{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:48:06Z","timestamp":1792788486216,"version":"4.5.0"},"reference-count":28,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Society of Endocrinology and Nutrition"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To validate the diagnostic performance of UFC \u00d7 ULN for distinguishing EAS from CD and explore complementary biochemical markers, including late-night salivary cortisol (LNSC \u00d7 ULN) and hypokalemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome Measures<\/jats:title>\n                    <jats:p>Diagnostic accuracy of UFC \u00d7 ULN and LNSC \u00d7 ULN for discriminating EAS from CD, expressed as area under the ROC curve (AUC), sensitivity, specificity, and predictive value.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EAS patients were older (median 59.0 vs 44.9 years; P &amp;lt; .001) and showed higher UFC \u00d7 ULN (16.6 vs 3.6; P &amp;lt; .001) and LNSC \u00d7 ULN (9.3 vs 1.5; P &amp;lt; .001). UFC \u00d7 ULN and LNSC \u00d7 ULN achieved excellent discriminative performance (AUC 0.90 and 0.92). No EAS occurred with UFC \u00d7 ULN &amp;lt; 3 \u00d7 ULN, while 40.5% of patients with UFC \u2265 10 \u00d7 ULN had EAS. The combination of severe hypercortisolism (UFC \u2265 10 \u00d7 ULN and LNSC \u2265 9 \u00d7 ULN) plus hypokalemia identified 75% of EAS with 98% specificity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>UFC \u00d7 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag187","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:47:19Z","timestamp":1777625239000},"page":"2785-2795","source":"Crossref","is-referenced-by-count":2,"title":["Urinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation study"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8837-4343","authenticated-orcid":false,"given":"Betina","family":"Biagetti","sequence":"first","affiliation":[{"name":"Endocrinology and Nutrition Department, Department of Medicine, Hospital Universitario Vall d\u2019Hebr\u00f3n and Vall d\u2032Hebron Research Institute (VHIR), Autonomous University of Barcelona, 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