> Table of Contents > Cushing Disease and Cushing Syndrome
Cushing Disease and Cushing Syndrome
Linda Paniagua, MD
Geetha Gopalakrishnan, MD
image BASICS
DESCRIPTION
  • Clinical abnormalities associated with chronic exposure to excessive amounts of cortisol (the major adrenocorticoid)
  • Cushing syndrome is defined as excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor. Exogenous intake of steroids is the primary cause of Cushing syndrome.
  • Cushing disease is defined as glucocorticoid excess due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor, the most common cause of primary Cushing syndrome.
  • System(s) affected: endocrine/metabolic, musculoskeletal, skin/exocrine, cardiovascular; neuropsychiatric
Pediatric Considerations
  • Rare in infancy and childhood
  • Cushing disease accounts for approximately 75% of all cases of Cushing syndrome in children >7 years.
  • In children <7 years, adrenal causes of Cushing syndrome (adenoma, carcinoma, or bilateral hyperplasia) are more common.
  • Most common presenting symptom is lack of growth consistent with the weight gain.
Pregnancy Considerations
  • Pregnancy may exacerbate disease.
  • Cortisol levels increase in normal pregnancy states.
EPIDEMIOLOGY
Incidence
Uncommon: 0.7 to 2.4/1 million per year (1)
Prevalence
2-5% prevalence reported in difficult-to-control diabetics with obesity and hypertension (HTN)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Syndrome: excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor
  • Disease: pituitary tumor causing excess ACTH (corticotropin)
  • General population
    • Exogenous glucocorticoids
    • Endogenous ACTH-dependent hypercortisolism: 80-85%
      • ACTH-secreting pituitary tumor: 75%
      • Ectopic ACTH production (e.g., small cell carcinoma of lung, bronchial carcinoid): 20%
    • Endogenous ACTH-independent hypercortisolism: 15-20%
      • Adrenal adenoma
      • Adrenal carcinoma
      • Macronodular or micronodular hyperplasia
  • Pediatric/adolescent (1)
    • Adrenal hyperplasia secondary to McCune-Albright: mean age 1.2 years
    • Adrenocortical tumors: mean age 4.5 years
    • Ectopic ACTH syndrome: mean age 10.1 years
    • Primary pigmented nodular adrenocortical disease: mean age 13.0 years
    • Cushing disease: mean age 14.1 years
  • Pregnancy (2)
    • Pituitary-dependent Cushing syndrome: 33%
    • Adrenal causes: 40-50%
    • ACTH-independent adrenal hyperplasia: 3%
Genetics
  • Multiple endocrine neoplasia
  • Carney complex (an inherited multiple neoplasia syndrome)
  • McCune-Albright syndrome (mutation of GNAS1 gene)
  • Familial isolated pituitary adenomas (mutations in the aryl hydrocarbon receptor-interacting protein gene)
RISK FACTORS
  • Prevalent sex: female > male (3:1) (3)
  • Most often occurs between the ages of 25 and 40 years
  • Prolonged use of corticosteroids
GENERAL PREVENTION
Avoid corticosteroid exposure, when possible.
image DIAGNOSIS
PHYSICAL EXAM
  • Obesity (usually central): 95%
  • Facial plethora: 90%
  • Moon face (facial adiposity): 90%
  • Thin skin: 85%
  • Hypertension: 75%
  • Skeletal growth retardation in children (epiphyseal plates remain open): 70-80%
  • Hirsutism: 75%
  • Proximal muscle weakness: 60%
  • Purple striae on the skin
  • Increased adipose tissue in neck and trunk
  • Acne
DIFFERENTIAL DIAGNOSIS
  • Obesity
  • Diabetes mellitus
  • HTN
  • Metabolic syndrome X
  • Polycystic ovarian disease
  • Pseudo-Cushing (e.g., alcoholism, physical stress, severe major depression)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Recent guidelines (4)[C]
    • The 2008 Endocrine Society guidelines recommend against widespread testing for Cushing syndrome except in patients with the following:
      • Adrenal incidentaloma
      • Multiple progressive features suggestive of Cushing syndrome
      • Unusual features for their age such as osteoporosis and HTN
      • Abnormal growth (children)
  • Late-night salivary cortisol, 24-hour urinary free cortisol, or low-dose dexamethasone suppression testing
    • Elevated late-night salivary cortisol: Obtain at least two measurements. Cortisol secretion is highest in the morning and lowest between 11 PM and midnight. The nadir of serum cortisol is maintained in pseudo-Cushing (e.g., obesity, alcoholism, depression) but not in Cushing syndrome. Sensitivity and specificity are >90-95% (5,6)[B].
    • 24-hour urinary free cortisol level: Obtain ≥2 samples to rule out intermittent hypercortisolism if results are normal and suspicion is high. Also measure 24-hour urinary creatinine excretion to verify adequacy of collection. Results may be falsely low if glomerular filtration rate <30 mL/min. Overall sensitivity and specificity varies, 90-97% and 85-96%, respectively (5)[B]. Avoid drinking excessive amounts of water due to risk of false-positive values. False-positive values can be seen in the presence of pseudo-Cushing states.
    • Low-dose dexamethasone suppression testing: Dexamethasone 1 mg is given between 11 PM and midnight, and fasting plasma cortisol is measured between 8 and 9 AM the following morning. A serum cortisol level below 1.89 &mgr;g/dL excludes Cushing syndrome, but specificity is limited. The presence of pseudo-Cushing states (depression, obesity, etc.), hepatic or renal disease, or any drug that induces cytochrome P-450 enzymes may cause a false result.
  • High-dose dexamethasone suppression test may be useful when baseline ACTH levels are indeterminate:
    • 8 mg overnight dexamethasone suppression test: 8 mg of oral dexamethasone is given at 11 PM, with measurement of an 8-AM cortisol level the next day. A baseline 8-AM cortisol measurement is also obtained the morning prior to ingesting dexamethasone. Suppression of serum cortisol level to <50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH or primary adrenal disease. Sensitivity and specificity are 95% and 100%, respectively (7)[B].
  • If the initial results are positive or if clinical suspicion is high, perform additional studies to confirm diagnosis. Other tests to consider include the following:
    • Awake midnight plasma cortisol: Obtain samples on three consecutive nights. A late-evening serum cortisol >7.5 &mgr;g/dL has a sensitivity of 96% and specificity of 100% (8)[B]. Persistently elevated serum cortisol implies Cushing syndrome; nadir of serum cortisol is maintained in obese patients but not in Cushing.
    • Corticotropin-releasing hormone (CRH) after dexamethasone: used to distinguish Cushing syndrome from pseudo-Cushing syndrome. Dexamethasone 0.5 mg is given q6h for 48 hours starting at noon. CRH (1 &mgr;g/kg) is given 2 hours after the last dose of dexamethasone. Plasma cortisol is >1.4 &mgr;g/dL 15 minutes after CRH in patients with Cushing syndrome but not in those with pseudo-Cushing (9)[B].
  • Pituitary MRI scan if pituitary tumor is suspected
  • Abdominal CT scan if adrenal disease is suspected
  • Chest CT scan if ectopic ACTH secretion is suspected
  • Octreotide scintigraphy to look for occult ACTH-secreting tumor
  • Dual energy x-ray absorptiometry to evaluate for osteoporosis
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Follow-Up Tests & Special Considerations
  • Once the diagnosis of Cushing syndrome is confirmed, localization is the next step:
    • ACTH level: elevated in ACTH-dependent Cushing syndrome (e.g., pituitary and ectopic tumor) and low in ACTH-independent Cushing syndrome (e.g., adrenal tumors and exogenous glucocorticoids)
    • High-dose dexamethasone suppression testing: used to distinguish between an ACTH-secreting pituitary tumor and ectopic ACTH-secreting tumors. 0.5 mg dexamethasone is given q6h for 8 doses, with serum cortisol measured at 2 and 6 hours after last dose (sensitivity 79%, specificity 74%) (7)[B].
  • Diagnosis of Cushing syndrome is complicated by the nonspecificity and high prevalence of clinical symptoms in patients without the disorder and involves a variety of tests of variable sensitivity and specificity. Efficient screening and confirmatory procedures are essential before considering therapy.
Diagnostic Procedures/Other
Diagnostic procedure depends on clinical judgment. Inferior petrosal sinus sampling with CRH stimulation can be considered if ACTH-dependent tumor is suspected but not localized.
Test Interpretation
  • Thyroid function suppressed
  • HTN
  • Dyslipidemia
  • Polycystic ovarian syndrome/hyperandrogenism
  • Oligomenorrhea/hypogonadism
  • Myopathy/cutaneous wasting
  • Neuropsychiatric problems
  • Ipsilateral adrenal gland hyperplasia and contralateral adrenal gland atrophy
  • Hypercoagulable state
  • Osteoporosis
  • Nephrolithiasis
  • Growth hormone reduced
image TREATMENT
MEDICATION
  • Drugs usually not effective for primary long-term treatment; used in preparation for surgery or as adjunctive treatment after surgery, pituitary radiotherapy, or both.
  • Metyrapone, ketoconazole, and mitotane all lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland. Replacement glucocorticoid therapy is often required. As initial treatment, remission rates up to 85% (10,11)[C].
  • Mifepristone is a potent glucocorticoid receptor antagonist. It is FDA approved to control hyperglycemia in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance secondary to hypercortisolism that has not responded to (or who are not candidates for) surgery.
  • Pasireotide is a somatostatin receptor ligand with affinity for somatostatin receptor 5. It has been approved for adult Cushing disease treatment by the FDA.
SURGERY/OTHER PROCEDURES
  • Transsphenoidal surgery
    • Primary treatment for Cushing disease due to remission range of 65-90% (12)[C]
    • Resection of the ACTH-producing ectopic tumor
  • Adrenal surgery
    • For unilateral adrenal adenomas, laparoscopic surgery is the treatment of choice.
    • For nodular hyperplasia, bilateral adrenalectomy is usually recommended.
    • For patients with Cushing disease, bilateral laparoscopic adrenalectomy can be considered if the patient has persistent disease even after pituitary surgery and radiotherapy.
  • RADIOTHERAPY and stereotactic radiosurgery (SRS) can be used to treat persistent hypercortisolism after transsphenoidal surgery in Cushing disease.
  • Fractionated radiotherapy
    • Rates of remission range from 56% to 84% [B].
    • Its related complications of hypopituitarism has limited its usefulness [A].
  • Stereotactic radiosurgery
  • Rates of remission range from 17% to 83% [A].
  • Can be used as primary treatment without resection in patients with cavernous sinus tumors
image ONGOING CARE
PATIENT EDUCATION
  • Teaching regarding diet and monitoring daily weight, early treatment of infections, emotional lability
  • National Adrenal Disease Foundation. Great Neck, NY 11021; 516-407-4992
PROGNOSIS
  • Guardedly favorable prognosis with surgery for Cushing disease; generally chronic course with cyclic exacerbations and rare remissions
  • Better prognosis following surgery for benign adrenal tumors; long-term recurrence rate is 20%.
  • Poor with small cell carcinoma of the lung producing ectopic hormone; neuroendocrine tumors (bronchial carcinoid) have much better prognosis.
REFERENCES
1. Storr HL, Chan LF, Grossman AB, et al. Pediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances. Trends Endocrinol Metab. 2007;18(4):167-174.
2. Lindsay JR, Nieman LK. Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am. 2006;35(1):1-20.
3. Newell-Price J, Bertagna X, Grossman AB, et al. Cushing's syndrome. Lancet. 2006;367(9522): 1605-1617.
4. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
5. Putignano P, Toja P, Dubini A, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing's syndrome. J Clin Endocrinol Metabol. 2003;88(9):4153-4157.
6. Yaneva M, Mosnier-Pudar H, Dugué MA, et al. Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. J Clin Endocrinol Metab. 2004;89(7):3345-3351.
7. Aytug S, Laws ER Jr, Vance ML. Assessment of the utility of the high-dose dexamethasone suppression test in confirming the diagnosis of Cushing disease. Endocr Pract. 2012;18(2):152-157.
8. Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metabol. 2006;91(2):371-377.
9. Yanovski JA, Cutler GB Jr, Chrousos GP, et al. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA. 1993;269(17):2232-2238.
10. Findling JW, Raff H. Cushing's syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab. 2006;91(10):3746-3753.
11. Nieman LK, Ilias I. Evaluation and treatment of Cushing's syndrome. Am J Med. 2005;118(12):1340-1346.
12. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462.
See Also
&NA;
Algorithm: Cushing Syndrome
Codes
&NA;
ICD10
  • E24.9 Cushing's syndrome, unspecified
  • E24.0 Pituitary-dependent Cushing's disease
  • E24.2 Drug-induced Cushing's syndrome
Clinical Pearls
&NA;
  • Cushing disease is due to excessive ACTH secretion from a pituitary tumor, resulting in corticosteroid excess.
  • Cushing syndrome is due to excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor.
  • Depression, alcoholism, medications, eating disorders, and other conditions can cause mild clinical and laboratory findings similar to those in Cushing syndrome (pseudo-Cushing syndrome).