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The Changing Face of Cushing's Syndrome: Mild and Periodic Cases Makes the Diagnosis More Difficult
By Theodore C. Friedman, M.D., PhD, Erik Zuckerbraun M.D., Kimberly Daigle, Hrayr Shahinian, M.D., FACS


Many of the articles on Cushing's syndrome have examined patients with sustained and severe hypercortisolemia. Because CBG limits the amount of free cortisol (F) in circulation as F production increases, many of the tests used to diagnose Cushing's syndrome, such as UFC or night-time salivary cortisol may not detect a mild increase in F production. Furthermore, the periodic nature of Cushing's syndrome may lead to a normal measurement of F status when a patient is tested during a quiescent phase. Therefore, we determined the usefulness of several tests when performed on multiple occasions in consecutive patients with mild and/or periodic Cushing's syndrome.


24 h UFC and urinary 17OHS, 11 PM salivary F measurements, overnight dexamethasone suppression (DEX) test, evening plasma F and imaging studies was performed between 1 and 6 occasions in 36 consecutive patients with signs and symptoms of hypercortisolemia. 19 of these patients were eventually diagnosed with pituitary Cushing's disease by biochemical testing and their diagnosis was confirmed by positive pathology at the time of surgery and/or post-operative hypo-cortisolism and clinical remission and are included in this analysis.


13 of 19 patients had at least 1 elevated UFC, 13 of 15 patients had at least 1 elevated 17-OHS, 12 of 16 patients had at least 1 elevated night-time salivary F, 6 of 12 patients had an elevated evening plasma F and 2 of 14 patients failed to suppress to DEX and 18 of 19 patients had a microadenoma on their pituitary MRI. In contrast, 16 of 19 patients had at least 1 normal UFC, 9 of 14 patients had at least 1 normal 17-OHS, 13 of 16 patients had at least 1 normal night-time salivary F, 6 of 12 patients had a normal evening plasma F and 12 of 14 patients suppressed to DEX. These findings support that the large majority of patients have periodic Cushing's syndrome and that if only 1 test was performed on 1 occasion, most of these patients would be excluded from correct diagnosis.


We conclude that the great majority of patients presenting to this tertiary Endocrinology clinic had periodic Cushing's syndrome as evident by normal testing on 1 or more occasions. Urinary 17-OHS was at least as sensitive as the more widely used test, UFC. We conclude that there is no single test that can always diagnose Cushing's syndrome and that the diagnosis needs to be made by a careful history and physical coupled with multiple tests assessing hypercortisolism.


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