Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension

Pierre-François Plouin1, Laurence Amar1 and Gilles Chatellier2 on behalf of the COMETE-Conn Study Group

1Hypertension Unit and 2Department of Medical Informatics, Hôpital Européen Georges Pompidou, Paris, France

Correspondence and offprint requests to: Dr P. F. Plouin, Hypertension Unit, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris cedex 15, France. Email: pierre-francois.plouin{at}egp.ap-hop-paris.fr

Keywords: aldosterone; hypertension; secondary; hyperaldosteronism; renin



   Introduction
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 Introduction
 Primary aldosteronism in a...
 Primary aldosteronism subtypes
 Primary aldosteronism,...
 A pragmatic approach to...
 References
 
Although primary aldosteronism (PA) has long been considered a rare cause of hypertension, recent reports suggest that the prevalence of PA among hypertensive patients may exceed 10% [1,2]. An actual increase in the true prevalence of PA is unlikely [3,4], but diagnostic advances may result in a more frequent and effective screening for the condition. Screening for PA is no longer limited to patients with hypokalaemia [19]. Using the aldosterone to renin ratio (ARR) is a more convenient screening test than separate determinations of plasma renin activity (PRA) and urinary aldosterone excretion [16,8,10,11] and, according to some [16,10] but not all [1114] reports, is less influenced by antihypertensive medication.

The diagnosis of PA is not synonymous with the diagnosis of aldosterone-producing adenoma (APA) or a surgically correctable form of hypertension, however. Among recently diagnosed cases of PA, the proportion of idiopathic hyperaldosteronism (IH), which should be treated medically [59], may have increased more than that of APA, and among cases with APA, less selective indications for surgery could have reduced the blood pressure (BP) benefit of intervention. Swales proposed 20 years ago a pessimistic hypothesis: "The harder we look, the more patients with aldosteronism we are likely to find, though the yield in term of disorder correctable by surgery is likely to decline spectacularly, the more widely we cast our net" [15]. This review addresses the following questions. What is PA in a clinical perspective? Has there been a recent ‘epidemic’ [3] of diagnosed PA? Is there a decline in the proportion of APA among patients diagnosed with PA and in the rate of hypertension cure following adrenal surgery?



   Primary aldosteronism in a clinical perspective
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 Introduction
 Primary aldosteronism in a...
 Primary aldosteronism subtypes
 Primary aldosteronism,...
 A pragmatic approach to...
 References
 
Conn stated 40 years ago that "The combination of suppressed PRA, unresponsive to stimuli which elevate this activity in normal people, together with abnormally elevated aldosterone secretion or excretion rates, is unique, and this is characteristic only of PA" [16]. The renin–aldosterone dissociation is the landmark of all contemporary definitions of PA and the rationale for the use of a high ARR as a screening test [16,811]. Yet there is no gold standard for PA because the separation between normal renin–aldosterone regulation and PA is not dichotomous: there is clinical, biochemical and pathological evidence that PA is part of a continuum which includes low-renin essential hypertension, IH and APA [17]. Weinberger and Fineberg [5] stated that "the ARR alone provides complete separation of patients with PA from essential hypertensive subjects", but their statement was derived from between-group comparisons and they provided no definite cut-off ARR value for diagnosing PA in individuals. In a comprehensive review of the literature to establish the test characteristics of the ARR, Montori and Young [11] found that proposed cut-off values ranged from 200 to 2774 pmol/l per ng/ml per h, i.e. 14-fold, and concluded that there are no published valid estimates for the test. Gordon [6] defined PA as non-suppressible aldosteronism on the basis of the absence of "suppression of upright mid-morning plasma aldosterone concentration to less than 5 ng/100 ml after 4–5 days of fludrocortisone acetate 0.1 mg 6 hourly, with supplemental dietary salt in the form of Slow Na, two 10 mmol tablets three times a day". The procedure that involves exposure to a mineralocorticoid plus supplementary sodium for 4–5 days is complex. It may raise BP and lower serum potassium in patients with PA. Gordon did not provide the validation for the proposed threshold of 5 ng/100 ml. Blumenfeld et al. [7], Ganguly [8] and Stewart [9] took up again the concept of PA being defined by the association of low renin and non-suppressible aldosterone. They proposed various non-standardized suppression tests but did not provide thresholds for renin and aldosterone levels before and after the tests.



   Primary aldosteronism subtypes
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 Introduction
 Primary aldosteronism in a...
 Primary aldosteronism subtypes
 Primary aldosteronism,...
 A pragmatic approach to...
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PA subtypes include adrenal carcinoma, familial hyperaldosteronism type I and II, IH, primary adrenal hyperplasia and APA, which is either renin-responsive or renin-unresponsive [6,1820]. Adrenal carcinoma and familial forms of PA are rare and are not discussed here. Some patients with APA retain a renin-dependent control of aldosterone, aldosterone levels being raised by postural stimulation and suppressed by sodium loading or fludrocortisone administration. Their condition is termed renin-responsive APA, as opposed to renin-unresponsive APA in which aldosterone secretion is autonomous, unaffected by standing or sodium loading. Primary adrenal hyperplasia is a subtype of PA with unilateral aldosterone secretion documented by adrenal venous sampling and no detectable adenoma.

Surgically correctable subsets of PA include renin-unresponsive APA, renin-responsive APA and primary adrenal hyperplasia [1820]. Studies in patients with PA who underwent adrenal surgery showed that increasing age or duration of hypertension are associated with poor post-operative BP outcome [7,21,22], and that a large reduction in BP during spironolactone administration or the presence of a lateralized secretion of aldosterone are associated with favourable outcome [7,18,21]. They found no association between BP outcome and the pre-operative ARR [7,21] or plasma aldosterone concentrations following suppression (captopril administration or sodium loading [21]) or stimulation (upright posture or furosemide administration [23]) tests. Consequently, definitions of PA based on a non-suppressible aldosterone secretion expose to the risk of missing useful indications for surgery in patients with renin-responsive APA. Omitting adrenal vein sampling in patients with PA and no adenoma at CT scan also exposes to the risk of missing primary adrenal hyperplasia, another surgically correctable form of PA.



   Primary aldosteronism, aldosterone-producing adenoma, and cure rate following surgery
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 Introduction
 Primary aldosteronism in a...
 Primary aldosteronism subtypes
 Primary aldosteronism,...
 A pragmatic approach to...
 References
 
To estimate the prevalence of PA, we reviewed prospective studies which described criteria used to establish the presence of PA and included at least 100 screened patients with hypertension. We did not include a study whose goal was to screen for PA among hypertensive patients with low PRA [23]. The seven eligible studies [1,2,10,2427] have been sorted by date of publication in Table 1. Using each authors’ criteria, the prevalence of PA ranged from 4.6 to 14.4%, with an average of 6.6%. To estimate the proportion of APA among patients with PA, we selected papers reporting diagnostic tests for PA and at least 50 patients with definite PA. To avoid an indication bias, we excluded surgical series in which all patients had been operated on. Among the nine eligible reports sorted by publication date in Table 2 [5,7,25,2833], the proportions of APA among patients with PA ranged from 24.2 to 77.4%, with an average of 56.6%. Finally, to estimate the frequency of hypertension cure or improvement following surgery, we analyzed series from single centres reporting post-operative BP follow-up in at least 50 patients with PA [3439]. The frequency ranged from 33.3 to 70.0% (average 52.1%) (Table 3). In brief, PA is diagnosed in ~6% of hypertensive patients referred to specialized centres. One patient in two with documented PA harbours an APA, and one in two with an APA benefits from adrenal surgery. There is no suggestion for a temporal trend in the apparent prevalence of PA, nor for a recent decrease in the proportion of APA or in the cure rate following surgery.


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Table 1. Prevalence of PA in hypertensive patients (prospective studies including at least 100 screened patients)

 

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Table 2. Percentage of APAs among patients with PA (series reporting diagnostic tests for PA and at least 50 patients)

 

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Table 3. Frequency of hypertension cure or improvement following unilateral adrenalectomy in patients with PA (data from single centres reporting 50 interventions or more)

 


   A pragmatic approach to primary aldosteronism
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 Introduction
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Screening for PA is recommended in hypokalaemic or resistant hypertension with a view to improve patient management. In selected cases, the presence of PA may lead one to consider adrenal surgery in order to overcome the failure of medication to normalize BP or to provide an alternative to life-long antihypertensive treatment. The first step is then to document PA and the second step to document the presence of a surgically correctable subtype of PA. Several teams with extensive experience in the management of patients with PA use various diagnostic strategies with cut-off values adapted to their methods, procedures and reference values. In our division [21,40], we discontinue diuretics, betablockers and renin–angiotensin system antagonists for 2 weeks (spironolactone for 6 weeks) and provide patients with potassium chloride in order to maintain serum potassium levels above 3 mmol/l. ARR is determined twice to take into account the spontaneous variability of aldosterone secretion. Renin is measured as active renin concentration rather than ARP. Active renin concentration is set at >=5 mU/l to avoid overestimating the ARR in cases where renin is very low or undetectable. We consider PA to be present if (i) the ARR is twice >=64 pmol/mU and (ii) supine aldosterone concentration is >=500 pmol/l or urinary aldosterone excretion is >=63 nmol/day. The second step, i.e. documenting the presence of a surgically correctable subtype of PA, is taken in patients who consider surgery acceptable and are aged 55 or less or have resistant hypertension, i.e. whose BP cannot be lowered to 140/90 mmHg or less despite a triple drug regimen. We consider surgery if a thin-slice CT scan shows a unilateral radioluscent adenoma of >=10 mm. If it shows no tumour, a tumour of less than 10 mm, or an enlarged contralateral adrenal, we proceed to adrenal venous sampling and consider surgery if the aldosterone to cortisol ratio between both adrenals is >=5 [40].

In summary, there is no gold standard for PA. Hypokalaemia, when present, is usually controlled by distal diuretics and APA are benign tumours. Therefore, the goal of clinical care in patients with PA is to normalize BP without surgical treatment or at least to obtain adequate BP control in patients with refractory hypertension. Clinical research in PA should aim at determining genetic, clinical and biochemical parameters that are independently related to BP outcome following surgery and at selecting simple and safe surgical methods.



   Acknowledgments
 
The COMETE (COrtico and MEdullo-surrenale: les Tumeurs Endocrines) network is supported by grant AOM 02068 from the Assistance Publique-Hôpitaux de Paris, Délégation à la Recherche Clinique, and the Société Française d’Hypertension Artérielle. Members of the COMETE-Conn Study Group are P. Gosse and A. Tabarin, Bordeaux; Y. Reznik, Caen; J. P. Baguet and O. Chabre, Grenoble; A. Prost, Le Mans; J. L. Wemeau, Lille; F. Berthezène, J. P. Fauvel, H. Milon and M. Vincent, Lyon; B. Conte-Devolx, Marseille; X. Bertagna, G. Chatellier, D. Mouradian and P. F. Plouin (Chairman), Paris; D. Herpin, Poitiers; C. Croisier-Lukas, Reims; H. Lefebvre, Rouen; J. L. Imbs, Strasbourg; and B. Chamontin, Toulouse.

Conflict of interest statement. None declared.



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