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An untargeted metabolomics approach to evaluate enzymatically deconjugated steroids and intact steroid conjugates in urine as diagnostic biomarkers for adrenal tumors

  • Nora Vogg ORCID logo EMAIL logo , Eleanor North , Arne Gessner ORCID logo , Felix Fels , Markus R. Heinrich , Matthias Kroiss , Max Kurlbaum ORCID logo , Martin Fassnacht and Martin F. Fromm ORCID logo
Published/Copyright: January 7, 2025
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 63 Issue 5

Abstract

Objectives

Urinary steroid profiling after hydrolysis of conjugates is an emerging tool to differentiate aggressive adrenocortical carcinomas (ACC) from benign adrenocortical adenomas (ACA). However, the shortcomings of deconjugation are the lack of standardized and fully validated hydrolysis protocols and the loss of information about the originally conjugated form of the steroids. This study aimed to evaluate the quality of the deconjugation process and investigate novel diagnostic biomarkers in urine without enzymatic hydrolysis.

Methods

24 h urine samples from 40 patients with ACC and 40 patients with ACA were analyzed by untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry both unmodified and after hydrolysis with arylsulfatase/glucuronidase from Helix pomatia. Both approaches were compared regarding the differentiation of ACC vs. ACA via ROC analyses and to evaluate the hydrolyzation efficiency of steroid conjugates.

Results

Steroid glucuronides were fully deconjugated, while some disulfates and all monosulfates were still largely detectable after enzymatic hydrolysis, suggesting incomplete and variable deconjugation. In unhydrolyzed urine, steroid monosulfates showed the best differentiation between ACC and ACA (highest AUC=0.983 for C21H32O6S, followed by its isomer and two isomers with the molecular formula C21H32O7S). Moreover, several disulfates were highly abundant and increased in ACC compared to ACA.

Conclusions

This work highlights the limitations of hydrolyzing steroid conjugates before analysis and shows a possible superiority of a direct analysis approach compared to a hydrolysis approach from a methodological point of view and regarding diagnostic accuracy. Several steroid conjugates were found as promising diagnostic biomarkers for differentiation between ACC and ACA.

Keywords: adrenocortical adenoma; adrenocortical carcinoma; enzymatic hydrolysis; LC-MS; mass spectrometry; conjugated steroids
Corresponding author: Nora Vogg, PhD, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany, E-mail:

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: 314061271

Award Identifier / Grant number: INST 90/1048-1 FUGG

Funding source: Interdisciplinary Center for Clinical Research (IZKF), University Hospital Erlangen

Award Identifier / Grant number: J115

Award Identifier / Grant number: P134

  1. Research ethics: This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and has been approved by the Ethics Committee of the Julius-Maximilians University Würzburg and the Ethics Committee of the Friedrich-Alexander Universität Erlangen-Nürnberg.

  2. Informed consent: Informed consent was obtained from all individuals included in this study.

  3. Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: This study was funded by the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg (ELAN pilot project P134 and junior project J115). It was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (CRC/Transregio 205/2). The Orbitrap mass spectrometer was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – INST 90/1048-1 FUGG.

  7. Data availability: The raw data can be obtained on reasonable request from the corresponding author.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2024-1337).

Received: 2024-09-17
Accepted: 2024-12-19
Published Online: 2025-01-07
Published in Print: 2025-04-28

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2024-1337
Keywords for this article
adrenocortical adenoma; adrenocortical carcinoma; enzymatic hydrolysis; LC-MS; mass spectrometry; conjugated steroids

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Are the benefits of External Quality Assessment (EQA) recognized beyond the echo chamber?
  4. Reviews
  5. Behind the scenes of EQA – characteristics, capabilities, benefits and assets of external quality assessment (EQA): Part I – EQA in general and EQA programs in particular
  6. Behind the scenes of EQA – characteristics, capabilities, benefits and assets of external quality assessment (EQA): Part II – EQA cycles
  7. Behind the scenes of EQA – characteristics, capabilities, benefits and assets of external quality assessment (EQA): Part III – EQA samples
  8. Behind the scenes of EQA–characteristics, capabilities, benefits and assets of external quality assessment (EQA): Part IV – Benefits for participant laboratories
  9. Behind the scenes of EQA – characteristics, capabilities, benefits and assets of external quality assessment (EQA): Part V – Benefits for stakeholders other than participants
  10. Opinion Papers
  11. Not all biases are created equal: how to deal with bias on laboratory measurements
  12. Krebs von den Lungen-6 (KL-6) as a diagnostic and prognostic biomarker for non-neoplastic lung diseases
  13. General Clinical Chemistry and Laboratory Medicine
  14. Evaluation of performance in preanalytical phase EQA: can laboratories mitigate common pitfalls?
  15. Point-of-care testing improves care timeliness in the emergency department. A multicenter randomized clinical trial (study POCTUR)
  16. The different serum albumin assays influence calcium status in haemodialysis patients: a comparative study against free calcium as a reference method
  17. Measurement of 1,25-dihydroxyvitamin D in serum by LC-MS/MS compared to immunoassay reveals inconsistent agreement in paediatric samples
  18. Knowledge among clinical personnel on the impact of hemolysis using blood gas analyzers
  19. Quality indicators for urine sample contamination: can squamous epithelial cells and bacteria count be used to identify properly collected samples?
  20. Reference Values and Biological Variations
  21. Biological variation of cardiac biomarkers in athletes during an entire sport season
  22. Increased specificity of the “GFAP/UCH-L1” mTBI rule-out test by age dependent cut-offs
  23. Cancer Diagnostics
  24. An untargeted metabolomics approach to evaluate enzymatically deconjugated steroids and intact steroid conjugates in urine as diagnostic biomarkers for adrenal tumors
  25. Cardiovascular Diseases
  26. Comparative evaluation of peptide vs. protein-based calibration for quantification of cardiac troponin I using ID-LC-MS/MS
  27. Infectious Diseases
  28. The potential role of leukocytes cell population data (CPD) for diagnosing sepsis in adult patients admitted to the intensive care unit
  29. Letters to the Editor
  30. Concentrations and agreement over 10 years with different assay versions and analyzers for troponin T and N-terminal pro-B-type natriuretic peptide
  31. Does blood tube filling influence the Athlete Biological Passport variables?
  32. Influence of data visualisations on laboratorians’ acceptance of method comparison studies
  33. An appeal for biological variation estimates in deep immunophenotyping
  34. Serum free light chains reference intervals for the Lebanese population
  35. Applying the likelihood ratio concept in external quality assessment for ANCA
  36. A promising new direct immunoassay for urinary free cortisol determination
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