Download Diagnosis and Management of Primary Aldosteronism

Acta Nephrologica 26(3): 111-120, 2012
DOI: 10.6221/AN.2012005
111
Mini Review
Diagnosis and Management of Primary
Aldosteronism
Vin-Cent Wu1, Chia-Ter Chao 1, Chin-Chi Kuo 1, Yen-Hung Lin 1, S. Jeff Chueh 2,
and Kwan-Dun Wu 1
1
Renal Division, Department of Internal Medicine, National Taiwan University Hospital
College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
2
Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Avenue
Cleveland, OH 44195, USA
Abstract
Primary aldosteronism (PA or Conn’ syndrome) is the most common secondary form of arterial
hypertension, with an estimated prevalence ranging between 6% and 20% in patients with resistant
hypertension. The use of aldosterone-renin ratio (ARR) for screening contributes to the increased
diagnostic rate of this disease. Diagnosis of primary aldosteronism consists of an initial screening test
and subsequent confirmatory tests. A prompt recognition of this disease and early institution of treatment is vital to protecting patients from aldosterone-related blood pressure control and attenuated
cardiovascular events. Aldosterone-producing adenoma and bilateral adrenal hyperplasia (microor macro-nodular) are the two main subtypes, constituting more than 90% of primary aldosteronism
cases.
Aldosterone-producing adenoma (APA) is typically managed with laparoscopic adrenalectomy.
Idiopathic hyperaldosteronism (IHA) is amenable to medical therapy with mineralocorticoid receptor
antagonists. Adrenal image is not accurate for distinguishing between an APA and IHA. Adrenal venous
sampling (AVS) is therefore essential for selecting the appropriate therapy for patients with a high
probability of PA who require surgical treatment. Short-term treatment outcome is determined by
factors such as pre-operative blood pressure level and hypertension duration, but evidence on long-term
outcome and survival after therapy is still lacking.
The purpose of this review is to provide up-to-date information on the etiology as well as strategies
for the subtype lateralization and the management of PA.
KEY WORDS: aldosteronism, adenoma, hyperplasia, hypertension
Introduction
Since Conn’s initial description of the primary
aldosteronism (PA) more than 50 years ago, subsequent validation of laboratory renin and aldosterone
assay in the 70 s has brought the identification of PA
from qualitatively clinical-based decision-making to
quantitatively laboratory-based diagnostic process,
which increases dramatically the diagnostic yield (1).
With the aid of plasma aldosterone concentration
(PAC) to plasma renin activity (PRA) ratio, which
was first introduced by Hiramatsu in 1981, the
screening of PA becomes more feasible and has greatly
facilitated the estimation of disease prevalence though
intense debate surrounds this important issue. There
are wide variations of estimate regarding the prevalence of PA, ranging from 3-4% to nearly 20% (2).
However, inconsistent diagnostic procedures, for
instance, different cut-off values of aldosterone/renin
ratio (ARR), various confirmatory and subtype differential tests, and different measure sensitivities
also play a role in obscuring the accurate estimation
of prevalence of PA. Aldosterone is produced in the
zona glomerulosa of adrenal glands in response to
Corresponding author: Dr. Kwan-Dun Wu, Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, No.
7, Chung-Shan South Rd., Taipei 10002, Taiwan, R.O.C. Tel: +886-2-23123456, Fax: +886-2-23123456, E-mail: [email protected]
Received: February 6, 2012; Revised: April 6, 2012; Accepted: May 7, 2012.
.
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Wu, Chao, Kuo, Lin, Chueh and Wu
renin-dependent angiotensin II stimulation, and further
modified by other hormones such as adrenocorticotropic hormone (ACTH) and dopamine (3).
Growing evidence has shown that high plasma aldosterone level leads to a risk of cardiovascular diseases
(CVD), including fatal stroke and sudden cardiac
death (4). In addition, long-term exposure to increased aldosterone levels resulted in renal and
metabolic sequelae independent of the blood pressure
level (5). A history of stroke, myocardial infarction
and atrial fibrillation were 4-fold (12.9% vs. 3.4%),
6-fold (4.0% vs. 0.6%), and 12-fold (7.3% vs. 0.6%)
more common in patients with PA than essential hypertension, respectively (4).
Optimal BP control and specific management of
aldosterone excess by either adrenalectomy or medical
treatment with mineralocorticoid receptor (MR)
antagonists are fundamental to the prevention of hypertension and cardiovascular events in patients with PA.
From this perspective, a thorough understanding of
the clinical presentations, the current diagnostic armamentarium for PA and its corresponding therapeutic
choices is vital for early diagnosis and treatment.
Clinical Manifestations
The diagnosis of primary aldosteronism is
usually made in patients who are in the third to sixth
decade of life (6) . Patients with marked hypokalaemia
may present with muscle weakness and cramping,
headaches, palpitations, polydipsia, polyuria, nocturia,
or a combination of these. Polyuria and nocturia are
attributed to the hypokalaemia-induced renal concentrating defect (6).
Hypokalemia is not as common as we would
expect in PA patients (7). Kuo et al. found that the
plasma level of potassium was lower than 3.3 mEq/L
in only 18% of all patients with confirmed PA. However, in Taiwan, the Taiwan Primary Aldosteronism
Investigator (TAIPAI) group identified that initial
hypokalemia occurred in only 50% of cases, which
reflects potential delayed or mistaken diagnosis of
PA according to hypokalemia in usual practice (8).
Because of a reset osmostat, the serum sodium concentration tends to be high-normal or slightly above
the upper limit of normal. Autonomous aldosterone
secretion in PA patients also antagonizes parathyroid
hormone (PTH) secretion, and induces hypercalciuria by lowering serum calcium (9). Sonino and coworkers have recently demonstrated that psychiatric
illnesses, such as generalized anxiety disorders,
occurred more often in PA patients (10). Blood
pressure may be normal in patients with welldocumented PA. In normotensive patients, diastolic
blood pressure and upright aldosterone correlated
negatively with kalemia.
Subtypes of Primary Aldosteronism
The most common form of PA are idiopathic
bilateral hyperplasia (IHA) and aldosterone-producing
adenoma (APA), accounting for more than 90% of
clinical cases (11). Unilateral adrenal hyperplasia is
less commonly identified, but this diagnosis should
be considered if lateralization test (e.g., adrenal venous
sampling (AVS)) is positive but radiological and
histological examination does not detect an adenoma.
Approximately 1% of patients are shown to have
aldosterone-producing carcinoma, and 10% of patients
manifest initial metastasis (12).
There are three familial forms of PA, namely
glucocorticoid-remediable aldosteronism (GRA),
familial occurrence of adenoma or hyperplasia type II
(FH-II) and FH-III. GRA, inherited in an autosomal
dominant fashion, is caused by the presence of a
chimeric gene originating from an unequal cross-over
between the CYP11B1 and CYP11B2 genes, leading
to ACTH-sensitive aldosterone production. The main
features comprises increased level of hybrid steroid
products (18-OH-cortisol and 18-oxo-cortisol), and
suppressible with exogenous corticosteroid (13).
FH-II is slightly more common than GRA, and could
link to several chromosomal loci (7p22) with genetic
heterogeneity. FH-III is a recently described clinical
entity, and the culprit gene has been linked to KCNJ5,
a cellular potassium channel located over zona
glomerulosa cells (14).
Case Detection and Diagnosis
When to Screen Patient?
A consensus held by the endocrine society (15)
indicates that testing should be performed in patients with the following features: [1] Joint National
Commission stage 2 (systolic/diastolic > 160-179/
100-109 mmHg) and stage 3 (> 180/110 mmHg)
hypertension, [2] drug-resistant hypertension, [3]
hypertension with spontaneous hypokalemia or
diuretic-induced hypokalemia, [4] hypertension with
adrenal incidentaloma, [5] hypertension and a family
history of early-onset hypertension, or cerebrovascular
accident at a young age (< 40 years old), and [6]
patients with first-degree relatives diagnosed with
PA. Whenever secondary hypertension is suspected,
a diagnosis of PA should be executed.
How Is Diagnosis Obtained?
Aldosterone-Renin Ratio (ARR)
ARR is currently the most reliable and available
means of screening for PA. Many studies have demon-
Primary Aldosteronism
strated that ARR is superior to other laboratory markers
(serum potassium, aldosterone concentration or renin
alone) owing to its higher sensitivity (16). It should
be performed in the morning, with serum potassium
level restored to normal level (hypokalemia reduces
aldosterone production), and without postural stimuli.
An attempt to correct hypokalemia should be accompanied by accurate determination of serum potassium level.
How to Prepare for ARR Test?
Before making correct interpretation of the paired
hormonal values, several issues should be considered.
First, several medications can interfere with the ARR
value. Most notably, mineralocorticoid antagonists
(spironolactone and eplerenone) and amiloride will
significantly compromise the test result (false negativity
from stimulating more renin than aldosterone secretion), and should therefore be discontinued at least 6
weeks before testing (17). Angiotensin-converting
enzyme (ACE) inhibitors and angiotensin-receptor
blockers (ARB) can all result in a falsely negative ARR
value due to their suppression of aldosterone secretion
and enhancement of renin level. Direct renin inhibitor
(aliskiren) is also reported to skew ARR interpretations (decreased when measured with PRA or increased direct renin concentration (DRC), then ARR
will be false positive or false negative, respectively)
(15). Other anti-hypertensive medications including
β-adrenergic blockers, central α2-agonists (clonidine
and methyldopa) and diuretics (loop and thiazide)
will suppress more the level of renin than that of
aldosterone, leading to a false positive ARR result.
Dihydropyridine calcium-channel blockers will elevate renin level, resulting in a falsely low ARR value
(18). It is then prudent to discontinue these medications for 2-4 weeks before starting on the test. For
controlling blood pressure during the drug washout
period, it is preferable to use effect-neutral antihypertensive drugs, such as verapamil (slow-release
form), hydralazine (combined with verapamil to avoid
reflex tachycardia) and α1-antagonists (prazosin,
doxazosin, and terazosin) (15).
In addition, several agents can also potentially
introduce interpretation difficulties, such as products
derived from licorice (e.g., chewing tobacco), nonsteroidal anti-inflammatory agents (NSAID), and
oral contraceptives (15). Patients should be told to
refrain from these medications before they receive
ARR test.
There are hints that can assist in interpreting
ARR results: a high PAC in a patient receiving drugs
that should suppress PAC level suggests that this
patient could have PA (19). From this viewpoint,
knowledge of each drug’s tendency to divert ARR
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is of much importance.
How to Interpret ARR?
A lack of uniform assay method and diagnostic
protocols in ARR determination creates a high
variability in cut-off values among various investigation
groups, ranging from 20 to 100 (using PAC in ng/dL
and PRA in ng/mL/hr) (20). Several groups urge that
elevated aldosterone level (> 15 ng/dL) is required for
a positive ARR test to avoid bias from extremely low
renin measurements, but the variability of assay between
laboratories and different normal ranges of plasma
aldosterone level constitute a major obstacle. Some
investigators proposed that post-captopril ARR value
was as sensitive as saline infusion for screening or
confirmation, but the evidence is also insufficient (21).
The TAIPAI group conducted a prospective study to
compare the diagnostic yield of post-captopril ARR
according to ARC and standard ARR, and a cut-off
value of 35.5 was identified (22). Therefore, a cut-off
value of ARR (according to PRA) of 35 (ng/dL per
ng/mL/hr) with highest sensitivity and specificity is
recommended for screening purpose (8).
Confirmatory Test for Identification of
Primary Aldosteronism
What Tests Can Be Used for PA Confirmation?
An increased ARR is not diagnostic by itself,
but points out that further testing is warranted. An
accurate confirmatory test can spare the patients from
subsequent invasive and costly examinations. However, the reference standard for diagnosis of PA has
not been established to date. The tests include oral
salt loading (OST) or intravenous salt infusion test
(SIT), fludrocortisone stimulation test (FST), captopril or losartan challenge test (15), each with their
proponents. In the following section, we will briefly
introduce the procedure of each test (Table 1).
Oral Salt/Saline Loading Test (OST)
After a high sodium diet (salt tablet supplementation if needed) for 3 days (total 218 mmol of
sodium, about 12.8 g NaCl given), a 24-hour urine
specimen is collected (23). Urinary aldosterone
excretion of more than 12 µg/day in this setting is
consistent with insuppressible aldosterone secretion (15). The sensitivity and specificity of OST are
around 96% and 93%, respectively (23).
Saline Infusion Test (SIT)
This is the most popular confirmatory test for
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Table 1. Available confirmatory tests for diagnosis of primary aldosteronism
Confirmatory test
Procedure
Interpretation
Oral salt loading test (OST)
Preceding 3 days of high salt intake (6 g
NaCl/day), as verified by 24-hour urine
Na content (should >200 mmol);
Urine aldosterone > 12 µg/day
Saline infusion test (SIT)
2 liters of 0.9% saline infusion over 4
hours, when patients are recumbent;
PAC > 10 ng/dL (277 pmol/L) confirms
patients with PA
Fludrocortisone suppression test
(FST)
Administration of fludrocortisone
(0.1 mg 4 times a day) and NaCl tablets
(2 g three times a day) for 4 days;
PAC > 6 ng/dL confirms the diagnosis
of PA
Captopril-suppression test (CST)
Administration of 50 mg captopril
orally after sitting or standing for at least
1 hour;
ARC/PAC (ng/dL per ng/mL/hr) remained elevated more than 35.5 after
captopril challenge confirms the diagnosis
Losartan-suppression test (LST)
Similar to CST, with losartan 50 mg
given instead.
Interpretation similar to CST
Abbreviations: PAC, plasma aldosterone concentration; PRA, plasma renin activity.
PA (20). An overnight fasting is needed for preparation. Patients receive infusion of 2 liters of 0.9%
saline over 4 hours and post-infusion plasma aldosterone level lower than 5 ng/dL excludes the diagnosis
of PA, while that exceeding 10 ng/dL confirms the
diagnosis (24).
Fludrocortisone Stimulation Test (FST)
In this test, fludrocortisone acetate is administered for 4 days (0.1 mg every 6 hours) in combination with sodium chloride tablet (2 g, thrice daily).
At day 4, an upright plasma aldosterone level at 10
AM higher than 6 ng/dL confirms the diagnosis of
PA (25)
Captopril/Losartan Challenge Test (CST/LST)
Patients are prescribed 50 mg captopril orally
after sitting or standing for at least 1 hour. Blood
sampling is performed for measuring serum renin,
aldosterone, and cortisol before captopril and 1 or 2
hours after challenge. Normal suppression is defined
as PAC < 15 ng/dL and ARR < 50 (15). Comparable
sensitivity has been shown by some groups between
SIT and CST. This test is not influenced by sodium
intake, and is more suitable for patients with heart
failure or other fluid overloading status (21).
The losartan challenge test (LST) is an alternative form of the captopril-based test, with the
assumption that changes in ARR may be larger if
ARB is used instead of ACE inhibitor (26).
Subtyping of PA
Is There a Lateralization?
To establish a lateralization is the most critical
step to guide the further treatment of PA. Lateralization is to localize the aldosterone secreting activity on
one side of the adrenal glands in preference to the
other. Distinguishing between unilateral and bilateral
adrenal disease is also vital, since prompt operation
of unilateral adenoma results in normalization of
hypokalemia and hypertension, but bilateral diseases
are usually managed medically (27). Imaging cannot
reliably visualize microadenoma or provide definite
clues for lateralization. CT contributed to lateralization in about 50% of cases only, and this number
decreased further to lower than 25% if APAs were
smaller than 1 cm in diameter (15). This makes
adrenal venous sampling (AVS) a procedure of choice
for differentiating unilateral from bilateral forms of
PA, despite its being expensive and invasive. The
sensitivity and specificity of successful AVS (95%
and 100%) for detecting unilateral disease are significantly better than those of adrenal CT (28).
AVS is a difficult procedure and usually required
a dedicated doctor with experienced hands, since
cannulating the smaller right adrenal vein, described
as “the crux of AVS”, is technically demanding. According to a review of 47 reports, the success rate was
74%, but rose to 90-96% if angiographers were
experienced (29). The addition of intraprocedural
measurement of adrenal vein cortisol concentrations
Primary Aldosteronism
further facilitates the accuracy of catheter placement.
Patients may be spared AVS if they are younger than
40 years old with solitary unilateral apparent adenoma on CT, with still high biochemical and clinical
cure rates (28).
The aim of continuous cosyntropin infusion
during AVS is to minimize stress-induced fluctuations
in aldosterone secretion during sequential AVS, to
maximize the gradient of cortisol between adrenal
vein and IVC (to ensure optimal cannulation), and to
stimulate the secretion of aldosterone from APAs
(28). Dividing the right and left adrenal vein PAC by
their respective cortisol level can neutralize the
diluting interference of inferior phrenic vein or IVC,
draining into the right and left adrenal vein, respectively. In the absence of cosyntropin infusion, a
cortisol-corrected aldosterone lateralization ratio of
more than 2:1 confirms unilateral disease (30). Some
groups compared adrenal vein aldosterone-cortisol
ratios to those in a simultaneously collected peripheral
venous sample (cubital) or IVC. The acceptable cutoff points in this setting will be a unilateral hypersecretion (ratio of more than 2.5:1) with contralateral
suppression (ratio no higher than 1:1).
The TAIPAI experience confirmed the potential
usefulness of dexamethasone suppression adrenocortical scintigraphy with CT (NP-59, I- 131 -6-betaiodomethyl-19- norcholesterol & NP59-SPECT/CT)
(31). NP59-SPECT/CT is not only non-invasive but
also avoids the adverse effects of intravenous contrast agents in conventional CT/MR, especially for
elderly patients and patients with kidney diseases
(32).
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history of young stroke (32).
Testing for Familial Forms of PA – Familial
Hyperaldosteronism Type II
FH-II is a genetically heterogeneous disorder.
FH-II families can present clinically with APA or
IHA, and are not distinguishable from patients with
nonfamilial PA (15). The exact prevalence of FH-II
is not known, but a high percentage of affected patients (7%) has been reported (33). The molecular
basis of this syndrome is also unknown, but chromosomal region 7p22 has been implicated as an associated area. Further clinical testing is not available
to date.
Testing for Familial Forms of PA – Familial
Hyperaldosteronism Type III
FH-III is a particularly aggressive form of hyperaldosteronism, with medication-resistant hypertension
(34). The genetic cause of this syndrome is attributed
to KCNJ5, which encoded the potassium channel Kir
3.4. Recurrent somatic mutation of KCNJ5 results in
increased sodium conductance and cell depolarization
of adrenal zona glomerulosa cells in unselected
patients of approximately 34%, with subsequent enhanced aldosterone production and cell proliferation
(14). Clinically, patients present with severe hypertension and variable hypokalemia, with radiological
bilateral massive adrenal hyperplasia. Treatment
with bilateral adrenalectomy is frequent (34).
Aldosterone-Related Cardiovascular Events
Testing for Familial Forms of PA – Familial
Hyperaldosteronism Type I (GRA)
It is characterized by early-onset hypertension,
usually severe, and refractory to conventional antihypertensive medications. The culprit is a chimeric
gene duplication resulting from unequal crossing over
between the promoter sequence of 11β-hydroxylase
(CYP11B1), which is responsible for corticotrophin
stimulation, and coding sequence of aldosterone
synthase (CYP11B2), both on chromosome 8 (13).
The result is ectopic expression of aldosterone synthase in adrenal zona fasciculate, which produces
cortisol and mineralocorticoid regulation depending
upon corticotropin. To diagnose this rare disorder,
several methods are available, namely measurement
of urinary 18-hydroxycortisol or 18-oxocortisol,
dexamethasone suppression test, and genetic testing
for chimeric gene. Genetic test was suggested for the
following settings: patients with a family history of
PA, patients with onset of PA at a younger age (< 20
years old), and patients with PA who have a family
Aldosterone-related detrimental effects are
mediated through the activation of MR, which are
widely expressed in endothelial cells, smooth muscle
cells, myocardiocytes, endothelial progenitor cells,
(35) and neutrophils. Aldosterone exerts its actions
on sodium and potassium handling through upregulation of the activity of the distal tubule sodium
epithelial channel. Aldosterone may possess more
than direct endothelial effects. These include increased oxidative stress and collagen remodeling,
triggering endothelial dysfunction, delayed endothelial recovery (35) and subsequent ventricular
hypertrophy and myocardial as well as renal fibrosis.
Regarding kidney damage, the possible hyperfiltration
phenomenon may mask decreased kidney function,
leading to underestimation of the burden of chronic
kidney disease in PA patients (36). We have recently
demonstrated that even a mild impairment of renal
function may predict residual hypertension after unilateral adrenalectomy in PA patients. This indicates
that subtle kidney impairment may be masked by
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Wu, Chao, Kuo, Lin, Chueh and Wu
hyperfiltration before treatment and intra-renal hemodynamic adaptation to the effects of aldosterone
excess (37). In addition, aldosterone has recently
been reported to elevate risk of metabolic syndrome
and bone loss, possibly due to increased calciuria
and magnesiuria. Blockade of mineral-ocorticoid
receptors improves significantly the volume retention reaction and also ameliorates the inflammatory
reaction, and this effect may be independent of blood
pressure reduction per se (38). Furthermore, patients
with PA have a greater risk of developing left ventricular hypertrophy, myocardial fibrosis, and diastolic dysfunction than EH patients. Moreover, excessive aldosterone is known to induce endothelial
dysfunction, increase arterial stiffness, and atherosclerosis. In research on vascular smooth muscle
cells, aldosterone contributed to enhancement of
collagen synthesis. Moreover, compared with EH
patients, PA patients have shown to have increasing
arterial stiffness measured by pulse wave velocity,
and greater carotid intima-media thickness (39). In
primary aldosteronism, escape of renin from suppression by excess aldosterone is associated with
evidence of more severe target organ damage (e.g.,
kidney) and predicts intrarenal vascular injury, worse
BP and renal outcomes after either surgical or medical
treatment (40).
Treatment of PA
Treatment of PA is targeted to prevent the excess
morbidity and mortality associated with hypertension,
hypokalemia and aldosterone-associated organ
damage. Blood pressure reduction should not be the
only goal in managing PA patients, since mineralocorticoid receptors (MR) have been found in a variety
of tissues including myocardium, brain and blood
vessels. The treatment strategy should be chosen
according to the subtyping and the underlying cause
of PA. The general principle is that patients with
unilateral PA (i.e., APA or unilateral adrenal hyperplasia) should be offered unilateral laparoscopic
adrenalectomy (15). For patients with PA from bilateral adrenal disease, medical treatment with MR
antagonist is the first-line treatment of choice (15).
An algorithm of case detection, confirmation, differential subtyping testing, and management of PA
according to the TAIPAI group experience is summarized in Fig. 1.
Unilateral Adrenalectomy for APA and Unilateral
Hyperplasia
Unilateral adrenalectomy in patients with unilateral PA can effectively improve hypertension and
hypokalemia in these patients. Hypertension is cured
(defined as medication-free and blood pressure < 140/
90 mmHg) in around half of the operated patients with
APA. In the TAIPAI database, we found that patients
with unilateral hyperaldosteronism receiving unilateral
adrenalectomy displayed reversal of changes in myocardial structure (as evidenced in cardiac ultrasonographic findings) and of carotid intimal thickness (41,
42). The longitudinal changes of CysC-based GFR,
proteinuria and the kidney-resistive index provide
convincing evidence that the vasculotoxic effect of
hyperaldosteronism can be mitigated after adrenalectomy but not through the use of conservative medical
treatment (15). Laparoscopic adrenalectomy is the
preferred surgical approach, and is associated with
shorter hospitalization and lower morbidity compared
with the conventional open approach The surgical
approach usually involves removal of the entire gland
since APAs are commonly small and multiple, but
laparoscopic partial adrenalectomy or enucleation has
also been utilized by some, with shorter operative time
but more blood loss, and infrequently, post-operative
persistent hypertension (43).
Factors associated with resolution of hypertension in the post-operative period include having
one or no first-degree relative with hypertension and
pre-operative use of less than three types of antihypertensive agents (44). Other predictive factors
like higher pre-operative serum creatinine level and
longer duration of hypertension have also been found.
The most common reasons for persistent post-operative hypertension are hypertension of unknown
etiology, advanced age, and pre-operatively longer
duration of hypertension (44). Blood pressure becomes normal or improves maximally within 1-6
months after unilateral adrenalectomy, but some
reports indicate that this improvement period can
lag up to one year (15).
Mineralocorticoid Receptor (MR) Antagonist
Bilateral adrenal diseases including IHA,
bilateral APAs, and GRA are often managed medically
with MR antagonists. However, no randomized
placebo-controlled trials have evaluated the efficacy
of each drug in the treatment of PA.
Spironolactone
This drug has been the treatment of choice for
PA for more than four decades. The dosage is 12.5 mg
to 25 mg per day initially and titrated upward to 400
mg per day if necessary to achieve normokalemia
without potassium supplementation. The response of
hypokalemia usually occurs promptly, but blood pressure response may take months to be fully achieved
(23). Observational studies in patients with IHA have
Primary Aldosteronism
New patients without
previous HTN
Define Severity
CV Risk assessment and
treatment planning
117
Referral patients
Elevated ARR
Hypokalemia with hypertension
Hypertensive crisis
Adrenal incidentaloma
New patients with HTN
Resistant HTN clarification
Severe HTN (Stage 2 & 3 in TSC guideline) & confirmed resistant HTN
Hypokaleimia (spontaneous or diuretic-induced)
Early onset (age < 40 years old)
Family history of PA (first-degree relatives)
A 21 days anti-HTN drug washout period if tolerable
No diuretics, beta-blocker, RAAS inhibitor,
dihydropyridine CCB, and MR antagonist
PA unlikely
Standard ARR > 35 and PAC > 10
Oral sodium
loading test
(OST)
or
Saline infusion test
or
(SIT)
Fludrocortisone
stimulation test
(FST)
or
Captorpil/Losartan
challenge test
(CST/LST)
Confirmatory ARR > 35 and PAC > 10
Urine aldosterone ≥ 12 µg/24 hour
Is patient a surgical candidate?
Surgical risk evaluation
Patients’ consent
PA unlikely
No
Medical Therapy
Yes
Adrenal CT/MR
Unilateral adrenal lesion ≥ 1 cm
Age ≥ 40
NP-59-SPECT/CT
adrenal scientigraphy
Non-Lateralization
IHA
Medical Therapy
or
AVS
Lateralization
Age < 40
Repeat subtyping tests
Equivocal finding
APA
Adrenalectomy
Fig. 1. TAIPAI Algorithm for the screening, confirmation, differential sub-typing testing, and management of primary aldosteronism.
Abbreviations: APA, aldosterone-producing adenoma; ARR, aldosterone/renin ratio; AVS, adrenal venous sampling; CCB,
calcium channel blocker; HTN, hypertension; IHA, idiopathic hyperaldosteronism; MR, mineralocorticoid receptor; NP-59SPECT/CT, I-131-6-beta-iodomethyl-19-norcholesterol single-photon emission computed tomography; PAC, plasma aldosterone concentration; RAAS, renin-angiotensin-aldosterone system; PA, primary aldosteronism; TSC guideline, 2010 guidelines
of the Taiwan Society of Cardiology for the management of hypertension.
Units: Age, years; ARR, ng/dL per ng/mL/hr; PAC, ng/dL
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Wu, Chao, Kuo, Lin, Chueh and Wu
reported a mean reduction in systolic blood pressure
of 25% and diastolic pressure of 22% with spironolactone dosage ranging from 50 mg to 400 mg per
day (45). Most of the patients require as low as 25 to
50 mg per day after several months of therapy.
Side effects of spironolactone include mainly
gynecomastia, decreased libido and erectile dysfunction in men or menstrual abnormality in women, a
phenomenon stemming from concomitant sex steroid
effect (11). The incidence is dose-related, with one
study reporting an incidence of 5-10% at a dose of
25-50 mg per day for 6 months but increasing to 50%
at a dose of more than 150 mg per day (46). In addition, spironolactone has several important drug-drug
interactions. Spironolactone can increase the halflife of digoxin, and digoxin dosage adjustment should
be considered when used simultaneously. Salicyclate also interferes with tubular secretion of the
active metabolite of spironolactone, decreasing its
effectiveness.
Eplerenone
Eplerenone is a more selective MR antagonist,
with minimal anti-androgen and progesterone agonist
effects and lower incidence of adverse effects (15).
The main structural modification leading to low androgenic and progesterone effect resides in the 9,11epoxide group. It is approved for the treatment of
essential hypertension and for heart failure after
myocardial infarction (47). It is reasonable to start
with a dosage of 25 mg twice daily (owing to the
short half-life of eplerenone), and titrated upward for
normokalemia and blood pressure effect. The maximal
dosage for hypertension is 100 mg twice daily.
Parthasarathy et al. reported a randomized study
comparing eplerenone with spironolactone in treating
PA patients, and spironolactone was found to outperform eplerenone with regard to anti-hypertensive efficacy (48). The contraindications of eplerenone are
similar to those of spironolactone. Side effects include dizziness, headache, fatigue, diarrhea, abnormal
liver enzyme, and hypertriglyceridemia (23). The
contraindications of eplerenone include hyperkalemia
(serum potassium > 5.5 mEq/L), clinically significant
renal insufficiency (serum creatinine > 2.0 mg/dL in
men and > 1.8 mg/dL in female), or combination
therapy with other potassium-sparing diuretics.
Other Pharmacologic Agents
Amiloride and triamterene are also distal sodium
epithelial channel antagonists, and amiloride in
particular has been studied most extensively in PA
patients. Amiloride can ameliorate both hypertension
and hypokalemia and is well tolerated, without the
notorious side effects of spironolactone, but is also
devoid of the beneficial effects on endothelial function
(49). However, the impact of its clinical use is still
not elucidated.
Conclusion
PA has once been regarded as a rare disorder
with very low prevalence among unselected hypertensive patients, but it is now realized that PA may
constitute up to 10-20% of patients with hypertension.
More importantly, the detrimental effect brought about
by aldosterone in multiple tissues may go far beyond
a pure complication from hypertension, and early
treatment, surgically (adrenalectomy) or medically
(spironolactone) will effectively relieve these adverse
events and potentially restore organ injury. It is then
important for physicians to recognize this disorder
early and arrange proper diagnostic tests, with corresponding therapeutic modality instituted, to avoid
missing curable hypertension in the primary care
clinic.
Acknowledgments
This study was supported by the Ta-Tung Kidney
Foundation, Taiwan National Science Council (grant
NSC 96-2314-B-002-164, grant NSC 96-2314-B-002033- MY3, and grant NSC 97-2314-B-002-155-MY2),
NTUH (98-N1177, 99-N1408, 100-N1776), and
NTUH-TVGH Joint Research Program (VN9803,
VN9906 and VN10009).
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