Published online Apr 27, 2021. doi: 10.4254/wjh.v13.i4.433
Peer-review started: January 5, 2021
First decision: January 25, 2021
Revised: February 11, 2021
Accepted: March 22, 2021
Article in press: March 22, 2021
Published online: April 27, 2021
Bile acids (BA) have been extensively investigated for decades as biomarkers for numerous hepatobiliary diseases. However, these efforts never translated into a widespread in the clinic, due to the extreme inter-and intra-individual variability of total and individual BA concentrations and the marked differences in the physiological and pathological properties of the different individual BA. To this end, we have developed the concept of “BA indices”, which demonstrated their use as diagnostic biomarkers for cholestatic liver diseases.
Biomarkers currently used in the clinic are not specific to the liver or bile duct injurie. BA were extensively investigated for decades as biomarkers for numerous hepatobiliary diseases. This could be attributed to the marked differences in the physiological and pathological properties of the different individual BA. BA indices have much lower variability than the absolute BA concentrations used to calculate them. Indeed, we have demonstrated that BA indices offered numerous advantages over absolute total and individual BA concentrations including low inter- and intra-individual variability and were resistant to covariate influences such as age, gender, body mass index, food consumption, and moderate alcohol consumption.
The objective of this project was to discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. We have developed the concept of “BA indices”, which are ratios calculated from the absolute concentrations of individual BA and their metabolites. BA indices have much lower variability than the absolute BA concentrations used to calculate them, which enabled their use as diagnostic biomarkers for cholestatic liver diseases.
We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between patients with hepatobiliary diseases vs healthy controls by statistical analysis (independent sample-t-test, Mann-Whitney test, Mixed effects models, by pairwise comparisons using Bonferroni’s adjustment, receiver operating characteristic curve analyses, Univariate and multivariate logistic regression analysis).
The results of this study demonstrated that total and all individual BA increased in patients with 11 different cholestatic diseases. However, the high inter-individual variability of BA absolute concentrations makes most of them statistically insignificant and prevent their utilization as diagnostic markers. In contrast, BA indices had much lower inter- and intra-individual variability, which allowed their use as diagnostic and prognostic markers for liver diseases. Furthermore, we have shown that several BA indices outperformed non-BA markers, currently used in the clinic, as diagnostic markers to differentiate our patient pool as well as individual cholestatic diseases against healthy controls.
BA indices demonstrated high area under the receiver operating characteristic curves, and changes of BA indices were associated with the risk of having a liver disease as determined by the logistic regression analysis, which demonstrated their use as diagnostic biomarkers for cholestatic liver diseases.
We have developed survival models based on BA indices to predict the prognosis of hepatobiliary diseases which is illustrated in the second paper of this series.