Aldosterone & Resistant Hypertension: Investigation & Treatment

Curr Hypertens Rep (2014) 16:439
DOI 10.1007/s11906-014-0439-7
RESISTANT HYPERTENSION (E PIMENTA, SECTION EDITOR)
Aldosterone Excess and Resistant Hypertension:
Investigation and Treatment
Michael Stowasser
Published online: 3 May 2014
# Springer Science+Business Media New York 2014
Abstract Among patients with resistant hypertension, primary aldosteronism (PA) is worth detecting as it appears to be
particularly common in this cohort. It is associated with excessive cardiovascular morbidity in relation to the degree of
hypertension and reduced quality of life, both of which can be
abrogated with specific surgical or medical treatment. Knowledge concerning factors (including medications) which can
influence the results of screening by aldosterone/renin ratio
(ARR) testing is expanding, and is important to appreciate,
particularly in patients with resistant hypertension, in whom
the need for multiple medications can render interpretation
challenging. Advances in approaches to confirmatory testing,
subtype differentiation and assay methodology are helping to
improve feasibility and reliability of the diagnostic workup for
PA and new treatment approaches are emerging. Major developments in understanding the genetic bases for PA hold promise towards further improvements and options in diagnosis
and therapy.
Keywords Aldosterone . Primary aldosteronism .
Prevalence . Complications . Quality of life . Screening .
Aldosterone/renin ratio . Confirmation . Subtype
differentiation . Adrenal venous sampling . Treatment .
Genetics . Familial
This article is part of the Topical Collection on Resistant Hypertension
M. Stowasser
Endocrine Hypertension Research Centre, Greenslopes and Princess
Alexandra Hospitals, University of Queensland School of Medicine,
Ipswich Road, Woolloongabba, Queensland 4102, Australia
M. Stowasser (*)
Hypertension Unit, Princess Alexandra Hospital, University of
Queensland School of Medicine, Ipswich Road, Woolloongabba,
Queensland 4102, Australia
e-mail: [email protected]
Introduction
Within the context of resistant hypertension, primary aldosteronism (PA) holds particular relevance as it is highly prevalent
in this population (affecting possibly 15 – 20 % of patients [1,
2]), associated with excessive morbidity in relation to degree
of hypertension [3], and yet can be specifically treated or even
cured with marked beneficial outcomes in terms of control of
hypertension, target organ function, risk of morbid events and
quality of life. This report will review some of the advances
that have been made over the last few years in the diagnostic
workup and treatment of this important condition.
Non-Blood Pressure-Dependent Adverse Effects
of Aldosterone Excess: Why Detection of PA is Important
Numerous published studies have demonstrated aldosterone
excess to have adverse cardiovascular and renal effects which
are at least partly independent of its effects on blood pressure
[3-6]. Savard and co-workers [7•] recently provided further
confirmation of this by comparing the prevalence of cardiovascular events in 459 patients with PA and 1,290 controls
with essential hypertensives matched for sex, age and office
systolic blood pressure. The prevalence of left ventricular
hypertrophy was about twice as high in patients with PA, even
after adjustment for hypertension duration, and PA patients
had significantly higher prevalence rates for coronary artery
disease, nonfatal myocardial infarction, heart failure and atrial
fibrillation. Similarly, Mulatero et al. [8] reported patients with
PA (n=270) to have a higher rate of cardiovascular events
(and especially strokes and arrhythmias) than essential hypertensives (n=810), matched 1:3 in a case-control fashion for
sex, age, blood pressure levels, duration of hypertension, body
mass index, smoking habits, and comorbidity for type II
diabetes mellitus. This was the case for both patients with
439, Page 2 of 11
aldosterone-producing adenoma (APA) and those with bilateral adrenal hyperplasia (BAH). Patients with PA were also
more likely to develop type II diabetes during a 12-year period
of follow up after diagnosis, in keeping with findings of others
of a higher prevalence of diabetes and metabolic syndrome in
PA patients compared with essential hypertensives [9, 10], and
a role of aldosterone in disturbed glucose metabolism and
insulin resistance [11, 12]. In a recent German study, mean
glucose-induced, first-phase insulin secretion was reduced in a
group of 22 patients with PA compared to that in 11 patients
with essential hypertension, and improved in nine with APA
following unilateral adrenalectomy [13]. These findings are
consistent with a negative effect of aldosterone excess on
pancreatic beta-cell function as being another potential explanation for higher rates of diabetes in PA.
Using cardiovascular magnetic resonance imaging (MRI)
to measure aortic distensibility, Mark and colleagues [14]
reported that PA patients (n=14) displayed increased arterial
stiffness compared with matched essential hypertensives (n=
33). Su et al. reported MRI evidence of increased myocardial
fibrosis and stiffening among 25 patients with PA versus 12
age- (but not blood pressure-) matched normotensive controls
[15]. Lin and co-workers found cyclical variation of integrated
backscatter (a marker of left ventricular systolic function) on
echocardiography to be lower, and plasma procollagen levels
higher, among 20 patients with APA compared to 20 with
essential hypertension, with improvements in the APA group
following adrenalectomy [16]. In a separate report, these investigators described higher carotid intima-medial thicknesses on
duplex ultrasound scanning, and higher arterial pulse wave
velocities in the patients with APA, again improving after surgery
[17]. These findings are consistent with those of previous experimental and clinical studies demonstrating that aldosterone excess can lead in a non-blood pressure-dependent way to cardiovascular remodelling via inflammation and fibrosis, and that
specific treatment can abrogate these effects. In a multivariate
regression analysis of 54 patients with PA followed for a mean of
6.4 years after unilateral adrenalectomy or commencement of
spironolactone, Catena et al. found that the degree of reduction in
left ventricular mass was independently predicted not only by
change in systolic blood pressure, but also by pre-treatment
plasma aldosterone levels [18], further supporting a role for
aldosterone in promoting left ventricular hypertrophy that is
independent of the hypertension-related hemodynamic load.
Evidence is mounting that PA brings about adverse psychological effects and is associated with reduced quality of
life. Some of these could be attributable to nocturia and
consequent reduced sleep, frequently seen in both hypokalemic and normokalemic PA. Other symptoms may be related to
hypokalemia, medications and obstructive sleep apnoea
(which is common in PA and possibly a pathophysiological
consequence of it [19]), and putatively direct effects of aldosterone excess, in conjunction with salt, on the central nervous
Curr Hypertens Rep (2014) 16:439
system. Sonino and co-workers [20•] found a higher incidence
of anxiety disorder (52.2 %) among patients with PA compared with essential hypertensives (17.4 %) and normotensive
controls (4.3 %). Houlihan [21] described a patient with
episodic rage which resolved after unilateral adrenalectomy
for APA. Sukor et al. [22] found quality of life, measured
across eight domains by SF-36 questionnaire, to be reduced in
22 Australian patients with unilateral PA when compared to
general Australian population norms. Within 3 months postunilateral adrenalectomy, scores had returned to normal and
remained so at 6 months. Repeating this study in 21 patients
with bilateral PA treated medically with aldosterone antagonists, Ahmed et al. [23•] reported similar reductions in quality
of life scores to those of patients with unilateral disease, but
improvements after commencement of treatment took longer
and were less complete.
The above findings argue for early diagnosis and institution
of specific treatment of PA.
Screening for PA: Special Considerations in Resistant
Hypertension
As has been described in detail in previous reviews [24-26]
(Table 1), a number of factors (including antihypertensive
medications, posture, time of day, sodium intake, plasma
potassium level, renal impairment, pregnancy and malignant
hypertension) can affect the results of plasma ARR testing and
need to be avoided if possible, or their effects should at least
be taken into account when screening for PA. For patients with
resistant hypertension, the need for multiple medications can
make it difficult to obtain ARR results that are free of potential
drug-induced influences. Ideally, this is achieved without
losing control of hypertension by gradually replacing (if necessary in an inpatient setting) each potentially interfering
agent with others (for example, verapamil slow-release±hydralazine, and prazosin or doxazosin) which have lesser effects on the ratio and then waiting several weeks (at least four
after ceasing diuretics and at least two for other interfering
agents) before blood collection, but this is not always possible.
In cases where a potentially interfering medication cannot be
withdrawn, useful information can still be obtained by taking
into account its known effects when interpreting the ARR
result. For example, a raised ratio in patients receiving a
diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker or dihydropyridine calcium blocker
(which can all cause false negatives) would make PA very
likely, whereas a normal ARR in the presence of beta-blocker,
clonidine or alpha-methyldopa treatment (which can cause
false positives) would make the diagnosis very unlikely.
Where patients are receiving drugs from both categories (for
example, a beta-blocker and an ACE inhibitor), an initial ARR
result can at least inform as to which to try to withdraw first
Curr Hypertens Rep (2014) 16:439
Page 3 of 11, 439
Table 1 Previously established and newly reported factors affecting the aldosterone/renin ratio (ARR) in screening for primary aldosteronism (PA).
Factors potentially causing false positive ARRs
Factors potentially causing false negative ARRs
Previously established
(reviewed in [24-26])
Beta-adrenoceptor blockers
Clonidine
α-methyldopa
Non-steroidal anti-inflammatory drugs
Age > 65 years
High sodium dietary intake
Chronic renal impairment
Newly reported (since 2011)
Female gender (especially premenopausal
and during luteal phase [29])*
Estrogen-containing oral contraceptive agents [30]*
Potassium-sparing diuretics
Potassium-wasting diuretics
Angiotensin converting enzyme inhibitors
Angiotensin II receptor blockers
Dihydropyridine calcium channel blockers
Low dietary sodium intake
Pregnancy
Concomitant renal artery stenosis
Hypokalemia
Selective serotonin reuptake inhibitors [31]
*False positives occur in these situations only if renin is measured as direct renin concentration and not as plasma renin activity
(that is, the beta-blocker if the ARR is positive, or the ACE
inhibitor if it is negative) before repeating it.
In a subset of patients with resistant hypertension, ARR
results will remain inconclusive because of the inability to
withdraw an agent or agents that could have produced the
result in question. In the case of a positive ARR in a patient on
a beta-blocker (or other drug that can cause false positives)
which cannot be safely ceased, confirmatory suppression testing (see next section below) should “clear the air” in terms of
whether the patient does or does not have PA. The more
difficult issue arises when an ARR is normal in a patient
obliged to receive one or more drugs (for example, a loop
diuretic or an ACE inhibitor for heart failure) which stimulate
renin and thereby cause false negatives. This is because an
unsuppressed renin/angiotensin II system can complicate interpretation of both confirmatory suppression testing by potentially preventing suppression of aldosterone in patients
who do not have PA, and adrenal venous sampling (AVS)
by stimulating aldosterone production by an otherwise suppressed gland contralateral to an APA. In those circumstances,
options would include maintaining patients on suitable, effective, non-specific antihypertensive treatment, or given the
particularly high prevalence of PA among patients with resistant hypertension, an empiric trial with an agent that antagonizes aldosterone action (see below under “Approaches to
Treatment”). For patients in this category in whom surgery
might have otherwise been a treatment option and who face a
poor prognosis due to poorly controlled hypertension despite
maximal medical therapy (including an antagonist of aldosterone action), adrenal CT should be considered because detection of a unilateral mass lesion, particularly if PA is likely on
other clinical grounds (for example, unprovoked hypokalemia
and/or very high plasma aldosterone levels), may occasionally
prompt consideration for AVS, despite renin being
unsuppressed, in the “hope” that it lateralizes. Furthermore,
large (for example, > 2.5 cm) potentially aldosterone-secreting
lesions may warrant removal based on malignant potential.
Screening for PA: What’s New?
Recent studies have revealed further factors that can affect the
ARR (Table 1). Kerstens and co-workers reported the ARR to
be higher in normotensive women than in men [27]. This may
help to explain why women show a higher rate of false
positive ARR results [28]. We also reported the ARR to be
higher in normotensive pre-menopausal women than in agematched normotensive men, and suggested a need to consider
different reference ranges according to gender [29]. When
direct renin concentration (DRC), but not plasma renin activity (PRA), was used to measure renin, higher ARR values
were seen in the luteal phase than during the menses or
follicular phases and false positives occurred [29]. False positives also occurred using DRC (but not PRA) in women
receiving an oral contraceptive agent containing ethinyl estradiol and drosperinone, but not in those receiving a subdermal
implant containing etonogestrel [30]. These findings led us to
propose that PRA is preferable to DRC in determination of the
ARR, at least in premenopausal women, and that the menses
or follicular phases are the best times to collect blood for ARR
testing.
We recently reported that selective serotonin reuptake inhibitor antidepressants, which have been used with ever increasing frequency in recent years, significantly reduce the
ARR in normotensive subjects and, therefore, potentially
increase the risk of false-negative results when screening for
PA [31]. Further studies in hypertensive patients, including
patients with confirmed PA, are required to confirm this
possibility.
Given the complexity of factors now known to influence
the ARR, any development that can improve its performance
as a screening test would be a welcome achievement. Pizzolo
and co-workers very recently reported on the use of Nterminal pro-brain natriuretic peptide (NT-proBNP) measurement as an adjunct to ARR testing in the diagnostic evaluation
of patients suspected of having PA [32]. Among 132
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Curr Hypertens Rep (2014) 16:439
hypertensive subjects who underwent ARR testing, of whom
81 with high ARR underwent intravenous saline infusion
suppression testing (SST), NT-proBNP levels correlated positively with ARR and negatively with renin level, were higher
in patients with high ARR and in those with positive SST, and
were an independent predictor of positive SST. The proportion
of patients with a positive SST ranged from only 23 % in
females with a low NT-proBNP to 93 % in males with a high
NT-proBNP, leading the authors to conclude that NT-proBNP
may prove useful to identify which patients with a high ARR
should receive formal confirmatory testing [32].
(eight unilateral, 11 bilateral and five undetermined subtype),
23 (96 %) tested positive by SSST compared to eight (33 %)
by RSST. RSST missed one unilateral, all 11 bilateral and four
with as yet undetermined subtype. RSST was positive in seven
of 10 (70 %) posture-unresponsive versus one of 14 (7.1 %)
posture-responsive patients. Although larger studies are required, these preliminary results suggest that SSST may be
superior to RSST in terms of sensitivity for detecting PA,
especially posture-responsive forms, and may represent a
reliable alternative to FST.
Confirmation of PA: In Search of the Optimal Approach
Subtype Differentiation
Because the ARR is a screening test only, and because adrenal
venous sampling (AVS, required to differentiate unilateral,
surgically correctable forms of PA from bilateral forms which
are usually treated medically) is invasive and relatively costly,
confirmatory testing is necessary to definitely confirm or
exclude the diagnosis of PA in patients who screen positive.
Four tests are commonly used to establish the diagnosis of PA,
namely, oral sodium loading, saline infusion, fludrocortisone
administration with oral sodium loading, and captopril challenge testing. Of these, fludrocortisone suppression testing
(FST) has been considered the most reliable [33], but is
cumbersome, difficult to perform and relatively expensive,
requiring hospital admission for several days. Westerdahl
and colleagues recently reported captopril challenge testing
(in which the ARR is measured 120 minutes after administration of a single 25 mg dose of captopril) to have poor discriminatory power for PA in hypertensive patients with high basal
ARR [34]. We previously found SST, performed in the recumbent position, to lack sensitivity for PA, missing the
majority of patients (including those with APA) who tested
positive by FST [35]. In keeping with our experience,
Willenburg and co-workers found SST to lead to greater
suppression of plasma aldosterone than FST [36]. Because
aldosterone levels can be higher upright (e.g. seated) than
recumbent in patients with PA, and upright levels are used
during FST, we have hypothesized that seated SST (SSST) is
more sensitive than recumbent SST (RSST), especially for
posture-responsive PA. In a pilot study of 31 patients who
underwent FST (upright plasma aldosterone levels measured
at 10 a.m. basally, after 4 days of fludrocortisone 0.1 mg every
6 h, and oral salt loading) and SST (aldosterone levels measured basally at 8 a.m. and after infusion of 2 L normal saline
over 4 h) both recumbent and seated in randomised order and
at least 2 weeks apart, FST confirmed PA in 23 patients,
excluded PA in three, and was originally “inconclusive” in
five [unpublished data]. However, one with “inconclusive”
FST had PA confirmed by lateralizing AVS and was
reclassified “unilateral PA”. Of the 24 with confirmed PA
Traditionally, PA has been divided into four main subtypes:
APA, BAH, aldosterone-producing carcinoma and a rare familial form which is glucocorticoid-remediable (familial
hyperaldosteronism type I or FH-I). From the practical management point of view, it is helpful to subdivide patients
according to the following issues: (1) Does the patient have
FH-I? If so, an excellent clinical response to glucocorticoids,
given in low doses, would be expected and family screening
should be undertaken to identify similarly affected relatives;
(2) If FH-I has been excluded or at least is highly unlikely, is
autonomous aldosterone production confined to one adrenal
(consistent with APA), in which case unilateral adrenalectomy
would be expected either to cure hypertension or at least result
in a substantial improvement in control, or is it bilateral
(consistent with BAH), in which case medical management
with an agent that antagonizes aldosterone action such as
spironolactone, eplerenone or amiloride would be the preferred approach; (3) Does the patient have a large adrenal
mass lesion (for example, > 2.5 cm) on adrenal computed
tomography (CT) scanning? If so, it deserves at least longterm follow-up and may warrant consideration of removal
based on its malignant potential.
The first and third of the above questions can be answered
by performing genetic testing on peripheral blood for the
“hybrid gene” mutation that causes FH-I [37, 38] and adrenal
CT scanning, respectively. Addressing the second is more
challenging. The presence of a mass lesion in one adrenal
gland on CT does not confirm unilateral PA as the lesion could
be non-functioning, and the aldosterone excess could be bilateral or even contralateral to it. Conversely, the lack of a
mass lesion on CT does not prove bilateral PA as around 50 %
of APAs (mainly those <1 cm in size) are missed on CT [39,
40]. Furthermore, unilateral PA can exist without a definable
tumor (so-called unilateral adrenal hyperplasia), with two
recent studies both reporting that this entity was not rare,
and was associated with similar excellent long-term results
following unilateral adrenalectomy [41, 42]. For these reasons, the only reliable way to differentiate unilateral from
Curr Hypertens Rep (2014) 16:439
bilateral PA and to lateralize PA pre-operatively is by adrenal
venous sampling (AVS).
Achieving high success rates for cannulation of the adrenal
veins (and especially the right, which is more difficult to
locate) represents a challenge to institutions offering AVS.
Recent studies have demonstrated that limiting the number
of proceduralists at each institution to one or two and providing them with a higher throughput of procedures probably
have the most profound effects on improving cannulation
success rates [43, 44••]. Rapid, point-of-care cortisol assays
have proven useful in being able to alert the proceduralist at
the time of AVS, whether adrenal venous blood has been
successfully obtained and, if not, whether further attempts
should be made at sampling before the procedure is terminated. These have also resulted in higher success rates in centers
using this technique [45-47]. We previously reported on the
use of CT to localize the right adrenal vein prior to AVS [35,
48]. In a novel twist to this approach, the use of CT during
angiography to determine correctness of catheter placement
was recently reported by two groups to lead to catheter repositioning in a substantial proportion (approximately 10 % in
each study) of patients and to be associated with the achievement of high (>90 %) rates of successful cannulation [49, 50].
Several groups have reported apparently improved success
rates (based on adrenal/peripheral venous cortisol gradients)
with the use of corticotrophin (ACTH) stimulation during
AVS [51, 52]. Presumably, at least in some of these instances,
cannulation had already been achieved but not confirmed by
cortisol gradients because of a transient lack of cortisol production at the time of sampling. A concern about ACTH
stimulation has been that, in a patient with APA, ACTH could
lead to stimulation of the contralateral gland, causing results to
suggest bilateral, rather than unilateral, disease. In the study by
Monticone and co-workers [52], use of more stringent (for
example, adrenal/peripheral venous cortisol gradients of > 3.0
basally and > 4.0 post-ACTH) criteria for cannulation proved
important, and strongly advised, for optimizing pre- versus
post-ACTH diagnostic reproducibility.
Recent studies have reported on relatively high prevalence
rates (>10 %) of autonomous tumorous co-secretion of cortisol in patients with APA, even in the absence of obvious
clinical features of Cushing syndrome (so-called subclinical
Cushing syndrome) [53, 54]. This has implications not only
for peri-operative management with the need, at least some
patients, to consider glucocorticoid replacement, but also for
interpretation of AVS results, given that cortisol levels are
required for assessment of both cannulation success and lateralization. Co-secretion of cortisol would be expected to raise
cortisol levels in the adrenal vein draining the APA, while
causing chronic suppression of ACTH, and thus lowering of
cortisol secretion by the contralateral gland. One potential
solution to this problem is the measurement of an alternative
adrenal hormone to cortisol, and preferably one not influenced
Page 5 of 11, 439
substantially by prevailing ACTH levels. Dekkers and coworkers [55], for example, reported on the measurement of
plasma metanephrine during AVS and found it to be superior
to measuring cortisol in assessing success of cannulation
during AVS when performed without ACTH stimulation, with
adrenal/peripheral rations sixfold higher among procedures
deemed to be successful according to cortisol criteria. Baba
et al. [56] reported catecholamine levels to be useful for
judging not only cannulation success but also lateralization.
Because AVS is relatively costly, invasive and requires
considerable expertise, many attempts have been made to
develop reliable alternative approaches, but with limited success. Using a clinical prediction score similar to those reported
in the 1970s, Küpers et al. [57] found presence of a unilateral
mass lesion on CT “typical” for APA plus a serum potassium
of < 3.5 mmol/L or an estimated glomerular filtration rate of at
least 100 ml/min/1.73 m2 to have 100 % specificity but only
53 % sensitivity for unilateral PA. Applying this score to the
German Conn’s Registry, Riester and co-workers [58] were
not able to reproduce this high specificity, except in individuals under 40 years of age. Candy et al. [59] also found a
lower specificity of 88 % for the clinical prediction score
among a UK cohort of patients with PA, and were unable to
show superiority over an imaging-based strategy. Other promising new approaches for differentiating APA from BAH,
which require validation in different centers and with larger
numbers, have included the use of semiquantification of 131I6β-iodomethyl-norcholesterol (NP-59) single photon emission computed tomography (SPECT)/CT [60] and 11Cmetomidate positron emission tomography (PET)-CT [61].
A major barrier to the validation of various approaches to
distinguishing unilateral from bilateral PA has been the lack of
a robust “gold standard” for diagnosing APA. Many studies
have relied on suboptimal approaches, including the demonstration of an adenoma in surgically removed adrenals (without firm evidence as to whether it was actually producing
aldosterone), the blood pressure response to surgery (which
may be incomplete if the patient is studied too soon after
adrenalectomy or has other causes of residual hypertension)
and the response to surgery of plasma aldosterone plus or
minus renin levels (which is better, but still imperfect as cutoff criteria are arbitrary to some extent, and the ARR is
associated with false positives and negatives). Our own approach is to repeat the FST post-operatively [62], but, as stated
above, this is time consuming and cumbersome to perform.
Recent studies have reported on the use of immunohistochemical staining of removed adrenals in an attempt to confirm
APA removal [63-65]. Using isoform-specific monoclonal
antibodies against the 3β-hydroxysteroid dehydrogenase/
isomerase family, Doi and co-workers reported hyperplasia
of zona glomerulosa seen in BAH to be accompanied by a
robust expression of the HSD3B1 isoform [63]. In contrast,
tumor cells in APA were not immunopositive to HSD3B1 but
439, Page 6 of 11
showed expression of HSD3B2. Volpe and colleagues found
APAs to show strong immunoreactivity for aldosterone synthase [65]. In adrenals from seven patients, they found either
“adenomas” (presumably defined as adrenocortical tumors of
at least 1 cm in diameter) that were not CYP11B2 positive (n=
4) or no “adenoma” at all (n=3), but smaller nodules with
strong CYB11B2 immunoreactivity, indicating aldosteroneproducing nodular hyperplasia. Nanba et al., in a study of 32
patients with PA who underwent unilateral adrenalectomy,
found 22 to show positive CYP11B2 immunostaining in their
tumors (designated APAs), and eight with either CYP11B2negative adenomas (n=4) or without tumors on CT to show
aldosterone-producing cell clusters (APCCs) with CYP11B2
immunostaining in the zona glomerulosa [64]. In APAs,
CYP11B2 score adjusted for tumor volume was positively
correlated with plasma aldosterone and negatively with serum
potassium. APAs with either similar or greater amounts of
CYP11B1 (11β-hydroxylase, which catalyzes the last step of
cortisol biosynthesis) to CYP11B2 staining showed significantly higher serum cortisol after 1 mg dexamethasone and
larger tumor size than the CYP11B2-dominant APA group.
Importance of Subtype Differentiation
It has been argued that, given the effort and expense involved,
diagnostic workup for PA (and especially subtype differentiation) can be avoided by simply using spironolactone or
eplerenone as first-line agents in every patient suspected of
having the condition [66, 67] or even in every new hypertensive [68, 69]. However, this approach would deny patients
with unilateral PA (who constitute approximately 30 % of PA
patients [70]) the chance of a surgical cure or at least a marked
reduction in medication requirements. Perhaps surprisingly,
the mean number of medications taken by PA patients to
control hypertension after commencing an aldosterone antagonist (if the antagonist is counted as one) does not fall [39]. By
contrast, 40 – 80 % of patients who had surgery are cured of
hypertension and able to come off all antihypertensive medications, and the great majority of the remainder are on fewer
antihypertensives than pre-operatively [22, 39, 62, 71].
For both cardiovascular outcomes [72, 73, 74••] and quality of life [22, 23•], beneficial effects of surgery in unilateral
PA have been reported to be superior (more marked and/or
more rapid) to those of medical therapy in bilateral PA. A
nationwide epidemiological study conducted in Japan which
analysed data from 1,706 patients with PA found that, among
those with APA, surgical, but not medical, treatment was
significantly associated with amelioration of hypertension
[75•]. By contrast, among patients with hyperplastic forms
of PA (mostly BAH), there was no relationship between
surgical or medical treatment and the prognosis of hypertension. In an observational study reported by Reinke and
Curr Hypertens Rep (2014) 16:439
colleagues on 300 patients with PA, adrenalectomy (presumably mostly for unilateral PA) was associated with reduced allcause mortality when compared with medical treatment [76].
Most of our patients who undergo unilateral adrenalectomy
for unilateral PA report a marked improvement in general
wellbeing that is much less apparent in patients with bilateral
disease treated medically. Even in doses as low as 12.5 to
50 mg daily, treatment with spironolactone can be accompanied by side effects such as gynaecomastia, loss of libido and
menstrual irregularities [39], and eplerenone (a more selective
mineralocorticoid receptor antagonist which minimises sex
steroid-related side effects) is not available as a costsubsidized agent for treatment of hypertension in many countries, making the cost prohibitive for most patients with PA.
Towards High Quality Assay Development
Because each phase of the diagnostic workup of PA (screening, confirmation and subtype differentiation) is dependent on
accurate measurement of plasma aldosterone, and because the
ARR is predominantly renin-dependent, it is critical that the
methods used to assay aldosterone and renin in clinical samples are of high quality. Recent years have seen laboratories
moving towards using autom ated platforms and
immunometric methodology, primarily on the basis of faster
throughput and lower cost, and potentially at the expense of
lower reliability. In an attempt to address such concerns, we
recently reported on the development of a high-throughput
method of measuring plasma aldosterone using high performance liquid chromatography and tandem mass spectrometry
(LC-MS/MS) which proved to be highly accurate and reproducible [77]. Since then, several other investigators have
established similar assays for aldosterone [78, 79], and at least
two groups have developed assays which use LC-MS/MS to
measure angiotensin I and thereby determine PRA [80, 81].
As discussed above, PRA is less likely than DRC to result in
falsely elevated ARR values in pre-menopausal women [29,
30]. Incorporation of LC-MS/MS technology into routine
clinical laboratory practice for measuring aldosterone and
renin promises to be a major step forward for optimal detection and diagnosis of PA and its subtypes.
Approaches to Treatment
The mainstays of treatment for PA continue to be unilateral
adrenalectomy for most patients with unilateral forms (in our
experience leading to cure of hypertension in 60 – 80 % and
improvement in almost all of the remainder [22, 39, 62]), and
medications that antagonise aldosterone action (for example,
spironolactone 12.5 – 50 mg daily, eplerenone 25 – 100 mg
daily or amiloride 2.5 – 20 mg daily) for most with bilateral
Curr Hypertens Rep (2014) 16:439
PA. Both treatment approaches can result in marked blood
pressure lowering in patients with hypertension, including
those with resistant forms.
Recent surgical developments have included reports of
single incision laparoscopic adrenalectomy [82, 83], which
offers superior cosmetic results to multiple incision approaches but requires further experience to establish its value
from a risk versus benefit perspective.
On the medical front, a long-awaited paper reporting results from a randomized, double blinded trial comparing the
efficacy, safety and tolerability of eplerenone to that of
spironolactone (given in relatively large daily doses of 100 –
300 mg and 75 – 225 mg respectively) in patients with PA
declared spironolactone to be superior in terms of blood
pressure lowering, but to be associated, as expected, with
higher rates of male gynecomastia (21 % versus 5 % for
eplerenone) and female mastodynia (21 % versus 0 %) [84].
Aldosterone synthase inhibitors remain a promising new treatment approach, despite a recent study showing that in patients
with PA, the effects on blood pressure and plasma potassium
and renin concentrations of eplerenone treatment (50 –
100 mg twice daily) were more marked than those of 4 weeks
of treatment with the aldosterone synthase inhibitor LCI699
(0.5 – 1 mg twice daily) [85]. As expected, eplerenone raised
while LC1699 lowered plasma aldosterone concentrations.
An ongoing concern for these new drugs is the potential
for inhibiting cortisol production in addition to that of
aldosterone.
Non-steroidal dihydropyridine-based mineralocorticoid receptor antagonists [86, 87] are a new drug class which have
displayed similar in vitro potency to spironolactone, and without apparent effects on androgen and progesterone receptors.
These drugs therefore hold the promise of blood pressure
lowering effects in PA that are at least equivalent to those of
spironolactone but without the sex steroid-related side-effects,
and superior to those of eplerenone. BAY 94-8862, the firstin-class of this new generation of mineralocorticoid receptor
antagonists, is currently in development for treatment of heart
failure [86], with early results showing considerable promise
[88], and studies in PA are eagerly awaited.
Recent studies in humans have demonstrated that, similarly
to animals, endogenous aldosterone and dietary salt intake
interact to accelerate target-organ deterioration. Pimenta and
colleagues demonstrated both the left ventricular mass [89]
and the degree of proteinuria [90] in patients with PA to be
dependent on 24-h sodium excretion rate (as a marker of
dietary salt intake). Increased dietary sodium and aldosterone
were also shown by these workers to be related to severity of
obstructive sleep apnea in patients with resistant hypertension
[91]. It therefore, stands to reason that incorporation of dietary
salt restriction in the management of patients with PA may
help to limit and even reverse target organ damage and
morbidity.
Page 7 of 11, 439
The New Genetics
Although perhaps less obviously associated with investigation
and treatment in the immediate sense, no update on PA would
be complete without mention of the major recent advances
that have been made in understanding the genetic basis of this
disorder. Perhaps the most exciting of these is the finding that
not only are germline mutations in the KCNJ5 potassium
channel gene associated with familial primary aldosteronism
[92••, 93-95], but somatic mutations in the same channel have
been identified within APAs with a frequency of approximately 40 % in Caucasian patients [92••, 96-100] and even
higher in Japanese patients [101]. Somatic mutations within
APAs have also been described in CACNA1D (encoding a
voltage-gated calcium channel), ATP1A1 (encodes the αsubunit of Na+/K+ ATPase) and ATP2B3 (encodes a Ca2+
ATPase calcium channel) [102•, 103•, 104]. We resequenced the flanking and coding region of KCNJ5 in peripheral blood DNA from 251 Caucasian subjects with PA to
look for rare variants that might be important for the pathophysiology of sporadic forms and identified three heterozygous missense mutations (R52H, E246K and G247R) in the
cohort and found that 12 (5 % of the cohort) were carriers for
the rare non-synonymous single nucleotide polymorphism
rs7102584 causing E282Q substitution of KCNJ5 [105]. Unlike other previously described mutations associated with PA,
these three mutations and rare polymorphism were all remote
from the potassium channel selectivity filter. By expressing
the channels in Xenopus oocytes and human adrenal H295R
cells, we showed that the R52H, E246K and E282Q (but not
G247) substitutions were functional, affecting the inward
rectification, the ability of the KCNJ5 channels to conduct
Na + currents and angiotensin II-induced aldosterone release
from the H295R cell line [105]. Together these data suggest
that germline variation in the KCNJ5 gene has a role to play in
the common sporadic form as well as the much rarer
syndromic forms of PA.
Conclusions
The difficulty of obtaining hypertension control, the high
prevalence of PA, and the fact that aldosterone excess adds
to the burden of morbidity in ways that go above and beyond
hypertension itself, all argue for the need to screen for PA in
patients with resistant hypertension. In fact, given the confounding effects of medications on the ARR, an argument can
be made for screening before hypertension reaches the stage
of needing multiple (or even before commencing) drug treatment. Advances in approaches to confirmatory testing, subtype differentiation, assay technology and treatment are helping to allow treating physicians to diagnose and provide
optimal management to patients with this condition. New
439, Page 8 of 11
knowledge concerning the genetic basis for PA may also
ultimately lead to new ways of detecting and treating these
patients among the resistant hypertension population.
Curr Hypertens Rep (2014) 16:439
12.
13.
Compliance with Ethics Guidelines
Conflict of Interest Michael Stowasser declares that he has no conflict
of interest.
14.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
15.
16.
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