Stressed Out: New Treatment Guidelines for Primary Aldersteronism

A new Endocrine Society Clinical Practice Guideline calls primary aldosteronism a major public health challenge. Research shows that an excessive level of aldosterone, far from being a rare and benign condition, is a common, damaging, and treatable cause of hypertension.

A new clinical guideline issues a “clarion call” to physicians to substantially ramp up the screening of patients at risk for primary aldosteronism (PA) because the condition — once considered rare — should be recognized as a major public health issue.

“The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline” appeared in the May issue of The Journal of Clinical Endocrinology & Metabolism and substantially revises the previous guideline published in 2008.

“In the past eight years, we have come to recognize that primary aldosteronism, despite being quite common, frequently goes undiagnosed and untreated,” says John W. Funder, MD, PhD, of the Hudson Institute of Medical Research in Clayton, Australia, and chair of the task force that wrote the guideline. “This is a major public health issue. Many people with primary aldosteronism are never screened due to the associated costs. Better screening processes are needed to ensure no person suffering from primary aldosteronism and the resulting risks of uncontrolled high blood pressure goes untreated.”

Many physicians were taught that less than 1% of patients with mild-to-moderate essential hypertension had this condition, in which the adrenal glands secrete too much aldosterone, leading to hypertension, cardiovascular damage, sodium retention, suppression of plasma renin, and increased potassium excretion. But cross-sectional and prospective studies have indicated its prevalence is closer to 10% among hypertensive patients. “In no country are more than 1% of patients with primary aldosterone ever screened, diagnosed, and treated,” Funder says.

It is commonly caused by a unilateral adrenal adenoma or bilateral adrenal hyperplasia. Rare causes include adrenal carcinoma or inherited familial hyperaldosteronism.

Accurate diagnosis and treatment are important because studies of patients matched by age, sex, and blood pressure show that “people with primary aldosteronism have a considerably higher cardiovascular risk profile than people with essential hypertension,” Funder says.

Expansion of Screening

Given that prevalence and its consequences, the guideline recommends increased screening of patients at risk.

“We have recommended that all patients with blood pressures greater than or equal to 150/100 should be screened for primary aldosteronism,” says Robert M. Carey, MD, a professor of medicine at the University of Virginia who also served on the guideline committee.

In addition to that rather straightforward standard, the guideline also recommends screening patients:

• whose hypertension is resistant to three conventional anti-hypertensive drugs;
• whose hypertension is controlled by four or more medications;
• who have both hypertension and low blood potassium levels;
• who have both hypertension and sleep apnea;
• who have hypertension and a family history of early-onset hypertension or stroke before age 40; or
• who have hypertension and a first-degree relative with primary aldosteronism.

How to Screen

The guideline recommends screening patients using the plasma aldosterone/renin ratio (ARR) test. The guideline notes that the test is more sensitive when samples are collected in the morning after patients have been out of bed for two hours. And ideally, patients should not restrict sodium intake before the test, should be potassium replete, and should have taken no mineralocorticoid receptor antagonists for four weeks prior to the test.

Patients with plasma renin below detection levels, a high plasma aldosterone concentration, and spontaneous hypokalemia require no further confirmatory testing.

But in other cases, patients with a positive ARR test should have one or more confirmatory tests. There is no gold standard confirmatory test, but useful possibilities include an oral sodium loading test, saline infusion test, fludrocortisone suppression test, and captopril challenge test.

Patients with positive confirmatory tests indicating the diagnosis of PA should next have an adrenal computed tomography (CT) scan to exclude the large masses that may represent adrenocortical carcinoma. Aldosterone-producing adrenal carcinomas are very rare, but are identifiable because they are almost always greater than 4 cm in diameter.

“This is a major public health issue. Many people with primary aldosteronism are never screened due to the associated costs. Better screening processes are needed to ensure no person suffering from primary aldosteronism and the resulting risks of uncontrolled high blood pressure goes untreated.”-  John W. Funder, MD, PhD, Hudson Institute of Medical Research, Clayton, Australia, and chair, guideline task force

The next step is the identification of which adrenal gland is the aldosterone source, which can be done by an experienced radiologist using adrenal venous sampling to distinguish between unilateral and bilateral adrenal disease.

Treatment Options

In cases of patients with unilateral PA, the guideline recommends removal of the affected organ via a laparoscopic procedure. Blood pressure and serum potassium concentrations improve in nearly all these patients after the procedure, with hypertension cured — defined as blood pressure brought below 140/90 mm Hg without drugs — in about 50% of patients.

Patients with bilateral disease and those unable or unwilling to undergo surgery for unilateral PA should receive medical treatment with a mineralocorticoid receptor (MR) antagonist. The guideline suggests spironolactone as the primary agent, with epleronone as an alternative. “MR antagonists appear to be effective at controlling blood pressure and protecting target organs independent of effects of blood pressure,” the guideline says.

Spironolactone has been the MR antagonist agent of choice in the medical treatment of PA for decades. Its side effects are dose-dependent and include gynecomastia, breast engorgement, erectile dysfunction, muscle cramps, and menstrual disturbances. The side effect profile may lead to compliance issues as much from a patient being worried by Internet research as their actual incidence, Funder says.

Epleronone is a newer, selective MR antagonist without spironolactone’s androgen- and progesterone-related side effects. However, epleronone’s better tolerability profile needs to be balanced against its higher cost; its lower MR antagonist potency and potential to lower blood pressure in PA compared with spironolactone; and its shorter half-life.

The guideline also notes that the diagnosis can be difficult and involve many steps. In cases in which the evaluation is getting bogged down or a patient is resistant to more tests, treating the patient’s hypertension with an MR antagonist can be an acceptable option.

Evaluating the Guideline

“There was a huge amount of literature published in the years since the first guideline, and it is summarized nicely,” says Richard J. Auchus, MD, PhD, professor of internal medicine and pharmacology at the University of Michigan, who was not involved in writing the guideline. “The guideline committee did a really good job of assembling all of this and doing justice to the new developments.”

Auchus also praised the guideline’s writers for streamlining the diagnosis process. “The problem with this disease is that the evaluation can be really complicated, but they try to keep it appropriately simple, without dismissing the caveats,” Auchus says. He notes that endocrinologists are not likely to be on the front lines of the diagnosis so they “are obligated to educate primary care doctors about the importance of screening the indicated patients for primary aldosteronism.”

Alerting Primary Care Physicians

The guideline committee takes this obligation seriously, noting: “Many practicing physicians were taught that PA is a rare and benign cause of hypertension, and … thus merely a footnote to the management of hypertension as a whole. In the next five years, cardiologists and endocrinologists need to work together so that those whose responsibility is primary care are made keenly aware [of the high prevalence] of PA … in hypertensives.”

To further this goal, the Endocrine Society is working to develop “a simple and accessible guideline for screening and referral for widespread national use, and, if possible, international distribution,” with primary care doctors as a main target.

Funder notes that primary aldosteronism “is clearly a hormone disease,” and primary care physicians should be made aware that many of their patients with hypertension should be referred to an endocrinologist rather than a cardiologist.

– Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the rift between endocrine-disrupting chemical researchers and regulators in the August issue.