Primary Hyperaldosteronism

Etiology

The most prevalent cause of primary hyperaldosteronism is aldosterone-producing adenomas. Other causes include aldosterone-producing adrenal carcinoma, ectopic aldosterone secretion from the kidneys or ovaries, and bilateral zona glomerulosa hyperplasia. Familial causes are also recognized.

• Type I, known as glucocorticoid-remediable hyperaldosteronism, results from the formation of a chimeric gene that combines the regulatory portion of 11β-hydroxylase (normally regulated by adrenocorticotropic hormone [ACTH]) with the aldosterone synthase gene. As a result, ACTH stimulates aldosterone synthase, leading to increased aldosterone production.
• The causes of type II hyperaldosteronism remain unclear; however, it has been associated with a gene located on chromosome 7p22 (band 11q13), with histological findings typically showing adrenal hyperplasia or adenomas.[1] 
• Type III hyperaldosteronism is caused by a mutation in the KCNJ5 gene, which encodes a potassium channel. This mutation increases intracellular calcium availability in zona glomerulosa cells, leading to excessive aldosterone synthesis.[2][3]

Epidemiology

Primary hyperaldosteronism is a condition that occurs worldwide, with no evidence suggesting a higher prevalence in any specific region. Aldosterone-producing adenomas are more common in women than in men. Some reports indicate a potentially higher prevalence of the condition among African Americans or individuals of African descent, particularly the idiopathic adrenal hyperplasia variant of the disease.[4][5]

History and Physical

Patients with suspected primary hyperaldosteronism typically present with uncontrolled hypertension at a relatively young age. They often require up to 3 antihypertensive medications, including a diuretic, to achieve only suboptimal blood pressure control. A family history of early-onset hypertension or cerebrovascular disease at a young age may also be noted. Symptoms related to hypokalemia, such as severe muscle weakness, palpitations, fatigue, and muscle cramps, may be present. Additionally, polydipsia and polyuria can occur due to nephrogenic diabetes insipidus, likely secondary to hypokalemia. 

Hypokalemia has traditionally been considered a hallmark sign in the diagnosis of primary hyperaldosteronism. However, recent estimates suggest that less than 37% of patients with primary hyperaldosteronism present with hypokalemia.[5] Patients with adequate sodium intake may experience more significant hypokalemia, as increased sodium delivery to the cortical collecting tubules promotes further potassium excretion in the presence of excess aldosterone.[5] Although hypokalemia is not always present, the diagnosis of primary hyperaldosteronism should be considered in patients with drug-resistant hypertension, particularly those who develop hypokalemia after starting a low dose of a diuretic.

Primary hyperaldosteronism cannot be diagnosed solely based on physical exam findings. However, excessive hypertension and increased stress on the heart can lead to left ventricular hypertrophy, which may result in an S4 heart sound. This occurs due to blood attempting to enter a noncompliant, stiff ventricle during atrial contraction. Other signs of longstanding hypertension may be observed across various organ systems, including heart failure, proteinuria from renal involvement, hypertensive retinal changes, carotid bruits or stroke symptoms due to vascular damage, muscle weakness, and altered mental status from hypertensive encephalopathy.

Evaluation

The Endocrine Society recommends screening for primary hyperaldosteronism in specific clinical scenarios. These include patients with hypertension who are on triple-drug therapy and develop diuretic-induced hypokalemia; those with hypertension and an adrenal incidentaloma; individuals with hypertension and a family history of early-onset cerebrovascular accident; and patients with hypertension who have first-degree relatives diagnosed with confirmed primary hyperaldosteronism.[6]

Suspect primary hyperaldosteronism in patients who present with early-onset hypertension, hypokalemia, and poorly controlled blood pressure despite medical therapy. The next step is to measure morning plasma aldosterone and renin activity. If the ratio of the morning aldosterone-to-plasma renin activity exceeds 20:1, the excess aldosterone is likely originating from the adrenal glands.

Any of the 4 confirmatory tests may be used—oral sodium loading, saline infusion, fludrocortisone suppression, and the captopril challenge test. These tests are designed to suppress aldosterone secretion; however, in patients with primary hyperaldosteronism, aldosterone levels remain inappropriately elevated. Once the diagnosis of primary aldosteronism is confirmed, an adrenal computed tomography (CT) scan is recommended as the initial imaging study for all suspected patients to exclude adrenocortical carcinoma. Adrenal venous sampling should follow to localize the source of aldosterone excess.[7]

The most effective diagnostic test involves measuring cortisol and aldosterone levels in both the bilateral adrenal venous effluent and a peripheral vein, before and during an ACTH infusion. Cortisol is used to verify proper catheter placement in the adrenal veins, as levels should be similar on both sides. In the presence of an adenoma, the aldosterone-to-cortisol ratio on one side is typically at least 5 times higher than on the other side, indicating suppression. In contrast, bilateral hyperplasia usually results in similar aldosterone-to-cortisol ratios on both sides. If the study suggests a unilateral adenoma, laparoscopic adrenalectomy is the preferred treatment. For patients who decline surgery, have bilateral disease, or are otherwise not surgical candidates, medical management with a mineralocorticoid antagonist, such as spironolactone, is recommended.[8]

Treatment / Management

The treatment for primary hyperaldosteronism typically involves laparoscopic resection of aldosterone-producing adenomas. This procedure usually resolves hypokalemia; however, hypertension may persist in up to 65% of patients following adrenalectomy. Surgery is the preferred treatment for patients with a unilateral aldosterone-producing adenoma. After unilateral adrenalectomy, most patients experience resolution of hypokalemia and moderate improvement in blood pressure.[9] In some cases, partial adrenalectomy may be considered, as it offers similar outcomes with fewer postoperative complications. However, there is a risk of leaving residual aldosterone-secreting tissue behind.[10]

For patients who cannot undergo surgery or have bilateral adrenal hyperplasia, mineralocorticoid antagonists such as spironolactone or eplerenone are recommended. A randomized study comparing the antihypertensive effects of spironolactone and eplerenone in patients with primary hyperaldosteronism found that spironolactone was more effective than eplerenone in controlling blood pressure.[11] Amiloride, a sodium channel blocker, may also be beneficial in treating this condition. Additional antihypertensive medications can be used as needed to achieve optimal blood pressure control. Spironolactone remains the first-line medical therapy for patients with hyperaldosteronism who cannot undergo surgical resection.  (A1)

Differential Diagnosis

In patients with refractory hypertension, differential diagnoses to consider include renal artery stenosis, secondary aldosteronism, pheochromocytoma (both spontaneous and drug-induced), deoxycorticosterone-secreting tumors, renin-secreting tumors originating from the juxtaglomerular apparatus, and renovascular ischemia.[12][13]

Excessive licorice intake can lead to the impairment of the conversion of cortisol to cortisone in the kidneys due to the glycyrrhizinic acid in licorice, which inhibits 11β-hydroxysteroid dehydrogenase. This results in excess cortisol binding to mineralocorticoid receptors, mimicking the effects of a mineralocorticoid.[14][15]

Other genetic conditions that may present with features similar to primary hyperaldosteronism include, but are not limited to:

• Chrétien syndrome is a rare disorder caused by excessive secretion of proopiomelanocortin (POMC)—a precursor of ACTH—due to a pituitary adenoma, resulting in adrenocortical hypertension.[16]

• Gitelman syndrome is caused by a loss of function of the sodium-chloride cotransporter in the renal tubules, leading to salt wasting and secondary hyperaldosteronism.[17] Please see StatPearls' companion resource, "Gitelman Syndrome," for more information.

• Liddle syndrome is a rare autosomal dominant disorder that causes pseudohyperaldosteronism. This condition is characterized by hyperactive renal epithelial sodium channels, leading to increased sodium reabsorption in the distal tubules.[18] In this condition, both renin and aldosterone levels are low.[18] Please see StatPearls' companion resource, "Liddle Syndrome (Pseudohyperaldosteronism)," for more information.

Prognosis

Studies show that morbidity and mortality rates associated with primary hyperaldosteronism are directly related to chronic hypertension, which increases the risk of cardiovascular diseases, including coronary artery disease, stroke, and congestive heart failure secondary to left ventricular hypertrophy.[19][20]

Other research highlights an elevated risk of cardiac arrhythmias, primarily due to persistent hypokalemia in patients with primary hyperaldosteronism.[14] Research has demonstrated that surgical correction through adrenalectomy significantly improves prognosis by reducing hypertension and hypokalemia more effectively than medical therapy.[21]

Complications

Patients with primary aldosteronism are at heightened cardiovascular risk, largely due to increased left ventricular mass and reduced left ventricular function compared to individuals with other forms of hypertension.[22][23] Additional cardiovascular risks include stroke, atrial fibrillation, and myocardial infarction.

A prospective study compared 54 patients with primary hyperaldosteronism treated with either spironolactone, a mineralocorticoid receptor antagonist, or surgical resection of an adrenal adenoma. The control group consisted of patients with primary hypertension, matched for age, sex, body mass index (BMI), and duration of hypertension. The study found that before treatment, individuals with primary hyperaldosteronism had a greater prevalence of cardiovascular events than those with primary hypertension.

Following treatment of mineralocorticoid excess, whether by surgical resection of adenomas or spironolactone therapy, there was no longer an elevated cardiovascular risk for those with primary hyperaldosteronism. The patients received follow-ups for approximately 7 years, with no significant difference between the 2 groups in terms of primary outcomes, including myocardial infarction, revascularization procedures, sustained arrhythmia, or stroke.[24]

Metabolic syndrome occurs more frequently in individuals with primary hyperaldosteronism compared to matched controls with similar blood pressure, sex, age, and BMI.[25]

Increased aldosterone blood levels lead to an increase in glomerular filtration rate (GFR) and renal perfusion pressure, often resulting in elevated urinary albumin excretion in these patients. In a study involving 50 patients with primary aldosteronism treated with either adrenalectomy or spironolactone, outcomes were compared to those in patients with primary hypertension receiving standard antihypertensive therapy. The results showed that at baseline, patients with primary aldosteronism demonstrated higher GFRs and albumin excretion than patients with primary hypertension.

After a 6-month follow-up of treated primary aldosteronism patients, significant reductions in both albuminuria and GFR were observed compared to the primary hypertension group.[26] This research suggests that treatment, whether through surgical resection or medical therapy, can uncover underlying renal insufficiency by reversing the hyperfiltration state seen in primary hyperaldosteronism.

A retrospective study comparing 124 patients with primary hyperaldosteronism to 465 patients with primary hypertension found that prior stroke was significantly more common in those with primary hyperaldosteronism (12.9%) compared to those with primary hypertension (3.4%). Both groups had similar ages, genders, and mean blood pressures of 175/107.[27]