What is the recommended workup for a patient with suspected hypercortisolism?

Workup for Suspected Hypercortisolism

Initial Screening Tests

All patients with suspected hypercortisolism should undergo screening with one or more of the following tests, obtaining 2–3 separate measurements of each to account for biological variability and detect cyclic disease: 1, 2

Recommended First-Line Screening Options

• 1-mg overnight dexamethasone suppression test (DST): Administer 1 mg dexamethasone at 11 PM–midnight and measure serum cortisol at 8 AM; cortisol ≥1.8 μg/dL (≥50 nmol/L) indicates abnormal suppression, while cortisol >5 μg/dL (>138 nmol/L) strongly suggests overt Cushing's syndrome 1, 2

• Late-night salivary cortisol (LNSC): Collect saliva between 11 PM–midnight on 2–3 separate nights; levels >3.6 nmol/L are abnormal, with sensitivity 92–100% and specificity 93–100% 1, 2, 3

• 24-hour urinary free cortisol (UFC): Obtain 2–3 complete 24-hour collections; values >100 μg/24 hours (>1.6 μmol/24 hours) in symptomatic patients are diagnostic, though 40 μg/24 hours represents a better threshold for initial screening 1, 2, 4

The DST is the preferred initial test when clinically appropriate, particularly for patients with disrupted sleep schedules or suspected adrenal tumors. 1 However, multiple LNSC measurements may be easier for patients to complete and are particularly useful when cyclic disease is suspected. 1

Critical Pre-Test Considerations

Before initiating any biochemical testing, you must exclude exogenous glucocorticoid exposure from all sources: 2, 4

• Oral corticosteroids (prednisone, dexamethasone)
• Inhaled steroids (fluticasone, budesonide)
• Topical preparations (hydrocortisone creams)
• Intra-articular or epidural injections (triamcinolone, methylprednisolone)
• Over-the-counter supplements containing undeclared steroids

Failure to exclude exogenous glucocorticoids leads to unnecessary testing and misinterpretation of suppressed endogenous cortisol. 2, 4

Additional Interfering Factors to Address

• Oral estrogens/contraceptives: Increase cortisol-binding globulin, falsely elevating total cortisol without true hypercortisolism 1, 2, 4

• CYP3A4 inducers (phenytoin, rifampin, carbamazepine): Accelerate dexamethasone metabolism, causing false-positive DST 1, 2, 4

• CYP3A4 inhibitors (ketoconazole, ritonavir): Increase dexamethasone levels, causing false-negative DST 2, 4

• Pseudo-Cushing's states: Severe obesity, depression, alcoholism, and polycystic ovary syndrome can activate the HPA axis and mimic mild hypercortisolism 1, 2, 4

Enhancing DST Accuracy

Measure dexamethasone levels concomitantly with cortisol during the DST to confirm adequate drug absorption and reduce false-positive results. 1, 2, 5 A dexamethasone level ≥4.5 nmol/L confirms adequate suppression; levels below this threshold indicate inadequate drug bioavailability and invalidate the test. 5

This approach reduces false-positive results from 10% to 6% in patients with adrenal incidentalomas and improves specificity from 63% to 91% at the 138 nmol/L cortisol cutoff. 5

Confirming the Diagnosis

If ≥2 screening tests are abnormal, proceed to measure 9 AM plasma ACTH to determine whether hypercortisolism is ACTH-dependent or ACTH-independent. 2, 4

ACTH Interpretation

• ACTH >5 ng/L (>1.1 pmol/L): Indicates ACTH-dependent Cushing's syndrome (pituitary adenoma or ectopic ACTH source) 2, 4

• ACTH >29 ng/L (>6.4 pmol/L): Provides 70% sensitivity and 100% specificity for pituitary Cushing's disease specifically 2

• ACTH <5 ng/L or undetectable: Indicates ACTH-independent Cushing's syndrome (adrenal source) 2, 4

Localization Based on ACTH Results

For ACTH-Dependent Disease (ACTH >5 ng/L)

Obtain high-resolution 3-Tesla pituitary MRI with 1-mm thin slices and gadolinium contrast to detect corticotroph adenomas. 1, 2 MRI has only 63% sensitivity, missing approximately one-third of microadenomas. 2

MRI-Based Algorithm

• Adenoma ≥10 mm: Proceed directly to transsphenoidal surgery without further testing 1, 2

• Adenoma 6–9 mm: Perform CRH or desmopressin stimulation test; a cortisol rise >38 nmol/L at 15 minutes supports pituitary source with >70% sensitivity 1, 2

• No adenoma or lesion <6 mm: Bilateral inferior petrosal sinus sampling (BIPSS) is mandatory to differentiate pituitary from ectopic ACTH secretion 1, 2

BIPSS Diagnostic Criteria

BIPSS is the gold standard for distinguishing pituitary Cushing's disease from ectopic ACTH syndrome, with 96–100% sensitivity and near-100% specificity. 1, 2

• Central-to-peripheral ACTH ratio ≥2:1 at baseline OR ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 1, 2

• Inter-petrosal ACTH gradient ≥1.4 after stimulation suggests tumor lateralization (58–87.5% concordance with surgical findings) 2

BIPSS must be performed only in specialized centers by experienced interventional radiologists, with confirmation of active hypercortisolism on the morning of the procedure. 1, 2 All steroidogenesis inhibitors must be discontinued with appropriate washout periods before testing. 2

For ACTH-Independent Disease (ACTH <5 ng/L)

Obtain adrenal CT or MRI to identify the adrenal lesion(s). 1, 2 Treatment options include:

• Adrenal adenoma: Laparoscopic adrenalectomy 1, 2
• Adrenal carcinoma: Open adrenalectomy with possible adjuvant therapy 2
• Bilateral hyperplasia: Medical management or unilateral adrenalectomy 2

Evaluation for Ectopic ACTH Syndrome

If BIPSS indicates a peripheral source (central-to-peripheral ratio <2:1 baseline or <3:1 after stimulation), pursue imaging to localize neuroendocrine tumors: 1, 2

• Neck-to-pelvis thin-slice CT scan as initial imaging 1, 2
• ⁶⁸Ga-DOTATATE PET imaging if CT is negative; identifies approximately 65% of ectopic ACTH-secreting tumors not visible on conventional imaging 2

Pulmonary carcinoid tumors account for up to 40% of ectopic ACTH cases, making them the most common ectopic source. 2

Special Considerations

Cyclic Cushing's Syndrome

Patients with cyclic disease can have weeks to months of normal cortisol secretion interspersed with hypercortisolism episodes. 1, 2 When cyclic disease is suspected:

• Obtain serial measurements over 3–6 months during symptomatic periods 1, 2
• Confirm active hypercortisolism immediately before performing BIPSS or other dynamic testing 1, 2

Mild or Subclinical Hypercortisolism

The overnight DST has poor sensitivity (18–41%) in patients with mild or periodic Cushing's syndrome, even at the stringent 1.8 μg/dL cutoff. 6, 7 In these patients:

• Rely more heavily on LNSC and UFC measurements 1, 2
• Obtain multiple measurements (2–3 of each test) 1, 2
• Consider extended monitoring if initial tests are equivocal 1, 2

Discordant Results

When screening tests yield conflicting results (e.g., abnormal DST but normal UFC): 2, 4

• Repeat both tests 2–3 times to account for 50% random variability in UFC 2, 4
• Measure dexamethasone levels during DST to exclude abnormal drug metabolism 2, 4, 5
• Consider Dex-CRH test to distinguish true Cushing's from pseudo-Cushing's states 1, 2

Common Pitfalls to Avoid

• Never use BIPSS to diagnose hypercortisolism—it is only for localization after biochemical confirmation 1

• Do not rely on a single screening test—obtain 2–3 measurements of each modality 1, 2

• Avoid testing night-shift workers with LNSC due to disrupted circadian rhythm 1, 2

• Do not interpret elevated total cortisol as pathologic without considering cortisol-binding globulin status—always inquire about oral contraceptives, estrogen therapy, and pregnancy 2, 4

• Never delay treatment of suspected acute adrenal crisis for diagnostic testing—draw blood for cortisol and ACTH before administering 100 mg hydrocortisone IV 4