Hyperaldosteronism for the ABIM
Hyperaldosteronism for the American Board of Internal Medicine Exam
- Pathophysiology
- Excess Aldosterone Production: Hyperaldosteronism results from excessive secretion of aldosterone, a mineralocorticoid produced by the adrenal cortex. Aldosterone acts on the kidneys, promoting sodium retention and potassium excretion, which leads to increased water reabsorption and hypertension.
- Primary vs. Secondary Hyperaldosteronism:
- Primary Hyperaldosteronism (PA): Caused by autonomous aldosterone secretion from the adrenal glands, independent of the renin-angiotensin system. PA accounts for most cases of hyperaldosteronism.
- Secondary Hyperaldosteronism: Caused by conditions that activate the renin-angiotensin-aldosterone system (RAAS), such as heart failure, cirrhosis, or renal artery stenosis, resulting in increased renin levels.
- Etiology
- Primary Hyperaldosteronism:
- Aldosterone-Producing Adenoma (APA): The most common cause of primary hyperaldosteronism, also known as Conn’s syndrome. It involves a unilateral adrenal adenoma that secretes aldosterone.
- Bilateral Adrenal Hyperplasia (BAH): Represents diffuse or nodular hyperplasia of both adrenal glands. It is the second most common cause of primary hyperaldosteronism.
- Familial Hyperaldosteronism: A rare, genetic form of hyperaldosteronism, including familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism) and type II (APA or BAH).
- Adrenal Carcinoma: Rarely, an adrenal carcinoma may secrete aldosterone, though it usually produces other hormones as well.
- Secondary Hyperaldosteronism:
- Renal Artery Stenosis: Narrowing of the renal arteries decreases blood flow to the kidneys, which stimulates renin release and increases aldosterone production.
- Heart Failure and Cirrhosis: These conditions cause a perceived reduction in renal perfusion, leading to activation of the RAAS and secondary hyperaldosteronism.
- Clinical Features
- Hypertension: Often resistant to treatment and may be severe. The hypertension is primarily due to sodium retention, increased plasma volume, and enhanced sensitivity to vasoconstrictive agents.
- Hypokalemia: A hallmark of hyperaldosteronism. Potassium wasting occurs due to increased renal excretion, leading to symptoms such as muscle weakness, cramps, paresthesias, and in severe cases, paralysis. Hypokalemia can also cause metabolic alkalosis.
- Fatigue: Non-specific but common, particularly in those with hypokalemia.
- Polyuria and Polydipsia: Increased urine output and thirst result from hypokalemia-induced renal tubular dysfunction.
- Metabolic Alkalosis: Increased excretion of hydrogen ions in exchange for sodium retention leads to a mild metabolic alkalosis, contributing to muscle symptoms.
- Diagnosis
- Initial Screening:
- Plasma Aldosterone-to-Renin Ratio (ARR): The screening test of choice. A high ARR (>20) suggests primary hyperaldosteronism, particularly in the setting of suppressed plasma renin activity (PRA) and elevated plasma aldosterone concentration (PAC).
- Confirmatory Testing:
- Oral Sodium Loading Test: Patients are given a high-sodium diet or oral salt tablets for several days, and 24-hour urine aldosterone is measured. Elevated aldosterone levels (>12 µg/day) confirm the diagnosis.
- Saline Infusion Test: After a 2-liter saline infusion, normal individuals will suppress aldosterone levels, while those with primary hyperaldosteronism will have persistent elevation of aldosterone.
- Captopril Challenge Test: Captopril inhibits the RAAS and should suppress aldosterone in normal individuals. Lack of suppression suggests primary hyperaldosteronism.
- Imaging:
- Adrenal CT Scan: Performed to differentiate between an adrenal adenoma and bilateral adrenal hyperplasia. Adrenal CT is also used to rule out adrenal carcinoma.
- Adrenal Venous Sampling (AVS): The gold standard for distinguishing unilateral from bilateral disease. Aldosterone is measured from blood samples obtained from both adrenal veins. It is primarily used if surgery is being considered.
- Genetic Testing: Considered in patients with a family history of hyperaldosteronism or in cases where familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism) is suspected.
- Differential Diagnosis
- Essential Hypertension: The most common cause of hypertension. Unlike hyperaldosteronism, essential hypertension is not associated with hypokalemia or metabolic alkalosis.
- Liddle Syndrome: A genetic disorder of sodium channels in the kidneys that causes hypertension and hypokalemia but with low aldosterone levels.
- Cushing’s Syndrome: Excess cortisol can mimic hyperaldosteronism by activating mineralocorticoid receptors, causing hypertension, hypokalemia, and metabolic alkalosis.
- Renal Artery Stenosis: Causes secondary hyperaldosteronism due to activation of the RAAS.
- Treatment
- Primary Hyperaldosteronism:
- Aldosterone-Producing Adenoma (APA):
- Surgical Treatment: Laparoscopic adrenalectomy is the treatment of choice for unilateral aldosterone-producing adenomas, which can cure hypertension and reverse hypokalemia.
- Medical Management: For patients who are not surgical candidates, or in cases of bilateral adrenal hyperplasia, medical therapy is preferred.
- Mineralocorticoid Receptor Antagonists: Spironolactone is the first-line medical therapy. It blocks the effects of aldosterone on the kidneys, reducing sodium retention, potassium excretion, and blood pressure. However, spironolactone can cause gynecomastia and impotence due to its anti-androgenic effects. Eplerenone, a selective mineralocorticoid receptor antagonist, is an alternative with fewer anti-androgenic side effects.
- Other Antihypertensives: Thiazide diuretics, calcium channel blockers, or ACE inhibitors may be used to control hypertension, though they do not correct the underlying pathophysiology.
- Secondary Hyperaldosteronism:
- Renal Artery Stenosis: Treatment typically involves angioplasty or stenting to restore blood flow to the kidneys. Medical management of hypertension with RAAS blockers such as ACE inhibitors or angiotensin receptor blockers (ARBs) is also common.
- Heart Failure or Cirrhosis: The treatment focuses on managing the underlying condition, with medications like RAAS blockers, diuretics, and fluid restriction playing key roles.
- Complications
- Cardiovascular: Long-standing hyperaldosteronism increases the risk of cardiovascular complications such as left ventricular hypertrophy, myocardial infarction, stroke, and atrial fibrillation due to chronic hypertension and hypokalemia.
- Kidney Damage: Chronic hypokalemia can lead to nephropathy and impaired renal function.
- Metabolic Abnormalities: Persistent hypokalemia can result in muscle cramps, arrhythmias, and severe metabolic alkalosis.
Key Points
- Pathophysiology: Hyperaldosteronism results from excessive aldosterone production, leading to sodium retention, hypertension, potassium excretion, and hypokalemia.
- Etiology: Primary hyperaldosteronism is most commonly caused by aldosterone-producing adenomas or bilateral adrenal hyperplasia. Secondary hyperaldosteronism arises from conditions that activate the renin-angiotensin-aldosterone system, such as renal artery stenosis or heart failure.
- Clinical Features: Resistant hypertension, hypokalemia, muscle weakness, fatigue, metabolic alkalosis, and polyuria.
- Diagnosis: Elevated aldosterone-to-renin ratio (ARR) is the primary screening test, followed by confirmatory tests such as saline infusion or oral sodium loading tests. Imaging and adrenal venous sampling help localize the cause.
- Treatment: Laparoscopic adrenalectomy is the treatment of choice for unilateral adenomas. Spironolactone or eplerenone is used for bilateral hyperplasia or non-surgical candidates. Secondary hyperaldosteronism is managed by treating the underlying cause.
- Complications: Cardiovascular disease, kidney damage, and metabolic abnormalities are major risks if hyperaldosteronism is untreated.