Lying in Wait: The Hidden Threat of Primary Aldosteronism

A new study finds that primary aldosteronism is behind many more cases of uncontrolled high blood pressure than common diagnostic tests show. Despite the potential for severe consequences, inexpensive treatments are available for this often overlooked condition.

 

Some endocrinologists have long argued that primary aldosteronism is not the rare disease that it is commonly considered. That argument got a big boost with a recent study in the Annals of Internal Medicine that found that the “prevalence of primary aldosteronism is high and largely unrecognized” — some three to five times higher than previous tests have indicated.

The new study is a “game changer,” says John Funder, MD, PhD, of the Hudson Institute of Medical Research in Victoria, Australia. Funder chaired the panel that wrote the 2016 Endocrine Society guideline on primary aldosteronism, an update of which is currently under consideration by the Clinical Guidelines Committee.

“The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion,” Funder writes in an editorial that accompanied the Annals article. “The study shows that the single-spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading.”

24-Hour Test

The study involved more than 1,800 participants at four U.S. academic centers, classified in four groups: normal blood pressure, stage 1 hypertension, stage 2 hypertension, and resistant hypertension. The participants were prescribed a high-sodium diet and standardized potassium intake before completing a 24-hour urine collection. The researchers diagnosed primary aldosteronism when urinary aldosterone levels exceeded 12 micrograms over 24 hours.

“Primary aldosteronism represents an independent cardiovascular risk, just like we view diabetes as an independent cardiovascular risk. For patients with primary aldosteronism, the goals of treatment go beyond blood pressure control and must include strategies to buffer the cardiovascular and renal morbidity.” –  Adina Turcu, MD, MS, assistant professor, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Mich.

This cut-off led to the conclusion that “the prevalence of primary aldosteronism is high and largely unrecognized. The aldosterone-renin ratio (ARR) had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism.”

But in addition to identifying a high number of patients over the cut-off, the study found that every blood pressure category had a continuum of renin-independent aldosterone production, with higher aldosterone production associated with higher blood pressure and lower serum potassium levels.

A Continuum

“For decades, primary aldosteronism has been considered a binary or categorical disease,” says Anand Vaidya, MD, director of the Center for Adrenal Disorders at Brigham & Women’s Hospital in Boston and lead author of the study. “People have used arbitrary thresholds of what a high aldosterone was. What we showed is that excess aldosterone exists across a broad continuum. It is not a binary diagnosis. It exists across a severity spectrum from mild to severe and is very common. You can find it very frequently in patients with hypertension.”

This finding is significant given that almost half the American population has high blood pressure, which is “the world’s leading risk factor for death,” according to Robert M. Carey, MD, professor of medicine at the University of Virginia. Carey was a member of the team that wrote the 2016 Endocrine Society guideline and is also a co-author of the Annals article.

Beyond Blood Pressure

But the dangers go well beyond simply blood pressure. “Primary aldosteronism is a deadly disease from the standpoint of cardiovascular target-organ damage,” Carey says.

Adina Turcu, MD, MS, assistant professor in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan, agrees that the study’s findings are important when “at the most, only about 50% of patients with hypertension are effectively treated. The proportion of patients who have their hypertension under control hasn’t really increased over the past 20 years. This reflects the ‘one size fits all’ approach to hypertension treatment, and is a missed opportunity to identify and customize care patients with specific types of hypertension.”

“Primary aldosteronism represents an independent cardiovascular risk, just like we view diabetes as an independent cardiovascular risk,” she says. “For patients with primary aldosteronism, the goals of treatment go beyond blood pressure control and must include strategies to buffer the cardiovascular and renal morbidity.”

From his study of the literature, Funder estimates that “the prevalence of primary aldosteronism in hypertensive patients may be on the order of 45% to 50%. There is very good evidence that for the same blood pressure, patients with primary aldosteronism have at least three times higher morbidity and mortality.”

The failure to find and treat patients with primary aldosteronism is doubly troubling considering that its effects can be easily counteracted with mineralocorticoid receptor blockers, which are safe and inexpensive. “If we are missing a substantial number of people that could receive a mineralocorticoid blocker and be improved or cured, this is a great opportunity for us that we are missing,” Carey says.

Screening Schemes

And that point raises the fundamental question of when and how to screen hypertensive patients for primary aldosteronism. Funder believes every patient newly diagnosed with hypertension could be screened by determining the amount of aldosterone in a 24-hour urine collection. He believes that would be a practical means of overcoming the pulsatile nature of hormone secretion. He notes that endocrinologists are not likely to see these patients until their disease is progressing, so he hopes to raise awareness of the need for screening among primary-care physicians.

The Annals article says that “clinicians should consider screening for primary aldosteronism much more frequently, especially in the general hypertensive population” without specifying a particular test. The authors note that “the ARR can be a simple and useful screening method” but that levels can vary and “a single ARR is insensitive, even among patients with resistant hypertension.”

Carey notes: “Although we are not to the point of being able to recommend specific testing for clinical medicine at large,” the AAR is a simple test and “if the renin is suppressed, then the likelihood goes way up that the patient has autonomous aldosterone production.”

“The prevalence of primary aldosteronism in hypertensive patients may be on the order of 45% to 50%. There is very good evidence that for the same blood pressure, patients with primary aldosteronism have at least three times higher morbidity and mortality.” – John Funder, MD, PhD, Hudson Institute of Medical Research, Victoria, Australia; Chair, 2016 guideline writing committee of “The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment”

Turcu notes that the AAR can be repeated, and if the patient’s hypertension is uncontrolled and continues to progress, physicians may catch primary aldosteronism if they are more aware that they should be looking for it.

A recommended testing regimen is the sort of question that a guideline-writing process could help elucidate, but all these experts agreed that the study had proven its point that “primary aldosteronism is grossly underdiagnosed, even among high-risk patients with hypertension who clearly meet indications for diagnostic testing.”

“We have had cheap generic medications available for decades that are relatively safe to block aldosterone. So, the impetus to diagnose or consider this diagnosis needs to be underscored,” lead author Vaidya concludes.

Seaborg is a freelance writer based in Charlottesville, Va. In the November issue, he wrote about the potential links between air pollution and diabetes.

 

 

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