What are the next steps if a patient has an elevated 24-hour urine cortisol level but a normal decamethasone (dexamethasone) suppression test?

Diagnostic Approach for Discordant Screening Tests in Cushing's Syndrome

When you have an elevated 24-hour urine cortisol (100 μg/24h, assuming this exceeds your laboratory's upper limit of normal) but a normal dexamethasone suppression test, you should repeat both tests multiple times and add late-night salivary cortisol measurements, as discordant results are common in mild or cyclic Cushing's syndrome and no single test is definitive. 1

Understanding the Discordance

• Intra-patient variability is substantial - 24-hour urine free cortisol can vary by up to 50% between collections, which is why at least 2-3 collections are recommended before making diagnostic decisions 1

• Mild Cushing's syndrome frequently presents with discordant results - patients with early or mild disease may have only intermittent elevations in UFC while maintaining some degree of cortisol suppressibility on dexamethasone testing 2

• Cyclic Cushing's syndrome can produce weeks to months of normal cortisol secretion interspersed with episodes of excess, leading to inconsistent test results depending on when sampling occurs 1

Recommended Diagnostic Algorithm

Step 1: Repeat Initial Screening Tests

• Obtain 2-3 additional 24-hour urine free cortisol collections to account for the high random variability and establish whether elevation is consistent 1

• Repeat the overnight 1-mg dexamethasone suppression test and consider measuring dexamethasone levels concomitantly with cortisol to exclude false-negative results from abnormal drug metabolism 1

• Verify the normal cutoff for your dexamethasone suppression test - the appropriate threshold is cortisol <1.8 μg/dL (50 nmol/L), not <5 μg/dL, as values between 1.8-5 μg/dL can represent partial suppression seen in mild Cushing's syndrome 1, 3

Step 2: Add Late-Night Salivary Cortisol

• Obtain at least 2-3 late-night salivary cortisol measurements (collected at 11 PM-midnight), as this test has >90% sensitivity and the highest specificity among screening tests for Cushing's syndrome 4, 5

• Late-night salivary cortisol is particularly valuable because it is independent of corticosteroid-binding globulin changes and dexamethasone compliance issues that can confound other tests 1

• An abnormal threshold is >3.6 nmol/L, though patients with mild disease may have values just above the upper limit of normal 5

Step 3: Exclude Pseudo-Cushing's States and Interfering Factors

Before proceeding with extensive workup, systematically evaluate for conditions that cause false-positive results: 1

• Medications affecting dexamethasone metabolism:

  • CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) accelerate dexamethasone clearance, causing false-positive DST 1
  • Oral estrogens/contraceptives increase corticosteroid-binding globulin, elevating total cortisol without true hypercortisolism 1, 5

• Physiologic states mimicking Cushing's:

  • Severe obesity, psychiatric disorders (especially depression), alcohol use disorder, and polycystic ovary syndrome can activate the HPA axis 1
  • These pseudo-Cushing's states typically produce UFC elevations <3-fold above normal 1

• Collection issues:

  • Verify adequate 24-hour urine collection (check creatinine excretion) 1
  • Renal impairment (CrCl <60 mL/min) or significant polyuria (>5 L/24h) invalidates UFC results 1

Step 4: If Discordance Persists with Repeated Testing

When multiple UFC collections show elevation but dexamethasone suppression remains normal, consider: 1

• Dex-CRH test or desmopressin test to distinguish true Cushing's syndrome from pseudo-Cushing's states - these tests have shown good diagnostic performance and excellent agreement when both are performed 1

• Extended monitoring for cyclic disease - if clinical suspicion remains high, periodic sequential testing over weeks to months may be necessary to capture episodes of cortisol excess 1

Critical Pitfalls to Avoid

• Do not rely on a single abnormal test result - neither a normal UFC nor a normal dexamethasone suppression test excludes mild Cushing's syndrome when used in isolation 2

• Do not proceed to ACTH measurement and localization studies until you have definitively established hypercortisolism with concordant abnormalities on multiple screening tests 4

• Ensure proper dexamethasone dosing and timing - the standard overnight test uses 1 mg given between 11 PM-midnight with cortisol measured at 8 AM 1, 6

• Consider measuring dexamethasone levels during suppression testing if results remain equivocal, as this can identify patients with abnormal drug absorption or metabolism 1

When to Suspect Mild or Early Cushing's Syndrome

Maintain high clinical suspicion and continue periodic testing if the patient has: 1, 2

• Progressive clinical features suggestive of Cushing's syndrome (proximal muscle weakness, wide purple striae, easy bruising, facial plethora)
• Young age with features atypical for metabolic syndrome alone
• Hypertension and diabetes that are difficult to control
• Progressive osteoporosis or fractures

1, 4, 5, 2, 3