Studies on Novel Diagnostic and Predictive Biomarkers of Intrahepatic Cholestasis of Pregnancy Through Metabolomics and Proteomics

Abstract

BackgroundIntrahepatic cholestasis of pregnancy (ICP) usually occurs in the third trimester and is associated with increased risks in fetal complications. Currently, the exact mechanism of this disease is unknown. The purpose of this study was to develop potential biomarkers for the diagnosis and prediction of ICP.MethodsWe enrolled 40 pregnant women diagnosed with ICP and 40 healthy pregnant controls. The number of placental samples and serum samples between the two groups was 10 and 40 respectively. Ultra-performance liquid chromatography tandem high-resolution mass spectrometry was used to analyze placental metabolomics. Then, we verified the differentially expressed proteins and metabolites, both placental and blood serum, in the first, second, and third trimesters.ResultsMetabolomic analysis of placental tissue revealed that fatty acid metabolism and primary bile acid biosynthesis were enriched. In the integrated proteomic and metabolomic analysis of placental tissue, peroxisomal acyl-CoA oxidase 1 (ACOX1), L-palmitoylcarnitine, and glycocholic acid were found to be three potential biomarkers. In a follow–up analysis, expression levels of both placental and serum ACOX1, L-palmitoylcarnitine, and glycocholic acid in both placenta and serum were found to be significantly higher in third-trimester ICP patients; the areas under the ROC curves were 0.823, 0.896, and 0.985, respectively. Expression levels of serum ACOX1, L-palmitoylcarnitine, and glycocholic acid were also significantly higher in first- and second-trimester ICP patients; the areas under the ROC curves were 0.726, 0.657, and 0.686 in the first trimester and 0.718, 0.727, and 0.670 in the second trimester, respectively. Together, levels of the three aforementioned biomarkers increased the value for diagnosing and predicting ICP (AUC: 0.993 for the third, 0.891 for the second, and 0.932 for the first trimesters).ConclusionsL-palmitoylcarnitine, ACOX1, and glycocholic acid levels taken together may serve as a new biomarker set for the diagnosis and prediction of ICP.

Application of metabolomics in intrahepatic cholestasis of pregnancy: a systematic review

“…Five studies [ 9 , 13 , 15 , 16 , 18 ] evaluated the potential of metabolic biomarkers or biomarker panels to predict and diagnose ICP (Table 4 ). These studies all calculated the area under the receiver operating curve (AUC) of single metabolites, resulting AUC values ranging from 0.642 to 1.000.…”

“…Besides, Cui et al [ 9 ] and Zheng et al [ 18 ] both used bile acids panels to predict or diagnose ICP. Adding Complementary other biomarkers to bile acids was also shown to be effective in Dong et al and Ma et al’s studies [ 13 , 16 ]. In addition, Dong et al [ 13 ] indicated that metabolites at different stages of pregnancy had different predictive and diagnostic abilities.…”

“…In addition, Dong et al [ 13 ] indicated that metabolites at different stages of pregnancy had different predictive and diagnostic abilities.…”

Circulatory Metabolomics Reveals the Association of the Metabolites With Clinical Features in the Patients With Intrahepatic Cholestasis of Pregnancy

“…Notably, all metabolic pathways are interrelated and constitute a complicated metabolic network (Figure 10). Dong et al (2021) have recently shown the placental metabolomic profile in ICP patients, and demonstrated that fatty acid metabolism, primary bile acid synthesis, tryptophan metabolism, and arginine and proline metabolism are enriched. Interestingly, our study about the maternal circulatory metabolomic profile has revealed the enriched pathways including bile acid biosynthesis and secretion, fatty acid biosynthesis and lipid metabolism, and tryptophan metabolism and arginine and proline metabolism in ICP patients.…”

“…Using targeted metabolomics, Li et al (2018 ) have demonstrated that the urinary levels of sulfated bile acids (SBAs) are remarkably increased in ICP patients and the levels of glycine cholic acid 3-sulfate (GCA-3S) and sulfated dihydroxy glycine bile acid (di-GBA-S) are correlated with ICP severity, suggesting that these SBAs could be a potential biomarker for the diagnosis and grading of ICP. More recently, Dong et al ( Dong et al, 2021 ) have shown placental metabolomics in ICP patients. However, there are few studies regarding circulatory metabolomic profiles in ICP patients.…”