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cushing_s_syndrome_diagnosis

Cushing's syndrome diagnosis

Cushing's syndrome is usually easy to diagnose clinically owing to its characteristic features.

Laboratory tests

Morning and midnight serum cortisol levels

24h urine free cortisol excretion

Midnight salivary cortisol levels

Serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone

The dexamethasone suppression test (DST) is used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone. It is typically used to diagnose Cushing's syndrome.

Plasma ACTH and serum cortisol levels after Desmopressin stimulation test 1).

Magnetic resonance imaging (MRI)

Anatomical localization of source of excess ACTH Cushing's disease can be quite challenging. Sometimes, it becomes very difficult to differentiate ectopic ACTH source from Cushing's disease 2) 3).

Subsequent to the diagnosis of ACTH-dependent Cushing's syndrome, the next step involves anatomical localization of the source of the ACTH secretion. Various biochemical and radiological techniques have been established to help in localization of the neoplastic lesion. Radiological techniques including computed tomography (CT)/magnetic resonance imaging (MRI) have poor sensitivity (around 60%) 4).

Salivary cortisol measurement

The clinical features of Cushing's syndrome (such as obesity, hypertension, and diabetes) are commonly encountered in clinical practice. Patients with Cushing's syndrome have been identified by an abnormal low-dose dexamethasone suppression test, elevated urine free cortisol (UFC), an absence of diurnal rhythm of plasma cortisol, or an elevated late-night plasma cortisol. Because the concentration of cortisol in the saliva is in equilibrium with the free (active) cortisol in the plasma, measurement of salivary cortisol in the evening (nadir) and morning (peak) may be a simple and convenient screening test for Cushing's syndrome.

It is a simple and reliable screening test for spontaneous Cushing's syndrome. In addition, late-night salivary cortisol measurements may simplify the evaluation of suspected intermittent hypercortisolism, and they may facilitate the screening of large high-risk populations (e.g. patients with diabetes mellitus) 5).


Late-night salivary cortisol (LNSC) may accurately establish remission after transsphenoidal surgery (TSS) and identify recurrence more accurately than 24-hour urine free cortisol [UFC], during long-term follow-up 6).

Salivary cortisol circadian rhythm is established by one month corrected age in preterm infants. Establishment of salivary cortisol circadian rhythm is related to gestational age rather than to postnatal age. Salivary cortisol circadian rhythm development is not related to behavioral regularity 7).

A study also provides first year age-related reference intervals for salivary cortisol levels in healthy, full-term infants 8).


Increase in late-night salivary cortisol (LNSC) concentration is an early abnormality during post-surgical recurrence of CD. However, due to a major within-patient variability of LNSC from 1 day to another, a screening strategy using three or four samples collected on successive days may be recommended to detect early-stage recurrence of CD with a high accuracy 9).


Repeated determinations of the circadian rhythm of cortisol in saliva samples in combination with an overnight 1 mg dexamethasone suppression and an insulin stimulation test, are recommended to diagnose patients with suspicion on ICD even in an outpatient clinic 10).

The measurement of cortisol in saliva is becoming more widely accepted as a screening test for the diagnosis of hypercortisolism. Since 1986, cortisol measurement in saliva has been continuously used in our department. In this study we compared salivary cortisol profiles from proven Cushing's disease patients with profiles from healthy subjects and obese children. The purpose was to evaluate the predictive value of the method for the diagnosis of hypercortisolism and to define cut-off levels to exclude or identify hypercortisolism. Cortisol in saliva was measured in 150 Cushing's disease patients (30 children, 120 adults, ranging from age 4-70), 100 healthy subjects (55 children, 45 adults, ranging from age 6-60), and 31 children (age 7-15) with an age-related body-mass-index above the 90th percentile. Generally, five saliva samples were taken over the day at 6:00-8:00 a.m., 11:00-12:00 a.m., 4:00-6:00 p.m., 7:00-8:00 p.m., and 10:00 p.m. The samples were measured using a radioimmuno-assay (INCSTAR Corporation, Stillwater, Minnesota, USA). For healthy subjects, morning levels of cortisol in saliva between 3-19 microg/l were found. These levels dropped to levels in between <1-11 microg/l at 11:00-12:00 a.m., <1-6 microg/l at 4:00-6:00 p.m., <1-4.5 microg/l at 7:00-8:00 p.m., and <1-2.9 microg/l at 10:00 p.m. The measured values showed a correlation with age, height, and weight. In Cushing's disease patients, the circadian salivary cortisol rhythm was missing, compared to healthy subjects. There was no significant difference in salivary cortisol levels or circadian rhythm between healthy or obese children. We found a high sensitivity for the detection of hypercortisolism at the 10:00 p.m. salivary cortisol measurement. The following, age dependent cut-off levels for salivary cortisol at 10:00 p.m. were calculated for the exclusion of hypercortisolism. Age 6-10: 1.0 microg/l (specificity 100%, sensitivity 87.5%); age 11-15: 1.7 microg/l (specificity 100%, sensitivity 100%); age 16-20: 1.6 microg/l (specificity 100%, sensitivity 76.2%); age 21-60: 1.6 microg/l (specificity 100%, sensitivity 90.9%) [corrected] For the proof of Cushing's syndrome, the following age-dependent cut-off levels at 10:00 p.m. were found: age 6-10: 1.9 microg/l (specificity 100%, sensitivity 80%); age 11-15: 1.7 microg/l (specificity 100%, sensitivity 100%); age 16-20: 2.5 microg/l (specificity 100%, sensitivity 84.2%); age 21-60: 1.9 microg/l (specificity 100%, sensitivity 97.6 %) [corrected] The cortisol assessment in saliva is a sensitive and reliable method to discriminate normocortisolemic from hypercortisolemic patients. From our view, the major advantages of this method are the reliability, non-invasiveness, and use in ambulatory patients 11).

References

1)
Leal-Cerro A, Martín-Rodríguez JF, Ibáñez-Costa A, Madrazo-Atutxa A, Venegas-Moreno E, León-Justel A, García-Hernández N, Luque RM, Castaño JP, Cano DA, Soto-Moreno A. Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease. Endocrinol Nutr. 2014 Feb;61(2):69-76. doi: 10.1016/j.endonu.2013.04.017. Epub 2013 Oct 30. English, Spanish. PubMed PMID: 24183946.
2)
Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, et al. The prevalence of pituitary adenomas: A systematic review. Cancer. 2004;101:613–9.
3)
Utz A, Biller BM. The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome. Arq Bras Endocrinol Metabol. 2007;51:1329–38.
4)
Aron DC, Raff H, Findling JW. Effectiveness versus efficacy: The limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab. 1997;82:1780–5.
5)
Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing's syndrome. J Clin Endocrinol Metab. 1998 Aug;83(8):2681-6. PubMed PMID: 9709931.
6)
Amlashi FG, Swearingen B, Faje AT, Nachtigall LB, Miller KK, Klibanski A, Biller BM, Tritos NA. Accuracy of Late-Night Salivary Cortisol in Evaluating Postoperative Remission and Recurrence in Cushing's Disease. J Clin Endocrinol Metab. 2015 Oct;100(10):3770-7. doi: 10.1210/jc.2015-2107. Epub 2015 Jul 21. PubMed PMID: 26196950.
7)
Ivars K, Nelson N, Theodorsson A, Theodorsson E, Ström JO, Mörelius E. Development of salivary cortisol circadian rhythm in preterm infants. PLoS One. 2017 Aug 10;12(8):e0182685. doi: 10.1371/journal.pone.0182685. eCollection 2017. PubMed PMID: 28797126.
8)
Ivars K, Nelson N, Theodorsson A, Theodorsson E, Ström JO, Mörelius E. Development of Salivary Cortisol Circadian Rhythm and Reference Intervals in Full-Term Infants. PLoS One. 2015 Jun 18;10(6):e0129502. doi: 10.1371/journal.pone.0129502. eCollection 2015. Erratum in: PLoS One. 2016;11(3):e0151888. PubMed PMID: 26086734; PubMed Central PMCID: PMC4472813.
9)
Danet-Lamasou M, Asselineau J, Perez P, Vivot A, Nunes ML, Loiseau H, San-Galli F, Cherifi-Gatta B, Corcuff JB, Tabarin A. Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing's disease following pituitary surgery. Clin Endocrinol (Oxf). 2015 Feb;82(2):260-6. doi: 10.1111/cen.12534. Epub 2014 Jul 25. PubMed PMID: 24975391.
10)
Bals-Pratsch M, Hanker JP, Hellhammer DH, Lüdecke DK, Schlegel W, Schneider HP. Intermittent Cushing's disease in hirsute women. Horm Metab Res. 1996 Feb;28(2):105-10. PubMed PMID: 8867908.
11)
Trilck M, Flitsch J, Lüdecke DK, Jung R, Petersenn S. Salivary cortisol measurement–a reliable method for the diagnosis of Cushing's syndrome. Exp Clin Endocrinol Diabetes. 2005 Apr;113(4):225-30. Erratum in: Exp Clin Endocrinol Diabetes. 2005 Jul;113(7):409. PubMed PMID: 15891959.
cushing_s_syndrome_diagnosis.txt · Last modified: 2017/08/11 12:56 by administrador