Cushing's Syndrome: Diagnosis

Many Cushing’s patients endure years of symptoms prior to diagnosis. There are several factors that contribute to the difficulty of a Cushing's diagnosis. First, Cushing's is a rare disorder with an incidence rate of 5 cases per million. In contrast, diabetes is a very common disorder. Many physicians in private practice will never encounter a patient with Cushing's, whereas most will see a number of diabetic patients. Thus, doctors are inclined to diagnose the most common disorder and in most cases, that diagnosis will be correct. The second reason for the difficulty in diagnosis is the minimal amount of training on Cushing's that MD's receive during medical school and their internships. This relates to the fact that Cushing's is a rare disorder. Patient groups, such as yourselves, can be instrumental in increasing the awareness of Cushing's in medical schools and teaching hospitals by sponsoring physician speakers who are experts in Cushing's. A third reason for the difficulty in diagnosis has to do with non-specific symptoms. In other words, the symptoms associated with Cushing's are symptoms that are also associated with more common disorders such as diabetes, high blood pressure, depression and obesity. There are other rare illnesses that are easier to diagnose simply because the symptoms are more specific.
As with most conditions, if the diagnosis is obvious clinically, then biochemical confirmation is usually simple; if the diagnosis is not clear, then biochemical confirmation or exclusion of the diagnosis is often much more difficult. This is especially true for Cushing's syndrome and several attempts over a period of weeks or months may be necessary to establish or exclude the diagnosis in particularly difficult cases. Even then, the possibility of error will remain. This is especially early in the disease process or in mild cases. One reason for the problem has to do with how normal ranges are calculated. Frequently, that normal range is developed by using a reference group of people assumed (or shown) to be disease-free. Ideally, when using a test to exclude the diagnosis of Cushing's syndrome, the reference group should be made up of individuals who look like they have the disease, but do not. However, reference groups are usually made up of individuals who are readily accessible (medical students, lab technicians, etc.) and not more appropriate comparisons. Another reason has to do with the levels chosen to indicate disease. This level is usually a compromise between detecting everyone who has the disease and avoiding falsely identifying disease-free individuals as having the disease.
One strategy to expedite the diagnostic process is through photographs which show changes over time. A photo from several years before can illustrate a rapid change in appearance. Relatively rapid changes in appearance, without dramatic changes in lifestyle, usually indicate medical problems that warrant further evaluation.
Because Cushing's Syndrome is a rare but serious disorder, it is very important to carefully exclude (rule out) other disorders and then separate the different types, leading eventually to a specific cause that can be treated. This process of testing and excluding usually takes days to weeks and requires a lot of patience and cooperation by the person being tested.
After the initial history, physical exam and routine blood tests, the first step is to prove cortisol excess with specific blood and 24 hour urine tests for cortisol. Inappropriate cortisol production will then be evaluated by doing a dexamethasone suppression test. Dexamethasone (steroid) pills are given by mouth, then blood and urine are collected for cortisol and other adrenal hormones. A screening test might be done initially with an overnight test, but if it is abnormal, usually a 4 day test divided into low and high dose dexamethasone is needed. To separate ACTH dependent from independent types, a blood test for ACTH in the morning is done. Blood and urine tests for adrenal androgens are useful. Testing with other drugs, such as metyrapone and CRH (corticotropin releasing hormone) may also be needed.
Once all of the blood and urine results are analyzed, they will establish whether some type of Cushing's Syndrome is present, and should indicate whether the disease is ACTH dependent (pituitary or ectopic) or independent (an adrenal tumor). Localizing techniques such as CT or MRI are then used to find the tumor. Often a pituitary tumor is tiny and hard to find, so a special test of the release of ACTH from both sides of the pituitary (petrosal sinus sampling) might be needed. Small tumors producing ectopic ACTH are also sometimes difficult to localize and require repeated scans and x-rays.
Alcohol-induced elevation of cortisol can be distinguished from other causes by the fact that when alcohol consumption is ceased, the biochemical abnormalities usually return to normal within a few days.
Previously, differentiation between some types of pseudo-Cushing's and Cushing's syndrome could be difficult. Recently, the NIH group has described a new combined dexamethasone/CRH test which discriminates between endogenous Cushing's syndrome and pseudo-Cushing's syndrome with close to a 100 % accuracy. Dexamethasone is given at 0.5 mg every 6 hrs. for 48 hours and two hours after the last dose, CRH is administered at the dose of 1ug/kg of body weight, intravenously; plasma cortisol is measured 15 minutes later. In endogenous Cushing's syndrome cortisol levels are elevated at the 15 minute time point, whereas in pseudo-Cushing's syndrome, the levels of cortisol are below 1.4 mcg/dl at the 15 minute time point.