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Cushing Syndrome

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Laboratory Tests
No single laboratory test is ideal to diagnose Cushing syndrome and more than one is often used. Since cortisol levels change over the course of a day, a single cortisol result from a blood sample drawn at most times of the day is of little value. Testing for Cushing syndrome is typically done in two stages. Initial tests are used to verify that there is excess cortisol present. The second set of tests is used to determine the cause of the increased cortisol: pituitary, adrenal, or other.

Initial tests to diagnosis Cushing syndrome
The three most common tests are measurement of midnight plasma cortisol or late-night salivary cortisol, 24-hour urinary free cortisol test, and the dexamethasone suppression screening test.

  • Midnight plasma cortisol and late-night salivary cortisol measurements: Normally, cortisol production is suppressed at midnight but in Cushing syndrome, this does not happen. Therefore, an elevated blood (plasma) level at midnight suggests Cushing syndrome. Blood is the preferred sample, but this usually requires a hospital stay. Alternatively, a saliva sample can be collected late at night at home and then tested. It is recommended that a sample be collected three nights in a row. If only a single sample is collected and tested, the test should be repeated if the result is outside the established reference range, to confirm the results and to avoid false positives.
  • 24-hour urine cortisol: 24-hour urine cortisol (or urine free cortisol, UFC) is often used to evaluate overall cortisol production. One out of four 24-hour urine samples may be normal and other testing may have to be performed. Like the midnight cortisol test, it is recommended that this test be repeated if results are abnormal, to avoid false positives.
  • Dexamethasone suppression screening test: Dexamethasone is a synthetic steroid that mimics cortisol in the feedback inhibition of corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) production. A normal response to dexamethasone is suppression of cortisol secretion.

    Dexamethasone can be used in different dosages for different purposes as a diagnostic test. One version involves giving a fairly low dose (1 mg) at bedtime to prevent the rise in ACTH and cortisol that normally occurs during sleep. Between 8 and 9 am the next morning, a blood sample is drawn and the cortisol level is measured. In healthy individuals, the level will be low (suppressed); in those with Cushing syndrome, the level will not be suppressed.

    Less commonly, a different approach involves giving 0.5 mg every 6 hours for two days and collecting a 24-hour urine sample on the second day for urine free cortisol. As with the overnight version, in healthy persons, urine free cortisol should be suppressed to very low levels, while high levels will continue to be present in those with Cushing syndrome.

If one of these tests shows an increased cortisol level, then it is likely that cortisol levels are not varying normally. Additional testing is then ordered to help determine the reason for the increased level.

Follow-up tests

  • Corticotrophin releasing hormone (CRH) stimulation test: The CRH stimulation test is used once Cushing syndrome has been diagnosed, to discern people with a pituitary condition from those with adrenal tumors and people with tumors outside the pituitary that produce ACTH (called ectopic ACTH). For this test, ACTH levels are measured at baseline. CRH is then injected and cortisol and ACTH levels are measured at timed intervals after the injection, for example, at 30 and 60 minutes. The normal response is a peak in ACTH levels followed by a peak in cortisol levels. Most people with Cushing syndrome caused by adrenal tumors or ACTH-secreting tumors outside the endocrine system do not respond to CRH.
  • High-dose dexamethasone suppression test (HDDST): This test is similar to the low-dose version. A higher dose of dexamethasone can be given to distinguish between an ACTH-producing pituitary tumor and other causes of Cushing syndrome. High doses of dexamethasone usually suppress cortisol levels in people with pituitary tumors but not in those with ACTH-producing tumors outside the endocrine system.
  • Dexamethasone-corticotropin-releasing hormone test: Some people may have pseudo-Cushing syndrome, sometimes found in people who are severely obese, drink excess alcohol, have poorly controlled diabetes, or have depression or anxiety disorders. Pseudo-Cushing does not have the same long-term health effects as Cushing syndrome or require hormone treatment. People with pseudo-Cushing can have a high cortisol level but do not develop the progressive effects of the syndrome, such as muscle weakness, bone fractures, or thinning skin. The dexamethasone-CRH test rapidly distinguishes pseudo-Cushing from mild cases of Cushing. This test combines the Dexamethasone suppression screening test and a CRH stimulation test (see above). An elevation of cortisol during this test suggest Cushing syndrome, while a level that does not rise suggests pseudo-Cushing.
  • Petrosal sinus sampling: This test is usually combined with a CRH stimulation test. ACTH levels may be measured in samples obtained through a catheter placed in the neck to draw blood from the inferior petrosal sinuses, veins that carry blood away from the pituitary gland. The level of ACTH in the petrosal sinuses is compared with the level in the forearm vein. A higher level of ACTH in the sinuses indicates a pituitary tumor. If the levels in the sinuses and forearm are about the same, it suggests the ACTH is produced by a tumor outside of the pituitary gland.

Some general laboratory tests that may be performed include:

Non-Laboratory Tests

  • Computed tomography (CT) – scan of the chest, particularly the lung, and abdomen; may be used to help locate adrenal, pituitary, and other ectopic tumors 
  • Magnetic resonance imaging (MRI) – sometimes ordered to help evaluate pituitary and adrenal glands for the presence of a tumor
  • Ultrasound
  • Octreotide scan – a drug called octreotide, similar to somatostatin, is labeled with a radioactive tag and injected into the person tested; the radioactive drug attaches to receptors on the hormone-producing tumor, allowing detection with a radiologic scan.

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