- Hormonal disorder caused by prolonged exposure to high levels of glucocorticoids.
- May be due to exogenous glucocorticoids (iatrogenic) or endogenous hypercortisolism.
- May be ACTH dependent or independent. Cushing syndrome due to an ACTH-secreting pituitary adenoma is referred to as Cushing disease.
- More common in women particularly in reproductive age 
- Overt endogenous Cushing incidence in general population: 2.4 cases per 1 million persons per year with standardized mortality ratio of 3.8 for affected persons in Spain 
- Iatrogenic Cushing more common but measurements of incidence rate are imprecise.
- Approximately 25% of overweight, type-2 diabetes patients have impaired morning cortisol suppression after a low-dose overnight dexamethasone suppression test but do not necessarily have Cushing .
- Most common hormonal abnormality in patients with adrenal incidentaloma.
- Detailed history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled).
- CYP3A4 inhibitors (especially ritonavir) inhibit glucocorticoid clearance and contribute to Cushingoid symptoms when taken with concurrent inhaled, oral or injectable steroids.
- Screening: late night salivary cortisol x 2, 24-hour urine free cortisol (UFC) x 2, low-dose dexamethasone suppression test (after 1mg dexamethasone at 11pm, normal 8AM cortisol < 1.8 mcg/dL)
- At least two clearly abnormal (e.g. UFC > 3 times upper limit of normal) tests using different test methods needed to establish diagnosis .
- Use of estrogen containing OCPs can contribute to false positive dexamethasone suppression test due to increased cortisol binding globulin and may be discontinued prior to testing.
- After confirming hypercortisolism must measure ACTH to identify if ACTH dependent or independent.
- ACTH< 5 pg/mL suggests ACTH-independent adrenal disease: usually adrenal adenoma, adrenal carcinoma or bilateral adrenal hyperplasia. Requires thin-slice abdominal CT imaging. Houndsfield Unit < 10 suggestive of adrenal adenoma. Adrenal mass >4 cm , presence of necrosis, calcifications, hemorrhage, absolute contrast medium washout < 50% at 10 minutes after contrast administration suggestive of carcinoma.
- Fine needle aspiration biopsy of adrenal mass may be used to distinguish primary adrenal malignancy from metastases, however pheochromocytoma must be ruled out prior to biopsy.
- ACTH >20 pg/mL suggests ACTH dependent. Most commonly due to pituitary ACTH-secreting tumor (Cushing disease), less commonly ectopic ACTH-secreting tumor (e.g. bronchial carcinoid tumor, pancreatic or thymic neuroendocrine tumor)
- To distinguish pituitary dependent Cushing vs ectopic ACTH syndrome: MRI pituitary (>6mm less likely incidentaloma), high-dose 8mg dexamethasone test (pituitary tumors more likely to suppress cortisol >50%), CRH stimulation (pituitary tumors more likely to stimulate cortisol post CRH), presence of hypokalemia (more common with ectopic disease), degree of ACTH elevation (may be greater with ectopic), age (ectopic less likely in young patients), inferior petrosal sinus sampling (most direct test).
- Inferior petrosal sampling (IPSS) is gold standard to distinguish pituitary-dependent disease from ectopic disease, uses gradient in ACTH between petrosal sinus and peripheral blood with CRH stimulated central-to-peripheral ACTH ratio >3:1 diagnostic of pituitary dependent Cushing. Requires skilled interventional radiologist and adequate catheter placement.
- Detection of ectopic ACTH-secreting tumors may involve CT, MRI, PET, or octreotide scintigraphy.
- Pseudo-Cushing: physiologic excess cortisol secretion seen in patients with marked obesity, severe stress, severe depression, or chronic alcoholism. May have non-specific manifestations of Cushing and mildly elevated cortisol (1-3 times upper limit of normal) which revert to normal with treatment of underlying etiology.
SIGNS AND SYMPTOMS
- Symptoms may be dependent on severity and duration of hypercortisolism.
- Common: centripetal obesity with dorsocervical and supraclavicular fat pads, facial plethora and "moon face," fatigue, hyperglycemia, hypertension, mood lability, easy bruisability and skin atrophy, oligo/amenorrhea, hirsutism/acne (ACTH-dependent)
- More specific: broad (> 1cm) purple striae, proximal muscle weakness
- Other: increased risk of infection, increased cardiovascular risk, thromboembolism, bone loss, fractures, kidney stones, polydipsia, polyuria
- Ectopic ACTH: more severe hypertension, hypokalemia, skin hyperpigmentation
- Adrenal carcinoma: acute onset of virilization (temporal balding, clitoromegaly, deepening voice) seen in Cushing due to co-secretion of androgens, associated with weight loss and constitutional symptoms.
- Pseudo-Cushing: may have some but not all typical clinical signs of hypercortisolism. Needs evaluation and diagnostic testing to differentiate from Cushing.
- Exogenous Cushing: wean and discontinue glucocorticoid therapy if possible.
- Cushing disease: first line: transphenoidal pituitary surgery; secnd line: pituitary irradiation; Definitive/third line: bilateral total adrenalectomy requiring lifelong glucocorticoid and mineralocorticoid replacement therapy, and monitoring for Nelson syndrome (rapid enlargement of residual pituitary adenoma).
- Ectopic ACTH: surgical excision of tumor if possible. Non-resectable tumors treated with adrenal enzyme inhibitor (e.g. ketoconazole, metyrapone), medical adrenalectomy (mitotane), or bilateral surgical adrenalectomy.
- ACTH-independent adrenal adenomas: unilateral adrenalectomy generally curative. Laparoscopic surgery preferred. Need to give post-operative glucocorticoid therapy due to suppression of ACTH and atrophy of contralateral gland, and monitor for clinical and biochemical recovery.
- ACTH-independent bilateral adrenal hyperplasia: most cases treated with bilateral adrenalectomy.
- Adrenal carcinoma: surgery and mitotane for resectable disease; mitotane and chemotherapy for advanced, unresectable disease; adrenal enzyme inhibitors for persistent hypercortisolemia
- Pseudo-Cushing: treat primary disease (i.e. depression, diabetes, alcoholism)
- For those whom surgery is contraindicated or not curative or for pre-operative control of hypercortisolism, can use medical therapy with ketoconazole (FDA has blackbox warning requiring weekly LFTs), metyrapone, IV etomidate (for rapid control), mitotane.
- Newer medical options include cabergoline  and pasireotide (somatostatin receptor antagonist)  for those unable to have surgery or with persistent hypercortisolism. Mifepristone(glucorticoid receptor antagonist and anti-progestin) indicated for persistent pituitary disease complicated by diabetes or glucose intolerance .
- Hyperglycemia management in Cushing syndrome similar to exogenous steroid-induced hyperglycemia.
- Physiologic glucocorticoid replacement until recovery of endogenous adrenal function, which may take many months.
- Follow cortisol levels, not ACTH, for evidence of cure.
- Late relapse common after apparent surgical cure of Cushing disease. Long-term periodic assessment of the hypothalamic-pituitary-adrenal axis required.
- Hyperglycemia, psychiatric symptoms, and osteoporosis improve but often partially persist after effective therapy for Cushing .
- Although testing for Cushing not recommended in all patients with diabetes, screening is recommended for those with specific findings (myopathy, thin skin, bruising) or accumulation of new features over time .
- Pseudo-Cushing more common than Cushing syndrome in diabetes and requires no specific treatment except for usual diabetes management.
- Incidental pituitary and adrenal tumors are common in the general population. Imaging studies should only be performed in patients after confirming hypercortisolism.
- In patients with clinically suspected Cushing and equivocal screening test results, repeat testing and clinical evaluation after several months is advisable.
- Untreated Cushing associated with high risk of mortality, poor prognosis seen in ectopic ACTH syndrome and adrenocortical carcinoma
Basis for recommendation
- Nieman LK et al: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93:1526, 2008 [PMID:18334580]
Comment: Most recent Endocrine Society consensus guidelines on diagnosis of Cushing's syndrome.
- Prevedello DM et al: Management of Cushing's disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J Neurosurg 109:751, 2008 [PMID:18826366]
Comment: 13% of Cushing's disease patients in postoperative remission relapsed after average of 50 months.
- Colao A et al: A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med 366:914, 2012 [PMID:22397653]
- Etxabe J, Vazquez JA: Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol (Oxf) 40:479, 1994 [PMID:8187313]
Comment: Established Cushing's incidence of 2.4 cases per million people per year with standardized mortality ratio of 3.8 for affected persons.
- Fleseriu M et al: Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab 97:2039, 2012 [PMID:22466348]
- Carroll T, Raff H, Findling JW: Late-night salivary cortisol measurement in the diagnosis of Cushing's syndrome. Nat Clin Pract Endocrinol Metab 4:344, 2008 [PMID:18446140]
Comment: Late night salivary cortisol testing has 92-100% sensitivity and 93-100% specificity for Cushing's syndrome.
- Mantero F et al: A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 85:637, 2000 [PMID:10690869]
- Newell-Price J et al: Cushing's syndrome. Lancet 367:1605, 2006 [PMID:16698415]
- Catargi B et al: Occult Cushing's syndrome in type-2 diabetes. J Clin Endocrinol Metab 88:5808, 2003 [PMID:14671173]
Comment: Occult Cushing's syndrome seen in up to 5.5% of overweight or obese, type 2 diabetic patients.
- Oldfield EH et al: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med 325:897, 1991 [PMID:1652686]
Comment: Reported 100% sensitivity and 100%specificity using inferior petrosal sinus sampling after CRH for diagnosis of Cushing's disease.
- Swearingen B et al: Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metab 89:3752, 2004 [PMID:15292301]
Comment: Reported 90% sensitivity, 67% specificity, 99% PPV, 20% NPV using inferior petrosal sinus sampling after CRH for diagnosis of Cushing's disease.
- Vilar L et al: Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease. Pituitary 13:123, 2010 [PMID:19943118]
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