Cushing’s disease physical examination

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Cushing's disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease)[1][2] is a cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome,[3] when excluding Cushing's syndrome from exogenously administered corticosteroids.

This should not be confused with ectopic Cushing syndrome or exogenous steroid use.[4]

Physical Examination

Diagnosis is made first by diagnosing Cushing's Syndrome, which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients.[5] Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test (DST), and bilateral inferior petrosal sinus sampling (BIPSS). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis.[6] Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists.[6] For non-Cushing or healthy patients, the false-positive rate is 30%.[6] The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction.[6] Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma corticotropin concentrations. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with X-ray computed tomography|CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary MRI.

Two dexamethasone suppression tests (DSTs) are generally used, the overnight and 48-h DSTs.[6] For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease.[6] However, 3-8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities.[6] For non-Cushing or healthy patients, the false-positive rate is 30%.[6] The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction.[6] In the high-dose 48-h DST, 2 mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8 mg is given.[6] This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%.[6] These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors.[6]

Administration of corticotropin releasing hormone (CRH) can differentiate this condition from ectopic ACTH secretion. In a patient with Cushing's disease, the tumor cells will be stimulated to release corticotropin and elevated plasma corticotropin levels will be detected.[6] This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions.[6] If ectopic, the plasma ACTH and cortisol levels should remain unchanged; if this is pituitary related, levels of both would rise. The CRH test uses recombinant human or ovine-sequence CRH, which is administered via a 100μg intravenous bolus dose. The sensitivity of the CRH test for detecting Cushing's disease is 93% when plasma levels are measured after fifteen and thirty minutes.[6] However, this test is used only as a last resort due to its high cost and complexity.[5]

A CT or MRI of the pituitary may also show the ACTH secreting tumor if present. However, in 40% of Cushing's disease patients MRI is unable to detect a tumor.[6] In one study of 261 patients with confirmed pituitary Cushing's Disease, only 48% of pituitary lesions were identified using MRI prior to surgery. The average size of tumor, both those that were identified on MRI and those that were only discovered during surgery, was 6 mm.[7]

A more accurate but invasive test used to differentiate pituitary from ectopic or adrenal Cushing's syndrome is inferior petrosal sinus sampling.[8] A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive.[6] A basal central:peripheral ratio of over 3:1 when CRH is administered is indicative of Cushing’s disease.[6] This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome.[6] The BIPSS has a sensitivity and specificity of 94% for Cushing's disease but it is usually used as a last resort due to its invasiveness, rare but serious complications, and the expertise required to perform it.[5]

Another diagnostic test used is the urinary free cortisol (UFC) test, which measures the excess cortisol excreted by the kidneys into the urine. Results of 4x higher cortisol levels than normal are likely to be Cushing's disease.[6][5] This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism.[5] The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to pseudo-Cushing states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.[5]

The late-night or midnight Saliva testing#Cortisol and melatonin aberrations|salivary cortisol test has been gaining support due to its ease of collection and stability at room temperature, therefore it can be assigned to outpatients.[6] The test measures free circulating cortisol and has both a sensitivity and specificity of 95-98%.[6][5] This test is especially useful for diagnosing children.[6]


  1. "Whonamedit - Nikolai Mikhailovich Itsenko". "Nikolai Mikhailovich Itsenko investigated neural infections, vegetative nervous system diseases and cerebral tumors. In 1926 he was the first one who described Itsenko-Cushing's disease, six years before Cushing."
  2. A.I. Gozhenko, I.P. Gurkalova, W. Zukow, Z. Kwasnik, B. Mroczkowska (2009). "Trematoda". Pathology: Medical Student's Library. Radomska Szkola Wyžsza uk. Zubrzyckiego. p. 280. ISBN 978-83-61047-18-6.
  3. Lanzino, Giuseppe; Maartens, Niki F.; Laws, Edward R. (2002). "Cushing's case XLV: Minnie G.". Journal of Neurosurgery. 97 (1): 231–234. doi:10.3171/jns.2002.97.1.0231. PMID 12134925. |access-date= requires |url= (help)
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Nieman, L.K.; Ilias, I. (2005). "Evaluation and treatment of Cushing's syndrome". The American Journal of Medicine. 118 (12): 1340–1346. doi:10.1016/j.amjmed.2005.01.059. PMID 16378774. Retrieved 30 January 2014.
  6. 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 6.20 6.21 6.22 Newell-Price, J.; Bertagna, X.; Grossman, A.B.; Nieman, L.K. (2006). "Cushing's syndrome". The Lancet. 367 (9522): 1605–1617. doi:10.1016/S0140-6736(08)61345-8. Retrieved 30 January 2014.
  7. Jagannathan, J. et al, Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease, Journal of Neurosurgery, 25 September 2010, Retrieved 2014-01-27
  8. Deipolyi, A; Karaosmanoglu, A; Habito, C; Brannan, S; Wicky, S; Hirsch, J; Oklu, R (2011-02-23). "The role of bilateral inferior petrosal sinus sampling in the diagnostic evaluation of Cushing disease". Diagnostic and interventional radiology (Ankara, Turkey). 18 (1): 132–8. doi:10.4261/1305-3825.DIR.4279-11.0. PMID 21348009.