Cushing's Syndrome Workup
Initial Step: Exclude Exogenous Glucocorticoid Use
Before any biochemical testing, you must definitively rule out iatrogenic Cushing's syndrome from exogenous glucocorticoid use, as this is the most common cause and failure to exclude it leads to unnecessary testing and mismanagement. 1, 2
Review all medications including:
- Oral, inhaled, topical, and injectable corticosteroids 1
- Over-the-counter preparations and supplements that may contain steroids 2
Step 1: Confirm Hypercortisolism with First-Line Screening Tests
Perform 2-3 of the following first-line screening tests to confirm hypercortisolism (no single test has 100% accuracy): 1, 2, 3
Recommended Initial Tests:
24-hour urinary free cortisol (UFC): Collect 2-3 samples on separate days; abnormal if >193 nmol/24h (>70 μg/m²) with 89% sensitivity and 100% specificity 1, 4
Late-night salivary cortisol (LNSC): Collect ≥2 samples on consecutive days; abnormal based on local assay cut-off (typically >14.46 nmol/L) with 95% sensitivity and 100% specificity 1, 2
Overnight 1-mg dexamethasone suppression test (DST): Give 1 mg dexamethasone at 11 PM, measure serum cortisol at 8-9 AM; abnormal if ≥50 nmol/L (≥1.8 μg/dL) with 95% sensitivity and 80% specificity 1, 3
If any test is abnormal, repeat 1-2 screening tests to confirm the diagnosis. 1, 2
Important Pitfalls to Avoid:
Consider false positives in these conditions before confirming diagnosis: 1, 2, 5
- Severe obesity
- Uncontrolled diabetes mellitus
- Depression or psychiatric illness
- Alcoholism
- Pregnancy
- Medications that induce CYP3A4 (rifampin, phenytoin, carbamazepine) affecting dexamethasone metabolism 6
- Oral estrogen therapy (increases cortisol-binding globulin) 6
Measuring dexamethasone levels alongside cortisol during DST improves test interpretability and rules out abnormal dexamethasone metabolism. 1, 2
Step 2: Determine ACTH Dependency
Once hypercortisolism is confirmed, measure morning (8-9 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome. 1, 6, 2, 3
ACTH Interpretation:
ACTH >5 ng/L (>1.1 pmol/L): ACTH-dependent Cushing's syndrome (pituitary or ectopic source) with 68% sensitivity and 100% specificity 1, 6
ACTH >29 ng/L (>6.4 pmol/L): Strongly suggests Cushing's disease with 70% sensitivity and 100% specificity 1, 6
ACTH low or undetectable (<5 ng/L): ACTH-independent Cushing's syndrome (adrenal source) 6, 2
Step 3A: ACTH-Dependent Cushing's Syndrome Workup
If ACTH is detectable/elevated, proceed with pituitary MRI using high-quality imaging (3T preferred over 1.5T) with thin slices to detect pituitary adenomas. 1, 6, 2, 3
MRI Interpretation and Next Steps:
Adenoma ≥10 mm: Presume Cushing's disease (pituitary source); proceed to transsphenoidal surgery 1, 6, 3
Adenoma 6-9 mm: Consider CRH stimulation test or proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1, 6
No adenoma or <6 mm lesion: Perform BIPSS to definitively distinguish pituitary from ectopic ACTH source 1, 6, 3
BIPSS Diagnostic Criteria (Gold Standard):
- Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin stimulation 1, 6, 3
- Central-to-peripheral ACTH ratio ≥3:1 after CRH/desmopressin stimulation with 100% sensitivity 1, 6, 3
- Inter-petrosal sinus ACTH gradient ≥1.4 suggests tumor lateralization 6
BIPSS must be performed at a specialized center with experienced interventional radiologists due to procedural risks. 1, 6
Additional Testing for Ectopic ACTH:
If ectopic ACTH syndrome is suspected (very high UFC, profound hypokalemia, rapid onset, skin hyperpigmentation): 1, 6
- Perform neck-to-pelvis thin-slice CT scan 6
- Consider 68Ga-DOTATATE PET imaging for neuroendocrine tumor localization 6
- Bronchial carcinoid and small cell lung cancer are common ectopic sources 1
Step 3B: ACTH-Independent Cushing's Syndrome Workup
If ACTH is low/undetectable, perform adrenal CT (non-contrast preferred) or MRI to identify adrenal lesion(s). 1, 6, 2
Adrenal Imaging Interpretation:
Unilateral adenoma with HU <10 on non-contrast CT: Benign adrenocortical adenoma; proceed to laparoscopic adrenalectomy 1, 2
Unilateral mass with HU >10 or indeterminate features: Perform washout CT or chemical-shift MRI to characterize lesion 1
Suspicious for adrenocortical carcinoma (large size, irregular borders, heterogeneous enhancement): Consider open adrenalectomy with possible adjuvant therapy 1
Bilateral adrenal hyperplasia: Consider medical management or unilateral adrenalectomy depending on clinical context 6
Special Populations
Children and Adolescents:
Screen only children with unexplained weight gain PLUS either decreased height velocity or declining height standard deviation score. 1
Key differences in pediatric presentation: 1
- Growth failure (subnormal growth velocity) is highly sensitive and specific for Cushing's syndrome in prepubertal children
- Microadenomas ≤2 mm account for 98% of Cushing's disease cases in children
- Refer to multidisciplinary centers with pediatric endocrinology expertise 2, 3
Cyclic Cushing's Syndrome:
Hypercortisolism must be confirmed immediately prior to diagnostic procedures like BIPSS to ensure the patient is in an active disease phase. 6
Requires periodic re-evaluation with repeated screening tests during symptomatic periods. 6
Critical Clinical Pearls
- None of the diagnostic tests reach 100% specificity, and results may be discordant in up to one-third of patients 6
- Stop medical therapy for Cushing's disease (steroidogenesis inhibitors) before BIPSS to enable accurate interpretation 6
- The combination of clinical context and multiple test results guides management more reliably than any single test 6, 5, 7
- UFC measured by LC-MS/MS achieves the best diagnostic accuracy among first-line screening tests 4