What is the appropriate workup and treatment for a patient suspected of having Cushing's syndrome?

Cushing's Syndrome Workup

Initial Screening: Rule Out Exogenous Causes First

Before any testing, immediately exclude all sources of exogenous glucocorticoid exposure, including oral steroids, inhaled corticosteroids, topical preparations, and injectable formulations 1, 2, 3. This is the most common cause of Cushing's syndrome and must be addressed before pursuing an endogenous workup 2.

Screening Tests for Endogenous Cushing's Syndrome

Once exogenous causes are excluded, perform any one or combination of these first-line screening tests 1, 3, 4:

• 24-hour urinary free cortisol (UFC) - elevated levels confirm hypercortisolism 1, 3, 4
• Late-night salivary cortisol - loss of normal circadian rhythm indicates autonomous cortisol production 1, 3, 4
• 1 mg overnight dexamethasone suppression test (DST) - failure to suppress cortisol to <1.8 μg/dL indicates Cushing's syndrome 1, 3, 4

Important caveats: False positives occur with severe obesity, uncontrolled diabetes, depression, alcoholism, and medications affecting CYP3A4 metabolism 1. Oral estrogens increase corticosteroid-binding globulin and can falsely elevate results 1. If screening tests are mildly abnormal or equivocal, consider pseudo-Cushing's states and repeat testing 1.

Determining ACTH-Dependent vs. ACTH-Independent Disease

After confirming hypercortisolism, measure morning (8-9 AM) plasma ACTH levels to classify the etiology 1, 5:

• ACTH >5 ng/L (detectable) = ACTH-dependent Cushing's syndrome 1, 5
• ACTH <5 ng/L (low/undetectable) = ACTH-independent (adrenal) Cushing's syndrome 1, 5
• ACTH >29 ng/L = 70% sensitivity and 100% specificity for Cushing's disease 1

Workup for ACTH-Independent Cushing's Syndrome

Proceed directly to adrenal imaging with CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 1, 5.

Management based on imaging:

• Unilateral adrenal adenoma → laparoscopic adrenalectomy 6, 1
• Suspected adrenocortical carcinoma → open adrenalectomy with possible adjuvant therapy 6, 1
• Bilateral hyperplasia → medical management or bilateral adrenalectomy 1

Workup for ACTH-Dependent Cushing's Syndrome

Step 1: Pituitary MRI

Obtain high-quality pituitary MRI with thin slices (3T preferred over 1.5T) to identify pituitary adenomas 1:

• Adenoma ≥10 mm → strongly suggests Cushing's disease, proceed to transsphenoidal surgery 1
• Adenoma 6-9 mm → consider CRH stimulation test or proceed to BIPSS 1
• No adenoma or <6 mm lesion → proceed to BIPSS 1

Step 2: Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard for distinguishing pituitary from ectopic ACTH sources when MRI is inconclusive 1, 5. This must be performed at a specialized center by an experienced interventional radiologist 1.

Diagnostic criteria for pituitary source:

• Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin stimulation 1, 5
• Central-to-peripheral ACTH ratio ≥3:1 after CRH/desmopressin stimulation 1, 5

Critical timing: For cyclic Cushing's disease, confirm active hypercortisolism immediately before BIPSS, and stop all steroidogenesis inhibitors prior to testing 1.

Step 3: If Ectopic ACTH Suspected

Perform neck-to-pelvis thin-slice CT scan to localize ectopic ACTH-secreting tumors 1. Consider 68Ga-DOTATATE PET imaging for neuroendocrine tumors not visible on conventional imaging 1.

Additional Diagnostic Tests

CRH or Desmopressin Stimulation Test

Use when pituitary adenoma is 6-9 mm on MRI or to distinguish true Cushing's from pseudo-Cushing's states 1:

• Cortisol rise >38 nmol/L at 15 minutes after CRH indicates Cushing's disease 1
• Measure plasma dexamethasone levels during testing to confirm adequate suppression and rule out false positives 1

Dex-CRH Test

This combined test has 90% sensitivity and 95% specificity for Cushing's disease and helps distinguish from pseudo-Cushing's states 1.

Management of Mild Autonomous Cortisol Secretion (MACS)

Previously called "subclinical Cushing's syndrome," MACS is defined by failed cortisol suppression on 1 mg DST without overt Cushing's features 6:

• MACS does not progress to overt Cushing's syndrome but is associated with diabetes, hypertension, cardiovascular events, vertebral fractures, and mortality 6
• Consider adrenalectomy for younger patients with progressive metabolic comorbidities attributable to cortisol excess after shared decision-making 6
• Annual clinical screening for new or worsening comorbidities if managed non-surgically 6

Common Pitfalls to Avoid

• Never rely solely on DST without measuring ACTH levels - this can lead to misdiagnosis 1
• Confirm adequate dexamethasone absorption by measuring plasma dexamethasone levels during testing 1
• Remember that up to one-third of patients may have discordant test results - use clinical context to guide management 1
• For adrenal incidentalomas, always screen for hormonal hypersecretion including cortisol, catecholamines, and androgens (if virilization present) 6
• Cyclic Cushing's requires periodic re-evaluation as single tests may miss active disease phases 1