What is the workup for a patient with suspected Cushing (Cushing's) disease?

From the Guidelines

The workup for a patient with suspected Cushing's disease begins with screening tests to establish hypercortisolism, followed by tests to determine its cause, as recommended by the most recent guidelines 1. The initial screening includes a 24-hour urinary free cortisol measurement, late-night salivary cortisol test, and an overnight or low-dose dexamethasone suppression test.

• If these tests indicate hypercortisolism, the next step is to measure ACTH levels to differentiate between ACTH-dependent (Cushing's disease or ectopic ACTH) and ACTH-independent (adrenal) causes.
• For patients with elevated ACTH, a high-dose dexamethasone suppression test can help distinguish pituitary from ectopic sources, as pituitary tumors typically show cortisol suppression.
• Pituitary MRI with contrast should be performed to locate a pituitary adenoma.
• If the MRI is negative or inconclusive but Cushing's disease is still suspected, bilateral inferior petrosal sinus sampling may be necessary, comparing central to peripheral ACTH levels before and after CRH stimulation, as recommended by the guidelines 1. This invasive procedure is considered the gold standard for confirming a pituitary source. Throughout the workup, it's essential to rule out exogenous glucocorticoid use and pseudo-Cushing's states (depression, alcoholism, etc.) which can cause similar laboratory findings. The diagnostic process often requires multiple tests as no single test has perfect sensitivity and specificity. The most recent and highest quality study 1 recommends a protocol for diagnosis of Cushing disease, including confirmation of hypercortisolism and determination of its cause, with specific diagnostic cut-offs and tests. The treatment options for Cushing's disease include selective adenomectomy as first-line treatment, repeat surgery for persistent or recurrent disease, and radiotherapy for recurrent disease not amenable to curative surgery, as recommended by the guidelines 1.

From the Research

Cushing's Disease Workup

The workup for a patient with suspected Cushing's disease involves several steps:

• Initial screening tests to confirm the presence of hypercortisolism, such as:
  • Overnight dexamethasone suppression test 2
  • Low-dose dexamethasone suppression test 2, 3
  • Late night salivary cortisol measurement 2
  • 24-hour urinary free cortisol (UFC) measurement 4, 3, 5
• If the initial test is positive, the patient should be referred to a specialist endocrinologist for in-patient assessment 2
• Further testing to establish the etiology of Cushing's syndrome, including:
  • Plasma ACTH measurement at 9 am 2
  • MRI scan of the pituitary gland 2, 3
  • Corticotrophin releasing hormone (CRH) test to distinguish pituitary from ectopic ACTH-dependent Cushing's syndrome 2, 6, 3
  • Bilateral petrosal sinus sampling to confirm the source of ACTH secretion 2, 3

Diagnostic Tests

The following diagnostic tests are used to confirm the diagnosis of Cushing's syndrome:

• 24-hour urinary free cortisol (UFC) measurement: a classic screening test, but its use is limited by drawbacks in sample collection and laboratory methods 4
• Dexamethasone suppression test: a high-dose test (8 mg or 32 mg) can be used to differentiate between pituitary and ectopic ACTH-dependent Cushing's syndrome 6
• Midnight cortisol measurement: can be used to identify true Cushing's syndrome in patients with mild hypercortisolism 5
• CRH stimulation test: can be used in combination with the dexamethasone suppression test to identify true Cushing's syndrome 5

Special Considerations

• Patients with suspected Cushing's disease should be managed in specialist endocrine centers, as the expertise of multidisciplinary team members predicts the best outcome 2
• The diagnosis of Cushing's syndrome can be challenging, and additional observation and testing may be necessary to confirm the diagnosis 5