Endocrine

, Volume 43, Issue 2, pp 327–333 | Cite as

Concordance of the late night salivary cortisol in patients with Cushing’s syndrome and elevated urine-free cortisol

  • Suhail A. R. Doi
  • Justin Clark
  • Anthony W. Russell
Meta-Analysis

Abstract

The concordance of the late night salivary cortisol (LNSC) results with the 24-h urine-free cortisol (UFC) results in the biochemical screening for Cushing’s syndrome is unknown. We investigated this in a population of Cushing’s syndrome subjects. We used meta-analytic methods to pool proportions of LNSC-positive subjects from diagnostic evaluations of Cushing’s syndrome subjects where both tests were performed and the UFC was elevated (any level). Cushing’s syndrome was confirmed in all subjects by two out of three conventional tests. LNSC was collected between 22:00 to 24:00 h and measured around the same time period as the UFC. Minimum cutoffs of ≥4 and ≥10 nmol/L were used to determine concordance with the UFC and studies were limited to those that used radioimmunoassays or electrochemiluminiscence immunoassays for LNSC. The concordance of LNSC ≥4 nmol/L was 97 % (95 % CI 95–99 %) and studies were homogeneous. With LNSC ≥10 nmol/L, there was heterogeneity and two groups were discernible with a pooled concordance of 69 % (95 % CI 60–77 %) and 95 % (95 % CI 92–97 %). Within these sub-groups, studies were homogeneous and there was no difference between them in collection methods, assays used, geographic location, year of publication, or the quality of the underlying studies. The LNSC at a very specific cutoff detects at best 95 % of cases and at worst 69 % of cases of Cushing’s syndrome that are UFC positive. The two tests become equivalent at the more sensitive cutoff (>4 nmol/L). We conclude that, given its many benefits and the currently documented equivalence to the UFC, the LNSC should replace the conventional 24-h UFC as the frontline test when screening for Cushing’s syndrome.

Keywords

Late night salivary cortisol Cushing’s syndrome Diagnosis Screening 

References

  1. 1.
    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)PubMedCrossRefGoogle Scholar
  2. 2.
    H. Raff, Salivary cortisol and the diagnosis of Cushing’s syndrome: a coming of age. Endocrine 41, 353–354 (2012)PubMedCrossRefGoogle Scholar
  3. 3.
    T. Carroll, H. Raff, J.W. Findling, Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocr. Pract. 15, 335–342 (2009)PubMedCrossRefGoogle Scholar
  4. 4.
    M.B. Elamin, M.H. Murad, R. Mullan, D. Erickson, K. Harris, S. Nadeem, R. Ennis, P.J. Erwin, V.M. Montori, Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses. J. Clin. Endocrinol. Metab. 93, 1553–1562 (2008)PubMedCrossRefGoogle Scholar
  5. 5.
    K.I. Alexandraki, A.B. Grossman, Novel insights in the diagnosis of Cushing’s syndrome. Neuroendocrinology 92(Suppl 1), 35–43 (2010)PubMedCrossRefGoogle Scholar
  6. 6.
    B.A. Jonsson, B. Malmberg, A. Amilon, A. Helene Garde, P. Orbaek, Determination of cortisol in human saliva using liquid chromatography–electrospray tandem mass spectrometry. J. Chromatogr. B. 784, 63–68 (2003)CrossRefGoogle Scholar
  7. 7.
    W.J. Inder, G. Dimeski, A. Russell, Measurement of salivary cortisol in 2012-laboratory techniques and clinical indications. Clin. Endocrinol. (Oxf.) 77(5), 645–651 (2012)CrossRefGoogle Scholar
  8. 8.
    A. Leon-Justel, M.A. Mangas, R. Infante Fontan, J. Castro Luque, E. Venegas Moreno, A. Madrazo Atutxa, T. Herrera del Rey, J.F. Martin-Rodriguez, A. Soto-Moreno, A. Leal-Cerro, Budget impact of using midnight salivary cortisol in the diagnosis of hypercortisolism. Clin. Chim. Acta 412, 2248–2253 (2011)PubMedCrossRefGoogle Scholar
  9. 9.
    C.A. Carrasco, M. Garcia, M. Goycoolea, J. Cerda, J. Bertherat, O. Padilla, D. Meza, N. Wohllk, T. Quiroga, Reproducibility and performance of one or two samples of salivary cortisol in the diagnosis of Cushing’s syndrome using an automated immunoassay system. Endocrine 41, 487–493 (2012)PubMedCrossRefGoogle Scholar
  10. 10.
    C. Carrozza, S.M. Corsello, R.M. Paragliola, F. Ingraudo, S. Palumbo, P. Locantore, A. Sferrazza, A. Pontecorvi, C. Zuppi, Clinical accuracy of midnight salivary cortisol measured by automated electrochemiluminescence immunoassay method in Cushing’s syndrome. Ann. Clin. Biochem. 47, 228–232 (2010)PubMedCrossRefGoogle Scholar
  11. 11.
    E.M. Cardoso, A.L. Arregger, O.R. Tumilasci, L.N. Contreras, Diagnostic value of salivary cortisol in Cushing’s syndrome (CS). Clin. Endocrinol. (Oxf.) 70, 516–521 (2009)CrossRefGoogle Scholar
  12. 12.
    P.F. Whiting, M.E. Weswood, A.W. Rutjes, J.B. Reitsma, P.N. Bossuyt, J. Kleijnen, Evaluation of QUADAS, a tool for the quality assessment of diagnostic accuracy studies. BMC Med. Res. Methodol. 6, 9 (2006)PubMedCrossRefGoogle Scholar
  13. 13.
    B. Takkouche, C. Cadarso-Suarez, D. Spiegelman, Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis. Am. J. Epidemiol. 150, 206–215 (1999)PubMedCrossRefGoogle Scholar
  14. 14.
    S.A. Doi, J.J. Barendregt, A.A. Onitilo, Methods for the bias adjustment of meta-analyses of published observational studies. J. Eval. Clin. Pract. (2012). doi:10.1111/j.1365-2753.2012.01890.x PubMedGoogle Scholar
  15. 15.
    S.A. Doi, J.J. Barendregt, E.L. Mozurkewich, Meta-analysis of heterogenous clinical trials: an empirical example. Contemp. Clin. Trials 32, 288–298 (2011)PubMedCrossRefGoogle Scholar
  16. 16.
    H. Raff, J.L. Raff, J.W. Findling, Late-night salivary cortisol as a screening test for Cushing’s syndrome. J. Clin. Endocrinol. Metab. 83, 2681–2686 (1998)PubMedCrossRefGoogle Scholar
  17. 17.
    R.I. Gafni, D.A. Papanicolaou, L.K. Nieman, Nighttime salivary cortisol measurement as a simple, noninvasive, outpatient screening test for Cushing’s syndrome in children and adolescents. J. Pediatr. 137, 30–35 (2000)PubMedCrossRefGoogle Scholar
  18. 18.
    D.A. Papanicolaou, N. Mullen, I. Kyrou, L.K. Nieman, Nighttime salivary cortisol: a useful test for the diagnosis of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 87, 4515–4521 (2002)PubMedCrossRefGoogle Scholar
  19. 19.
    P. Putignano, P. Toja, A. Dubini, F. Pecori Giraldi, S.M. Corsello, F. Cavagnini, Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J. Clin. Endocrinol. Metab. 88, 4153–4157 (2003)PubMedCrossRefGoogle Scholar
  20. 20.
    M. Yaneva, H. Mosnier-Pudar, M.A. Dugue, S. Grabar, Y. Fulla, X. Bertagna, Midnight salivary cortisol for the initial diagnosis of Cushing’s syndrome of various causes. J. Clin. Endocrinol. Metab. 89, 3345–3351 (2004)PubMedCrossRefGoogle Scholar
  21. 21.
    A. Viardot, P. Huber, J.J. Puder, H. Zulewski, U. Keller, B. Muller, Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test. J. Clin. Endocrinol. Metab. 90, 5730–5736 (2005)PubMedCrossRefGoogle Scholar
  22. 22.
    C.A. Carrasco, J. Coste, L. Guignat, L. Groussin, M.A. Dugue, S. Gaillard, X. Bertagna, J. Bertherat, Midnight salivary cortisol determination for assessing the outcome of transsphenoidal surgery in Cushing’s disease. J. Clin. Endocrinol. Metab. 93, 4728–4734 (2008)PubMedCrossRefGoogle Scholar
  23. 23.
    M.L. Nunes, S. Vattaut, J.B. Corcuff, A. Rault, H. Loiseau, B. Gatta, N. Valli, L. Letenneur, A. Tabarin, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing’s syndrome in hospitalized and ambulatory patients. J. Clin. Endocrinol. Metab. 94, 456–462 (2009)PubMedCrossRefGoogle Scholar
  24. 24.
    L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, V.M. Montori, The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008)PubMedCrossRefGoogle Scholar
  25. 25.
    J. Newell-Price, X. Bertagna, A.B. Grossman, L.K. Nieman, Cushing’s syndrome. Lancet 367, 1605–1617 (2006)PubMedCrossRefGoogle Scholar
  26. 26.
    G. Beko, I. Varga, E. Glaz, M. Sereg, K. Feldman, M. Toth, K. Racz, A. Patocs, Cutoff values of midnight salivary cortisol for the diagnosis of overt hypercortisolism are highly influenced by methods. Clin. Chim. Acta 411, 364–367 (2010)PubMedCrossRefGoogle Scholar
  27. 27.
    Z.E. Belaya, A.V. Iljin, G.A. Melnichenko, L.Y. Rozhinskaya, N.V. Dragunova, L.K. Dzeranova, S.A. Butrova, E.A. Troshina, I.I. Dedov, Diagnostic performance of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay in obese and overweight patients referred to exclude Cushing’s syndrome. Endocrine 41, 494–500 (2012)PubMedCrossRefGoogle Scholar
  28. 28.
    C. Jung, J.T. Ho, D.J. Torpy, A. Rogers, M. Doogue, J.G. Lewis, R.J. Czajko, W.J. Inder, A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J. Clin. Endocrinol. Metab. 96, 1533–1540 (2011)PubMedCrossRefGoogle Scholar
  29. 29.
    D.A. Vassiliadi, S. Tsagarakis, Subclinical hypercortisolism: debatable or visible on the lightbox? Endocrine 42, 7–8 (2012)PubMedCrossRefGoogle Scholar
  30. 30.
    S. Tsagarakis, D. Vassiliadi, N. Thalassinos, Endogenous subclinical hypercortisolism: diagnostic uncertainties and clinical implications. J. Endocrinol. Invest. 29, 471–482 (2006)PubMedGoogle Scholar
  31. 31.
    S. Kidambi, H. Raff, J.W. Findling, Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur. J. Endocrinol. 157, 725–731 (2007)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Suhail A. R. Doi
    • 1
    • 3
  • Justin Clark
    • 2
  • Anthony W. Russell
    • 3
    • 4
  1. 1.School of Population Health, University of QueenslandBrisbaneAustralia
  2. 2.Research Computing Centre, University of QueenslandBrisbaneAustralia
  3. 3.Department of EndocrinologyPrincess Alexandra HospitalBrisbaneAustralia
  4. 4.School of Medicine, University of QueenslandBrisbaneAustralia

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