Adrenal Hyperfunction - Cushing Syndrome

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • High clinical suspicion based on discriminatory physical features and refractory hypertension
  • 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

Adrenal Hyperfunction (Cushing Syndrome) Testing Algorithm

Adrenal hyperfunction (Cushing syndrome) causes excess cortisol secretion by the adrenal gland and is manifested by a constellation of symptoms, including weight gain, easy bruisability, and myopathy.

Epidemiology

  • Incidence – 2-3/100,000 (Endocrine Society, 2008)
  • Age – uncommon in children; peaks in 20s-50s
  • Sex – M<F, 1:4-6

Etiology

  • Endogenous
    • Pituitary (Cushing syndrome)
      • Hyperplasia
      • Adenoma
    • Adrenal
      • Adenoma
      • Carcinoma – most are sporadic tumors
        • Hereditary syndromes (eg, Li-Fraumeni) may present as carcinoma
    • Ectopic production of adrenocorticotropic hormone (ACTH)
  • 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, reddish-purple striae
  • Hypertension
  • Menstrual abnormalities (eg, amenorrhea)
  • Irritability, impaired memory
  • Osteoporosis
  • Fatigue, weakness
  • Proximal myopathy
  • Impaired glucose tolerance

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

Cortisol, Saliva 0081117
Method: Quantitative Enzyme Immunoassay

Limitations

Do not use for patients taking glucocorticoids

Cortisol Urine Free by LC-MS/MS 0097222
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations

Do not use for patients taking glucocorticoids

Cortisol, Serum 0070030
Method: Quantitative Chemiluminescent Immunoassay

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay

ACTH by Immunohistochemistry 2003427
Method: Immunohistochemistry

Additional Tests Available

Adrenocorticotropic Hormone Stimulation, 0 Minutes 0070031
Method: Quantitative Chemiluminescent Immunoassay

Comments

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Adrenocorticotropic Hormone Stimulation, 30 Minutes 0070032
Method: Quantitative Chemiluminescent Immunoassay

Comments

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Adrenocorticotropic Hormone Stimulation, 60 Minutes 0070033
Method: Quantitative Chemiluminescent Immunoassay

Comments

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Dexamethasone, Serum or Plasma by LC-MS/MS 2003248
Method: Liquid Chromatography-Tandem Mass Spectrometry

Comments

Compliance assessment of dexamethasone suppression testing

Cortisol, Free by Equilibrium Dialysis/LC-MS/MS 2012697
Method: Equilibrium Dialysis/Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Comments

Screen, diagnose, and monitor diseases associated with excess or deficient cortisol production

Guidelines

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Sep 2015]

Nieman L, Biller B, Findling J, Newell-Price J, Savage M, Stewart P, Montori V. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008; 93(5): 1526-40. PubMed

General References

Alexandraki K, Grossman A. Novel insights in the diagnosis of Cushing's syndrome. Neuroendocrinology. 2010; 92 Suppl 1: 35-43. PubMed

Batista D, Riar J, Keil M, Stratakis C. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007; 120(3): e575-86. PubMed

Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009; 23(5): 607-23. PubMed

Elamin M, Murad H, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin P, Montori V. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008; 93(5): 1553-62. PubMed

Findling J, Raff H. Cushing's Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab. 2006; 91(10): 3746-53. PubMed

Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012; 25(2): 199-208. PubMed

Jehle S, Walsh J, Freda P, Post K. Selective use of bilateral inferior petrosal sinus sampling in patients with adrenocorticotropin-dependent Cushing's syndrome prior to transsphenoidal surgery. J Clin Endocrinol Metab. 2008; 93(12): 4624-32. PubMed

Newell-Price J. Diagnosis/differential diagnosis of Cushing's syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab. 2009; 23 Suppl 1: S5-14. PubMed

Pivonello R, De Martino M, De Leo M, Lombardi G, Colao A. Cushing's Syndrome. Endocrinol Metab Clin North Am. 2008; 37(1): 135-49, ix. PubMed

Raff H. Cushing's syndrome: diagnosis and surveillance using salivary cortisol. Pituitary. 2012; 15(1): 64-70. PubMed

Turpeinen U, Hämäläinen E. Determination of cortisol in serum, saliva and urine. Best Pract Res Clin Endocrinol Metab. 2013; 27(6): 795-801. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Kushnir M, Rockwood A, Nelson G, Terry A, Meikle W. Liquid chromatography-tandem mass spectrometry analysis of urinary free cortisol. Clin Chem. 2003; 49(6 Pt 1): 965-7. PubMed

La'ulu S, Roberts W. Performance characteristics of the Architect cortisol immunoassay. Clin Chim Acta. 2008; 388(1-2): 219-21. PubMed

Medical Reviewers

Last Update: December 2015