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Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome

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Abstract

Background

The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.

Methods

Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 μmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 μmol/L at the last follow-up.

Results

We found that the concentrations of two poly-hydroxylated bile acids, tauro‐2β,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro‐2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662–63.753), P = 0.002].

Conclusions

We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.

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Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files. And the primary data would be available on request from the authors.

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Acknowledgements

The authors are grateful for the support of the families we have studied, and would also like to thank the referring physicians, nurses, and technical staff. We thank Prof. Ying-Jie Zheng (yjzheng@fudan.edu.cn) as an independent statistician for his statistical guidance. This research was supported by the National Key Research and Development Program of China (Grant No. 2021YFC 2700800), the National Natural Science Foundation of China (81741056, 81873543), and the Natural Science Foundation of Shanghai (20YF1402900).

Funding

National Key Research and Development Program of China (No. 2021YFC 2,700,800 to J-S W. National Natural Science Foundation of China (No. 81741056 to WJS). National Natural Science Foundation of China (No. 81873543 to WJS). Natural Science Foundation of Shanghai (20YF1402900 to T L).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, 201508, China

    Meng-Xuan Wang & Jing-Yu Gong

  2. The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai, 201102, China

    Meng-Xuan Wang, Teng Liu, Li-Ting Li, Zhong-Die Li, Lang-Li Liu, Yi Lu, Xin-Bao Xie, Shi-Yu Li & Jian-She Wang

  3. University of Victoria-Genome BC Proteomics Centre and Division of Medical Sciences, Victoria, British Columbia, Canada

    Jun Han & Jun-Cong Yang

  4. BC Cancer Research Centre, Vancouver, British Columbia, Canada

    Ren-Xue Wang & Victor Ling

  5. Institutes of Biomedical Sciences, Fudan University, Shanghai, 201199, China

    Lei Zhang

  6. Shanghai Key Laboratory of Birth Defect, Shanghai, 201102, China

    Jian-She Wang

Authors
  1. Meng-Xuan Wang
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Contributions

WMX, HJ, and LT contributed equally to this paper. WMX: data curation, formal analysis, investigation, project administration, software, validation, visualization, writing–original draft. HJ: formal analysis, methodology, software, writing–review and editing. LT: conceptualization, funding acquisition, project administration. WRX: writing–review and editing. LLT: data curation. LZD: data curation. YJC: formal analysis, methodology. LLL: data curation. LY: data curation. XXB: data curation. GJY: data curation. LSY: data curation. ZL: formal analysis, methodology, software. LV: writing–review and editing. WJS: conceptualization, funding acquisition, project administration, supervision, writing–original draft, writing–review and editing.

Corresponding author

Correspondence to Jian-She Wang.

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Conflict of interest

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Ethical approval

The study was approved by the Ethics Committee of Children’s Hospital of Fudan University (Shanghai, China) (No. 2017-99) following the ethical standards of the institutional committee on human experimentation and with the Helsinki Declaration of 1964, as revised in 2000. Informed consent to participate in the study has been obtained from participants or their parent or legal guardian in the case of children under 16.

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Wang, MX., Han, J., Liu, T. et al. Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome. World J Pediatr 19, 652–662 (2023). https://doi.org/10.1007/s12519-022-00676-5

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