Evaluation and Diagnosis of Cushing's Syndrome

Confirming the Diagnosis

The Endocrine Society recommends using multiple tests to confirm Cushing's syndrome, as no single test is perfect 1, 2
Low-dose dexamethasone suppression test (1 mg overnight or 2 mg/day for 2 days) is recommended as the next step to confirm the diagnosis 1, 3
Multiple late-night salivary cortisol measurements can also be used as an alternative or additional confirmatory test 1, 2
It's essential to exclude iatrogenic Cushing's syndrome (from exogenous glucocorticoid use) before proceeding with biochemical testing 4

Measure plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent Cushing's syndrome 5, 6
ACTH levels >5 ng/L suggest ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 6
Low or undetectable ACTH levels suggest ACTH-independent Cushing's syndrome (adrenal source) 6
For ACTH-dependent disease, pituitary MRI is recommended to look for adenoma 3, 6
For ACTH-independent disease, adrenal CT or MRI is indicated to identify adrenal lesion(s) 3, 6

Pituitary MRI with contrast to look for adenoma can be used in ACTH-dependent Cushing's syndrome 1, 3
CRH stimulation test may help differentiate pituitary from ectopic sources in ACTH-dependent Cushing's syndrome 2, 6
Bilateral inferior petrosal sinus sampling (BIPSS) can be used if MRI is negative or inconclusive in ACTH-dependent Cushing's syndrome 1, 3
Adrenal CT or MRI to identify adrenal adenoma, carcinoma, or hyperplasia can be used in ACTH-independent Cushing's syndrome 5, 6

Measuring dexamethasone levels during the suppression test can improve interpretation and rule out abnormal dexamethasone metabolism 3, 6
Cyclic Cushing's syndrome can produce inconsistent results, requiring periodic re-evaluation 5, 6
False positive results can occur with severe obesity, alcoholism, depression, and disrupted sleep-wake cycles 5, 6

Relying on a single test for diagnosis can lead to false positives or negatives 1, 2
Failing to exclude exogenous glucocorticoid use before testing can lead to misdiagnosis 4
Not considering pseudo-Cushing's states (depression, alcoholism, obesity) that can cause mild hypercortisolism can lead to misdiagnosis 5, 6
Proceeding directly to imaging without biochemical confirmation and ACTH determination can lead to incidental findings and misdiagnosis 1, 3

For patients with mild or fluctuating hypercortisolism, additional testing such as the desmopressin test may be needed, as recommended by the Endocrine Society 7

Bilateral inferior petrosal sinus sampling (IPSS) is the gold standard diagnostic test to confirm Cushing's disease when MRI findings are negative or equivocal, according to the Endocrine Society 8, 9
IPSS should be performed when the patient is hypercortisolemic to avoid false negatives, as suggested by the Endocrine Society 8
A central-to-peripheral ACTH gradient ≥2 before or ≥3 after CRH stimulation confirms a pituitary source, as per the Endocrine Society 9
Measuring prolactin can improve diagnostic accuracy in IPSS, as recommended by the Endocrine Society 9

No single laboratory test or combination of tests can absolutely differentiate between pituitary and ectopic ACTH-secreting tumors with 100% accuracy, highlighting the importance of clinical context and test results in guiding management, as noted by the Endocrine Society 8, 9
IPSS should preferably be performed in specialized centers due to potential patient risks, as suggested by the Endocrine Society 9