Primary aldosteronism ‘common and unrecognized’ cause of hypertension

Researchers are urging clinicians to screen for primary aldosteronism more often after finding evidence that the condition is more common than previously thought and could be a primary cause of high BP.

“These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” Jenifer M. Brown, MD, an internist at Brigham & Women’s Hospital in Boston, and colleagues wrote in Annals of Internal Medicine.

Primary aldosteronism is usually considered a secondary cause of hypertension, according to the researchers. It is characterized by non-suppressible renin-independent aldosterone production, which has been linked to hypertension, hypokalemia and an increased risk for adverse cardiovascular outcomes.

Targeted treatments are available to mitigate CVD in patients with primary aldosteronism, but the condition is “grossly underdiagnosed, even among high-risk patients with hypertension who clearly meet indications for diagnostic testing,” Brown and colleagues wrote.

Current guidelines recommend that physicians screen for primary aldosteronism in patients who have severe hypertension or hypertension along with hypokalemia, sleep apnea or an adrenal mass. Primary aldosteronism is measured by a patient’s aldosterone-renin ratio (ARR). An elevated ARR and aldosterone level are indicative of positive screening results, according to the researchers. A diagnosis can be confirmed with dynamic testing, such as oral sodium or intravenous saline loading, fludrocortisone suppression or captopril challenge.

Primary aldosteronism is often detected in patients with hypertension who are screened, but the researchers cited growing evidence that renin-independent aldosterone production is more prevalent that currently believed, even among patients who do not have a high ARR, hypertension or hypokalemia

“Recognizing the scope of abnormal renin-independent aldosterone production in the general population could better define the prevalence of primary aldosteronism and inform the understanding of the pathogenesis and treatment of hypertension,” Brown and colleagues wrote.

The researchers conducted a cross-sectional study to evaluate the presence of non-suppressible renin-independent aldosterone production and “biochemically overt primary aldosteronism” — defined by international guidelines as an aldosterone excretion rate of at least 12 g per 24 hours in the context of high sodium balance and suppressed renin activity — in relation to BP among 1,015 patients at four academic medical centers in the United States.

The cohort included participants with normal BP (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203) and resistant hypertension (n = 408). All participants were assigned to a high-sodium diet and standardized potassium intake for 5 to 7 days. They then completed a 24-hour urine collection and were assessed for BP and circulating levels of renin, aldosterone and electrolytes.

Biochemically overt primary aldosteronism diagnoses were confirmed with an oral sodium suppression test — a well-known and recommended strategy, according to the researchers.

The mean adjusted levels of urinary aldosterone were:

• 6.5 μg per 24 hours (95% CI, 5.2-7.7) among patients with normal BP;
• 7.3 μg per 24 hours (95% CI, 5.6-8.9) among patients with stage 1 hypertension;
• 9.5 μg per 24 hours (95% CI, 8.2-10.8) among patients with stage 2 hypertension; and
• 14.6 μg per 24 hours (95% CI, 12.9-16.2) among patients with resistant hypertension.

The adjusted prevalence of biochemically overt primary aldosteronism corresponded with urinary aldosterone levels, and primary aldosteronism was “much higher” than normally seen in every BP category, Brown and colleagues wrote. The condition was diagnosed in 11.3% (95% CI, 5.9-16.8) of patients with normal BP, 15.7% (95% CI, 8.6-22.9) of patients with stage 1 hypertension, 21.6% (95% CI, 16.1-27) of patients with stage 2 hypertension, and 22% (95% CI, 17.2-26.8) of patients with resistant hypertension.

Among patients with confirmed primary aldosteronism, the sensitivity and negative predictive value of ARR were both poor, “which highlights the limitations of this diagnostic ratio in screening for — and excluding — true cases of primary aldosteronism,” the researchers wrote.

“Our results highlight the fact that the conventional approach of requiring an arbitrarily ‘high’ ARR and circulating aldosterone level to screen for potential cases of primary aldosteronism is insensitive and likely contributes to underdiagnosis,” they concluded. “Collectively, these findings show that primary aldosteronism may be a common and unrecognized ‘primary’ cause of hypertensive disease and progression.”

In a related editorial, John W. Funder, MD, PhD, Distinguished Scientist at the Hudson Institute of Medical Research and chair of the Endocrine Society’s Taskforce for Revision of Guidelines for Management of Primary Aldosteronism, called the study a “game changer.”

“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,” he wrote. “The authors caution readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere.”

The prevalence of primary aldosteronism in the study was three- to fivefold higher than other estimates based on conventional spot testing of plasma aldosterone concentration, according to Funder.

Data from Germany and the United Kingdom show that only one in 1,000 patients with hypertension are screened for primary aldosteronism, Funder wrote, adding that primary care physicians “just try to control BP.”

“One in 1,000 is an appallingly low capture rate, and the risk profile for patients without appropriate levels of targeted therapy is at least three times higher than that for patients with essential hypertension matched on age, sex and BP,” he wrote. “Much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed to guide clinicians treating hypertensive patients. With their study, Brown and colleagues sound a call to arms and start the process of bringing the management of primary aldosteronism into the 21st century. For this, the authors deserve congratulations, thanks and unstinting praise.” – by Stephanie Viguers

Disclosures: Brown reports receiving grants from the National Heart, Lung and Blood Institute. Funder reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.