Cushing's Syndrome: Diagnosis

Diagnosing Cushing's syndrome can be complex. Diagnosis must not only identify the cortisol excess, but also locate its source. Many of the symptoms listed above can be attributed to numerous other diseases. Although a number of these symptoms seen together would certainly suggest Cushing's syndrome, the symptoms are still not specific to Cushing's syndrome. Following a review of the patient's medical history, physical examination, and routine blood tests, a series of more sophisticated tests is available to achieve a diagnosis.

This is the most specific diagnostic test for identifying Cushing's syndrome. It involves measuring the amount of cortisol present in the urine over a 24-hour period. When excess cortisol is present in the bloodstream, it is processed by the kidneys and removed as waste in the urine. This 24-hour free cortisol test requires that an individual collect exactly 24-hours' worth of urine in a single container. The urine is then analyzed in a laboratory to determine the quantity of cortisol present. This technique can also be paired with the administration of dexamethasone, which in a normal individual would cause urine cortisol to be very low. Once a diagnosis has been made using the 24-hour free cortisol test, other tests are used to find the exact location of the abnormality causing excess cortisol production.

This test is useful in distinguishing individuals with excess ACTH production due to a pituitary adenoma from those with ectopic ACTH-producing tumors. Patients are given dexamethasone (a synthetic glucocorticoid) orally every six hours for four days. Low doses of dexamethasone are given during the first two days; for the last two days, higher doses are administered. Before dexamethasone is administered, as well as on each day of the test, 24-hour urine collections are obtained.

Because cortisol and other glucocorticoids signal the pituitary to decrease ACTH, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Thus, the cortisol response to dexamethasone differs depending on whether the cause of Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing tumor.

However, the dexamethasone suppression test may produce false-positive results in patients with conditions such as depression, alcohol abuse, high estrogen levels, acute illness, and stress. On the other hand, drugs such as phenytoin and phenobarbital may produce false-negative results. Thus, patients are usually advised to stop taking these drugs at least one week prior to the test.

The CRH stimulation test is given to help distinguish between patients with pituitary adenomas and those with either ectopic ACTH syndrome or cortisolsecreting adrenal tumors. In this test, patients are given an injection of CRH, the corticotropin-releasing hormone that causes the pituitary to secrete ACTH. In patients with pituitary adenomas, blood levels of ACTH and cortisol usually rise. However, in patients with ectopic ACTH syndrome, this rise is rarely seen. In patients with cortisol-secreting adrenal tumors, this rise almost never occurs.

Although this test is not always necessary, it may be used to distinguish between a pituitary adenoma and an ectopic source of ACTH. Petrosal sinus sampling involves drawing blood directly from veins that drain the pituitary. This test, which is usually performed with local anesthesia and mild sedation, requires inserting tiny, flexible tubes (catheters) through a vein in the upper thigh or groin area. The catheters are then threaded up slowly until they reach veins in an area of the skull known as the petrosal sinuses. X rays are typically used to confirm the correct position of the catheters. Often CRH is also given during the test to increase the accuracy of results.

When blood tested from the petrosal sinuses reveals a higher ACTH level than blood drawn from a vein in the forearm, the likely diagnosis is a pituitary adenoma. When the two samples show similar levels of ACTH, the diagnosis indicates ectopic ACTH syndrome.

Imaging tests such as computed tomography scans (CT) and magnetic resonance imaging (MRI) are only used to look at the pituitary and adrenal glands after a firm diagnosis has already been made. The presence of a pituitary or adrenal tumor does not necessarily guarantee that it is the source of increased ACTH production. Many healthy people with no symptoms or disease whatsoever have noncancerous tumors in the pituitary and adrenal glands. Thus, CT and MRI is often used to image the pituitary and adrenal glands in preparation for surgery.

— Rosalyn Carson-DeWitt