Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism

Abstract

Due to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing’s disease and Cushing’s disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.

Key words

Cushing’s syndrome - Cushing’s disease - late-night salivary cortisol - immunoassay

Publikationsverlauf

Eingereicht: 06. Mai 2021

Angenommen nach Revision: 13. August 2021

Artikel online veröffentlicht:
04. Oktober 2021

• References

• 1 Pivonello R, De Leo M, Cozzolino A. et al The treatment of Cushing’s disease. Endocr Rev 2015; 36: 385-486
• 2 Nieman LK, Biller BM, Findling JW. et al The diagnosis of Cushing’s syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
• 3 Abraham SB, Rubino D, Sinaii N. et al Cortisol, obesity, and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature. Obesity (Silver Spring, Md) 2013; 21: E105-E117
• 4 Kahn JP, Rubinow DR, Davis CL. et al Salivary cortisol: A practical method for evaluation of adrenal function. Biol Psychiatr 1988; 23: 335-349
• 5 Viardot A, Huber P, Puder JJ. et al 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 2005; 90: 5730-5736
• 6 Badrick E, Kirschbaum C, Kumari M. The relationship between smoking status and cortisol secretion. J Clin Endocrinol Metab 2007; 92: 819-824
• 7 Kivlighan KT, Granger DA, Schwartz EB. et al Quantifying blood leakage into the oral mucosa and its effects on the measurement of cortisol, dehydroepiandrosterone, and testosterone in saliva. Horm Behav 2004; 46: 39-46
• 8 Antonelli G, Ceccato F, Artusi C. et al Salivary cortisol and cortisone by LC-MS/MS: Validation, reference intervals and diagnostic accuracy in Cushing’s syndrome. Clin Chim Acta 2015; 451: 247-251
• 9 Papanicolaou DA, Mullen N, Kyrou I. et al Nighttime salivary cortisol: A useful test for the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 2002; 87: 4515-4521
• 10 Putignano P, Toja P, Dubini A. et al Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J Clin Endocrinol Metab 2003; 88: 4153-4157
• 11 Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing’s syndrome. J Clin Endocrinol Metab 1998; 83: 2681-2686
• 12 Aberle J, Schulze Zur WieschC, Flitsch J. et al Specificity of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay for Cushing’s disease in an obese population. J Endocrinol Invest 2018; 41: 1325-1331
• 13 Baid SK, Sinaii N, Wade M. et al Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: A comparison of assays to establish hypercortisolism. J Clin Endocrinol Metab 2007; 92: 3102-3107
• 14 Carroll T, Raff H, Findling JW. Late-night salivary cortisol measurement in the diagnosis of Cushing’s syndrome. Nat Clin Pract Endocrinol Metab 2008; 4: 344-350
• 15 Bäcklund N, Brattsand G, Israelsson M. et al Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing’s syndrome. Eur J Endocrinol 2020; 182: 569-582
• 16 Zerikly RK, Amiri L, Faiman C. et al Diagnostic characteristics of late-night salivary cortisol using liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2010; 95: 4555-4559
• 17 Mészáros K, Karvaly G, Márta Z. et al Diagnostic performance of a newly developed salivary cortisol and cortisone measurement using an LC-MS/MS method with simple and rapid sample preparation. J Endocrinol Invest 2018; 41: 315-323
• 18 Fassnacht M, Arlt W, Bancos I. et al Management of adrenal incidentalomas: European society of endocrinology clinical practice guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2016; 175: G1-G34
• 19 Lages AS, Frade JG, Oliveira D. et al Late-night salivary cortisol: cut-off definition and diagnostic accuracy for Cushing’s syndrome in a Portuguese population. Acta Med Portug 2019; 32: 381-387
• 20 Amlashi FG, Swearingen B, Faje AT. et al Accuracy of late-night salivary cortisol in evaluating postoperative remission and recurrence in Cushing’s disease. J Clin Endocrinol Metab 2015; 100: 3770-3777
• 21 Ceccato F, Marcelli G, Martino M. et al The diagnostic accuracy of increased late night salivary cortisol for Cushing’s syndrome: A real-life prospective study. J Endocrinol Invest 2019; 42: 327-335
• 22 Belaya ZE, Iljin AV, Melnichenko GA. et al Diagnostic performance of late-night salivary cortisol measured by automated electrochemiluminescence immunoassay in obese and overweight patients referred to exclude Cushing’s syndrome. Endocrine 2012; 41: 494-500
• 23 Carrasco CA, Coste J, Guignat L. et al Midnight salivary cortisol determination for assessing the outcome of transsphenoidal surgery in Cushing’s disease. J Clin Endocrinol Metab 2008; 93: 4728-4734
• 24 Ceccato F, Barbot M, Zilio M. et al Performance of salivary cortisol in the diagnosis of Cushing’s syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur J Endocrinol 2013; 169: 31-36
• 25 Erickson D, Singh RJ, Sathananthan A. et al Late-night salivary cortisol for diagnosis of Cushing’s syndrome by liquid chromatography/tandem mass spectrometry assay. Clin Endocrinol 2012; 76: 467-472
• 26 Sturmer LR, Dodd D, Chao CS. et al Clinical utility of an ultrasensitive late night salivary cortisol assay by tandem mass spectrometry. Steroids 2018; 129: 35-40
• 27 Raff H. Update on late-night salivary cortisol for the diagnosis of Cushing’s syndrome: methodological considerations. Endocrine 2013; 44: 346-349
• 28 Bäcklund N, Imamovic M, Brattsand G. et al Salivary cortisol and cortisone - effects of liquorice and blood contamination. Endocr Abst 2020; 70: AEP604
• 29 Brescia V, Cardinali R, Zecca C. et al Influence of blood contamination on the salivary cortisol level. Ital J Lab Med 2016; 12: 59-61
• 30 Raff H, Phillips JM. Bedtime salivary cortisol and cortisone by LC-MS/MS in healthy adult subjects: evaluation of sampling time. J Endocr Soc 2019; 3: 1631-1640
• 31 Sandouk Z, Johnston P, Bunch D. et al Variability of late-night salivary cortisol in Cushing disease: a prospective study. J Clin Endocrinol Metab 2018; 103: 983-990
• 32 Petersenn S, Newell-Price J, Findling JW. et al High variability in baseline urinary free cortisol values in patients with Cushing’s disease. Clin Endocrinol 2014; 80: 261-269
• 33 Wajchenberg BL, Mendonça B, Liberman B. et al Ectopic ACTH syndrome. J Steroid Biochem Mol Biol 1995; 53: 139-151
• 34 Schoorlemmer RM, Peeters GM, van Schoor NM. et al Relationships between cortisol level, mortality and chronic diseases in older persons. Clin Endocrinol 2009; 71: 779-786
• 35 Melin EO, Hillman M, Landin-Olsson M. Midnight salivary cortisol secretion associated with high systolic blood pressure in type 1 diabetes. Endocr Connect 2019; 8: 1520-1528
• 36 Filipovský J, Ducimetiére P, Eschwége E. et al The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men. J Hypertens 1996; 14: 229-235
• 37 Repetto EM, Gonzalez D, Jacobsen D. et al Evaluation of an automated chemiluminescent immunoassay for salivary cortisol measurement. Utility in the diagnosis of Cushing’s syndrome. Clin Chem Lab Med 2017; 55: e65-e68
• 38 Montskó G, Tarjányi Z, Mezősi E. et al A validated method for measurement of serum total, serum free, and salivary cortisol, using high-performance liquid chromatography coupled with high-resolution ESI-TOF mass spectrometry. Anal Bioanal Chem 2014; 406: 2333-2341
• 39 Bianco AC, Anderson G, Forrest D. et al American thyroid association guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 2014; 24: 88-168
• 40 Elias PCL, Martinez EZ, Barone BFC. et al Late-night salivary cortisol has a better performance than urinay free cortisol in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 2014; 99: 2045-2051
• 41 Baid SK, Sinaii N, Wade M. et al Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: A comparison of assays to establish hypercortisolism. J Clin Endocrinol Metab 2007; 92: 3102-3107
• 42 Klee GG. Interferences in hormone immunoassays. Clin Lab Med 2004; 24: 1-18
• 43 Monaghan PJ, Keevil BG, Trainer PJ. The use of mass spectrometry to improve the diagnosis and the management of the HPA axis. Rev Endocr Metab Disord 2013; 14: 143-157
• 44 Blair J, Adaway J, Keevil B. et al Salivary cortisol and cortisone in the clinical setting. Curr Opin Endocrinol Diabetes Obes 2017; 24: 161-168
• 45 Perogamvros I, Keevil BG, Ray DW. et al Salivary cortisone is a potential biomarker for serum free cortisol. J Clin Endocrinol Metab 2010; 95: 4951-4958
• 46 Bakusic J, De Nys S, Creta M. et al Study of temporal variability of salivary cortisol and cortisone by LC-MS/MS using a new atmospheric pressure ionization source. Sci Rep 2019; 9: 19313
• 47 Kannankeril J, Carroll T, Findling JW. et al Prospective evaluation of late-night salivary cortisol and cortisone by EIA and LC-MS/MS in suspected Cushing syndrome. J Endocr Soc 2020; 4: bvaa107
• 48 Monaghan PJ, Owen LJ, Trainer PJ. et al Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone. Ann Clin Biochem 2011; 48: 441-446
• 49 Raff H, Singh RJ. Measurement of late-night salivary cortisol and cortisone by LC-MS/MS to assess preanalytical sample contamination with topical hydrocortisone. Clin Chem 2012; 58: 947-948