Cushing's Syndrome
A rare challenge for diagnosing.
Could your practice have a patient with Cushing’s syndrome?
A Cushing’s syndrome (CS) diagnosis can often be delayed for years due to variations in CS presentation.1 The mean time to diagnosis for CS is reported as 34 months, but can vary by subtype.2
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Ectopic CS: 14 months
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ACTH-Independent Adrenal CS: 30 months
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Cushing’s disease (CD): 38 months
Early diagnosis is key to helping address CS, potentially improving symptoms and quality of life,3 yet symptoms can vary greatly by patient, further complicating the path to diagnosis.4
Steps to determine a CS diagnosis1,4,5
Diagnosing CS requires biochemical confirmation and determination of an underlying cause.5 From clinical suspicion of CS to initial biochemical screening tests, followed by confirmatory testing and tests to determine the underlying cause, the path to diagnosis can be complex and challenging.
Diagnosing Endogenous Cushing’s Syndrome
Steps to determine a CS diagnosis1,4,5
Diagnosing CS requires biochemical confirmation and determination of an underlying cause.5 From clinical suspicion of CS to initial biochemical screening tests, followed by confirmatory testing and tests to determine the underlying cause, the path to diagnosis can be complex and challenging.
Diagnosing Endogenous Cushing’s Syndrome
Tests to help determine CS
Being familiar with the testing methods and interpreting results according to validated diagnostic measures is valuable in diagnosing CS.5
First-line testing
Use 2 different tests to demonstrate elevated cortisol levels for a diagnosis.5
24-h urinary free cortisol (UFC)
Should be performed 2-3 times to improve reliability.5
Late-night salivary cortisol (LNSC)
Should be performed 2-3 times to improve reliability.5
1-mg overnight dexamethasone suppression test (DST)
Measures elevated cortisol levels based on impaired glucocorticoid feedback, as dexamethasone suppresses cortisol production in normal cortisol regulation.1
Second-line testing
Use additional tests to exclude nonneoplastic hypercortisolism if repeat screening tests show normal or discordant results.1,5
Desmopressin test
Measures ACTH levels as ACTH-secreting adenomas express vasopressin 3 receptors, which produce an increase in plasma ACTH concentration after desmopressin injection. Can also be used to differentiate CD vs CS.1,5
Dexamethasone-CRH test
(Not available in the United States)1
Measures ACTH and cortisol levels as dexamethasone suppresses serum cortisol levels in individuals without CS. However, when given CRH, patients with CD should respond with an increase in ACTH and cortisol.3
Confirming a CS diagnosis
Determine the source of excess cortisol
Use to determine ACTH-dependent or ACTH-independent CS.5
Morning plasma corticotropin test
Measures plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent source.5
Determine the subtype (ACTH-dependent CS)
Pituitary MRI
Differentiates between ectopic CS and CD.5
Bilateral inferior petrosal sinus sampling
Measures ACTH levels in the pituitary (petrosal sinus) vs peripheral venous drainage to determine if the source of ACTH is from the pituitary gland or an ectopic source.1
Determine the subtype (ACTH-independent CS)
Adrenal CT
Differentiates between adrenal adenoma, carcinoma, and hyperplasia.5
Cushing’s disease is the most prevalent of endogenous CS cases5
In some cases, certain signs and symptoms in patients with suspected CS may signal Cushing’s disease.6 Diagnosis always begins with evaluating clinical signs and symptoms, and screening to confirm whether the patient has elevated endogenous cortisol.7
~70%
are caused by an ACTH-secreting pituitary tumor (Cushing’s disease)
~30%
are caused by primary adrenocortical tumors (adrenal adenoma, adrenal carcinoma, or primary adrenal hyperplasia)
~10-20%
are caused by Ectotopic ACTH Syndrome (EAS) (e.g., lung, mediastinal, pancreas, or medullary thyroid neuroendocrine tumors)
Adrenal carcinomas and ectopic ACTH-secreting tumors may be cancerous, while ACTH-secreting pituitary tumors and other adrenal tumors are non-cancerous growths.
Join our community of healthcare professionals interested in and dedicated to diagnosing and treating rare endocrine disorders.
REFERENCES: 1. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7. 2. Rubinstein G, Osswald A, Hoster E, et al. Time to diagnosis in Cushing’s syndrome: A meta-analysis based on 5367 patients. J Clin Endocrinol Metab. 2020;105(3):dgz136. doi:10.1210/clinem/dgz136. 3. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125. 4. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015;173(4):M33-8. doi: 10.1530/EJE-15-0464. 5. Reincke M, Fleseriu M. Cushing syndrome: a review. JAMA. 2023;330(2):170-181. doi:10.1001/jama.2023.11305. 6. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;17(7):281-293. doi:10.2147/CLEP.S44336. 7. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017;126(2):404-417. doi: 10.3171/2016.1.JNS152119.