What is the diagnostic workup and treatment approach for a patient with suspected Cushing syndrome?

Diagnostic Workup and Treatment Approach for Cushing's Syndrome

The diagnostic workup for suspected Cushing's syndrome should begin with one of three first-line screening tests: 24-hour urinary free cortisol (UFC), overnight 1-mg dexamethasone suppression test (DST), or late-night salivary cortisol (LNSC), followed by determining the source through ACTH levels and appropriate imaging, with surgical removal of the causative tumor as first-line treatment. 1

Initial Diagnostic Screening

First-Line Screening Tests

• Late-night salivary cortisol (LNSC):

  • High sensitivity (>90%) and specificity (100%) 1
  • Advantages: easy collection, stability at room temperature
  • Preferred for longitudinal surveillance of cyclic Cushing's syndrome
  • Best for patients with renal impairment 1
  • Strong negative predictive value for excluding Cushing's syndrome

• Overnight 1-mg dexamethasone suppression test (DST):

  • Strong negative predictive value
  • Preferred for shift workers or patients with disrupted circadian rhythm
  • Recommended for evaluating adrenal incidentalomas 1
  • Measure dexamethasone concomitantly with cortisol to reduce false positives

• 24-hour urinary free cortisol (UFC):

  • Measured by liquid chromatography-tandem mass spectrometry for best accuracy
  • Requires multiple collections (at least 2-3) to account for variability
  • Not recommended for patients with renal impairment or significant polyuria 1

Important caveat: In mild Cushing's syndrome, a single normal test does not exclude the diagnosis. Multiple samples and testing modalities may be needed for diagnosis 2.

Determining the Cause

After confirming hypercortisolism, the next step is to determine the source:

1. Measure plasma ACTH levels to differentiate between:

   • ACTH-dependent causes (normal to elevated ACTH): Pituitary adenoma (Cushing's disease) or ectopic ACTH production
   • ACTH-independent causes (suppressed ACTH): Adrenal tumors 1, 3

2. Imaging studies based on ACTH results:

   • For ACTH-dependent disease:
     • Pituitary MRI (microadenomas may be very small and difficult to detect)
     • Bilateral inferior petrosal sinus sampling (IPSS) if MRI is negative or inconclusive 3
   • For ACTH-independent disease:
     • Adrenal CT or MRI to identify adrenal tumors 1, 3

Treatment Approach

First-Line Treatment

• Surgical intervention is the first-line treatment for all forms of endogenous Cushing's syndrome 1, 3, 4:
  • Cushing's disease (pituitary adenoma): Transsphenoidal surgery by an expert neurosurgeon
  • Adrenal adenoma: Laparoscopic unilateral adrenalectomy
  • Adrenal carcinoma: Extended adrenalectomy by an expert surgeon
  • Ectopic ACTH production: Surgical removal of the source tumor

Second-Line Treatments

When surgery is contraindicated, unsuccessful, or while awaiting its effects:

• Medical therapy:

  • Steroidogenesis inhibitors:
    • Metyrapone: Inhibits 11-beta-hydroxylation in the adrenal cortex, reducing cortisol production 5
    • Ketoconazole
  • Pituitary-targeted drugs (for Cushing's disease):
    • Pasireotide 1
  • Glucocorticoid receptor blockers

• Radiation therapy for pituitary-dependent disease 1, 4

• Bilateral adrenalectomy as a last resort for refractory cases 1, 4

  • Requires lifelong glucocorticoid replacement (hydrocortisone 15-25 mg daily in divided doses)
  • Mineralocorticoid replacement with fludrocortisone (0.05-0.2 mg daily) 1

Special Considerations

• Pseudo-Cushing's states can cause false positive results and should be considered in the differential diagnosis:

  • Psychiatric disorders
  • Alcohol use disorder
  • Polycystic ovary syndrome
  • Obesity 1

• Pediatric patients: Growth failure combined with weight gain is a key indicator for testing 1

• Post-treatment monitoring:

  • LNSC is excellent for monitoring post-operative Cushing's disease patients for surgical failure or recurrence 6
  • Clinical evaluation should be prioritized over cortisol levels when monitoring glucocorticoid replacement therapy 1

Common Pitfalls to Avoid

• Relying on a single random cortisol measurement
• Failing to account for medications that can interfere with test results
• Not ensuring complete 24-hour urine collection for UFC
• Using inappropriate cutoff values for interpretation
• Not considering pseudo-Cushing's states in the differential diagnosis 1
• Overlooking mild cases of Cushing's syndrome where UFC may be normal or only mildly elevated 2