Cortisol Cutoffs for Adrenal Insufficiency Using Elecsys II: A Systematic Review

Adrenal insufficiency (AI) is associated with increased risk of morbidity and mortality if improperly managed. Adrenocorticotrophin (ACTH) stimulation testing is the most widely used AI diagnostic test. Historically, a serum cortisol threshold of 500 nmol/L (18.1 µg/dL), derived using polyclonal assays, was widely used. Improved monoclonal immunoassays show reduced cross-reactivity and lower cortisol values, but no universally accepted ACTH-stimulated cortisol threshold exists. Suggestions ranging between 348 and 485 nmol/L [12.6-17.6 µg/dL] reflect methodology and cohort differences. Our objective was to systematically review the literature and recommend a revised cortisol threshold.

We searched MEDLINE, Web of Science, and Google Scholar for English language studies published between January 2016 and 19 September 2023 (PROSPERO CRD42023479405). Eligible studies reported original data, used the Roche Elecsys II assay, and recommended a cortisol threshold. Quality of evidence was assessed using the GRADE framework, and risk of bias with the ArRoWS questionnaire. Multiple suggested thresholds based on ROC, sensitivity/specificity, or regression analysis were identified.

Six studies involving 1799 samples from 430 adult and paediatric patients were included. A serum cortisol cutoff of 405 nmol/L (14.7 µg/dL) was defined based on synthesis, sensitivity analysis, and a conservative approach to reduce false‑negatives.

We affirm recommendations to lower the cortisol threshold for AI when using monoclonal assays. A peak threshold of 405 nmol/L (14.7 µg/dL) is suggested for a standard-dose ACTH test on the Elecsys II assay for diagnosis of AI, acknowledging limitations related to the small number and GRADE quality of included studies.