Scalp hair cortisol for diagnosis of Cushing’s syndrome

Objective Current first-line screening tests for Cushing’s syndrome (CS) only measure time-point or short-term cortisol. Hair cortisol content (HCC) offers a non-invasive way to measure long-term cortisol exposure over several months of time. We aimed to evaluate HCC as a screening tool for CS. Design Case-control study in two academic referral centers for CS. Methods Between 2009 and 2016, we collected scalp hair from patients suspected of CS and healthy controls. HCC was measured using ELISA. HCC was available in 43 confirmed CS patients, 35 patients in whom the diagnosis CS was rejected during diagnostic work-up and follow-up (patient controls), and 174 healthy controls. Additionally, we created HCC timelines in two patients with ectopic CS. Results CS patients had higher HCC than patient controls and healthy controls (geometric mean 106.9 vs 12.7 and 8.4 pg/mg respectively, P < 0.001). At a cut-off of 31.1 pg/mg, HCC could differentiate between CS patients and healthy controls with a sensitivity of 93% and a specificity of 90%. With patient controls as a reference, specificity remained the same (91%). Within CS patients, HCC correlated significantly with urinary free cortisol (r = 0.691, P < 0.001). In two ectopic CS patients, HCC timelines indicated that cortisol was increased 3 and 6 months before CS became clinically apparent. Conclusions Analysis of cortisol in a single scalp hair sample offers diagnostic accuracy for CS similar to currently used first-line tests, and can be used to investigate cortisol exposure in CS patients months to years back in time, enabling the estimation of disease onset.

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First-line screening tests for Cushing’s syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS

Journal of Endocrinological Investigation ◽

10.1007/s40618-017-0644-8 ◽

2017 ◽

Vol 40 (7) ◽

pp. 753-760 ◽

Cited By ~ 14

Author(s):

F. Ceccato ◽

G. Antonelli ◽

A. C. Frigo ◽

D. Regazzo ◽

M. Plebani ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Adrenal Incidentaloma ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Screening Tests ◽

First Line ◽

Free Cortisol

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Screening and diagnosis of Cushing's syndrome

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000800004 ◽

2007 ◽

Vol 51 (8) ◽

pp. 1191-1198 ◽

Cited By ~ 17

Author(s):

Margaret de Castro ◽

Ayrton C. Moreira

Keyword(s):

Cushing’S Syndrome ◽

Salivary Cortisol ◽

Linear Growth ◽

Fat Distribution ◽

Cushing's Syndrome ◽

First Line ◽

Late Night ◽

Late Night Salivary Cortisol ◽

Free Cortisol ◽

Pituitary Adrenal Axis

Cushing's syndrome (CS) results from sustained pathologic hypercortisolism. The clinical features are variable and the most specific features for CS include abnormal fat distribution, particularly in the supraclavicular and temporal fossae, proximal muscle weakness, wide purple striae, and decreased linear growth with continued weight gain in a child. Clinical presentation of CS can be florid and in this case the diagnosis is usually straightforward. However, the diagnosis can be difficult particularly in states of mild or cyclical or periodical hypercortisolism. Several tests based on the understanding of the physiologic characteristics of the hypothalamic-pituitary-adrenal axis have been used extensively to confirm the diagnosis of Cushing's syndrome, but none has proven fully capable of distinguishing all cases of CS from normal and/or pseudo-Cushing individuals. Three first-line diagnostic tests are currently used to screen for CS: measurement of free cortisol in 24-hour urine (UFC), cortisol suppressibility by low doses of dexamethasone (DST), and assessment of cortisol circadian rhythm using late-night serum and/or salivary cortisol. This paper discusses the effectiveness regarding best cut-off values, the sensitivity and the specificity of these tests to screen for CS. Late-night salivary cortisol appears to be the most useful screening test. UFC and DST should be performed to provide further confirmation of the diagnosis.

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SUN-LB34 A Case of BMAH With Aberrant Vasopressin Adrenal Receptors

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2272 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Faheem Seedat ◽

Nazeer Ahmed Mohamed ◽

Nereshni Lutchman

Keyword(s):

Cushing’S Syndrome ◽

Salivary Cortisol ◽

Incidental Finding ◽

Serum Cortisol ◽

Cushing's Syndrome ◽

Screening Tests ◽

Pathological Examination ◽

Unilateral Adrenalectomy ◽

Urine Free Cortisol ◽

Free Cortisol

Abstract We report on a 42 - year old woman was referred following an incidental finding of bilateral macronodular (nodules > 1cm) adrenal glands after a computed tomography scan for investigation of an unrelated urological problem. Clear features of Cushing’s syndrome were elicited on initial clincal evaluation and screening tests confirmed the diagnosis biochemically: midnight salivary cortisol 15.4nmol/L (0.2 - 3nmol/L), 24 hour urine free cortisol > 662.4nmol/L (8.3 - 118.7nmol/L per 24 hours) and an 8am serum cortisol measured 951nmol/L following 1mg dexamethasone suppression test (< 50nm/L). A serum adrenocorticotropic hormone (ACTH) measured 0.3pmol/L (1.6 - 13.9pmol/L) suggesting, in light of the CT findings, an adrenal source of the elevated cortisol. Screening for aberrant adrenal receptors to catecholamines, Gastric inhibitory peptide, ACTH, vasopressin and Gonadotropin releasing hormone was performed. A positive biochemical response to ACTH and vasopressin was noted as measured serum cortisol increased to 1600pmol/L (upper limit of the assay). Following a unilateral adrenalectomy, were pathological examination of the respected adrenal gland confirmed adrenal hyperplasia, the patient had both clinical and biochemical resolution of hypercortisolemia. 2 weeks following surgery her midnight salivary cortisol measured 2.1nmol/L (0.2 - 3nmol/L) and 24 hour urine free cortisol 218nmol/L (8.3 - 118.7nmol/L per 24 hours). Her 8am ACTH also increased to 2.9pmol/L (1.6 - 13.9pmol/L). Biochemical screening of her sister showed no evidence of Cushing’s syndrome. Bilateral macronodualr hyperplasia (BMAH) represents a rare cause of Cushing’s syndrome may be diagnosed incidentally and is often associated with an insidious onset. We use this case to highlight the complexities of provocative testing for aberrant adrenal receptors which occur with BMAH and the utilization of unilateral adrenalectomy to achieve clinical and biochemical remission of Cushing’s syndrome thus, removing the need for post - operative steroid replacement following bilateral adrenalectomy.

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Midnight Salivary Cortisol Versus Urinary Free and Midnight Serum Cortisol as Screening Tests for Cushing’s Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030312 ◽

2003 ◽

Vol 88 (9) ◽

pp. 4153-4157 ◽

Cited By ~ 112

Author(s):

Pietro Putignano ◽

Paola Toja ◽

Antonella Dubini ◽

Francesca Pecori Giraldi ◽

Salvatore Maria Corsello ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Cushing’S Syndrome ◽

Salivary Cortisol ◽

Diagnostic Performance ◽

Serum Cortisol ◽

Cushing's Syndrome ◽

Screening Tests ◽

Late Night ◽

Free Cortisol ◽

Simple Obesity

The diagnosis of Cushing’s syndrome (CS) is often a challenge. Recently, the determination of late night salivary cortisol levels has been reported to be a sensitive and convenient screening test for CS. However, no studies have included a comparison with other screening tests in a setting more closely resembling clinical practice, i.e. few patients with CS to be distinguished from patients with pseudo-Cushing states (PC), including the large population of obese patients. The aim of this study was to compare the diagnostic performance of midnight salivary cortisol (MSC) measurement with that of midnight serum cortisol (MNC) and urinary free cortisol (UFC) in differentiating 41 patients with CS from 33 with PC, 199 with simple obesity, and 27 healthy normal weight volunteers. Three patients with CS had MSC levels lower than the cut-off point derived from receiver operator characteristic analysis (9.7 nmol/liter), yielding a sensitivity for this parameter of 92.7%. In the whole study population, no statistically significant differences in terms of sensitivity, specificity, diagnostic accuracy, and predictive values were observed among tests. In particular, the overall diagnostic accuracy for MSC (93%; 95% confidence interval, 90.1–95.9%) was similar to those of UFC (95.3%; 94.1–96.5%) and MNC (95.7%; 93.4–98%; both P = NS). The diagnostic performance of MSC was superimposable to that of MNC also within the area of overlap in UFC values (≤569 nmol/24 h) between CS and PC. In conclusion, MSC measurement can be recommended as a first-line test for CS in both low risk (simple obesity) and high-risk (i.e. PC) patients. Given its convenience, this procedure can be added to tests traditionally used for this purpose, such as UFC and MNC.

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Screening for Cushing Syndrome at the Primary Care Level: What Every General Practitioner Must Know

International Journal of Endocrinology ◽

10.1155/2017/1547358 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Ernest Yorke ◽

Yacoba Atiase ◽

Josephine Akpalu ◽

Osei Sarfo-Kantanka

Keyword(s):

Primary Care ◽

Cushing’S Syndrome ◽

Cushing Syndrome ◽

Cushing's Syndrome ◽

Screening Tests ◽

Screening Methods ◽

Endocrine Society ◽

Late Night ◽

Free Cortisol ◽

Clinical Awareness

Cushing’s syndrome is a rare entity, and a high index of suspicion is needed for screening in a primary care setting. The clinical awareness of the primary care physician (PCP) to the highly indicative signs and symptoms such as facial plethora, proximal myopathy, reddish purple striae, and easy bruisability should alert him to look for biochemical evidence of Cushing’s syndrome through any of the first-line screening tests, namely, 24-hour urinary free cortisol, overnight dexamethasone suppression test, or late-night salivary cortisol. Commonly used random cortisol measurements are unreliable; hence, general practitioners are encouraged to understand the use of these more reliable tests with increased sensitivity and specificity for screening Cushing’s syndrome. In this write-up, we set out to increase awareness about the presentation of Cushing’s syndrome and current recommended screening methods as well as their strengths and weaknesses. We relied mainly on the recommendations by the Endocrine Society Guidelines.

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Screening Tests for Cushing's Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2507 ◽

2015 ◽

Vol 100 (10) ◽

pp. 3856-3861 ◽

Cited By ~ 41

Author(s):

Filippo Ceccato ◽

Mattia Barbot ◽

Marialuisa Zilio ◽

Anna Chiara Frigo ◽

Nora Albiger ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Screening Tests ◽

Free Cortisol

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The diagnostic performance of urinary free cortisol is better than the cortisol:cortisone ratio in detecting de novo Cushing's syndrome: the use of a LC–MS/MS method in routine clinical practice

Acta Endocrinologica ◽

10.1530/eje-14-0061 ◽

2014 ◽

Vol 171 (1) ◽

pp. 1-7 ◽

Cited By ~ 25

Author(s):

Filippo Ceccato ◽

Giorgia Antonelli ◽

Mattia Barbot ◽

Marialuisa Zilio ◽

Linda Mazzai ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Medical Therapy ◽

Cushing’S Syndrome ◽

Diagnostic Performance ◽

De Novo ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Healthy Controls ◽

Endocrine Society ◽

Free Cortisol

ObjectiveThe Endocrine Society Clinical Guidelines recommend measuring 24-h urinary free cortisol (UFF) levels using a highly accurate method as one of the first-line screening tests for the diagnosis of Cushing's Syndrome (CS). We evaluated the performance of UFF, urinary free cortisone (UFE), and the UFF:UFE ratio, measured using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method.Subjects and methodsThe LC–MS/MS was used to analyze UFF and UFE levels in 43 surgically confirmed CS patients: 26 with Cushing's disease (CD, 16de novoand ten recurrences), 11 with adrenal CS and six with ectopic CS; 22 CD patients in remission; 14 eu-cortisolemic CD patients receiving medical therapy; 60 non-CS patients; and 70 healthy controls. Sensitivity and specificity were determined in the combined groups of non-CS patients, healthy controls, and CD in remission.ResultsUFF>170 nmol/24 h showed 98.7% specificity and 100% sensitivity forde novoCS, while sensitivity was 80% for recurrent CD patients, who were characterized by lower UFF levels. The UFF:UFE and UFF+UFE showed lower sensitivity and specificity than UFF. Ectopic CS patients had the highest UFF and UFF:UFE levels, which were normal in the CD remission patients and in those receiving medical therapy.ConclusionsOur data suggest high diagnostic performance of UFF excretion measured using LC–MS/MS, in detectingde novoCS. UFF:UFE and UFF+UFE assessments are not useful in the first step of CS diagnosis, although high levels were found to be indicative of ectopic CS.

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How useful is 24 hour Urinary Free Cortisol as a screening tool for Cushing's syndrome?

Endocrine Abstracts ◽

10.1530/endoabs.59.p028 ◽

2018 ◽

Author(s):

Ahmed Hanafy ◽

Chinnadorai Rajeswaran ◽

Saad Saddiq ◽

Warren Gillibrand ◽

John Stephenson

Keyword(s):

Cushing’S Syndrome ◽

Screening Tool ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Free Cortisol

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Pitfalls in the diagnosis and management of Cushing's syndrome

Neurosurgical FOCUS ◽

10.3171/2014.11.focus14704 ◽

2015 ◽

Vol 38 (2) ◽

pp. E4 ◽

Cited By ~ 34

Author(s):

Vivek Bansal ◽

Nadine El Asmar ◽

Warren R. Selman ◽

Baha M. Arafah

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Salivary Cortisol ◽

Clinical Symptoms ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Biochemical Tests ◽

Late Night ◽

Late Night Salivary Cortisol ◽

Free Cortisol

Despite many recent advances, the management of patients with Cushing's disease continues to be challenging. Cushing's syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone–secreting pituitary adenomas account for nearly 70% of all cases of Cushing's syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushing's syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushing's syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushing's disease require the thorough and close coordination and involvement of all members of the management team.

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