What serum laboratory findings are typically found in patients with Cushing's syndrome?

Serum Laboratory Findings in Cushing's Syndrome

The key serum laboratory findings in Cushing's syndrome include elevated late-night salivary cortisol, failure to suppress cortisol after dexamethasone administration, elevated 24-hour urinary free cortisol, and ACTH levels that help differentiate between ACTH-dependent and ACTH-independent forms. 1

Diagnostic Tests for Cushing's Syndrome

First-Line Screening Tests

• Late-night salivary cortisol (LNSC): Normal values should be <50 nmol/L (<1.8 μg/dL), with elevated levels indicating loss of normal circadian rhythm of cortisol secretion 1, 2
• Overnight 1-mg dexamethasone suppression test (DST): Normal response is serum cortisol <1.8 μg/dL (50 nmol/L) at 0800h the morning after dexamethasone administration; failure to suppress indicates abnormal feedback inhibition 1
• 24-hour urinary free cortisol (UFC): Normal values typically <193 nmol/24h (<70 μg/m²/24h); elevated values indicate increased cortisol production 1, 3

ACTH Measurement for Differential Diagnosis

• Plasma ACTH levels: Used to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome 1, 4
  • ACTH-dependent (elevated or normal ACTH): Pituitary adenoma (Cushing's disease) or ectopic ACTH source 4
  • ACTH-independent (low or undetectable ACTH): Adrenal tumor or hyperplasia 4
• Any ACTH level >5 ng/L is detectable and suggests ACTH-dependent Cushing's syndrome 4
• ACTH level >29 ng/L has 70% sensitivity and 100% specificity for diagnosing Cushing's disease 4

Interpretation of Laboratory Findings

Diagnostic Accuracy

• LNSC: Highest specificity among first-line tests, with sensitivity >90% 1, 5
• DST: High sensitivity (>90%) but lower specificity; measuring dexamethasone levels concomitantly improves test interpretability 1
• UFC: Sensitivity above 90% but lowest among the three first-line tests; requires multiple collections (at least 2-3) due to high intra-patient variability 1

Potential Pitfalls and False Results

• False positive DST results may occur due to:

  • Rapid absorption/malabsorption of dexamethasone 1
  • Concomitant treatment with CYP3A4 inducers (e.g., phenobarbital, carbamazepine) 1
  • Increased corticosteroid binding globulin (CBG) levels from oral estrogens, pregnancy, or chronic active hepatitis 1

• False negative results are less common but may occur with:

  • Inhibition of dexamethasone metabolism by medications like fluoxetine, cimetidine, or diltiazem 1
  • Decreased CBG and albumin levels (e.g., in nephrotic syndrome) 1
  • Cyclic Cushing's syndrome with intermittent hypercortisolism 1, 6

• UFC limitations include:

  • Dependence on accurate 24-hour collection 1
  • Influence by renal function (not recommended if CrCl <60mL/min) 1
  • Significant polyuria (>5 L/24h) affects results 1

Special Considerations

• Multiple tests are recommended as no single test has 100% diagnostic accuracy 7, 6
• Mild Cushing's syndrome may present with normal or only mildly elevated UFC, requiring multiple samples and additional testing 6
• Non-neoplastic hypercortisolism (pseudo-Cushing's) can occur in psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, and obesity 1, 4
• Morning cortisol levels show significant overlap between Cushing's syndrome patients and normal subjects, making them less useful for diagnosis 5
• Measuring dexamethasone levels along with cortisol during DST improves test interpretability 1, 4

Diagnostic Algorithm

1. Initial screening: Perform at least two of the three first-line tests (LNSC, DST, UFC) 1
2. Confirm hypercortisolism: Positive results on multiple tests strongly suggest Cushing's syndrome 1, 7
3. Determine ACTH dependency: Measure plasma ACTH levels 1, 4
4. Localize the source:
   • ACTH-dependent: Pituitary MRI; if inconclusive, proceed to CRH stimulation test and/or inferior petrosal sinus sampling 1, 4
   • ACTH-independent: Adrenal CT or MRI 1, 4