Resolution of paradoxical bilateral aldosterone suppression with mass spectrometry

Objective: Adrenal vein sampling (AVS) is the standard-of-care for primary aldosteronism (PA) subtyping. Paradoxical bilateral aldosterone suppression (BAS), defined by lower aldosterone/cortisol ratio in both adrenal veins compared to peripheral circulation, has been reported in AVS studies, but the underlying causes remain poorly understood. We aimed to assess the prevalence of BAS in AVS without and with cosyntropin stimulation based on clinical immunoassays, and to probe the BAS results using liquid chromatography mass spectrometry (LC-MS/MS). Methods: We retrospectively assessed the BAS prevalence among patients with confirmed PA who underwent AVS in a referral center between 2015 and 2023. Simultaneous AVS was performed both before and after cosyntropin stimulation. LC-MS/MS quantitation of cortisol and aldosterone was performed in patients with serum available. Results: Of 402 patients, BAS was observed in 102 (25%): Pre-cosyntropin in 31, post-cosyntropin in 48 (including 10 who did not meet successful catheterization criteria in baseline samples), and both pre- and post- cosyntropin in 23. Paradoxically, AVS indicated lateralized PA in 36% and 43% of patients with BAS based on pre- and post-cosyntropin data, respectively. Using LC-MS/MS, BAS was not present in 42/53 (79%) patients with serum available. Compared to LC-MS/MS, immunoassays overestimated cortisol across the analytical range. In contrast, for aldosterone, immunoassays overestimated low concentrations, but underestimated high concentrations, such as those measured in adrenal veins. Conclusions: Apparent BAS derives primarily from artifacts in clinical immunoassays. These data caution against assuming that aldosterone suppression indicates contralateral aldosterone lateralization in cases with partial adrenal vein catheterization failure.