What are the steps to diagnose and manage Cushing's syndrome?

Diagnosis and Management of Cushing's Syndrome

The diagnosis of Cushing's syndrome requires a systematic stepwise approach starting with screening tests to confirm hypercortisolism, followed by determining its etiology, and implementing appropriate treatment based on the cause. 1

Initial Diagnostic Approach

Step 1: Clinical Suspicion and Screening

• Key clinical features to look for:

  • Weight gain with concurrent height deceleration (especially important in children)
  • Facial plethora, easy bruising, purple striae
  • Proximal muscle weakness
  • Central obesity, buffalo hump, supraclavicular fat pads
  • Hypertension, hyperglycemia
  • Menstrual irregularities, hirsutism

• Initial screening tests (perform at least 2-3 tests): 1

  • Late night salivary cortisol (LNSC) - collect ≥2 samples on consecutive days
  • 24-hour urinary free cortisol (UFC) - collect 2-3 specimens
  • 1mg overnight dexamethasone suppression test (DST)

Step 2: Confirming Hypercortisolism

• Interpretation of screening tests:

  • Abnormal results require repeat testing to confirm
  • Consider test-specific factors:
    • DST is preferred for shift workers but unreliable in women on estrogen therapy
    • Measure dexamethasone levels with DST to improve interpretation
    • For UFC, obtain 2-3 collections to account for variability

• Rule out pseudo-Cushing's states: 1

  • Consider conditions that can cause false positives:
    • Severe obesity, uncontrolled diabetes
    • Depression, alcoholism
    • Pregnancy, polycystic ovary syndrome
  • For equivocal cases:
    • Monitor for 3-6 months
    • Consider Dex-CRH test at specialized centers
    • Serial LNSC measurements over time

Determining Etiology

Step 3: ACTH Measurement

• Measure plasma ACTH levels: 1, 2
  • Low ACTH: ACTH-independent (adrenal causes)
  • Normal/high ACTH: ACTH-dependent (pituitary or ectopic sources)

Step 4: Imaging Based on ACTH Status

• For ACTH-independent CS: 1

  • Adrenal CT or MRI to identify adrenal tumors

• For ACTH-dependent CS: 1

  • Pituitary MRI (preferably with contrast)
    • If adenoma ≥10mm: Presumed Cushing's disease
    • If adenoma <6mm or no visible tumor: Proceed to IPSS
    • If adenoma 6-9mm: Consider IPSS based on clinical features

Step 5: Additional Testing for ACTH-dependent CS

• Bilateral inferior petrosal sinus sampling (IPSS): 1

  • Gold standard for differentiating pituitary from ectopic ACTH sources
  • Central-to-peripheral ACTH gradient ≥3 after CRH/desmopressin confirms pituitary source
  • Should be performed when patient is in active hypercortisolemic state
  • Not recommended for initial diagnosis of hypercortisolism

• If IPSS suggests ectopic source:

  • Whole-body CT to locate ectopic ACTH-secreting tumors

Management Approach

Step 6: First-line Treatment

• Surgical approach based on etiology: 1, 2

  • Cushing's disease (pituitary source):

    • Transsphenoidal surgery (TSS) by experienced neurosurgeon
    • Remission rates 65-90% for microadenomas, lower for macroadenomas

  • Adrenal causes:

    • Unilateral adrenalectomy for adrenal adenoma/carcinoma
    • Bilateral adrenalectomy for bilateral disease

  • Ectopic ACTH syndrome:

    • Surgical removal of the ACTH-secreting tumor

Step 7: Second-line Treatments

• For persistent/recurrent Cushing's disease: 1

  • Repeat pituitary surgery
  • Medical therapy
  • Pituitary radiation therapy
  • Bilateral adrenalectomy

• Medical therapy options: 1, 3

  • Steroidogenesis inhibitors:

    • Ketoconazole (400-1200 mg/day)
    • Metyrapone (500 mg/day to 6 g/day)
    • Osilodrostat (2-7 mg/day)

  • Pituitary-directed therapy:

    • Pasireotide (FDA-approved for Cushing's disease)

  • Glucocorticoid receptor antagonists:

    • Mifepristone

Step 8: Monitoring and Follow-up

• Post-surgical monitoring: 1

  • Morning serum cortisol to assess for remission
  • Glucocorticoid replacement if adrenal insufficiency develops
  • Long-term surveillance for recurrence (clinical evaluation, UFC, LNSC, or DST)

• Monitoring during medical therapy: 1

  • UFC, late-night salivary cortisol, or morning serum cortisol
  • Drug-specific adverse effects (liver function, electrolytes, QTc interval)

Special Considerations for Children

• Diagnostic approach in children: 1

  • Growth failure with weight gain is a key discriminating feature
  • Same screening tests as adults but with age-appropriate cutoffs
  • In children >6 years, Cushing's disease is most common cause
  • In children <6 years, adrenal causes are more common

• Management in children: 1

  • Surgical approach similar to adults
  • Avoid routine thromboprophylaxis due to bleeding risk
  • Evaluate for growth hormone deficiency 3-6 months post-surgery
  • For medical therapy, ketoconazole or metyrapone preferred; pasireotide not recommended

Common Pitfalls to Avoid

• Diagnostic pitfalls:

  • Relying on a single positive test for diagnosis
  • Failing to rule out exogenous glucocorticoid use
  • Not considering cyclic Cushing's syndrome in cases with fluctuating results
  • Performing IPSS when patient is not hypercortisolemic

• Management pitfalls:

  • Delaying treatment (increases morbidity and mortality)
  • Not monitoring for adrenal insufficiency after successful treatment
  • Inadequate follow-up for recurrence

By following this systematic approach, clinicians can effectively diagnose and manage Cushing's syndrome, improving outcomes and reducing morbidity and mortality associated with prolonged hypercortisolism.