Adrenal Hyperfunction - Cushing Syndrome

Indications for Testing

• High clinical suspicion based on discriminatory physical features and refractory hypertension
  • Clinical evaluation has ruled out metabolic syndrome or polycystic ovarian syndrome in females
• Do not test patients who have hypercortisolism secondary to administration of glucocorticoids

Laboratory Testing (recommendations from Endocrine Society, 2008; National Comprehensive Cancer Network [NCCN], 2015)

• Initial testing – salivary cortisol (collected between 2300 and midnight) or 24-hour urine free cortisol (UFC)
  • Repeat either test at least once to confirm elevated values
  • If cortisol elevated – follow up with low-dose (1 mg) dexamethasone suppression testing (DST) with serum cortisol level and adrenocorticotropic hormone (ACTH) test (see the Adrenal Hyperfunction [Cushing Syndrome] Testing algorithm)
    • Likelihood ratios for positive test result (Elamin, 2008)
      • UFC – 10.6
      • Salivary cortisol – 8.8
      • Overnight DST (serum cortisol) – 11.6
      • Combination UFC and DST (1 night) – 15.4
      • Negative testing has likelihood ratio <0.5 for all tests
      • False-positive results may be seen in up to 50% of women taking oral contraceptives (Endocrine Society, 2008)
    • If low dose test, follow up with overnight high-dose DST (4-8 mg/day) and serum ACTH, cortisol at 0800; or longer low-dose DST (2 mg/day for 48 hours)
      • Likelihood ratio with positive test – 7.3
    • Negative suppression testing – suggests against Cushing disease
  • Once hypercortisolism is confirmed, further evaluations should include an endocrinologist
  • If results after DST are consistent with hypercortisolism
    • Serum ACTH – determine whether disease is adrenal, pituitary, or ectopic ACTH-based

Histology

• Pathology review of specimen (biopsy tumor) to classify type of tumor
  • Immunohistochemistry stain – ACTH stain most common

Imaging Studies

• CT/MRI to visualize adenomas/hyperplasia after hypercortisolism is identified
  • MRI of pituitary demonstrates abnormality – perform inferior bilateral petrosal sampling of ACTH to differentiate between Cushing disease and ectopic source
    • If ACTH is low – MRI of adrenal glands
    • If ACTH >200 pg/mL – search for ectopic ACTH-secreting tumor

Prognosis

• Untreated Cushing syndrome – associated with excess morbidity/mortality secondary to cardiovascular disease
• If tumor is benign and removed – mortality associated with comorbid diseases developed in association with tumor may normalize
• Malignant tumors – poor prognosis

Differential Diagnosis

• Obesity/metabolic syndrome
• Diabetes mellitus type 2
• Polycystic ovarian syndrome (PCOS)
• Depression
• Hypertension
• Malignancy associated with ectopic ACTH production – most common are small-cell lung cancer, thymoma, medullary carcinoma of the thyroid