ACTH after 15 min distinguishes between Cushing's disease and ectopic Cushing's syndrome: a proposal for a short and simple CRH test

Abstract

Objective: The aim of the present study was to validate criteria of corticotropin-releasing hormone (CRH) stimulation and 8 mg dexamethasone suppression (high-dose dexamethasone suppression, HDDS) to distinguish the etiology of ACTH-dependent Cushing's syndrome. Subjects and methods: We retrospectively analyzed cortisol and ACTH after the injection of 100 mg human CRH in confirmed Cushing's disease (CD, nZ78) and confirmed ectopic Cushing's syndrome (ECS, nZ18). Cortisol and ACTH increase (in percentage above basal (% B )) at each time point, maximal increase (Dmax % B ), and area under the curve (AUC % B ) were analyzed using receiver operator characteristics (ROC) curve analyses. Cortisol suppression (% B ) after 8 mg of dexamethasone was evaluated as a supplementary criterion. Results: An increase in ACTH of R43% B at 15 min after CRH was the strongest predictor of CD, with a positive likelihood ratio of 14.0, a sensitivity of 83%, a specificity of 94%, a positive predictive value of 98% and a negative predictive value of 58%. All of the other criteria of stimulated ACTH and cortisol levels were not superior in predicting CD in response to CRH injection. The addition of cortisol suppression by dexamethasone did not increase the discriminatory power. However, the combination of a positive ACTH response at 15 min and a positive HDDS test excluded ECS in all cases. Conclusion: The present findings support the use of plasma ACTH levels 15 min after the injection of human CRH as a response criterion for distinguishing between CD and ECS. The addition of the HDDS test is helpful for excluding ECS when both tests are positive.

Reliability of the Corticotropin Releasing Hormone Stimulation Test for Differentiating Between Acth Dependent and Independent Cushing Syndrome

“…In our study, the time to reach the peak concentrations of ACTH and cortisol following intravenous administration of CRH was consistent with literature (7,8,10,14). However, we demonstrated that a much higher increase (115%) of ACTH concentrations was needed for the best predictor of CD.…”

“…The corticotropin-releasing hormone (CRH) stimulation test is a second-line non-invasive dynamic test for precise localization of disease in which at least a 35-50% increase of ACTH and 20% increase of cortisol concentrations from baseline indicate the pituitary gland as the origin of hypercortisolemia (7)(8)(9). In the literature, publications concerning the CRH stimulation test have been mostly conducted in groups of patients with definite ACTH-dependent CS (8)(9)(10)(11)(12)(13)(14). However, it is also suggested that the CRH stimulation test can be used in patients whose origin of disease is uncertain (4)(5)(6)15).…”

Diagnostic tests for Cushing's syndrome differ from published guidelines: data from ERCUSYN

“…Diagnosis of Cushing's syndrome (CS) is a major clinical issue, due to the rarity of this condition and its variable clinical presentation (1). Several biochemical tests have been proposed for the evaluation of suspected hypercortisolism (2,3,4,5,6,7,8,9,10,11,12), but their diagnostic accuracy depends upon etiology of CS, patient's comorbidities, robustness of the assays, concomitant medications and the setting of investigations (13,14,15,16,17,18,19,20,21,22,23).…”

Second-Line Tests in the Diagnosis of Adrenocorticotropic Hormone-Dependent Hypercortisolism

“…Vilar, et al [20] found that a decrease in serum cortisol below 50% is suggestive of CD, achieving 71.4% specificity, which could be further improved to 100% using a cortisol suppression cut-off of 80%. Ritzel, et al [22] found the highest positive likelihood ratio with a cut-off value of 71% suppression of basal cortisol. In our case series, a cut-off value of 52.7% for cortisol suppression showed the best performance in diagnosing CD [17].…”