How should I evaluate and treat a patient with elevated serum cortisol?

Evaluation and Management of Elevated Serum Cortisol

When you encounter an elevated serum cortisol, immediately measure morning (08:00-09:00h) plasma ACTH to determine whether this represents ACTH-dependent or ACTH-independent disease—this single test directs your entire diagnostic and therapeutic pathway. 1

Initial Diagnostic Algorithm

Step 1: Confirm True Hypercortisolism

Before pursuing any differential diagnosis, you must biochemically confirm pathologic hypercortisolism using at least two of the following screening tests 2, 1:

• 24-hour urinary free cortisol (≥2 collections; values above upper limit of normal suggest Cushing's syndrome) 3
• Late-night salivary cortisol (≥2-3 measurements; values >upper limit of normal indicate loss of circadian rhythm) 2, 3
• 1-mg overnight dexamethasone suppression test (cortisol >50 nmol/L or >1.8 μg/dL at 08:00h is abnormal) 2, 3
• Midnight serum cortisol (≥50 nmol/L or ≥1.8 μg/dL has 100% sensitivity in pediatric populations and excellent accuracy in adults) 3, 4

Critical pitfall: Do not proceed with differential diagnosis until hypercortisolism is confirmed. Single elevated random cortisol values can occur with stress, oral contraceptives (which increase cortisol-binding globulin), severe obesity, depression, or alcoholism—these represent physiologic/non-neoplastic hypercortisolism, not true Cushing's syndrome. 5, 6

Step 2: Measure Morning Plasma ACTH

Once hypercortisolism is confirmed, obtain morning (08:00-09:00h) plasma ACTH to classify the etiology 1, 4:

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

Why morning timing matters: ACTH follows circadian rhythm with peak levels at 08:00-09:00h. All established diagnostic cutoffs are based on morning measurements; afternoon values are unreliable and cannot be interpreted using these thresholds. 1

Pathway A: ACTH-Independent Disease (Low/Undetectable ACTH)

Imaging and Localization

Obtain adrenal CT or MRI immediately to identify the adrenal lesion 1, 4:

• Adrenal adenoma: Well-circumscribed unilateral mass, typically <4 cm
• Adrenal carcinoma: Larger mass (often >6 cm), irregular borders, heterogeneous enhancement
• Bilateral adrenal hyperplasia: Bilateral nodular enlargement

Treatment Based on Imaging

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

Pathway B: ACTH-Dependent Disease (ACTH >5 ng/L)

Pituitary MRI

Obtain high-resolution 3-Tesla pituitary MRI with 1-mm thin slices and gadolinium contrast as the initial imaging study 1, 4. However, recognize that MRI detects ACTH-secreting adenomas with only 63% sensitivity—it misses approximately one-third of cases. 1

Interpretation Based on MRI Findings

If adenoma ≥10 mm: Proceed directly to transsphenoidal surgery without additional testing 1

If adenoma 6-9 mm: Perform CRH or desmopressin stimulation test 1:

• Cortisol rise >38 nmol/L at 15 minutes (with corresponding ACTH increase) confirms pituitary source with >70% sensitivity 1
• If positive, proceed to surgery
• If negative or equivocal, proceed to BIPSS

If no adenoma or lesion <6 mm: Bilateral inferior petrosal sinus sampling (BIPSS) is mandatory to differentiate pituitary from ectopic ACTH sources 1, 4

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

BIPSS is the gold standard test with 96-100% sensitivity and near-100% specificity for distinguishing pituitary from ectopic ACTH secretion. 1

Diagnostic criteria 1:

• Central-to-peripheral ACTH ratio ≥2:1 at baseline OR ≥3:1 after CRH/desmopressin stimulation confirms pituitary source
• Ratio <2:1 baseline and <3:1 after stimulation indicates ectopic ACTH source

Critical prerequisites before BIPSS 1:

• Confirm active hypercortisolism on the morning of the procedure (essential for cyclic Cushing's)
• Discontinue all steroidogenesis inhibitors with appropriate washout periods
• Perform only at specialized centers with experienced interventional radiologists

If BIPSS indicates ectopic source: Obtain neck-to-pelvis thin-slice CT scan to locate neuroendocrine tumor. If CT is negative, consider ⁶⁸Ga-DOTATATE PET imaging, which identifies approximately 65% of ectopic ACTH-secreting tumors not visible on conventional imaging. 1 Pulmonary carcinoid tumors account for up to 40% of ectopic ACTH cases. 1

Medical Management Considerations

Severity-Based Treatment Selection

For severe hypercortisolism (profound hypokalemia, psychosis, uncontrolled diabetes, severe hypertension): Rapid cortisol normalization is the primary goal to prevent life-threatening complications 2, 3:

• First-line: Osilodrostat or metyrapone (response within hours) 2
• Alternative: Ketoconazole (response within days) 2
• If hospitalized and unable to take oral medications: IV etomidate 2
• If refractory to optimized medical therapy: Consider bilateral adrenalectomy 2

For mild-to-moderate disease 2:

• Ketoconazole, osilodrostat, or metyrapone are typically preferred
• Cabergoline may be used for mild disease (slower onset, less effective, but requires less frequent dosing and may cause tumor shrinkage)
• Pasireotide can shrink tumors but has high hyperglycemia risk (avoid in diabetics)

Mifepristone (glucocorticoid receptor blocker): Effective for controlling metabolic effects regardless of etiology, particularly useful for glucose intolerance and hypertension. Critical caveat: Cortisol levels remain elevated during treatment, so you cannot use biochemical markers to assess for adrenal insufficiency—only clinical features can guide dosing. Monitor for hypokalemia (may require spironolactone) and endometrial hypertrophy. 2

Monitoring During Medical Therapy

Use multiple serial measurements of both urinary free cortisol and late-night salivary cortisol to monitor treatment response 2, 3. Watch closely for signs of adrenal insufficiency (fatigue, hypotension, hyponatremia) as overtreatment can be life-threatening.

Common Pitfalls to Avoid

1. Do not diagnose Cushing's syndrome based on a single elevated random cortisol—always confirm with proper screening tests 5, 6

2. Do not skip ACTH measurement—proceeding directly to imaging without knowing ACTH status leads to misdiagnosis and inappropriate treatment 1

3. Do not rely solely on pituitary MRI in ACTH-dependent disease—63% sensitivity means you will miss one-third of pituitary adenomas 1

4. Do not perform BIPSS without confirming active hypercortisolism that morning—cyclic Cushing's patients may be in remission phase, yielding false-negative results 1

5. Exclude pseudo-Cushing's states (depression, alcoholism, severe obesity, uncontrolled diabetes) before pursuing invasive testing. These conditions resolve with treatment of the underlying disorder over 3-6 months. 2, 5

6. Check for medication interference: CYP3A4 inducers (phenytoin, rifampin, carbamazepine) accelerate dexamethasone metabolism causing false-positive suppression tests; oral estrogens increase cortisol-binding globulin causing falsely elevated total cortisol 3, 7

Urgency of Treatment

Untreated Cushing's syndrome carries significant morbidity and mortality from cardiovascular disease, diabetes, osteoporosis, infections, and thromboembolic complications. 4 The duration of hypercortisolism directly correlates with the extent of comorbidities and overall survival. 8 Therefore, once the diagnosis is confirmed and localized, proceed expeditiously to definitive treatment—either surgical resection or, if surgery is contraindicated, aggressive medical management to normalize cortisol levels.