Metabolic fingerprint of progression of chronic hepatitis B: changes in the metabolome and novel diagnostic possibilities

Abstract

Introduction

Chronic hepatitis B (CHB) affects 257 million individuals worldwide with an annual estimated mortality rate of 880,000 individuals. Accurate diagnosis of the stage of disease is difficult, and there is considerable uncertainty concerning the optimal point in time, when treatment should be started.

Objectives

By analyzing and comparing the metabolomes of patients at different stages of CHB and comparing them to healthy individuals, we want to determine the metabolic signature of disease progression and develop a more accurate metabolome-based method for diagnosis of disease progression ultimately giving a better basis for treatment decisions.

Methods

In this study, we used the combination of transient elastography and serum metabolomics of 307 serum samples from a group of 90 patients with CHB before and under treatment (with a follow-up time up to 10 years) at different progression stages over the clinical phases and 43 healthy controls..

Results

Our data show that the metabolomics approach can successfully discover CHB changing from the immune tolerance to the immune clearance phase and show distinctive metabolomes from different medical treatment stages. Perturbations in ammonia detoxification, glutamine and glutamate metabolism, methionine metabolism, dysregulation of branched-chain amino acids, and the tricarboxylic acid (TCA) cycle are the main factors involved in the progression of the disease. Fluctuations increasing in aspartate, glutamate, glutamine, methionine and 13 other metabolites are fingerprints of progression.

Conclusions

The metabolomics approach may expand the diagnostic armamentarium for patients with CHB. This method can provide a more detailed decision basis for starting medical treatment.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We wish to thank the laboratory technicians Anne Bentzen-Petersen and Camilla Rosenkilde Larsen for their help.

Funding

This work was funded by the Innovation Fund Denmark. The NMR laboratory at Aalborg University is supported by the Obel Family, SparNord and Carlsberg Foundations.

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Authors

Contributions

HTTN wrote the manuscript, contributed to study design, performed and analyzed samples with NMR, NMR data processing, statistical analysis and data interpretation. RW contributed to study design, NMR data analysis, data interpretation, and critical revision of the manuscript. VQL contributed to study design, statistical analysis, data analysis feature enhancement, debugging and code revising. HBK designed the study, clinical data advising, data interpretation, and critical revision of the manuscript.

Corresponding author

Correspondence to Henrik Bygum Krarup.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by The North Denmark Region Committee on Health Research Ethics (Protocol N-20120028: Liver fibrosis – A translational study on the mechanisms of hepatic fibrogenesis).

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Informed consent was obtained from all individual participants included in the study. All of the authors have read and approved the paper and it has not been published previously nor is it being considered by any other peer-reviewed journal.

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Nguyen, H.T.T., Wimmer, R., Le, V.Q. et al. Metabolic fingerprint of progression of chronic hepatitis B: changes in the metabolome and novel diagnostic possibilities. Metabolomics 17, 16 (2021). https://doi.org/10.1007/s11306-020-01767-y

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Keywords

  • Chronic hepatitis B
  • Liver fibrosis
  • FibroScan
  • Biomarker
  • Metabolomics
  • NMR