Pseudo Cushings

Things may not always be what they seem.

By Ted Friedman, M.D., Ph.D., Cedars-Sinai Medical Center

Cushings syndrome is a rare disorder which can severely affect the patient. Symptoms of patients with Cushings syndrome include weight gain, easy bruising, menstrual irregularities, increased appetite, trouble sleeping, depression or mood swings, anxiety, fatigue and altered mentation (trouble concentrating or decreased memory).

Physical abnormalities include new onset obesity (primarily in the abdominal and buttock regions), buffalo hump, filling in of the regions above the collarbone, thinning of the extremities, rounding and reddening of the face, thin skin, decreased muscle strength, high blood pressure, stretch marks and excess hair growth in women. Although some patients may have most or all of these signs and symptoms so that the diagnosis of Cushings syndrome may be easy to make, other patients may have mild Cushings syndrome and come to their health care providers at an early stage of the disease. These patients may have trouble being diagnosed with Cushings syndrome. Furthermore, other medical conditions may also result in some of the signs, symptoms and laboratory abnormalities seen in patients with Cushings syndrome, although the patient doesnt actually have Cushings syndrome. These conditions are called pseudo-Cushings states and include conditions such as severe stresses (illness or emotional stress), alcoholism or alcohol withdrawal and psychiatric conditions such as depression, panic disorders and psychotic conditions.

The psychiatric conditions, such as depression, which lead to a high production of the hormone, cortisol, are quite common and a patient with one of these conditions may appear similar to a patient with Cushings syndrome.

It is quite important to determine if the patient has Cushings syndrome or a pseudo-Cushings state because if a patient with a pseudo-Cushings state is incorrectly diagnosed as having Cushings syndrome, that patient could undergo needless and potentially harmful testing and also unnecessary surgery which would permanently impair the patients health. On the other hand, if a patient truly has Cushings syndrome, it would be important to confirm the diagnoses and eliminate the possibility of a pseudo-Cushings state so that the cause of the Cushings syndrome can be determined.

The most common cause of Cushings syndrome is a pituitary tumor (Cushings disease). Other causes of Cushings syndrome include adrenal tumors or cancers and tumors in other parts of the body, such as the lung, thymus or pancreas making the hormone ACTH (ectopic ACTH syndrome). It is important to determine that the patient has Cushings syndrome before the type of Cushings syndrome is investigated.

What should your health care provider do if you have a few of the signs and symptoms of Cushings syndrome? The first thing she/he should do is a careful history and physical looking for the items discussed above. Attention should be directed to the time course of the symptoms (new, sudden onset of weight gain and other symptoms suggest Cushings syndrome, while long-standing, non-progressing symptoms suggest pseudo-Cushings states).

Comparison with old pictures is often very helpful. I would then recommend that your health care provider obtain between one and three 24-hour urine samples and have them measured for urinary free cortisol (UFC). This test is a good screen to help determine if you have Cushings syndrome, are completely normal, or have intermediate values which require further testing to distinguish between pseudo-Cushings states and Cushings syndrome. If all your UFCs are in the normal range (usually less than 50 or 90 mg/day, depending on the assay), it is very unlikely that you have Cushings syndrome. If some of your UFCs are more than 3.5 times the upper limit of normal (usually more than 175 or 315 mg/day, depending on the assay), you probably have Cushings syndrome and you should have a work-up to determine the etiology of the Cushings syndrome.

If your UFCs fall in the range between the upper limit of normal and 3.5 times the upper limit of normal, you need to have further tests to distinguish between Cushings syndrome and pseudo-Cushings states. If your UFCs are either clearly high or mildly high, you should be referred to an Endocrinologist who specializes in Cushings syndrome for further work-up.

There are two good tests to help the Endocrinologist distinguish between mild Cushings syndrome and pseudo-Cushings states in those patients with a mildly elevated UFC. One test is called a diurnal cortisol test and takes advantage of the fact that normal patients and patients with pseudo-Cushings states have high plasma cortisol levels in the morning and much lower levels in the evening and at night, while patients with Cushings syndrome have high cortisol levels in both the morning and at night. The diurnal cortisol test takes advantage of this by having a blood sample drawn at midnight which is sent for plasma cortisol. Because of the timing of the required blood draw, this test may require a hospital admission. A plasma cortisol level of greater than 7.5 mg/dl probably means that you have Cushings syndrome, while a value less than 7.5 mg/dl probably indicates that you dont have Cushings syndrome. This test is quite accurate, but it requires blood collection at an inconvenient time. Because of the difficulty in obtaining blood at midnight, Endocrinologists are evaluating whether cortisol in a saliva sample can be used to distinguish between Cushings syndrome and pseudo-Cushings states. This test looks promising, however, it is still too early to recommend it instead of the diurnal plasma cortisol test.

The other test to help Endocrinologists distinguish between mild Cushings syndrome and pseudo-Cushings states in those patients with a mildly elevated UFC is the dexamethasone-CRH test. This test combines two tests, the dexamethasone suppression test and the CRH test which individually are good but not great at distinguishing between pseudo-Cushings states and Cushings syndrome. The dexamethasone test uses a drug called dexamethasone which in normal people and those with pseudo-Cushings states, suppresses the production of ACTH by the pituitary leading to low cortisol levels. In patients with Cushings syndrome, dexamethasone is ineffective and the cortisol usually doesnt decrease to low levels. CRH is a hormone which stimulates the pituitary to make more ACTH which leads to an increase in cortisol levels. Patients with Cushings syndrome have a larger increase in plasma ACTH and cortisol levels than in normal individuals or those patients with pseudo-Cushings states. Although these tests individually are helpful to diagnose Cushings syndrome, many patients with pseudo-Cushings states also respond to them in a similar manner as those with Cushings syndrome, making them not the ideal test to use individually. However, when these tests are combined, the distinction between Cushings syndrome and pseudo-Cushings states is almost always made. In the combined test, you take dexamethasone 4 times a day for 2 days and then get a injection of CRH. Your cortisol is measured 20 minutes after the CRH injection and a value of greater than 1.4 mg/dl means that you probably have Cushings syndrome. The main drawbacks to this test is that it requires a lot of steps and the drug (CRH) is expensive.

There are other tests (listed in Table) that may help your Endocrinologist determine if you have Cushings syndrome or pseudo-Cushings states. There are also tests (Table) that are not helpful in making the distinction between these two conditions and may actually confuse both you and your Endocrinologist if done at this time. One test called inferior petrosal sinus sampling (IPSS) is very good to determine what type of Cushings syndrome you have, but not good to determine if you have Cushings syndrome or pseudo-Cushings states and should not be done at this stage. Pituitary MRI is also very good for localizing a pituitary tumor once the diagnosis of Cushings syndrome is made, however it is not recommended to distinguish between Cushings syndrome and pseudo-Cushings states. This is because up to 10% of normal individuals have what radiologists read as a pituitary tumor on MRI (incidentalomas).

The distinction between Cushings syndrome and pseudo-Cushings states is often difficult leading to frustration for both patient and physician. To prevent this frustration, working closely with a good Endocrinologist who sees many patients with Cushings syndrome is needed. Patience is also needed. With time, most patients will declare themselves and develop a clearer picture consistent with either Cushings syndrome or a pseudo-Cushings state. While waiting, treating the underlying psychiatric condition (if present) is often helpful. The tincture of time is the best cure!