Aldosteronismo Primario

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Review
doi: 10.1111/joim.12831
Diagnosis and treatment of primary aldosteronism: practical

clinical perspectives
W. F. Young Jr
From the Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
Abstract. Young WF (Mayo Clinic, Rochester, MN, surgery or whether it should be treated medically;
USA). Diagnosis and treatment of primary this step is guided by computed tomography scan
aldosteronism: practical clinical perspectives of the adrenal glands and adrenal venous sam-
(Review). J Intern Med 2019; 285: 126–148. pling. With appropriate surgical expertise, laparo-
scopic unilateral adrenalectomy is safe, efficient
Primary aldosteronism (PA), the most common and curative in patients with unilateral adrenal
form of secondary hypertension, can be either disease. In patients who have bilateral aldosterone
surgically cured or treated with targeted pharma- hypersecretion, the optimal management is a low-
cotherapy. PA is frequently undiagnosed and sodium diet and lifelong treatment with a miner-
untreated, leading to aldosterone-specific cardio- alocorticoid receptor antagonist administered at
vascular morbidity and nephrotoxicity. Thus, clin- a dosage to maintain a high–normal serum
icians should perform case detection testing for PA potassium concentration without the aid of oral
at least once in all patients with hypertension. potassium supplements.
Confirmatory testing is indicated in most patients
with positive case detection testing results. The Keywords: adrenal vein sampling, aldosterone,
next step is to determine whether patients with hypertension, hypokalaemia.
confirmed PA have a disease that can be cured with
micronodular or macronodular hyperplasia of the

Introduction
zona glomerulosa of predominantly one adrenal
Hypertension, increased adrenal aldosterone gland. Familial hyperaldosteronism (FH) is rare,
secretion and suppressed renin are the three and germline mutations in four different genes
hallmarks of primary aldosteronism (PA), which have been described (see section on FH below).
was first fully described in 1955 [1]. Although
estimates vary [2], the prevalence of PA is approx-
Clinical presentation
imately 5% in patients with hypertension [3] and
up to 20% in those with treatment-resistant hyper- Primary aldosteronism is usually diagnosed
tension [4, 5]. Cardiovascular and cerebrovascular between 20 and 60 years of age. There is no
morbidity and mortality rates in patients with PA reliable clinical phenotype to guide the clinician
are increased compared with subjects with appar- on which patients should be tested for PA. A
ent essential hypertension matched for age, sex hypokalaemia-induced renal-concentrating defect
and blood pressure [6–10]. The early diagnosis of can result in polyuria and nocturia; this presenta-
PA provides the opportunity to either cure hyper- tion is frequently mistaken for prostatism in men.
tension or to direct targeted pharmacotherapy, The degree of hypertension is typically moderate to
both of which can prevent end-stage PA (i.e. end- severe and may be resistant to usual pharmaco-
stage renal disease and irreversible cardiovascular logic treatments [12, 13]. The mean blood pressure
damage). (SD) was 184/112 28/16 mmHg in the first
262 patients with PA who were diagnosed at Mayo
Aldosterone-producing adenoma (APA) and bilat- Clinic (1957–1986) [13]. In general, patients with
eral idiopathic hyperaldosteronism (IHA) are the APA tend to have higher aldosterone levels and
two most common subtypes of PA (Table 1) [11]. A higher blood pressures than patients with IHA.
less common form of PA, unilateral hyperplasia or Because hypokalaemia is present in only 28% of
primary adrenal hyperplasia (PAH), is caused by patients with PA [14, 15], all patients with
126 ª 2018 The Association for the Publication of the Journal of Internal Medicine
13652796, 2019, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12831 by Cochrane Mexico, Wiley Online Library on [02/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Primary aldosteronism / W. F. Young
Table 1 Types of primary aldosteronism mellitus, in which 754 surgically treated patients
with APA were matched with 3016 control subjects
Type of primary aldosteronism Cases
with essential hypertension [18]. The patients with
Aldosterone-producing adenoma (APA) 30% PA who underwent adrenalectomy had a statisti-
Bilateral idiopathic hyperplasia (IHA) 60% cally significant reduced risk for incident diabetes
Primary (unilateral) adrenal hyperplasia 2% and all-cause mortality compared with matched
Aldosterone-producing adrenocortical carcinoma <1% hypertensive controls [18].
Familial hyperaldosteronism (FH)
Deep-seated renal cysts are found in up to 60% of
Glucocorticoid-remediable aldosteronism <1%
patients with PA who have chronic hypokalaemia
(FH type I) [19]. Because of a reset osmostat, the serum
FH type II (APA or IHA) <6% sodium concentration tends to be high–normal or
FH type III (germline KCNJ5 mutations) <1% slightly above the upper limit of normal [20]. This
FH type IV (germline CACNA1H mutations) <0.1% clinical sign is very useful in the initial assessment
for potential PA, especially in patients treated with
Ectopic aldosterone-producing adenoma or <0.1%
thiazide diuretics (where the serum sodium con-
aldosterone-producing carcinoma centration tends to be low–normal).
Quality of life
hypertension are potential candidates for this
disorder. There is a unique subset of young Several studies have demonstrated the negative
patients (typically <35 years of age) who present impact of PA on quality of life (QoL) [21–24]. A
with marked hypokalaemia but are not technically recent systematic review assessed the impact of
hypertensive with systolic/diastolic blood pres- PA on health-related QoL and mental health [25]. A
sures of 130s/80s mmHg. These patients usually literature search yielded 15 studies that met the
have APA and their pre-PA baseline blood pres- study inclusion criteria. Untreated patients with
sures average 100/60 mmHg. Thus, although they PA (APA and IHA) showed an impaired physical and
do not meet the criteria for hypertension, there is a mental QoL compared to the general population.
clinically significant change from baseline and Symptoms of anxiety, demoralization, stress,
presumably their young age and blood pressure depression and nervousness were more frequently
counter regulatory mechanisms prevent hyperten- reported in untreated patients with PA than in the
sion, at least in the first year or two of the disease. general population and in patients with hyperten-
sion [25]. Adrenalectomy improved QoL and the
The prevalence of target-organ damage to the heart symptoms of psychopathology. In the studies
and kidney is increased in patients with PA com- included in this systematic review, there were
pared to those with essential hypertension [7, 10, conflicting results on the impact of medical man-
16]. Long-standing undiagnosed PA frequently agement [25].
leads to chronic kidney disease [17]. In a recent
meta-analysis of 31 studies, including 3838 A recently published prospective QoL study com-
patients with PA and 9284 patients with essential pared patients with PA who were managed surgi-
hypertension, patients with APA and IHA had an cally (n = 92) to those managed medically (n = 92)
increased risk of stroke [odds ratio (OR) 2.58], [26]. QoL was assessed with two validated ques-
coronary artery disease (OR 1.77), atrial fibrillation tionnaires [RAND 36-Item Health Survey 1.0
(OR 3.52) and heart failure (OR 2.05) [10]. In (RAND SF-36) and the European Quality of Life-5
addition, the diagnosis of PA increased the risk of Dimensions (EQ-5D)] at baseline, 6 months and
diabetes (OR 1.33), metabolic syndrome (OR 1.53) 1 year. At baseline, seven of eight RAND SF-36
and left ventricular hypertrophy (OR 2.29) [10]. subscales and both summary scores, as well as
Thus, the cardiovascular toxicity in PA extends three of five EQ-5D dimensions and the visual
beyond hypertension; there is an aldosterone- analog scale, were lower in patients with PA
specific toxicity. compared with the general population, especially
among women. The beneficial effects of surgical
The risk of developing new-onset diabetes mellitus treatment were greater than for treatment with
was also demonstrated in a study of 2367 patients mineralocorticoid receptor antagonists (MRAs) on
with PA who had no prior diagnosis of diabetes seven of the RAND SF-36 subscales and both
ª 2018 The Association for the Publication of the Journal of Internal Medicine 127
Journal of Internal Medicine, 2019, 285; 126–148
summary scores. Surgical management was also adrenal incidentaloma; (v) patients with hyperten-
superior on the EQ-5D in two dimensions and the sion and sleep apnoea; (vi) patients with hyperten-
visual analog scale. After 1 year, almost all QoL sion and a family history of early onset
measures had normalized for surgically managed hypertension or cerebrovascular accident at a
patients, whereas most QoL measures had young age (<40 years); and (vii) all hypertensive
improved but not to the level of the general popu- first-degree relatives of patients with PA [11].
lation for patients on medical treatment [26]. It is Unfortunately, these guidelines are not followed
not clear whether these QoL differences between by practising clinicians. For example, in a recent
surgical and medical management were due in part survey of 500 general practitioners in Italy and
to suboptimal dosages of MRAs in the medically Germany, case detection testing for PA was per-
managed cohort. formed in only 7–8% of 3135 patients with hyper-
tension [40]. Another study in Italy found that PA
was dramatically underdiagnosed and under-
Prevalence
treated [41].
Before 1981, PA was thought to be a rare cause of
hypertension [27–33]. Over time, it has been shown Over more than three decades, it has been frus-
that most patients with PA are not hypokalaemic trating to see patients who were not tested for PA
[11, 12, 14, 34] and that case detection testing can when they were first diagnosed with hypertension,
be completed without stopping antihypertensive but rather only after they have developed irre-
medications [35]. Case detection testing is per- versible stage 4 to 5 chronic kidney disease.
formed with a morning venipuncture for the mea- Clinical practice guidelines have not been effective
surement of plasma aldosterone concentration in driving more clinicians to consider case detec-
(PAC) and plasma renin activity (PRA) or plasma tion testing for PA [42]. Could the guidelines be too
renin concentration (PRC) [11, 35]. Thus, current complicated with regard to rules on medications
prevalence estimates for PA are 5–10% of all and by focusing on recommending subsets of
patients with hypertension [2, 3, 14, 15, 34, 36– patients for PA testing? The diagnostic algorithm
39]. In a recent study of 1672 unselected patients should be simplified, and all patients with hyper-
with hypertension, the prevalence of PA was 5.9% tension should be recommended for case detection
and was associated with the severity of hyperten- testing for PA at least once (Fig. 1). An initially
sion: 3.9% and 11.8% in patients with stage 1 and normal case detection testing result for PA should
stage 3 hypertension, respectively [15].
Who should be screened for PA?

Unlike other adrenal disorders (e.g. Cushing syn-
drome), there is no typical PA phenotype to guide
the clinician to suspect PA. Serum potassium
status is not a reliable guide for screening for PA
because 72% of patients with PA are normokalemic
[11, 14, 15].
In efforts to conserve medical costs and limit the

consequences of false-positive case detection test-
ing, the Endocrine Society guidelines on PA [11]
recommend testing high-risk groups for PA. These
groups include: (i) patients with sustained blood
pressure above 150/100 mmHg on each of three
measurements obtained on different days; (ii)
patients with hypertension resistant to three con-
Fig. 1 Algorithm provides guidance on when to consider
ventional antihypertensive drugs (including a testing for primary aldosteronism and use of plasma
diuretic) or controlled blood pressure on four or aldosterone concentration and plasma renin activity as a
more antihypertensive drugs; (iii) patients with case detection tool. PAC, plasma aldosterone concentra-
hypertension and spontaneous or diuretic-induced tion; PRA, plasma renin activity; PRC, plasma renin
hypokalaemia; (iv) patients with hypertension and concentration.
be repeated if and when there is deterioration in PA. Therefore, the finding of a PRA level
hypertension control [43]. ≥1.0 ng mL 1 h 1 or a PRC that is not suppressed
in a patient taking an ACE inhibitor or ARB does
Advancing clinician and public awareness about not exclude the diagnosis of PA. However, a PRA
PA has been challenging because: (i) PA does not level <1.0 ng mL 1 h 1 or a PRC below the refer-
have a unique clinical phenotype; (ii) PA is not a ence range in a patient taking an ACE inhibitor or
cancer and therefore does not receive attention ARB is diagnostic of low-renin hypertension and
from the media or clinical press; (iii) physicians possible PA. MRAs (e.g. spironolactone and epler-
continue to learn in medical school that PA is enone) prevent aldosterone from activating the
uncommon and that the diagnosis is complicated; receptor, resulting sequentially in sodium loss, a
and (iv) PA is not recognized by patients (unlike decrease in plasma volume and an elevation in
cancer, heart attack or high cholesterol). Greater renin. If PRA or PRC is not suppressed in a patient
efforts need to be made to provide up-to-date treated with an MRA, then no further PA-related
information in medical schools and family practice testing can be performed and the MRA should be
and internal medicine residencies, focusing on the discontinued for 6 weeks before re-testing. How-
prevalence of PA, morbidity related to untreated PA ever, if the patient is hypokalaemic despite treat-
and how to perform case detection testing. In ment with an MRA, then the mineralocorticoid
addition, public awareness campaigns for PA receptors are not fully blocked and PRA or PRC
should be initiated. Examples of effective public should be suppressed in such a patient with PA. In
awareness and education campaigns have addition, in the author’s experience, most patients
included breast cancer screening [44], reducing with PA are treated with suboptimal dosages of
delays in prehospital response to stroke [45], MRAs and the mineralocorticoid receptors are not
depression awareness [46] and colon cancer fully blocked. Thus, for case detection testing,
screening [47]. blood pressure medications, including MRAs,
should not be discontinued. Clinicians can proceed
with case detection testing in all patients treated
Diagnosis
with MRAs, and the MRA does not need to be
The diagnosis of PA starts with case detection, discontinued for confirmatory or subtype testing
followed by confirmatory tests and finally subtype with adrenal vein sampling (AVS) if PRA or direct
evaluation. Each step may be completed, whilst the renin concentration is suppressed [49]. Other
patient is taking antihypertensive medications potassium-sparing diuretics, such as amiloride
[12]. Although hypokalaemia reduces the secretion and triamterene, usually do not interfere with
of aldosterone, it rarely normalizes aldosterone testing unless the patient is treated with high
secretion in patients with PA; these patients are doses, which may result in elevated PRA or PRC.
hypokalaemic because of excess aldosterone secre-
tion. Nevertheless, restoring the serum potassium
Measurement of renin
level to normal before performing diagnostic stud-
ies is optimal (although not necessary in most Renin can be measured based on its enzymatic
cases). activity (PRA) or on its mass (PRC). PRA is deter-
mined with an enzyme-kinetic bioassay by mea-
The list of drugs and hormones capable of affecting surement of angiotensin I generation with a
the renin–angiotensin–aldosterone axis in patients radioimmunoassay and expressed as the amount
without PA is extensive [48]. However, it is essen- of angiotensin I generated per unit of time (e.g.
tial for clinicians to understand that although ng mL 1 h 1 or nmol L 1 h 1). PRC is measured
medications used to treat hypertension can poten- by an automated immunometric assay that
tially cause false-negative testing results in detects both prorenin and renin and is ex-
patients with mild PA, there is no medication that pressed as mU L 1 [50]. Normal morning PRA for
causes false-positive results, as long as a cut-off seated individuals ranges from approximately
level for aldosterone is used. Calcium channel 1–4 ng mL 1 h 1 (0.8–3.0 nmol L 1 h 1). The cor-
blockers and a1-adrenergic receptor blockers do responding normal reference range for PRC is 8 to
not affect the diagnostic accuracy in most cases 35 mU L 1. For convenience, automation and
[11]. Angiotensin-converting enzyme (ACE) inhibi- speed, many clinical laboratories have switched
tors and angiotensin receptor blockers (ARBs) have from PRA to PRC assays. In general, there is a good
the potential to elevate PRA in patients with mild correlation between PRA and PRC [51, 52].
However, PRC can be affected by oestrogen status a patient with hypertension is the clinical setting of
in women. For example, false-positive results on spontaneous hypokalaemia with PAC >555
case detection testing for PA can occur when PRC is pmol L 1 (>20 ng dL 1) and PRA <1 ng mL 1 h 1
measured in women receiving oestrogen-contain- (or PRC below the lower limit of the reference
ing preparations [48, 53, 54]. In addition, the pre- range); this presentation is diagnostic of PA [11].
ovulatory surge in oestrogen in premenopausal All other patients should have PA confirmed by
women is associated with false-positive case detec- demonstration of aldosterone secretory auton-
tion testing when using PRC, but not PRA [54]. omy with aldosterone-suppression testing, which
Thus, although both methods to measure renin are can be performed with orally administered
suitable for case detection testing for PA, use of sodium chloride and measurement of urinary
PRA is preferred. aldosterone excretion or with intravenous
sodium chloride loading and measurement of PAC
[12, 57].
Case detection tests
Case detection testing involves the measurement of Oral sodium loading test
PAC and PRA (or PRC) in a random morning At Mayo Clinic, we use the oral sodium loading test
ambulatory blood sample (Fig. 1). In 1981, Hira- as our preferred test to confirm PA. Before initiat-
matsu and colleagues proposed the PAC/PRA ratio ing the high-sodium diet, it is important to nor-
as a case detection test for PA [35]. In a patient with malize serum potassium concentration and
hypertension and hypokalaemia, secondary hyper- achieve hypertension control. Patients should
aldosteronism (e.g. renovascular hypertension) receive a high-sodium diet for 3 days. The goal is
should be considered if both PAC and PRA are a sodium intake of 5000 mg (equivalent to
increased and the PAC/PRA ratio is <277 (with PAC 218 mmol sodium or 12.8 g sodium chloride), an
measured in pmol L 1 and PRA in ng mL 1 h 1; amount that most patients can achieve with dietary
PAC/PRA ratio <10 if PAC is measured in ng dL 1 changes [13]. However, some patients find high-
and PRA in ng mL 1 h 1). If both PAC and PRA (or sodium foods unpalatable and may need to sup-
PRC) are suppressed in a patient with hypertension plement their oral sodium intake with sodium
and hypokalaemia, an alternate source of agonism chloride tablets. The serum potassium concentra-
at the mineralocorticoid receptor should be con- tion should be monitored daily and oral potassium
sidered (e.g. hypercortisolism, licorice use). Fur- chloride supplements administered as needed. On
thermore, PA should be suspected if the PRA is the morning of the third day of the high-sodium
suppressed to <1.0 ng mL 1 h 1 (or PRC below the diet, a 24-h urine collection is started for the
lower limit of the reference range) and the PAC is measurement of aldosterone, sodium and creati-
inappropriate for the PRA or PRC [e.g. PAC nine. In normal individuals, when the 24-h urinary
>277 pmol L 1 (>10 ng dL 1)]. Interpretation of sodium excretion exceeds 200 mEq there is no
the PAC/PRA ratio has proven to be confusing reason to release renin or secrete aldosterone.
due to the wide variation in the lower limits of Thus, a urinary aldosterone excretion of more than
detection for PRA. Thus, it is more practical to use 33.2 nmol day 1 (>12 lg/24 h) in the setting of
absolute values for PAC and renin (PRA or PRC) low PRA (or PRC) is consistent with autonomous
(Fig. 1). The measurement of PAC and PRA or PRC aldosterone secretion [13]. The sensitivity and
is widely accepted as the case detection test of specificity of the oral sodium loading test are 96%
choice for PA [11, 55, 56]. A PAC >277 pmol L 1 and 93%, respectively [58].
(>10 ng dL 1) and a PRA <1.0 ng mL 1 h 1 or a
PRC lower than the lower limit of the reference Intravenous saline infusion test
range is a positive case detection test result, a The intravenous saline infusion test may also be
finding that warrants further testing (Fig. 1) [11]. used to demonstrate aldosterone secretory auton-
omy [34, 57]. Following an overnight fast, 0.9%
sodium chloride solution (2 L) is infused intra-
Confirmatory tests
venously over 4 h with the patient in the seated
With one exception, a high PAC and low PRA test position [59]. Heart rate and blood pressure are
result is not diagnostic by itself, and PA must be monitored during the infusion. At the completion of
confirmed by demonstration of inappropriate the infusion, blood is collected for measurement of
aldosterone secretion [11]. The one exception to PAC. PAC levels in normal subjects decrease to less
the requirement for formal confirmatory testing in than 139 pmol L 1 (<5 ng dL 1), whereas levels
are not suppressed to less than 277 pmol L 1

(<10 ng dL 1) in most patients with PA. Postinfu-
sion PAC values between 139 pmol L 1 (5 ng dL 1)
and 277 pmol L 1 (10 ng dL 1) are indeterminate
and may be seen in some patients with IHA and
less often in patients with APA.
Other confirmatory tests

The fludrocortisone suppression and captopril
stimulation tests are less commonly used confir-
matory tests. These are described in detail else-
where [13].
Subtype studies
The optimal treatment of PA depends on whether
the aldosterone secretory autonomy is based on
one or both adrenal glands. Thus, the goal of
subtype testing is to determine whether the source
of aldosterone excess is from the right, left or both
adrenal glands. When localized to one adrenal
gland (APA or PAH), unilateral adrenalectomy
results in normalization of hypokalaemia in all
patients; hypertension is improved in all patients
and is cured in 30–60% [60–65]. In patients with
bilateral adrenal aldosterone hypersecretion (IHA
and familial forms of hyperaldosteronism), unilat- Fig. 2 A 53-year-old woman with primary aldosteronism.
eral adrenalectomy debulks the disease but does (a) Noncontrast axial computed tomography (CT) scan
not cure the excess aldosterone secretion [13]. image shows a small nodule (arrow) in the right adrenal
Thus, IHA and the familial forms of hyperaldos- gland with a CT attenuation of 3 Hounsfield units. Adrenal
venous sampling demonstrated that the right adrenal gland
teronism should be treated medically. APAs are
was the source of aldosterone hypersecretion. (b) Gross
usually small (mean diameter 1.6 cm; <1.0 cm in adrenal pathology specimen showing a golden yellow
16.5% of patients) [65] adrenal nodules with low aldosterone-producing adenoma (1.5 9 1.4 9 0.8 cm).
computed tomography (CT) attenuation [<10
Hounsfield units (HU)] on noncontrast CT and are
golden yellow in colour when resected (Fig. 2). The
adrenal glands in patients with IHA may be normal unilateral nodule with low CT attenuation (<10 HU)
on CT, may show thickening or nodular changes, on noncontrast CT is found in conjunction with
or may show incidental nonfunctioning adrenal normal contralateral adrenal morphology in a young
cortical nodules. When PA is caused by an aldos- patient (<35 years) with severe PA [e.g. sponta-
terone-producing adrenal carcinoma, it is usually neous hypokalaemia and PAC >832 pmol L 1 (>30
characterized by marked biochemical abnormali- ng dL 1)], unilateral adrenalectomy is a reasonable
ties (e.g. serum potassium <2.5 mmol L 1), severe treatment option (Fig. 3) [11, 65, 68]. However, more
hypertension and a unilateral adrenal mass larger than 95% of patients with PA are older than 35 years
than 4 cm in diameter with high noncontrast CT of age [65]. In addition, in young patients with PA,
attenuation (e.g. >20 HU) [66]. normal-appearing adrenals, minimal unilateral
adrenal limb thickening, unilateral microadenomas
Computed tomography (≤1 cm) or bilateral macroadenomas may be
Adrenal-directed CT scan should be the first test in observed on adrenal CT. If the patient wants to
the subtype evaluation of PA (Fig. 3). However, pursue the surgical option, a more accurate subtype
because of the age-related prevalence of nonfunc- test than adrenal CT is required.
tioning adrenocortical nodules [67], the reliability of
CT in localizing APAs declines with patient age. For In general, compared to patients with IHA, those
example, if a solitary small (>1 cm and <2 cm) with APAs have more severe disease, which
Fig. 3 Subtype evaluation of primary aldosteronism. For patients who want to pursue surgical treatment for their
hypertension, adrenal venous sampling is frequently a key diagnostic step (see text for details). ACC, adrenocortical cancer;
AVS, adrenal venous sampling; CT, computed tomography; MRA, mineralocorticoid receptor antagonist. Modified from
Young [89].
includes marked hypertension, spontaneous hypo- surgery and 19% would have been offered medical
kalaemia and higher levels of plasma aldosterone therapy instead of curative adrenalectomy [70]. In
[e.g. >832 pmol L 1 (>30 ng dL 1)] and urinary patients seeking a surgical cure for PA, AVS is an
aldosterone [>83 nmol day 1 (>30 lg/24 h)] [13, essential step.
69]. Patients fitting this more severe PA phenotype
are considered to have a high probability of APA. It should be noted that Dekkers and colleagues, in
Indeed, 35–41% of patients with a high probability a recent publication, caused some confusion
of APA clinical phenotype and a normal adrenal CT regarding the well-documented superiority of AVS
scan prove to have unilateral aldosterone hyper- compared to CT [71]. These authors randomly
secretion [61, 69]. assigned 200 patients with PA to undergo subtype
classification by either AVS or CT. At the 1-year
Adrenal CT is not able to distinguish accurately follow-up, there was no statistical difference in the
between APA and IHA [61, 65, 69, 70]. In one study antihypertensive treatment intensity between the
of 203 patients with PA who were evaluated with two groups. Of the 92 patients (46 in each group)
both CT and AVS, CT was accurate in only 53% of who underwent surgery, PA was persistent in nine
patients; based on the CT findings, 42 patients (20%) versus five (11%) patients in the CT-directed
(22%) would have been incorrectly excluded as and AVS-directed surgery groups, respectively. The
candidates for adrenalectomy and 48 (25%) might reported success rate of CT and failure rate of AVS
have had unnecessary or inappropriate surgery were much higher than in any other series. In
[61]. In another study, CT findings coincided with addition, the interpretation of these data was
the lateralization determined by AVS in 80/158 complicated by the use of MRAs postoperatively,
(51%) patients [69]. In a systematic review of 38 leading to blood pressure control in the patients
studies involving 950 patients with PA, adrenal CT with persistent PA from both groups. Dekkers and
and magnetic resonance imaging (MRI) results did colleagues performed cosyntropin-stimulated AVS
not agree with the findings from AVS in 359 and used an inappropriately low cut-off value for
patients (38%); based on CT/MRI, 19% of the 950 the gradient in cortisol from adrenal vein to inferior
patients would have undergone noncurative vena cava (adrenal-to-IVC cortisol gradient) of
>3 : 1 [71]. When cosyntropin is used during AVS, Multiple interventional radiologists at one centre
the minimal cortisol gradient cut-off to determine participating in the AVS programme leads to
successful catheterizations is >5 : 1 (see AVS dis- decreased volume of cases per radiologist and poor
cussion below) [11, 61, 69, 72]. Indeed, at our catheterization success rates [73, 74, 78, 79]. In
centre, the mean adrenal-to-IVC cortisol gradient addition, a centre-specific, written protocol should
was 33.9 : 1 on the right side and 23.8 : 1 on the be developed by an interested group of endocrinol-
left [61]. Centres sometimes use lower adrenal-to- ogists, hypertension specialists, internists, inter-
IVC cortisol cut-off values to improve apparent ventional radiologists and laboratory personnel
catheterization success rates and allow AVS data to [72, 78].
be ‘useable’; however, this will lead to incorrect
interpretation of AVS results, incorrect treatment At Mayo Clinic, we use continuous cosyntropin
assignment and failed treatment outcomes. The infusion (50 lg h 1 starting 30 min before sam-
persistent postoperative PA in 11% of the AVS- pling and continuing throughout the procedure)
directed treatment group reflects the lack of reli- during sequential AVS. The rationale for cosyn-
able AVS data, which is likely related to multiple tropin-stimulated AVS includes: (i) to minimize
factors [72] including low-volume AVS programmes stress-induced fluctuations in aldosterone secre-
at two of the centres and three participating tion during sequential sampling of the adrenal
radiologists at one of the centres [71, 73, 74]. veins; (ii) to maximize the adrenal-to-IVC cortisol
Finally, five patients in the CT-directed treatment gradient and thus confirm successful sampling of
group were not treated with surgery as was dic- the adrenal veins [69, 80, 81]; and (iii) to maximize
tated by the protocol, likely leading to better than the secretion of aldosterone from an APA [61, 72,
expected CT-directed outcomes [71]. The key mes- 80]. The percutaneous femoral vein approach is
sage from this study is not that CT and AVS were used to obtain blood from both adrenal veins and
equivalent in subtype testing, but rather that from the external iliac vein (labelled ‘IVC’), which
centres that have a suboptimal AVS programme are assayed for aldosterone and cortisol concen-
will have poor AVS-directed outcomes. Thus, cen- trations. The left adrenal vein blood sample is
tres that have low-volume AVS programmes or typically obtained from the common phrenic trunk
enlist multiple interventional radiologists (and immediately adjacent to the entrance to the left
dilute the expertise) or simply do not want to put adrenal vein, whereas the blood sample from the
the effort into ensuring accurate AVS [72], should right adrenal vein is obtained just at the orifice of
refer their patients with PA to centres that cham- the vein. A guide wire may be used to stabilize the
pion expertise in AVS. catheter in the correct position and avoid advanc-
ing the catheter tip too deep into the adrenal vein
Adrenal vein sampling [82]. The cortisol concentrations from the adrenal
This method remains the gold standard test to veins and IVC are used to confirm successful
distinguish unilateral from bilateral disease in catheterization (the minimal adrenal-to-IVC corti-
patients with PA [11, 34, 61, 65, 69, 70, 75]. AVS sol gradient is ≥5 : 1). As noted above, at Mayo
is a technically demanding procedure because the Clinic the mean adrenal-to-IVC cortisol gradient
right adrenal vein is small and may be difficult to was 33.9 : 1 on the right side and 23.8 : 1 on the
locate and cannulate; the success rate depends on left [61].
the expertise and engagement of the interventional
radiologist [72, 74]. The success rate for cannula- To correct for the dilutional effect of the inferior
tion of the right adrenal vein in 384 patients from phrenic vein flow into the common phrenic trunk,
47 studies was 74% [13]. However, the AVS the right and left adrenal vein PAC values are
success rate can be as high as 96%, an outcome divided by their respective cortisol concentrations;
attributed to focusing expertise to one or two these are cortisol-corrected ratios and are used to
radiologists at high-volume referral centres [61, determine the aldosterone lateralization ratio (ALR)
69, 72, 74, 76, 77]. (Fig. 4). In patients with APA, the mean cortisol-
corrected ALR (i.e. the ratio of PAC/cortisol from
Several years ago, we reported five key factors for a the APA side to that from the normal side) is 18 : 1
successful AVS programme: (i) appropriate patient [61]. An ALR cut-off of ≥4 : 1 is used to indicate
selection; (ii) careful patient preparation; (iii) unilateral aldosterone excess (Fig. 4). In patients
focused technical expertise; (iv) a defined written with IHA, the mean cortisol-corrected ALR is
protocol; and (v) accurate data interpretation [72]. 1.8 : 1 (high side to low side), and a ratio of <3 : 1
ALRs greater than ≥3.0 but <4.0 represent a zone of

overlap.
In addition to the AVS ALR, a contralateral sup-

pression index (CSI) can be calculated: the con-
tralateral (nondominant adrenal) aldosterone/
cortisol ratio is divided by the IVC aldosterone/
cortisol ratio. In the early Mayo Clinic series, the
CSI was <1.0 in 93.4% of patients with surgically
confirmed APA [61]. Although a supportive finding,
if the ALR is ≥4.0, a CSI <1.0 is not associated with
better postoperative blood pressure outcomes and
should not be a requirement for surgery [83, 84].
However, there are several situations in which the
CSI can be very helpful. For example, when the
ALR is in the grey zone (3.0–<4.0), a CSI of <1.0 is
predictive of good surgical outcomes [85]. In addi-
tion, if AVS is not bilaterally successful, a CSI of
<0.5 is highly predictive of contralateral disease
[86]. Also, patients with a CSI of <0.47 are at
increased risk for postoperative hyperkalemia (see
treatment section below) [87].
The test characteristics of AVS using an ALR of

≥4.0 for detection of unilateral aldosterone hyper-
secretion (APA or PAH) are 95% sensitivity and
98.6% specificity [61, 65]. The complication rate is
less than 2.5% at centres with experience of AVS
[61, 76]. Complications include symptomatic groin
haematoma, adrenal haemorrhage and dissection
of an adrenal vein [88]. An approach to the selective
use of AVS is outlined in Fig. 3 [89].
Fig. 4 A 67-year-old man had a 20-year history of Noninvasive alternatives to AVS

hypertension poorly controlled on four antihypertensive
Several centres are exploring noninvasive alterna-
medications and an 8-year history of hypokalaemia
requiring potassium supplementation. The case detection
tives to AVS. For example, metomidate is an
test for primary aldosteronism was positive, with a plasma inhibitor of adrenal steroidogenic enzymes and
11
aldosterone concentration (PAC) of 583 pmol L 1 C-metomidate can be used as a positron emis-
(21 ng dL 1) and low plasma renin activity (PRA) of less sion tomography (PET) radiotracer. In an initial
11
than 0.6 ng mL 1 h 1. Formal confirmatory testing for C-metomidate PET-CT receiver-operator charac-
primary aldosteronism was not needed based on the teristics analysis of 25 patients with PA, a maxi-
spontaneous hypokalaemia and positive case detection mum standardized uptake value [SUV(max)] ratio
testing. A, Axial cuts on adrenal computed tomography of 1.25 : 1 provided a specificity of 87% and
show bilateral adrenal micronodularity. B, Aldosterone sensitivity of 76%; in tumours with SUV(max)
secretion was lateralized to the right adrenal gland by
greater than 17, the specificity rose to 100% [90].
adrenal venous sampling. A 6-mm cortical adenoma was
found at laparoscopic right adrenalectomy. The postoper-
However, due to the low selectivity for CYP11B2
ative plasma aldosterone concentration was less than versus CYP11B1 of 11C-metomidate, pretreatment
<111 pmol L 1 (<4.0 ng dL 1). Hypokalaemia was cured, with dexamethasone was required. In addition,
and blood pressure was controlled with two antihyperten- and due to the short half-life of 11C, proximity to a
sive medications. cyclotron is essential. There have been few addi-
tional reports using 11C-metomidate PET-CT [91].
suggests bilateral aldosterone hypersecretion [61]. It was recently reported that there is a high
Therefore, most patients with a unilateral source of expression of CXC chemokine receptor type 4
aldosterone have cortisol-corrected ALRs ≥4.0, and (CXCR4) in adrenal glands and APAs, which
correlates with the expression of CYP11B2 (aldos- hyperaldosteronism in which the hypersecretion
terone synthase) [92]. The specific CXCR4 ligand of aldosterone can be reversed with physiologic
68
Ga-pentixafor was used as a PET imaging doses of glucocorticoid to suppress corticotropin
molecule in nine patients with PA due to APAs. In secretion [95]. FH type I was first described in a
this small number of patients, 68Ga-pentixafor single family in 1966 [96]. The aetiology was
localized to the APAs [92]. Further studies will discovered 26 years later: a nonhomologous cross-
determine whether 68Ga-pentixafor has clinically ing over on chromosome 8q24.3 between CYP11B1
acceptable sensitivity and specificity for the detec- gene (encoding 11-beta-hydroxylase) and CYP11B2
tion of APAs. Finally, in vitro and animal studies (encoding aldosterone synthase) resulting in the
have shown a high selectivity of a 18F-PET imaging CYP11B1/CYP11B2 chimeric gene where miner-
molecule (CDP2230) for CYP11B2 versus CYP11B1 alocorticoid production is regulated by corti-
with a favourable biodistribution for imaging cotropin instead of the normal secretagogue
CYP11B2 [93]. Clinical studies will be needed to angiotensin II [97]. As illustrated by a study of
determine whether this, or similar, 18F-based PET 300 consecutive patients with PA, the CYP11B1/
imaging molecules will be clinically useful. CYP11B2 chimeric gene is rare; only two patients
were detected for a prevalence of 0.67% [98]. The
CYP11B1/CYP11B2 chimeric gene is characterized
Familial hyperaldosteronism
by early onset hypertension that can be mild to
FH should be considered when PA is diagnosed severe. The diurnal nature of the aldosterone
before the age of 20 years or when PA is diagnosed excess in these patients might explain the infre-
in more than one family member. To date, four quency of hypokalaemia. The chimeric enzyme is
forms of FH have been described [94]. However, it is expressed throughout the adrenal cortex and cor-
very likely that many more disease-causing germ- tisol in the adrenal zona fasciculata is subject to C-
line mutations will be described in the coming 18 hydroxylation and C-18 oxidation, resulting in
years and the labelling of each mutation with FH increased production of the hybrid steroids 18-
type V, VI, VII, VIII, IX, etc., will likely become hydroxycortisol and 18-oxycortisol. In the absence
unmanageable. A more practical approach will be of treatment with a corticosteroid, the CYP11B1/
to indicate familial hyperaldosteronism due to the CYP11B2 chimeric gene results in overproduction
specific mutation (see Table 2). of aldosterone and 18-hydroxycortisol and 18-
oxycortisol. Genetic testing for the CYP11B1/
CYP11B2 chimeric gene should be considered for
FH type I: CYP11B1/CYP11B2 germline chimeric gene
patients with PA who have a family history of the
Glucocorticoid-remediable aldosteronism (GRA; disease, onset of PA at a young age (<20 years) or a
FH type I; OMIM #103900) is a form of family history of strokes at a young age.
Table 2 Forms of familial hyperaldosteronism
Familial
hyperaldosteronism Germline mutation and future OMIM
type classification Other terminology classification
Type I CYP11B1/CYP11B2 germline Glucocorticoid-remediable 103900
chimeric gene aldosteronism
Type II Germline CLCN2 chloride channel
mutations
Type III Germline KCNJ5 mutations 613677
Type IV Germline CACNA1H mutations 607904
Germline CACNA1D mutations Primary aldosteronism with seizures 615474
and neurologic abnormalities (PASNA)
Germline armadillo repeat Bilateral macronodular adrenal 615954
containing 5 (ARMC5) mutations hyperplasia (BMAH)
germline KCNJ5 mutations is 0.3% in patients

FH type II: CLCN2 chloride channel germline mutations
with PA and 8% among patients with familial PA
FH type II was first reported in 1991 and is [109]. Most patients with germline KCNJ5 muta-
inherited in an autosomal dominant manner [99– tions present with polyuria, polydipsia and refrac-
102]. Families with FH type II have had APAs and tory hypertension in childhood; investigations
IHA. FH type II is more common than FH type I, but show both marked hypokalaemia and PA. In most
accounts for fewer than 6% of all patients with PA cases, the degree of aldosterone hypersecretion is
[98]. A linkage analysis study showed an associa- so high that bilateral adrenalectomy is required.
tion with chromosomal region 7p22 [100, 102]. However, there is some heterogeneity in age at
presentation (as old as 48 years) [114] and the
In a recent report of a family with FH type II and 80 hypertension and hypokalaemia in some patients
additional probands with unsolved early onset PA, can be controlled with MRAs [108–111] One patient
the authors found germline CLCN2 chloride chan- with a germline KCNJ5 mutation was reported
nel mutations in eight of the probands [103]. All to have concurrent adrenal-dependent Cushing
relatives with early onset PA carried the CLCN2 syndrome [116].
variant found in the proband. CLCN2 encodes a
voltage-gated chloride channel expressed in adre-
FH type IV: germline CACNA1H gene mutations
nal glomerulosa cells. The chloride channels open
at hyperpolarized membrane potentials and FH type IV (OMIM #617027) is inherited in an
mutant channels show gain of function, with autosomal dominant fashion and with incomplete
higher open probabilities at the zona glomerulosa penetrance and is caused by mutations in the
resting potential [103, 104]. Mutations in the CACNA1H gene (located on chromosome 16p13),
CLCN2 chloride channel may be responsible in all which encodes the alpha subunit of an L-type
or some of the individuals who have been classified voltage-gated calcium channel (Cav3.2) [117, 118].
with FH type II. As mentioned above, FH type II is A novel germline CACNA1H mutation (p.Met1549-
likely to prove to be a ‘place holder’ for a series of Val) was identified in five out of 40 unrelated
mutations that contribute to PA (Table 2). patients affected by hypertension and PA in child-
hood [117]. Four additional germline CACNA1H
mutations have been reported in patients with PA
FH type III: germline KCNJ5 mutations
(p.Met1549Ile, p.Ser196Leu, p.Pro2083Leu and
FH type III (OMIM #613677) was first described in p.Val1951Glu) [118].
1959 in a 5-year-old boy [105], just 4 years after
the initial description of PA by Conn [1]. The true A commercial test for germline CACNA1H muta-
familial nature of this disorder was evident in 2008 tions is available and should be considered in
when the index patient’s two daughters at ages 4 children with hyperaldosteronism and in families
and 7 years were diagnosed with severe PA [106]. with more than one member with PA. The treat-
Due to refractory hypertension, the father and two ment of patients with germline CACNA1H muta-
daughters were treated with bilateral adrenalec- tions should be identical to that of patients with
tomy in childhood. The adrenal glands showed apparent sporadic PA due to IHA. However, in
massive hyperplasia [106]. In 2011, the causative selected cases of refractory disease associated with
germline mutation in this family was discovered: a massive bilateral adrenal hyperplasia, bilateral
point mutation (Thr158Ala) in and near the selec- laparoscopic adrenalectomy may need to be con-
tivity filter of the potassium channel Kir3.4 (GIRK4) sidered.
encoded by KCNJ5 [107]. This KCNJ5 mutation
causes a lack of ion selectivity and sodium entry
PA with seizures and neurologic abnormalities: germline CACNA1D
results in cell depolarization, triggering calcium
mutations
entry into glomerulosa cells; this is the signal for
increased CYP11B2 expression, aldosterone pro- PA with seizures and neurologic abnormalities
duction and cell proliferation. Thus far, 12 kin- (PASNA) is caused by de novo germline mutations
dreds carrying six different KCNJ5 mutations have in CACNA1D (OMIM #615474). CACNA1D encodes
been identified: p.Thr158Ala [107]; p.Gly151Glu for the a1D subunit of an L-type voltage-gated
[108–110]; p.Gly151Arg [108, 111, 112]; p.Ile157- calcium channel (Cav 1.3) and is located on chro-
Ser [113]; p.Tyr152Cys [114]; and p.Glu145Gln mosome 3p14.3. PASNA has have been reported in
[110, 115, 116]. The estimated prevalence of two children with PA, seizures and neurologic
abnormalities. The severe neurologic abnormalities peripheral (APA, n = 344; bilateral IHA, n = 174)
do not allow these individuals to reproduce and DNA of patients with PA [130]. Somatic KCNJ5
thus, although due to a germline mutation, it is not mutations (G151R or L168R) were found in 34% of
technically a familial form of PA. In addition, a APAs; mutations were more prevalent in women
missense CACNA1D germline mutation (p.Val104- (49%) than men (19%) (P < 0.001) and associated
Leu) was reported in a patient affected by autism with higher pre-operative aldosterone levels but
and epilepsy [119]. The clinical phenotypes asso- not with therapeutic outcome after surgery [130].
ciated with germline mutations in CACNA1D will
likely prove to be variants of that seen with PASNA. In a meta-analysis including 13 studies with 1636
patients, the overall prevalence of somatic KCNJ5
mutations in patients with APAs was 43% [131]. This
PA and ARMC5 mutations
study also found that the prevalence rates of KCNJ5
Heterozygous germline mutations of the armadillo mutations were higher in East Asian populations
repeat containing 5 (ARMC5) gene are most com- compared to Western populations, centres that used
monly linked to subclinical glucocorticoid secre- strict criteria for AVS and women more than in men.
tory autonomy or Cushing syndrome in patients
with bilateral macronodular hyperplasia [120, Somatic APA mutations have been identified in
121]. However, there are reports of ARMC5 muta- three other genes: ATP1A1 encoding Na+/K+-
tions in patients with PA and Cushing syndrome ATPase 1; ATP2B3 encoding Ca2+-ATPase 3; and
due to bilateral macronodular hyperplasia, a co- CACNA1D, encoding a voltage-gated calcium chan-
occurrence seen most commonly in African Amer- nel [125, 132]. In a recent study, somatic APA
ican patients [122, 123]. mutations in KCNJ5, ATP1A1 and ATP2B3 were
present in 39.2%, 6.3% and 0.9% of 112 APAs,
respectively [133]. To date, 13 different ATP1A1
Somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and
and nine ATPB3 somatic mutations have been
CTNNB1 genes
reported [134].
A major advance in the past decade has been the
discovery of the underlying pathophysiology of the In addition, 31 different CACNA1D mutations have
majority of APAs [101, 124]. Somatic mutations been described and account for approximately 9%
account for more than half of APAs and include of sporadic APAs [134, 135]. CACNA1D APAs are
mutations in genes encoding components of the Kir composed of zona glomerulosa-like cells and are
3.4 (GIRK4) potassium channel (KCNJ5) [108], the smaller than those with either no somatic mutation
sodium/potassium and calcium ATPases (ATP1A1 or KCNJ5 APAs [128, 129, 135]. The clinical
and ATP2B3) [125], and a voltage-dependent C- correlate is that APAs with somatic CACNA1D
type calcium channel (CACNA1D) [126]. In a mul- mutations are the most common somatic mutation
ticentre study of 351 APAs from patients with PA in patients with APAs with negative or minimal
and 130 other adrenocortical lesions, two somatic nodularity (<1 cm) on pre-operative cross-sectional
mutations in KCNJ5 (G151R or L168R) were iden- imaging [136]. Of interest, up to three different
tified in 47% of APAs [127]. Somatic KCNJ5 muta- somatic driver mutations (two KCNJ5 and one
tions were absent in adrenal tissue from patients CACNA1D) have been found in the three different
with PA due to unilateral hyperplasia and in 130 APAs in the same patient [137].
nonaldosterone-secreting adrenal lesions. KCNJ5
mutations were over-represented in APAs from The CTNNB1 gene encodes b-catenin and activating
women compared with men (63% vs. 24%), and CTNNB1 mutations have been found in 3% of
APAs with KCNJ5 mutations had larger lesional sporadic APAs [138, 139]. Similar to KCNJ5 APAs,
diameters than those without the mutation (2.7 vs. CTNNB1 APAs are associated with female sex and
1.7 cm) [127]. The larger size of KCNJ5 APAs is larger adenomas. It is likely that close to 100% of
explained in part by the zona fasciculata-like cells APAs will eventually be associated with somatic
and lower levels of aldosterone synthase expres- driver mutations.
sion compared to APAs caused by somatic muta-
tions in ATP1A1, ATP2B3 or CACNA1D [128, 129].
Aldosterone-producing cell clusters
In a separate multicentre study, KCNJ5 sequenc- Aldosterone synthase (CYP11B2) expression is
ing was performed on somatic (APA, n = 380) and limited to the zona glomerulosa of the adrenal
gland. However, CYP11B2 and CYP11B1 immuno- withdrawal in surgically treated patients with
histochemical staining studies have detected focal APAs.
subcapsular nests of adrenocortical cells that
extend into the zona fasciculata and stain strongly APAs can co-secrete cortisol that may be clinically
for CYP11B2 and are termed aldosterone-produ- important for peri-operative management [154,
cing cell clusters (APCCs) [140]. APCCs have been 155]. When should clinicians test for cortisol co-
identified in normal adrenal glands and in pathol- secretion in patients with APAs? In general, clini-
ogy specimens from patients with PA, where APCCs cally important cortisol secretion from an adrenal
may occur adjacent to APAs [140]. APCCs have adenoma is correlated with tumour size. Unlike
been shown to harbour somatic mutations in aldosterone secretion from an adenoma, clinically
CACNA1D and ATP1A1, and this raises the possi- important cortisol secretion requires a ‘large fac-
bility that APCCs may secrete aldosterone auton- tory’ (typically with adenoma diameters >2 cm)
omously and could be precursors to APAs [141]. It [155]. Thus, it is reasonable to test patients with
is interesting that the presence of APCCs increases PA for cortisol co-secretion when the adrenal
with age and may in part reflect the ageing adrenal adenoma is >1.5 cm in diameter. Such testing
gland [142, 143]. Studies to determine the clinical includes baseline dehydroepiandrosterone sul-
relevance of APCCs are underway. phate and an overnight 1-mg dexamethasone sup-
pression test [156]. When glucocorticoid secretory
autonomy is observed in a patient with PA who has
Cortisol co-secretion
a single cortical adenoma >1.5 cm in diameter, it
Patients with PA have been shown to be at could be argued that AVS is not needed. Clinicians
increased risk for insulin resistance and metabolic do not have a good long-term medical management
syndrome [144–149], depression [23, 24] and option for Cushing syndrome, whereas PA can be
osteoporotic fractures [150–152]. These associa- treated effectively with MRAs. Rarely, PA and
tions would seem to be consistent with glucocorti- Cushing syndrome can co-exist due to separate
coid secretory autonomy or excess. A steroid aldosterone- and cortisol-secreting adenomas
metabolome study compared the following patient [157].
groups: 174 patients with PA (103 APA, 71 IHA);
162 healthy controls; 56 patients with endocrine
Principles of treatment
inactive adrenal adenoma; 104 patients with mild
subclinical glucocorticoid secretory autonomy; and The treatment objectives for patients with PA
47 patients with adrenal-dependent Cushing syn- include resolution of hypokalaemia as well as
drome [153]. The key findings were that: (i) patients prevention of the morbidity and mortality associ-
with PA (APA and IHA) had significantly increased ated with hypertension, progressive chronic kidney
cortisol and total glucocorticoid metabolite excre- disease and further cardiovascular damage. The
tion compared to controls and patients with sub- cause of PA dictates the optimal treatment option.
clinical Cushing syndrome (P < 0.001); (ii) It is essential for clinicians to understand that
surrogate parameters of metabolic risk correlated normalization of blood pressure is not the only
with glucocorticoid but not mineralocorticoid goal. In the presence of sodium, excessive auton-
excretion; and (iii) unilateral adrenalectomy in omous secretion of aldosterone is associated with
patients with APA resolved both mineralocorticoid an increased risk of cardiovascular disease and
and glucocorticoid excess [153]. These findings morbidity. Thus, either curative surgery or opti-
suggest that some degree of cortisol co-secretion is mized mineralocorticoid receptor blockade should
highly prevalent in patients with PA and is linked to be part of the management plan for all patients
metabolic risk, which may indicate that treatment with PA. As highlighted above, a recent QoL study
with MRAs in patients with IHA and APA may not found that the beneficial effects of surgical treat-
prevent glucocorticoid-dependent metabolic risk ment were greater than for treatment with MRAs
[153]. However, these data should be interpreted [26]. Thus, surgical management is the optimal
with caution because this study was not simply treatment approach for patients with unilateral
identifying cortisol co-secretion from APAs, but disease. By contrast, in patients with PA caused by
rather increased corticosteroid metabolome in bilateral adrenal disease, bilateral adrenalectomy
patients with APA and IHA. The hypothalamic– is not a ‘good trade’ due to the resultant primary
pituitary–adrenal axis is not suppressed in these adrenal insufficiency and need for lifelong gluco-
patients, and there is no adrenal crisis or steroid corticoid and mineralocorticoid replacement.
Unilateral adrenalectomy for APA is cost-effective

Surgical treatment of APA and unilateral hyperplasia
[164] and significantly less expensive than long-
The optimal treatment of APA or unilateral hyper- term medical therapy [165]. As mentioned above, a
plasia is curative surgery because hypertension recent QoL study compared patients with PA who
control is improved in all patients and no blood were managed surgically (n = 92) to those who
pressure medications are required in 30–60% of were managed medically (n = 92) [26]. After 1 year,
individuals [60, 65, 84, 158–161]. In a retrospec- almost all QoL measures had normalized for sur-
tive case series from 12 centres with data for 705 gically managed patients, whereas most QoL mea-
patients with PA who were treated surgically, 259 sures had improved but not to the level of the
(37%) were cured of hypertension and 334 (47%) general population for patients receiving medical
were improved; complete clinical success was more treatment [26].
likely in female and younger patients [64]. In a
retrospective observational study of 119 patients Risk for postoperative hyperkalemia
who underwent AVS, an ALR >8 was statistically Postoperatively, there is a risk of short-term
significantly associated with blood pressure hypoaldosteronism leading to clinically important
improvement after surgery [84]. Pre-operative fac- hyperkalemia [87, 166, 167]. In a multicentre
tors predictive of some degree of persistent hyper- study of 142 surgically treated patients, the preva-
tension after adrenalectomy include more than lence of postoperative hyperkalemic was 9.9%; the
one-first-degree relative with hypertension, use of hyperkalemic patients were older and had worse
more than two antihypertensive agents, older age, renal function than the nonhyperkalemic patient
increased serum creatinine level and longer dura- group [168]. In a study of 192 patients with PA who
tion of hypertension [60, 162]. were treated surgically, 12 (6.3%) developed post-
operative hyperkalemia (median serum potassium
Unilateral laparoscopic adrenalectomy by an 5.5 mmol L 1, range 5.2–6.2 mmol L 1); median
expert laparoscopic adrenal surgeon is the optimal time to onset was 13.5 days (range 7–55 days) [87].
surgical approach; patients typically require only Five patients had transiently increased serum
one night of hospitalization and are able to return potassium concentrations that normalized sponta-
to work and usual activities in 7–10 days. Because neously. In four patients, the hyperkalemia was
APAs are small and may be multiple and not treated with mineralocorticoid-replacement ther-
distinguishable by the surgeon intra-operatively, apy (fludrocortisone). On univariate analysis,
the entire adrenal gland should be removed [163]. hyperkalemic patients had slightly greater pre-
In a report on 55 patients with PA who underwent operative serum creatinine levels (106.1 vs.
adrenalectomy, three (5.5%) had persistent PA 88.4 lmol L 1, P = 0.01), higher postoperative cre-
postoperatively; all three patients underwent par- atinine (115 vs. 88.4 lmol L 1, P = 0.02), lower
tial adrenalectomy to remove a CT-detected nodule median AVS CSI (0.14 vs. 0.27, P = 0.03) and
that was co-localized with AVS, and immunohisto- larger adenomas (1.9 vs. 1.4 cm, P = 0.02). Multi-
chemistry showed CYP11B2-negative nodules [69]. variable logistic regression showed that the CSI
Thus, the intra-operative nodule visible to the remained the only significant predictor of postop-
surgeon was not the source of aldosterone hyper- erative hyperkalemia (P = 0.04) with an optimal
secretion [69]. cut-off of <0.47 [87]. At Mayo Clinic, we monitor
serum potassium weekly for 4 weeks after surgery,
Prior to surgery, blood pressure should be con- and a high-sodium diet should be followed to avoid
trolled and hypokalaemia corrected with potas- the hyperkalemia of hypoaldosteronism. Short-
sium supplements or an MRA. PAC should be term fludrocortisone supplementation may be
measured the morning after the operation to con- required if the serum potassium concentration
firm a biochemical cure [65]. Following surgery, rises above 5.2 mEq L 1. In some exceptional
MRAs and potassium supplements should be dis- cases, long-term mineralocorticoid replacement
continued. In general, the number and dosages of may be needed.
antihypertensive medications can be cut by 50%
postoperatively. Any medications that may con- Renal function after surgery
tribute to hyperkalemia (e.g. ACE inhibitors and Clinicians should recognize that most patients with
ARBs) should be discontinued. The proportion of long-standing PA have some degree of renal
hypertension that was associated with aldosterone insufficiency that is masked by the glomerular
excess resolves in 1–3 months after surgery. hyperfiltration associated with aldosterone excess
[169–171]. Approximately 40% of patients with PA been the drug of choice to treat PA. Available as 25-
show a clinically important decrease in renal , 50- and 100-mg tablets, the initial dosage is 12.5–
function after surgery [172]. Glomerular hyperfil- 25 mg per day and increased to 400 mg day 1 if
tration pre-operatively masks mild to moderate necessary to achieve a high–normal serum potas-
underlying renal failure. In one study, the average sium concentration without the aid of oral potas-
decrease in estimated glomerular filtration rate sium chloride supplementation. During the first
was 16.7 mL min 1/1.73 m2 (a decrease of 19.7%) 6 weeks of treatment, serum potassium and crea-
[173]. Effective treatment of PA with either surgery tinine should be monitored frequently (e.g. weekly).
or an MRA will unmask the underlying chronic Concomitant therapy with salicylates should be
kidney disease. avoided as they decrease the effectiveness of
spironolactone. Because spironolactone is not
selective for the mineralocorticoid receptor, side
Pharmacologic treatment
effects are common. Due to antagonism at the
Medical management with MRAs is the treatment androgen receptor, spironolactone at dosages of
of choice for IHA and GRA. Although not the more than 50 mg per day may result in painful
optimal treatment option, MRAs may also be used gynaecomastia, erectile dysfunction and decreased
to treat patients with PA that is caused by an APA libido in men. Agonist activity at the progesterone
[26, 174]. The general guidance that should be receptor may result in menstrual irregularity in
provided to all patients with hypertension is also women [177].
appropriate for patients with PA: maintain ideal
body weight, avoid tobacco, participate in a regular Eplerenone, a competitive and selective MRA, was
exercise programme and follow a sodium-restricted approved by the FDA for the treatment of uncom-
diet. Randomized placebo-controlled trials have plicated essential hypertension in 2003. Compared
not been performed to evaluate the relative efficacy with spironolactone, eplerenone has 0.1% of the
of drugs in the treatment of PA [175]. binding affinity to androgen receptors and less
than 1% of the binding affinity to progesterone
In a longitudinal study assessing 602 patients with receptors. In a randomized double-blind trial that
PA treated with MRAs matched with 41,853 compared the efficacy, safety and tolerability of
patients with essential hypertension (with compa- eplerenone to that of spironolactone (100–300 vs.
rable cardiovascular disease risk profiles and blood 75–225 mg, respectively) in patients with PA, it was
pressure control), the incidence of cardiovascular found that spironolactone was superior to epler-
events was higher in patients with PA treated with enone for blood pressure lowering and associated
MRAs than in those with essential hypertension with higher rates of male gynaecomastia (21% vs.
[56.3 vs. 26.6 events per 1000 person-years, 5%) and female mastodynia (21% vs. 0%) [178]. A
adjusted hazard ratio (HR) 1.91] [176]. Patients shared decision-making discussion with the
with PA also had higher adjusted risks for incident patient determines the optimal initial MRA. Epler-
mortality (HR 1.34), diabetes (HR 1.26) and atrial enone is available as 25- and 50-mg tablets and
fibrillation (HR 1.93). Of interest, the excess risk should be administered twice daily because of its
for cardiovascular events and mortality was limited short half-life; a typical starting dosage is 25 mg
to patients with PA who had suppressed PRA on twice daily with the plan to titrate upward for a
medical treatment, suggesting inadequate dosing target high–normal serum potassium concentra-
of MRAs [176]. Thus, if medical management is to tion without the aid of potassium supplements.
be pursued, it is essential that the MRA dosage is Although the maximum dose approved by the FDA
adequate to fully block the toxic effects of hyper- for hypertension is 100 mg per day, potency stud-
aldosteronism. Due to concomitant low-renin ies have shown that eplerenone is 25–50% less
essential hypertension in some patients with PA, potent compared with spironolactone. When
measurement of PRA may not be optimal to guide titrated for a serum potassium concentration
management; a high–normal serum potassium between 4.0 and 5.0 mmol L 1, typical doses of
without the aid of oral potassium supplements eplerenone are 200–300 mg per day in patients
may be a more practical treatment target to deter- with PA. In the initial phase of treatment, it is
mine the effective MRA dosage. important to closely monitor blood pressure and
serum levels of potassium and creatinine. Because
Spironolactone was approved by the US Food and the hypertension in patients with IHA is multifac-
Drug Administration (FDA) in the 1960s and has torial and frequently coincident with essential
hypertension, a second antihypertensive agent Pregnancy does not impact the performance of case
is often needed to achieve good blood pressure detection testing for PA. As in the nonpregnant
control. Nonloop diuretics (e.g. 12.5–50 mg woman, a morning blood sample should be
hydrochlorothiazide daily) are very effective in obtained for the measurement of PAC and renin
combination with the MRA. (PRA or PRC). If spontaneous hypokalaemia is
present in the pregnant woman with suppressed
In patients with GRA confirmed by germline muta- renin and the PAC is >555 pmol L 1 (>20 ng dL 1),
tion testing, chronic treatment with physiologic additional confirmatory testing is not needed.
doses of a glucocorticoid corrects hypokalaemia However, confirmatory testing should be pursued
and normalizes blood pressure. However, the if the patient is normokalemic. Confirmatory test-
clinician should be mindful to avoid iatrogenic ing in the setting of pregnancy can be challenging
Cushing syndrome with excessive doses of because the captopril stimulation test is con-
glucocorticoids. Shorter-acting glucocorticoids traindicated in pregnancy and the saline infusion
such as hydrocortisone should be prescribed, test may not be well tolerated because of oedema.
using the smallest effective dose in relation to body The optimal confirmatory test in the setting of
surface area (e.g. hydrocortisone 10–12 mg m 2 pregnancy is measurement of aldosterone excre-
per day). Age-specific blood pressure percentiles tion in a 24-h urine collection on an ambient
should be used to determine the target blood sodium diet. In order to avoid exposure to radiation
pressure. In addition, children should be moni- or contrast material, subtype testing in pregnancy
tored by paediatricians with expertise in glucocor- should start with abdominal MRI without gadolin-
ticoid therapy. Another treatment option for ium. Unilateral APA can be diagnosed in the
patients with GRA includes MRAs; this option unique clinical setting of pregnancy with marked
avoids iatrogenic subclinical or clinical Cushing PA [spontaneous hypokalaemia and PAC
syndrome. In addition, treatment with an MRA or a >832 pmol L 1 (>30 ng dL 1)] and a clear unilat-
glucocorticoid may have a role in normotensive eral adrenal adenoma on MRI [65].
patients with GRA [16].
The severity of hypertension and hypokalaemia
Aldosterone synthase inhibitors, although not yet dictates the treatment of PA in pregnancy. For
available for clinical use, are in development [179]. example, in the subset of patients who have
remission in the degree of PA, surgery or treatment
with an MRA can be avoided until after delivery.
PA in the setting of pregnancy
However, surgical and/or medical intervention is
PA is uncommon in pregnancy and fewer than 50 indicated if hypertension and hypokalaemia are
cases have been reported in the literature; most marked. Unilateral laparoscopic adrenalectomy
pregnant patients with PA have APA [180–185]. PA during the second trimester can be considered in
in pregnancy can lead to preterm delivery, those women with severe PA and documented
intrauterine growth retardation, placental abrup- unilateral APA (see above).
tion and intrauterine foetal demise [185–187]. An
unusual feature of PA during pregnancy is that the Spironolactone is listed by the FDA as a pregnancy
degree of disease may be either improved or category C drug because feminization of newborn
aggravated. In some women with PA, the high male rats has been documented. However, only one
blood concentrations of pregnancy-related proges- human case has been reported where treatment
terone are antagonistic at the mineralocorticoid with spironolactone in pregnancy led to ambiguous
receptor and partially block the action of aldos- genitalia in a male infant due to spironolactone
terone; these patients in fact have an improvement treatment for polycystic ovary syndrome prepreg-
in the degree of hypertension and hypokalaemia nancy and through the fifth week of gestation
during pregnancy [188, 189]. In other pregnant [192]. Eplerenone is listed by the FDA as a preg-
women, increased expression of the luteinizing nancy category B drug. When PA is managed
hormone–choriogonadotropin receptor in APAs medically in pregnant women, the hypertension
harbouring beta-catenin mutations has been doc- should be treated with standard antihypertensive
umented, and the degree of hypertension and drugs that are approved for use during pregnancy.
hypokalaemia can be aggravated by the increased Hypokalaemia should be treated with oral potas-
pregnancy-related blood levels of human chorionic sium supplements. In those cases of severe PA in
gonadotropin [190, 191]. pregnancy where surgery is not an option, low-
dose eplerenone may be considered [180, 193, • Surgery for an APA should be unilateral
194]. adrenalectomy (not partial adrenalectomy)
because the surgeon cannot reliably identify
small APAs intra-operatively.
Summary of practical considerations
• PA is a relatively common cause of hypertension • Because of the risk for postoperative hyper-
kalemia, all patients should be followed with
and the hypertension can be either cured with
serum potassium monitoring weekly for 4 weeks.
surgery or specifically targeted with pharmaco-
logic therapy.
• All patients with PA who are not treated surgi-
cally should be treated with an MRA. For effective
• Undetected or ineffectively treated PA results in
mineralocorticoid receptor blockade, the dosage
increased cardiovascular morbidity and nephro-
of the MRA should be titrated to a high–normal
toxicity.
level of serum potassium without oral potassium
supplements.
• All patients with hypertension should be tested
for PA at least once.
Conflict of interest statement
• Case detection testing for PA should be per-
In the past 5 years, the author has received con-
formed by measuring a morning blood sample for
sultancy fees from Nihon Medi-Physics, Ltd.
PAC and renin (PRA or PRC). This test should be
performed without changing blood pressure
medications. No blood pressure medication
causes a false-positive testing result as long as References
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Aldosteronismo Primario

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13652796, 2019, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.12831 by Cochrane Mexico, Wiley Online Library on [02/11/2022].

Diagnosis and treatment of primary aldosteronism: practical

micronodular or macronodular hyperplasia of the

Who should be screened for PA?

In efforts to conserve medical costs and limit the

are not suppressed to less than 277 pmol L 1

Other confirmatory tests

ALRs greater than ≥3.0 but <4.0 represent a zone of

In addition to the AVS ALR, a contralateral sup-

The test characteristics of AVS using an ALR of

Fig. 4 A 67-year-old man had a 20-year history of Noninvasive alternatives to AVS

Table 2 Forms of familial hyperaldosteronism

germline KCNJ5 mutations is 0.3% in patients

Unilateral adrenalectomy for APA is cost-effective

• For most patients with PA who want to pursue

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