High prevalence of normal tests assessing hypercortisolism in subjects with mild and episodic Cushing's syndrome suggests that the paradigm for diagnosis and exclusion of Cushing's syndrome requires multiple testing

Abstract

Many Endocrinologists believe that a single determination of eucortisolism or a single demonstration of appropriate suppression to dexamethasone excluded Cushing's syndrome, except in what was previously thought to be the rare patient with episodic or periodic Cushing's syndrome. We hypothesize that episodic Cushing's syndrome is relatively common and a single test assessing hypercortisolism may not be sufficient to accurately rule out or diagnose Cushing's syndrome and retrospectively examined the number of normal and abnormal tests assessing hypercortisolism performed on multiple occasions in 66 patients found to have mild and/or episodic Cushing's syndrome compared to a similar group of 54 patients evaluated for, but determined not to have Cushing's syndrome. We found that 65 of the 66 patients with Cushing's syndrome had at least one normal test of cortisol status and most patients had several normal tests. The probability of having Cushing's syndrome when one test was negative was 92% for 23:00 h salivary cortisol, 88% for 24-h UFC, 86% for 24-h 17OHS, and 54% for nighttime plasma cortisol. These results demonstrated that episodic hypercortisolism is highly prevalent in subjects with mild Cushing's syndrome and no single test was effective in conclusively diagnosing or excluding the condition. Rather, the paradigm for the diagnosis should be a careful history and physical examination and in those patients in whom mild Cushing's syndrome/disease is strongly suspected, multiple tests assessing hypercortisolism should be performed on subsequent occasions, especially when the patient is experiencing signs and symptoms of short-term hypercortisolism.

Fig. 1

The 23:00 h salivary cortisol levels performed 1–6 times on patients with Cushing’s syndrome (a) and patients determined not to have Cushing’s syndrome (b). Red line indicates upper limit of normal of 4.3 nmol/l [23]. Male subjects are in open diamonds and appear on the right.

Fig. 2

24-h urinary free cortisol (UFC) performed 1–6 times on patients with Cushing’s syndrome (a) and patients determined not to have Cushing’s syndrome (b). Blue lines indicates upper limit of normal for females [34 µg/d (94 nmol/d)] and green lines indicates upper limit of normal for males [84 µg/d (224 nmol/d)] (established by laboratory). Male subjects are in open diamonds and appear on the right.

Fig. 3

24-h urinary 17-hydroxycorticosteroids/g creatinine performed 1–6 times on patients with Cushing’s syndrome (a) and patients determined not to have Cushing’s syndrome (b). Blue lines indicate upper limit of normal for females [3.6 mg/g creatinine/d (9.9 µmol/g creatinine/d)] and green lines indicates upper limit of normal for males [4.3 mg/g creatinine/d (11.8 µmol/g creatinine/d)] (established by laboratory). Male subjects are in open diamonds and appear on the right.

Fig. 4

Night-time plasma cortisol performed one time on patients with Cushing’s syndrome (a) and patients determined not to have Cushing’s syndrome (b). Blue line indicates upper limit of normal of 7.5 µg/dl (207 nmol/d) [22]. Male subjects are in open diamonds and appear on the right.