What is the role of blood tests in diagnosing Cushing's syndrome?

Blood Tests for Diagnosing Cushing's Syndrome

Blood tests play a critical role in diagnosing Cushing's syndrome, with measurement of plasma ACTH levels being essential to determine the etiology after hypercortisolism is confirmed. 1

Initial Screening Tests for Hypercortisolism

The diagnosis of Cushing's syndrome follows a two-step approach: first confirming hypercortisolism, then determining its etiology.

First-line Screening Tests:

• Late-night salivary cortisol (LNSC): Highly sensitive (95%) and specific (100%) test based on the loss of normal circadian rhythm of cortisol secretion in Cushing's syndrome. At least 2-3 samples should be collected on consecutive days. 1

• 24-hour urinary free cortisol (UFC): Measures overall cortisol production with high sensitivity (89%) and specificity (100%). Collect at least 2-3 samples to account for variability, which can be as high as 50%. 1

• Overnight dexamethasone suppression test (DST): Measures the inability to suppress cortisol with dexamethasone. A serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight indicates normal response. 1

Test Selection Considerations:

• For suspected Cushing's disease: Start with either UFC and/or LNSC; DST is an option if LNSC not feasible 1
• For shift workers: DST may be preferred due to disrupted circadian rhythm 1
• For patients with renal impairment: Avoid UFC and prefer LNSC 1
• For women on estrogen-containing contraceptives: DST may be less reliable 1

Blood Tests for Determining Etiology

Once hypercortisolism is confirmed, blood tests are crucial for determining the cause:

• Morning plasma ACTH level: Essential to differentiate ACTH-dependent from ACTH-independent causes 1

  • Normal/elevated ACTH (>5 ng/L or >1.1 pmol/L): Suggests ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 1
  • Low/undetectable ACTH: Indicates ACTH-independent Cushing's syndrome (adrenal source) 1

• CRH stimulation test: In ACTH-dependent cases, a ≥20% increase in cortisol from baseline during CRH testing supports pituitary origin 1

Special Considerations

• Multiple testing is essential: No single test has 100% diagnostic accuracy; combining tests improves diagnostic yield 2, 3
• Cyclic Cushing's syndrome: May require repeated testing during symptomatic periods 1, 3
• Mild Cushing's syndrome: May have normal or only mildly elevated UFC; multiple NSC measurements may be needed 2
• Pseudo-Cushing's states: Conditions like severe obesity, uncontrolled diabetes, depression, and alcoholism can cause false-positive results 1

Diagnostic Algorithm

1. Rule out exogenous glucocorticoid use 1
2. Perform 2-3 first-line screening tests based on clinical suspicion:
   • High suspicion: Perform multiple tests (LNSC, UFC, DST) 1
   • Low suspicion: Start with LNSC 1
3. If screening tests are abnormal, measure plasma ACTH 1
   • Normal/high ACTH: Proceed with pituitary MRI 1
   • Low ACTH: Proceed with adrenal imaging 1
4. For ACTH-dependent cases with equivocal findings: Consider bilateral inferior petrosal sinus sampling (BSIPSS) 1

Common Pitfalls to Avoid

• Relying on a single test: Due to test limitations and potential for cyclic cortisol secretion 2, 3
• Inadequate urine collection: Affects UFC reliability; ensure complete 24-hour collection 1, 4
• Medication interference: Some medications can affect test results (e.g., CYP3A4 inducers affecting DST) 1
• Ignoring mild cases: Patients with mild Cushing's syndrome may have normal UFC but abnormal LNSC or DST 2
• Overlooking test timing: LNSC should be collected at bedtime, not at a fixed time, as cortisol nadir is related to sleep onset 1

By following this systematic approach to blood testing, clinicians can effectively diagnose Cushing's syndrome and determine its etiology, leading to appropriate treatment and improved patient outcomes.