Skip to main content

Advertisement

SpringerLink
Log in

Urinary free cortisol is a reliable index of adrenal cortisol production in patients with liver cirrhosis

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Background

The measurement of total and free cortisol has been studied as a clinical index of adrenal cortisol production in patients with liver cirrhosis. Correlations between free plasma and salivary cortisol have previously been reported in stable cirrhotic patients. Urinary free cortisol constitutes an index of adrenal cortisol production; however, it has never been used in assessing adrenal function in patients with liver cirrhosis.

Aims

The aim of this observational study was to determine associations between urinary free cortisol, serum total, salivary, measured and calculated plasma free cortisol levels in cirrhotics, determining which of them can be used as an indirect index of free cortisol levels. Moreover, we investigated the potential use of 24 h urinary free cortisol as a prognostic factor for mortality.

Methods

Seventy-eight outpatients with liver cirrhosis were included. Serum, salivary and urinary free cortisol were measured using the electrochemiluminenscence immunoassay. Plasma free cortisol determination was conducted using a single quadrupole mass spectrometer. The quantification of free cortisol was achieved by determining the signal response on negative ESI-MS mode.

Results

Twenty-four hour urinary free cortisol levels correlated with free cortisol determined by mass spectrometer, total cortisol and calculated free cortisol levels. Patients with low levels of urinary free cortisol presented a significantly higher mortality rate compared to those with high levels. The factors associated with death risk were determined by Cox regression. In the multivariate analysis, two models were applied; in the first model, CP score, PVT and urinary free cortisol were found to be significantly related to patients’ survival, whereas in the second, MELD score, ascites and urinary free cortisol were independently related to survival.

Conclusions

This study suggests that 24 h urinary free cortisol could be considered as a potential index of adrenal cortisol production in patients with liver cirrhosis and it potentially detects patients with a high mortality risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. L. Thau, J. Gandhi, S. Sharma, Physiology, Cortisol In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, (2022)

  2. R.H. Oakley, J.A. Cidlowski, The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J. Allergy Clin. Immunol. 132, 1033–1044 (2013)

    Article  CAS  Google Scholar 

  3. D.C. Aron, Basic and Clinical Endocrinology. F.S.A.G.D.G. Greenspan (Ed.), Glucocorticoids and Adrenal Androgens, Vol. 6, New York: Lange Medical Books/McGraw-Hill (2001), pp. 334–376

  4. R.R. Singh, R. Walia, N. Sachdeva et al. Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome). Dig. Liver Dis. 50, 1232–1237 (2018)

    Article  Google Scholar 

  5. A. Pazderska, S.H. Pearce, Adrenal insufficiency–recognition and management. Clin. Med. 17, 258 (2017)

    Article  Google Scholar 

  6. J.S. Davidson, M.J. Bolland, M.S. Croxson et al. A case of low cortisol-binding globulin: use of plasma free cortisol in interpretation of hypothalamic-pituitary-adrenal axis tests. Ann. Clin. Biochem. 43, 237–239 (2006)

    Article  CAS  Google Scholar 

  7. U. Mueller, J.M. Potter, Binding of cortisol to human albumin and serum: the effect of protein concentration. Biochem. Pharm. 30, 727–733 (1981)

    Article  CAS  Google Scholar 

  8. J.F. Dunn, B.C. Nisula, D. Rodbard, Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J. Clin. Endocrinol. Metab. 53, 58–68 (1981)

    Article  CAS  Google Scholar 

  9. R. Ekins, Measurement of free hormones in blood. Endocr. Rev. 11, 5–46 (1990)

    Article  CAS  Google Scholar 

  10. C.M. Mendel, M.B. Miller, P.K. Siiteri et al. Rates of dissociation of steroid and thyroid hormones from human serum albumin. J. Steroid Biochem. Mol. Biol. 37, 245–250 (1990)

    Article  CAS  Google Scholar 

  11. R.P. Dellinger, M.M. Levy, J.M. Carlet et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 36, 296–327 (2008)

    Article  Google Scholar 

  12. P.E. Marik, S.M. Pastores, D. Annane et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit. Care Med. 36, 1937–1949 (2008)

    Article  CAS  Google Scholar 

  13. S. Tunn, H. Möllmann, J. Barth et al. Simultaneous measurement of cortisol in serum and saliva after different forms of cortisol administration. Clin. Chem. 38, 1491–1494 (1992)

    Article  CAS  Google Scholar 

  14. U. Teruhisa, H. Ryoji, I. Taisuke et al. Use of saliva for monitoring unbound free cortisol levels in serum. Clin. Chim. Acta 110, 245–253 (1981)

    Article  Google Scholar 

  15. G. Read, R. Walker, D. Wilson et al. Steroid analysis in saliva for the assessment of endocrine function. Ann. NY Acad. Sci. 595, 260–274 (1990)

    Article  CAS  Google Scholar 

  16. B.M. Arafah, F.J. Nishiyama, H. Tlaygeh et al. Measurement of salivary cortisol concentration in the assessment of adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol. J. Clin. Endocrinol. Metab. 92, 2965–2971 (2007)

    Article  CAS  Google Scholar 

  17. E. Cardoso, G. Persi, N. González et al. Assessment of adrenal function by measurement of salivary steroids in response to corticotrophin in patients infected with human immunodeficiency virus. Steroids 72, 328–334 (2007)

    Article  CAS  Google Scholar 

  18. E. Aardal-Eriksson, B.E. Karlberg, A.-C. Holm, Salivary cortisol-an alternative to serum cortisol determinations in dynamic function tests. Clin. Chem. Lab Med. 36, 215–222 (1998)

    Article  CAS  Google Scholar 

  19. N. Kamodyová, L. Baňasová, K. Janšáková, et al. Blood contamination in saliva: impact on the measurement of salivary oxidative stress markers. Dis. Markers. 2015, 479251 (2015)

  20. T. Thevenot, S. Borot, A. Remy‐Martin et al. Assessment of adrenal function in cirrhotic patients using concentration of serum‐free and salivary cortisol. Liver Int. 31, 425–433 (2011)

    Article  CAS  Google Scholar 

  21. K.I. Alexandraki, A.B. Grossman, Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome? Curr. Opin. Endocrinol. Diabetes Obes. 18, 259–263 (2011)

    Article  CAS  Google Scholar 

  22. G. Fede, L. Spadaro, T. Tomaselli et al. Assessment of adrenocortical reserve in stable patients with cirrhosis. J. Hepatol. 54, 243–250 (2011)

    Article  Google Scholar 

  23. A. Galbois, M. Rudler, J. Massard et al. Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred. J. Hepatol. 52, 839–845 (2010)

    Article  CAS  Google Scholar 

  24. R. de Franchis, Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J. Hepatol. 63, 743–752 (2015)

    Article  Google Scholar 

  25. G. Garcia-Tsao, J.G. Abraldes, A. Berzigotti et al. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 65, 310–335 (2017)

    Article  Google Scholar 

  26. G. Garcia-Tsao, J. Lim; Program VAHCRC, Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am. J. Gastroenterol. 104, 1802–1829 (2009)

    Article  Google Scholar 

  27. J. Wiegand, T. Berg, The etiology, diagnosis and prevention of liver cirrhosis: part 1 of a series on liver cirrhosis. Dtsch. Arztebl. Int. 110, 85–91 (2013)

    PubMed  PubMed Central  Google Scholar 

  28. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol. 69, 406–460 (2018)

  29. W. De Keyzer, I. Huybrechts, A.L.M. Dekkers et al. Predicting urinary creatinine excretion and its usefulness to identify incomplete 24 h urine collections. Br. J. Nutr. 108, 1118–1125 (2012)

    Article  Google Scholar 

  30. L. Wood, D.H. Ducroq, H.L. Fraser et al. Measurement of urinary free cortisol by tandem mass spectrometry and comparison with results obtained by gas chromatography-mass spectrometry and two commercial immunoassays. Ann. Clin. Biochem. 45, 380–388 (2008)

    Article  CAS  Google Scholar 

  31. A. Trifan, S. Chiriac, C. Stanciu, Update on adrenal insufficiency in patients with liver cirrhosis. World J. Gastroenterol. 19, 445–456 (2013)

    Article  Google Scholar 

  32. R. Chawlani, A. Arora, P. Ranjan et al. Adrenal insufficiency predicts early mortality in patients with cirrhosis. U. Eur. Gastroenterol. J. 3, 529–538 (2015)

    Article  CAS  Google Scholar 

  33. J. Ho, H. Al-Musalhi, M. Chapman et al. Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J. Clin. Endocrinol. Metab. 91, 105–114 (2006)

    Article  CAS  Google Scholar 

  34. J.-L. Coolens, H. Van Baelen, W. Heyns, Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J. Steroid Biochem. 26, 197–202 (1987)

    Article  CAS  Google Scholar 

  35. T. Thevenot, S. Borot, A. Remy-Martin et al. Assessing adrenal function in cirrhotic patients: is there a reliable test? Gastroenterol. Clin. Biol. 33, 584–588 (2009)

    Article  CAS  Google Scholar 

  36. N.C. Nicolaides, G.P. Chrousos, E. Charmandari, Adrenal insufficiency (2015)

  37. L.K. Nieman, B.M. Biller, J.W. Findling et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008)

    Article  CAS  Google Scholar 

  38. C. Jung, S. Greco, H.H. Nguyen et al. Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers. BMC Endocr. Disord. 14, 91 (2014)

    Article  Google Scholar 

  39. K.I. Alexandraki, A.B. Grossman, Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome? Curr. Opin. Endocrinol. Diabetes Obes. 18, 259–263 (2011)

    Article  CAS  Google Scholar 

  40. T. Tan, L. Chang, A. Woodward et al. Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J. Hepatol. 53, 841–848 (2010)

    Article  CAS  Google Scholar 

  41. G. Fede, L. Spadaro, T. Tomaselli et al. Comparison of total cortisol, free cortisol, and surrogate markers of free cortisol in diagnosis of adrenal insufficiency in patients with stable cirrhosis. Clin. Gastroenterol. Hepatol. 12, 504–512. e508 (2014)

    Article  CAS  Google Scholar 

  42. J. Acevedo, J. Fernández, V. Prado et al. Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death. Hepatology 58, 1757–1765 (2013)

    Article  CAS  Google Scholar 

  43. T. Thevenot, R. Dorin, E. Monnet et al. High serum levels of free cortisol indicate severity of cirrhosis in hemodynamically stable patients. J. Gastroenterol. Hepatol. 27, 1596–1601 (2012)

    Article  CAS  Google Scholar 

  44. P.E. Marik, Adrenal-exhaustion syndrome in patients with liver disease. Intensive Care Med. 32, 275–280 (2006)

    Article  Google Scholar 

Download references

Funding

This work has been supported by “Hellenic Association for the Study of the Liver”.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece

    Maria Michailidou, Ioanna Aggeletopoulou, Konstantinos Zisimopoulos, Efthymios P. Tsounis, Katerina Karaivazoglou, Evanthia Tourkochristou, Georgia Diamantopoulou, Konstantinos Thomopoulos & Christos Triantos

  2. Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Maria Kouskoura, Nikolaos Koutras & Catherine K. Markopoulou

  3. Department of Biochemistry, University Hospital of Patras, Patras, Greece

    Martha Mandellou

  4. Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Internal Medicine, University of Patras, Patras, Greece

    Marina Michalaki

  5. Department of Internal Medicine, University Hospital of Patras, Patras, Greece

    Charalampos Gogos & Dimitrios Velissaris

Authors
  1. Maria Michailidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ioanna Aggeletopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Kouskoura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Konstantinos Zisimopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Efthymios P. Tsounis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katerina Karaivazoglou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evanthia Tourkochristou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martha Mandellou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Georgia Diamantopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nikolaos Koutras
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marina Michalaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Charalampos Gogos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dimitrios Velissaris
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Catherine K. Markopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Konstantinos Thomopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christos Triantos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. Michailidou: acquisition of data and analysis and interpretation of data; I.A.: acquisition of data, analysis and interpretation of data, and drafting of the manuscript; M.K. and K.Z.: acquisition of data and analysis and interpretation of data; E.P.T. and K.K.: analysis and interpretation of data, statistical analysis; E.T.: analysis and interpretation of data; M. Mandellou and G.D.: acquisition of data; N.K.: analysis of data; M. Michalaki, C.G., D.V., C.K.M., and K.T.: analysis and interpretation of data, critical revision of the manuscript for important intellectual content; C.T.: study concept and design, drafting of the manuscript, critical revision of the manuscript for important intellectual content, final approval of the version to be published. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.

Corresponding author

Correspondence to Christos Triantos.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

All study participants, or their legal guardian, provided informed written consent prior to study enrollment. The study protocol was reviewed and approved by the Ethics committee of the University Hospital of Patras. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki for medical research involving human subjects. All the experiments were performed in accordance with relevant guidelines and regulations of the concerned Ethics committee.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Michailidou, M., Aggeletopoulou, I., Kouskoura, M. et al. Urinary free cortisol is a reliable index of adrenal cortisol production in patients with liver cirrhosis. Endocrine 76, 697–708 (2022). https://doi.org/10.1007/s12020-022-03055-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-022-03055-2

Keywords

Search

Navigation