What is the appropriate diagnostic workup and treatment for a patient with elevated serum cortisol?

Diagnostic Workup and Treatment for Elevated Serum Cortisol

Initial Diagnostic Approach

The first critical step when encountering elevated serum cortisol is to exclude exogenous glucocorticoid use, then confirm true hypercortisolism with first-line screening tests, and finally determine whether the cause is ACTH-dependent or ACTH-independent. 1, 2

Exclude Exogenous Steroids First

• Any patient taking oral, inhaled, topical, or injected corticosteroids will have elevated cortisol measurements and suppressed endogenous production 1, 3
• Exogenous glucocorticoid use is the most common cause of Cushing syndrome and must be ruled out before pursuing further workup 2, 4
• Common culprits include prednisone, dexamethasone, inhaled fluticasone, and topical steroid preparations 3

Confirm Hypercortisolism with Screening Tests

Once exogenous steroids are excluded, perform at least two of the following first-line screening tests to confirm endogenous hypercortisolism 1, 5:

• 24-hour urinary free cortisol (UFC): Elevated levels confirm hypercortisolism, with values rising proportionally more than plasma cortisol because cortisol-binding globulin saturates around 500 nmol/L 1, 6
• 1-mg overnight dexamethasone suppression test (DST): Administer 1 mg dexamethasone at 11 PM and measure morning cortisol at 8 AM; failure to suppress cortisol to <1.8 μg/dL (50 nmol/L) indicates Cushing syndrome 1, 6
• Late-night salivary cortisol: Loss of normal circadian rhythm with elevated midnight cortisol is characteristic of Cushing syndrome 1, 2

Important caveat: Pseudo-Cushing states (severe depression, alcoholism, severe obesity, uncontrolled diabetes) can cause false-positive screening results 1, 7. In obese patients, repeated (2-3) midnight salivary cortisol measurements improve specificity 1.

Determine ACTH-Dependent vs. ACTH-Independent

Measure Morning Plasma ACTH

Morning (08:00-09:00h) plasma ACTH measurement is the definitive test to classify Cushing syndrome 1:

• ACTH >5 ng/L (>1.1 pmol/L): Indicates ACTH-dependent Cushing syndrome (pituitary or ectopic source) 1
• ACTH >29 ng/L (>6.4 pmol/L): Provides 70% sensitivity and 100% specificity for Cushing disease (pituitary adenoma) 1
• ACTH <5 ng/L or undetectable: Indicates ACTH-independent Cushing syndrome (adrenal source) 1

Morning timing is critical because ACTH follows a circadian rhythm; afternoon measurements are unreliable 1. The patient does not need to be fasting 1.

Workup for ACTH-Dependent Cushing Syndrome (Elevated ACTH)

ACTH-dependent disease accounts for 75-80% of endogenous Cushing syndrome cases 1, 2. The goal is to distinguish pituitary Cushing disease from ectopic ACTH secretion.

Step 1: High-Resolution Pituitary MRI

• Obtain a 3-Tesla pituitary MRI with 1-3 mm thin slices and gadolinium contrast to detect microadenomas 1
• MRI sensitivity for ACTH-secreting adenomas is only ~63%, missing approximately one-third of cases 1
• If adenoma ≥10 mm: Proceed directly to transsphenoidal surgery 1
• If adenoma 6-9 mm: Perform CRH or desmopressin stimulation test 1
• If no adenoma or <6 mm lesion: Proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1

Step 2: CRH or Desmopressin Stimulation Test (for 6-9 mm lesions)

• A cortisol rise >38 nmol/L at 15 minutes after CRH administration supports pituitary Cushing disease with >70% sensitivity 1
• This test helps distinguish pituitary from ectopic sources, as ectopic tumors typically show blunted responses 1

Step 3: Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard for differentiating pituitary from ectopic ACTH secretion when MRI is inconclusive, with 96-100% sensitivity and near-100% specificity 1:

• Diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 at baseline or ≥3:1 after CRH/desmopressin stimulation confirms pituitary source 1
• Inter-petrosal gradient ≥1.4 after stimulation suggests tumor lateralization (58-87.5% concordance with surgical findings) 1
• Must be performed in a specialized center by an experienced interventional radiologist 1
• Confirm active hypercortisolism on the morning of the procedure 1
• Discontinue all steroidogenesis inhibitors before BIPSS with appropriate washout periods 1
• Measure prolactin simultaneously from petrosal sinuses to confirm adequate catheter placement 1

Consider Ectopic ACTH Syndrome

Clinical clues suggesting ectopic ACTH secretion include 1:

• Rapid symptom onset
• Marked hypokalemia (extremely high cortisol overwhelms 11β-HSD2, producing mineralocorticoid effect)
• Very high urinary free cortisol levels

If ectopic ACTH suspected or BIPSS indicates peripheral source 1:

• Obtain neck-to-pelvis thin-slice CT scan to locate neuroendocrine tumors
• Consider ⁶⁸Ga-DOTATATE PET imaging if CT is negative (identifies ~65% of occult tumors)
• Pulmonary carcinoid tumors account for up to 40% of ectopic ACTH cases 1

Workup for ACTH-Independent Cushing Syndrome (Low/Undetectable ACTH)

Adrenal Imaging

• Obtain adrenal CT or MRI to identify adrenal lesion(s) 1
• Evaluate for adrenal adenoma, carcinoma, or bilateral hyperplasia 1

Treatment Based on Imaging Findings

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

Treatment Approach

First-Line: Surgical Resection

Surgery to remove the source of excess cortisol production is first-line therapy for all forms of endogenous Cushing syndrome 2, 4:

• Cushing disease: Transsphenoidal resection of pituitary adenoma
• Adrenal adenoma: Laparoscopic adrenalectomy 1
• Ectopic ACTH: Surgical removal of ectopic tumor when possible 1

Medical Management

For patients not responsive to surgery or awaiting definitive treatment 2:

• Steroidogenesis inhibitors: Ketoconazole, metyrapone (block cortisol synthesis)
• Pituitary-targeted drugs: Pasireotide (for Cushing disease)
• Glucocorticoid receptor blockers: Mifepristone

Additional Options

• Radiation therapy: For persistent or recurrent pituitary disease 2
• Bilateral adrenalectomy: Last resort for refractory cases 1, 2

Critical Pitfalls to Avoid

• Never rely on a single screening test: At least two abnormal tests are needed to confirm hypercortisolism 1, 5
• Do not skip ACTH measurement: This is the definitive factor distinguishing ACTH-dependent from ACTH-independent disease 1
• Do not proceed to BIPSS without confirming active hypercortisolism: Cyclic Cushing disease requires confirmation of active phase 1
• No single test reaches 100% specificity: Discordant results occur in up to one-third of patients; integrate clinical, biochemical, and imaging data 1
• Measure dexamethasone levels during DST: Confirms adequate absorption and rules out false-positives from abnormal metabolism 1
• Consider drug interactions: CYP3A4 inducers (rifampin, anticonvulsants) can cause false-positive DST results 1

Monitoring and Complications

While awaiting definitive treatment 1:

• Closely monitor blood pressure, glucose, and electrolytes
• Initiate steroidogenesis inhibitors in severe hypercortisolism with complications
• Screen for and treat hypertension, diabetes, infections, and osteoporosis
• Lifelong post-therapy monitoring is required to treat comorbidities and detect recurrence 4