Key words
somatic mutations - screening - lateralization - public health - health policy
Background
The initial invitation to contribute to PiPA6 was flattering but implausible
– as final speaker, to review the previous presentations (37 orals, 24
posters). To do them justice would take at least a week, in itself a Sisyphean task:
in 25 min, impossible. The organizers responded generously to my protests,
and we settled amicably on the above title. A number of presentations at PiPA 6 have
informed both questions posed by the title: many were in the area of benchtop
discovery science, with others translational and clinical. As was only tangentially
addressed were the public health issues around primary aldosteronism, covered in
some detail in ‘Where to from Here?’.
Current obstacles to optimal management of PA and possible remedies for obstacles
to
current management are outlined in [Table
1].
Table 1 Current obstacles to optimal management of PA and
possible remedies.
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Current Obstacles to optimal management of PA are
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Reluctance of G.P.s to refer candidate patients, given
the complexity of current screening and the costs of
confirmatory tests, imaging, adrenal venous sampling (in
particular), plus or minus surgery.
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Possible Remedies for obstacles to current management
include
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These advances represent at best marginal advances in management,
which needs radical disruption. Disruption requires empowering
general practice, as follows.
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If older, moderate UA/BP elevation, normokalemic:
include low-dose MRA with standard antihypertensives:
watch and wait, PRC/PRA after 6 months.
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If young, high UA, high BP, hypokalemic,
↓↓renin – refer to expert
center.
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‘Where Are We Now?’, were it to be broken down into basic and
clinical, would merit 4.5/5 for the former and a very generous 1.5/5
for the latter: in terms of the policy issues needed to address the public policy
lacuna it scores a resounding 0/5. First, inevitably, is the good news. Over
the past nine years we have witnessed major breakthroughs in the molecular
mechanisms underpinning primary aldosteronism: not yet complete, more to come, but
the future looks bright. The last nine years have been revolutionary in terms of
discovery – a variety of somatic mutations underpinning aldosterone
producing adenomas (APA); expansion of hyperaldosteronism (FH) familiar to FH-II,
FH-III, and FH-IV to join the time honored FH-I; recognition of aldosterone
producing cell clusters (APCCs) largely replacing the zona glomerulosa with age, and
somatic mutations thereof almost certainly underpinning bilateral adrenal
hyperplasia, at least to a major extent if not totally.
2011: What Started the Ball Rolling?
2011: What Started the Ball Rolling?
The trigger for this cornucopia was a study from the Lifton laboratory on a series
of
large APAs from around the world. The authors found that 8/22 had one of two
somatic mutations (6 L168R , 2 G151R ) in the gene encoding KCNJ5, a component of
the Kir1.3.4 potassium channel [1]. The dam
broke: within the same year (2011) at least five corroborative studies were
submitted for publication, which extended and refined several aspects of the first
[2]
[3]
[4]
[5]
[6]. A corollary of the initial study was the
recognition that a previously described [7]
fulminating version of BAH, necessitating bilateral adrenalectomy in the father and
two infant daughters, reflected a germ-line mutation in KCNJ5 – and
so the second cause of familial hyperaldosteronism was established as FH-III. FH-II,
of which more later, described kindreds of up to five generations with primary
aldosteronism, and with – at the time – no known genetic cause [8].
…And it Kept Rolling
Somatic mutations in KCNJ5 in Caucasian populations represent
35–40% of all APA, with a clearly higher incidence in women than
men; in Japan and China the overall percentage of KCNJ5 mutations is reported
as 65–80% [9]
[10]. A series of additional somatic mutations
was rapidly defined – in CACNA1D, CACNA1H, ATP1A1,
ATP2A3, CTNNB
[ [11]
[12]
[13]
[14]
[15] – and more recently CNCL2,
now recognized as causing FH-II [16]
[17]: it should be noted that this covered
some but not all of the kindred previously studied. Since these initial discoveries,
the percentage of APAs classified as ‘wild type’ – like
essential (or primary) hypertension an admission of ignorance – shrank to
<10% reflecting technical improvements with identification of
CYPIIB2 expressing cells by antibody staining of sections, and next generation
rather than Sanger sequencing. Very recently, somatic mutations in CACNA1H
[18] have been found in three of 75 patients
undergoing next generation sequencing of CYP11B2 positive cells from APAs, further
reducing the percentage of ‘wild type’ APAs.
On the basis of these data clear patterns have emerged, in terms of the different
prevalence of the various mutations.
Yet to be Explained Variation
Yet to be Explained Variation
In men, CACNA1D is the most common mutation; in women, as noted earlier, it is
KCNJ5. Patterns between Caucasian [19] and African-Americans [20]
differ significantly: whether Africans from the West Coast of Africa, with
putatively considerably less Caucasian genetic material, are even more different is
to date moot. Some mutations are extremely rare: it thus seems likely that over the
course of the next few years additional somatic mutations will be added to the
present tally of 93–94%: ‘wild type’ is perhaps
better expressed as ‘not yet identified’. One major difference
between KCNJ5 and the other mutations is the apparent cell of origin, with
KCNJ5 mutations being in fasciculata-type cells, where CYP11B2 is
co-expressed with CYP11B1, the enzyme responsible for cortisol production.
It is Probably not just APAs
It is Probably not just APAs
The other area in which somatic mutations appear potentially to be causative is that
of bilateral adrenal hyperplasia. In studies on archival material, it was noted not
only that the prevalence of APCCs increased with age [21], but that in material from putatively
normotensive patients some APCC appeared positive for CACNA1D, and to a
lesser extent ATP1A1/ATP2B3 – but not KCNJ5
[22]. There had been a series of suggestions
for a driver of bilateral hypersecretion of aldosterone above and beyond the
physiological stimuli (angiotensin II, elevated plasma [K+],
ACTH) – agonist anti-AT1R antibodies, leptin, etc. The scene
changed radically with the publication of a joint Brisbane/Sendai ANN ARBOR
manuscript, which examined the adrenal unilaterally removed for a variety of
reasons, not all annotated – from patients with bilateral adrenal
hyperplasia [23]. Of 15 specimens one proved
technically lacking; all the other 14 proved to harbor CACNA1D mutations in
some but not all of the APCCs present. All 14 adrenals had at least one, and up to
10, mutation-bearing APCCs. There were a total of 27 different mutations: of which
9
were found more than once, of which one was novel, as were the 18 mutations
occurring only once. Tellingly, the authors found a highly significant correlation
between the number of mutation-bearing APCCs and the previously measured plasma
aldosterone concentration.
Questions yet to be Answered
Questions yet to be Answered
At this stage, to recapitulate. Over the past nine years a series of somatic
mutations have been shown to underpin>90% of APAs, and the
recognition of germline familial hyperaldosteronism (a much less common form of
primary aldosteronism) extended. FH-II is caused by CNCL2 mutation; FH-III by
KCNJ5 mutation, with severity varying with different mutation sites;
FH-IV, very rare, reflecting germline mutations in CACNA1H. Somatic mutations
at this point in time also appear as drivers of bilateral aldosterone secretion:
given the proclivity of KCNJ5 mutations to occur in zona fasciculata cells,
it is perhaps not surprising that they are not found in APCCs. The male prevalence
of CACNA1D mutations, contrasting with that of KCNJ5 in females, and
the different somatic mutation profiles between Caucasians/African
Americans/East Asians remain to be resolved, as does the diminishing
percentage of APAs with a currently unidentified somatic mutations. Whether
CACNA1D mutations can be confirmed to cause FH-V – it certainly
can be germline expressed – and the erstwhile FH-II lineages negative for
CNCL2 mutation shown to be FH-VI - remain to be established.
Advances Elsewhere: PA Remains a Cottage Industry
Advances Elsewhere: PA Remains a Cottage Industry
This is a truly remarkable advance: nothing remotely similar has occurred beyond the
laboratory, in terms of screening, confirmation/exclusion, imaging,
lateralization (or not), surgery (for APA), targeted medical therapy for BAH,
follow-up or, as previously noted, public health. There have been isolated,
incremental advances, most yet to be adopted into the canon. Before detailing these
it needs to be stated front and center that the management of primary aldosteronism,
by expert groups between centers and countries, is the medical equivalent of a
cottage industry. For those not familiar with the term, it harks back to the days
when goods were made in the home, in workshops, ateliers, forges – rather
than made in factories and sold in malls. A present day example might be a dozen
grandmothers baking an apple pie for the church fair – different apples,
plus or minus rhubarb, cinnamon, egg wash, etc. One or two excellent, most not too
bad, one or two not up to scratch. This is PA today: one problem is that it is
orders of magnitude more demanding that making a superior apple pie.
Prescriptive Measures No: Harmonization Yes
Prescriptive Measures No: Harmonization Yes
If one is to take three areas of management – screening, confirmation and
lateralization – the possible variations are mind-numbing. Possible
candidates for primary aldosteronism are screened on the basis of their aldosterone
to renin ratio (ARR). It is true that measurement of plasma aldosterone
concentration and plasma renin activity have advanced over the past decade; what
needs harmonization are the circumstances (on or off anti-hypertensives for
4–6 weeks) of the initial blood draw, the ‘cut offs’ for a
positive ARR (20 or 30), whether the PAC needs to be above a certain value
(14/14.5/15/16 ng/dl) to proceed to
confirmatory/exclusion testing. One of half a dozen such tests are commonly
used – or in some circumstances none; again, the cut-offs vary between
centers in terms of the extent of lowering PAC levels needed to be
‘positive’. Finally, in terms of lateralization,
regular/tailored/super selective adrenal venous catheters; with
cosyntropin (bolus, infusion, bolus plus infusion), without, or both; simultaneous
or sequential catheterization; variation in selectivity index (SI) and
lateralization index (LI); concomitant measurement of bilateral and peripheral
cortisol, androstenedione, or metanephrines…put all this together, and you
don’t get to the grains of rice on the final square of the chessboard
– but you are almost half-way there.
Diagnosis: Towards Uniformity in Confirmatory Testing
Diagnosis: Towards Uniformity in Confirmatory Testing
To date, essentially nothing has been done to simplify screening: a proposal to do
so
forms part of the ‘where to from here’ section. There have been
three advances in the area of confirmation/exclusion. The first is the
emerging consensus that a patient who has clearly florid primary aldosteronism on
the basis of their ARR might be spared confirmatory/exclusion testing and
proceed directly to imaging. The second is the recent development of the seated
saline suppression confirmatory test [24]
[25], results of which align very closely with
the four day sodium and fludrocortisone suppression test, clearly the most laborious
and on occasion termed ‘the gold standard’.
The third are the pioneering studies from Athens underscoring the long-neglected role
of ACTH as an aldosterone secretagogue [26].
When normotensive volunteers underwent a fludrocortisone suppression test, plus
1 mg dexamethasone at 11:00 PM on the last day (FDST), 97.5% of the
72 subjects had a PAC less than 74 pm/l, and an ARR of
32 pm/l/mu/l, thus taken as the normal range. When
hypertensives underwent the same dexamethasone-enhanced fludrocortisone suppression
test, 31% (56/180) had values for both PAC and ARR above the upper
limit of normal. A subsequent study [27] on
113 hypertensives negative on the FDST test divided them into two groups. One
(30/113:27%) proved hyper-responsive (in terms of elevated
aldosterone secretion) to ultra-low dose ACTH/treadmill at 80%
capacity, while the other (83/113:73%) was not different from
normotensive controls: cortisol responses were the same for all three groups.
There is Nothing New Under the Sun: An Example
There is Nothing New Under the Sun: An Example
A step back 40 years. In 1980, a group in Cologne published a study [28] in which patients and controls were
maintained for 6 days on a 175 mEq sodium intake. Control patients responded with
24 h urinary aldosterone levels of
≤6 μg/day. Of 100 ‘essential’
hypertensives 36 showed urinary aldosterone levels above the upper limit of normal.
When patients below the 6 μg/day cut-off were treated with
spironolactone, their blood pressure on average fell by 9 mmHg: in those
above the cut-off it fell by 23 mmHg. The study also included 16 patients
with established primary aldosteronism, whose blood pressure on spironolactone fell
by 21 mmHg. Taken together, these findings suggest that hyperaldosteronism,
whether screened on the basis of hypokalemia or occult, might account for
~45% of hypertension – a figure very close to that suggested
by the two Greek studies [26]
[27].
Even in Normotensives…
The necessity of 24 h urinary aldosterone measurement, rather than a single
spot plasma aldosterone concentration, was recently elegantly underlined by a study
from Boston [29]. In a group of 210
normotensive study subjects, 14% (29/210) were found to have urinary
aldosterone above 12 μg/day, a very generous cut-off given current
sodium intake: only 6/29 of these subjects screened positive for primary
aldosteronism on the basis of their plasma aldosterone to renin ratio. The obvious
inference is that such subjects have primary aldosteronism, presumably engendered
by
episodic stress causing spikes in ACTH secretion. They may well become hypertensive
over time: but hypertension in itself is not a sine qua non for primary
aldosteronism, as demonstrated by a small but convincing study [30] on young subjects, normotensive despite a
definitive diagnosis of familial hypertension type 1.
Parsing Medical Management of Bilateral Hyperaldosteronism
Parsing Medical Management of Bilateral Hyperaldosteronism
A second recent study from Boston [31] broke
new ground in the medical management of bilateral hyperaldosteronism. A number of
previous studies had documented the heightened risk profile of primary aldosteronism
compared with age-, sex-, and blood pressure-matched essential hypertensives. The
first of these [32] from Paris reported
extraordinarily elevated levels (4- to 12-fold higher) for stroke, non-fatal
myocardial infarct and atrial fibrillation: subsequent studies [33]
[34]
[35] have been less apocalyptic, but
reaffirmed lesser but significant differences. The Boston study showed that patients
with an APA resected and biochemically cured post-surgery had a risk profile
slightly better than that in matched essential hypertensives, perhaps not surprising
if some of the ‘essential hypertensive’ controls had low grade
occult primary aldosteronism as previously discussed [29].
The real breakthrough was seen when the bilateral hyperaldosteronism subjects were
divided into two groups – those who at 6 months after starting medical
therapy had a suppressed (<1 ng/ml/h) plasma renin
activity, and those in whom PRA was>1 ng/ml/h, that
is, no longer suppressed. The former group had a ~three-fold higher risk
profile than controls; the latter the same risk profile as controls. There was
tellingly no difference in blood pressure between-groups; the renin suppressed group
received slightly but significantly lower daily doses of MRA: (spironolactone 43 vs.
50 mg; eplerenone 53 vs 65 mg). The authors suggest increasing
spironolactone in patients with suppressed renin: either a modestly lower sodium
diet, or adjuvant amiloride/triamterene, might be more effective, given the
relatively high non-compliance rate of male patients on spironolactone. The key
advance, however, remains: that of measuring plasma renin, activity or
concentration, after six months of medical therapy.
Sixty Years After Spironolactone: A Very New Player
Sixty Years After Spironolactone: A Very New Player
The final, very promising advance has been in the development of generation 3 and
generation 4 mineralocorticoid receptor antagonists (MRAs). If
spironolactone/canrenone/potassium canrenoate represent generation
1, and eplerenone generation 2, then an ideal generation 3 MRA would be
nonsteroidal, with affinity for mineralocorticoid receptors (MR) as high or higher
than that of spironolactone, specificity for MR as high or higher than that of
eplerenone, cheap to make and with a relatively long half-life. A generation 4 MRA
is all of the above, plus tubule sparing, to lessen the risk of hyperkalemia: an
example of this class, targeted to the heart, is finerenone. Given its apparent
tubule sparing, finerenone (and probably the third recently described MRA,
aparerenone) is inappropriate as an MRA for primary aldosteronism. What may be
appropriate is esaxerenone [36], a generation
3 compound thus and a possible major player in future management of primary
aldosteronism.
The Dilemma of Lateralization
The Dilemma of Lateralization
These are truly green shoots, and point the way to substantial change in aspects of
the management of primary aldosteronism: whether these changes can be widely
embedded in practice remains to be determined. There is a justifiable belief that
the major impediments to the unwillingness of general practitioners to refer
hypertensive patients for assessment of possible primary aldosteronism is the
complexity of the screening process and, more importantly, the cost of
lateralization by adrenal venous sampling (AVS). Imaging alone – by CT or
any other modality - is not an appropriate method of localization except in very
rare circumstances (and at the discretion of the physician) – in a patient
with florid hyperaldosteronism, very high aldosterone and suppressed renin, under
the age of 35, with a single unilateral adenoma and an unremarkable contralateral
adrenal [37].
These are rare cases and currently there are various initiatives to increase the
number of patients with confirmed primary aldosteronism in whom it would appear
relatively safe to forego AVS. A number of studies have used
11C-metomidate, which binds to the key enzyme (CYP11B2) in aldosterone
biosynthesis, to localize (or not) the site of aldosterone overproduction [38]. The first problem is the requirement of a
cyclotron at the site to generate the very short-lived radiotracer; the second is
that the tracer has ~3-fold higher affinity for CYP11B1, the key enzyme in
cortisol biosynthesis, entailing three days of suppression of ACTH by dexamethasone
administration. Parallel studies with 125I-metomidate, a much longer
lived tracer, are currently in progress. Perhaps the most promising agent for
specifically imaging CYP11B2 (aldosterone synthase) is an 18F-derivative
of a specific and very high affinity aldosterone synthase inhibitor (CDP-2230)
developed by Merck but not taken further into clinical use [39].
A further possible route towards foregoing AVS may lie in measurement of one
particular (and unusual) adrenal steroid, or a selection of adrenal steroids in
peripheral plasma. As previously noted, KCNJ5 mutation-bearing APAs appear to
be of fasciculata cell type origin, thus expressing CYP11B1 and CYP11B2. Again, as
previously noted, 70–85% of APA in Japan (and China) reflect a
KCNJ5 mutation; on measurement of peripheral levels APA fell into three
groups [40] – those with high, low and
intermediate levels of circulating 18-oxocortisol. The inference from these studies
is probably limited to the high and low 18-oxocortisol groups, as almost certainly
having/not having a KCNJ5 mutation, so that with careful imaging and
consideration of the hybrid steroid levels many patients might reasonably forego
AVS.
Where Are We Now; An Interim Summary
Where Are We Now; An Interim Summary
The molecular drivers of APA have been largely established, with interesting infill
questions remaining (gender/ethnicity/?FH-V/ ?FH-VI). Those
for bilateral hyperaldosteronism are less advanced, and the ground breaking
Brisbane–Sendai study needs to be repeated, perhaps by a consortium which
pools material from their patients who lateralized on AVS but showed no APA on
histology.
What has received scant attention is the mechanism(s) underlying the increased
cardiovascular risk in primary aldosteronism. It is unthinkingly, and
non-physiologically, generally assumed that this is a direct effect of aldosterone
on cardiac/renal/vascular mineralocorticoid receptors, which is not
the case. In sodium deficiency aldosterone levels rise to those seen in florid
primary aldosteronism, with no evidence for cardiovascular damage, and the crucial
role of sodium in primary aldosteronism is neglected. This is covered in further
detail in one of the sections to follow.
Screening is complicated, cumbersome and dependent on single estimates of plasma
aldosterone and renin, and increasingly done without the recommended 4–6
week period off prior medication. Confirmatory testing is increasingly omitted in
patients with a high ARR, and has the possibility of being harmonized if the will
for acceptance is there. Currently perhaps 1–2% of PA patients can
reasonably progress to surgery without AVS: there are different avenues (tracers,
hybrid steroids) being pursued to increase this percentage. Nothing has changed in
terms of the public health and policy issues.
Where to from Here?
The Problem
In his brief welcoming introduction to PiPA6 Martin Reincke showed the data from
Germany, where only one in a thousand subjects with primary aldosteronism is
ever diagnosed and appropriately treated: there is no reason to believe that the
figure would be significantly different elsewhere. In 2020, it is hard to
imagine any other disorder with such a low rate of recognition: herein lies the
problem, and the issue for health policy makers. This is what faces us;
‘Where to from Here?’ must address as soon as possible, and as
best we can, this medically appalling situation. Current interest and current
practice perhaps almost inevitably focus on potentially curable primary
aldosteronism, that is, APA, with bilateral disease and lifetime medication a
less appealing outcome. Most of the occult primary aldosteronism will be
bilateral disease: APA are more florid, and when current figure for prevalence
are compared across centers, those with straitened cut-offs report 5%,
of which ~3% are APA and ~2% BAH; those at the
more inclusive end (up to 13%) report ~3–4% APA
and ~9–10% BAH. If occult hyperaldosteronism is
~45–50% of essential hypertension, it is likely that
≥90% will be BAH, the less florid form – less florid,
but with a substantially higher risk profile than comparable essential
hypertension unless specifically targeted and treated.
Let not the Perfect Drive out the Good
The current guidelines on screening – for 50% [37] to 100% [41] of hypertensive patients –
present a massive discouragement for general practitioners to whom a
hypertensive patient presents. Many general practitioners are not well informed
about primary aldosteronism, which in medical school and post-graduate training
may fall between three rather than two stools – endocrinology,
cardiology, and nephrology. In a very well designed survey of German and Italian
general practitioners [42], among their
many hundreds of hypertensive patients, 18% in Germany and 30%
in Italy reported no patients with primary aldosteronism. For Gian Paolo Rossi
in Padua, fewer than 20% of his patients come from referrals, with the
majority from his website. What needs to change, and to change radically, is the
way that patients are screened for primary aldosterone in the first instance,
and that for most patients who screen positive adrenal venous sampling is not
the inevitable sequel.
This cuts right across current management, newly involves and recognizes the role
of general practice and thus needs to be carefully and sequentially justified.
All hypertensives should have blood taken by their GP for a plasma renin assay.
If the DRC is above 8, or plasma renin is>1, the patient is very
unlikely to have primary aldosteronism: standard first line antihypertensives,
watch and wait. If renin is suppressed, the next step is for the general
practitioner to order a 24-hour urinary collection for levels of aldosterone. If
the urinary 24-hour aldosterone (UA) is less than six, standard
antihypertensives, watch and wait; between 6 and 12 μg, include
an MRA with first line antihypertensive medication, watch and wait. If the
24 h UA is>12 μg, then the patient has primary
aldosteronism; GP to order plasma [K+]. If the patient is
young, has the signs of florid primary aldosteronism – very high blood
pressure, high UA, hypertension resistant to current therapy, hypokalemia, renin
below detection limit – imaging and possibly AVS. If, on the other hand
blood pressure and UA are modestly elevated, the patient normokalemic and not
young, which would be the majority of cases, include a low dose MRA in therapy,
watch and wait, and a second PRC/PRA at 6 months.
Given the many variations between centers in current screening protocols, it is
difficult to regard them as perfect: what they have in common is that they are
very similar in capturing florid (~3% of hypertensives)
hyperaldosteronism represented by APAs, but differ in their concern for those
with undoubted but less florid primary aldosteronism due to BAH. Whether - when
all the numbers are in – primary aldosteronism is 5–13%,
or 45–50% of hypertensives, current screening covers a minute
fraction of affected patients, and has to be radically simplified before even
well-informed general practitioners will embrace screening. The objection that
the very much simplified protocol as put forward might condemn some APA patients
to a lifetime of MRAs is hollow: for every such patient under the current
screening protocol perhaps 100 APAs remain suboptimally treated by conventional
hypertensives. The occasional APA would certainly be better off with an MRA
added…and let not the perfect drive out the good.
One of the objections currently voiced as ‘opening the
floodgates’ in terms of a major increase in patients diagnosed –
and thus needing to be treated – is that of costs that no health
service, however well informed and forward looking, can possibly afford. This is
true for the way we currently address the issue, and attempts to widen the net
beyond Martin Reincke’s one in a thousand need a coherent policy of
minimizing costs while maximizing benefits. The simplified screening test
proposed is much less confronting than the current 4–6 weeks of
medication withdrawal/substitution, covers episodic aldosterone
secretion – currently neglected – and allows the general
practitioner either to refer or to initially manage most patients by including
low dose mineralocorticoid receptor antagonists with the regime to lower blood
pressure, watch and wait. The florid cases, as previously suggested, are very
much in the minority, and should be referred to an expert center.
Part of the watching and waiting should include measurement of PRA/PRC at
6 months, to ensure that renin is no longer suppressed. Spironolactone as an MRA
has the advantage of being very cheap, and at 25 mg/day its
androgen receptor antagonist activity is very rarely an issue in terms of
compliance in male patients. If renin remains suppressed, a trial of
50 mg/day in women, and adjuvant amiloride/triamterene
in men, should be instituted, and salt intake lowered. The presumption is that
the overwhelming majority of the wait and watch patients will have bilateral
disease, but that occasionally a patient with unilateral disease will be caught
in the net: very suppressed renin, increasing blood
pressure/antihypertensive requirements/hypokalemia should then
prompt referral to an expert center. If esaxerenone is marketed at a reasonable
price – unlike the global price for eplerenone – then it may
become the ideal MRA for use in bilateral PA.
What this high-volume management regime dose is to limit AVS – the
bottleneck in terms of costs – to a population less than that currently
undergoing the procedure as mandated by present guidelines. Imaging by CT or MRI
has been repeatedly shown to be inferior to AVS; enhanced imaging/PET
scanning agents which bind to aldosterone synthase would appear some distance
off, and their cost is substantial. As previously discussed, levels of
18oxo-cortisol plus an adenoma on imaging may be of more assistance in Japan and
China than elsewhere, given their very high percentage of KCNJ5 mutations. What
will hopefully very substantially reduce lateralization by AVS, and at a
fraction of the cost, may be the possibility of multi-steroid fingerprints in
peripheral blood samples that distinguish unilateral from bilateral
hypersecretion with a high degree of accuracy.
In terms of policy, the situation is stark. If patients with BAH and suppressed
renin are at ~3 fold higher risk – despite being treated with an
MRA – it is difficult to imagine that with no MRA the risk would be the
same, let alone lower. The eventual health costs – for the individual,
for society – are substantial, and can be avoided even in the presence
of persistent hyperaldosteronism by increased sodium excretion/lowering
sodium intake. This is not the place for a detailed cost-benefit analysis
– which in any case is beyond the author’s capability –
except to express confidence that when it is done the case will be
irrefutable.
One final thought, for those interested in the pathophysiology of primary
aldosteronism. Aldosterone per se is not a cardiovascular risk; high levels in
homeostatic mode in response to sodium deficiency are testimony to its
innocence; what drives cardiovascular risk is the combination of aldosterone and
inappropriate sodium levels. In one sense aldosterone is the prime mover,
inasmuch as it retains more sodium via epithelia than would otherwise be the
case: in another sense the inappropriately elevated total body sodium is a
sine qua non for adverse cardiovascular risk, given that in states of
sodium deficiency very high aldosterone levels are harmless. What is currently
not known is how the two actors combine to produce cardiovascular damage.
One possibility, previously canvassed, [43]
is that of the vasoconstrictor action of endogenous ouabain/ouabain-like
molecules, released from the adrenal cortex in response to ACTH, angiotensin via
AT2R1 and sodium loading. Such a mechanism is
but one possible explanation: it may provide alternate therapeutic modalities;
for example, digibindin has been shown to reverse ACTH-induced hypertension in
mice [44]. Rather than blaming aldosterone
for the elevated risk profile and cardiovascular morbidity, it would be useful
if those involved in primary aldosteronism recognized the duality of causation,
and worked towards how it is established.
CODA
What is needed is a seismic shift in focus, from the expert center to public
health. This is not to denigrate expert centers, which are the sine qua
non for the management of unilateral hyperaldosteronism: it is just that
to date the sine qua non has become the ne plus ultra. This shift
will require us to return the management of the bulk of primary aldosteronism to
general practitioners, at minimal cost to cover the extraordinary number of
patients who never receive targeted treatment. It is a big ask –
disruptive, bridges to cross, bridges to burn – but it is time we got
real about how primary aldosteronism is optimally managed. Now is the time to
act.
