Subclinical Cushing’s Syndrome: Navigating a Gray Area

One of the more frequent conditions found in people with adrenal incidentalomas is subclinical Cushing’s syndrome. Subclinical Cushing’s differs from classic Cushing’s in that a patient has evidence of cortisol hypersecretion based on test results, but they don’t have the clinical manifestations of Cushing syndrome. These signs of overt Cushing’s syndrome include weight gain around the midsection, fatty deposits around the face, purple stretch marks and skin that bruises easily. Because the line between subclinical Cushing’s syndrome and early Cushing’s syndrome can be blurry, proper evaluation and monitoring of the condition is important until the distinction can be made.

Divya Yogi-Morren, MD, Medical Director of the Pituitary Tumor Center in Cleveland Clinic’s Endocrinology and Metabolism Institute, explains that there are typically three tests that are used to diagnose hypercortisolism. The first test is a saliva cortisol test that measures midnight salivary cortisol samples. One of the early indicators of Cushing’s syndrome is the loss of the normal circadian variation of cortisol secretion. The second test is a 24-hour urine cortisol test. A dexamethasone suppression test is also used. The patient is given one milligram of dexamethasone at midnight, which would usually suppress cortisol levels in someone who does not have Cushing’s. However, in people who have Cushing’s and sometimes in subclinical Cushing’s, their cortisol levels are not suppressed.

A complicated diagnosis

“In order for you to be diagnosed with Cushing’s, a patient has to have two out of three tests for hypercortisolism be concurrent. If you want to rule it out, you have to have two out of three tests that are negative,” says Dr. Yogi-Morren. “So a lot of people with subclinical Cushing’s will only have one out of these three tests being abnormal. And they may just go along for years in this gray area where just one test is abnormal.”

Further complicating this ambiguity is that many of the symptoms associated with Cushing’s syndrome are evident in other more common conditions. For example, obesity, insulin resistance and pre-diabetes can all present with weight gain. Classic Cushing’s syndrome is also quite rare, compared to the prevalence of these other conditions, which may preclude clinicians from considering it in instances where the more characteristic symptoms associated with Cushing’s are not present. Oftentimes, subclinical Cushing’s is diagnosed by chance after a patient presents with weight gain and returns a positive saliva cortisol test.

Treatment vs. monitoring

“People with subclinical Cushing’s do not usually undergo surgery unless they have a confirmed adrenal adenoma,” explains Dr. Yogi-Morren. “If the patient has adrenal adenoma, plus the clinical features of high cortisol as well as co-morbidities like hyperlipidemia, hypertension or cardiovascular risk, then you would likely be able to proceed to adrenalectomy. But if it’s a very mild subclinical Cushing’s, and it’s just one lab that’s abnormal, you would probably just continue to follow this patient. If you’re not certain that this needs treatment, then it needs to be followed up and the tests need to be repeated every three months until this reveals itself.”

Dr. Yogi-Morren notes that there is not a consensus in the current literature on whether patients with subclinical Cushing’s should be treated or monitored. She recommends retesting patients at three-month intervals to make sure there are no changes. If, after a certain amount of time, the tests remain consistent, those testing intervals can be expanded to every six months. Because it is very hard to rule out Cushing’s completely, Dr. Yogi-Morren says she would continue to monitor them as long as they show comorbidities because it’s possible that a patient actually has early Cushing’s rather than subclinical Cushing’s, which will progress to classic Cushing’s. There is also a rare possibility that the patient has cyclical Cushing’s where the symptoms wax and wane periodically.

As far as managing subclinical Cushing’s, Dr. Yogi-Morren mentions several strategies to treat patients, but she notes that each patient’s condition is unique and treatments must be adapted to the patient’s needs to be most effective. “If it’s weight management, or if weight gain is the presenting feature, then obviously weight management needs to be at the core of the treatment plan,” she explains. “If the patient exhibits hypertension, hyperglycemia, high cholesterol or any of the other comorbidities that may exist, then those also need to be managed accordingly. In prolonged subclinical Cushing’s, osteoporosis is another possible feature that needs to be evaluated and managed. It’s important to take a holistic approach in regard to management for this patient population.”