What is the approach to diagnose and manage Cushing's syndrome?

Diagnostic Workup of Cushing's Syndrome

The diagnostic approach to Cushing's syndrome requires a two-step process: first screening and confirming the diagnosis using one of three recommended tests (24-hour urinary free cortisol, overnight 1-mg dexamethasone suppression test, or late-night salivary cortisol), followed by determining the etiology through ACTH measurement and appropriate imaging. 1

Initial Screening and Confirmation

Recommended First-Line Screening Tests

• Late-night salivary cortisol (LNSC)

  • Advantages: Easy collection, stability at room temperature, strong negative predictive value 1
  • Best for: Longitudinal surveillance of cyclic Cushing's syndrome 1
  • Limitations: False results from inadequate sample collection, disrupted day/night cycles 1

• Overnight 1-mg dexamethasone suppression test (DST)

  • Advantages: Strong negative predictive value 1
  • Best for: Initial screening, adrenal incidentalomas, patients with disrupted circadian rhythm 1
  • Limitations: False positives due to rapid absorption/malabsorption of dexamethasone, CYP3A4 inducers 1
  • Recommendation: Measure dexamethasone concomitantly with cortisol to reduce false-positive results 1

• 24-hour urinary free cortisol (UFC)

  • Advantages: Best overall diagnostic accuracy when measured by liquid chromatography-tandem mass spectrometry 1
  • Best for: Supporting diagnosis, reflecting overall cortisol production 1
  • Limitations: Requires accurate 24-hour collection, influenced by BMI, age, urinary volume, sodium intake 1
  • Recommendation: Collect multiple samples (at least 2-3) to account for intra-patient variability 1

Important Considerations for Test Selection

• For suspected cyclic Cushing's syndrome: Use LNSC 1
• For shift workers or patients with disrupted circadian rhythm: Use DST 1
• For patients with renal impairment: Use LNSC over UFC 1
• For patients with suspected adrenal tumor: Start with DST 1
• For children and adolescents: Consider growth failure combined with weight gain as key indicators 1

Differential Diagnosis

Pseudo-Cushing's States

• Consider psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, and obesity as potential causes of false positive results 1
• These conditions can mimic the biochemical profile of true Cushing's syndrome 1

Determining the Etiology

ACTH Status Assessment

1. Measure plasma ACTH levels

   • ACTH-dependent (normal to high ACTH): Cushing's disease (pituitary) or ectopic ACTH syndrome
   • ACTH-independent (low ACTH): Adrenal causes 2

2. For ACTH-dependent cases:

   • Perform pituitary MRI imaging to detect pituitary adenoma 2
   • If MRI is negative or equivocal:
     • Perform bilateral inferior petrosal sinus sampling (BIPSS) to differentiate between pituitary and ectopic sources 2, 3
     • Consider high-dose dexamethasone suppression test and CRH stimulation test 3

3. For ACTH-independent cases:

   • Perform adrenal imaging (CT or MRI) to identify adrenal adenoma, carcinoma, or bilateral adrenal hyperplasia 2

Treatment Approach

First-Line Treatment

• Pituitary adenoma (Cushing's disease): Transsphenoidal surgery 1
• Adrenal adenoma: Unilateral adrenalectomy (minimally invasive when feasible) 1

Second-Line Treatment Options

• Medical therapy when surgery is contraindicated or unsuccessful:

  • Ketoconazole, metyrapone, or pasireotide 1
  • Pasireotide dosing: Initial dose 0.6 mg or 0.9 mg twice daily by subcutaneous injection, with titration based on response and tolerability 4
  • Monitor for pasireotide side effects: hypocortisolism, hyperglycemia, bradycardia, QT prolongation 4

• Other options:

  • Radiation therapy for Cushing's disease 5
  • Bilateral adrenalectomy for ACTH-dependent causes 5

Common Pitfalls to Avoid

• Relying on a single random cortisol measurement 1
• Failing to account for medications that interfere with test results 1
• Not ensuring complete 24-hour urine collection for UFC 1
• Using inappropriate cutoff values for test interpretation 1
• Not considering pseudo-Cushing's states in the differential diagnosis 1
• Not monitoring for hypocortisolism during treatment with pasireotide 4
• Not optimizing anti-diabetic therapy prior to starting pasireotide in patients with poor glycemic control 4

Follow-up and Monitoring

• Evaluate treatment response through clinically meaningful reduction in 24-hour UFC levels and/or improvement in signs/symptoms 4
• For patients on pasireotide: Monitor glycemic status weekly for first 2-3 months and after dose increases 4
• For patients with adrenal insufficiency after treatment: Consider glucocorticoid replacement with hydrocortisone (15-25 mg daily in divided doses) and mineralocorticoid replacement with fludrocortisone (0.05-0.2 mg daily) 1
• Prioritize clinical evaluation over cortisol levels when monitoring glucocorticoid replacement therapy 1