Aldosteronism, Primary

Essentials of Diagnosis

• Hypertension may be severe or drug-resistant

• Hypokalemia (in minority of patients) may cause polyuria, polydipsia, muscle weakness

• Low plasma renin; elevated plasma and urine aldosterone levels

General Considerations

• Excessive aldosterone production

  • Increases sodium retention and suppresses plasma renin

  • Increases renal potassium excretion that can lead to hypokalemia

• Cardiovascular events are more prevalent in patients with aldosteronism (35%) than in those with essential hypertension (11%)

• May be caused by a unilateral aldosterone-producing adrenal cortical adenoma (Conn syndrome, 25%)

  • More common in women with a 2:1 ratio

  • Peaks between ages 30 and 50 years

• More commonly caused by adrenal cortical hyperplasia (75%)

  • More common in men with a 4:1 ratio

  • Peaks between ages 50 and 60 years

• Bilateral aldosteronism may be corticosteroid suppressible due to an autosomal-dominant genetic defect allowing ACTH stimulation of aldosterone production

• Malignant ovarian tumors are rare cause of hyperaldosteronism

Demographics

• Accounts for about 8% of cases of stage 2 (mild) hypertension and about 13% of cases of stage 3 (moderate) hypertension

• Should also be suspected with early onset hypertension or stroke before age 50 years (or both)

• Patients of all ages may be affected, but the peak incidence is between 30–60 years

Symptoms and Signs

• Hypertension is typically moderate but may be severe

• Some patients have only diastolic hypertension, without other symptoms and signs

• Edema (rare)

• Muscle weakness (at times with paralysis simulating periodic paralysis), paresthesias with frank tetany, headache, polyuria, and polydipsia may be seen in patients with hypokalemia

Differential Diagnosis

• Essential hypertension

• Hypokalemic thyrotoxic periodic paralysis

• Renal vascular hypertension (hypertension and hypokalemia, but plasma renin activity is high)

• Hypokalemia due to other cause, eg, diuretics

• Secondary hyperaldosteronism (dehydration, heart failure)

• Congenital adrenal hyperplasia: 11beta-hydroxylase deficiency, 17alpha-hydroxylase deficiency

• Cushing syndrome

• Excessive real licorice ingestion

• Syndrome of cortisol resistance

Laboratory Tests

• Plasma potassium should be determined in hypertensive individuals; however, hypokalemia is present in only 37% of affected patients

• An elevated serum bicarbonate (HCO₃) concentration indicates metabolic alkalosis and is commonly present

• Testing for primary aldosteronism should be considered for all hypertensive patients with any of the following:

  • Sustained hypertension above 150/100 mm Hg on 3 different days

  • Hypertension resistant to three conventional antihypertensive drugs, including a diuretic

  • Controlled blood pressure requiring four or more antihypertensive drugs

  • Hypokalemia, particularly when unrelated to diuretics

  • Personal or family history of early onset hypertension or CVA at age ≤ 40 years

  • First-degree relative with primary aldosteronism

  • Presence of an adrenal mass

  • Low plasma renin activity

• Testing protocol

  • For at least 2 weeks prior to testing, patients should

    • Have any hypokalemia corrected and then consume a diet high in NaCl (> 6 g/day)

    • Hold certain medications: all diuretics, ACE inhibitors, ARBs (stimulate plasma renin activity [PRA]); beta-blockers, clonidine, NSAIDs (suppress PRA), oral estrogens, and oral contraceptives

    • Medications that are allowed include extended-release verapamil, hydralazine, terazosin, and doxazosin

  • The patient should be out of bed for at least 2 hours and seated for 15–60 minutes before blood is drawn, which should preferably be obtained between 8 AM and 10 AM

  • Patients with primary aldosteronism have a suppressed PRA that is below or near 1.0 ng/mL/h or direct renin assay (DRA) < 0.36 ng/mL

  • Suppressed PRA or DRA with a serum aldosterone concentration > 15 ng/dL (420 pmol/L) indicates probable primary hyperaldosteronism

  • Serum aldosterone (ng/dL):PRA (ng/mL/h) ratios

    • < 24 exclude primary aldosteronism

    • Between 24 and 30 are indeterminate

    • Between 30 and 64 are suspicious

    • > 64 helps confirm the diagnosis of primary aldosteronism

  • Diagnosis of primary aldosteronism is confirmed when

    • Patients have a suppressed PRA or DRA plus a serum aldosterone ≥ 20 ng/day

    • Suppressed PRA or DRA but lower serum aldosterone levels with a urine aldosterone over 12 mcg/24 h is present (33 nmol/24 h)

Imaging Studies

• Thin-section CT scan

  • Used to screen for a rare adrenal carcinoma

  • In the absence of a large adrenal carcinoma, scanning cannot reliably distinguish unilateral from bilateral aldosterone excess

Diagnostic Procedures

• Adrenal vein sampling

  • Most accurate way to determine whether primary aldosteronism is due to unilateral aldosterone excess

  • Indicated only to direct the surgeon to the correct adrenal and should be performed only if surgery is contemplated

  • Useful for patients who are not hypokalemic, over age 40 years, or who have an adrenal adenoma < 1 cm diameter

• Genetic testing for familial glucocorticoid remediable aldosteronism is recommended for patients with

  • Confirmed primary aldosteronism by age 20 years

  • A family history of primary aldosteronism or stroke at young age (< age 40)

Medications

• Spironolactone or eplerenone

  • Long-term therapy is an option for Conn syndrome

  • Used to treat bilateral adrenal hyperplasia

  • Spironolactone

    • Has anti-androgen activity and frequently causes breast tenderness, gynecomastia, or reduced libido

    • Initial dose: 12.5–25 mg once daily orally

    • Dose may be titrated to 200 mg daily

    • Contraindicated in pregnant women

  • Eplerenone

    • Does not have anti-androgen effects

    • Must be given twice daily in oral doses of 25–50 mg due to short half-life

• Blood pressure must be monitored daily when beginning these anti-mineralocorticoid medications

  • Significant drops in blood pressure have occurred when these drugs are added to other antihypertensive agents

  • Other antihypertensive drugs may be required, particularly amlodipine, ACE inhibitors, or ARBs

• Suppression with low-dose glucocorticoids for glucocorticoid-remediable aldosteronism (which is very rare)

Surgery

• Laparoscopic adrenalectomy for Conn syndrome (unilateral aldosterone-secreting adrenal adenoma)

Complications

• The incidence of cardiovascular complications from hypertension are higher in primary aldosteronism than in idiopathic hypertension

• Following unilateral adrenalectomy for Conn syndrome, suppression of the contralateral adrenal may result in temporary postoperative hypoaldosteronism, characterized by hyperkalemia and hypotension

Prognosis

• Hypertension remits after surgery in about two-thirds of cases but persists or returns despite surgery in one-third

• Prognosis much improved by early diagnosis and treatment

• Only 2% of aldosterone-secreting adrenal tumors are malignant