Adrenal Hyperfunction - Cushing Syndrome

Diagnosis

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 Biller, 2008)

• Initial testing – 24-hour free urine cortisol (UFC) or salivary cortisol between 2300 and 0000 hours (recommend repeat UFC testing to confirm)
  • If positive – follow up with low-dose (1 mg) dexamethasone suppression testing (DST) and plasma cortisol level and ACTH test (see the Adrenal Hyperfunction [Cushing Syndrome] Testing algorithm)
    • Likelihood ratios with positive test (recommendations from Elanin, 2008)
      • UFC – 10.6
      • Salivary cortisol – 8.8
      • Overnight DST – 11.6
      • Combination UFC and DST (1 night) – 15.4
      • Negative testing has likelihood ratio <0.5 for all tests
  • If equivocal – follow up with overnight high-dose DST (4-8 mg/dL) and serum ACTH, cortisol at 0800 hours
    • Likelihood ratio with positive test
      • DST – 7.3
  • 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 most common

Imaging Studies

• CT/MRI to visualize adenomas/hyperplasia after hypercortisolemia is identified
  • MRI of pituitary
    • Perform inferior bilateral petrosal sampling of ACTH to differentiate between Cushing disease and ectopic source
  • If ACTH 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 indicate poor prognosis

Differential Diagnosis

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

Clinical Background

Adrenal hyperfunction (Cushing syndrome) is manifested as excess cortisol secretion by the adrenal gland.

Epidemiology

• Incidence – 1/100,000
• Age – uncommon in children; peaks in 20s-50s
• Sex – M<F, 1:4-6

Etiology

• Endogenous
  • Pituitary (Cushing syndrome)
    • Hyperplasia
    • Adenoma
  • Adrenal
    • Adenoma
    • Carcinoma
  • Ectopic production of adrenocorticotropic hormone (ACTH)
    • Tumors (carcinoid, small cell lung cancer)
• Exogenous
  • Glucocorticoid administration

Pathophysiology

• Corticotropin-releasing hormone (CRH) in the hypothalamus stimulates release of ACTH from the pituitary gland
• ACTH acts on the adrenal glands to produce cortisol
• Most endogenous cases are caused by hypersecretion of pituitary ACTH or ectopic production of ACTH from non-pituitary source

Clinical Presentation

• Centripetal obesity, moon facies, buffalo hump, hirsutism, striae
• Hypertension
• Amenorrhea
• Emotional changes
• Osteoporosis
• Fatigue, weakness
• Proximal myopathy
• Impaired glucose tolerance

Treatment (surgical removal)

• Transsphenoidal removal of pituitary adenoma or hyperplasia
  • May recur or be refractory in spite of removal
• Removal of adrenal adenoma or carcinoma
• Removal of ectopic source of ACTH

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Adrenocorticotropic Hormone Stimulation, 0 Minutes 0070031 Method: Quantitative Chemiluminescent Immunoassay
Adrenocorticotropic Hormone Stimulation, 30 Minutes 0070032 Method: Quantitative Chemiluminescent Immunoassay
Adrenocorticotropic Hormone Stimulation, 60 Minutes 0070033 Method: Quantitative Chemiluminescent Immunoassay
Dexamethasone, Serum or Plasma by LC-MS/MS 2003248 Method: Liquid Chromatography-Tandem Mass Spectrometry	Compliance assessment of dexamethasone suppression testing Do not use for patients on glucocorticoids
Cortisol, Free 0098391 Method: Equilibrium Dialysis/Quantitative Electrochemiluminescent Immunoassay	Screen for Cushing syndrome Do not use for patients on glucocorticoids

Diagnostic Algorithm

  Adrenal Hyperfunction (Cushing Syndrome) Testing