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Who should be tested for Cushing’s syndrome and what is the best testing method?
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Screening should be based on clinical judgment.
Obesity, hypertension and depression are all very common illnesses. Nearly 60% of Americans are overweight or obese and screening all of these patients would be cost prohibitive and may uncover many false-positive screens. Screening should be based on clinical judgment, and some patients are very obvious in “Cushing’s” appearance. Others should be screened based on an out-of-the-ordinary diagnosis of hypertension or osteoporosis for age, progression of signs or symptoms of Cushing’s syndrome or an adrenal cortical adenoma found incidentally on CT or MRI.
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The most reliable option for testing for Cushing’s syndrome appears to be the midnight salivary cortisol. This option has not been tested for all patient variables and may not be readily available to all clinicians. Multiple 24-hour urine free cortisol measurements are widely available and have been thoroughly examined. The test is cumbersome, as patients have to collect urine for 24 hours. Lastly, the 1-mg dexamethasone test can be used for patients who have low suspicion for disease. Using a combination of all three may be necessary to get a diagnosis.
Unfortunately, elevations in cortisol may be due to other medical conditions, medications or changes in cortisol-binding globulin, and until there is a substance secreted by corticotroph or adrenal adenomas that is different than normal tissue, testing will be imperfect.
Prakash Seshadri, MD, is an Attending Physician and Faculty Member in the Department of Endocrinology at Christiana Care Health System in Newark, Del.
Look for multiple indices of Cushing’s syndrome.
Because the symptoms and signs of Cushing’s syndrome overlap with common medical conditions of obesity, diabetes and hypertension, it is important to consider the overall clinical situation and to look for multiple indices of Cushing’s syndrome rather than focusing on a single sign or symptom. Similarly, it is unusual for a single sign or symptom to indicate Cushing’s syndrome.
The following should increase suspicion for Cushing’s:
- New onset or marked worsening of symptoms/signs of Cushing’s syndrome with no obvious reason in terms of changes in social situation, exercise, diet, medications, medical conditions, etc.
- Relatively rapid increase in symptom/signs (ie, over several years in a patient who had had a stable clinical course before this). A rapid change over months can occur with cancers (adrenocortical or ectopic ACTH). New and rapid onset of hirsutism along with other symptoms/signs of Cushing’s syndrome raises the possibility of an adrenocortical cancer.
- History of lung cancer in a patient with new or worsening symptoms of Cushing’s syndrome raise concerns regarding ectopic ACTH — in this case hyperglycemia, hypokalemia and hypertension may be the predominant symptoms rather than weight gain.
- On physical exam the patient may show signs of violaceous striae, bruising, plethorae, proximal muscle weakness, buffalo hump, moon facies and hypertension. On routine laboratory examination hyperglycemia and sometimes hypokalemia may be present.
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As for testing options, both the 24-hour urine collection for total volume, creatinine, cortisol and, if adrenocortical tumor is in the differential, 17-ketosteroids, and the overnight 1-mg dexamethasone suppression test and late-evening salivary cortisol determinations are all useful.
However, all the tests have drawbacks. The overnight 1-mg dexamethasone suppression test requires that the patient takes the dexamethasone and that the patient is not on a drug that acclerates metabolism of dexamethasone. Further, 1-mg dexamethasone suppression may be abnormal in patients with psychiatric problems. The 24-hour urine collections are cumbersome and some patients are unable to accurately collect a 24-hour urine. Salivary cortisol determinations need to be interpreted relative to an individual’s usual sleep-wake cycle as well as the conditions under which the sample was collected. Also, laboratories with accurate salivary cortisol measurements and good normative data are scarce. For all of these tests, false positives and false negatives can occur so that it is important to consider the clinical picture when interpreting the laboratory data.
Gail K. Adler, MD, PhD, is an Assistant Professor of Medicine in the Division of Endocrinology, Hypertension and Diabetes at Brigham and Women’s Hospital, Harvard Medical School in Boston.