Three Discrete Patterns of Primary Aldosteronism Lateralization in Response to Cosyntropin During Adrenal Vein Sampling

Abstract

Context Cosyntropin [ACTH (1–24)] stimulation during adrenal vein (AV) sampling (AVS) enhances the confidence in the success of AV cannulation and circumvents intraprocedure hormonal fluctuations. Cosyntropin’s effect on primary aldosteronism (PA) lateralization, however, is controversial. Objectives To define the major patterns of time-dependent lateralization, and their determinants, after cosyntropin stimulation during AVS. Methods We retrospectively studied patients with PA who underwent AVS before, 10, and 20 minutes after cosyntropin stimulation between 2009 and 2018. Unilateral (U) or bilateral (B) PA was determined on the basis of a lateralization index (LI) value ≥4 or <4, respectively. Available adrenal tissue underwent aldosterone synthase–guided next-generation sequencing. Results PA lateralization was concordant between basal and cosyntropin-stimulated AVS in 169 of 222 patients (76%; U/U, n = 110; B/B, n = 59) and discordant in 53 patients (24%; U/B, n = 32; B/U, n = 21). Peripheral and dominant AV aldosterone concentrations and LI were highest in U/U patients and progressively lower across intermediate and B/B groups. LI response to cosyntropin increased in 27% of patients, decreased in 33%, and remained stable in 40%. Baseline aldosterone concentrations predicted the LI pattern across time (P < 0.001). Mutation status was defined in 61 patients. Most patients with KCNJ5 mutations had descending LI, whereas those with ATP1A1 and ATP2B3 mutations had ascending LI after cosyntropin stimulation. Conclusion Patients with severe PA lateralized robustly regardless of cosyntropin use. Cosyntropin stimulation reveals intermediate PA subtypes; its impact on LI varies with baseline aldosterone concentrations and aldosterone-driver mutations.

Utility of adrenocorticotropic hormone in adrenal vein sampling despite the occurrence of discordant lateralization

“…However, almost all patients had repeat biochemical testing to assess for a biochemical cure. Evaluation for somatic mutations in the resected lesions may be interesting in light of recent study findings that the underlying genetic mutation determines the response of LI to ACTH, with KCNJ5 mutations associated with descending LI, while ATP1A1 and ATP2B3 mutations associated with an ascending LI 32 . Ongoing research which explores alternative strategies, such as nuclear medicine imaging and venous steroid profiling, for subtyping in the setting of discordant AVS results will also facilitate the accurate diagnosis of unilateral versus bilateral PA.…”

Developments in Primary Aldosteronism Subtyping Using Steroid Profiling

“…African American patients with APAs commonly harbor CACNA1D mutations [29]. We found that, overall, patients with CACNA1D-mutated APAs had the least predictable impact of cosyntropin on the lateralization index [42], which could explain, at least in part, the higher proportion of discordant AVS results in this population. Stratified PA subtyping combining AVS results from both pre-and post-cosyntropin stimulation, revealed that cases consistently classified as unilateral had the highest adrenal vein and peripheral aldosterone concentrations, and the most profound contralateral suppression [42].…”

“…We found that, overall, patients with CACNA1D-mutated APAs had the least predictable impact of cosyntropin on the lateralization index [42], which could explain, at least in part, the higher proportion of discordant AVS results in this population. Stratified PA subtyping combining AVS results from both pre-and post-cosyntropin stimulation, revealed that cases consistently classified as unilateral had the highest adrenal vein and peripheral aldosterone concentrations, and the most profound contralateral suppression [42]. As the impact of cosyntropin on autonomous vs. normal aldosterone-producing cells remains elusive, cases with inconsistent lateralization might represent either small APAs or asymmetrical BHA.…”

“…For instance, recent evidence suggests that ATP2B3 mutations lead to distinct histopathological features [34] and PA phenotypes from those with ATP1A1 mutations. In a study that included 61 patients with known APA mutation status (24 KCNJ5, 22 CACNA1D, 10 ATP1A1, 4 ATP2B3, and 1 CTNNB1), we found that peripheral venous aldosterone concentrations were higher in patients with ATP2B3 and KCNJ5 mutations than in those with ATP1A1 or CACNA1D mutations [42]. In-depth understanding of the molecular mechanisms and histopathology of APAs will further leverage the development of non-invasive diagnostic tools.…”

“…Potential sources of variability in PA subtyping based on AVS include use of cosyntropin, differences in AVS data interpretation, and concomitant glucocorticoid excess [60]. Data from referral centers that perform AVS both prior to and after stimulation with cosyntropin have shown that subtyping can be discordant between the two protocols in approximately a quarter of PA patients [42,61]. Notably, in a study of 222 PA patients who underwent AVS at the University of Michigan and had successful catheterization both pre-and post-cosyntropin stimulation [42], the proportion of patients with discordant AVS subtyping based on pre-and post-cosyntropin AVS results was higher in African American than in Caucasian patients (45 vs. 17 %, p = 0.003).…”