Assessment for Elevated Morning Cortisol (541 nmol/L)
Your patient requires immediate confirmation of hypercortisolism with additional first-line screening tests, followed by ACTH measurement to determine the source, and then targeted imaging based on ACTH dependency. 1
Immediate Diagnostic Workup
Confirm Hypercortisolism with Additional Screening Tests
Your morning cortisol of 541 nmol/L is elevated above the normal range (200-650 nmol/L), but a single morning cortisol alone is insufficient for diagnosis since it falls within the upper normal range. 2 You must confirm true hypercortisolism using:
24-hour urinary free cortisol (UFC) - This measures integrated cortisol exposure over 24 hours and is markedly elevated in clinically apparent Cushing's syndrome. 1, 2 Ensure complete urine collection with appropriate total volume to avoid false results. 3
Late-night salivary cortisol (11 PM) - This detects loss of normal circadian rhythm, which is a hallmark of Cushing's syndrome. 1, 4 Normal values should be <3.6 nmol/L; elevated values (>3.6 nmol/L) have 92% sensitivity for Cushing's syndrome. 4
Low-dose dexamethasone suppression test (1 mg overnight) - Give 1 mg dexamethasone at 11 PM and measure cortisol at 8 AM. 1, 2 Normal suppression is cortisol <50 nmol/L (<1.8 μg/dL); failure to suppress indicates Cushing's syndrome. 2, 3
Important: Using at least two different screening tests increases diagnostic accuracy, as combining elevated late-night salivary cortisol and elevated UFC identifies 100% of Cushing's syndrome cases. 4
Determine ACTH Dependency
Once hypercortisolism is confirmed, measure morning (8-9 AM) plasma ACTH to classify the syndrome: 1, 5
- ACTH >5 ng/L (>1.1 pmol/L) = ACTH-dependent Cushing's syndrome (pituitary adenoma or ectopic ACTH source) 6, 5
- ACTH >29 ng/L = 70% sensitivity and 100% specificity for Cushing's disease (pituitary source) 6, 5
- Low or undetectable ACTH = ACTH-independent Cushing's syndrome (adrenal source) 5
Physical Examination - Specific Features to Assess
Look for these specific clinical manifestations of hypercortisolism: 6, 7
- Skin changes: Facial plethora, easy bruising, wide purple striae (>1 cm), thin skin 6, 3
- Body habitus: Central obesity, dorsocervical fat pad (buffalo hump), supraclavicular fat pad enlargement 6, 7
- Musculoskeletal: Proximal muscle weakness (difficulty rising from chair or climbing stairs) 6, 3
- Cardiovascular: Hypertension 6, 3
- Metabolic signs: Evidence of hyperglycemia or diabetes 6, 3
- Other: Hirsutism, psychiatric disturbances, mood disorders 6, 7
Subsequent Imaging Based on ACTH Results
If ACTH-Dependent (ACTH >5 ng/L):
Pituitary MRI with thin slices (3T preferred over 1.5T) to identify pituitary adenoma 5
BIPSS (if MRI inconclusive) - This is the gold standard for differentiating pituitary from ectopic ACTH sources, with diagnostic criteria of central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH or desmopressin stimulation. 6, 5 This must be performed at a specialized center by an experienced interventional radiologist. 6
If ACTH-Independent (Low/Undetectable ACTH):
Critical Pitfalls to Avoid
False positives can occur with severe obesity, uncontrolled diabetes, alcoholism, depression, and disrupted sleep-wake cycles. 1, 3 Clinical correlation is essential.
Cyclic Cushing's syndrome may show intermittently normal cortisol levels, requiring repeated testing if clinical suspicion remains high. 1, 3
Incomplete urine collections invalidate UFC results - verify adequate total volume. 3
Drug interactions with dexamethasone suppression testing (CYP3A4 inducers, oral estrogens) can cause false results. 5
Never rely on a single morning cortisol alone - the diagnosis requires demonstration of autonomous cortisol secretion through loss of normal feedback or circadian rhythm. 1, 2