Criteria for Diagnosis of Cushing’s Syndrome (CS)

The evaluation of patients with suspected Cushing’s syndrome (CS) is complex and expensive, and the diagnosis is often a challenge for clinicians. Most patients initially suspected of having CS will not have this condition, and therefore efficient screening procedures are needed to identify the few patients who will need additional investigation in specialized centers.

Atypical clinical presentations (mild hypercortisolism, cyclical CS, subclinical CS) or forms of pseudo-CS (depression, alcoholism) further complicate the assessment.
The laboratory investigations of CS are based on the demonstration of inappropriate cortisol secretion with loss of its physiological negative feedback. Several tests have been used extensively, but none has proven fully capable of distinguishing all cases of CS, and an appropriate ordered cascade of tests is necessary. Measurement of cortisol in more than one 24-h urinary collection and/or the low-dose DST are recommended as first line screening test, with the recognition that false-positive tests are common, depending on the criterion for interpretation that is used. Late-night salivary cortisol also is proposed as a useful screening test, although published data are still preliminary. The diagnostic evaluation should not proceed to attempt to establish the precise etiology of hypercortisolism unless the diagnosis of CS is unequivocal. ACTH levels, the CRH stimulation test, the high-dose DST, and appropriate imaging are the most useful noninvasive investigations for the differential diagnosis of CS. BIPSS for ACTH measurement is recommended in patients with ACTH-dependent CS whose clinical, biochemical, or radiological studies are discordant or equivocal.
Clinical suspicion

  • Increased Urinary Free Cortisol (three 24h collections)
  • Lack of suppression after low-dose dexamethasone testing
  • Increased “late-evening” salivary cortisol (test incompletely evaluated

When necessary

  • midnight plasma cortisol
  • cortisol diurnal rhythm
  • 2 mg/day 48-hour low-dose DST and the CRH test

Cushing’s Syndrome (Hypercortisolism)

Adrenal Pituitary Ectopic
ACTH low normal/high normal/very high
CRH test no response response rare response
DEX 8 mg no suppression suppression rare suppression
CT/MRI adrenal mass(es) normal/hyperplasia normal/hyperplasia
MRI pituitary normal tumor (60%) normal
BIPSS not applicable gradient (pit/periph.) no gradient (pit/periph.)

Abbreviations: Adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), dexamethasone suppression tests (DSTs), Bilateral Inferior Petrosal Sinus Sampling (BIPSS), dexamethasone (DEX).
 
 
References:

  1. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M.. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602. [Medline]
  2. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best Pract Res Clin Endocrinol Metab. 2009 Oct;23(5):607-23. [Medline]
  3. Elamin MB, Murad MH, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin PJ, Montori VM. Accuracy of diagnostic tests for Cushing’s syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008 May;93(5):1553-62. [Medline]

Created Jul 21, 2011.

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