Urinary free cortisol is an independent predictive factor for early distinction between ectopic ACTH secretion and pituitary Cushing’s disease

Abstract

Abstract Purpose: To identify potential predictors for early suspicion of Cushing’s syndrome due to ectopic ACTH secretion (ECS) in comparison with pituitary Cushing’s disease (CD). Methods: Retrospective case-nested study of 18 patients with ECS compared with 36 patients with CD matched for the time of diagnosis. Results: Serum potassium level ≤ 3.65 mmol/L had a sensitivity and a specificity of 77% and LDH level > 1.3xULN had a sensitivity of 69% and a specificity of 68% for the diagnosis of ECS. Both parameters were correlated with 24h urinary-free cortisol (UFC) which was markedly higher in the ECS group (p<0.05). On univariate analysis, older age at diagnosis, male sex, hypokalemia, higher LDH and UFC values were significant predictors of ECS. Male sex increased the relative risk of ECS by 6.8 times and hypokalemia increased this risk by 52 times for each 1.0 mmol/L-decrease in potassium. Only UFC (expressed as log10) remained as independent predictive factor in the multivariate analysis (p=0.0009). A discriminant decision-tree approach showed that UFC ≥ 633 µg/24h (10.5-fold the ULN) was the best cut-off with a sensitivity of 87% and a specificity of 92% for the diagnosis of ECS. Conclusion: While severe hypokalemia and higher LDH values are linked to a more severe degree of hypercortisolism in patients with ECS, 24h UFC at diagnosis appears to be the most reliable independent predictor of ECS, with the best cut-off value determined at 10.5-fold the ULN, above which clinicians should rapidly suspect ECS and perform a thoraco-abdominal CT scan.