S P E C I A L F E A T U R E

C o m m e n t a r y

Primary Aldosteronism: Seismic Shifts

John W. Funder
Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia

erome Conn, the father of primary aldosteronism (PA), Before the discussion of all three papers, a review of
J proposed that the syndrome may account for approx-
imately 20% of patients with blood pressure (BP) eleva-
additional background is necessary. Currently, the
5–10% prevalence figure reflects differences in cutoff val-
tion. For decades thereafter, conventional wisdom con- ues for ARR, different normal ranges for plasma aldoste-
sidered PA a rare (⬍1%) and relatively benign form of rone concentration (PAC), plus variability in assay accu-
hypertension, which we now know is not the case. The first racy and reproducibility. Patients with an ARR above the
seismic shift came with the introduction of screening for local cutoff, plus at least modestly elevated levels of PAC,
PA by the aldosterone-to-renin ratio (ARR); on this basis, constitute 10 –20% of hypertension cases, necessitating
followed by confirmatory/exclusion testing, it is now rec- confirmation/exclusion by one of at least five commonly
ognized that PA represents 5–10% of hypertension. used tests, determined by historic local usage and to some
Over the past 5 years, there have been two more major extent by cost. The most expensive test—sometimes called
advances. The first is the demonstration that a variety of the “gold standard”—is the 4-day fludrocortisone plus
somatic—ie, confined to the adrenal cortex—mutations saline test (FST); a diagnosis of PAC is confirmed if after
have been found in what are now most aldosterone-produc- 4 days PAC is not suppressed to very low levels.
ing adenomas. The first, and most common, mutation was Key to understanding the first two of the contributions
that in KCNJ5, a component of the Kir3.4 potassium chan- (3, 4) is their modification of the FST by the addition of 2
nel; subsequently, mutations in Na⫹ and Ca⫹⫹ ATPases, mg of dexamethasone at midnight on the last day of testing
Ca⫹⫹ channels, and ␤-catenin have been described. The ini- to produce a dexamethasone-enhanced fludrocortisone
tial findings have been confirmed and replicated worldwide suppression test (FDST), in recognition that the levels of
(1), ongoing exploration is intense, and the diagnostic and PAC are regulated by ACTH, in addition to plasma [K⫹]
therapeutic aspects are yet to be determined. and angiotensin. In 80 control subjects—normotensive,
The second seismic shift is an increasing body of evi- negative on adrenal screening, standard exclusion crite-
dence that the current figures for the prevalence of PA are ria—the FDST produced a range of PAC values, with the
far too low. This has attracted much less attention than the upper limit of normal set at the 97.5th percentile value of
somatic mutations, which are novel and exciting, as again the group.
challenging received wisdom, always to some extent When the FDST was applied to a group of outpatients
threatening. The mutations are a tour de force of labora- referred to the endocrine clinic for evaluation of thyroid
tory-based molecular medicine; the expanded prevalence, function or osteoporosis, 29 –32% showed PAC levels
in contrast, is the result of demanding clinical studies. above the 97.5 upper limit of normal. Whatever the gen-
Over the past decade, the groundbreaking insights—in- esis, almost one-third of unselected hypertensives appear
cluding those in the paper by Markou et al (2) in this issue to have inappropriate aldosterone secretion independent
of the JCEM— have come from Athens. If the results of of the classic regulators—ACTH, plasma [K⫹], and
that study (2) and the previous studies from Athens (3, 4) angiotensin.
can be generalized, Conn’s figure of approximately 20% History has a habit of repeating itself: there is nothing
will be shown to be a very conservative estimate. new under the sun. Thirty years ago, Helber et al (5) com-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: ARR, aldosterone-to-renin ratio; BP, blood pressure; FDST, fludrocortisone
Printed in USA suppression test; FST, fludrocortisone plus saline test; HYPER, hyper-responsive; MRA,
Copyright © 2015 by the Endocrine Society mineralocorticoid receptor antagonist; PA, primary aldosteronism; PAC, plasma aldoste-
Received July 7, 2015. Accepted July 17, 2015. rone concentration; SSST, seated saline suppression test.

For related article see page 2857

doi: 10.1210/jc.2015-2800 J Clin Endocrinol Metab, August 2015, 100(8):2853–2855 press.endocrine.org/journal/jcem 2853

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2854 Funder PA: Seismic Shifts
pared 24-hour urinary aldosterone levels in response to
sodium loading in normotensives, patients with confirmed
PA, and “essential hypertensives.” Among this latter
group of 100 patients, 36 had urinary aldosterone levels
above the upper limit of the range in control subjects—
10.0 ⫾ 3.0 vs 2.7 ⫾ 1.4 ␮g/d in the remaining 64 essential
hypertensives—and with mean plasma [K⫹] levels of 3.81
vs 4.26 meq/L in the essential hypertensives. Finally, the
36 with higher urinary aldosterone levels and lower
plasma [K⫹] responded to spironolactone by an average
fall in BP of 21 mm Hg, vs 9 mm Hg in the remaining
hypertensives.
The inference from the original FDST studies was that
under the circumstances of testing, ACTH plays a consid-
erable role in raising PAC, which distorts the normal range
of basal, unstimulated aldosterone secretion; thus, many
of the less florid cases of PA are missed because their post-
FST PAC values fall in the upper level of this distorted range.
The paper under review (2) proposes an additional role for
ACTH in the genesis of another, distinct cohort of patients
with inappropriate aldosterone secretion—patients who are
hyper-responsive (HYPER) to low levels of ACTH stimula-
tion. The data are impressive, and the authors’ conclusions
do not appear explicable on any other basis.
Briefly, the entire cohort (113 hypertensive subjects, 61
normotensive controls) underwent baseline clinical eval-
uation and blood sampling. This was followed in order by
an ultra-low (0.03 ␮g) ACTH test on day 2 and a treadmill
test on day 3. The FDST test was then administered on
days 4 –7, and on day 8 the post-FDST levels of aldoste-
rone, cortisol, renin, and ACTH were determined. The
97.5th percentile in control subjects (PAC, 47 ␮g/dL;
ARR, 2.7 ␮g/dL/␮U/mL) was taken as the cutoff after
ultra-low ACTH; of the 113 hypertensive subjects, 83 had
values below this cutoff, and 30 (HYPER, 27%) had val-
ues for PAC and ARR above. When cortisol and aldoste-
rone levels were determined after treadmill exercise (to
80% of age-adjusted maximal pulse rate), the hyper-re-
sponders to ACTH showed a highly significant elevation
of PAC over the remaining 83 “essential hypertensives”
and control subjects; levels of ACTH and cortisol in all
three groups were indistinguishable.
Given the authors’ previous studies demonstrating that
29 –32% of hypertensives have an FDST response above
the normal control levels, they suggest that a total of ap-
proximately 60% of hypertensive patients have inappro-
priate secretion of aldosterone as a major contributor to
their elevated BP. Before discussing this possibility, there
are several other aspects of the present study that are wor-
thy of comment.
First, in 26 subjects (presumably, but not explicitly)
drawn from the group of 113 hypertensives as a whole,
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J Clin Endocrinol Metab, August 2015, 100(8):2853–2855
genetic studies were undertaken. No instance of familial
hyperaldosteronism type 1 (CYP11B1/CYP11B2 chi-
mera) was found. In contrast, two of the 26 patients are
reported to harbor a heterozygous germline mutation in
the KCNJ5 gene. Both were in the HYPER group; each
showed a previously undocumented germline mutation
(V259M, Y34IN); both had baseline systolic BP of 150 –
160 mm Hg and diastolic BP of 85–90 mm Hg; both were
normokalemic (plasma [K⫹], 4.1– 4.2 meq/L; but with rel-
atively high urinary K⫹ levels, 78 and 91 meq/24 h). It
would be of interest to know how many of the 26 subjects
tested were in the HYPER group and whether examina-
tion of their relatives is to be undertaken.
Second, the authors appropriately highlight the re-
sponse to mineralocorticoid receptor antagonists (MRAs)
among their 30 HYPER subjects. In this group as a whole,
BP fell markedly, from a basal value of 154/92 mm Hg
(Table 1 in Ref. 2; 155/92 mm Hg) to 124/77 mm Hg. In
25 of the 30 hyper-responders, MRAs as monotherapy
(spironolactone, 12.5–100 mg/d; median, 50 mg/d in 18 of
25; eplerenone, 25–100 mg/d; median, 100 mg/d in seven
of 25) were sufficient. In five subjects, addition of a cal-
cium channel blocker (three of the five), a beta blocker, or
an angiotensin receptor blocker was necessary.
It would have been useful to parse the group of 30
further and give both baseline and post-medication BP
values for those on monotherapy and those requiring ad-
ditional agents. The choice of a comparator group among
the 83 hypertensives was suboptimal for reasons that are
not clear. The authors chose 22 subjects with average BP
of 134/84 mm Hg (in contrast with the group as a whole,
baseline BP of 152/90 mm Hg) on MRAs as monotherapy,
their BP “rebounded” to 143/88 mm Hg. A cleaner com-
parison would have been made by choosing a group of
essential hypertensives with baseline BP equivalent to the
HYPER group; the patients chosen do not vitiate the im-
pressive BP-lowering effect of MRAs in the HYPER group,
but they leave open the question of a (probably) lesser
effect in essential hypertensives.
As acknowledged by the authors, there is clear evidence
for a major effect of eplerenone titrated to effect on BP in
a majority of essential hypertensives (6). In subjects with
PA excluded on criteria current more than a decade ago,
eplerenone at 50/100/200 mg/d as monotherapy lowered
BP to below the goal (⬍90 mm Hg diastolic BP) in 44, 61,
and 80%, respectively. This was then, and continues to be,
attributed to antagonizing a major role in mineralocorti-
coid receptor activation not by aldosterone but by normal
levels of cortisol, acting as a mineralocorticoid receptor
agonist in the context of hypertension-induced tissue dam-
age. Such essential hypertensives may well have included
patients with PA on the FDST and hyper-responders in the
doi: 10.1210/jc.2015-2800 press.endocrine.org/journal/jcem 2855

study under review; the authors’ claim of approximately paper; subjects should include both sexes (no reference is
60% total, on median daily doses of 50 mg spironolactone made to gender in the study under review [Ref. 2]). When
or 100 mg eplerenone, is essentially identical to the figure validated, attention should focus on ACTH as the secre-
of 61% for 100 mg/d eplerenone in the dose-titration tagogue appearing to compromise current confirmatory
study. testing, and on the mechanism(s) whereby it elicits an ex-
One final question remains—that of a possible overlap aggerated aldosterone response in a substantial minority
between the two groups, the PA post-FDST and the hyper- of patients otherwise classified as essential hypertensives.
responders. In the present study, all the patients are stated
to have “. . . normal aldosterone suppression post-FDST
and normal adrenal computerized tomography.” In the Acknowledgments
following paragraph, “the diagnosis of PA was based on
Address all correspondence: Professor John W. Funder, Hudson
the combination of a post-FDST ARR ⱖ 26 pmol/mIU, Institute of Medical Research, 27–38 Wright Street, Clayton,
and post-FDST aldo ⱖ 82 pmol/L.” This cutoff value for Victoria 3168, Australia. Email: john.funder@hudson.org.au.
PAC is 3 mg/dL; the values for PAC post-FDST in Table 1 This work was supported by the Victorian Government’s Op-
(Ref. 2) are 2.8 ⫾ 1.8 (SD) for hyper-responders, 2.4 ⫾ 1.3 erational Infrastructure Support Program.
for essential hypertensives, and 1.7 ⫾ 0.6 mg/dL for nor- Disclosure Summary: The author has nothing to disclose.
motensive controls. At least for the hyper-responders, it is
difficult to see how such a mean ⫾ SD value does not
include a substantial minority with PAC ⬎ 3 mg/dL, who References
on the cutoff proposed levels have PA. They may be
1. Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP.
“saved” from the diagnosis of PA on the basis of their ARR A meta-analysis of somatic KCNJ5 K⫹ channel mutations in 1636
values after FDST, given that elevations of both are patients with an aldosterone-producing adenoma [published online
deemed necessary for a diagnosis of PA. In this context, it June 11, 2015]. J Clin Endocrinol Metab. doi:org/10.1210/jc.2015–
2149.
would be interesting to know the lower limit of the renin 2. Markou A, Sertedaki A, Kaltsas G, et al. Stress-induced aldosterone
assay. hyper-secretion in a substantial subset of patients with essential hy-
None of the above commentary detracts from the im- pertension. J Clin Endocrinol Metab. 2015;100:2857–2864.
3. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hy-
pact and potential importance of the findings in the paper peraldosteronism in resistant hypertension: a retrospective obser-
under review (2). Like all novel findings, they need to be vational study. Lancet. 2008;371:1921–1926.
independently replicated; given the nature of the FST/ 4. Gouli A, Kaltsas G, Tzonou A, et al. High prevalence of autonomous
aldosterone secretion among patients with essential hypertension.
FDST, additional studies might usefully compare the Eur J Clin Invest. 2011;41:1227–1236.
seated saline suppression test (SSST) (7) with a dexameth- 5. Helber A, Wambach G, Hummerich W, Bönner G, Meurer KA,
asone-enhanced SSST to establish range and cutoffs in Kaufmann W. Evidence for a subgroup of essential hypertensives
with non-suppressible excretion of aldosterone during sodium load-
both controls and hypertensives. The latter might be
ing. Klin Wochenschr. 1980;58:439 – 447.
screened de novo, in higher probability subjects, or rou- 6. Levy DG, Rocha R, Funder JW. Distinguishing the antihypertensive
tinely after ARR to compare with the previous findings. and electrolyte effects of eplerenone. J Clin Endocrinol Metab. 2004;
Hypertensives who do not have PA on the dexametha- 89:2736 –2740.
7. Ahmed AH, Cowley D, Wolley M, et al. Seated saline suppression
sone-enhanced SSST should then undergo an ultra-low testing for the diagnosis of primary aldosteronism: a preliminary
ACTH test, again to compare with findings in the present study. J Clin Endocrinol Metab. 2014;99:2745–2753.

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