Aldosterone and Primary Aldosteronism: Star Performers in Hypertension Research

Abstract

HomeHypertensionVol. 78, No. 3Aldosterone and Primary Aldosteronism: Star Performers in Hypertension Research Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessEditorialPDF/EPUBAldosterone and Primary Aldosteronism: Star Performers in Hypertension Research Michael Stowasser Michael StowasserMichael Stowasser Correspondence to: Michael Stowasser, Endocrine Hypertension Research Centre, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Brisbane 4102, Australia. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4317-8584 Endocrine Hypertension Research Centre, University of Queensland Diamantina Institute, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia. Search for more papers by this author Originally published11 Aug 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.17594Hypertension. 2021;78:747–750This article is a commentary on the followingSingle-Center Prospective Cohort Study on the Histopathology, Genotype, and Postsurgical Outcomes of Patients With Primary AldosteronismSee related article, pp 738–746In the current edition of Hypertension, Meyer et al1 report postsurgical outcomes, as defined by the Primary Aldosterone Surgical Outcomes criteria, for patients with unilateral forms of primary aldosteronism (PA) undergoing unilateral adrenalectomy, and compare these outcomes according to the histopathologic classification of the lesions seen on hematoxylin and eosin staining and CYP11B2 immunohistochemistry, and according to the type of somatic gene mutations detected within aldosterone-producing tumors. The senior authors were largely responsible for driving the development of both the Primary Aldosterone Surgical Outcomes criteria and the histopathologic classification used in this study.2,3 This article exemplifies the usefulness of these tools in studying a potentially wide array of applications, including refining methods of selecting patients for surgical management and better understanding the pathophysiology of PA. The major findings of this study were that patients with classical types of adrenal lesions (aldosterone-producing adenomas [APAs] or dominant aldosterone-producing nodules; n=45) had more florid PA and better biochemical surgical outcomes (with complete biochemical cure in 98% versus 67%; P<0.004) than those with only nonclassical lesions (multiple aldosterone-producing micronodules or nodules or diffuse aldosterone-producing hyperplasia; n=15). Nonclassical lesions were identified in over half of the 45 patients with classical lesions, making them a common finding among patients with unilateral PA. Those with classical histopathology whose lesions bore mutations in KCNJ5 (the gene most commonly mutated in APAs) showed similar, highly gratifying biochemical outcomes to those that did not. This is another important finding as it is contradictory to other reports that have suggested better outcomes with KCNJ5-mutated tumors, and which have even led to the proposal that identifying those tumors that are not KCNJ5-mutated may warrant a preference towards avoiding adrenal venous sampling (AVS) and treating medically rather than surgically. The current study findings question that viewpoint and rightly so—even if patients with non-KCNJ5-mutated tumors do fare less well postoperatively, the fact remains is that the majority are improved both clinically and (especially) biochemically.For reasons that are not immediately clear, the hypertension cure rate of 19% in this study was rather low compared with other reports. No detail has been provided on AVS technique or lateralization criteria, so it remains uncertain as to whether some patients with bilateral PA may have been misdiagnosed as unilateral. The data provided in Table S1 in the Data Supplement would tend to suggest that relatively strict lateralization criteria were used, given a median lateralization index of 13.7 and the presence of contralateral suppression in almost all. Hence, a higher rate of clinical cure might have been expected. Too often, however, studies that have examined outcome and its predictors have focussed their attention only on cure of hypertension, despite the fact that patients who demonstrate improvement but not complete cure (in this study a further 57%) still benefit from better hypertension control, usually with substantially reduced pill burden and improved quality of life, and lower degrees of autonomous aldosterone production, predicting lower risk of future cardiovascular morbidity.Meyer et al1 provide data to suggest that patients with classical histopathology had a greater degree of contralateral suppression of aldosterone production on AVS than those with nonclassical lesions. This was evidenced by lower contralateral adrenal to peripheral venous aldosterone ratios. Given the fact that they had more florid PA, with higher peripheral plasma aldosterone concentrations and aldosterone/renin ratios, a more intense degree of contralateral suppression might have been expected. Intriguingly, however, this difference was evident only when the authors examined absolute aldosterone but not when they corrected aldosterone for cortisol levels, which is the more standard approach. A possible explanation would be concurrent secretion of cortisol by the classical lesions, which, by suppressing corticotropin, would lead to suppression of cortisol secretion by the contralateral gland and hence a rise in the adrenal venous aldosterone/cortisol ratio on that side. It would, therefore, be of interest to compare these 2 groups of lesions in terms of immunohistochemistry for CYP11B1 or CYP17A (which are necessary for cortisol but not aldosterone production).It could be argued that, in recent years, aldosterone-related research has been among the most exciting and productive within the hypertension domain, in terms of enhancing understanding of the pathogenesis of hypertension and associated cardiovascular and renal disease states and impacting on clinical practice and outcomes (Figure). There have been marked shifts in thinking, most notably with the realization that PA, once thought to be rare, is highly prevalent within the hypertensive population and that aldosterone excess has adverse cardiovascular effects that are in part independent of its effects on blood pressure. As a result, it is predicted that there are millions of patients with PA in existence today, and, given the higher rates of cardiovascular events in PA compared with essential hypertensives, this cohort represents a potentially enormous contributor to the global burden of cardiovascular disease. Furthermore, not only do patients with PA show impressive BP responses to specific surgical (unilateral laparoscopic adrenalectomy) or medical (usually mineralocorticoid receptor antagonists) treatment, but the excess in cardiovascular morbidity also resolves, making it essential to identify these patients so that they may benefit from targeted, optimal management.Download figureDownload PowerPointFigure. Examples of recent advances in the understanding of physiology of aldosterone biosynthesis and pathophysiology and clinical aspects of aldosterone excess achieved through research into primary aldosteronism. APAs indicates aldosterone-producing adenomas; APCCs, aldosterone-producing cell clusters; AVS, adrenal venous sampling; BP, blood pressure; CV, cardiovascular; IHC, immunohistochemistry; MRAs, mineralocorticoid receptor antagonists; POC, point-of-care; QOL, quality of life; and SST, saline suppression testing.With the above developments has come a resurgence of research and clinical interest in PA, leading to (1) major improvements in diagnostic workup, including the recent development of a highly accurate, yet streamlined method of confirming the diagnosis (seated saline suppression testing),4 point-of-care cortisol testing to enhance success of adrenal venous cannulation during AVS (used to differentiate unilateral, surgically correctable from bilateral forms)5 and metomidate radioisotope scanning (a highly promising alternative approach to subtype differentiation)6; (2) development of new mineralocorticoid receptor antagonists and their successful wide application among a diverse array of cardiovascular conditions; and (3) rapidly expanding knowledge regarding the genetics of PA (both familial and apparently sporadic) and its pathogenesis and histopathology as defined by peripheral blood and adrenal tissue DNA and immunohistochemistry using new, highly specific monoclonal antibodies to aldosterone synthase (CYP11B2).Genetic testing and immunohistochemistry have proven to be enormously useful, already helping to shed light on a growing number of pathogenetic and clinical conundrums. Germline mutations in several different genes have been found to explain excessive, autonomous adrenal aldosterone production in familial/inherited forms of PA including an adrenocorticotropic hormone-regulated hybrid CYP11B1/CYP11B2 gene causing glucocorticoid-remediable aldosteronism and channelopathies arising from point mutations in KCNJ5, CLCN2, CACNA1H, or CACNA1D which promote zona glomerulosa cell depolarization and raised intracellular Ca2+ followed by increased CYP11B2 expression.7 Perhaps, even more importantly, these findings have opened up an entirely new understanding concerning the physiology of aldosterone production. Somatic mutations in these same ion channel genes (especially KCNJ5 and, less frequently, CACNA1D) and also in the ion pump genes ATP1A1 and ATP2B3 appear to be responsible for excessive aldosterone production in the large majority of APAs.7 The use of CYP11B2 immunohistochemistry has demonstrated that adrenal tumors identified preoperatively by computed tomography in patients with PA may not be the source of aldosterone excess, although AVS shows lateralization of aldosterone production to the same gland. Instead, some other, smaller lesion has been shown to be the culprit.3,8 This underscores the danger in relying on computed tomography to lateralize APAs and in being tempted to remove the tumor only in an attempt to preserve adrenal tissue. Even when the visualized tumor does show CYP11B2 expression, it may be restricted to only a portion of the lesion rather than being diffusely distributed. This probably explains why adrenal DNA sequencing targeted by immunohistochemistry (so that only CYP11B2-expressing cells are sampled) has led to a marked increase in the proportion of APAs demonstrating aldosterone-diver mutations that now nears 100%.8 In bilateral PA, excessive aldosterone production has traditionally been thought to be due to diffuse hyperplasia of the aldosterone-producing zona glomerulosa. Instead, immunohistochemistry has demonstrated an excess in the number and size of aldosterone-producing cell clusters (otherwise known as micronodules) compared with normal adrenals.9 Like APAs, these frequently bear aldosterone-producing driver mutations (most commonly in CACNA1D).9In the 1980s, Gordon et al10 described 2 types of APA: those that showed responsiveness of plasma aldosterone to upright posture or angiotensin II infusion (which they termed angiotensin II– or posture-responsive APA) and those that did not (angiotensin II– or posture-unresponsive APA).10 They went on to demonstrate that unresponsive APAs differed histopathologically by being predominantly composed of zona fasciculata-like cells, whereas responsive APAs were made up mainly of zona glomerulosa cells or cells with histological characteristics of both zona glomerulosa and zona fasciculata.11 Furthermore, patient with unresponsive (but not responsive) APAs demonstrated abnormally high levels of so-called hybrid steroids 18-oxo- and 18-hydroxycortisol. Recently, we were able to confirm Gordon’s suspicion that these phenotypic differences were genetically based by showing that unresponsive APAs were predominantly associated with KCNJ5 mutations, whereas responsive APAs were predominantly CACNA1D mutated.12 With the use of immunohistochemistry, it was further found that while both tumors expressed CYP11B2 to a similar degree, the unresponsive APAs showed much higher expression of CYP17A. From this, we have been able to postulate that the excessive production of hybrid steroids by posture-unresponsive APAs may relate to their zona fasciculata-like tumor cell composition, resulting in strong expression of CYP17A1 (in addition to somatic gene mutation-driven CYP11B2 expression), thereby allowing production of cortisol which acts as the substrate for CYP11B2-generated hybrid steroids.12These are exciting times indeed for aldosterone and PA research, and more is yet to come. The wide (and hopefully subsidized for treatment of PA) clinical availability of newer mineralocorticoid receptor antagonists that lack the sex-steroid–related side effects of spironolactone and of highly specific CYP11B2 inhibitors is keenly awaited. Exploration of the pathogenesis of PA will continue to deliver new insights into aldosterone physiology and pathophysiology. There is certainly room for improvement in approaches to diagnostic workup of PA, which currently remains relatively complex but is steadily becoming more feasible for a growing number of investigative units, and novel techniques are already on the horizon. Perhaps one of the biggest hurdles, however, is getting clinicians to look for PA in the first place. With its low cost, reliability (provided that interfering medications are withdrawn or their effects at least taken into account), high rate of positivity and potentially immense clinical significance of a positive test to the individual patient, surely the time has come to advocate screening by aldosterone/renin ratio testing in the great majority of hypertensives, and certainly in all at the time of initial diagnosis of hypertension.Sources of FundingNone.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.121.17594.For Sources of Funding and Disclosures, see page 750.Correspondence to: Michael Stowasser, Endocrine Hypertension Research Centre, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Brisbane 4102, Australia. Email m.[email protected]edu.au