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 Testing

• High clinical suspicion based on discriminatory physical features and/or 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 11 p.m. and midnight (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 initial testing is equivocal – follow up with overnight high-dose DST (4-8 mg/dL) and serum ACTH, cortisol at 8 a.m.
  • Likelihood ratio with positive test
    • DST – 7.3
• If initial testing results after DST are consistent with hypercortisolism
  • Serum ACTH – to differentiate if 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

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Arnaldi G, Mancini T, Kola B, Appolloni G, Freddi S, Concettoni C, Bearzi I, Masini A, Boscaro M, Mantero F. Cyclical Cushing's syndrome in a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptors. J Clin Endocrinol Metab. 2003; 88 (12) :5834-5840.PubMed

General

• Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab. 2008; 4 (10) :560-568.PubMed
• Batista DL, Riar J, Keil M, Stratakis CA. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007; 120 (3) :e575-e586.PubMed
• Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing's disease. Best Pract Res Clin Endocrinol Metab. 2009; 23 (5) :607-623.PubMed
• Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008; 93 (7) :2454-2462.PubMed
• Brown RL, Weiss RE. An approach to the evaluation and treatment of Cushing's disease. Expert Rev Anticancer Ther. 2006; 6 Suppl 9 :S37-S46.PubMed
• Elamin MB, Murad MH, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin PJ, Montori VM. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008; 93 (5) :1553-1562.PubMed
• Findling JW, Raff H. Cushing's Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab. 2006; 91 (10) :3746-3753.PubMed
• Gross BA, Mindea SA, Pick AJ, Chandler JP, Batjer HH. Diagnostic approach to Cushing disease. Neurosurg Focus. 2007; 23 (3) :E1-.PubMed
• Jehle S, Walsh JE, Freda PU, Post KD. 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) :4624-4632.PubMed
• Labeur M, Theodoropoulou M, Sievers C, Paez-Pereda M, Castillo V, Arzt E, Stalla GK. New aspects in the diagnosis and treatment of Cushing disease. Front Horm Res. 2006; 35 :169-178.PubMed
• Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. 2006; 367 (9522) :1605-1617.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 MC, De Leo M, Lombardi G, Colao A. Cushing's Syndrome. Endocrinol Metab Clin North Am. 2008; 37 (1) :135-49, ix.PubMed
• Stratakis CA. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin- independent Cushing syndrome). Endocr Dev. 2008; 13 :117-132.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Kushnir MM, Rockwood AL, Nelson GJ, Terry AH, Meikle AW. Liquid chromatography-tandem mass spectrometry analysis of urinary free cortisol. Clin Chem. 2003; 49 (6 Pt 1) :965-967.PubMed
• La'ulu SL, Roberts WL. Performance characteristics of the Architect cortisol immunoassay. Clin Chim Acta. 2008; 388 (1-2) :219-221.PubMed

Acromegaly
Aldosteronism
Amenorrhea
Diabetes Mellitus
Infertility
Lung Cancer
Metabolic Syndrome
Osteoporosis
Polycystic Ovarian Syndrome
Thyroid Cancer