What is the workup for Cushing's syndrome?

From the Guidelines

The workup for Cushing syndrome involves a systematic approach to confirm the diagnosis and identify the underlying cause, starting with initial 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 guidelines 1. The initial screening tests are crucial in determining the presence of hypercortisolism, which is a hallmark of Cushing syndrome.

• 24-hour urinary free cortisol measurement is a sensitive test with a sensitivity of 89% and specificity of 100% 1.
• Late-night salivary cortisol testing is also a useful screening test with a sensitivity of 95% and specificity of 100% 1.
• The overnight dexamethasone suppression test is another screening test that can be used, with a sensitivity of 11% and specificity of 75% 1. If the screening tests are positive, confirmatory testing is needed to confirm the diagnosis of Cushing syndrome.
• The 2-day low-dose dexamethasone suppression test or the dexamethasone-CRH test can be used as confirmatory tests 1. Once Cushing syndrome is confirmed, determining the etiology requires measuring plasma ACTH levels.
• High ACTH levels suggest an ACTH-dependent cause, such as a pituitary adenoma or ectopic ACTH production, while low ACTH indicates an ACTH-independent cause, typically adrenal tumors 1. For ACTH-dependent cases, an MRI of the pituitary and high-dose dexamethasone suppression test can help differentiate between pituitary and ectopic sources.
• Bilateral inferior petrosal sinus sampling for ACTH can also be used to confirm a central source of ACTH excess, with a ratio of central-to-peripheral ACTH of ≥2:1 before CRH or desmopressin and ≥3:1 after CRH or desmopressin stimulation 1. Adrenal imaging with CT or MRI is performed for ACTH-independent cases.
• The choice of imaging modality depends on the clinical suspicion and the availability of resources, as recommended by recent guidelines 1. This stepwise approach is essential because Cushing syndrome can cause serious complications, including hypertension, diabetes, osteoporosis, and increased infection risk if left untreated, highlighting the importance of prompt and accurate diagnosis and treatment, as emphasized in recent consensus guidelines 1.

From the Research

Diagnostic Approach

The diagnostic workup for Cushing's syndrome involves a stepwise process that includes screening and confirming the diagnosis, and establishing the aetiology of the syndrome 2, 3, 4, 5, 6.

Screening Tests

The tests currently used to confirm the diagnosis of Cushing's syndrome include:

• Urinary free cortisol measurements
• The dexamethasone suppression test
• Late-night salivary cortisol or midnight serum cortisol measurements 2, 3, 6
• Scalp-hair cortisol/cortisone analysis to assess long-term glucocorticoid exposure and detect transient periods of hypercortisolism 3

Establishing the Aetiology

Once the diagnosis of Cushing's syndrome is confirmed, the next step is to establish the aetiology of the syndrome. This involves:

• Measuring ACTH to differentiate between ACTH-dependent and non-ACTH dependent causes of Cushing's syndrome 2, 3, 4, 5, 6
• Adrenal imaging to provide clues for the aetiology of non-ACTH dependent forms 2, 5
• 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 ACTH-dependent forms 2, 3, 5, 6

Imaging Modalities

Imaging modalities used in the diagnostic workup of Cushing's syndrome include:

• Pituitary MRI to diagnose pituitary adenomas 2, 5, 6
• Adrenal protocol CT or MRI to diagnose adrenal abnormalities 5
• CT and MRI scans of the chest and abdomen to detect ectopic sources of ACTH 5, 6