Primary aldosteronism (PA), also known as hyperaldosteronism, is a clinical syndrome caused by excessive aldosterone secretion due to adrenal cortical abnormalities. This condition leads to sodium retention, potassium excretion, extracellular fluid volume expansion, and suppression of the renin-angiotensin system. Clinically, it manifests as hypertension and hypokalemia. The prevalence of primary aldosteronism is estimated to be approximately 10% among hypertensive patients.
Etiological Classification
Aldosterone-Producing Adenoma (APA)
This is the most common cause and is typically characterized by a unilateral adrenal adenoma with a diameter of 1–2 cm. In these cases, plasma aldosterone levels parallel the diurnal rhythm of plasma ACTH but show no significant response to changes in plasma renin. In rare cases, adenomas may produce aldosterone in response to renin elevation induced by upright posture, which is referred to as renin-responsive adenoma.
Idiopathic Hyperaldosteronism (IHA)
This also occurs frequently and involves bilateral adrenal zona glomerulosa hyperplasia, sometimes accompanied by nodules. The condition is thought to be related to heightened sensitivity to angiotensin II, as aldosterone secretion may decrease and hypertension and hypokalemia may improve with the use of angiotensin-converting enzyme (ACE) inhibitors.
Glucocorticoid-Remediable Aldosteronism (GRA)
This typically presents in adolescence, and it can be familial, with an autosomal dominant inheritance pattern, or sporadic. The adrenal glands show macro- and micronodular hyperplasia. Plasma aldosterone levels follow the diurnal rhythm of ACTH. Administration of physiological doses of glucocorticoids for a few weeks normalizes aldosterone secretion, blood pressure, and potassium levels. Pathogenesis involves the fusion of the 5′ regulatory sequence of the 11β-hydroxylase gene and the coding region of the aldosterone synthase gene, forming a chimeric gene. The gene product exhibits aldosterone synthase activity in the zona fasciculata, regulated by ACTH rather than angiotensin II.
Aldosterone-Producing Carcinoma
Rarely, adrenal cortical carcinoma secretes large amounts of aldosterone and, in some cases, glucocorticoids or androgens as well. Histological differentiation from adenomas can be challenging. Tumors are usually large, with diameters exceeding 5 cm, and often exhibit hemorrhage and necrosis on cross-section. CT or ultrasound frequently detects calcifications.
Ectopic Aldosterone-Secreting Adenoma or Carcinoma
Extremely uncommon, these may arise from ectopic adrenal tissue within the kidney or ovary.
Pathophysiology
Excessive aldosterone secretion leads to sodium retention and potassium excretion. This results in increased extracellular fluid volume, expanded blood volume, and heightened sodium concentration within vascular walls and circulating blood. These effects contribute to hypertension. The expansion of extracellular fluid volume activates sodium-excreting mechanisms, including reduced sodium reabsorption in the renal proximal tubule and increased secretion of atrial natriuretic peptide, which helps stabilize sodium balance. This phenomenon is referred to as the "escape from the effects of mineralocorticoids."
Significant potassium loss causes a range of functional impairments in nerve, muscle, cardiac, and renal systems. Intracellular potassium depletion is accompanied by an increase in sodium and hydrogen ions, resulting in a decrease in intracellular pH. Meanwhile, extracellular hydrogen ion levels decline, leading to an increase in extracellular pH, which manifests as metabolic alkalosis. During alkalosis, reduced ionized calcium in the extracellular fluid, along with aldosterone-induced renal magnesium loss, may contribute to symptoms such as paresthesia and muscle cramps in the extremities.
Clinical Manifestations
The progression of primary aldosteronism can be categorized into the following stages:
Early Stage
This is characterized by hypertension without symptoms of hypokalemia. Increased aldosterone secretion and suppression of the renin-angiotensin system result in an elevated plasma aldosterone-to-renin activity ratio.
Hypertension with Mild Potassium Deficiency
This is characterized by a slight or intermittent decrease in serum potassium levels, which may become more apparent under certain triggers, such as the use of diuretics.
Hypertension with Severe Potassium Deficiency
This is accompanied by more prominent clinical features.
The main clinical manifestations include:
Hypertension
This is the most common symptom. Blood pressure gradually increases as the condition progresses. Responses to commonly used antihypertensive medications are less effective compared to essential hypertension. In some cases, patients may present with refractory hypertension, accompanied by cardiovascular complications or strokes.
Neuromuscular Dysfunction
Muscle Weakness and Periodic Paralysis
The severity of muscle involvement increases as serum potassium levels decrease. Triggers commonly include physical exertion or the use of potassium-wasting diuretics such as hydrochlorothiazide or furosemide. Paralysis typically affects the lower limbs but may extend to all four limbs in severe cases, even causing respiratory or swallowing difficulties.
Paresthesia and Tetany
Severe hypokalemia reduces neuromuscular excitability, which may result in mild or absent tetany. However, after potassium supplementation, tetany symptoms may become more prominent.
Renal Manifestations
Chronic potassium loss leads to vacuolar degeneration of renal tubular epithelial cells and impairment of urine concentration, resulting in polyuria, particularly nocturnal polyuria, accompanied by secondary thirst and increased water intake.
Patients often have a predisposition to urinary tract infections.
Proteinuria and, in rare cases, renal function impairment may also occur.
Cardiac Manifestations
Electrocardiographic Findings of Hypokalemia
This includes prolongation of the QT interval, broadening and flattening or inversion of the T wave, a prominent U wave, and a camel-hump appearance (fusion of T and U waves).
Arrhythmias
Paroxysmal supraventricular tachycardia is relatively common, with ventricular fibrillation being the most severe cardiac complication.
Other Manifestations
Growth retardation in pediatric patients may occur, likely related to chronic potassium deficiency and accompanying metabolic disturbances.
Potassium deficiency may impair insulin secretion and sensitivity, leading to glucose intolerance.
Laboratory Investigations
Serum and Urine Biochemical Tests
Hypokalemia
Serum potassium levels are typically between 2–3 mmol/L and may be even lower in severe cases. Hypokalemia is often persistent but may be intermittent. Serum potassium remains normal in early-stage patients.
Hypernatremia
Serum sodium levels are usually at the upper limit of normal or slightly elevated.
Metabolic Alkalosis
Blood pH and bicarbonate (CO2 bound) are at the upper limit of normal or slightly elevated.
High Urinary Potassium: Despite hypokalemia (serum potassium <3.5 mmol/L), 24-hour urinary potassium excretion exceeds 25 mmol.
Urine pH
This is neutral or slightly alkaline.
Aldosterone Measurement
Plasma aldosterone concentration and urinary aldosterone excretion are influenced by posture and sodium intake, generally increasing in upright posture and during low sodium intake. Both plasma and urinary aldosterone levels are elevated in primary aldosteronism. Normal reference values for plasma aldosterone are 50–250 pmol/L in the supine position and 80–970 pmol/L in the upright position (to convert plasma aldosterone concentration from pmol/L to ng/dL, divide by 27.7). For urinary aldosterone, reference values with normal sodium intake are 6.4–86 nmol/24h; values are 47–122 nmol/24h with low sodium intake and 0–13.9 nmol/24h with high sodium intake. In cases of primary aldosteronism with severe hypokalemia, aldosterone secretion may be suppressed, making elevations in plasma and urinary aldosterone levels less prominent.
Renin Activity and Angiotensin II Levels
Plasma renin activity and baseline angiotensin II levels are reduced in patients and may fall below detectable limits. Normal reference values for plasma renin activity are 0.55 ± 0.09 ng/(mL·h), while angiotensin II levels are 26.0 ± 1.9 pg/mL. After intramuscular administration of furosemide (0.7 mg/kg body weight) followed by 2 hours of upright posture, plasma renin activity and angiotensin II levels in healthy individuals increase significantly from baseline. In contrast, patients with primary aldosteronism show only a minimal increase or no response.
Diagnosis and Etiological Diagnosis
The diagnosis of primary aldosteronism is established in patients with hypertension and hypokalemia who exhibit elevated plasma and urinary aldosterone levels alongside reduced plasma renin activity and angiotensin II levels. Correction of electrolyte disturbances and reduction in blood pressure with spironolactone further supports the diagnosis. Once primary aldosteronism is confirmed through screening and confirmatory tests, further evaluation is needed to identify the cause. This primarily involves differentiation between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA), although rare causes should also be considered. Patients with APA generally present with higher blood pressure, more pronounced hypokalemia and metabolic alkalosis, and higher plasma and urinary aldosterone levels compared to those with IHA.
Dynamic Testing
Evaluation of plasma aldosterone concentration (PAC) in response to positional changes in the morning is utilized. In normal individuals, after lying supine overnight, PAC measured at 8:00 a.m. decreases by noon, consistent with declines in plasma ACTH and cortisol levels. Upon standing, PAC increases due to the predominant effect of renin-angiotensin activation over the influence of ACTH. In contrast, PAC in patients with IHA increases significantly during upright posture between 8:00 a.m. and 12:00 p.m., exceeding levels observed in healthy individuals. However, in patients with APA, PAC does not increase and may even decrease.
Screening Test
The plasma aldosterone (ng/dL) to plasma renin activity [ng/(mL·h)] ratio (ARR) is considered the best screening test for primary aldosteronism. An ARR greater than 30 is suggestive of the condition, with plasma aldosterone levels in affected patients typically exceeding 15 ng/dL.
Confirmatory Test
For patients with ARR above the threshold and only mildly elevated or normal plasma aldosterone levels without hypokalemia, confirmatory testing is required to establish the diagnosis of primary aldosteronism. During this test, 2,000 mL of normal saline is infused intravenously over four hours while the patient remains supine. In healthy individuals, PAC is usually suppressed to less than 5 ng/dL. In patients with primary aldosteronism, PAC remains at 10 ng/dL or higher.
Imaging Studies
Imaging techniques help distinguish between adrenal adenomas and hyperplasia, as well as localizing adenomas. Large tumors measuring 5 cm or more strongly suggest adrenal carcinoma.
Adrenal Ultrasound
It can detect aldosterone-producing adenomas larger than 1.3 cm in diameter. Differentiation between small adenomas and idiopathic hyperplasia is challenging.
Adrenal CT and MRI
High-resolution CT can detect tumors as small as 5 mm, although smaller lesions completely surrounded by normal tissue may be harder to identify. For patients with IHA, CT typically shows normal findings or bilateral diffuse adrenal enlargement. MRI is also used for tumor localization. MRI has greater sensitivity but lower specificity than CT in detecting aldosterone-producing adenomas.
Adrenal Venous Hormone Measurements
When the above methods fail to determine the etiology, adrenal venous sampling (AVS) may be performed. This involves collecting blood samples from both adrenal veins to measure aldosterone-to-cortisol ratios. AVS assists in distinguishing unilateral from bilateral aldosterone overproduction, which is crucial for subtype diagnosis, treatment selection, disease progression assessment, and prognosis prediction.
Differential Diagnosis
Differential diagnosis is crucial in patients presenting with hypertension and hypokalemia, as misdiagnosis could lead to inappropriate treatment. The following conditions require differentiation:
Non-Aldosterone-Related Mineralocorticoid Excess Syndrome
This condition is characterized by hypertension, hypokalemic alkalosis, and suppression of the renin-angiotensin system, but plasma and urinary aldosterone levels are reduced rather than elevated. Based on etiology, it can be subdivided into two groups:
True Mineralocorticoid Excess Syndrome
This condition results from defects in adrenal corticosteroid synthetic enzymes, leading to the excessive production of steroids with mineralocorticoid activity (e.g., deoxycorticosterone). Glucocorticoid supplementation is required.
17α-Hydroxylase Deficiency: Biochemical and clinical abnormalities include:
- Impaired androgen and estrogen synthesis, resulting in sexual infantilism in females and pseudohermaphroditism in males.
- Impaired glucocorticoid synthesis, with low blood and urinary cortisol, low 17-hydroxyprogesterone levels, and elevated ACTH.
- Overactivation of the mineralocorticoid synthesis pathway, with elevated levels of progesterone, deoxycorticosterone, and corticosterone, causing sodium retention, potassium wasting, hypertension, increased blood volume, and suppression of renin-angiotensin activity, leading to reduced aldosterone synthesis.
11β-Hydroxylase Deficiency: Biochemical and clinical abnormalities include:
- Low cortisol in blood and urine, with elevated ACTH levels.
- Increased androgen synthesis, causing partial precocious puberty in males and varying degrees of masculinization or pseudohermaphroditism in females.
- Excessive production of deoxycorticosterone, resulting in mineralocorticoid excess syndrome.
Both enzyme deficiencies are accompanied by bilateral adrenal hyperplasia, which may be misdiagnosed as hyperplastic primary aldosteronism, potentially leading to unnecessary adrenalectomy.
Apparent Mineralocorticoid Excess Syndrome (AME)
This condition results from a congenital deficiency of 11β-hydroxysteroid dehydrogenase (11β-HSD), which is unable to convert cortisol to the inactive cortisone. Cortisol activates mineralocorticoid receptors, producing clinical features of mineralocorticoid excess. It is more commonly seen in children and young adults, presenting with severe hypertension, hypokalemic alkalosis, low plasma renin activity and aldosterone levels, normal plasma cortisol, and reduced urinary 17-hydroxycorticoid and free cortisol levels. Treatment with spironolactone is effective, and some patients also respond to dexamethasone.
Liddle Syndrome
This autosomal dominant disorder is caused by mutations in genes encoding epithelial sodium channels in renal tubular cells, resulting in their constitutive activation. This leads to excessive sodium reabsorption and increased potassium and hydrogen ion excretion. Patients present with hypertension, low plasma renin activity and aldosterone levels, and frequent hypokalemia. Treatment with spironolactone is ineffective, while amiloride or triamterene can correct hypokalemia and reduce blood pressure.
Secondary Hyperaldosteronism with Hypertension and Hypokalemia
Secondary hyperaldosteronism caused by elevated renin levels can also present with hypertension and hypokalemia and needs to be differentiated from primary aldosteronism. Renin excess can be primary or secondary in origin. Primary renin excess is caused by renin-secreting tumors, while secondary renin excess is a consequence of renal ischemia.
Renin-Secreting Tumors
This condition is more common in young individuals, with severe hypertension and hypokalemia. Plasma renin activity is markedly elevated. Tumors causing this condition include:
- Juxtaglomerular cell tumors (reninomas)
- Wilms tumors and ovarian tumors
Secondary Renin Elevation Leading to Hyperaldosteronism
This includes:
- Malignant Hypertension: Renal ischemia increases plasma renin activity, with some patients developing hypokalemia. The condition progresses rapidly and often leads to azotemia or uremia.
- Renal Artery Stenosis: Hypertension progresses rapidly, and a vascular bruit may be auscultated in the mid-abdominal region or costovertebral area. Renal scans with radionuclides frequently reveal renal dysfunction, and renal angiography confirms the diagnosis.
- Unilateral Renal Atrophy: This condition can induce severe hypertension and hypokalemia.
Treatment
The definitive treatment for aldosterone-producing adenomas (APA) involves surgical removal. Idiopathic hyperaldosteronism (IHA) responds poorly to surgery and is typically managed with medication. In cases where it is difficult to differentiate between adenoma and IHA, initial medical treatment combined with regular imaging follow-ups is recommended, as previously undetectable small adenomas may become evident over time.
Surgical Treatment
Unilateral laparoscopic adrenalectomy is the preferred treatment for patients with unilateral primary aldosteronism, including APA and unilateral adrenal nodular hyperplasia. Preoperative preparation typically includes a low-sodium diet and oral spironolactone to correct hypokalemia and reduce hypertension. Spironolactone is administered at 120–240 mg per day in divided doses, and surgery is performed once potassium levels normalize and blood pressure declines, with the dose tapered to a maintenance level. Surgical outcomes for adenomas are generally favorable, with correction of electrolyte abnormalities and resolution of polyuria and polydipsia. Most patients achieve normalization or near-normalization of blood pressure postoperatively.
Medical Treatment
For patients unable to undergo surgery or for those with IHA, spironolactone therapy is the treatment of choice, with a regimen similar to preoperative preparation. However, long-term spironolactone use may cause side effects such as gynecomastia and erectile dysfunction in men, and menstrual irregularities in women. In such cases, triamterene or amiloride may be substituted to aid in sodium excretion while conserving potassium. Antihypertensive medications can be added as needed to manage blood pressure.
Calcium channel blockers can reduce aldosterone production in some patients with primary aldosteronism, leading to normalization of potassium levels and blood pressure. Angiotensin-converting enzyme inhibitors (ACEIs) may also be effective in certain cases of IHA.
For glucocorticoid-remediable aldosteronism (GRA), glucocorticoids are used for treatment. Adults are commonly treated with dexamethasone at 0.5–1 mg daily. Symptoms typically improve within 3–4 weeks, with potassium levels rising more rapidly than blood pressure, which may require adjunct treatment with antihypertensive agents, such as calcium channel blockers. For children, dexamethasone is dosed at 0.05–0.1 mg/(kg·day), or hydrocortisone at 12–15 mg/m2 body surface area, divided into three doses. Hydrocortisone has a lesser impact on growth and development in children.
Aldosterone-producing carcinomas carry a poor prognosis, as they are often diagnosed at a stage where surgical cure is no longer feasible. Chemotherapeutic agents such as mitotane, aminoglutethimide, and ketoconazole may temporarily alleviate clinical symptoms arising from excessive aldosterone secretion but do not significantly alter disease progression.