Morning plasma free cortisol: inability to distinguish patients with mild Cushing syndrome from patients with pseudo-Cushing states.

Patients with Cushing syndrome have elevated 24 h urinary free cortisol excretion and loss of diurnal rhythm of plasma cortisol, however, morning total plasma cortisol concentrations are often similar to those of normal individuals. To test the hypothesis that an elevated morning plasma free cortisol could distinguish patients with Cushing syndrome from those without the disorder, we measured plasma free cortisol levels at 08:00 in 20 patients with surgically-confirmed mild Cushing syndrome, 19 patients with pseudo-Cushing states, and 9 normal volunteers. We then determined the sensitivity, specificity and diagnostic accuracy of plasma free cortisol for the diagnosis of hypercortisolism and for the diagnosis of Cushing syndrome. Plasma free cortisol was compared to 08:00 total plasma cortisol and to basal 24 hour urinary free cortisol. Morning plasma free cortisol was significantly elevated in patients with mild Cushing syndrome (58 +/- 6 nmol/L; mean +/- SE) compared to plasma free cortisol in patients with pseudo-Cushing states (36 +/- 6 nmol/L) (p < 0.005) and normal volunteers (22 +/- 4 nmol/L) (p < 0.0005). Total morning cortisol was significantly greater in patients with mild Cushing syndrome (470 +/- 28 nmol/L) than in normal volunteers (310 +/- 33 nmol/L, p < 0.05) but was not different from patients with pseudo-Cushing states (410 +/- 47 nmol/L, p = NS). Urinary free cortisol was also significantly greater in mild Cushing syndrome (540 +/- 50 nmol/d) than in patients with pseudo-Cushing states (430 +/- 41 nmol/d, p < 0.05) or normal volunteers (160 +/- 28 nmol/d, p < 0.0001). However, there was considerable overlap of plasma free cortisol, plasma total cortisol and urinary free cortisol between the three groups precluding these tests alone from being useful to distinguish patients with mild Cushing syndrome from patients with pseudo-Cushing states. To achieve 100% sensitivity for the diagnosis of Cushing syndrome, the specificity for plasma free cortisol, plasma total cortisol and urinary free cortisol was 0.11, 0.32 and 0.32, respectively. We conclude that plasma free cortisol is of limited value in the differential diagnosis of hypercortisolism.