European Society of Hypertension Scientific Newsletter:Update on Hypertension Management PRIMARY ALDOSTERONISM
Franco Mantero1, Gian Paolo Rossi2, Enrico Agabiti Rosei3
1Endocrine Unit, Department of Medical and Surgical Sciences, University of Padua, Italy
2Internal Medicine 4, Department of Clinical and Experimental Medicine, University of Padua, Italy
3Clinica Medica, Department of Medical and Surgical Sciences, University of Brescia, Italy

Primary aldosteronism (PA) is a common form of endocrine hypertension in Diagnosis of PA is divided into different steps including: case detection, case which aldosterone production is inappropriate and at least partially autono- confirmation, and subtype classification.
mous of the renin-angiotensin system. The inappropriate production of aldos-terone results in sodium retention and suppression of renin. PA is commonly caused by an adrenal adenoma or bilateral hyperplasia of the adrenocorticalzona glomerulosa, and in very rare cases by the inherited condition of gluco- Case detection of PA is recommended in patient groups with relatively high preva- corticoid-remediable aldosteronism (GRA) also known as Familial Hyperaldos- lences of PA. These include patients with: stage 2 (>160-179/100-109 mm Hg), stage 3 (>180/110 mm Hg), or drug-resistant hypertension; hypertension and Some misconceptions concerning PA must be addressed. PA was held to spontaneous or diuretic-induced hypokalaemia; hypertension with adrenal account for less than 1% of hypertensive patients and, moreover, hypokalaemia incidentaloma; or hypertension and a family history of early-onset hyperten- was considered a prerequisite for pursuing the diagnostic tests for PA [1] sion or cerebrovascular accident at a young age (< 40 yr).
However, recent studies carried out by applying the plasma aldosterone/plas- The Aldosterone-Renin Ratio (ARR) is currently the most reliable means ma renin activity (PRA) ratio (ARR) as a screening test in hypertensive patients, available for screening for PA. It is recommended that hypokalaemia be cor- regardless of the presence or absence of hypokalaemia, have found a much rected and that those drugs which could cause false-positive or false-negative higher prevalence of this disease, with PA accounting for up to 12% of hyper- results be removed for at least 2-3 weeks, before measuring the ARR. Like all tensive patients. In recent studies, only a minority of patients with PA (9 to biochemical case detection tests, the ARR is not without false positives and 37%) had hypokalaemia [2]. Thus, normokalaemic hypertension constitutes the false negatives and can be affected by numerous conditions (see Table 1) most common presentation of the disease, with hypokalaemia probably being [3, 6]. The ARR should therefore be regarded as a detection test only and present only in the more severe cases [3]. An early diagnosis of PA is crucially should be repeated if the initial results are inconclusive or difficult to interpret important not just because PA is common and if overlooked exposes the patient because of suboptimal sampling conditions. It should also be appreciated to the need for long-life treatment, but even more so because if undiagnosed that the ARR conveys quantitative information: in other words a markedly and not properly treated these patients have higher cardiovascular morbidity elevated value should be taken as a strong indication for the presence of PA, and mortality than age-, sex, blood-, and pressure-matched patients with es- which can warrant adrenal vein sampling without any further confirmation, sential hypertension, including a greater incidence of left ventricular hypertro- while borderline elevated values should be repeated and perhaps followed by phy, fibrosis, atrial fibrillation, myocardial infarction, and stroke [4]. In fact, aldosterone has been shown to induce endothelial dysfunction, norepinephrine In recent years it has become more common to use the direct active renin release, cardiovascular fibrosis, and proteinuria, independently from increase of assay instead of the plasma renin activity (PRA) to evaluate the renin-angio- blood pressure. Furthermore, specific treatments are available that ameliorate tensin system. A major problem is that there are important and confounding the impact of this condition on patient-important outcomes (Figure 1).
differences across laboratories regarding the methods and units used to reportvalues of renin and aldosterone; this, together with the lack of uniformity indiagnostic protocols, has been associated with substantial variability in cut-off Diagnosis
values used by different groups, ranging from 20 to 100 as ng/dl Aldo over ng/ The growing recognition of PA as a common and important contributor to /dl/hr (or 68 to 338 as pMol/L over mU/L) [7]. Most groups, however, use cut-offs hypertension development and cardiovascular disease has led to a "Renais- of 20-40 (for Aldo in ng/dl over PRA in ng/ml/h) (68-135) when testing is sance" in interest regarding the detection and diagnostic workup of this performed in the morning on a seated ambulatory patient. In the largest avail- disorder by clinicians involved in the treatment of hypertensive patients. The able study in which the ARR was used to identify the only PA subtype that could Clinical Guidelines Committee of The Endocrine Society [5] has developed be conclusively diagnosed based on the "four corners" criteria, the optimal cut- clinical practice guidelines for the diagnosis and treatment of patients with PA.
off for the ARR (PAC in ng/dl, PRA in ng/ml/h) was 25.86 [3].
Table 1. Factors that may affect the aldosterone-renin ratio and thus lead to falsepositive or false negative results [5] Effect on
Effect on
aldosterone levels
renin levels
Potassium status
Dietary sodium
Advancing age
Other conditions
*Renin inhibitors lower PRA but raise DRC. This would be expected to result in false--positive ARR levels for renin measured as PRA and false negatives for renin measu- Figure 1. Flowchart outlining the suggested work-up of patients with hypertension red as DRC; PHA-2 - pseudohypoaldosteronism type 2 (familial hypertension and and increased risk of hyperaldosteronism [5] hyperkalemia with normal glomerular filtration rate) ty of this test depends heavily on the size of the adenoma; consequently, Once a high ARR has been determined confirmatory tests should be per- this method is useless in interpreting micronodular findings obtained with formed to definitively confirm or exclude PA [5]. At present, four confirmatory high-resolution CT and has no major role in subtype evaluation [14] in most tests to definitively confirm or exclude the diagnosis are used: oral sodium centres. Moreover, the shortage of the radiotracer currently makes this test loading, saline infusion, fludrocortisone suppression, and captopril challenge.
These four tests are in common use even though their usefulness is supported • 18-Hydroxycorticosterone levels. 18-Hydroxycorticosterone is formed by at best by a level of evidence C by the AHA criteria, and therefore the level of 18-hydroxylation of corticosterone. Patients with APA generally have re- recommendation for their use is only Iib. Moreover, there is currently insuffi- cumbent plasma 18-hydroxycorticosterone levels greater than 100 ng/dl at cient direct evidence to recommend any one of these above the others. These 0800 h, whereas patients with IHA have levels that are usually less than tests may differ in terms of sensitivity, specificity, and reliability, but the 100 ng/dl. However, this test lacks the accuracy needed to guide the clini- choice of a confirmatory test is usually determined by considerations of cost, cian in the subtype evaluation of PA [5].
patient compliance, laboratory facilities, and local expertise. The most com- • Testing for familiar forms of PA[FH-I (GRA)]. FH-1 syndrome is responsible monly used test is the saline infusion test (2 L over 4 hrs) with a temptative for less than 1% of cases of PA and it is inherited in an autosomal dominant cut-off for post infusion plasma aldosterone above 7 ng/dl [8]. It should be fashion. It may be diagnosed in patients with onset of PA earlier than at noted that confirmatory tests requiring oral or IV sodium loading should be 20 years of age and in those who have a family history of PA or of strokes administered with caution in patients with uncontrolled hypertension or con- at young age. Genetic testing by either Southern blot [15] or long PCR gestive heart failure. As all these tests rely on the presumed autonomy of the techniques is sensitive and specific for GRA. FH-II syndrome us clinically aldosterone production from angiotensin II, which apparently is not the case indistinguishable from non-familiar PA. It is an autosomal dominant disor- in all aldosterone-producing adenoma, these tests are fraught with a large der. GRA mutation testing is negative. Its prevalence has not been estab- number of false negative and false positive results, and therefore some ex- lished. An association with chromosomal region 7p22 has been shown [16].
perts support the view that they should not be used as they can lead to • A further approach that is being tested to identify lateralizedaldosterone curative adrenalectomy not being given to many patients.
excess entails C11methomidate positrone emissiontomography. However, itremains to be demonstrated if it couldidentify the majority of APAs that, asmentioned above, are small.
Subtype classificationAll patients with primary aldosteronism should undergo adrenal computed Treatment
tomography (CT) as the initial subtype study, to exclude large masses thatmay represent adrenocortical carcinoma and to ascertain the right adrenal Treatment of choice in documented unilateral PA (APA or UHA) is unilateral vein anatomy, which is useful for planning and adrenal vein sampling. Of laparoscopic adrenalectomy, whereas medical treatment with mineralocorti- these indications, adrenal CT has no place for differentiation of PA subtypes.
coid receptor antagonists is indicated in patients with bilateral adrenal dis- In fact, small APAs may be overlooked, and/or non-functioning adenoma ease (idiopathic adrenal hyperplasia, bilateral APA, GRA).
("incidentaloma") on one side can be considered the "culprit" for PA while Surgical treatment in patients with unilateral PA shows improvement of instead the latter is due to a small CT-undetectable APA or unilateral hyperpla- serum potassium concentrations in nearly 100% of patients postoperatively [5] sia on the contralateral side. Moreover, apparent adrenal microadenomas when the diagnosis and the indication of adrenalectomy are made based on may actually represent areas of hyperplasia, and unilateral adrenalectomy AVS. Hypertension is cured (defined as blood pressure < 140/90 mm Hg with- would be inappropriate. In addition, non-functioning unilateral adrenal mac- out the aid of antihypertensive drugs) in about 50% (range 35-60%) of patients roadenomas are not uncommon, especially in older patients (> 40 years old) with APA after unilateral adrenalectomy, with a cure rate as high as 56-77% and are indistinguishable from APAs on CT. Unilateral UAH (unilateral adrenal when the cure threshold is blood pressure less than 160/95 mm Hg [5].
hyperplasia) may be visible, but also invisible on CT. Magnetic resonance Factors associated with resolution of hypertension in the postoperative imaging has no advantage over CT in subtype evaluation of PA, being more period include having no more than one first-degree relative with hyperten- expensive and more prone to motion artefacts than CT.
sion, preoperative use of one or two antihypertensive drugs [17], known Lateralization of the source of excessive aldosterone secretion is critical to duration of hypertension, and the presence of vascular remodelling [18]. As guide the management of PA. Imaging cannot reliably visualize microade- compared with open adrenalectomy, laparoscopic adrenalectomy is associat- nomas or distinguish incidentalomas from APAs with confidence [9], making ed with shorter hospital stays and fewer complications [19].
Adrenal Vein Sampling (AVS) the most accurate way of differentiating unilat- In patients who do not undergo surgery and in those presenting bilateral adrenal disease, medical treatment is indicated as follows: • MR antagonists appear to be effective in the control of blood pressure and It must be understood that AVS should be offered to the patients only if surgical treatment is possible and desired by the patient. The sensitivity and • Spironolactone has been the agent of choice in the medical treatment of specificity of AVS (95 and 100%, respectively) for detecting unilateral aldoster- PA for more than four decades. Several observational studies in patients one excess are superior to those of adrenal CT (78 and 75%, respectively) [10].
with IHA have reported a mean reduction in systolic blood pressure of 25% Although AVS can be a difficult procedure, especially on the right adrenal and diastolic blood pressure of 22% in response to spironolactone 50- vein (which is smaller than the left and usually empties directly into the IVC -400 mg/d for 1-96 months [5]. The incidence of gynaecomastia with rather than the renal vein), the success rate usually improves quickly as the spironolactone therapy is dose related, whereas the exact incidence of angiographer becomes more experienced [9]. Currently, three protocols for menstrual disturbances in premenopausal women with spironolactone ther- AVS are used: 1) unstimulated sequential or simultaneous bilateral AVS, 2) un- apy is unknown. Where available, canrenone (an active metabolite of spirono- stimulated sequential or simultaneous bilateral AVS followed by bolus co- lactone) or potassium canrenoate, might be considered because they possi- syntropin-stimulated sequential or simultaneous bilateral AVS, and 3) con- bly have fewer sex steroid-related side effects. In addition, a small dose of tinuous cosyntropin infusion with sequential bilateral AVS. There are actually a thiazide diuretic, triamterene, or amiloride can be added to avoid no clear guidelines which recommend any particular protocol and data are a higher dose of spironolactone which may cause side effects. The starting lacking on the impact of AVS on clinical outcomes [11]. Some form of patient dose for spironolactone should be 12.5-25 mg daily in a single dose. The stratification is required, possibly firstly identifying which patients should lowest effective dose should be found by very gradually titrating upward to proceed to surgery set against those who can be managed on effective medi- cal therapy with Mineralocorticoid Receptor antagonists. The use of AVS must • Eplerenone is a newer, selective MR antagonist without antiandrogen and be justified on a case-by-case basis, asking how it will improve patient care progesterone agonist effects, thus reducing the rate of adverse endocrine and outcome, and be undertaken in centres of excellence to achieve optimal side effects. Eplerenone has 60% of the MR antagonist potency of spirono- lactone; its better tolerability profile needs to be balanced against its high-er cost, shorter duration of action requiring multiple daily dosing, and the lack of current clinical trial evidence for its use in PA [20]. The starting dose • Posture stimulation test. In patients with unsuccessful AVS and with a CT for eplerenone is 25 mg once or twice daily.
scan showing a unilateral adrenal mass, some experts use the posturestimulation test. This test, developed in the 1970s, was based on the find- ing that the PAC in patients with APA showed diurnal variation and was Up-regulation of distal tubular sodium epithelial channel activity is a major relatively unaffected by changes in angiotensin II levels, whereas IHA was mechanism whereby aldosterone exerts its actions on sodium and potassium characterized by enhanced sensitivity to small changes in angiotensin II handling. Of the available epithelial sodium channel antagonists, amiloride that occur with standing. Recent reviews showed an accuracy of 85% of has been the most studied as a mode of treatment for PA. Although less this test. The lack of accuracy is explained by the fact that some APAs are efficacious than spironolactone, amiloride may be useful. Being a potassium- sensitive to angiotensin II and some patients with IHA have diurnal varia- -sparing diuretic, amiloride can ameliorate both hypertension and hy- tion in aldosterone secretion. Thus, the posture stimulation test may have pokalaemia in patients with PA and is generally well tolerated, lacking the sex an ancillary role, for example, in those patients for whom AVS was unsuc- steroid-related side effects of spironolactone, but without the beneficial ef- cessful and CT shows a unilateral adrenal mass [13].
fects on endothelial function [21]. Calcium channel blockers, angiotensin- • Iodocholesterol scintigraphy. [131I]19-Iodocholesterol scintigraphy was first -converting enzyme inhibitors, and angiotensin receptor blockers have been used in the early 1970s, and an improved agent, [6b-131I]iodomethyl-19- evaluated in very few patients with PA, and in general they are antihyperten- -norcholesterol (NP-59), was introduced in 1977. The NP-59 scan, per- sive drugs without a major effect on aldosterone excess. Supportive studies formed with dexamethasone suppression, had the putative advantage of are small and methodologically weak and have not measured patient-impor- correlating function with anatomical abnormalities. However, the sensitivi- tant outcomes. Aldosterone synthase inhibitors may play a role in the future.
11. Seccia TM, Miotto D, De Toni R, et al. Adrenocorticotropic hormone stimulation during adrenal vein sampling for identifying surgically curable subtypes of primary aldosteronism: comparison of 3 dif- 1. Kaplan NM. Clinical hypertension. 6th ed. Williams & Wilkins, Baltimore 1994: 389-408.
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2. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgi- 12. Stewart PM, Allolio B. Adrenal vein sampling for Primary Aldosteronism: time for a reality check.
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13. Espiner EA, Ross DG, Yandle TG, Richards AM, Hunt PJ. Predicting surgically remedial primary aldos- 3. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism teronism: role of adrenal scanning, posture testing, and adrenal vein sampling. J Clin Endocrinol in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293-2300.
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