What is Primary Aldosteronism (Conn’s Syndrome)?
Primary aldosteronism, also known as Conn’s syndrome or primary hyperaldosteronism, is a hormonal disorder caused by changes to the adrenal glands (located near the kidney) that produce aldosterone. Primary aldosteronism ultimately leads to the overproduction of aldosterone.
Aldosterone is a hormone produced in the adrenal glands. It is a key component along the renin-angiotensin-aldosterone-system (RAAS) axis, an endocrine system that helps regulate blood pressure, electrolytes and fluids. When activated, aldosterone causes the body to hold onto more salt and water, causing blood pressure to go up.
In patients with primary aldosteronism, however, the overproduction of aldosterone leads to an increase in salt and water retention that causes elevated blood pressure levels, or hypertension.
An increasingly common condition, primary aldosteronism is one of the main causes of secondary hypertension, and it often leads to hypertension that is hard to treat. In fact, an overwhelming number of hypertensive patients fail to meet their target blood pressure goals, despite taking at least three or more medications. An estimated 20% to 30% of people in the U.S. with treatment-resistant hypertension have primary aldosteronism. This is a worrisome trend because hypertension is one of the world’s leading causes of heart disease, early death and complications like stroke or atrial fibrillation.
Who is Likely to Have Primary Aldosteronism?
An estimated 5% to 10% of people in the U.S. with hypertension have primary aldosteronism. However, that number is likely an underestimate because primary aldosteronism is not commonly diagnosed. Common indications of this condition include the following:
- People under 30 years of age with hypertension (early-onset hypertension)
- The presence of a benign tumor (adenoma) or cancerous mass on an adrenal gland
- Hypokalemia (low blood potassium levels)
- Treatment-resistant hypertension (e.g., persistent hypertension despite taking medications, usually three or more)
What are Common Causes of Primary Aldosteronism?
A common cause of primary aldosteronism is the presence of adrenal tumors on one or both glands. Adrenal glands can also be hyperactive, generating more aldosterone production than necessary.
Patients are usually categorized as having unilateral or bilateral disease. In people with unilateral disease, one gland is affected. For example, there may be the presence of a benign, noncancerous adrenal gland tumor (adenoma) on a single adrenal gland.
In people with bilateral disease, both adrenal glands are affected. Bilateral adrenal hyperplasia (the presence of multiple nodules, or abnormal tissue growths, that cause overactivity in the gland) is the most common cause of bilateral disease. Adrenal carcinomas (cancerous tumors) can happen, but these are rare.
Genetic conditions like congenital adrenal hyperplasia also affect the ability of the adrenal glands to work properly.
Changes to an adrenal gland cause aldosterone production to operate independent of signals from the RAAS system. Normally, the RAAS regulates aldosterone production closely. In fact, the RAAS usually tells the adrenal glands to produce aldosterone.
When blood volume goes down, the kidneys activate and promote the secretion of renin into the bloodstream. Renin eventually leads to the production of angiotensin I upon being released into the bloodstream. ACE receptors on endothelial cells in the lungs help convert angiotensin I into angiotensin II. Angiotensin II then activates the adrenal glands and promotes aldosterone secretion. Once secreted into the bloodstream, aldosterone binds to and activates the mineralocorticoid receptor in the kidneys. This process causes an increase in sodium absorption and increases water retention, causing high blood pressure. As sodium is absorbed, potassium is released into the urine to be excreted. The overall effect of aldosterone binding to cellular receptors (which control the transcription of certain genes) is called aldosterone’s genomic effect.
What are the Symptoms of Primary Aldosteronism?
Usually, primary aldosteronism does not cause symptoms other than hypertension and low potassium levels, which can cause the following symptoms:
- Fatigue
- Frequent need to urinate
- Headaches
- Cramps
- Numbness or tingling feelings
How is Primary Aldosteronism Diagnosed?
A diagnosis of primary aldosteronism is usually made with a blood test called an aldosterone to renin ratio (ARR) test. The goal is to measure the amount of aldosterone compared to plasma renin activity, or how active renin is. Given the relationship between these two hormones in the RAAS system, they should be relatively balanced and equal. An ARR test can detect any imbalances.
Testing blood samples for serum potassium levels may also be used as a diagnostic tool, because potassium levels drop when aldosterone initiates the process of holding onto salt. Potassium levels that are consistently low suggest too much aldosterone in the blood.
However, the aldosterone to renin ratio test is only the first step in diagnosing primary aldosteronism. Additional testing is usually needed to confirm a diagnosis. These tests include attempts to lower aldosterone by other means, such as high salt diets or medications designed to reduce aldosterone. If aldosterone remains high, it can help confirm a primary aldosteronism diagnosis.
If blood tests show abnormal aldosterone excess in the blood, an MRI or CT scan can also be used to determine the exact cause of aldosterone overproduction, such as an aldosterone-producing adenoma or bilateral adrenal hyperplasia. However, if the adrenal glands are not the cause of aldosterone overproduction, a diagnosis of secondary aldosteronism may be more appropriate.
While standardized guidelines are used to diagnose primary aldosteronism, they are often complex. There is also an inherent variability in plasma aldosterone measurements that makes diagnosis challenging. As a result, this condition is likely underdiagnosed.
How is Primary Aldosteronism Treated?
There is no way to cure primary aldosteronism. Instead, treatment is focused on reducing the morbidity and mortality of hypertension, hypokalemia or cardiovascular damage. Hypertension is the most pressing concern related to this condition because it can lead to several complications.
Common treatments include hypertension medications like angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or mineralocorticoid receptor antagonists (MRAs). The goal of most medications is to interfere with the RAAS, limit the effects of aldosterone and get hypertension back under control. However, medications like ACE inhibitors and ARBs often lose their effectiveness over time. Patients taking these medications can experience aldosterone breakthrough, which means aldosterone levels rise again despite being on medication.
Other hypertension medications also lack specificity. In targeting the production of aldosterone, many treatments also affect the production of cortisol, for example, which impacts immunologic reactions in the body. Other hypertension medications used for hypertension caused by primary aldosteronism, such as spironolactone and eplerenone, are commonly used because of their specific ability to inhibit aldosterone activity. However, these medications have their own set of challenges. For example, they can increase potassium to dangerous levels.
In some cases, patients may need surgery to remove masses on an adrenal gland. For people with unilateral disease (one gland affected), an adrenalectomy may be performed as an elective procedure to remove the affected gland. This procedure can usually be done laparoscopically, and many patients experience either a reduction in blood pressure or, at least, need fewer medications to manage their condition.
To best determine whether medication or surgery is the right approach for treating this condition, a doctor must confirm the source of aldosterone overproduction. A technique called adrenal vein sampling can help determine if an adrenal gland is causing aldosterone overproduction. Adding a scan to verify whether there are masses present can help determine whether surgery or medication is needed.
Despite the importance of managing hypertension, there has been no meaningful change in the standard of care for people with hypertension. Many standard high blood pressure medications have several side effects, limited efficacy and a limited-duration aldosterone lowering effect. CinCor believes the development of CIN-107 potentially offers new solutions for patients by targeting and inhibiting aldosterone synthase, the enzyme responsible for synthesizing aldosterone, at a highly selective level.