What is the appropriate workup for Cushing syndrome?

From the Guidelines

The appropriate workup for Cushing syndrome involves a stepwise approach beginning with screening tests to confirm hypercortisolism, followed by tests to determine the cause, as recommended by the most recent guideline update 1. The initial screening should include 24-hour urinary free cortisol measurement, late-night salivary cortisol testing, and the overnight 1-mg dexamethasone suppression test, with at least two abnormal results from different tests needed to confirm the diagnosis 1. Once hypercortisolism is established, the next step is measuring plasma ACTH levels to differentiate ACTH-dependent (pituitary or ectopic source) from ACTH-independent (adrenal) causes, with a cut-off value of 29 ng/l (6.4 pmol/l) for ACTH having a 70% sensitivity and 100% specificity for diagnosing Cushing disease 1. For ACTH-dependent cases, a high-dose dexamethasone suppression test (8 mg) and CRH stimulation test help distinguish between pituitary and ectopic sources, with a ≥2:1 ratio of central-to-peripheral ACTH before CRH or desmopressin and ≥3:1 ratio after CRH or desmopressin stimulation confirming a pituitary source 1. Imaging studies are then performed based on biochemical results: MRI of the pituitary for ACTH-dependent disease with likely pituitary origin, CT/MRI of the chest and abdomen for suspected ectopic ACTH production, or adrenal imaging for ACTH-independent cases, with bilateral inferior petrosal sinus sampling necessary in difficult cases to confirm a pituitary source by demonstrating a central-to-peripheral ACTH gradient 1. This systematic approach is essential because proper identification of the underlying cause directly determines the appropriate treatment strategy, whether surgical, medical, or radiation-based, and is supported by the most recent and highest quality study 1. Key considerations in the workup include excluding iatrogenic Cushing syndrome before biochemical testing, as recommended by the Endocrine Society clinical practice guidelines 1, and recognizing the importance of diagnosing paraneoplastic Cushing syndrome in patients with lung cancer to initiate treatment of hypercortisolism and permit more-effective cancer treatment with less risk 1. The use of metyrapone, ketoconazole, etomidate, mitotane, and mifepristone to decrease circulating glucocorticoids, as well as laparoscopic bilateral adrenalectomy to rapidly decrease circulating cortisol levels, may be necessary in certain cases, particularly in patients with rapidly progressive SCLC and ectopic Cushing syndrome 1. Overall, the workup for Cushing syndrome requires a comprehensive and systematic approach, incorporating the latest guideline recommendations and evidence-based practices to ensure optimal patient outcomes.

From the FDA Drug Label

High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours). Treatment with mifepristone at a lower dose can be resumed after resolution of adrenal insufficiency Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).

The appropriate workup for Cushing syndrome is not directly addressed in the provided drug label. Key points to consider in the management of Cushing syndrome include:

• Evaluation for precipitating causes of hypoadrenalism
• Consideration of the long half-life of mifepristone in deciding the duration of glucocorticoid treatment
• Monitoring for hypokalemia and other adverse reactions However, the FDA drug label does not provide a comprehensive workup for Cushing syndrome. 2

From the Research

Diagnostic Approach

The diagnostic workup for Cushing syndrome involves a stepwise process that includes screening and confirming the diagnosis, and establishing the aetiology of the syndrome 3. The initial workup should start with excluding local and systemic corticosteroid use 4.

Screening Tests

The following tests are recommended for screening:

• Urinary free cortisol measurements
• The dexamethasone suppression test
• Late-night salivary cortisol or midnight serum cortisol measurements 3
• 1-mg dexamethasone suppression test
• 24-hour urinary free cortisol excretion
• Late-night salivary cortisol measurement 4
• Midnight salivary cortisol and/or the 1 mg overnight or low-dose dexamethasone suppression tests 5
• Scalp-hair cortisol/cortisone analysis to assess long-term glucocorticoid exposure and detect transient periods of hypercortisolism 4

Establishing the Aetiology

Once the diagnosis of Cushing syndrome is confirmed, the following steps can be taken to establish the aetiology:

• Measurement of ACTH to discriminate between ACTH-dependent and non-ACTH dependent causes of Cushing syndrome 3
• Adrenal imaging to provide clues for the aetiology of non-ACTH dependent forms 3
• Pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling, and imaging modalities to detect ectopic ACTH secreting lesions to differentiate between the ACTH-dependent forms 3
• Bilateral inferior petrosal sinus sampling to differentiate pituitary-dependent from ectopic ACTH-dependent Cushing syndrome 5
• Imaging modalities such as MRI, CT scanning of the chest and abdomen to look for an ectopic source 5

Additional Considerations

• Each screening test has caveats and the choice of tests should be individualized based on each patient's characteristics and lifestyle 6
• The clinical presentation of Cushing's syndrome varies, and the signs and symptoms are not always unmistakable 6
• Cyclical Cushing syndrome should be considered in the differential diagnosis 7
• Radiological evaluation involves different imaging modalities including MRI with or without different radio-nuclear imaging techniques 7