Primary Aldosteronism

HomeHypertensionVol. 77, No. 3Primary Aldosteronism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBPrimary AldosteronismThree Strikes and Out John W. Funder John W. FunderJohn W. Funder Correspondence to: John W. Funder, Hudson Institute of Medical Research and Monash University, Clayton 3800, Victoria, Australia. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7733-7005 From the Hudson Institute of Medical Research and Monash University, Clayton, Victoria, Australia. Originally published10 Feb 2021https://doi.org/10.1161/HYPERTENSIONAHA.120.16585Hypertension. 2021;77:900–903This article is a commentary on the followingIntraindividual Variability of Aldosterone Concentrations in Primary AldosteronismIn the current issue of the Journal Nicholas Yolamp and his colleagues have published a article entitled "Intraindividual Variability in Aldosterone Concentrations in Primary Aldosteronism: Implications for Case Detection."1 When a patient is referred for possible primary aldosteronism, the first thing done is to withdraw for 4 to 6 weeks many/all of their antihypertensive medications, if necessary replaced by alpha blockers or calcium channel blockers. Subsequently case detection—more colloquially, screening—depends in 3 ways on the plasma aldosterone concentration measured as a single morning blood draw. The measured plasma aldosterone concentration is used as the numerator for the so-called aldosterone to renin ratio. The combination of a certain plasma aldosterone concentration—commonly 15 ng/dL, and an aldosterone to renin ratio of 20, 30, or sometimes even 40 ng/dL per ng/mL/h—establishes the patient as a possible candidate for primary aldosteronism. Finally, patients screening positive are then in most circumstances offered any one of half a dozen confirmatory tests, the outcomes of which are dependent on the extent of suppression of the plasma aldosterone concentration.See related article, pp 891–899If you thought that the current steps in the investigation of possible primary aldosteronism are a disincentive for physicians to refer (or for patients to accede to any suggestion made) you are correct. On my reckoning—and that of many others—fewer than 1% of hypertensives are ever screened for primary aldosteronism, testimony to the effectiveness of the disincentives; it also reflects the magisterial indifference of many leaders of the hypertension community to its prevalence. In the recent 24 page "2020 International Society of Hypertension Global Practice Guidelines"2 the total coverage of primary aldosteronism was 6 lines in Table 11, on page 14. Similarly, primary aldosteronism received just one of a total of 143 references, like licorice; a dozen addressed nonadherence to prescribed regimens.In the present article, the authors have shown, in a closely curated cohort of 51 patients with primary aldosteronism and resistant hypertension, that when such patients underwent two, up to six, blood draws individual levels of plasma aldosterone concentration ranged from 4.9 to 51 ng/dL, and those for aldosterone to renin ratio a staggering over 50-fold range, from 8.2 to 427 ng/dL per ng/mL/h. Within subjects, the coefficient of variation for plasma aldosterone concentration was 31%, and for aldosterone to renin ratio 45%. Almost half the patients had at least one plasma aldosterone concentration reading below 15 ng/dL, 31% 2 below 15 ng/dL, and 30% a plasma aldosterone concentration below 10 ng/dL.The authors neatly sum up their take on the study—methodology exemplary, data irrefutable—in the final sentence of the perspectives section. "Given the high prevalence of primary aldosteronism, the low rates of diagnosis, and the cardiometabolic morbidity and mortality associated with untreated disease, these findings suggest that a recalibration toward more permissive screening criteria, and reliance on more than one screening assessment, could improve detection of more true cases of primary aldosteronism and decrease false negative screening interpretations." Quite so: but which of at least 2, and up to 6, plasma aldosterone concentrations should we choose to guide us? Which one of multiple screening assessments, similarly?This might be construed as hand-wringing: what is needed is not recalibration but squarely facing up to the demonstrated fallibility of spot blood draws for estimating a patient's aldosterone secretory status; the only way this can be done is by measuring the 24-hour urinary excretion of aldosterone. Anand Vaidya has been senior author on 3 telling studies over the past 6 months. The first, entitled "The Unrecognized Prevalence of Primary Aldosteronism,"3 was the game-changer, on the basis of 24 hour collection for the urinary excretion of aldosterone. In over 1000 subjects with suppressed renin, sodium loaded (200–300 meq/day), and with a generous figure of 12 mcg/day as the upper limit of normal urinary excretion of aldosterone, the coauthors found levels of primary aldosteronism 3- to 5-fold higher than currently recognized. If the cutoff in the face of less enthusiastic sodium were 10 mcg/day, the authors for instance found primary aldosteronism in 60% of resistant hypertension patients.That was Strike One. Strike Two is a second article, currently in press,4 in which the Boston group address the question of the variability of spot plasma aldosterone concentration measurements before and during adrenal venous sampling. Of the 340 subjects who underwent adrenal venous sampling, 116 in addition had their plasma aldosterone concentration measured on average 2.5 hours before the procedure began. In this latter group, mean plasma aldosterone concentration fell by 51%, a median decline of 7.0 ng/dL; over a quarter of the patients at the beginning of adrenal venous sampling had a plasma aldosterone concentration of <5 ng/dL. Within adrenal venous sampling, the mean coefficient of variation for triplicate aldosterone concentrations in the adrenal veins was 30% (left) and 39% (right). The present article confirms and extends the fallibility of single spot plasma aldosterone concentration, completing the case for change: Strike Three.It is not as though this has come out of left field, to stretch the analogy. A previous study from Boston by Baudrand et al5 measured the urinary excretion of aldosterone in 210 normotensives. On the same take-no-prisoners criteria (sodium loading, urinary aldosterone concentration above 12 mcg/day), 29 tested positive for primary aldosteronism; when the current single blood draw plasma aldosterone concentration was used, only 6 of the 29 tested positive. In a series of studies from the laboratory of George Piaditis and colleagues in Athens,6,7 the crucial role of ACTH (adrenocorticotrophic hormone)—long neglected in the field—as a potent episodic elevator of plasma aldosterone concentration has been demonstrated, suggesting an overall prevalence of primary aldosteronism in hypertension of ≈50%.Apparently lost in the mists of time is a telling study from Cologne,8 vintage 1980, which until very recently had garnered only 39 citations, of which roughly half have been by the author of the present commentary. Professor Helber and his colleagues put 3 groups of subjects—56 normotensive controls, 100 essential hypertensives, and 16 patients with confirmed primary aldosteronism—on a 175 meq sodium diet for 6 days, and then measured their 24-hour urinary excretion of aldosterone. The normotensives had urinary excretion of aldosterone levels up to 6 µg/24/h, and the confirmed primary aldosteronism patients predictably far higher. In the group of essential hypertensives, 64 had urinary excretion of aldosterone levels within the established normal range, and 36 above. Patients within the normal range challenged with spironolactone showed a 9 mm Hg mean fall in systolic blood pressure; in those with urinary excretion of aldosterone above the normal range mean systolic blood pressure fell by 23 mm Hg in response to spironolactone. The take-home message is in the article's title "Evidence for a subgroup of essential hypertensives with nonsuppressible excretion of aldosterone during sodium loading"—that is, they really have primary aldosteronism.If so, why does this matter? There are at least 3 compelling reasons for action. First, under the current guidelines, many of those who are referred for possible primary aldosteronism are categorized as negative—as would have been the case in the Baudrand study cited above. Second, it matters because there is very persuasive evidence that—unless appropriately treated—patients with hypertension with primary aldosteronism are in double jeopardy, in terms of a 3-fold higher cardiovascular risk profile than age-, sex-, and blood pressure-matched essential hypertensives.9 Third—and here I must differ with the authors—there is no country in the world where the capture rate of primary aldosteronism is above 1% of hypertensives; their higher figures reflect selected populations, and the first author (Martin Reincke) of one of the publications cited as evidence is on the record as confessing that in Germany the figure is below 0.1%. We recognize the increased morbidity and premature mortality in diabetes, obesity, high blood pressure and substance abuse, but in very large part are ignorant of, rather than dismissive of, the appallingly low capture rate in primary aldosteronism.Where to from here? First, we need new guidelines, not just for endocrinologists published in the Journal of Clinical Endocrinology and Metabolism, but for internists and primary care providers. Primary care providers commonly are the first point of contact for newly presenting hypertensives; crucially, as shown in Figure [A], their first response should not be antihypertensives, but a blood draw for measurement of plasma renin. If plasma renin activity is above 1 ng/mL per hour (or plasma renin concentration above 8 mU/L), onto antihypertensives, diet, and exercise, etc. If plasma renin is suppressed, show the patient how best to collect a 24-hour urine and bring it in for determination of sodium excretion and levels of urinary excretion of aldosterone. If they are below 6 µg/day, onto antihypertensives, and a word about lowering salt intake. If they are between 6 and 12 µg/day—possible primary aldosteronism—onto spironolactone 25 mg/day and check blood pressure after 4 weeks. If they are above 12 mcg/day, the patient has primary aldosteronism. A shorter, less refined but potentially more practical form of assessing newly presenting hypertensives by a trial of spironolactone alone is shown in Figure [B].Download figureDownload PowerPointFigure. Steps in the diagnosis of primary aldosteronism.A, For newly presenting hypertensives. B, Alternative for newly presenting hypertensives. C, For patients with established hypertension.Getting onto primary aldosteronism from the get-go produces outcomes unmatched even by the best results of the Primary Aldosteronism Surgical Outcomes study,10 as shown by Hu et al in China.11 These authors do yearly check-ups on 147 000 subjects and found over a thousand newly presenting hypertensives, with a primary aldosteronism rate of 7% on the existing criteria. All patients with unilateral disease were biochemically cured, and all but one clinically cured, by surgery; four-fifths of the patients with bilateral disease were normotensive on low-dose spironolactone. It may take 30 years to substantially reduce the prevalence of PA across the community, but such a relatively simple baby step—first measure plasma renin—is the only way forward.For patients already on antihypertensives—even if blood pressure is below 140/90—the short way home is a relatively low-dose (50 mg/day) spironolactone trial with review after 4 weeks (Figure [C]). If the fall in blood pressure is trivial, discontinue; if it is consistently >10 mm Hg, parse the patients. If the patient is young, has high blood pressure, and is hypokalemic or close to—refer to a specialized center. If the patient is mature, well controlled on blood pressure medication, continue on spironolactone, and if side effects are an issue lower the dose and add epithelial sodium channel inhibitors. These are suggestions, not tablets of stone, and need to be considered, discussed, amended, refined and a consensus statement/set of guidelines ultimately produced. The authors of the article under review have provided a final blow to the existing order: after 3 strikes, we need new batters at the plate.Sources of FundingThis work is supported by The Victorian Government's Operational Infrastructure Support Program.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the American Heart Association.For Disclosures, see page 903.Correspondence to: John W. Funder, Hudson Institute of Medical Research and Monash University, Clayton 3800, Victoria, Australia. Email john.[email protected]org.auReferences1. Yozamp N, Hundemer G, Moussa M, Underhill J, Fudim T, Sacks B, Vaidya A. Intraindividual variability of aldosterone concentrations in primary aldosteronism: implications for case detection.Hypertension2021; 77:891–899. doi: 10.1161/HYPERTENSIONAHA.120.16429LinkGoogle Scholar2. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, et al.. 2020 International Society of hypertension global hypertension practice guidelines.Hypertension. 2020; 75:1334–1357. doi: 10.1161/HYPERTENSIONAHA.120.15026LinkGoogle Scholar3. Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH, Vaidya A. The unrecognized prevalence of primary aldosteronism: a cross-sectional Study.Ann Intern Med. 2020; 173:10–20. doi: 10.7326/M20-0065CrossrefMedlineGoogle Scholar4. Yozamp N, Hundemer G, Moussa M, Underhill J, Fudim T, Sacks B, Vaidya A. Variability of aldosterone measurements during arenal venous sampling for primary aldosteronism [published online November 12, 2020].Am J Hypertens. hpaa151. doi: 10.1093/ajh/hpaa151MedlineGoogle Scholar5. Baudrand R, Guarda FJ, Fardella CE, Brown J, Williams GH, Vaidya A. Continuum of renin-independent aldosteronism in normotension.Hypertension. 2017; 69:950–956. doi: 1161/HYPERTENSIONAHA.116.08952LinkGoogle Scholar6. Gouli A, Kaltsas G, Tzonou A, Markou A, Androulakis II, Ragkou D, Vamvakidis K, Zografos G, Kontogeorgos G, Chrousos GP, et al.. High prevalence of autonomous aldosterone secretion among patients with essential hypertension.Eur J Clin Invest. 2011; 41:1227–1236. doi: 10.1111/j.1365-2362.2011.02531.xCrossrefMedlineGoogle Scholar7. Markou A, Sertedaki A, Kaltsas G, Androulakis II, Marakaki C, Pappa T, Gouli A, Papanastasiou L, Fountoulakis S, Zacharoulis A, et al.. Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension.J Clin Endocrinol Metab. 2015; 100:2857–2864. doi: 10.1210/jc.2015-1268CrossrefMedlineGoogle Scholar8. Helber A, Wambach G, Hummerich W, Bonner G, Meurer KA, Kaufmann W. Evidence for a subgroup of essential hypertensives with non-suppressible secretion of aldosterone during sodium loading.Klin Wochenschr. 1980; 58:439–447. doi: 19.1007/BF01476798CrossrefMedlineGoogle Scholar9. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study.Lancet Diabetes Endocrinol. 2018; 6:51–59. doi: 10.1016/S2213-8587(17)30367-4CrossrefMedlineGoogle Scholar10. Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar L, Quinkler M, Deinum J, et al.; Primary Aldosteronism Surgery Outcome (PASO) investigators. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort.Lancet Diabetes Endocrinol. 2017; 5:689–699. doi: 10.1016/S2213-8587(17)30135-3CrossrefMedlineGoogle Scholar11. Xu Z, Yang J, Hu J, Song Y, He W, Luo T, Cheng Q, Ma L, Luo R, Fuller PJ, et al.. Primary aldosteronism in patients in china with recently detected hypertension.J Am Coll Cardiol. 2020; 75:1913–1922. doi: 1016/j.jacc2020.02.052CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesIntraindividual Variability of Aldosterone Concentrations in Primary AldosteronismNicholas Yozamp, et al. Hypertension. 2021;77:891-899 March 2021Vol 77, Issue 3Article InformationMetrics Download: 1,808 © 2021 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.16585PMID: 33566688 Originally publishedFebruary 10, 2021 PDF download SubjectsHypertension