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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Bile acid indices as biomarkers for liver diseases I: Diagnostic markers
Jawaher Abdullah Alamoudi, Wenkuan Li, Nagsen Gautam, Marco Olivera, Jane Meza, Sandeep Mukherjee, Yazen Alnouti
Jawaher Abdullah Alamoudi, Wenkuan Li, Nagsen Gautam, Yazen Alnouti, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
Jawaher Abdullah Alamoudi, Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh 11564, Saudi Arabia
Marco Olivera, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
Jane Meza, Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States
Sandeep Mukherjee, Department of Internal Medicine, College of Medicine, Creighton University Medical Center, Omaha, NE 68124, United States
Author contributions: Alamoudi JA is the primary researcher, collected and analyzed data, wrote the manuscript, prepared figures and formatted manuscript for publication; Li W and Gautam N helped in the liquid chromatography-tandem mass spectrometry sample analysis; Meza J supervised, reviewed, and approved all statistical analysis and provided intellectual input and feedback on manuscript; Olivera M and Mukherjee S helped in recruiting and consenting patients and sample collection as well as experimental design; Alnouti Y is the primary investigator who was responsible for the experimental design and supervising all aspects of this project and manuscript preparation.
Supported by University of Nebraska Medical Center-Clinical Research Center and Great Plains Health Research Consortium; and Society of American Gastrointestinal and Endoscopic Surgeons, No. 36-5360-2186-001.
Institutional review board statement: The study was reviewed and approved by the University of Nebraska Medical Center Institutional Review Board (approval No. 487-10-EP).
Clinical trial registration statement: This study is registered at ClinicalTrials.gov. The registration identification number is NCT01200082.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that there is no conflict of interests in this study.
Data sharing statement: Technical appendix, statistical code, and data set available from the corresponding author at yalnouti@unmc.edu. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yazen Alnouti, PhD, Professor, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 557 S 42nd Street, Omaha, NE 68198, United States. yalnouti@unmc.edu
Received: January 5, 2021
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
BACKGROUND
Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis.
AIM
To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile.
METHODS
We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases.
RESULTS
Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases.
CONCLUSION
BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.
Core Tip: We have developed the concept of “bile acids (BA) indices” based on the detailed quantitative analysis of the urinary BA profile in patients with cholestatic liver diseases. We demonstrated the use of BA indices as diagnostic biomarkers for cholestatic liver diseases. BA indices had much lower inter- and intra-individual variability compared to absolute concentrations of the total and individual BA. In addition, 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.
