The Journal of clinical endocrinology and metabolism · 2026
Urinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation study.
СтатьяВалидационное исследованиеМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Biagetti Betina, Marques Pedro, Soto-Moreno Alfonso, García-Centeno Rogelio, González-Fernández Laura, Ollero García María Dolores, Irigaray Echarri Ana, Cardona-Arias Andres, Moure Rodríguez María Dolores, Paja Miguel, Castro Ana, Manzano Valero Lucía, Guerrero-Pérez Fernando, Lamas Cristina, Alcázar Lázaro Victoria, Gracía Paola, Sanchis-Pascual David, Álvarez-Escolá Cristina, Lozano-Aida Claudia, Hanzu Felicia A, Araujo-Castro Marta, Neuroendocrinology Task Force of Spanish Society of Endocrinology (SEEN)
Аннотация
CONTEXT: Differentiating ectopic ACTH secretion (EAS) from Cushing disease (CD) remains one of the most challenging steps in the diagnostic workup of ACTH-dependent Cushing syndrome (CS). Urinary-free cortisol (UFC) expressed as times above the upper limit of normal (ULN) has been proposed as a simple, noninvasive discriminator, but external validation in independent populations is lacking.
OBJECTIVE: To validate the diagnostic performance of UFC × ULN for distinguishing EAS from CD and explore complementary biochemical markers, including late-night salivary cortisol (LNSC × ULN) and hypokalemia.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study from the Spanish Cushing Registry including 269 patients with ACTH-dependent Cushing's syndrome (208 CD, 61 EAS) diagnosed and managed in tertiary referral centers.
MAIN OUTCOME MEASURES: Diagnostic accuracy of UFC × ULN and LNSC × ULN for discriminating EAS from CD, expressed as area under the ROC curve (AUC), sensitivity, specificity, and predictive value.
RESULTS: EAS patients were older (median 59.0 vs 44.9 years; P < .001) and showed higher UFC × ULN (16.6 vs 3.6; P < .001) and LNSC × ULN (9.3 vs 1.5; P < .001). UFC × ULN and LNSC × ULN achieved excellent discriminative performance (AUC 0.90 and 0.92). No EAS occurred with UFC × ULN < 3 × ULN, while 40.5% of patients with UFC ≥ 10 × ULN had EAS. The combination of severe hypercortisolism (UFC ≥ 10 × ULN and LNSC ≥ 9 × ULN) plus hypokalemia identified 75% of EAS with 98% specificity.
CONCLUSION: UFC × ULN thresholds reliably stratify the probability of EAS vs CD. Severe hypercortisolism and hypokalemia strongly predict EAS, supporting a pragmatic diagnostic approach that prioritizes whole-body imaging in high-risk patients and pituitary-centered evaluation in mild cases.
OBJECTIVE: To validate the diagnostic performance of UFC × ULN for distinguishing EAS from CD and explore complementary biochemical markers, including late-night salivary cortisol (LNSC × ULN) and hypokalemia.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study from the Spanish Cushing Registry including 269 patients with ACTH-dependent Cushing's syndrome (208 CD, 61 EAS) diagnosed and managed in tertiary referral centers.
MAIN OUTCOME MEASURES: Diagnostic accuracy of UFC × ULN and LNSC × ULN for discriminating EAS from CD, expressed as area under the ROC curve (AUC), sensitivity, specificity, and predictive value.
RESULTS: EAS patients were older (median 59.0 vs 44.9 years; P < .001) and showed higher UFC × ULN (16.6 vs 3.6; P < .001) and LNSC × ULN (9.3 vs 1.5; P < .001). UFC × ULN and LNSC × ULN achieved excellent discriminative performance (AUC 0.90 and 0.92). No EAS occurred with UFC × ULN < 3 × ULN, while 40.5% of patients with UFC ≥ 10 × ULN had EAS. The combination of severe hypercortisolism (UFC ≥ 10 × ULN and LNSC ≥ 9 × ULN) plus hypokalemia identified 75% of EAS with 98% specificity.
CONCLUSION: UFC × ULN thresholds reliably stratify the probability of EAS vs CD. Severe hypercortisolism and hypokalemia strongly predict EAS, supporting a pragmatic diagnostic approach that prioritizes whole-body imaging in high-risk patients and pituitary-centered evaluation in mild cases.