S P E C I A L
F E A T U R E
U p d a t e
Update in Primary Aldosteronism
Michael Stowasser
Endocrine Hypertension Research Center, University of Queensland School of Medicine, Greenslopes and
Princess Alexandra Hospitals, Brisbane 4102, Australia
Primary aldosteronism (PA) is a condition well worth detecting because it is a common cause of
hypertension and is associated with excessive morbidity for the degree of hypertension and reduced quality of life, all of which can be abrogated with specific surgical or medical treatment.
Recent years have seen an explosion in knowledge concerning the genetic bases of this disorder,
and particularly of somatic mutations associated with aldosterone-producing adenomas and germline mutations causing rare familial forms, both involving genes encoding ion channels. Inroads
have also been made into understanding molecular pathways that may be involved in the development of PA. With evidence continuing to mount for non-blood pressure-dependent adverse
effects of aldosterone excess and for superior effects of specific over non-specific treatment, the
need for accurate yet readily applicable and available diagnostic approaches and methodologies
has become a matter of urgency. 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. (J Clin Endocrinol Metab
100: 1–10, 2015)
rimary aldosteronism (PA) remains in a “golden era”
in terms of clinical and research interest that has
evolved over the past two to three decades with the realization that it is highly prevalent among hypertensive populations and, through non-blood pressure-dependent
means, is associated with cardiovascular, renal, and psychological morbidity that appears to be excessive for the
degree of hypertension. The last few years have seen ongoing, intense research activity into its causations, diagnostic workup, and management that appears unlikely to
wane anytime soon. Perhaps the most exciting advances
have been in understanding the pathophysiology of PA,
and especially its genetic bases, opening doors to newer
and better methods of diagnosis and treatment. Evidence
that the adverse effects of aldosterone excess go way beyond merely causing hypertension has been further
strengthened. Challenges to physicians keen to pursue the
diagnosis of this condition, correctly determine the subtype, and offer optimal specific treatment have received
P
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2015 by the Endocrine Society
Received September 27, 2014. Accepted October 27, 2014.
First Published Online November 3, 2014
doi: 10.1210/jc.2014-3663
considerable attention and, in some cases, have been met
by the development of better diagnostic methodologies,
more accurate assays, and new therapies. This report will
review some of these advances.
The New Genetics of PA
It would be impossible to complete an update on PA without including the major recent developments that have
been made in understanding the genetic bases of this disorder. In 2011, Choi et al (1) reported somatic mutations
(G151R and L168R) in KCNJ5, encoding an inwardly
rectifying potassium channel (Kir 3.4), in eight of 22 aldosterone-producing adenomas (APAs) removed from
Swedish patients. In the same report, a third germline mutation (T158A) in KCNJ5 was identified in an American
family with familial, florid PA with severe childhood-onset hypertension, hypokalemia, and markedly elevated alAbbreviations: APA, aldosterone-producing adenoma; ARR, aldosterone/renin ratio;
AT1RAA, agonistic autoantibodies against angiotensin-II type-1 receptor; AVS, adrenal
venous sampling; BAH, bilateral adrenal hyperplasia; CT, computed tomography; FST,
fludrocortisone suppression testing; miRNA, microRNA; mTOR, mammalian target of rapamycin; NT-proBNP, N-terminal probrain natriuretic peptide; PA, primary aldosteronism;
RSST, recumbent SST; SSST, seated SST; SST, saline suppression testing; TASK-2, TWIKrelated acid-sensitive K⫹ channel 2.
J Clin Endocrinol Metab, January 2015, 100(1):1–10
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Update in Primary Aldosteronism
dosterone and hybrid steroid (18-hydroxy- and 18oxo-cortisol) levels, which, unlike in glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type I),
was not glucocorticoid-suppressible. Resected adrenals
(the hypertension could not be controlled with medications, including spironolactone) were grossly enlarged and
showed marked, diffuse hyperplasia of the zona fasciculata (2). Subsequently, several groups confirmed the presence of somatic KCNJ5 mutations with a prevalence of
approximately 40% of APAs among Caucasian patients
(3– 6) and even higher in Japanese patients (7). Patients
with APAs bearing these mutations have shown a female
predominance and younger mean age than those with nonmutated tumors (1, 3– 8), with a tendency to more severe
PA (1, 5–7), unresponsiveness of plasma aldosterone to
upright posture (4), and larger tumors (3, 4) composed
predominantly of cells resembling zona fasciculata (9).
In vitro, reported KCNJ5 mutations are almost always
located within the selectivity filter and associated with loss
of selectivity of the mutated Kir 3.4 channels to potassium,
with enhanced sodium conductance predisposing to cell
membrane depolarization, influx of calcium, and ultimately stimulation of aldosterone synthesis (1, 3, 6,
9 –11). How they lead to adrenal cell proliferation and
tumor development remains less well understood and a
fascinating area of ongoing research (12).
Among reported families with germline KCNJ5 mutations, severity of phenotype has varied considerably from
mild PA readily treated with spironolactone with adrenals
of apparently normal morphology on computed tomography (CT) to very florid PA requiring bilateral adrenalectomy yielding massively enlarged adrenals, and appears
to be at least partly related to the KCNJ5 mutation genotype (1, 2, 10, 13–15). Surprisingly, G151E-mutated
channels, which tend to be associated with a milder clinical phenotype, showed markedly higher (more abnormal)
sodium conductance and conferred greater lethality to
transfected HEK 293T cells than G151R-mutated channels associated with a much more florid phenotype. This
increased lethality may explain the lack of adrenal hyperplasia occurring clinically in patients bearing germline
G151E (vs G151R) mutations (14).
In a study of 251 Caucasian subjects with PA, we identified three heterozygous missense mutations (R52H,
E246K, and G247R) and found that 12 subjects (5% of the
cohort) were carriers for the rare nonsynonymous single
nucleotide polymorphism rs7102584 causing E282Q substitution (16). Unlike previously described mutations associated with PA, these three mutations and rare polymorphism were all remote from the potassium channel
selectivity filter. In vitro studies showed R52H, E246K,
and E282Q (but not G247) substitutions to be functional,
J Clin Endocrinol Metab, January 2015, 100(1):1–10
affecting the inward rectification, the ability of the Kir 3.4
channels to conduct Na⫹ currents, and angiotensin II-induced aldosterone release from the H295R cell line (16).
Hence, germline variation in the KCNJ5 gene may have a
role to play in the common sporadic form as well as the
much rarer syndromic forms of PA.
Somatic mutations within APAs have since also been
described in ATP1A1 (encoding the ␣-subunit of Na⫹/K⫹
ATPase), ATP2B3 (encodes a Ca2⫹ ATPase calcium channel), and CACNA1D (encodes a voltage-gated calcium
channel), but with much lower frequency (8, 17–20). As
with KCNJ5 mutations, in vitro studies suggest that these
mutations also lead to zona glomerulosa cell membrane
depolarization, resulting in increased aldosterone production (17–20). Unlike patients with KCNJ5-mutated APAs,
however, those with APAs carrying the newer mutations
have tended to be more commonly males (17, 19), with
smaller APAs (8, 19) containing predominantly zona glomerulosa-like cells (19).
Pathophysiology
Several groups of investigators have recently begun to shed
some light on the molecular pathways that may be involved in the development of PA. Lenzini et al (21) reported blunted expression of the TWIK-related acid-sensitive K⫹ channel 2 (TASK-2) gene in APAs compared with
normal adrenal cortex. H295R adrenocortical cells transfected with a TASK-2 dominant-negative mutant construct showed increased aldosterone production and expression of the genes encoding aldosterone synthase
(CYP11B2) and the steroidogenic acute regulatory protein. Two microRNAs (miRNAs), hsa-miR-23 and hsamiR-34, the expression of which was shown to negatively
correlate with that of TASK-2 in APAs, were found to
decrease TASK-2 expression by binding to the 3⬘ untranslated region of the TASK-2 gene. These data suggest that
lower expression of the TASK-2 channel in APA cells,
perhaps induced by miRNAs, could contribute to excessive aldosterone secretion in human PA.
Robertson et al (22) investigated further the role of
miRNA in APA development. Knockdown of Dicer1, a
key enzyme in miRNA maturation, significantly enhanced
CYP11B1 and CYP11B2 expression in H295R cells, suggesting a regulatory role for Dicer-dependent miRNAs. In
vitro manipulation of one of these (miR-24, which was
down-regulated in APA vs normal human adrenal cortex)
confirmed its ability to modulate CYP11B1 and CYP11B2
expression, as well as cortisol and aldosterone production.
If specificity to CYP11B2 could be conferred, adrenal
doi: 10.1210/jc.2014-3663
miRNA may therefore be a therapeutic target for the treatment of PA.
Berthon et al (23) reported constitutive activation of
WNT/␤-catenin signaling, possibly due to decreased expression of the WNT inhibitor SFRP2, to be present in
70% of APAs and postulated that this may be an important step in APA development. In support of this, mice
lacking Sfrp2 demonstrated increased aldosterone production and ectopic differentiation of zona glomerulosa
cells. Furthermore, in vitro studies in H295R cells revealed
a role for ␤-catenin to play in the control of both basal and
angiotensin II-induced aldosterone secretion by activating
AT1R, CYP21, and CYP11B2 transcription. The authors
concluded that aberrant WNT/␤-catenin activation is associated with APA development and that the WNT pathway may be worth considering as another therapeutic target in PA.
The role of the phosphoinositide 3-kinase/protein kinase B (or AKT)/mammalian target of rapamycin (mTOR)
signaling pathway (involved in tumor development and
metastasis in adrenocortical carcinoma, pheochromocytoma, and many other human tumors) in the pathogenesis
of PA was assessed by Su et al (24). Compared with normal
zona glomerulosa, the levels of phospho-AKT, phosphomTOR, phospho-S6, and vascular endothelial growth factor were significantly up-regulated in APA and hyperplastic adrenal cortex from patients with PA. No significant
differences in the expression of these proteins were found
between APA and hyperplasia. The mTOR inhibitor rapamycin inhibited both cell proliferation and aldosterone
production by H295R cells. The authors concluded that
the phosphoinositide 3-kinase/AKT/mTOR signaling
pathway may mediate aldosterone hypersecretion and
contribute to the development of PA.
Two groups have recently studied the potential role for
agonistic autoantibodies against the angiotensin-II type-1
receptor (AT1RAA) in PA. Rossitto et al (25) found titers
of AT1RAA to be higher in both PA patients (n ⫽ 46; 26
with APA, 20 with bilateral PA) and essential hypertensive
patients (n ⫽ 62) than in normotensive subjects (n ⫽ 45).
The titer was higher in patients with APA than in bilateral
PA and appeared to allow discrimination of these two PA
subtypes by receiver operator characteristics curve analysis. Plasma aldosterone concentrations fell more in
AT1RAA-positive than AT1RAA-negative PA patients in
response to captopril, in keeping with an agonistic role for
these autoantibodies. In a smaller but more detailed analysis by Kem et al (26), sera from each of 13 patients with
PA (three APA, two bilateral, and eight with indeterminate
subtype) significantly increased angiotensin-II type-1 receptor (AT1R) activation in AT1R-transfected HAC15
adrenocortical cells compared with 20 control subjects,
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and this activity was inhibited by the selective AT1R
blocker losartan. Both sera and IgG purified from
AT1RAA-positive sera demonstrated vasoconstrictive effects in isolated rat cremaster arterioles (again blocked by
losartan), and the IgG stimulated basal and angiotensininduced aldosterone production by HAC15 cells (blocked
by candesartan). These suggest the possibility that, at least
in some individuals, the acquisition of antibodies directed
against and capable of activating AT1R may contribute to
the development of PA.
Non-Blood Pressure-Dependent Adverse
Effects of Aldosterone Excess: Evidence
Continues to Mount
Numerous published studies have demonstrated aldosterone excess to have adverse cardiovascular and renal effects that are at least partly independent of its effects on
blood pressure and that appear to be reversible with specific treatment directed against aldosterone excess (27–
32). Savard et al (33) compared the prevalence of cardiovascular events in 459 patients with PA and 1290 essential
hypertensives matched for sex, age, and office systolic
blood pressure. Patients with PA had a 2-fold greater prevalence of left ventricular hypertrophy (even after adjustment for hypertension duration) and significantly higher
prevalence rates for coronary artery disease, nonfatal
myocardial infarction, heart failure, and atrial fibrillation.
Mulatero et al (34) reported a higher rate of cardiovascular events (and especially strokes and arrhythmias) among
patients with PA (n ⫽ 270) than among essential hypertensives (n ⫽ 810) matched 1:3 in a case control fashion for
blood pressure levels and several other risk factors. This
was the case both for patients with 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 this context, Fischer et al (35) reported mean glucose-induced first
phase insulin secretion to be reduced in a group of 22
patients with PA, compared to that in 11 patients with
essential hypertension, and to improve in nine with APA
after unilateral adrenalectomy, suggesting a negative effect of aldosterone excess on pancreatic ␤-cell function.
Su et al (36) reported magnetic resonance imaging evidence of increased myocardial fibrosis and stiffening
among 25 patients with PA vs 12 age-matched normotensive controls. Using magnetic resonance imaging to measure aortic distensibility, Mark et al (37) reported that PA
patients (n ⫽ 14) displayed increased arterial stiffness
compared with matched essential hypertensives (n ⫽ 33).
Lin et al (38) found plasma procollagen levels to be higher
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Update in Primary Aldosteronism
and cyclical variation of integrated backscatter (a marker
of left ventricular systolic function) on echocardiography
to be lower among 20 patients with APA compared to 20
with essential hypertension. Parameters improved in the
APA group after adrenalectomy. These investigators also
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 (39). 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 (40) found that the degree of reduction in left ventricular mass was independently predicted
not only by change in systolic blood pressure but also by
pretreatment plasma aldosterone levels, further supporting a role for aldosterone in promoting left ventricular
hypertrophy that is independent of the hypertension-related hemodynamic load.
Detection and Diagnosis of PA: What’s
New?
Although still regarded as the most reliable available
screening test for PA, the plasma aldosterone/renin ratio
(ARR) can be affected, and results thereby can be confounded by many factors (41), indicating a need for improved approaches. Pizzolo et al (42) reported on the use
of N-terminal probrain natriuretic peptide (NT-proBNP)
measurement as an adjunct to the ARR. Among 132 hypertensive subjects who underwent ARR testing, 81 with
high ARR underwent iv 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 (42).
In patients who screen positive for PA, confirmatory
testing is necessary to definitely confirm the diagnosis before proceeding to adrenal venous sampling (AVS) to differentiate unilateral, surgically correctable forms of PA
from bilateral forms usually treated medically. Four confirmatory tests are commonly used, 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 (43), but it is cumber-
J Clin Endocrinol Metab, January 2015, 100(1):1–10
some, difficult to perform, and relatively expensive, requiring hospital admission for several days. Gouli et al
(44) recently reported on a modified form of the test in
which 1 mg of dexamethasone was administered on the
last day of the FST to eliminate any stimulatory effect of
endogenous stress-induced adrenocorticotropin on aldosterone secretion, a recognized confounder of test results
(43). Westerdahl et al (45) recently reported captopril
challenge testing to have poor discriminatory power for
PA in hypertensive patients with high basal ARR. We previously found SST, performed in the recumbent position,
to lack sensitivity for PA, missing most patients (including
those with APA) who tested positive by FST (46). Willenberg et al (47) similarly found SST to lead to greater suppression of plasma aldosterone than FST. Because aldosterone levels can be higher upright (eg, seated) than
recumbent in patients with PA and upright levels are used
during FST, we 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 AM basally and after 4 d of fludrocortisone 0.1
mg every 6 h and oral salt loading) and SST (aldosterone
levels measured basally at 8 AM and after infusion of 2 L
normal saline over 4 h), both recumbent and seated in
randomized order, FST confirmed PA in 23 patients, excluded PA in three, and was originally “inconclusive” in
five (48). However, one patient with inconclusive FST had
PA confirmed by lateralizing AVS and was reclassified
“unilateral PA.” Of the 24 with confirmed PA (eight unilateral, 11 bilateral, and five undetermined subtype), 23
(96%) tested positive by SSST compared to only eight
(33%) by RSST (P ⬍ .001) (Table 1). RSST missed one
unilateral, all 11 bilateral, and four with as yet undeterTable 1. Comparison of Results of SSST vs RSST in 24
Patients With Confirmed PA
Total patients with PA
Unilateral PA
Bilateral PA
PA subtype yet
to be determined
Posture-responsive
Posture-unresponsive
n
SSST
Positive
RSST
Positive
24
8
11
5
23 (96)**
8 (100)
10 (91)**
5 (100)*
8 (33)
7 (88)
0 (0)
1 (20)
14
10
13 (93)**
10 (100)
1 (7)
7 (70)
Data are expressed as number or number (percentage). Postureresponsive denotes plasma aldosterone responsive to upright posture
(levels measured at 1000 AM after 3 hours of upright posture at least
50% higher than those measured basally at 7 AM after overnight
recumbency). Posture-unresponsive denotes plasma aldosterone
unresponsive to upright posture (upright levels less than 50% higher
or lower than recumbent).
* P ⬍ .01; and ** P ⬍ .001 vs RSST.
doi: 10.1210/jc.2014-3663
mined subtype. RSST was positive in seven of 10 (70%)
posture-unresponsive vs one of 14 (7.1%) posture-responsive patients (P ⬍ .005). Clearly, larger studies are required, but 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, yet much simpler, cheaper, and quicker
alternative to FST.
Subtype Differentiation
Currently, the only reliable way to differentiate unilateral
(mainly APA) from bilateral PA and to lateralize APAs
preoperatively is by adrenal venous sampling (AVS).
However, 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 (judged by adrenal/
peripheral venous cortisol gradients) (49, 50). Rapid,
point-of-care cortisol assays can alert the proceduralist, at
the time of AVS, whether adrenal venous blood has been
successfully obtained, and have also resulted in higher success rates in centers using this technique (51–53). We previously reported on the use of CT to localize the right
adrenal vein before AVS (46, 54). The use of CT during
angiography to determine correctness of catheter placement was recently reported by two groups to lead to catheter repositioning in approximately 10% of patients and
to be associated with achievement of high (⬎90%) rates of
successful cannulation (55, 56). Improved success rates
have also been reported with the use of ACTH stimulation
during AVS (57, 58). Presumably, at least in some of these
instances, cannulation had already been achieved but was
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 et al (58), the use of more stringent (for
example, adrenal/peripheral venous cortisol gradients
of ⬎ 3.0 basally and ⬎ 4.0 post-ACTH) criteria for
cannulation proved critical for optimizing pre- vs postACTH diagnostic reproducibility.
Traditional AVS provides information about the relative degree of aldosterone production by an entire adrenal
gland vs the other gland. In a recent advance, Japanese
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workers have reported on the use of superselective AVS
that has the ability to sample different branches of the
adrenal vein and thereby compare aldosterone production
by different regions within a gland (59, 60). In this way, it
has been possible to localize small aldosterone-producing
lesions with sufficient resolution to permit their removal
by partial, rather than total unilateral, adrenalectomy (59,
60). Although this may only seem clinically relevant for a
minority of patients with PA (for example, those suspected
as having bilateral APAs, or who have only one functioning adrenal that may contain an APA, who otherwise
would require steroid replacement therapy postoperatively), it nevertheless represents a promising new approach with potentially wider future applications.
Once considered a rarity, autonomous tumorous cosecretion of cortisol has been recently reported by two
groups to be relatively common (⬎10%) among patients
with APA, even in the absence of obvious clinical features
of Cushing syndrome (“subclinical Cushing syndrome”)
(61, 62). This has implications not only for perioperative
management with the need, at least in some patients, to
consider glucocorticoid replacement, but also for interpretation of AVS results. Cosecretion of cortisol would be
expected to raise cortisol levels in the adrenal vein draining
the APA (thus lowering the ipsilateral aldosterone/cortisol
ratio), while causing chronic suppression of ACTH and
thus lowering of cortisol secretion by the contralateral
gland (thus raising the contralateral aldosterone/cortisol
ratio and lowering the adrenal/peripheral venous cortisol
ratio). This could result in loss of lateralization (and a lost
opportunity to offer potentially curative surgery) or give
the impression that cannulation had failed on the contralateral side (and thereby lead to inappropriate consideration for repeat AVS). One potential solution to this
problem is the measurement of an alternative, nonACTH-dependent adrenal hormone to cortisol. Dekkers
et al (63), for example, found measurement of plasma
metanephrine during AVS to be superior to measuring
cortisol in assessing success of cannulation, with adrenal/
peripheral ratios 6-fold higher among procedures deemed
to be successful according to cortisol criteria. Baba et al
(64) reported catecholamine levels to be useful for judging
not only cannulation success but also lateralization.
The search for reliable alternative approaches that are
less costly, invasive, and technically demanding than AVS
has been ongoing in recent years but has met with limited
success. A clinical prediction score developed by Küpers et
al (65), who reported the 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, was found to
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Update in Primary Aldosteronism
be much less reliable when applied to patients within the
German Conn’s Registry (66), except in those under 40
years of age. Sze et al (67) also found the clinical prediction
score to have a lower specificity (88%) among a UK cohort
of patients with PA and were unable to show superiority
over an imaging-based strategy. Other more 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
131
I-6␤-iodomethyl-norcholesterol (NP-59) single photon
emission CT/CT (68) and 11C-metomidate positron emission tomography/CT (69).
Studies attempting to assess (including by receiver operator characteristics analysis) and validate approaches to
distinguishing unilateral from bilateral PA have been challenged by the lack of a robust “gold standard” for diagnosing APA. The blood pressure response to surgery, for
example, may be incomplete if the patient is studied too
soon after adrenalectomy or has other causes of residual
hypertension. The response to surgery of plasma aldosterone plus or minus renin levels and the ARR is better, but
it is still imperfect because 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
postoperatively (70), but, as mentioned above, this is time
consuming, cumbersome, and expensive to perform.
Demonstration of an adenoma in surgically removed adrenals does not prove that it was actually producing aldosterone, and reliance on this would have the potential to
misclassify unilateral PA due to micronodular hyperplasia
as bilateral PA. Recent studies have reported on the use of
immunohistochemical staining of resected adrenals in an
attempt to confirm APA removal (71–75). Using isoformspecific monoclonal antibodies against the 3␤-hydroxysteroid dehydrogenase/isomerase family, Doi et al (71) reported hyperplasia of zona glomerulosa seen in bilateral
PA to be accompanied by a robust expression of the
HSD3B1 isoform. In contrast, tumor cells in APA were
immunonegative to HSD3B1 but showed expression of
HSD3B2. Volpe et al (72) found APAs to show strong
immunoreactivity for aldosterone synthase. In adrenals
from a significant minority of patients, they found either
“adenomas” (presumably defined as adrenocortical tumors of at least 1 cm in diameter) that were not CYP11B2
positive or no adenoma at all, but they found smaller nodules with strong CYB11B2 immunoreactivity, indicating
aldosterone-producing nodular hyperplasia. Nanba et al
(73), 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 CYP11B2-negative adenomas
(n ⫽ 4) or without tumors on CT to show aldosterone-
J Clin Endocrinol Metab, January 2015, 100(1):1–10
producing cell clusters with CYP11B2 immunostaining in
the zona glomerulosa. 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 (11␤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. High-quality antibodies produced in the laboratory of Celso Gomez-Sanchez (University of Mississippi)
have also been used to demonstrate correlations between
the degree of expression of CYP11B2 in APAs and preoperative plasma (and urinary) aldosterone levels (74). In
addition, this group has shown expression levels to be
similar in zona glomerulosa within normal adrenals and in
those removed from patients with PA due to BAH (and
cited increased expression of upstream enzymes to be a
possible explanation for the greater aldosterone production in the latter group), but lower in that in zona glomerulosa adjacent to an APA (75), consistent with suppression of aldosterone production.
Importance of Subtype Differentiation
For both cardiovascular outcomes (76 –78) and quality of
life (79, 80), 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. In
a prospective study of 54 patients with PA who were
treated by adrenalectomy (n ⫽ 24) or with spironolactone
(n ⫽ 30), Catena et al (76) reported left ventricular mass
to have decreased significantly by 1 year of follow-up only
in adrenalectomized patients. Although overall change
from baseline to the end of a mean of 6.4 years of follow-up was comparable in the two groups, there remains
the possibility that the apparent delay in benefit afforded
by medical (over surgical) treatment could translate to less
impressive reductions in cardiovascular morbidity and
mortality. A nationwide epidemiological study conducted
in Japan, which analyzed data from 1706 patients with
PA, found that among those with APA, surgical, but not
medical, treatment was significantly associated with amelioration of hypertension (81). By contrast, among patients with hyperplastic forms of PA (mostly BAH), there
was no relationship between either surgical or medical
treatment and the prognosis of hypertension. In an observational study reported by Reincke et al (82) on 300 patients with PA, adrenalectomy (presumably mostly for
unilateral PA) was associated with reduced all-cause mortality when compared with medical treatment.
doi: 10.1210/jc.2014-3663
Toward High-Quality Assay Development
Screening, confirmation, and subtype differentiation of
PA are all dependent on accurate measurement of plasma
aldosterone, and because the ARR is predominantly renindependent, it is critical that the methods used to assay
aldosterone and renin in clinical samples are of high quality. The recent push for using automated platforms and
immunometric methodology has been primarily on the
basis of faster throughput and lower cost and potentially
at the expense of lower reliability. In 2009, we reported on
the development of a high-throughput, highly accurate,
and reproducible method of measuring plasma aldosterone using HPLC and tandem mass spectrometry (LCMS/MS) (83). Since then, several other investigators have
established similar assays for aldosterone (84, 85), and at
least two groups have developed assays that use LCMS/MS to measure angiotensin I and thereby determine
plasma renin activity (86, 87). The hope for incorporation
of tandem mass spectrometry (LC-MS/MS) technology
into routine clinical laboratory practice for measuring aldosterone and renin (or alternatively angiotensin II, with
implications for the development of aldosterone/angiotensin II ratio testing as a new and possibly superior
screening approach) now appears to be well within reach.
New Approaches to Treatment
The mainstays of treatment for PA continue to be unilateral adrenalectomy for most patients with unilateral forms
and medications that antagonize aldosterone action (for
example, spironolactone 12.50 –50 mg daily, eplerenone
25–100 mg daily, or amiloride 2.5–20 mg daily) for most
with bilateral 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 (88, 89),
which offers superior cosmetic results to multiple incision
approaches but requires further experience to establish its
value from a risk vs benefit perspective.
On the medical front, a randomized, open-label,
blinded end-point study involving 34 patients with BAH
reported in 2009 by Karagiannis et al (90) found eplerenone and spironolactone to be of similar efficacy in reducing blood pressure. Conversely, a more recent 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 and 75–
225 mg, respectively) in patients with PA found spironolactone to be superior in terms of blood pressure lowering,
but to be associated, as expected, with higher rates of male
jcem.endojournals.org
7
gynecomastia (21 vs 5% for eplerenone) and female mastodynia (21 vs 0%) (91). Aldosterone synthase inhibitors
remain a promising treatment approach, although a recent
study showed that in patients with PA, the effects of eplerenone treatment (50 –100 mg twice daily) on blood pressure, plasma potassium, and renin were more marked than
those of 4 weeks of treatment with the aldosterone synthase inhibitor LCI699 (0.5–1 mg twice daily) (92). An
ongoing concern for these new drugs is the potential for
inhibiting cortisol production in addition to that of
aldosterone.
Nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists (93, 94) are a new drug class that
has displayed similar in vitro potency to spironolactone,
without apparent effects on androgen and progesterone
receptors, and therefore presumably without the same risk
of sex steroid-related side effects. BAY 94 – 8862, the firstin-class of this new generation of drugs, is currently in
development for treatment of heart failure (93), with early
results showing considerable promise (95), and studies in
PA are eagerly awaited.
In both animals and humans, endogenous aldosterone
and dietary salt intake appear to interact to induce targetorgan deterioration. Pimenta et al demonstrated that both
left ventricular mass (96) and degree of proteinuria (97) in
patients with PA were dependent on 24-hour 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 (98). Incorporation
of dietary salt restriction in the management of patients
with PA may therefore help to limit and even reverse target
organ damage and morbidity.
Conclusions
In an exciting time for research into PA, major inroads
have been made into understanding its pathophysiology,
including its underlying genetic bases, with the potential
for development of new treatment modalities. Advances in
approaches to confirmatory testing, subtype differentiation, assay technology, and treatment are helping to enable treating physicians to optimize diagnosis and management for patients with this important condition, with
the promises of reduced morbidity and mortality and improved quality of life.
Acknowledgments
Address all correspondence and requests for reprints to: Michael Stowasser, Hypertension Unit, University of Queens-
8
Stowasser
Update in Primary Aldosteronism
land School of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia.
E-mail: [email protected].
Work performed within the author’s laboratory described
herein was funded by The National Health and Medical Research council of Austrialia, The PA Research Support Scheme,
and the Irene Patricia Hunt Memorial Trust for Hypertension
Research.
Disclosure Summary: The author has nothing to disclose.
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