What are the steps for testing and diagnosing Cushing's syndrome?

From the Guidelines

Testing and diagnosing Cushing's syndrome involves a systematic approach beginning with screening tests, such as 24-hour urinary free cortisol measurement, late-night salivary cortisol testing, and the overnight dexamethasone suppression test, as recommended by the most recent guideline update 1. The initial step in diagnosing Cushing's syndrome is to assess the clinical likelihood of endogenous Cushing's syndrome and to stop exogenous glucocorticoid use if possible.

• The patient's medication history should be reviewed to identify any exogenous glucocorticoid use, including oral, injected, inhaled, or topical forms.
• If exogenous glucocorticoid use is identified, it should be stopped if possible to allow for accurate testing. The following screening tests are recommended:
• 24-hour urinary free cortisol measurement
• Late-night salivary cortisol testing
• Overnight dexamethasone suppression test (1 mg dexamethasone given at 11 PM with cortisol measured at 8 AM the next day; normal response is cortisol <1.8 μg/dL) If the screening tests are positive, confirmatory tests are performed, including:
• Low-dose dexamethasone suppression test (0.5 mg every 6 hours for 48 hours)
• Midnight serum cortisol test (elevated levels >7.5 μg/dL suggest Cushing's) Once hypercortisolism is confirmed, determining the cause requires measuring ACTH levels, as suggested by a recent study 1.
• High ACTH levels suggest an ACTH-dependent cause (pituitary adenoma or ectopic ACTH production), while low ACTH indicates an ACTH-independent cause (typically adrenal tumors). For ACTH-dependent cases, a high-dose dexamethasone suppression test (8 mg) and CRH stimulation test help differentiate between pituitary and ectopic sources. Imaging studies like pituitary MRI, chest/abdominal CT, or inferior petrosal sinus sampling provide anatomical localization, as recommended by a recent guideline update 1. This stepwise approach is necessary because Cushing's syndrome can have subtle presentations, and its various causes require different treatments. In cases where the diagnosis is unclear, bilateral inferior petrosal sinus sampling (BSIPSS) may be offered to confirm a central source of ACTH excess, as suggested by a recent study 1. It is essential to follow a systematic approach to diagnose and manage Cushing's syndrome, as the condition can have significant morbidity and mortality if left untreated or improperly managed 1.

From the Research

Cushing's Syndrome Testing

The diagnosis of Cushing's syndrome involves several steps and tests to confirm the presence of the condition. The following are some of the key tests used:

• 1-mg dexamethasone suppression test: This test is used to screen for endogenous Cushing's syndrome 2.
• 24-hour urinary free cortisol (UFC) excretion: This test measures the amount of cortisol in the urine over a 24-hour period 3, 4.
• Late-night salivary cortisol measurement: This test measures the level of cortisol in the saliva at night, which can be elevated in patients with Cushing's syndrome 3, 2, 5.
• Scalp-hair cortisol/cortisone analysis: This test can help assess long-term glucocorticoid exposure and detect transient periods of hypercortisolism 2.

Diagnostic Approach

The diagnostic approach to Cushing's syndrome typically involves the following steps:

• Excluding local and systemic corticosteroid use 2.
• Performing first-line screening tests, such as the 1-mg dexamethasone suppression test, 24-hour UFC excretion, and late-night salivary cortisol measurement 2.
• Interpreting the results of these tests, taking into account individual patient characteristics and test limitations 2.
• If endogenous Cushing's syndrome is confirmed, measuring plasma ACTH concentrations to differentiate between ACTH-dependent and ACTH-independent causes 2.
• Further assessment with imaging modalities and dynamic biochemical testing, such as bilateral inferior petrosal sinus sampling, to pinpoint the cause of Cushing's syndrome 2.

Test Performance

The performance of these tests can vary, with some studies suggesting that:

• UFC measurement by liquid chromatography tandem-mass spectrometry has high sensitivity and specificity for diagnosing Cushing's syndrome 4.
• Late-night salivary cortisol measurement is a simple and reliable screening test for Cushing's syndrome, but may have some limitations in certain patient populations 3, 5.
• The 1-mg dexamethasone suppression test has high specificity, but may have lower sensitivity for diagnosing Cushing's syndrome 4.