Diagnostic accuracy of increased urinary cortisol/cortisone ratio to differentiate ACTH‐dependent Cushing's syndrome

Summary Background and aim Differential diagnosis between Cushing's Disease ( CD ) and Ectopic ACTH Syndrome ( EAS ) may be a pitfall for endocrinologists. The increasing use in clinical practice of chromatography and mass spectrometry improves the measurement of urinary free cortisol ( UFF ) and cortisone ( UFE ). We have recently observed that cortisol to cortisone ratio ( FE r) was higher in a small series of EAS ; in this study we collected a larger number of ACTH ‐dependent Cushing's Syndrome ( CS ) to study the role of FE r to characterize the source of corticotropin secretion. Materials and methods High‐pressure liquid chromatography with UV detection ( HPLC ‐ UV , n=35) or liquid chromatography‐tandem mass spectrometry ( LC ‐ MS / MS , n=72) were used to measure UFF , UFE and FE r in 83 patients with CD and 24 with EAS . Results UFF , UFE and FE r levels were higher in EAS than in CD ( UFF : 6671 vs 549 nmol/24 hours; UFE : 2069 vs 464 nmol/24 hours; FE r: 4.13 vs 0.97; all P <.001). FE r >1.15 (the best ROC ‐based threshold) was able to distinguish CD from EAS with 75% sensitivity ( SE ) and 75% specificity ( SP ), AUC 0.811; results were similar between HPLC ‐ UV ( SE 73%, SP 79%, AUC 0.708) and LC ‐ MS / MS ( SE 77%, SP 73%, AUC 0.834; P =.727). The diagnostic accuracy of FE r was similar to that of CRH test or high‐dose dexamethasone suppression test (respectively P =.171 and P =.683), also combined. Finally, FE r was able to increase the number of correct diagnosis in patients with discordant dynamic tests. Conclusions Urinary FE r >1.15 was able to suggest EAS , with a diagnostic accuracy similar to that of other dynamic tests proposed to study ACTH ‐dependent CS .