From the Guidelines
The workup for Cushing's syndrome should start with initial screening tests including 24-hour urinary free cortisol measurement, late-night salivary cortisol testing, and the overnight 1mg dexamethasone suppression test, as these tests have high sensitivity and specificity for detecting hypercortisolism 1. The initial screening tests are crucial in confirming hypercortisolism, and the choice of test depends on the clinical presentation and patient factors.
- 24-hour urinary free cortisol measurement is a useful test, with a sensitivity of 89% and specificity of 100% 2.
- Late-night salivary cortisol testing has a sensitivity of 95% and specificity of 100% 2, making it a reliable test for detecting hypercortisolism.
- The overnight 1mg dexamethasone suppression test has a sensitivity of 75% and specificity of not applicable 2, but it is still a useful test in confirming hypercortisolism.
If the screening tests are positive, the next step is to determine the cause of hypercortisolism through ACTH level measurement.
- High ACTH levels suggest pituitary (Cushing's disease) or ectopic sources, while low ACTH levels indicate adrenal causes 2. Further testing includes high-dose dexamethasone suppression (8mg), CRH stimulation test, and imaging studies (pituitary MRI, adrenal CT/MRI, or whole-body imaging for ectopic sources).
- Inferior petrosal sinus sampling may be needed to differentiate pituitary from ectopic ACTH sources, with a central-to-peripheral ACTH ratio of ≥2:1 before CRH or desmopressin and ≥3:1 ratio after CRH or desmopressin stimulation confirming a pituitary source of ACTH excess 2. This stepwise approach is necessary because Cushing's syndrome can have serious complications, including diabetes, hypertension, osteoporosis, and increased cardiovascular risk if left untreated. The most recent and highest quality study recommends a systematic approach to diagnosing and managing Cushing's syndrome, with a focus on confirming hypercortisolism and determining its cause 2.
From the Research
Diagnostic Approach to Cushing's Syndrome
The diagnostic workup for Cushing's syndrome involves a stepwise process to confirm the diagnosis and establish the etiology of the condition.
- The initial step is to exclude exogenous steroid use 3, 4, 5.
- Screening tests for endogenous Cushing's syndrome include: + 24-hour urinary free cortisol test 3, 4, 6, 7 + Late-night salivary cortisol test 3, 4, 6, 5 + 1-mg dexamethasone suppression test 4, 5
- These tests help confirm hypercortisolism, which is essential before proceeding with further investigations.
Differentiating the Cause of Cushing's Syndrome
Once hypercortisolism is confirmed, the next step is to differentiate between ACTH-dependent and ACTH-independent causes by measuring plasma ACTH concentrations 3, 4, 6, 5.
- ACTH-dependent causes account for 80-85% of cases, while ACTH-independent causes account for 15-20% of cases 4.
- Further assessment with imaging modalities, such as pituitary magnetic resonance imaging and adrenal or whole-body imaging, can help identify the source of hypercortisolism 3, 4, 6, 5.
- Dynamic biochemical testing, including bilateral inferior petrosal sinus sampling, can also help differentiate between pituitary-dependent and ectopic ACTH-dependent Cushing's syndrome 4, 6, 5.
Importance of Accurate Diagnosis
Accurate diagnosis and localization of the source of Cushing's syndrome are crucial to optimize therapy for this complex disorder 5.
- A high level of urinary free cortisol can negate the need for other test procedures in patients with obvious symptoms and signs of Cushing's syndrome 7.
- However, the use of urinary free cortisol as a screening test has its limitations, and it is recommended to use it in combination with other screening tests to increase diagnostic yield 7.