What is the diagnostic approach for Cushing's disease?

Diagnostic Approach for Cushing's Disease

The diagnostic approach for Cushing's disease involves a three-step process: first screening for Cushing's syndrome with tests like late-night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), and 24-hour urinary free cortisol (UFC); then confirming ACTH-dependency with plasma ACTH measurement; and finally localizing the pituitary source through MRI and possibly inferior petrosal sinus sampling. 1

Initial Screening for Cushing's Syndrome

The Endocrine Society recommends the following first-line screening tests:

1. Late-Night Salivary Cortisol (LNSC)

   • Sensitivity >90%, specificity 100%
   • Collect multiple samples (≥2) on consecutive days
   • Ideal for initial screening and monitoring cyclic Cushing's syndrome
   • Patients should avoid strenuous physical activity for 24-48 hours before collection

2. 1mg Overnight Dexamethasone Suppression Test (DST)

   • Recommended for initial screening, especially in patients with adrenal incidentalomas or disrupted circadian rhythms
   • Very low false-negative rate (1.9%)

3. 24-hour Urinary Free Cortisol (UFC)

   • Reflects overall cortisol production
   • At least 2-3 samples should be collected to confirm diagnosis
   • Results affected by urine volume and glomerular filtration rate

Determining ACTH Dependency

After confirming hypercortisolism, the next step is to determine if the condition is ACTH-dependent:

• Plasma ACTH Measurement
  • Differentiates between ACTH-dependent and ACTH-independent cortisol excess
  • Elevated or normal levels suggest ACTH-dependent disease (pituitary or ectopic source)
  • Suppressed levels suggest ACTH-independent disease (adrenal source)

Localizing the Source

For ACTH-dependent Cushing's syndrome with suspected pituitary origin:

1. Pituitary MRI

   • First-line imaging modality for Cushing's disease
   • May identify pituitary microadenomas or macroadenomas

2. Bilateral Inferior Petrosal Sinus Sampling (IPSS)

   • Indicated when pituitary MRI is normal or inconclusive
   • Essential for confirming pituitary source versus ectopic ACTH production
   • Central-to-peripheral ACTH gradient confirms pituitary source

Important Considerations and Pitfalls

• Use of Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) is recommended over immunoassays for cortisol measurement, especially when patients are taking medications that can interfere with results 1

• False positives can occur in:

  • Estrogen therapy or pregnancy (increases cortisol-binding globulin)
  • Pseudo-Cushing states (depression, alcoholism, obesity)
  • Medications that interfere with dexamethasone metabolism

• False negatives can occur in:

  • Mild or cyclic Cushing's syndrome
  • Neither a normal UFC nor a normal NSC excludes mild Cushing's syndrome 2

• Multiple testing is often necessary:

  • Single tests may miss mild or cyclic disease
  • Multiple samples and different test modalities increase diagnostic accuracy 2

• Rule out exogenous glucocorticoid use before biochemical testing 1

Special Populations

• Children: Cushing's disease accounts for 75-80% of pediatric cases in children over age 6, while adrenal causes are more common in younger children 1

• Patients with hepatic impairment: May have impaired response to diagnostic tests using metyrapone 3

• Elderly patients: Clinical studies of metyrapone did not include sufficient numbers of patients 65 years and older to determine if they respond differently 3

By following this structured approach, Cushing's disease can be accurately diagnosed, allowing for appropriate treatment planning and improved outcomes for patients.