Diagnosis of Cushing’s Disease

Cushing’s disease is a form of Cushing’s syndrome that occurs when the brain’s pituitary gland releases excessive amounts of adrenocorticotropic hormone (ACTH), typically because of a tumor forming on that gland. High ACTH levels cause the adrenal glands — sitting atop the kidneys — to overproduce cortisol, leading to a condition known as hypercortisolism.

Cortisol helps regulate several processes in the body, including blood sugar, blood pressure, immune responses, and physical responses to stress.

As a result, symptoms of Cushing’s disease can vary and often overlap with those of other conditions, making diagnosis a challenge. The fact that the disorder develops gradually, with not all symptoms appearing together, makes diagnosis even more difficult.

A doctor’s initial suspicion of Cushing’s based on a patient’s medical history and physical appearance is usually the first step in diagnosing Cushing’s disease. This is then typically followed by tests that help to confirm the presence of hypercortisolism and its causes.

Assessing clinical suspicion

When Cushing’s disease is suspected, a physician will generally request and analyze a patient’s detailed medical history, looking for any evidence of symptoms in the past that might indicate the presence of the disease. These may include weight gain, especially in the face, neck, upper back, and torso; skin changes, including the appearance of purple stretch marks and easy bruising; and limb muscle weakness.

A doctor may also compare old and recent photographs, looking for classic physical changes associated with the disorder, such as the typical round “moon face” and central obesity (fat accumulation around the torso) many patients experience.

A detailed history of medications, particularly corticosteroids, will typically be requested and evaluated, since their long-term use can lead to the development of exogenous Cushing’s syndrome.

Assessing hypercortisolism

Hypercortisolism can be identified through urine, blood, and saliva tests.

A 24-hour urinary test measures the amount of cortisol expelled in the urine over the course of a day. More than 50 to 100 micrograms per day in an adult suggests the presence of Cushing’s. Sometimes multiple urine tests will be needed to confirm the presence of hypercortisolism, as people with mild cases of Cushing’s may have normal cortisol levels over the course of a day.

A blood test typically begins with the administration of low-dose dexamethasone. This medication suppresses cortisol production, considerably lowering its levels in the blood of healthy people. Cortisol levels failing to drop in response to dexamethasone is one of the telltale signs of hypercortisolism.

Measuring cortisol levels in the saliva late at night — when they are normally low — is another test that can be used to detect the presence of hypercortisolism. In people with hypercortisolism and possibly Cushing’s disease, hormone levels will remain elevated.

Determining the causes of hypercortisolism

Measuring ACTH levels is often the first step in determining the cause of hypercortisolism.

ACTH-producing tumors frequently lead to either normal or elevated levels of this hormone, while individuals in whom the adrenal glands produce too much cortisol without the presence of such tumors may have low ACTH levels.

A high-dose dexamethasone test may also be helpful to distinguish between these two possible scenarios. As with the low-dose test, a patient will take dexamethasone at night and doctors will measure cortisol levels in the blood the following morning. Healthy people and those with Cushing’s disease will tend to have low cortisol levels, while those with adrenal tumors in whom cortisol production is independent of ACTH will continue to have high levels of the hormone.

Sometimes these tests may be inconclusive, leading physicians to order additional tests to confirm the diagnosis. At this point, doctors may request MRI scans to attempt to locate tumors on the pituitary gland or elsewhere in the body, or an invasive procedure called petrosal sinus sampling.

In petrosal sinus sampling, physicians insert catheters into the veins draining the pituitary gland, called the inferior petrosal sinuses. The blood leaving the pituitary gland through these veins is then drawn and used to measure ACTH levels before and after giving the patient corticotropin-releasing hormone, which stimulates ACTH production, at various time intervals. Elevated ACTH levels typically indicate the presence of a pituitary tumor. Despite being invasive, this test is considered to be highly accurate.


Last updated: May 25, 2021


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