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Approximately 10% of people with hypertension, and up to 30% of those with resistant hypertension, have primary aldosteronism—which causes greater end-organ damage than high blood pressure alone. Early diagnosis can help prevent therapeutic failure and preserve function of vital organs, says Professor Jun Yang, consultant endocrinologist at Monash Health, Senior Research Fellow at Monash University and head of the endocrine hypertension research group at Melbourne’s Hudson Institute of Medical Research.
Once thought rare, primary aldosteronism (PA) is actually a leading cause of secondary hypertension, Professor Yang says.
“Research over the last decade from our centre and others has shown that primary aldosteronism affects about 5 to 10% of people with hypertension, and up to 20 to 30% of those with resistant hypertension.”
But it often remains overlooked, she says.
For example, one in seven patients with newly diagnosed hypertension was found to have PA when GPs screened for it, a Victorian primary care study led by her team showed. Yet before screening was implemented, “not even one in a thousand of the patients with hypertension had a diagnosis of PA,” she says. “So it’s out there if you look for it.”
A type of secondary hypertension, PA is caused by excessive production of aldosterone from one or both adrenal glands.
Under normal conditions, aldosterone secretion is tightly regulated by the renin–angiotensin system to maintain blood pressure and fluid homeostasis. In PA, this relationship breaks down, Professor Yang explains.
“Instead of aldosterone going up when renin levels go up here, aldosterone is inappropriately normal or high when renin level is low or suppressed. So you get that loss of negative feedback where low renin does not decrease aldosterone production. And it’s the sustained and dysregulated aldosterone release that leads to extracellular fluid volume expansion, hypertension, and hypokalaemia in some.”
Both animal and human research has shown excess aldosterone can cause direct cardiovascular, renal and metabolic damage, Professor Yang says.
“Patients with primary aldosteronism actually have higher risk of stroke, atrial fibrillation, heart failure, chronic kidney disease and diabetes compared to patients with essential hypertension who are matched for their blood pressure. So it’s adding injury on top of what hypertension can cause.”
Excess aldosterone directly activates mineralocorticoid receptors in the kidneys, heart, blood vessels and other tissues, she explains, leading to inflammation, fibrosis and end-organ damage.
Risk increases the longer PA persists, she adds.
Elevated blood pressure may be the only feature, Professor Yang says, noting most patients have normal potassium.
Some may report fatigue, muscle weakness or nocturia, which may be less specific features of PA.
The Victorian primary care study found patients with and without PA had virtually identical clinical features, highlighting the need for proactive case finding.
A screening blood test for aldosterone, renin and aldosterone to renin ratio (ARR) is the first investigation, Professor Yang advises. In PA, aldosterone will be normal or above the reference range and renin low or suppressed, so the ARR will be above a certain threshold. Cut points vary between laboratories depending on how they measure aldosterone levels (e.g. immunoassay or mass spectrometry).
Importantly, a normal aldosterone does not exclude this diagnosis, she says. “It can be PA if the renin is low because then it makes the aldosterone level inappropriately normal.”
The test is best done in the morning due to circadian variations in aldosterone production. While patients do not need to fast, it can be convenient to do it with fasting lipids and glucose as part of cardiovascular screening.
Patients should not be on a very low sodium diet, which can stimulate renin production and may mask the disease.
The test is covered by Medicare.
Current Endocrine Society guidelines recommend screening anyone with hypertension for PA, Professor Yang says, noting this may filter through to Australian hypertension guidelines.
Patients should ideally be screened before they start antihypertensives, most of which can confound results, she notes.
“ACE inhibitors, angiotensin 2 receptor blockers, amlodipine-type calcium channel blockers, diuretics, mineralocorticoid receptor antagonists like spironolactone—all these agents can increase your renin to the point that your ratio becomes completely normal. So it’s going to mask the underlying primary aldosteronism.” Beta blockers can cause a false positive result by suppressing renin production, she adds, although a high aldosterone level makes it more likely a true positive result.
In patients already taking these interfering medications, you can consider switching them to verapamil, prazosin, moxonidine and/or hydralazine—which are less likely to interfere with aldosterone-renin—before testing, she says.
If switching isn’t feasible, you can still do the screening test, she stresses.
“If the test comes back abnormal, then you know it’s abnormal. If the test comes back normal, you can still interpret it. For example, if the renin is at the lower end of the normal range despite them taking a diuretic, you know that’s very abnormal because diuretics should push your renin through the roof.”
Also, hypokalaemia can suppress aldosterone production and give a false negative result. If potassium is below 3.5 mmol/L in the baseline blood test, she advises aiming to get it above 4 mmol/L then retesting.
An elevated ARR warrants referral to endocrinology, with the condition usually confirmed via saline suppression testing. This involves measuring aldosterone levels before and after infusing two litres of saline over four hours in hospital, Professor Yang explains. “If the aldosterone level remains elevated then we say, yep, you have primary aldosteronism.”
Next, adrenal vein sampling and adrenal imaging are used to determine if the disease is unilateral or bilateral, which guides management.
If it’s difficult to access these tests, you can still commence treatment for possible PA after the initial abnormal screening test, Professor Yang says.
“That’s probably better than trying to go through impossible obstacles to complete the confirmatory or subtyping tests.”
Surgery to remove a unilateral aldosterone-producing adenoma can be curative—especially when it’s diagnosed early, Professor Yang says, noting some patients may still need antihypertensives.
“The later it’s diagnosed, the more complex the disease becomes—and the harder it is for there to be a complete clinical cure.”
If both adrenal glands are involved, patients need lifelong medical therapy. Mineralocorticoid receptor antagonists such as spironolactone are first line, she says, but can have side effects—such as gynaecomastia in men and irregular periods in premenopausal women.
Alternatively, eplerenone is “very specific for blocking aldosterone without those other sex hormone side effects,” she says.
It is significantly more expensive, however, at about $1000-$2000 per year—although some public hospital endocrine department subsidise it for their patients, she says.
Other agents in the research pipeline will hopefully mean more options over the next few years.
Medication Switching Guide | Hudson Institute of Medical Research
Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline | Endocrine Society
Australian Hypertension Guidelines | Heart Foundation
PA information for health professionals and consumers | Hudson Institute of Medical Research
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