Review

Diagnosis and treatment of primary aldosteronism

Martin Reincke, Irina Bancos, Paolo Mulatero, Ute I Scholl, Michael Stowasser, Tracy Ann Williams

Lancet Diabetes Endocrinol Primary aldosteronism is a common cause of secondary hypertension associated with excess cardiovascular
2021; 9: 876–92 morbidities. Primary aldosteronism is underdiagnosed because it does not have a specific, easily identifiable feature
Medizinische Klinik und and clinicians can be poorly aware of the disease. The diagnostic investigation is a multistep process of screening,
Poliklinik IV, Klinikum der
confirmatory testing, and subtype differentiation of unilateral from bilateral forms for therapeutic management.
Universität München, Munich,
Germany (Prof M Reincke MD, Adrenal venous sampling is key for reliable subtype identification, but can be bypassed in patients with specific
T A Williams PhD); Division of characteristics. For unilateral disease, surgery offers the possibility of cure, with total laparoscopic unilateral
Endocrinology, Metabolism adrenalectomy being the treatment of choice. Bilateral forms are treated mainly with mineralocorticoid receptor
and Nutrition, Department of
antagonists. The goals of treatment are to normalise both blood pressure and excessive aldosterone production, and
Internal Medicine, Mayo Clinic,
Rochester, MN, USA the primary aims are to reduce associated comorbidities, improve quality of life, and reduce mortality. Prompt
(I Bancos MD); Division of diagnosis of primary aldosteronism and the use of targeted treatment strategies mitigate aldosterone-specific target
Internal Medicine and organ damage and with appropriate patient management outcomes can be excellent. Advances in molecular
Hypertension, Department of
Medical Sciences, University of
histopathology challenge the traditional concept of primary aldosteronism as a binary disease, caused by either a
Turin, Turin, Italy unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Somatic mutations drive autonomous
(Prof P Mulatero MD, aldosterone production in most adenomas. Many of these same mutations have been identified in nodular lesions
T A Williams); Berlin Institute of adjacent to an aldosterone-producing adenoma and in patients with bilateral disease. In addition, germline mutations
Health at Charité –
Universitätsmedizin Berlin,
cause rare familial forms of aldosteronism (familial hyperaldosteronism types 1–4). Genetic testing for inherited
Center of Functional Genomics, forms in suspected cases of familial hyperaldosteronism avoids the burdensome diagnostic investigation in positive
Berlin, Germany (U I Scholl MD); patients. In this Review, we discuss advances and future management approaches in the diagnosis of primary
Endocrine Hypertension aldosteronism.
Research Centre, University of
Queensland Diamantina
Institute, Greenslopes and Introduction and overview of the renin chloride delivery to the juxtaglomerular apparatus and the
Princess Alexandra Hospitals, angiotensin aldosterone system rise in systemic blood pressure results in suppression of
Brisbane, QLD, Australia Arterial hypertension is a major cause of premature death, renin secretion. Consequently, the aldosterone-to-renin
(Prof M Stowasser PhD)
affecting more than 1·4 billion adults worldwide.1 Hyper­ ratio (ARR) is increased. Aldosterone secretion in primary
Correspondence to:
Prof Martin Reincke,
tension causes 7·0% of the worldwide disability-adjusted aldosteronism remains elevated, autonomous, and
Medizinische Klinik und life-years.2 The renin-angiotensin-aldosterone system inappropriately high for blood volume and blood
Poliklinik IV, Klinikum der (RAAS) is of paramount importance for homeostasis of pressure.5 Aldosterone excess is associated with excess
Universität München, plasma sodium concentrations, blood volume, and mean cardiovascular morbidity and mortality.5 Primary
80336 Munich, Germany
[email protected]
arterial blood pressure. The RAAS is a hierarchical cascade aldosteronism represents the most frequent curable form
muenchen.de that begins with the production of renin from the of secondary hypertension and the various patient groups
juxtaglomerular cells of the kidney (figure 1A). Renin that have been recommended for screening account for
release is stimulated by decreased renal perfusion, low around 50% of the hypertensive population. However,
sodium concentrations in the renal tubule, and central β1- currently fewer than 1% of patients with primary
adrenergic receptor-mediated sympathetic system aldosteronism are screened and treated during their
activation. Renin regulates the rate-limiting step of the lifetime.6–9
RAAS through the conversion of angiotensinogen to This Review provides a timely overview on primary
angiotensin I, which is activated to form the vasopressor aldosteronism, describing its characteristics and how it is
octapeptide angiotensin II by angiotensin I-converting screened, confirmed, and subtyped. We highlight the
enzymes in the endothelium of the lung and kidney. current standards of treatment and reflect controversial
Angiotensin II triggers the release of aldosterone from the areas and fields of uncertainty.
outer zone of the adrenal cortex (the zona glomerulosa)
and acts on the nephron to increase sodium and water Epidemiology of primary aldosteronism
reabsorption. RAAS inhibition is a cornerstone of blood- Once considered rare, primary aldosteronism is now
pressure management, with angiotensin-converting thought to be the most common secondary endocrine
enzyme (ACE) inhibitors, angiotensin receptor blockers form of hypertension.5 The introduction of the ARR as a
(ARBs), and mineralocorticoid receptor antagonists screening test10 and its application to a widening
blocking the RAAS at different levels of the RAAS population of patients with hypertension has led to a
cascade.3 Primary aldosteronism, first described by Jerome marked increase in the detection of primary aldosteronism,
Conn in 1954,4 results from excessive production of especially among patients who are normokalaemic. Most
aldosterone independent of renin and angiotensin II, and studies have reported primary aldosteronism prevalence
leads to increased renal tubular resorption of sodium and rates between 5% and 15%, with the majority of patients
volume expansion, resulting in hypertension and being normokalaemic.11,12 However, studies have suggested
hypokalaemia (figure 1B).5 The increase in sodium that primary aldosteronism or dysregulated aldosterone

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 Review

production could be even more frequent than currently

A Healthy B Primary aldosteronism
accepted in patients with hypertension.13,14 Variability in
prevalence rates reported in different studies is explained Angiotensinogen Angiotensinogen
Decreased
by the use of different diagnostic methods and cutoffs, Renin renin
and the variable degree of selectiveness of the cohorts that
were examined (table 1).
Angiotensin I Decreased
The prevalence of primary aldosteronism increases in angiotensin I
line with the severity of hypertension.15 In patients with ACE ACE
resistant hypertension, prevalence rates range from 11·3%
to 29·1% (table 1).13,17–19 The clinical need to continue Angiotensin II
Decreased
angiotensin II
antihypertensive medications that affect aldosterone and
renin concentrations in those studies raises some doubt
about the accuracy of the diagnosis in each case, with the
potential for either overdetection or underdetection of
primary aldosteronism. Nevertheless, mineralocorticoid
receptor antagonists have been reported to be particularly
effective at lowering blood pressure in cohorts of patients
Na+ retention
with resistant hypertension,26 which argues in favour of a K+ diuresis
Aldosterone
high prevalence of primary aldosteronism among them. Increased Volume overload
aldosterone Hypertension
High prevalence rates of primary aldosteronism have also Increased ARR
been reported in patients with hypertension and either
atrial fibrillation23 or diabetes mellitus (table 1).24,25 Among
Figure 1: Physiology and pathophysiology of the renin angiotensin aldosterone system
individuals who were normotensive in the Framingham
Physiological regulation (A). Dysregulation in primary aldosteronism (B). ACE=angiotensin converting enzyme.
Offspring Study, both a rise in blood pressure and the ARR=aldosterone–renin ratio.
incident development of hypertension during 4 years of
follow up were positively correlated with aldosterone and a excess risk of cardiovascular, cerebrovascular, and renal
rise in ARR, and negatively correlated with renin, as complications can be successfully reversed by specific
would be expected if aldosterone secretion was treatment of unilateral primary aldosteronism by
autonomous.27 adrenalectomy and of bilateral forms of primary
aldosteronism by mineralocorticoid receptor antagonist
Comorbidities in primary aldosteronism therapy.44–46 Higher aldosterone concentrations are
Aldosterone excess in primary aldosteronism is associated associated with increased all-cause mortality when renin
with deleterious effects on the heart, vessels, brain, and is suppressed in a general population of adults.47 Outside
kidney, which are partly independent of elevated blood the cardiovascular system, aldosterone excess is also
pressure determined by hyper­ aldosteronism.28 These associated with lower serum calcium and higher urinary
effects result in disproportionate degrees of organ damage calcium excretion, with consequent increased production
for blood pressure resulting in left ventricular hypertrophy, of parathyroid hormone,48 leading to an increased
fibrosis, and diastolic dysfunction,29–32 increased intima- prevalence of osteoporosis and risk of bone fractures,
media thickening, arterial stiffness, arterial wall which are reverted by primary aldosteronism treatment.49
inflammation, and endothelial dysfunction,33–36 and renal These observations emphasise the importance of early
hyperfiltration, albuminuria, and glomerulosclerosis.37–38 and systematic detection of patients with primary
Aldosterone excess is also associated with reduced insulin aldosteronism, to implement efficient surgical or medical
sensitivity and secretion39–40 and a higher rate of metabolic treatment to prevent or reverse the excess vascular events
syndrome and type 2 diabetes mellitus.32 Adipocyte- and mortality in this specific group of patients with
derived factors can stimulate aldosterone production,41 secondary hypertension.50
which provides the basis for a vicious circle between
obesity, metabolic alterations, and hyperaldosteronism. Screening for primary aldosteronism
Obesity could also be the common pathophysiological link Who should be screened?
between primary aldosteronism and obstructive sleep Patients with moderate–severe hypertension or those
apnoea: severity of sleep apnoea might be worsened by with hypertension and spontaneous or diuretic-induced
aldosterone-mediated fluid retention and ameliorated by hypokalaemia, adrenal incidentaloma, atrial fibrillation
primary aldosteronism treatment.42 in the absence of structural heart disease, or a family
Patients with primary aldosteronism therefore show a history of early onset hypertension or stroke at a young
substantially higher incidence of stroke, myocardial age (<40 years), and all first-degree relatives with
infarction, heart failure, atrial fibrillation, and hypertension of patients with primary aldosteronism are
deterioration of renal function32,38,43 than patients with candidates for screening.51,52 Some investigators suggest
essential hypertension with similar blood pressure. The screening all people with hypertension, given the high

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 Review

concentration (but not plasma renin activity) is used to

Prevalence of primary
aldosteronism confirmed calculate the ARR. Diuretics (including potassium-sparing
by suppression testing ones), ACE inhibitors, ARBs, and selective serotonin
Hypertension in a primary care setting receptor inhibitors can cause false negatives.55,56 In a
Buffolo et al (2017)15 5·9% (range 3·2–12·7) patient with suspected primary aldosteronism, screening
Hypertension in people referred to a can be done without stopping any medications in selected
referral centre patients if hypertension is uncontrolled. In such situations,
Buffolo et al (2017)15 7·2% (range 0·7–21·9) testing to detect positive patients will avoid the need for the
Stage 1 hypertension potentially unsafe periods of time needed for washout. In
Monticone et al (2017)16 44/1133 (3·9%) milder cases of hypertension, antihypertensives could
Rossi et al (2006)12 32/484 (6·6%) interfere with testing and should be withdrawn (optimally,
Brown et al (2020)13 15·7% (95% CI 8·6–27·0) for ≥4 weeks for diuretics and ≥2 weeks for other agents)
Stage 2 hypertension before screening. Antihypertensives with lesser effects on
Monticone et al (2017)16 40/413 (9·7%) the ARR and can therefore be used to control hypertension
Rossi et al (2006)12 54/349 (15·5%)
during diagnostic investigation of primary aldosteronism
Brown et al (2020)13 21·6% (95% CI 16·9–22·9)
include verapamil, hydralazine (used in combination with
Stage 3 hypertension
verapamil to avoid reflex tachycardia), prazosin, doxazosin,
and moxonidine.56
Monticone et al (2017)16 15/126 (11·9%)
ARR testing while patients are still on interfering
Rossi et al (2006)12 29/154 (19·0%)
See Online for appendix medications can still be informative (appendix pp 2–3).
Resistant hypertension
For example, a raised ARR with suppressed renin during
Calhoun et al (2002)17 18/88 (20·5%)
sole treatment with an ACE inhibitor, ARB, or a diuretic
Douma et al (2008)18 182/1616 (11·3%)
that includes a mineralocorticoid receptor antagonist,
Parasiliti-Caprino et al (2020)19 32/110 (29·1%)
would be highly suggestive of primary aldosteronism,
Brown et al (2020)13 22·0% (95% CI 17·2–26·8)
whereas a normal ARR in a patient on a β-blocker would
Hypertension and hypokalaemia
make primary aldosteronism unlikely.
False positives can
Burello et al (2020)20 226/804 (28·1%)
occur during the luteal phase of the menstrual cycle in
Adrenal incidentaloma
premenopausal women, and in patients with advancing
Mantero et al (2000)21 16/1004 (1·6%)
age, chronic kidney disease, a high dietary salt intake, or
Li et al (2017)22 82/1941 (4·2%) Gordon syndrome (ie, familial hyperkalaemic hyper­
Hypertension and atrial fibrillation tension). False negatives can also occur during pregnancy,
Seccia et al (2020)23 31/73 (42·5%) dietary salt restriction, vomiting or diarrhoea, uncorrected
Hypertension and diabetes mellitus hypokalaemia, and in patients with malignant hyper­
Murase et al (2013)24 14/124 (11·3%) tension or concomitant renovascular hypertension.56 The
Hu et al (2020)25 49/256 (19·1%) ARR has greater sensitivity if measured in the morning in
Data are n/N (%), median (range), or median (95% CI).
an upright (eg, seated) posture.57
Controlling for such factors, or at least taking them
Table 1: Prevalence of primary aldosteronism in study cohorts, by into account, enhances the usefulness of ARR testing in
presenting condition
selecting patients for further diagnostic investigation.
The ARR also shows good within-patient reproducibility
prevalence of this condition and the reported benefits in such cicumstances.58
from specific surgical or medical treatment.53 Screening In the presence of extremely low renin, the ARR can be
before commencing antihypertensive medications avoids elevated even if plasma aldosterone is also very low and
potentially confounding effects of these agents on renin clearly not consistent with primary aldosteronism. If
and aldosterone concentrations and permits earlier aldosterone is measured by immunoassay in ng/dL, and
initiation of specific treatment, which has been shown to plasma renin activity in ng/mL/h, ARR cutoffs mainly
be a major determinant of benefit achieved.54 range from 20–30 (55–83 if aldosterone is measured in
pmol/L). If aldosterone in measured by immunoassay in
How should patients be screened? pmol/L, and direct renin concentration in mU/L, ARRs
Measurement of the plasma ARR is currently the most mainly range from 55–100. These cutoffs are lower if
popular method of screening for primary aldosteronism. aldosterone is measured by tandem mass spectrometry.
False-positive and false-negative ARRs can result from Although some investigators have suggested including a
various pharmacological and physiological factors. minimum plasma aldosterone concentration (eg,
β-blockers, clonidine, α-methyldopa, and non-steroidal 416 pmol/L or 15 ng/dL) with an elevated ARR within the
anti-inflammatory drugs are prone to cause false positives. screening criteria to overcome this problem, others have
Oral contraceptives that contain oestrogen and hormone found that this concentration excludes patients who have
therapy can also cause false positives if the direct renin subsequently been confirmed to have primary

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 Review

aldosteronism.5 Patients who are normokalaemic with test, the oral saline load test, the intravenous saline load
aldosterone concentrations lower than the cutoff for test, and the captopril challenge test (the furosemide-
suppression testing (eg, 166 pmol/L or 6 ng/dL) almost upright test is used only in Japan; table 2).51,52,61
certainly do not have primary aldosteronism, and patients Confirmatory tests are based on the assumption that
with concentrations lower than 277 pmol/L or 10 ng/dL are complete suppression of renin production (for tests
unlikely to have unilateral forms. The ratio should be involving volume expansion) or the blockade of
regarded as a screening test only, and should be measured angiotensin II production (for the captopril test) should
more than once before deciding whether to go on to decrease aldosterone production if it is appropriately
confirmatory testing for primary aldosteronism. Because regulated. The fludrocortisone-suppression test has been
of the fluctuation of aldosterone concentrations, in cases of almost abandoned because it requires 5 days of
borderline but negative ARR, it is important to repeat ARR hospitalisation. 51,52,61 The two most used tests are the oral
testing to ensure that primary aldosteronism is not missed. and the intravenous saline load tests.51,52 In the oral saline
Following the widespread use of the ARR for screening, load test, salt supplements are given for 3 days to obtain
the diagnosis of primary aldosteronism substantially a urinary sodium excretion rate higher than
increased, with bilateral primary aldosteronism covering 200 mmoles/day, with potassium supplements to avoid
most of the newly diagnosed forms.11 Bilateral primary hypo­­­
kalaemia. If urinary aldosterone concentrations
aldosteronism detection is determined by cutoff values of remain higher than 12 μg/day (33 nmol/day) on the third
confirmatory testing and there is no histological day, primary aldosteronism is considered confirmed.51,52,63
confirmation of diagnosis, thus, false-positive diagnoses In the intravenous saline load test, 2 L of 0·9% sodium
cannot be ruled-out. Therefore, the use of cutoffs in post chloride are infused intravenously over 4 h. If aldosterone
confirmatory testing that maximise the detection of remains higher than a defined cutoff after the saline
unilateral forms is recommended. Bilateral primary infusion, primary aldosteronism is considered con­
aldosteronism is associated with a higher cardiovascular firmed. Traditionally, the test was done in the recumbent
risk compared with essential hypertension,32,44 and position. However, studies showed a higher accuracy for
patients with low-renin essential hypertension respond to detection of angiotensin II responsive forms of primary
low doses of mineralocorticoid antagonists. aldosteronism with the test done in the sitting position,57
which should therefore be the preferred approach.51,52
Confirmatory testing The cutoff for primary aldosteronism diagnosis is
Who to test? commonly 6 ng/dL (171 pmol/L) if aldosterone is
Once primary aldosteronism is suspected from a positive measured by mass spectrometry, and 8 ng/dL
screening test that found an increased ARR, primary (222 pmol/L) when measured by chemiluminescence.64
aldosteronism should be diagnosed or excluded, using If patients are at risk of volume overload, the captopril
one or more confirmatory tests.51,52 This confirmation is test is the preferred confirmatory test. In this test,
required because of the low specificity of the ARR as a 25–50 mg of captopril are administered, and aldosterone
screening test, even if done under ideal conditions, but and plasma renin activity (or renin concentration) are
especially if cutoffs are permissive to ensure high measured after 1–2 h. In patients without primary
sensitivity, as is usually required for screening. Confirma­ aldosteronism, plasma aldosterone concentrations are
tory testing is necessary to exclude patients with a falsely decreased by >30%, plasma renin is increased, and the
elevated ARR but without primary aldosteronism from ARR reduced. A study showed that the most accurate
undergoing expensive, difficult, and invasive lateralising parameter in this test is the postcaptopril plasma
procedures (including adrenal vein sampling [AVS]), aldosterone concentration, with a cutoff of 11 ng/dL
which should be reserved for patients with a definitive (305 pmol/L).65
diagnosis of primary aldosteronism.51,52
The ARR can be considered not only a qualitative test but Genetics and pathophysiology of primary
also a quantitative test, therefore the higher the ARR, the aldosteronism
more likely it is that a patient has primary aldosteronism. Major progress has been made in understanding the
Thus, current guidelines suggest bypassing confirmatory molecular and histopathological basis of primary
tests in patients with a particularly severe clinical aldosteronism. Elucidation of the genetic basis of
phenotype, that is, patients with hypokalaemia, undetect­ familial aldosteronism, single adenoma formation, and
able plasma renin, and plasma aldosterone concentrations the histology of adrenal hyperplasia has challenged the
higher than 20 ng/dL (555 pmol/L). To further reduce the traditional model of primary aldosteronism as a binary
burden of confirmatory tests, scores have been developed disease of unilateral adenoma versus bilateral adrenal
to select patients for testing.59 hyperplasia. The emerging concept implies an age-
dependent remodelling of the adrenal cortex with
How to test gradual accumulation of nodular lesions with somatic
Four tests are generally accepted to confirm or exclude mutations that contribute to autonomous aldosterone
primary aldosteronism: the fludrocortisone- suppression production.

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Who to screen How to screen Who to confirm How to confirm Subtype diagnosis
Endocrine Society Blood pressure >150/100 mHg; resistant Aldosterone– All patients with a positive Seated intravenous CT scanning for patients with confirmed primary
(2016)51 hypertension; hypokalaemia (spontaneous renin (or screening, except those with or oral saline load; aldosteronism, plus adrenal vein sampling for
or diuretic-induced); hypertension and aldosterone– hypokalaemia, undetectable captopril test; those patients who are candidates for surgery (can
adrenal incidentaloma; hypertension and plasma renin renin, and an aldosterone fludrocortisone omit adrenal vein sampling in patients with
sleep apnoea; suspected familial form activity) ratio concentration >20 ng/dL suppression test marked primary aldosteronism who are younger
(family history of early onset hypertension than 35 years and have unilateral lesion >10 mm at
or cerebrovascular accident at a young age; CT)
all first-degree relatives with hypertension
of patients with primary aldosteronism)
European Society Hypertension grade 2–3 or resistant; Aldosterone– All patients with a positive Seated intravenous CT scanning for patients with confirmed primary
of Hypertension hypokalaemia (spontaneous or diuretic- renin (or screening test, except patients saline load (if aldosteronism, plus adrenal vein sampling for
(2020)52 induced); hypertension and adrenal aldosterone– with hypokalaemia and considered risky, patients who are candidates for surgery (can omit
incidentaloma; hypertension and atrial plasma renin undetectable renin (direct renin use captopril test adrenal vein sampling patients with marked
fibrillation (without underlying cardiac activity) ratio concentration <5 µU/mL or instead) primary aldosteronism who are younger than 35
structural cause); or suspected familial plasma renin activity <0·2 ng/ years and have unilateral lesion >10 mm at CT)
forms mL/h) and aldosterone
concentration >20 ng/dL
American Hypertension and hypokalaemia Aldosterone– All patients with a positive Oral or intravenous CT scanning for patients with confirmed primary
Association of (spontaneous or diuretic-induced); plasma renin screening test saline load aldosteronism, plus adrenal vein sampling for
Clinical resistant hypertension activity ratio patients with a high probability of aldosterone-
Endocrinologists producing adenoma (can omit adrenal vein
(2006)60 sampling patients with marked primary
aldosteronism who are younger than 40 years and
have unilateral lesion >10 mm at CT)
Japan Society of All patients with hypertension irrespective Aldosterone– All patients with a positive Intravenous saline CT scanning for patients with confirmed primary
Endocrinology of severity plasma renin screening test using two load; captopril test; aldosteronism, plus adrenal vein sampling for
(2009)61 activity ratio confirmatory tests furosemide-upright patients who are candidate for surgery
test
French Society of Hypertension grade 3; resistant Aldosterone– All patients with a positive Intravenous saline CT scanning for patients with confirmed primary
Endocrinology hypertension, hypokalaemia (spontaneous renin (or screening test, except patients load (if considered aldosteronism, plus adrenal vein sampling for
(2016)62 or diuretic-induced), hypertension and aldosterone– with aldosterone concentration risky, use captopril patients who are candidates for surgery if older
adrenal incidentaloma, organ damage or plasma renin >20 ng/dL test instead) than 35 years
cardiovascular morbidity more severe than activity) ratio
expected

Table 2: Comparison of guideline recommendations for screening, confirming, and subtyping patients with primary aldosteronism

Adrenal histopathology overproduction is derived from multiple aldosterone-

Evaluation of morphology and CYP11B2 (aldosterone producing nodules or micronodules (previously referred
synthase) immunohistochemistry66 of resected adrenals to as nodular or micronodular hyper­ plasia) or, more
from patients with primary aldosteronism has helped seldomly, aldosterone-producing diffuse hyperplasia
determine the origin of aldosterone overproduction and (figure 2).76 Thus, the new classifi­ cation takes both
unmask the complex associated histopathology.67–69 This morphology and function into account, and emphasises
approach led to the identification of aldosterone-producing the value of CYP11B2 immuno­ histochemistry using
micronodules (formerly known as aldosterone-producing specific monoclonal anti-CYP11B2 antibodies66 for the
cell clusters; figure 2) that accumulate with age and might routine diagnostic investigation of primary aldosteronism.
represent a source of age-related abnormal aldosterone The HISTALDO consensus75 recom­mends, in support of
physiology.70,71 Aldosterone-producing micronodules drive previous studies,77 that the final histopathological
excess aldosterone production in some bilateral forms of diagnosis of primary aldosteronism requires evaluation of
primary aldosteronism67,72 and, in a subset of cases, might both morphology and CYP11B2 immunohistochemistry
transit into aldosterone-producing adenomas.73,74 The to establish the functional correlation of autonomous
Inter­national Histopathology Consensus for Unilateral aldosterone production. Assess­ ment of a prospective
Primary Aldosteronism (HISTALDO)75 established cohort of surgically treated patients for primary
standardised nomenclature and criteria for the main aldosteronism showed a higher incidence of persistent
histopathological features observed in surgically removed aldosteronism in 4 (33·3%) of 12 patients with the non-
adrenals from patients with primary aldosteronism and classic histopathology compared with 1 (2·4%) of 42 with
categorised adrenals into classic and non-classic histo­ the classic histopathology.76 Con­sistent with presurgical
pathological forms of unilateral primary aldosteronism. bilateral primary aldosteronism, these patients also
Classic forms are represented by a solitary showed a milder grade of hyper­aldosteronism at baseline,
aldosterone-producing adenoma or a dominant with lower plasma aldosterone concentrations and lower
aldosterone-producing nodule. By contrast, non-classic ARRs.76 Thus, the accuracy of subtyping for the
forms encompass specimens in which aldosterone differentiation of surgically treated unilateral primary

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A CYP11B2 B CYP11B2 C Haematoxylin-eosin staining D CYP11B2

E Haematoxylin-eosin staining F CYP11B2 G CYP11B2

Figure 2: Histopathological classification of primary aldosteronism

The scale bars indicate 2 mm in the main images and 200 μm in the inset images. CYP11B2 (aldosterone synthase) immunohistochemistry showing resected adrenals
with a well circumscribed solitary aldosterone-producing adenoma (≥10 mm diameter) with homogeneous (A) or heterogeneous (B) immunostaining. 5 mm
diameter aldosterone-producing nodule that is morphologically distinguishable from the surrounding cortex by haematoxylin-eosin staining (C and D). Multiple
aldosterone-producing micronodules, which are not morphologically distinguishable from adjacent cells by haematoxylin-eosin staining (E and F). Aldosterone-
producing diffuse hyperplasia (G).

aldosteronism from bilateral forms, and the interpretation CACNA1D

of AVS results, might influence the relative proportions of ACTH
ATP1A1 ATP2B3 KCNJ5 CLCN2
CACNA1H
Na+/H+ Na+ Na+ Ca2+
classic and non-classic forms.

Familial hyperaldosteronism
Cl
Familial hyperaldosteronism is a rare cause of primary
aldosteronism. All known subforms are autosomal
Depolarisation
dominant. Patients typically present with early-onset ↑Ca2+ influx

hypertension, but incomplete penetrance is common.

Familial hyperaldosteronism type 1 (glucocorticoid-
remediable hyperaldosteronism) was first described in
1966.78 Family history is often positive, and early cerebral CYP11B2
haemorrhage is an associated finding.79 The historical CYP11B1
diagnosis, based on a decrease of aldosterone upon giving
dexamethasone, has been largely replaced by genetic
testing. Familial hyperaldosteronism type 1 is caused by
Figure 3: Pathophysiology of somatic and germline mutations in primary
unequal crossing over between the genes CYP11B1, aldosteronism
encoding 11ß-hydroxylase (involved in cortisol synthesis) In familial hyperaldosteronism type 1, transcription of a hybrid CYP11B1/
and CYP11B2, encoding aldosterone synthase (figure 3).80 CYP11B2 gene is activated by ACTH. Channel-like permeability of mutant
ATPases ATP1A1 and ATP2B3 for Na+ or H+ ions, leads to depolarisation,
As a result, an excess of aldosterone and an increase in the
activation of voltage-gated calcium channels, calcium influx, and aldosterone
hybrid steroids 18-hydroxycortisol and 18-oxocortisol are production in adenomas. Similarly, abnormal Na+ permeability of mutant KCNJ5
produced under the control of adrenocorticotrophic channels causes depolarisation in familial hyperaldosteronism type 3 and in
hormone in the zona fasciculata. Therapy is mainly based adenomas, as does enhanced chloride efflux via mutant CLCN2 in familial
hyperaldosteronism type 2 and rare cases of adenomas. Gain-of-function
on dexamethasone, mineralocorticoid receptor an­
mutations in calcium channel genes CACNA1D (PASNA syndrome, adenomas, or
tagonists, and amiloride. Screening of family members is aldosterone-producing micronodules) and CACNA1H (familial
advised. Familial hyperaldosteronism type 2 refers to hyperaldosteronism type 4 or rare cases of adenomas) directly increase Ca2+
patients with germline mutations in the CLCN2 gene influx. ACTH=adrenocorticotropic hormone.
encoding the chloride channel ClC-2.81,82 Here, increased
chloride efflux from glomerulosa cells results in

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 Review

Adrenal vein sampling procedure Adrenal vein sampling criteria

Endocrine Society (2016)51 Unstimulated (sequential or simultaneous) or continuous Selectivity index threshold ≥2 (unstimulated) or ≥5 (after adrenocorticotropic
adrenocorticotropic hormone (1–24) infusion (continuous or hormone [1–24]) and lateralisation index ≥2 (unstimulated) or ≥4 (after
bolus) adrenocorticotropic hormone [1–24])
European Society of Hypertension Unstimulated or continuous adrenocorticotropic hormone Selectivity index threshold ≥2 (unstimulated) or ≥5 (after adrenocorticotropic
(2020)52 (1–24) infusion hormone [1–24]) and lateralisation index ≥4
American Association of Clinical Continuous adrenocorticotropic hormone infusion Selectivity index threshold ≥10 and lateralisation index ≥3
Endocrinologists (2006)60
Japan Society of Endocrinology (2009)61 Bolus adrenocorticotropic hormone (1–24) Selectivity index threshold ≥5 and lateralisation index ≥2·6 (or aldosterone
concentration >1400 ng/dL on one side
French Society of Endocrinology (2016)62 Simultaneous unstimulated cannulation Selectivity index threshold ≥2 and lateralisation index ≥4

Table 3: Comparison of guideline recommendations for adrenal vein sampling in patients with primary aldosteronism

depolarisation, calcium influx through voltage-gated KCNJ5 mutations (figure 3)90,94 The pathophysiology of
calcium channels, and increased aldosterone production. CTNNB1 mutations might be related to a block of cellular
Patients present with moderate–severe hypertension and differentiation and subsequent hyperplasia.95 Rare
optional hypokalaemia. Familial hyperaldosteronism mutations in the CACNA1H and CLCN2 genes were
type 3 encompasses patients with germline mutations in identified in aldosterone-producing adenomas.96,97 The
the KCNJ5 gene, which codes for an inward rectifier relative proportions of mutations in different disease
potassium channel. Mutations cause abnormal sodium genes varies between ethnicities and sexes. For example,
permeability of the channel and depolarisation, again KCNJ5 mutations, which account for approximately 40%
activating the calcium signalling pathway. Different of tumours, are more frequent in women than in men,89
disease severities are associated with distinct germline and possibly also in patients of east Asian ancestry,98
KCNJ5 mutations, with some showing massive bilateral whereas CACNA1D mutations appear to be more frequent
hyperplasia that require bilateral adrenalectomy, whereas in patients of African ancestry.99 A matter of debate has
others respond to therapy with mineralocorticoid receptor been whether known somatic mutations explain only
antagonists.83–85 Familial hyperaldosteronism type 4 is due aldosterone production or also increased proliferation of
to germline mutations in the CACNA1H gene encoding a adrenocortical cells. Adrenal hyperplasia in familial
T-type calcium channel;86 mutations directly increase hyperaldosteronism type 3 suggests that KCNJ5 mutations
calcium signalling. Finally, a complex syndrome of cause increased proliferation.84 Screening for aldosterone-
primary aldosteronism, seizures, and neurological producing adenoma mutations is not done in routine
abnormalities (PASNA syndrome) has been associated clinical practice because results would not affect therapy.
with de-novo germline gain-of-function mutations in the Somatic mutations in primary aldosteronism disease
CACNA1D gene encoding an L-type calcium channel.87 genes have also been identified in aldosterone-producing
Associated symptoms can include epilepsy, autism, micronodules. Such micronodules were found in healthy
hypoglycaemia, and heart defects. human adrenal glands,70 and, at increased size and density,
in rare surgical specimens from patients with bilateral
Somatic mutations adrenal hyperplasia who had unilateral adrenalectomy.72
Somatic mutations in genes that partly overlap with Mutations in CACNA1D are particularly common in
familial hyperaldosteronism disease genes have been aldosterone-producing micronodules. Owing to scant
identified in aldosterone-producing adenomas and in amounts of DNA, only targeted investigation of known
aldosterone-producing micronodules. If using CYP11B2 primary aldosteronism disease genes has been done, and
immunohistochemistry and targeted next-generation about 40% of aldosterone-producing micronodules
sequencing for mutation detection, approximately 90% of remain genetically unexplained.72
aldosterone-producing adenomas carry somatic mutations
in known disease genes. The most commonly mutated Subtyping of primary aldosteronism
gene is KCNJ5,84,88,89 followed by CACNA1D.87,90 Aldosterone- Subtyping is driven by the intention to identify suitable
producing adenomas with KCNJ5 mutations are associated candidates for unilateral adrenalectomy, that is, patients
with specific steroid profiles in plasma, which might in the who will be in biochemical remission postoperatively with
future aid in the diagnosis of these tumours.91 Somatic a low risk of recurrence. The two subtypes of primary
mutations not found in the germline include those in the aldosteronism—ie, unilateral and bilateral—represent
ATP1A1 gene (encoding a subunit of the Na+/K+-ATPase), extremes of a spectrum of histomorphological and
the ATP2B3 gene (encoding a calcium ATPase)92 and in biochemical phenotypes and are not totally distinct. In
CTNNB1 (encoding β-catenin).93 Mutations in ATPases other words, asymmetric bilateral primary aldosteronism
confer a channel-like permeability to Na+ or H+ ions, with some lateralisation is common, whereas true
causing depolarisation and similar pathophysiology as unilateral primary aldosteronism without any contralateral

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 Review

aldosterone secretion is rare. Some demographical, decisions in 184 patients, finding no differences in post-
clinical, biochemical, and imaging characteristics are surgery blood pressure outcomes. However, this study has
associated with the primary aldosteronism subtypes. been intensely discussed and criticised for its overall study
design and for being potentially underpowered.113 A
Adrenal imaging by CT and MRI multicentric international study using a non-randomised
Adrenal CT is the first step for primary aldosteronism retrospective approach supported the biochemical success
subtype evaluation and should be done in every patient.51,52 rates of the strategies in the SPARTACUS trial:
Adrenal imaging features in patients with primary biochemical remission occurred in 188 (80%) of 235
aldosteronism can include structurally unaltered adrenals, patients after a CT-based treatment decision versus 491
unilateral adenoma, bilateral adenoma, micronodular (93%) of 526 of patients after an AVS-based treatment
hyperplasia, bilateral macronodular hyperplasia, or (rarely) decision (p<0·001).114 AVS currently remains the gold
unilateral adrenocortical carcinoma.67 In addition to a rare standard for subtyping and is recommended by all
situation of adrenocortical carcinoma, CT imaging guidelines and consensus statements.51,52,60–62
phenotype informs further management with several According to an international study, 46% of major
examples provided as follows. In a younger person with centres use adrenocorticotropic hormone (1–24) infusion
unilateral adenoma, AVS can be bypassed, with unilateral during AVS.111 Arguments in favour of adrenocorticotropic
adrenalectomy as the next step. In a patient with bilateral hormone (1–24) use include decreasing stress-induced
macronodular hyperplasia, AVS can be bypassed because variations in aldosterone secretion, increasing the technical
the likelihood of bilateral primary aldosteronism is high. success rate of AVS, and maximising aldosterone secretion
In a patient with concomitant adrenal Cushing syndrome from aldosterone-producing adenomas. Arguments
and unilateral mass, AVS can be bypassed and treatment against its use include a reduction in the proportion of
targeted towards the removal of cortisol producing lateralised AVS results and, therefore, of surgically
adenoma can be initiated. An interventional radiologist treatable patients.115 A few studies have compared basal
should examine the imaging to better plan AVS. CT does and post-adrenocorticotropic hormone (1–24) AVS results,
not provide information about the secretory activity of a reporting discordant results in up to 25% of patients.115
detected nodule.100 Similarly, densitometry (Hounsfield Detailed steroid profiling other than cortisol and
units) and contrast washout do not distinguish secretory aldosterone have been suggested as of potential value
from non-secretory nodules.51,101,102 Because adrenal during AVS, especially when adrenocorticotropic hormone
adenomas become increasingly prevalent with age,103 the (1–24) is not used.116,117
accuracy of CT imaging in primary aldosteronism AVS is done using a percutaneous femoral vein approach.
subtyping is low in patients who are older.104,105 Overall, Adrenal veins can be catheterised sequentially or
adrenal CT imaging is discordant with AVS results in simultaneously.110 Blood is collected by slow aspiration from
around 40% of patients with primary aldosteronism.104,106 the left adrenal vein, which drains directly into the left renal
Conversely, because adenomas are uncommon in younger vein, and from the right adrenal vein, which usually drains
people,103 finding a unilateral small adenoma (usually directly into the inferior vena cava and can be challenging
<2 cm) in a patient with primary aldosteronism commonly to locate.102 The ratio of cortisol in each adrenal vein to
indicates unilateral disease. The accuracy of CT imaging in cortisol in a peripheral vein needs to be sufficiently high to
establishing primary aldosteronism subtype is highest in validate a technically successful AVS (table 3 and table 4).
patients younger than 35 years but is not perfect.104,107 Pre- Rapid cortisol measurements can be used to improve
AVS CT scanning also assists in localising adrenal veins. technical success rates as they allow for resampling of
MRI is inferior to CT because its spatial resolution is lower adrenal veins if the results are inconsistent with successful
and therefore it is a second-choice imaging technique.51,108 cannulation.122,123 Indices for AVS are calculated from
cortisol and aldosterone measurements in the adrenal
Adrenal vein sampling veins and in the inferior vena cava (table 3 and table 4).
AVS is a technically challenging, expensive, and a poorly Complications of AVS include most commonly a groin
standardised procedure with wide between-centre haematoma, but also rarely adrenal haemorrhage or
success rates, depending on the expertise of the adrenal vein dissection, with an overall complication rate of
interventional radiologist. In experienced hands (usually around 2% in experienced AVS centres.109,124,125
in a high-volume primary aldosteronism centre with AVS can be done regardless of concomitant medications
more than 30 patients per year), the technical AVS if the diagnosis was made correctly and case-detection
success rate can be 90% or higher.109,110 testing is positive. For example, AVS can be done in
Many studies supporting AVS use are based on low patients treated with suboptimal doses of mineralocorticoid
quality evidence, including retrospective design, no receptor blocker, such as spironolactone or eplerenone, if
comparator, and no clinical endpoint (eg, biochemical renin plasma activity remains suppressed.126 Concomitant
remission). Despite these limitations, AVS is consistently cortisol hyper­ secretion is prevalent in patients with
used worldwide.111 A single prospective randomised trial primary aldosteronism, and in most cases is mild.127 When
(SPARTACUS) 112 compared AVS with CT based treatment Cushing syndrome independent of adreno­corticotropic

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Adrenal vein sampling with adrenocorticotropic hormone (1–24) Adrenal vein sampling without adrenocorticotropic hormone (1–
stimulation 24) stimulation (preferably use simultaneous bilateral adrenal
vein sampling)
Step one: document successful Adrenal vein-to-inferior vena cava cortisol ratio should be at least 5:1 and is Adrenal vein-to-inferior vena cava cortisol ratio should be at least
adrenal vein catheterisation (ie, usually much higher (ie, 20–30:1)108,109,118 2:1108,110
determine the selectivity index)
Step two: correct for dilution Divide the adrenal vein aldosterone by the respective adrenal vein cortisol Divide the adrenal vein aldosterone by the respective adrenal vein
concentration, to give the cortisol-corrected adrenal vein aldosterone ratio cortisol concentration, to give the cortisol-corrected adrenal vein
aldosterone ratio
Step three: determine the Divide the higher (ipsilateral, dominant) adrenal vein cortisol-corrected Divide the higher (ipsilateral, dominant) adrenal vein cortisol-
aldosterone lateralisation ratio (ie, aldosterone ratio by the lower (contralateral, non-dominant) adrenal vein corrected aldosterone ratio by the lower (contralateral,
laterisation index) cortisol-corrected aldosterone ratio; lateralisation index ≥4 indicates unilateral non-dominant) adrenal vein cortisol-corrected aldosterone ratio;
aldosterone excess;104,108,118 lateralisation index <3 indicates bilateral aldosterone lateralisation index ≥4 indicates unilateral aldosterone excess;102,108,119
excess; lateralisation index 3–4 is indeterminate for bilateral versus unilateral lateralisation index <3 indicates bilateral aldosterone excess;
aldosterone excess lateralisation index 3–4 is indeterminate for bilateral versus unilateral
aldosterone excess
Step four: calculate the contralateral Divide the lower (ie, contralateral, non-dominant) adrenal vein cortisol corrected Divide the lower (contralateral, non-dominant) adrenal vein cortisol
suppression index aldosterone ratio by the inferior vena cava cortisol-corrected aldosterone ratio; a corrected aldosterone ratio by the inferior vena cava cortisol corrected
contralateral suppression index <1 might predict the surgical outcome in aldosterone ratio; a contralateral suppression index <1 might predict
unilateral primary aldosteronism, and helps in establishing the diagnosis of the surgical outcome in unilateral primary aldosteronism
unilateral primary aldosteronism if the lateralisation index is 3–4,118 but is not
valuable in decision making if the lateralisation index is >4;120 a contralateral
suppression index <0·5 predicts unilateral contralateral primary aldosteronism if
adrenal vein sampling was not successful bilaterally121

Several sequential steps are needed to correctly interpret adrenal vein sampling results.

Table 4: Steps for the correct interpretation of adrenal vein sampling, with and without adrenocorticotropic hormone (1–24) stimulation, in patients with primary aldosteronism

hormone is diagnosed in a patient with concomitant Steroid profiling

primary aldosteronism, in general, surgery targets the Several studies showed variable diagnostic accuracy of
cortisol excess. In such cases, AVS might not be needed, 18-oxocortisol and 18-hydroxycortisol when analysed in
either because therapy is targeted towards adrenalectomy AVS samples in an attempt to distinguish unilateral from
for cortisol excess (ie, when a unilateral adrenal mass is bilateral primary aldosteronism.130,131 An analysis of
present) or because a bilateral process is likely (ie, when 12 steroids in peripheral blood samples with a liquid
macronodular hyperplasia is evident on imaging). In mild chromatography mass spectrometry-based assay correctly
autonomous cortisol secretion, interpretation of AVS does identified the subtype of 172 (80%) of 216 of patients with
not seem to be substantially affected if done during primary aldosteronism.131 In another study, a seven
adrenocorticotropic hormone (1–24) stimulation.128 The steroid fingerprint correctly classified 73 (92%) of
diagnostic process of subtyping using AVS and the criteria 79 patients with unilateral primary aldosteronism
for interpretation of AVS results are given in figure 4 and according to their genotype;132 however, steroid profiling
table 4. was less accurate when tested on a larger cohort of
Prediction scores have been developed that combine patients. In a large multicenter study of patients with
clinical, biochemical, and adrenal imaging parameters for primary aldosteronism and patients with hypertension,
subtype prediction in primary aldosteronism.107,129 A simply steroid profiling combined with machine learning
applied score using a large cohort of 1936 patients with algorithms diagnosed primary aldosteronism with a
primary aldosteronism (randomly assigned into develop­ sensitivity of 69% and specificity of 94%, and identified
ment and validation datasets) did well for predicting primary aldosteronism associated with variants in the
bilateral primary aldosteronism (a score ≥8 had a positive KCNJ5 gene with a sensitivity of 85% and specificity of
predictive value of 93·5%).107 An additional prediction 97%.91 Steroid profiling is currently available in only a
For the prediction model see model, accessible via an online tool was developed using a few centres and the findings require validation before
https://github.com/ABurrello/ smaller cohort of 150 patients (sensitivity 91·7%; specificity use in routine clinical management.
SPACE-score/raw/master/
SPACE%20Score%20Calculator.
79·3%), and validated in an independent external cohort.129
xlsm Although prediction scores are of potential interest for Functional imaging
bypassing AVS in patients classified with bilateral disease Several functional imaging techniques have been explored
and to guide surgical decision making, scores not for primary aldosteronism subtyping. ¹¹C-metomidate
developed from large multicentre cohorts might not be PET has been used for primary aldosteronism diagnosis in
generalisable to other populations, considering the several small studies.133,134 However, the procedure presents
between-centre variability of aldosterone and renin assays, challenges, such as the need for pretreatment with
and the heterogeneity of imaging techniques, their dexamethasone owing to low selectivity of ¹¹C-metomidate
interpretation, and reporting. for CYP11B2 (aldosterone synthase) compared with

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 Review

Confirmed primary aldosteronism

Adrenal CT

Adrenal cortical carcinoma Unilateral adrenal adenoma

Concomitant adrenocorticotrophic hormone-independent cortisol

Bilateral adrenal adenomas excess?

Open adrenalectomy Bilateral macronodular hyperplasia Consider adrenalectomy for cortisol excess independent of primary
aldosteronism

Unilateral or bilateral micronodular hyperplasia

Normal adrenal imaging

• Established patient preference for surgery

• Informed decision making
• Availability of expert adrenal vein sampling centre
• Review interfering medications

Consider imaging-guided adrenalectomy in patients younger than 35 years if there is severe

primary aldosteronism plus unilateral adenoma on imaging

Adrenal vein sampling*

Lateralisation † No lateralisation†

Consider interpretation via

contralateral suppression index‡ or
functional imaging

Unilateral adrenalectomy Medical therapy

Figure 4: Flow diagram of subtyping in primary aldosteronism

*Selectivity indices according to table 4. †Lateralisation indices according to table 4. ‡Contralateral suppression indices according to table 4.

CYP11B1 (11β-hydroxylase) and the small number of specificity.137 Larger studies with an optimal reference
centres capable of doing the test owing to the short life of standard are needed to validate these initial findings
¹¹C. One study showed only a 51% concordance of before introduction into clinical practice.
¹¹C-metomidate PET imaging with AVS results, although
pretreatment with dexamethasone was not used in all Surgical management
patients.135 Goals of surgery
Subsequently, high expression of CXC chemokine Adrenalectomy should be offered, in principle, to all
receptor type 4 (CXCR4) was reported in aldosterone- patients with predominant unilateral aldosterone
producing adenomas that correlated with expression of secretion at AVS.51,108 The goal of surgery is to completely
CYP11B2.136 CXCR4 ligand ⁶⁸Ga-pentixafor PET remove the source of aldosterone excess and to normalise
successfully detected primary aldosteronism in an initial blood pressure, with the primary aims being to reduce
small study of nine patients.136 In a study of 36 patients hyperaldosteronism-associated comorbidities, improve
with a reference standard based on clinical follow up and quality of life, and reduce mortality. In the international
immunohistochemistry, ⁶⁸Ga-pentixafor PET diagnosed multicentre primary aldosteronism surgical outcome
primary aldosteronism with 88% sensitivity and 100% (PASO) study,138 surgical treatment for primary

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 Review

aldosteronism resulted in biochemical remission aldosteronism, and thus biochemical outcomes provide a
(complete biochemical success) with correction of quality measure of patient diagnosis, with complete
presurgical hypokalaemia and normalisation of the ARR biochemical success defining the correct diagnosis and
in 656 (94%) of 699 patients. This shows the gratifying appropriate treatment.138 It should be emphasised that a
role of adrenalectomy in abolishing inappropriate successful biochemical outcome with resolution of
aldosterone production in unilateral forms of the disease. aldosterone excess is, in itself, clinically important to
The PASO study reported normalisation of blood pressure prevent aldosterone-mediated cardiovascular toxicity.
(complete clinical success) in 259 (37%) of 705 patients
diagnosed with unilateral primary aldosteronism, with a Interventional approaches
further 334 (47%) of 705 achieving a substantial decrease Complete unilateral adrenalectomy is the treatment of
in blood pressure, or a reduction in antihypertensive choice for patients diagnosed with unilateral primary
medication use, or both.138 Patient data from a subset of aldosteronism.51,108 Laparoscopic adrenalectomy, done by
this cohort were used to establish a prediction model, an expert adrenal surgeon, is considered the technique of
For the prediction tool see available as an online prediction tool, to classify patients choice, because it is associated with a shorter duration of
https://github.com/ABurrello/ with postsurgical clinical remission (84·4% specificity, hospitalisation and a lower rate of clinical complications
PASO-Predictor/raw/
master/00%20-%20PASO%20
71·3% sensitivity).139 The prediction tool can be used in a compared with laparotomy.108,142 Correction of hypokalaemia
Predictor.xlsm clinical setting, not for surgical decision-making, but for and normalisation of blood pressure should be obtained
the management of patient expectations after preoperatively (ideally using mineralocorticoid receptor
adrenalectomy and to identify patients who are likely to antagonists) to minimise periprocedural complications.108
require close follow-up for remnant hypertension. To avoid postsurgical hyperkalaemia, mineralocorticoid
receptor antagonists and potassium supplementation
Glucocorticoid co-secretion should both be stopped. Except for specific cases identified
In some cases, aldosterone-producing adenomas can also by super-selective AVS,143,144 partial adrenalectomy (adrenal
produce detectable amounts of cortisol.127 Cortisol co- sparing nodulectomy) should be avoided. because AVS can
secretion from aldosterone-producing adenomas can only determine the side of aldosterone hypersecretion and
influence subtype diagnosis in primary aldosteronism102,108 the largest nodule is not always the culprit lesion causing
and postsurgical management140 and can be associated hyperaldosteronism. Unilateral adrenalectomy is an
with an increased incidence of metabolic alterations39 and option for selected patients with bilateral primary
organ damage.141 Therefore, cortisol co-secretion should aldosteronism, such as those with borderline lateralisation
always be investigated by an overnight 1 mg dexa­ index values and patients with intolerable side-effects to
methasone suppression test,108 especially in patients with mineralocorticoid receptor antagonists or requiring high
an adrenal nodule at CT scanning larger than 10 mm doses of this drug. These patients might benefit because
diameter. After adrenalectomy, these patients should be debulking surgery can decrease autonomous aldosterone
closely followed up to identify and treat potential adrenal concentrations to an appropriate range for sodium
insufficiency.140 status.145

Outcome assessment Medical therapy

The international PASO consensus138 established criteria Patients with bilateral primary aldosteronism should
to assess the clinical and biochemical response to receive mineralocorticoid receptor blockade using one of
adrenalectomy and timeline for follow-up evaluation. The the agents mentioned in this section and shown in table 5.
consensus recommended that postsurgical outcomes Patients with unilateral primary aldosteronism might
should first be assessed within 3 months, to adjust prefer medical therapy over surgery and can be effectively
medication if necessary, and final assessment should be treated accordingly. Retrospective cohort studies suggest
done at 6–12 months, when parameters used to evaluate that compared with mineralocorticoid receptor blockade,
surgical outcomes have stabilised.138 The PASO criteria surgery might be more effective in controlling blood
enabled comparison of reports from different inter­ pressure and reducing the number of hypertensive
national case series and, in some centres, form part of drugs,146 effectively reversing left ventricular hypertrophy,147
routine clinical care of patients who have been treated reducing the risk of atrial fibrillation148 or chronic kidney
surgically. Clinical and biochemical outcomes are failure,45 and normalising quality of life.149 Also, long-term
categorised as a complete, partial, or absent success. mortality appears to be lower after adrenalectomy than
Persistence of hypertension (partial or absent clinical after mineralocorticoid receptor blockade.150,151 The
success) can be determined by factors that are independent superiority of surgical treatment compared with medical
of aldosteronism, such as long duration of hypertension management is owing to the immediate effect of surgical
(associated with organ damage, which in turn maintains removal of aldosterone overproduction, compared with
high blood pressure) or concomitant primary hyper­ the progressive, and possibly incomplete, antagonism of
tension. Persistence of aldosteronism (partial or absent the mineralocorticoid receptor by medical treatment. This
biochemical success) indicates presurgical bilateral difference was clearly shown by Hundemer and

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 Review

Compound Mechanism of action Starting dose Application Typical side-effects

per day schedule
Spironolactone Competitive mineralocorticoid receptor antagonist 12·5–25 mg Once a day In males, gynecomastia and impotency;
(also a progesterone receptor agonist and an in females, menstrual irregularities; in
androgen receptor antagonist) both sexes, hyperkalaemia
Eplerenone Competitive mineralocorticoid receptor antagonist 50 mg Twice a day Hyperkalaemia
Amiloride Epithelial sodium channel blocker 5–20 mg Twice a day Hyperkalaemia, nausea, stomach pain,
and loss of appetite
Dexamethasone (in familial Glucocorticoid receptor agonist 0·125 mg At bedtime At higher doses, weight gain,
hyperaldosteronism type 1) osteoporosis, diabetes, Cushingoid
phenotype, adrenal insufficiency, and
growth failure

Table 5: Specific medical therapies in primary aldosteronism

colleagues,44 in the higher incidence of cardiovascular myocardial infarction.158 Eplerenone is not approved for
events in patients with primary aldosteronism on hypertension treatment or for treatment of primary
mineralocorticoid antagonist treatment compared with aldosteronism in every country. In clinical practice,
those who had surgery, especially if the amount of higher doses of up to 100–300 mg eplerenone twice daily,
mineralocorticoid antagonist was either insufficient, or can be required to lower blood pressure to a similar
compliance was inadequate, to completely block the extent as spironolactone.159
effects of aldosterone on its receptor.
Amiloride, other anti-hypertensives, and diet
Spironolactone Mineralocorticoid antagonist treatment can be substituted
Spironolactone is a competitive antagonist of the by, or complemented with, agents like amiloride, which
mineralocorticoid receptor, belonging to the group of directly block the epithelial sodium channel (table 5),
potassium-sparing diuretics. Oral spironolactone is although amiloride is less effective for blood pressure
converted after absorption into long-acting metabolites, control, and therefore preferably used in milder forms of
including canrenoate, which are responsible for the main primary aldosteronism. The relative potency of amiloride
pharmacological effects.152 Spironolactone has dose- versus spironolactone in correcting hypokalaemia was
dependent side-effects, including gynecomastia and 2·8:1.160 Thiazide diuretics and calcium channel blockers
impotency in males, and menstrual irregularities in can be synergistically combined with mineralocorticoid
females (table 4).153 In the RALES study,154 gynecomastia receptor antagonist treatment or amiloride, and
was seen in 61 (10%) of 603 of males at a dose of 25 mg/day theoretically, ACE inhibitors and ARBs are less favourable,
spironolactone, whereas its incidence increased to more because circulating renin and angiotensin concentrations
than 24 (52%) of 46 at doses of 150 mg/day and higher.153 are suppressed in primary aldosteronism. However, in
Long-term management is effective at doses ranging clinical practice, ACE inhibitors and ARBs often act
from 25 mg/day to 50 mg/day.108 In one study,155 using synergistically, possibly because effective blockade of the
these doses, systolic blood pressure was reduced by mineralocorticoid receptor will antagonise suppressed
15 mm Hg and diastolic by 8 mm Hg, and half of the renin concentrations and re-expose the RAAS to
patients were able to be managed with spironolactone pharmacological inhibition.5 The detection of agonistic
monotherapy and had a blood pressure lower than angiotensin receptor antibodies in the plasma of patients
140/90 mm Hg.155 If these doses are not sufficient, with primary aldosteronism161 bestows a pathophysiological
combination therapy using additional hypertension drugs basis for the use of angiotensin receptor blockers. Most
is effective. Severe and life-threatening hyperkalaemia is a patients with bilateral primary aldosteronism require
frequent side-effect in heart failure,156 but rarely seen in between one and three additional drugs to sufficiently
primary aldosteronism because of the underlying control blood pressure.
mineralo­ corticoid excess increasing tubular potassium Patients with primary aldosteronism consume on
losses. The onset of spironolactone’s action on blood average a high salt diet of more than 10 g sodium per
pressure is slow, requiring weeks to months, reaching day.162 Hyperaldosteronism-induced impaired sensory salt
20–25 mm Hg in systolic blood pressure reduction.157 tasting might contribute to this high-salt appetite.163
Unilateral adrenalectomy can restore the salt-tasting
Eplerenone threshold and is associated with spontaneous reduction
Eplerenone is an option in patients who cannot tolerate of dietary sodium intake.162 Because medically treated
spironolactone because of its side-effects (table 5). patients with primary aldosteronism tend to maintain a
Eplerenone is a selective steroidal mineralocorticoid high-salt diet during mineralocorticoid receptor
receptor antagonist with a short half-life of 3–6 h, and its blockade, dietary sodium restriction should be
main indication is left ventricular dysfunction after implemented because the deleterious consequences of

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 Review

while its high incidence and burden of disease is widely

Search strategy and selection criteria ignored in most, if not all, health-care systems. In a
We searched the Cochrane Central Register of Controlled society with a 20% prevalence of hypertension, every
Trials for articles published Jan 1, 1993, to July 30, 2021, 83rd individual will have primary aldosteronism, and
and MEDLINE for articles published Jan 1, 1959 to one in every 250 people will have a surgically curable
June 1, 2021) using the search terms “primary aldosteronism”, form of unilateral primary aldosteronism.16 Affected
“Conn’s syndrome”, “hyperaldosteronism”, “aldosterone to patients will often develop resistant hypertension
renin ratio”, “adrenal vein sampling”, and “genetics”. associated with a low quality of life and adverse
We included mainly articles published from Jan 1, 2016, to cardiovascular and cerebrovascular outcomes. An
July 30, 2021, in the English language without excluding astonishingly low proportion (around 1%) of patients
relevant and highly referenced older publications. with primary aldosteronism are ever evaluated and
treated for the condition. This screening paradox can
only be partly attributed to the monosymptomatic
hyperaldo­steronism are dependent on salt loading.157 A phenotype of hypertension or the challenging diagnostic
reduction of at least 10% in dietary salt consumption was cascade. The misconception that primary aldosteronism
independently associated with a decrease in left is a rare, distinct disease that must be treated by
ventricular mass index at follow-up, supporting the specialists underlies current ignorance of the disorder.
concept that dietary salt has a crucial role in aldosterone- Clinical recognition of its long-term effect on
related cardiac damage.164 hypertension outcomes, by introducing extended
screening, would be cost-saving167 and result in gains in
Goals and outcome of medical treatment quality-adjusted life-years, especially for unilateral forms
Medical management of primary aldosteronism aims to of primary aldosteronism. Contrary to the conception of
normalise systolic and diastolic blood pressure in primary aldosteronism as a distinct disease,168 it should
accordance with current guidelines,165 and to normalise be regarded as a cardiovascular risk factor, alongside
serum potassium concentrations. Long-term follow-up other classic risk factors (eg, diabetes mellitus,
should be provided to assess and treat cardiovascular and hypercholesterolaemia, and smoking) that aggravate and
metabolic comorbidities. Primary aldosteronism should potentiate adverse outcomes of hypertension. Therefore,
be considered as a relevant and independent risk factor instead of screening selected at-risk populations, general
for the adverse long-term outcome of hypertension. screening of people with hypertension should be the
Effective blockade of the mineralocorticoid receptor future strategy to reduce the disease-burden in a cost-
appears to be a cornerstone of optimal treatment for effective way.169 This strategy should be tailored both to
bilateral primary aldosteronism. In a large cohort study identify patients with unilateral forms with high
of patients treated with mineralocorticoid antagonists, sensitivity and to provide patients with a high likelihood
patients with consistently suppressed plasma renin for milder bilateral forms early on with targeted
activity (<1 ng/mL/h) had adverse cardiovascular, renal, mineralocorticoid receptor antagonist therapy
and metabolic outcomes and increased mortality, circumventing extensive subtyping.
compared with patients with primary hypertension. By Contributors
contrast, patients with unsuppressed renin concen­ MR conceptualised this Review. MR, IB, PM, UIS, MS, and TAW wrote
trations and patients after unilateral adrenalectomy had the original draft. MR, IB, PM, UIS, MS, and TAW reviewed and edited
the original draft. All authors searched the literature and reviewed the
no discernable excess risk.44–46 search results, extracted the data, created the tables and figures, and
Compared with patients with primary hypertension, revised the manuscript.
initiation of mineralocorticoid receptor blockade in Declaration of interests
patients with primary aldosteronism leads to a nominal MR, MS, UIS, and TAW declare no competing interests. PM received
decrease of the glomerular filtration rate in the first weeks speaker fees from DIASORIN, outside of the submitted work. IB reports
and months of treatment, and a restoration of normal advisory board participation, or consulting fees, or both, for Corcept
Therapeutics, Strongbridge, Sparrow Pharmaceutics, Adrenas
albuminuria. Thereafter follows a stable plateau phase of Pharmaceutics, and HRA Pharma, outside of the submitted work.
the GFR at this lower level.37 A similar decrease in
Acknowledgments
glomerular filtration rate and albuminuria is seen after MR received funding from the German Conn‘s Registry–Else Kröner-
unilateral adrenalectomy.37,38 Antagonism or ablation of Fresenius-Hyperaldosteronism Registry (2012_A103, 2015_A228, and
aldosterone excess normalises the increased renal 2019_A104), the European Research Council under the EU Horizon 2020
plasma flow and glomerular hyperfiltration and uncovers research and innovation programme (grant agreement number 694913),
and the German Research Foundation (DFG; project numbers
the already present structural renal damage induced by 314061271-TRR 205 and 444776998 [RE 752/31–1]). TAW received DFG
primary aldosteronism.166 funding (project numbers 314061271-TRR 205 and 444776998
[WI 5359/2–1]). UIS received funding from DFG (CRC 1365
Perspectives Renoprotection, CRC 1453 Nephrogenetics, and SCHO 1386/4–1) and
the Stiftung Charité (BIH PRO_406). IB is supported by the US National
Primary aldosteronism is characterised by the paradox of Institute of Diabetes and Digestive and Kidney Diseases of the National
being a common cause and augmenter of hypertension, Institutes of Health (NIH; award number K23DK121888). The views

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 Review

expressed are those of the authors and not necessarily those of the NIH. 22 Li L, Yang G, Zhao L, et al. Baseline demographic and clinical
No funders had a role in study design, data collection, data analysis, data characteristics of patients with adrenal incidentaloma from a
interpretation, or writing of this Review. single center in China: a survey. Int J Endocrinol 2017;
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