{'fraction_non_alphanumeric': 0.032743695897628905, 'fraction_numerical': 0.011479111780203237, 'mean_word_length': 5.442424242424242, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 2, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 1, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Segmental Adrenal Vein Sampling in Patients With Primary Aldosteronism: Superlative or Superfluous?

Primary aldosteronism (PA) is largely subtyped into unilateral and bilateral forms. Unilateral PA is commonly attributed to an aldosterone-producing adenoma (APA), for which surgical removal of the host adrenal gland has been the treatment of choice. Many studies have demonstrated that cross-sectional imaging is unreliable in identifying an APA, primarily because coexisting sizable nonfunctional adrenal nodules are common, whereas APAs are often small. As such, expert guidelines recommend adrenal vein sampling (AVS) in all patients with PA >35 years in whom surgery is considered. The development of highly-specific monoclonal antibodies against human aldosterone synthase (CYP11B2) has revealed a wider spectrum of PA pathologies than initially perceived based on H & E histology. Although CYP11B2 immunostaining remains primarily a research tool, most clinical pathology laboratories are only able to identify morphologically distinct cortical adenomas or cortical hyperplasia (irrespective of functionality in both cases). The implementation of CYP11B2 immunostaining has debunked the traditional PA subtyping, by demonstrating that the adrenal glands of patients with PA might harbor multiple APAs, micronodules, aldosterone-producing cell clusters (APCC), focal or continuous hyperplasia of the zona glomerulosa, in any combinations. A classical unilateral CYP11B2-positive APA might be neighbored by APCC or satellite micronodules within the same adrenal. Although in the overwhelming majority of cases the contralateral adrenal is not available for study, it is highly likely that similar APCC are present in the contralateral adrenal. To what extent small CYP11B2-positive areas outside of APAs contribute to the autonomous aldosterone excess in PA is difficult to evaluate. CYP11B2-guided DNA sequencing studies have recently identified aldosterone-driver somatic mutations in 94% of APA but also in 15 of 57 APCC adjacent to APA. Affected genes associated with APA include KCNJ5 (encoding inwardly rectifying potassium channel GIRK4), ATP1A1 (encoding the alpha 1 subunit of Na/K-ATPase), ATP2B3 (encoding a Ca-ATPase), CACNA1D (encoding subunit of L-type voltage-gated calcium channel Ca V 1.3), CACN1H (encoding subunit of T-type voltage-gated calcium channel Ca V 3.2), and CTNNB1 (encoding β-catenin). Data regarding the pathogenesis of bilateral hyperaldosteronism (BHA), previously called idiopathic hyperaldosteronism or bilateral adrenal hyperplasia (BHA) have been limited by the lack of tissue availability, as most such patients are treated medically. In a study of 15 adrenals removed from patients with BHA, true hyperplasia of the zona glomerulosa was observed in only 4 glands. Of 99 APCC from these BHA adrenals, 57 were found to harbor mutations in CACNA1D. Intriguingly, despite being acquired, and not inherited events, such APAassociated mutations have distinct racial and sex distributions, pointing to other predisposing factors, shared among specific populations. Taken together, these data suggest that, in many cases, multiple, yet asynchronous processes are likely to occur within both adrenal glands. AVS is used in many referral centers across the globe, however, standard protocols and criteria for data interpretation are lacking. In view of the complex spectrum of PA histopathologies discussed above, it is not surprising that establishing if one or both adrenal glands contribute to PA through AVS is not a simple task. What AVS can accomplish, in most cases, is to determine if one of the two adrenal glands overtakes the other in producing aldosterone. What is the minimum lateralization index that indicates a clinically meaningful difference between the two adrenal glands in regard to aldosterone production to warrant unilateral adrenalectomy, however, remains elusive. In part, this is due to limited postoperative follow up data available. Moreover, in selected cases, unilateral adrenalectomy might provide clinical and biochemical benefit even to patients with BHA, by attenuating the burden of aldosterone excess. In the current issue of the journal, Kitamoto et al report their experience with serum sampling from segmental adrenal veins during AVS as a tool to accurately identify the intraadrenal source(s) of aldosterone excess (Figure). Such an approach could guide partial adrenalectomy, a strategy particularly useful if distinct sources of PA are found in both adrenal glands. Using a threshold of >1400 ng/dL cosyntropin-stimulated aldosterone in the segmental adrenal vein (threshold The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor (A.F.T.); G.V. (Sonny) Montgomery VA Medical Center (C.E.G.-S.) and Department of Pharmacology and Toxicology and Medicine (C.E.G.-S.), University of Mississippi Medical Center, Jackson. Correspondence to Celso E. Gomez-Sanchez, G.V. (Sonny) Montgomery VA Medical Center, 1500 E. Woodrow Wilson Dr, Jackson, MS 39216. Email cgomez-sanchez@umc.edu Segmental Adrenal Vein Sampling in Patients With Primary Aldosteronism Superlative or Superfluous?