ArticleThe Journal of clinical endocrinology and metabolism2026
Urinary-free cortisol-based thresholds for differentiating ACTH-dependent Cushing: a Spanish validation study.
Article in The Journal of clinical endocrinology and metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
contextDifferentiating 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.
objectiveTo 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
participantsMulticenter 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 measuresDiagnostic 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.
resultsEAS 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.
conclusionUFC × 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.
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