The Diagnosis Of Asymptomatic Hypercholanaemia Of Pregnancy Based On The Metabolic Profiling Of Bile Acids

ObjectiveTo investigate the clinical feature and laboratory presentation of the asymptomatic hypercholanaemia of pregnancy(AHP).To establish the diagnosis model and biomarkers to diagnose AHP and differentiate AHP from intrahepatic cholestasis of pregnancy(ICP)based on the metabolic profiling of bile acids.Methods1.In this prospective,case-control study,55 cases of AHP,123 cases of ICP and 87 cases of normal pregnancies were recruited.Relevant clinical information was recorded,including age,parity,history of hypercholanemia and fetal outcome.2.Based on the method of validated ultrahigh performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry(UPLC-TripleTOF-MS/MS),26 kinds of known serum bile acids were quantified and 29 kinds of potential bile acids were identified and semiquantified.3.The partial least-squares discriminant analysis(PLS-DA)was performed to differentiate AHP,ICP and normal pregnancies based on the metabolic profiling of bile acids.PLS-DA model was used to diagnose AHP and distinguish AHP from ICP.4.Receiver operating characteristic curve analysis was performed to investigate the biomarkers to diagnose AHP.The diagnostic efficiencies of biomarkers and PLS-DA models were validated by an independent set of 64 individuals.5.Spearman correlation analysis and Logistic regression analysis was used to assess the association between bile acids indices and clinical features.Results1.The perinatal outcomes in AHP were better than that in ICP(P<0.05),but worse than that in normal pregnancies(P<0.05).2.AHP women had 43 and 27 kinds of individual bile acids significantly different from normal pregnancies and ICP patients,respectively(P<0.05).Glycine conjugated bile acids were predominant in AHP(52.8%),and the ratio of glycine conjugation / taurine conjugation in AHP was 1.75 fold-higher than that in ICP(P<0.05).3.Characteristic serum bile acids profiling in AHP,ICP and normal pregnancies were obtained from PLS-DA(R2=0.580,Q2=0.537),achieving the classification accuracies of 100% of controls,82.9% of AHP women and 78.9% of ICP patients,accounting for 87.5% of the total classification accuracy.In the validation set,the PLS-DA model had the total classification accuracy of 90.6% to discriminate the three groups.4.Glycolcholic acid(GCA)was the most effective to diagnose hypercholanaemia with the area under the ROC curve(AUC)of 0.971,a sensitivity of 87.5% and a specificity of 97.3%.A multiple logistic regression model was established,composed of four individual bile acids,which could differentiate AHP from ICP patients with the AUC of 0.971,a sensitivity of 97.8% and a specificity of 94.3%.These combined biomarkers were also effective for the differential diagnosis of AHP in the validation set with a sensitivity of 92.8% and a specificity of 90.0%.5.Tauro-?-muricholic acid(?-TMCA)may be the risk factor of cholestasis pruritus(adjusted odds ratio,1.319;1.205-1.445;p<0.001).The major indices in liver function tests such as direct bilirubin,total bilirubin,aspartate aminotransferase and alanine aminotransferase were strongly related to several individual bile acids(correlation coefficient>0.5,p<0.05).Conclusion:AHP women had a high risk of adverse fetal outcome.Serum bile acids profiling were different between AHP,ICP and normal pregnancies.Individual bile acids were effective in the diagnosis of AHP.Analysis of serum bile acids profiling helped to deepen the understanding of AHP and to provide important laboratory evidence for clinical practice.