What is the appropriate workup for Cushing's syndrome?

From the Guidelines

The workup for Cushing's syndrome involves a stepwise approach starting with screening tests to confirm hypercortisolism, followed by tests to determine the cause, as recommended by the most recent guidelines 1.

Initial Screening

Initial screening includes:

• 24-hour urinary free cortisol measurement
• Late-night salivary cortisol testing
• The overnight 1-mg dexamethasone suppression test At least two abnormal results from different tests are needed to confirm the diagnosis, as suggested by recent studies 1.

Determining the Cause

Once hypercortisolism is established, ACTH levels should be measured to differentiate ACTH-dependent (pituitary or ectopic source) from ACTH-independent (adrenal) causes.

• For ACTH-dependent disease, an 8-mg dexamethasone suppression test and CRH stimulation test help distinguish between pituitary and ectopic sources, as indicated by recent research 1.
• Imaging studies are then used based on biochemical results:
  • MRI of the pituitary for Cushing's disease
  • CT/MRI of the adrenals for adrenal causes
  • Chest/abdominal imaging for ectopic ACTH sources Bilateral inferior petrosal sinus sampling may be necessary when imaging is inconclusive but biochemical testing suggests Cushing's disease, as recommended by recent guidelines 1.

Importance of Accurate Diagnosis

This systematic approach is essential because Cushing's syndrome has significant morbidity if left untreated, and accurate localization of the source guides appropriate treatment, whether surgical removal of the responsible tumor or medical management with agents like ketoconazole, metyrapone, or mifepristone, as highlighted by recent studies 1.

Recent Guidelines

Recent guidelines suggest that patients with unilateral cortisol-secreting adrenal masses and clinically apparent Cushing's syndrome should undergo unilateral adrenalectomy of the affected adrenal gland, and minimally-invasive surgery should be performed when feasible for these procedures 1. Additionally, younger patients with mild autonomous cortisol secretion who have progressive metabolic comorbidities attributable to cortisol excess can be considered for adrenalectomy after shared decision making, as recommended by recent research 1.

From the FDA Drug Label

SIGNIFOR is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative. The FDA drug label does not answer the question about Cushing's workup.

From the Research

Cushing's Syndrome Workup

The workup for Cushing's syndrome involves several steps to diagnose and differentiate between various causes of the condition.

• Initial workup should start with excluding local and systemic corticosteroid use 2.
• First-line screening tests include:
  • 1-mg dexamethasone suppression test
  • 24-hour urinary free cortisol excretion
  • Late-night salivary cortisol measurement 2, 3, 4
• These tests help screen for endogenous Cushing's syndrome and can be used to assess long-term glucocorticoid exposure and detect transient periods of hypercortisolism 2.
• Measurement of plasma ACTH concentrations can differentiate between ACTH-dependent and ACTH-independent causes of Cushing's syndrome 2.
• Further assessment with imaging modalities and dynamic biochemical testing, including bilateral inferior petrosal sinus sampling, can help pinpoint the cause of Cushing's syndrome 2.

Screening Tests

The choice of screening test for Cushing's syndrome depends on various factors, including the patient's clinical condition and the availability of testing methods.

• Urinary free cortisol (UFC) measurement by liquid chromatography tandem-mass spectrometry has been shown to have high sensitivity and specificity for diagnosing Cushing's syndrome 3.
• The 1-mg dexamethasone suppression test (DST) is also a commonly used screening test, but it may have pitfalls in certain clinical conditions 4.
• Late-night salivary cortisol (LNSC) measurement is another option, but its sensitivity and specificity may vary depending on the cutoff values used 3.

Pitfalls and Limitations

The interpretation of screening test results for Cushing's syndrome can be challenging due to individual patient characteristics and the limitations of each test.

• The 1-mg DST may have false-negative results in patients with cyclic Cushing's syndrome or those taking certain medications 4.
• UFC measurement may be affected by renal function and other factors, leading to false-positive or false-negative results 3.
• LNSC measurement may be influenced by factors such as sleep quality and saliva collection methods 3.