Diagnostic And Therapeutic Profiles Of Serum Bile Acids In Women With Intrahepatic Cholestasis Of Pregnancy

ObjectiveBased on the metabolic profile of serum bile acids, to screen out a potential biomarker for diagnosing intrahepatic cholestasis of pregnancy(ICP); to investigate the characteristics of ursodeoxycholic acid(UDCA) therapeutic profiles of serum bile acids in women with ICP;to acquire the metabolic information among free bile acids to provide experimental basis for ICP diagnosis and therapy.Methods1. Based on the platform of ultrahigh-performance liquid chromatograpy-Triple quadrupole time-of-flight tandem mass spectrometer(UPLC- TripleTOF-MS/MS), targeted and untargeted scanning technologies were used to identify and quantify serum bile acids in pregnant women;2. Relative quantification and absolute quantification were used to determine the serum bile acids in healthy pregnant and women with ICP. Metabolic profile of serum bile acids were performed by partial least squares-discriminant analysis(PLS-DA). Receiver operating characteristic curve and logistic regression were utilized to screen out the potential biomarkers for diagnosing ICP;3. During the period of UDCA therapy, therapeutic serum bile acids of women with ICP who received UDCA were monitored and analyzed by PLS-DA. The dynamic metabolic information of bile acids were obtained in therapeutic profiles;4. Path analysis was used to calculate and explore the relationships among free bile acids in healthy pregnant women and women with ICP.Results1. 28 bile acid species were confirmed and 33 bile acid species were initially identified, including 12 free bile acids, 15 taurine conjugated bile acids, and 6 glycine conjugated bile acids. Compared with healthy prenant women, the profile of serum bile acids in women with ICP was obviously altered. In addition, the bile acid profile in ICP women who with a normal total bile acid was different from that of healthy pregnant women and that of ICP women who with an abnomal total bile acids.2. According to the metabolic profile of serum bile acids, a potential combination biomarker for diagnosing ICP, which composed of taurocholic acid(TCA), α-muricholic acid(α-MCA), and Gtri-8(glycine conjugated trihydroxy bile acid, m/z 464.3018, retention time 11.46 min) was screened out. The diagnostic efficiency was quite satisfactory because receiver operating characteristic curve(ROC) analysis showed that the area under curve(AUC) was 0.996, and the youden index was 0.940.3. During the period of UDCA therapy, the altered profile of serum bile acids in women with ICP became rosy, but their profiles were fully rectified after the delivery;4. Path analysis of bile acids profile show that chenodeoxycholic acid(CDCA) had significant effect on cholic acid and UDCA both in healthy pregnant women and women with ICP. In the healthy pregnant women, the effect from CDCA to UDCA was positive, but this effect turned to negative in the women with ICP. In addition, in women with ICP, the metabolite of α-MCA had significant effect on that of UDCA, and the metabolite of β-MCA had significant effect on that of UDCA and ω-MCA.ConclusionWomen with ICP have their own characteristics of serum bile acid profiles. TCA, α-MCA, and Gtri-8 compose a potential combination biomarker for diagsing ICP. UDCA therapy can improve, to some degree, the metabolic state of serum bile acids in women with ICP. Path analysis of free bile acids provides an experimental basis for screening better therapeutic drugs for ICP.