How to rule out Cushing's syndrome?

From the Guidelines

To rule out Cushing's syndrome, a stepwise diagnostic approach is recommended, starting with screening tests such as 24-hour urinary free cortisol measurement, late-night salivary cortisol test, or the overnight dexamethasone suppression test, as outlined in the most recent guideline update 1. The diagnostic process for Cushing's syndrome involves several steps, with the initial screening being crucial for identifying potential cases. According to the guideline update from 2021 1, the first step is to assess the clinical likelihood of endogenous Cushing's syndrome and to stop exogenous glucocorticoid (GC) use if possible. The screening tests recommended include:

• 24-hour urinary free cortisol (UFC) measurement
• Late-night salivary cortisol test
• Overnight 1 mg dexamethasone suppression test (DST)

If the screening tests are abnormal, confirmation is needed with additional tests such as the two-day low-dose dexamethasone suppression test or the midnight serum cortisol test, as supported by the 2024 consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence 1.

Key Diagnostic Steps

• Measure ACTH levels to determine if the cause is ACTH-dependent or independent
• Use imaging studies like MRI of the pituitary for ACTH-dependent cases or CT/MRI of the adrenal glands for ACTH-independent cases
• Consider specialized tests like the high-dose dexamethasone suppression test or inferior petrosal sinus sampling for complex cases, with the latter being recommended for patients with confirmed ACTH-dependent Cushing syndrome and no identified adenoma on pituitary MRI 1.

Important Considerations

• The diagnosis of Cushing's disease is supported by a >20% increase in cortisol from baseline during a corticotrophin-releasing hormone (CRH) test, as stated in the 2024 guideline 1.
• Bilateral inferior petrosal sinus sampling (BSIPSS) is recommended for CYP with confirmed ACTH-dependent Cushing syndrome and no identified adenoma on pituitary MRI to confirm a central source of ACTH excess, with a ≥2:1 ratio of central-to-peripheral ACTH before CRH or desmopressin and ≥3:1 ratio after CRH or desmopressin stimulation being diagnostic 1. The systematic approach to diagnosing Cushing's syndrome is crucial due to its potential to present with common symptoms that overlap with many other conditions, making accurate diagnosis essential for proper treatment, as emphasized in the recent medical literature 1.

From the FDA Drug Label

Because of these actions, Metopirone is used as a diagnostic test, with urinary 17‑hydroxycorticosteroids (17-OHCS) measured as an index of pituitary ACTH responsiveness.

To rule out Cushing's syndrome, metyrapone can be used as a diagnostic test. The test involves measuring urinary 17-hydroxycorticosteroids (17-OHCS), which serves as an index of pituitary ACTH responsiveness 2.

• The test is based on the ability of metyrapone to inhibit the 11-beta-hydroxylation reaction in the adrenal cortex, leading to an increase in adrenocorticotropic hormone (ACTH) production by the pituitary.
• The resulting increase in 11-desoxycortisol and desoxycorticosterone can be measured in the urine as 17-OHCS or 17-ketogenic steroids (17-KGS).
• This test can help assess the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and aid in the diagnosis of Cushing's syndrome 2.

From the Research

Ruling Out Cushing's Syndrome

To rule out Cushing's syndrome, several diagnostic tests and approaches can be employed, as outlined in various studies 3, 4, 5, 6, 7.

• Initial Assessment: The diagnosis of Cushing's syndrome often starts with the demonstration of clinical features and biochemical abnormalities that reflect hypercortisolism 3.
• Biochemical Tests: Key tests include the measurement of 24-hour urinary free cortisol (UFC) excretion, midnight cortisol measurements, the 2-day-2-mg dexamethasone suppression test, or the dexamethasone suppression-CRH stimulation test 3, 4, 5, 6, 7.
• Screening Tests: First-line screening tests should include the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement to screen for endogenous Cushing's syndrome 5.
• Limitations of Tests: It's crucial to understand the limitations of these tests, as individual patient characteristics can affect interpretation, and no single test is definitive for ruling out Cushing's syndrome 4, 6, 7.
• Combination of Tests: Using a combination of tests, such as UFC, midnight salivary cortisol, and dexamethasone suppression tests, can increase the diagnostic yield and help differentiate between true Cushing's syndrome and pseudo-Cushing states 3, 4, 5, 7.
• Further Assessment: Once endogenous Cushing's syndrome is suspected, further assessment with plasma ACTH concentrations, imaging modalities, and dynamic biochemical testing, including bilateral inferior petrosal sinus sampling, can help pinpoint the cause of Cushing's syndrome 5.