outcomes and can be effectively treated with UDCA and close obstetric monitoring [9]. Our study certainly needs confirmation in independent patient cohorts, as our results are based on a limited number of patients. A number of other issues need to be addressed. First, the diagnostic value of serum ATX activity as a biomarker for ICP should be compared to that of serum ATX protein levels after development of a reliable quantitative test. Second, total fasting serum bile salt levels are currently regarded as the gold standard for diagnosis of ICP, but our data suggest that determining the level of serum ATX activity is more accurate as an early marker of ICP. Thus, a combination of enhanced ATX activity and raised total fasting serum bile salt levels further improved the diagnostic accuracy for ICP in contrast to women with uncomplicated pregnant controls and pruritus gravidarum. In a small subset of samples, UDCA reduced serum ATX activity shortly after start of treatment. However, the effect on pruritus could not be analyzed in the current cohort due to lack of quantification of itch intensity, and remains to be evaluated in future prospective studies. Third, a cut-off value of 27nmolml−1min−1 (3.2×upperlimitofnormal) showed optimal sensitivity and specificity as a biomarker for ICP, using receiver operating characteristics curve analysis. This cut-off value requires extramural validation in subsequent large-scale studies. Fourth, our serum ATX activity assay may differ from those used in other studies. Thus, comparative studies of different ATX activity assays are needed. Finally, general application of such an assay would require the development of a simple enzymatic test, enzyme-linked immunosorbent assay (ELISA) or dye-coupled autotaxin antibodies. Similar to the common pregnancy test using the detection of human chorionic gonadotrophin in urine, one could think of a technique using a drop of blood to detect a threshold level of ATX, thereby diagnosing ICP. Pruritus is a common symptom during pregnancy and is estimated to occur in up to 18% of all pregnancies [27]. Itching is most frequently caused by specific dermatoses of pregnancy [5], such as atopic eruption of pregnancy and polymorphic eruption of pregnancy, which, in contrast to ICP, are not associated with increased risk for adverse fetal outcomes [3], [28]. In addition, itching may also be caused by other skin and systemic disorders, which coincide with pregnancy. A simple test, distinguishing ICP from these differential diagnoses, could help general practitioners and gynaecologists to adequately treat these women. UDCA is regarded as first-line therapy of ICP and has been shown to improve maternal symptoms, serum liver tests, and placental abnormalities [1], [2], [8], [29], [30], [31], although improvement of pruritus by UDCA seemed not to be clinically meaningful in a recent trial [32]. About 80% of affected women develop pruritus after 30weeks of gestation, but ICP has been reported as early as after 8weeks of gestation [2], [33]. In our cohort, there were two cases of ICP that presented already during weeks 10 and 12 of gestation. These unusual cases were characterized by a serum ATX activity above 31nmolml−1min−1 as cut-off value for 100% specificity. Thus, particularly in atypical cases, ATX may represent a suitable biomarker to diagnose ICP.
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