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Urinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation study

2026-04-30Artigo de investigação Acesso aberto
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dc.contributor.authorBiagetti, Betina
dc.contributor.authorMarques, Pedro
dc.contributor.authorSoto-Moreno, Alfonso
dc.contributor.authorGarcía-Centeno, Rogelio
dc.contributor.authorGonzález-Fernández, Laura
dc.contributor.authorGarcia, María Dolores Ollero
dc.contributor.authorEcharri, Ana Irigaray
dc.contributor.authorCardona-Arias, Andres
dc.contributor.authorRodríguez, Maria Dolores Moure
dc.contributor.authorPaja, Miguel
dc.contributor.authorCastro, Ana
dc.contributor.authorValero, Lucía Manzano
dc.contributor.authorGuerrero-Pérez, Fernando
dc.contributor.authorLamas, Cristina
dc.contributor.authorLázaro, Victoria Alcázar
dc.contributor.authorGracia, Paola
dc.contributor.authorSanchis-Pascual, David
dc.contributor.authorÁLvarez-Escolá, Cristina
dc.contributor.authorLozano-Aida, Claudia
dc.contributor.authorHanzu, Felicia A.
dc.contributor.authorAraujo-Castro, Marta
dc.date.accessioned2026-05-21T14:18:45Z
dc.date.available2026-05-21T14:18:45Z
dc.date.issued2026-04-30
dc.description.abstractContext: 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.eng
dc.identifier.doi10.1210/clinem/dgag187
dc.identifier.other9654b801-7417-4ea7-9e49-84106c593647
dc.identifier.pmid42063386
dc.identifier.urihttp://hdl.handle.net/10400.14/57798
dc.identifier.wos001760279200001
dc.language.isoeng
dc.peerreviewedyes
dc.publisherEndocrine Society
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCushing diseaseeng
dc.subjectCushing syndromeeng
dc.subjectEctopic cushingeng
dc.subjectHypercortisolismeng
dc.subjectUrinary-free cortisoleng
dc.titleUrinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation study
dc.typeresearch article
dspace.entity.typePublication
oaire.versionhttp://purl.org/coar/version/c_ab4af688f83e57aa

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