What are the initial laboratory tests for diagnosing Cushing's syndrome?

Initial Laboratory Tests for Diagnosing Cushing's Syndrome

The initial laboratory tests for diagnosing Cushing's syndrome should include 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), and overnight 1-mg dexamethasone suppression test (DST), with at least two different tests recommended for patients with intermediate to high clinical suspicion. 1, 2

Diagnostic Algorithm

Step 1: Assess Clinical Suspicion and Rule Out Exogenous Glucocorticoids

• First determine if the patient is taking exogenous glucocorticoids (oral, injections, inhalers, topical)
• If yes, stop glucocorticoids if possible and reassess
• Evaluate clinical likelihood of endogenous Cushing's syndrome (CS)

Step 2: Select Initial Screening Tests Based on Clinical Suspicion

For Low Clinical Suspicion:

• Single screening test (any of the following):
  • Late night salivary cortisol (LNSC)
  • 24-hour urinary free cortisol (UFC)
  • Overnight 1-mg dexamethasone suppression test (DST)

For Intermediate or High Clinical Suspicion:

• 2-3 screening tests from the options above

Step 3: Interpret Results and Follow-Up

• If normal: CS is unlikely
• If abnormal: Repeat 1-2 screening tests
• If still abnormal: Exclude non-neoplastic hypercortisolism
• If equivocal: Consider additional tests (Dex-CRH, DDAVP, midnight serum cortisol)

Key Considerations for Each Test

24-Hour Urinary Free Cortisol (UFC)

• Reflects overall cortisol production
• Collect 2-3 specimens for confirmation
• Avoid in patients with creatinine clearance <60 mL/min 2
• False positives can occur with high fluid intake, certain medications

Late Night Salivary Cortisol (LNSC)

• High sensitivity (>90%) and specificity (100%) 2
• Easier for patient collection (≥2 on consecutive days recommended)
• Particularly useful for detecting loss of normal circadian rhythm
• Excellent for longitudinal surveillance of cyclic CS

Overnight 1-mg Dexamethasone Suppression Test (DST)

• Useful in patients with disrupted circadian rhythms (e.g., shift workers)
• Not recommended in women taking estrogen-containing oral contraceptives
• Consider measuring dexamethasone levels along with cortisol to improve test interpretability 1, 2
• A cortisol cutoff of <1.8 μg/dL may increase sensitivity 3

Important Caveats and Pitfalls

False Positives

• Several conditions can cause false positive results:
  • Severe obesity
  • Pregnancy
  • Polycystic ovary syndrome (PCOS)
  • Uncontrolled diabetes mellitus
  • Anorexia/malnutrition
  • Acute illness/surgery
  • Excessive exercise
  • Depression and alcoholism (pseudo-Cushing's states) 2

Medication Interference

• Certain medications can alter cortisol metabolism or interfere with measurements:
  • Anticonvulsants
  • Oral estrogens
  • CYP3A4 inducers/inhibitors
  • Grapefruit juice
  • Licorice 2

Dexamethasone Bioavailability

• Inadequate dexamethasone levels can cause false positive DST results
• Consider measuring serum dexamethasone during DST
• Dexamethasone levels <1.8 ng/mL suggest inadequate absorption or compliance 3
• Renal dysfunction and diabetes can affect dexamethasone levels 3

Mild or Cyclic Cushing's Syndrome

• Standard tests may miss mild or episodic hypercortisolism
• The overnight DST has reduced sensitivity (as low as 18-41%) in mild/periodic CS 4
• Multiple tests over time may be necessary for diagnosis

Next Steps After Initial Testing

If initial tests suggest Cushing's syndrome, proceed to:

1. Measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent CS
2. Further imaging and specialized testing based on ACTH results

Remember that early diagnosis is critical given the significant morbidity and mortality associated with prolonged hypercortisolism 1.