Minding the gap between cortisol levels measured with second-generation assays and current diagnostic thresholds for the diagnosis of adrenal insufficiency: a single-center experience

Abstract

Purpose The current cut-offs for the diagnosis of adrenal insufficiency (AI) have been established using outdated immunoassays. We compared the cortisol concentrations measured with Roche Cortisol I (R1), the newly available Roche Cortisol II (R2), and liquid chromatography tandem mass spectrometry (LC-MS/MS), the gold standard procedure to measure steroids in patients undergoing the corticotropin (ACTH) test. Methods We enrolled 30 patients (age 47 ± 21 years) referred to undergo the ACTH test (1 or 250 μg). Cortisol was measured at 0, 30, and 60 min after stimulation with R1, R2, and LC-MS/MS. AI was diagnosed for R1-stimulated peak cortisol concentrations < 500 nmol/L. Results Mean cortisol concentrations measured with R2 and LC-MS/MS were comparable, while mean cortisol concentrations measured by R1 were higher than those of both R2 and LC-MS/MS (respectively, basal 411 ± 177, 287 ± 119, and 295 ± 119 nmol/L; at 30 min, 704 ± 204, 480 ± 132, and 500 ± 132 nmol/L; at 60 min, 737 ± 301, 502 ± 196, and 519 ± 201 nmol/L, p ≤ 0.01 for R1 vs. both R2 and LC-MS/MS at each point). Considering the 500 nmol/L cortisol peak cut-off, AI was diagnosed in 5/30 patients using R1 and in 12/30 using R2 (+ 140%). Based on the correlation between R1 and R2, the threshold of 500 nmol/L became 351 nmol/L (12.7 μg/dL) when cortisol was measured with R2, and 368 nmol/L (13.3 μg/dL) with LC-MS/MS. Conclusions The use of more specific cortisol assays results in lower cortisol concentrations. This could lead to misdiagnosis and overtreatment when assessing AI with the ACTH test if a different cut-off for cortisol peak is not adopted.

New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency after ACTH Stimulation using Specific Cortisol Assays

“…We have shown that the threshold cortisol response to CST of 14 to 15 μg/dL in a large group of patients with suspected secondary adrenal insufficiency is comparable to the 18 μg/dL cutoff previously used. Grassi et al also found lower cortisol cutoff values of 12.7 and 13.3 μg/dL using Elecsys II and LC-MS/MS assays, respectively [ 37 ]. Cutoff values 30 minutes after ACTH stimulation have been proposed to be 14.9 μg/dL for LC-MS/MS and 16 μg/dL for Elecsys II based on the 2.5 th centile in healthy controls [ 26 ].…”

Letter to the Editor From Powers Carson and Gronowski: “New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency After ACTH Stimulation Using Specific Cortisol Assays”

“…The new cutoffs varied from 14 to 15 µg/dL and were based on comparisons of 110 subjects using the Elecsys Cortisol I assay with a cutoff of 18 µg/dL as the standard. Others have proposed cutoffs of 12.7 µg/dL with the Roche Cortisol II assay and 13.3 µg/dL with LC-MS/MS [ 2 ]. A Roche-sponsored study also showed good agreement between the Cortisol II assay and LC-MS/MS methods at 3 separate institutions on 3 different instruments [ 3 ].…”

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

“…Similarly, the recent introduction of more specific cortisol assays results in lower cortisol concentrations and this may increase the number of patients diagnosed with adrenal insufficiency. The medical community should quickly adopt the new criteria, as this could lead to misdiagnosis and overtreatment in patients suspected of hypocortisolism (39).…”