Intended for healthcare professionals

Practice Easily Missed?

Primary aldosteronism

BMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2021-065250 (Published 20 April 2022) Cite this as: BMJ 2022;377:e065250
  1. Kay Weng Choy, chemical pathologist1,
  2. Peter J Fuller, professor and consultant endocrinologist234,
  3. Grant Russell, professor of primary care research and general practitioner5,
  4. Qifu Li, professor and consultant endocrinologist6,
  5. Marianne Leenaerts, patient and advocate7,
  6. Jun Yang, head of endocrine hypertension group, senior research fellow, consultant endocrinologist234
  1. 1Department of Pathology, Northern Health, Epping, Australia
  2. 2Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia
  3. 3Department of Endocrinology, Monash Health, Clayton, Australia
  4. 4Department of Medicine, Monash University, Clayton, Australia
  5. 5Department of General Practice, Monash University, Clayton, Australia
  6. 6Department of Endocrinology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  7. 7Governing Board, Primary Aldosteronism Foundation (primaryaldosteronism.org)
  1. Correspondence to: J Yang jun.yang{at}hudson.org.au

What you need to know

  • Aldosterone excess can cause cardiovascular, cerebrovascular, and renal disease

  • Consider primary aldosteronism in patients with moderate to severe hypertension, resistant hypertension, hypertension with an adrenal mass, or hypokalaemia

  • A minority of patients have hypokalaemia: most cases resemble essential hypertension, leading to missed or delayed diagnosis

  • The screening test of choice is plasma aldosterone-to-renin ratio (ARR) but testing may not be accurate (due to interfering medications) or available (in less resourced settings)—consider temporary medication changes before screening or a therapeutic trial of a mineralocorticoid receptor antagonist in these contexts

  • Unilateral disease is treated with adrenalectomy; bilateral disease is treated with a mineralocorticoid receptor antagonist

A 57 year old woman presented for a routine health check. She had an elevated blood pressure of 150/100 mm Hg. Her average blood pressure had remained above 140/90 mm Hg over three years, despite the introduction and up-titration of perindopril, amlodipine, and moxonidine. She has no other relevant medical history or family history of hypertension. Routine investigations were unremarkable, including serum potassium of 3.7 mmol/L (reference range 3.5-5.2 mmol/L) and estimated glomerular filtration rate (eGFR) of 90 mL/min/1.73 m2.

What is primary aldosteronism?

Primary aldosteronism, also known as Conn’s syndrome, is characterised by inappropriate aldosterone production despite suppressed renin secretion and, commonly, hypertension.1 Normally, in response to intravascular volume depletion, renin stimulates aldosterone secretion to increase sodium reabsorption and facilitate volume expansion.1 In primary aldosteronism, however, aldosterone is autonomously produced independent of renin (for example, aldosterone-producing adenomas or hyperplasia involving one or both adrenal glands).1 Renin levels are suppressed while unchecked aldosterone levels increase sodium reabsorption and lead to hypertension, the main presenting complaint (fig 1). As potassium excretion is paired with renal sodium reabsorption, patients may experience hypokalaemia and associated muscle cramps, weakness, or cardiac arrhythmia.2

Fig 1
Fig 1

The pathophysiology of primary aldosteronism (original created with BioRender.com)

How common is it?

Primary aldosteronism is the most common specifically treatable and potentially curable causes of hypertension.1 In a systematic review and meta-regression analysis of 39 studies (between 1 January 1990 and 31 January 2015) involving 42 510 patients with hypertension, prevalence estimates varied from 3.2% to 12.7% in primary care and from 1% to 29.8% in referral centres.3 Table 1 shows the range of prevalence data globally. In more recent prevalence studies in primary care the diagnosis was reported in 3.9-11.8% of 1672 hypertensive patients in Italy,7 at least 4% of 1020 patients in China with newly diagnosed hypertension,6 and 14% of 247 treatment-naïve hypertensive patients in Australia.8 A 2020 cross-sectional study at four US academic medical centres found that the prevalence estimates for biochemical primary aldosteronism (urinary aldosterone levels >12 µg/24 hours and urinary sodium excretion ≥190 mmol/24 hours) were 15.7%, 21.6%, and 22.0% in patients with stage 1 hypertension, stage 2 hypertension, and resistant hypertension, respectively.9 While prevalence is high in research studies, primary aldosteronism is not often diagnosed in real life. For example, a prevalence of 0.022% was reported in the Västra Götaland County in Sweden despite increasing incidence,10 while 0.1-0.45% of hypertensive patients were diagnosed with primary aldosteronism in a survey of Australian GPs.11 The low prevalence is expected where at-risk patients are not routinely screened for primary aldosteronism.

Table 1

Selected studies on the prevalence of primary aldosteronism in primary care

View this table:

Why is it missed?

Primary aldosteronism is missed because it has traditionally been considered rare and screening is not generally recommended in patients without hypokalaemia or resistant hypertension.2

  • Of hypertensive primary care patients in Italy and Germany, for example, <8% were screened for primary aldosteronism.12

  • Even in individuals with resistant hypertension who are at high risk of primary aldosteronism, the screening rate was low (2.1%) in 4660 people in a Stanford electronic registry.13

  • In a Canadian population-based cohort study of 1.1 million adults with hypertension, <1% of individuals expected to have primary aldosteronism (based on the expected population disease prevalence) were ever formally diagnosed and treated; the lack of simplified care pathway and dedicated hypertension programme were thought to be contributing factors for the under-detection.14

Further confounding diagnosis, primary aldosteronism can present like essential hypertension14: blood pressure can be anywhere from pre-hypertension (120-130/80-89 mm Hg) to resistant hypertension (resistant to three conventional antihypertensive drugs).15 Hypokalaemia, once thought to be an essential feature of primary aldosteronism, is now found to be present in only a minority of patients (box 1).1 In a large cohort of unselected patients with hypertension referred to a hypertension unit, plasma potassium was normal for approximately 70% of patients with primary aldosteronism.7

Box 1

Prevalence of hypokalaemia in primary aldosteronism

  • Australia 13% (Stowasser 200316)

  • China 17.5% (Xu 20206)

  • Italy 28.9% (Monticone 20177)

  • Italy, US, Singapore, Chile, Italy 9-37% (Mulatero 200417)

RETURN TO TEXT

The UK National Institute for Health and Care Excellence (NICE) 2019 guideline on hypertension does not specifically discuss primary aldosteronism in any detail,18 while the 2018 European Society of Cardiology and European Society of Hypertension guideline recommends screening for secondary hypertension (such as primary aldosteronism) only in patients with resistant hypertension.19

A range of additional symptoms, such as muscle weakness, cramping, paresthesias, palpitations, polyuria, and nocturia, have been described by patients with lived experience, but these are not known to be specific for primary aldosteronism.120

Why does it matter?

Accurate diagnosis enables targeted treatment, or complete cure, with a mineralocorticoid receptor antagonist (such as spironolactone) or adrenalectomy.21 There is also heightened cardiovascular risk due to aldosterone excess if primary aldosteronism is not identified.2122

  • In a meta-analysis of 31 studies including 3838 patients with primary aldosteronism and 9284 patients with essential hypertension, individuals with primary aldosteronism had significantly higher risk of stroke (~2.6 times), coronary artery disease (~1.8 times), atrial fibrillation (~3.5 times), and heart failure (~2.1 times) compared with controls matched by blood pressure with essential hypertension.22

  • A cross-sectional study of 2612 hypertensive patients in China observed that renin-independent aldosteronism (as seen in primary aldosteronism) was associated with a significantly higher risk of cardiovascular disease than normal aldosterone levels (odds ratio 2.57 (95% CI 1.13 to 5.86)).23

  • In a cohort study of 602 patients with primary aldosteronism and 41 853 age-matched individuals with essential hypertension, patients treated for primary aldosteronism with effective doses of mineralocorticoid receptor antagonists had a cardiovascular risk reduction that was comparable to that for essential hypertension.24

  • A retrospective cohort study of 205 patients with primary aldosteronism who underwent surgical adrenalectomy and did not have a prior cardiovascular event found that patients who underwent adrenalectomy had a significantly lower risk of incident cardiovascular events compared with essential hypertension (adjusted hazard ratio 0.58).24

Untreated primary aldosteronism has also been associated with chronic kidney disease,25 osteoporosis,26 metabolic syndrome,22 anxiety, and depression.27

How is primary aldosteronism diagnosed?

Consider screening for primary aldosteronism in patients with resistant hypertension, moderate to severe hypertension, and hypertension with an incidental adrenal mass or hypokalaemia (box 2).221

Box 2

Indications to screen for primary aldosteronism

  • Resistant hypertension (requiring four or more medications to control blood pressure or uncontrolled blood pressure despite three antihypertensive medications)

  • Moderate to severe hypertension (≥140/90 mm Hg)

  • Hypertension with an incidental adrenal mass

  • Hypertension with hypokalaemia

RETURN TO TEXT

Plasma aldosterone-to-renin ratio (ARR) is the standard screening test.21 Its sensitivity and specificity vary at different thresholds (table 2).28 Clinicians may use the ARR cut-off provided by local pathology laboratories.

Table 2

Diagnostic yield of the plasma aldosterone-to-renin ratio (ARR) at commonly used cut-off values (adapted from Rossi et al 201628)

View this table:

In a prospective study of 260 hypertensive patients referred to a specialist hypertension centre, the ARR at its most liberal threshold (>57 pmol/L:mU/L (>2.057 ng/dL:mU/L)) was 92.0% sensitive for a diagnosis of primary aldosteronism but only 91.6% specific, with a positive predictive value of 60.5% and negative predictive value of 98.8%.28

Serum potassium and estimated glomerular filtration rate (eGFR) are important baseline investigations to identify hypokalaemia and decreased GFR which may influence ARR interpretation.21 While the presence of hypokalaemia increases the likelihood of primary aldosteronism (and if associated with markedly elevated plasma aldosterone and suppressed renin, confirms primary aldosteronism), more than half of patients with primary aldosteronism are reported to have normokalaemia (box 1).1

  • The ARR is affected by many commonly used antihypertensives; where possible, switch the interfering medications to non-interfering agents (box 3).2129

  • Collect blood two hours after getting up and being ambulant, and remain seated for 15 minutes before blood collection.21

  • In patients with chronic kidney disease, renin levels tend to fall due to reduced renin secretory mass but conversely, renovascular disease can lead to higher plasma renin and therefore falsely lower ARR, complicating the diagnosis of primary aldosteronism.21

  • Ideally, withdraw oral contraceptives before ARR testing and advise patients to have the test during the follicular phase of the menstrual cycle, when endogenous oestrogen and progesterone are at a nadir and least likely to interfere with ARR.21

  • As potassium regulates aldosterone, uncorrected hypokalaemia can lead to false negative ARR.1 Maintain serum potassium concentrations at 4.0-5.0 mmol/L, using long acting potassium supplements if required.21

  • Consult a specialist for advice on conditions or medications that might interfere with ARR.

Box 3

Drugs that need to be changed before screening for primary aldosteronism with plasma aldosterone-to-renin ratio (ARR) test29

Group 1: Replace for accurate screening; stop ≥4 weeks before test

  • Thiazide diuretics (eg hydrochlorothiazide)

  • Loop diuretics (eg furosemide)

  • Mineralocorticoid receptor antagonists (eg spironolactone)

  • Epithelial sodium channel blockers (eg amiloride)

Group 2: Replace where possible; stop ≥2 weeks before test

  • Angiotensin receptor blockers (eg olmesartan)

  • Angiotensin converting enzyme (ACE) inhibitors (eg perindopril)

  • Dihydropyridine calcium channel blockers (eg amlodipine)

  • Selective and non-selective β blockers (eg atenolol)

Group 3: Non-interfering medications to use instead of the above two groups

  • Non-dihydropyridine calcium channel blockers (eg verapamil)

  • Hydralazine

  • α blockers (eg prazosin)

  • Moxonidine

RETURN TO TEXT

Despite it being an imperfect first-line test for detecting primary aldosteronism (affected by many common medications, time of day, posture, stage of menstrual cycle, and renal impairment), the ARR test may still be valuable for excluding primary aldosteronism when two ARR results on different days are negative and for identifying potential primary aldosteronism where there is a positive ARR or low plasma renin, especially if the patient is taking an ACE inhibitor, angiotensin receptor blocker, or diuretic that should increase renin.221 When the ARR test is positive, referral to a specialist unit for confirmatory primary aldosteronism testing (saline infusion test, fludrocortisone suppression test, captopril challenge test, or oral sodium loading test) is recommended.21

How is primary aldosteronism managed?

Once primary aldosteronism is confirmed, most patients undergo adrenal computed tomography (CT) and adrenal venous sampling (or, in some centres, nuclear medicine functional imaging) to differentiate between unilateral and bilateral disease.21 Laparoscopic adrenalectomy is indicated for unilateral aldosterone-producing adenoma and leads to biochemical cure in 83-100% of patients.30 Mineralocorticoid receptor antagonist therapy is indicated for patients with bilateral adrenal disease, those who are not surgical candidates, or those who prefer medical treatment.1

Side effects of spironolactone, especially at >50 mg/day, include gynaecomastia, mastodynia, reduced libido, and menstrual disturbances.1 Eplerenone is an alternative mineralocorticoid receptor antagonist if spironolactone is poorly tolerated.1 Amiloride (an epithelial sodium channel (ENaC) blocker) can also lower blood pressure and normalise plasma potassium.1 As mineralocorticoid receptor antagonists and ENaC blockers correct hypokalaemia swiftly, potassium supplementation is ceased when they are commenced.1 Treatment targets include normalisation of serum potassium, renin concentration, and blood pressure.21

A therapeutic trial of a mineralocorticoid receptor antagonist might be considered in conversation with patients regarding possible risks and benefits if (a) the patient has a positive ARR result but access to a specialist for confirmatory testing is not possible or (b) a patient has negative ARR results, or does not have access to an ARR test, but has moderate to severe or resistant hypertension.2

Case resolution

The patient has resistant hypertension and warrants screening for primary aldosteronism. Perindopril and amlodipine were switched to verapamil for four weeks before ARR testing. Her plasma aldosterone was 377 pmol/L (reference range 70-1090 pmol/L), direct renin was 4.2 mU/L (reference 4.4-46.0 mU/L), and ARR was elevated to 90 pmol/L:mU/L (equivalent to 3.2 ng/dL:mU/L, 144 pmol/L:ng/L, 5.2 ng/dL:ng/L). A seated saline suppression test confirmed the diagnosis of primary aldosteronism, and both adrenal CT and adrenal venous sampling were consistent with bilateral adrenal disease. The patient now maintains a blood pressure <130/80 mm Hg with spironolactone 37.5 mg per day as monotherapy.

A patient’s perspective

Like many patients with primary aldosteronism, I developed hypertension in my 30s. Over the following decade, the abnormal trending of my blood sodium and potassium was never noticed, and the progressive appearance of symptoms was dismissed. The symptoms included labile hypertension, weight fluctuations for no apparent reason, exhaustion on exercising, memory loss and cognitive impairment, hazy and blurred vision, joint and bone pain, sudden allergies and food intolerances, bouts of itching around the face and neck, twitching spams in eyes and muscles, bouts of tingling in extremities, constant bruising, and insomnia.

Only 10 years later, when additional antihypertensives failed to control my blood pressure, was the likelihood of primary aldosteronism entertained. Realising that my experience was shared by many patients, I co-founded the Primary Aldosteronism Foundation (https://www.primaryaldosteronism.org/), a non-profit organisation advocating adequate diagnosis and treatment of the disease.

Education into practice

  • How do you avoid missing early primary aldosteronism in patients with hypertension?

  • What medication changes will you prioritise prior to primary aldosteronism screening?

How patients were involved in the creation of this article

The patient co-author (ML) is a co-founder of the Primary Aldosteronism Foundation advocating timely adequate diagnosis and treatment of the disease. She provided her experience for the patient perspective box. She also reviewed and provided input on a draft version of the manuscript.

The Primary Aldosteronism Foundation underlined that, due to its spectrum of severity, primary aldosteronism often presents like essential hypertension in its earlier stages, leading to missed or delayed diagnoses. We have also emphasised that targeted treatment with adrenalectomy for unilateral disease, or mineralocorticoid receptor antagonist for bilateral disease, will improve blood pressure and ameliorate cardiovascular risks associated with aldosterone excess.

How this article was created

This article was based primarily upon clinical experience in managing patients with moderate to severe or resistant hypertension, including those with primary aldosteronism, within a specialist hypertension service setting. We also reviewed clinical practice guidelines and carried out a literature search using PubMed with search terms “primary aldosteronism” and “hyperaldosteronism.” A manual search of the reference lists of selected articles was also conducted to capture all relevant studies. Additional sources were sought in PubMed database to answer specific questions as they arose during the writing process.

Acknowledgments

We thank Jennifer Rasanathan and Sabreena Malik, clinical editors for the BMJ for their editorial suggestions and encouragement for this article.

Footnotes

  • This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. To suggest a topic for this series, please email us at practice@bmj.com.

  • Contributors: All authors substantially contributed to the conception and design of the work, had final approval of the version to be published, and agree to be accountable for the accuracy and integrity of the work. KWC and JY drafted the work; PJF, GR, QL, and ML critically revised the work for important intellectual content. KWC is guarantor.

  • Competing interests: All authors have read and understood the BMJ policy on declaration of interests and have nothing to declare.

  • Patient consent: Not required (patient anonymised, dead, or hypothetical).

  • Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed.

References