Cushing Syndrome

Background

• Cushing syndrome results from prolonged multiorgan exposure to excessive concentrations of circulating free glucocorticoid (hypercortisolism).
• The approach to suspected endogenous Cushing syndrome is to first confirm the presence of pathological hypercortisolism, and then to determine the cause of the excess cortisol.
• Identifying the cause begins with determining whether the hypercortisolism is adrenocorticotropin hormone (ACTH)-independent (adrenal source) or ACTH-dependent (pituitary or ectopic source).

Evaluation

• Test for Cushing syndrome in patients with: (Strong recommendation)
  • multiple and progressive symptoms or signs of Cushing syndrome, some of which are specific but insensitive, such as easy bruising, facial plethora, proximal myopathy, and striae
  • certain conditions that are unusual for an individual's age, such as osteoporosis or hypertension in a younger person
  • incidental adrenal tumor
  • weight gain with decreasing height percentile (pediatric patients)
• Do not test during an acute illness to minimize false-positives.
• Confirm hypercortisolism:
  • To confirm hypercortisolism, test urine, blood, and/or saliva for elevated cortisol levels (Strong recommendation).
  • Exclude the possibility of exogenous glucocorticoids as the cause of the patient's presentation or abnormal test results.
    
  • If the cortisol level is elevated on any one test, perform any additional recommended tests not already performed (Strong recommendation).
  • If the results of the above tests are equivocal, perform any of the following tests (Strong recommendation):
    • Midnight or late-night serum cortisol levels
    • Dex-CRH stimulation test
    • 48-hour (2 mg/24 hour) low-dose dexamethasone suppression test
• Determine the cause of hypercortisolism:
  • Consider non-Cushing causes of elevated cortisol levels (nontumoral hypercortisolism) before performing testing to determine the cause of Cushing syndrome.
  • Determine if the cause is ACTH-dependent or ACTH-independent by measuring the serum ACTH level.
    • Diagnose ACTH-dependent Cushing syndrome if the ACTH level is > 4.4 pmol/L (> 20 pg/mL).
    • Diagnose ACTH-independent Cushing syndrome if the ACTH level is < 1.1 pmol/L (< 5 pg/mL).
    • Consider corticotropin-releasing hormone (CRH) testing if the serum ACTH level is repeatedly equivocal.
  • For confirmed ACTH-independent Cushing syndrome:
    • Perform computed tomography (CT) imaging of adrenal glands to investigate for an adrenal lesion.
    • In patients with normal adrenal imaging, consider a Liddle test to test for primary pigmented nodular adrenal disease (PPNAD), and genetic testing to further aid diagnosis.
  • For confirmed ACTH-dependent Cushing syndrome:
    • Test for the presence of a pituitary adenoma (Cushing disease). Tests may include:
      • pituitary imaging
      • high-dose dexamethasone suppression test (HDDST)
      • CRH testing
      • bilateral inferior petrosal sinus sampling (BIPSS)
    • If a pituitary adenoma is excluded, perform imaging studies to locate the ACTH-secreting tumor. Imaging options include:
      • CT or magnetic resonance imaging (MRI) of the thorax and abdomen
      • nuclear medicine functional imaging tests (such as somatostatin receptor scintigraphy, fluoride 18-fluorodeoxyglucose-positron emission tomography [¹⁸F-FDG PET], gallium-68 DOTATATE positron emission tomography-computed tomography [PET-CT] scan, and octreotide scans)