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EDITORIAL COMMENTARIES

Primary aldosteronism: a consensus statement

Funder, John W.

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doi: 10.1097/HJH.0000000000002568
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The present issue of the journal includes an article with the very explicit title ‘Subtype Diagnosis, Treatment, Complications and outcomes of Primary Aldosteronism and Future Direction of Research: A Position Statement and Consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension’ [1]. It represents the second position statement/consensus from the European Society, with the first addressing genetic factors, the relatively high prevalence of primary aldosteronism, and the optimal strategies currently available for the diagnosis of primary aldosteronism, including screening and confirmation. That the society has entrusted the crafting of these consensus statements to a broad group of experts in endocrinology and hypertension, the majority from across Europe and input from Japan and Taiwan, is very appropriate. As previously shown by the lead author, general practitioners (GPs) in Italy and Germany – if and when they suspect that a patient may have primary aldosteronism – refer the patient to a cardiologist [2]. There are – depending on the country – five to 10 times more cardiologists than endocrinologists; most cardiologists would not consider themselves expert in the management of primary aldosteronism.

One criticism that might be levelled at the statement is that it differs only marginally from the Endocrine Society guideline for the management of primary aldosteronism published in 2016 [3]. This in fact is not an issue, for at least two reasons. First, what the consensus statement does is to extend and reinforce currently accepted best practice – where such can be defined – in management; in this regard, almost half the references are to articles published in the past 4 years. The target audience is clearly very different: the 2016 guideline was written by endocrinologists, for endocrinologists, and published in the Journal of Clinical Endocrinology and Metabolism – which is unlikely to be read, in all its 27 pages, by busy cardiologists in Europe – or for that matter, anywhere else.

The consensus statement under review follows the first, which covered screening and confirmation/exclusion as noted above. A brief commentary on the first will follow consideration of the second: this might be seen as an inversion of the natural order of things, but in this instance it is appropriate. The article under review has a number of strengths. It is comprehensive, the product of a set of major contributors to the management of primary aldosteronism – and it is unafraid to refrain from judgement when current practice varies between expert centres. This latter is a major strength; there are too many examples in the literature of ‘do it my way’ exhortations, often in the absence of an evidence base taking into account potential local differences.

The section on subtype diagnosis is divided into three major areas – adrenal imaging, adrenal vein sampling (AVS) procedure and AVS interpretation. The first of these is straightforward, and the concluding statement – ‘computed tomography (CT) scanning with contrast is the preferred method for adrenal imaging, but because functional information is not provided, AVS is the only reliable method to select patients for surgery’ – neatly sums up the evidence presented. The only major caveat is what might be seen as a cause of confusion, citation of the so-called Spartacus Trial [4], between citation of two studies that provide very compelling evidence for CT being not merely inferior to AVS but in fact dangerous as a basis for lateralization. Despite its indeed being the only prospective head-to-head comparison of CT and AVS, the consensus statement cites only two of the very many issues (others are patient age, sex imbalance, rejigging of CT results) that make it totally inappropriate for generalization. The authors concluding statement …‘that the results should be interpreted with caution’ is too kind; realistically, if the trial is to be cited it should be firmly identified as noninformative. A minor point is the last sentence: if the authors know that 18F-COP2230 ‘…displays inferior accuracy to AVS’ they could include an appropriate reference.

The second subsection addresses AVS procedures. There appears to be uniformity in preparing patients for AVS; beyond that, variations abound. Cannulation is currently sequential or simultaneous (bilateral); under basal conditions (unstimulated) or with cosyntropin stimulation (as a bolus, a constant infusion, or bolus and infusion). The suggestion that the choice between the techniques used is left to the preference of the interventional radiologist (or the time-honoured usage of the centre) is pragmatic – but does involve an unsettling number of variations. The paragraph on super-selective AVS, and the intraoperative use of the rapid cortisol assay, is clear, justified and appropriate. The two concluding overall statements are in themselves unexceptionable, but in fact what they do is to signal to the cardiologist to whom the patient has been referred that they need to prescind from further action and cede decision-making to the interventional radiologist.

In the third subsection – AVS interpretation criteria – the authors are similarly pragmatic, again with the attendant difficulty for a cardiologist grappling with the text. The reader is warned: the opening sentence reads ‘Despite efforts of two groups of experts towards standardization and uniformity, most centres still use criteria for AVS interpretation that are widely diverse’. The selectivity index demonstrates successful adrenal venous cannulation on both sides; the authors suggest caution if the selectivity index is less than 2 for unstimulated, and less than 5 for stimulated procedures. The lateralization index identifies (or not) the site of hyperaldosteronism: the authors suggest a four-fold difference between the two sides in both stimulated and unstimulated procedures as an indication of unilateral disease. In a study on 40 hypertensive patients without primary aldosteronism, 32 showed a selectivity index of 1–2, 8 of 3–4, and none more than 4 [5]. Totally reasonably, but perhaps not absolutely helpfully for the cardiologist to whom the patient has been referred, the authors then point out that an lateralization index between 2 and 4 may be indicative of unilateral disease when other measurements and clinical data are taken into account. The concluding statement ‘Adrenal vein sampling can be interpreted only when the selectivity indices demonstrate correct cannulation of the adrenal veins; stricter criteria for cannulation and lateralization provide more reproducible diagnoses’ is true, but also risks missing potentially curable unilateral disease: it's a fine line.

The section on complications is straightforward, with one exception. The authors describe…‘these detrimental effects of aldosterone…’. It's not just the elevated levels of aldosterone; in sodium deficiency equivalent or even higher levels do not have detrimental cardiovascular effects. It's the combination of elevated aldosterone and elevated sodium that is the culprit. Treatment is straightforward and noncontentious in terms of surgery for proven unilateral disease; that for bilateral hyperaldosteronism less so. Reaching target blood pressure (BP) is in fact a secondary consideration, as shown by Umakoshi et al.[5] subsequently cited by the authors; the crucial target is to use enough spironolactone to lower the sodium status of the patient to a level where renin is not suppressed. There are currently clear indications that going above 50 mg/day spironolactone is self-defeating in men, in particular, in terms of compliance; key to lowering the sodium status is adding amiloride or triamterene, and lowering salt intake, rather than increasing spironolactone dosage. The epithelial sodium channel (ENaC) active agents are not alternatives to spironolactone, but adjuvants; merely uptitrating spironolactone is a negative end-sum game.

The outcomes section: For both surgically and medically treated patients, the outcomes are clearly set out and very much evidence based. The authors adroitly steer the reader through the relevant studies, and offer guidance on how to obtain optimal outcomes for both unilateral (surgery) and bilateral disease (mineralocorticoid receptor antagonists: MRAs, supplemented as required), and for both regular follow-up. In the Medical treatment section, there is some ambiguity about spironolactone. The authors write ‘Spironolactone and its principal pharmacologically active metabolite canrenoate have been the agents of choice for decades. Both compounds have long-lasting biological effects allowing once per day or even every other day administration’. Spironolactone has a half-life in vivo of less than 90 min; its three major metabolites, including canrenone, have half lives of 14–17 h. There is scant evidence for deleterious effects of activation of the renin–angiotensin system when the mineralocorticoid receptor(s) are successfully blocked; as noted above, a nonsuppressed plasma renin is key to reduction of excess risk to levels not different from those with essential hypertension. The concluding statement could be challenged in two ways. First, uptitration of low-dose spironolactone alone, as noted above, is not the way to go; second, eplerenone may be a viable substitute, but ENaC active agents are adjuvants at modest doses of spironolactone/eplerenone, not substitutes.

Right now, the issue is not with this publication, but with its predecessor covering screening and confirmatory testing for primary aldosteronism. Both these procedures currently involve – and their outcomes crucially depend on – determination of plasma aldosterone concentration (PAC). Both use a single spot PAC measurement which is a deeply flawed index of aldosterone secretion. There have been studies (noted in [6]) over the past forty years – largely ignored – which point to this grossly underestimating the prevalence of primary aldosteronism; the game-changer was the recent publication [7] showing that when aldosterone secretion is determined in 24-h urine samples (urinary excretion of aldosterone), the prevalence of primary aldosteronism is three to five times higher than when the more convenient, but deeply fallible, PAC is used as the numerator for the aldosterone to renin (or to angiotensin) ratio.

There are ∼1.4 billion hypertensive patients world-wide. Of these, in no country are more than 1% ever screened, let alone appropriately treated with specifically targeted therapy (surgery/MRAs). If 30–40% of hypertension is due to primary aldosteronism, then half a billion hypertensive patients live in double jeopardy, of elevated BP and (untreated) an at least three-fold higher risk profile than uncomplicated essential hypertension. To address this will take time, and will cost; but the societal cost is miniscule compared with that of the increased morbidity and premature mortality that awaits patients with untreated primary aldosteronism. All guidelines and consensus statements need to be rewritten – and given the prevalence – the involvement of GPs in its management an essential part of the future.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

REFERENCES

1. Mulatero P, Sechi LA, Williams TA, Lenders JWM, Reincke M, Satoh F, et al. Subtype diagnosis, treatment, complications and outcomes of primary aldosteronism and future direction of research: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens 2020; 38:19291936.
2. Mulatero P, Monticone S, Burrello J, Veglio F, Williams TA, Funder J. Guidelines for primary aldosteronism: uptake by primary care physicians in Europe. J Hypertens 2016; 34:22532257.
3. Funder JW, Carey RM, Mantero G, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2016; 101:18891916.
4. Dekkers T, Prejbisz A, Kool LJS, Groenewoud HJMM, Velema M, Spiering W, et al. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes Endocrinol 2016; 4:739746.
5. Umakoshi H, Naruse M, Wada N, Ichijo T, Kamemura K, Matsuda Y, et al. Adrenal venous sampling in patients with positive screening but negative confirmatory testing for primary aldosteronism. Hypertension 2016; 67:10141019.
6. Funder JW. Primary aldosteronism: at the tipping point. Ann Inter Med 2020; https://doi.org/10.7326/M20-1758
7. Brown MJ, Siddiqui M, Calhoun MD, Carey RM, Hopkins PN, Williams GH, Vaidya A. The unrecognized prevalence of primary aldoteronism: a cross-sectional study. Ann Intern Med 2020; https://doi.org/10.7326/M20.0065
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