Abstract and Introduction
Context: Clinicians frequently rely on aldosterone thresholds derived from older immunoassays to diagnose primary aldosteronism. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) is increasingly widespread and reported to yield lower aldosterone concentrations.
Objective: Given the health impact of incorrect interpretations of aldosterone levels, we compared measurements using LC-MS/MS and immunoassay across the full range of aldosterone physiology by evaluating distinct regulation by angiotensin II and adrenocorticotropin (ACTH).
Methods: Normotensive volunteers underwent prospective characterization of aldosterone production by immunoassay and LC-MS/MS during 4 conditions (n = 188): oral sodium suppression and restriction (to assess angiotensin II–mediated aldosterone production) and dexamethasone suppression and cosyntropin stimulation (to assess ACTH-mediated aldosterone production).
Results: Serum aldosterone concentrations by LC-MS/MS and immunoassay had a correlation of 0.69 (P < .001), with good agreement (intraclass correlation 0.76; 95% CI 0.52–0.87). Aldosterone was lower by LC-MS/MS than immunoassay (median 10.5 [3.8, 21.9] vs 19.6 [9.5, 28.0] ng/dL; P < .001), with an average difference of 37.2%. The most notable discrepancy was in the clinically discriminatory range <20 ng/dL: 9.9 (7.1, 13.8) ng/dL using immunoassay corresponded to 5.5 (1.4, 8.9) ng/dL by LC-MS/MS (P < .001). Following oral sodium suppression, the aldosterone-to-renin ratio was 4-fold higher using immunoassay (27.2 [19.7, 62.4] vs 6.4 [3.5, 19.1] ng/dL per ng/mL/hour; P < .001).
Conclusion: Aldosterone measurements are substantially lower by LC-MS/MS than immunoassay across the full physiologic range, especially when aldosterone levels were less than 20 ng/dL. These findings highlight the need to recalibrate diagnostic interpretations when measuring aldosterone via LC-MS/MS and provide insights into potential biologic causes of assay differences.
Mounting evidence identifies primary aldosteronism as an underrecognized and prevalent cause of hypertension[1–7] and excess cardiovascular risk.[8–14] Recent studies have demonstrated a severity spectrum of renin-independent aldosterone production that extends continuously across the "normal range" into primary aldosteronism[1,15–18] and have shown that circulating aldosterone concentrations in primary aldosteronism can be highly variable,[19–21] often lower than conventional diagnostic thresholds.[1,20,22] Increasingly, older immunoassay technologies have been supplanted by liquid chromatography–tandem mass spectrometry (LC-MS/MS) for clinical measurement of aldosterone concentration; however, clinical guideline recommendations, and most clinical practice patterns, still generally rely on relatively arbitrary thresholds derived from older immunoassay measurements.
With the development and dissemination of the LC-MS/MS approach to aldosterone quantification, studies in clinical patients, largely with hypertension and suspected primary aldosteronism, have reported the performance of LC-MS/MS relative to several immunoassays.[23–34] These studies have demonstrated generally lower aldosterone values by LC-MS/MS, especially in the context of interpreting categorical thresholds for confirmatory testing,[26–30] thereby highlighting the importance of assay type in the establishment of diagnostic thresholds for primary aldosteronism and in the potential to confound the interpretation of screening and confirmatory tests. In contrast, prior studies have not compared LC-MS/MS measurements with immunoassay across the entire dynamic range of aldosterone physiology, from levels near the lower limits of detection, as might be seen following aldosterone suppression maneuvers, to those approximating maximally stimulated aldosterone production, as might be seen in states of hyperaldosteronism. Apparently low values may still be clinically relevant, for in some clinical contexts they may still signify states of pathologic aldosterone excess that are erroneously missed. We aimed to compare aldosterone quantification using immunoassay and LC-MS/MS to determine whether differences between assay type were detectable across the full dynamic range of aldosterone production and to quantify the magnitude of these potential differences. To accomplish this goal, we studied aldosterone measurements in participants who underwent 4 controlled physiologic protocols to suppress and to stimulate aldosterone by modifying angiotensin II and adrenocorticotropin (ACTH).
J Endo Soc. 2022;6(6) © 2022 Endocrine Society