Aldosterone
Hyperaldosteronism can be differentiated into primary aldosteronism and secondary aldosteronism, according to the etiology of the excess aldosterone production. In primary aldosteronism, the adrenal gland produces excess aldosterone. Secondary aldosteronism is due to excessive secretion of renin that results in elevations of angiotensin and aldosterone. Laboratory tests can differentiate primary from secondary aldosteronism. Most importantly, plasma renin is low in primary, but increased in secondary aldosteronism.
Primary aldosteronism is most commonly diagnosed in middle-aged adults and is more common in women than in men. It is the cause of approximately 10% of the cases of essential hypertension. The diagnosis of this disorder is important because it is a curable form of hypertension.
The two most common causes of primary aldosteronism are bilateral adrenal hyperplasia (65-70%) and unilateral aldosterone-producing adenoma (30-35%). Symptoms include tiredness, muscle weakness, thirst, polyuria and nocturia. Hypertension, hypokalemia, and metabolic alkalosis are the classic presentation of primary aldosteronism. However, only about 35% of patients present with hypokalemia. Therefore, normokalemia does not exclude the diagnosis of primary aldosteronism.
The best screening tests are the paired measurements of plasma renin activity and plasma aldosterone concentration. The principle underlying this test is that as aldosterone secretion increases, plasma renin activity should decrease because of sodium retention. Plasma aldosterone concentration is typically >200 ng/L (>20 ng/dL), whereas the plasma renin activity is low. A plasma aldosterone (ng/dL) to plasma renin activity (ng/mL/h) ratio of 20 or more (measured while the patient is upright) supports the diagnosis of an aldosterone-producing tumor.
If plasma aldosterone and plasma renin activity are increased and the ratio is </=10, the patient should be investigated for secondary causes of hyperaldosteronism, which include renovascular hypertension, diuretic use, renin secreting tumor, malignant phase hypertension, and coarctation of the aorta. If both aldosterone and renin are depressed, other adrenal and metabolic disorders should be considered.
Beta blockers and calcium channel blockers may interfere with the diagnostic reliability of the aldosterone to plasma renin ratio. They should be withheld for two weeks prior to testing. Spironolactone and loop diuretics induce secondary hyperaldosteronism and should be withheld for 6 weeks before testing. Diltiazem does not interfere and can be used to control blood pressure during testing.
After a positive screening test is obtained, autonomous aldosterone secretion should be confirmed with either a saline infusion test or a 24-hour urine aldosterone excretion during oral salt loading. The principle of these tests is that failure to suppress aldosterone excretion with intravascular volume expansion indicates autonomous aldosterone production. The saline infusion test is performed by administering 2 liters of isotonic saline over 4 hours and then measuring plasma aldosterone. A plasma aldosterone level greater than 10 ng/dL (277.4 pmol/L) is diagnostic of primary hyperaldosteronism, while a level between 5 and 10 ng/dL is considered borderline.
The oral salt loading test is performed by having the patient ingest 12-gram sodium chloride tablets for 3 days and then measuring 24-hour urinary aldosterone. A urinary aldosterone excretion value greater than 12 ug/day (27.7 to 38.8 nmol/day) with urine sodium greater than 250 mEq/24 hours confirms the diagnosis of primary hyperaldosteronism. A 24-hour urinary aldosterone less than 8 ug/d excludes the diagnosis.
Due to the increased mortality and morbidity of primary aldosteronism, the Endocrine Society has established guidelines to screen patients at high-risk. Patients with the following findings should be screened:
- Sustained blood pressure >150/100 mm Hg during three measurements obtained on different days
- Hypertension resistant to three conventional anti-hypertensive drugs
- Controlled blood pressure on four or more anti-hypertensive drugs
- Hypertension and hyperkalemia
- Hypertension and adrenal incidentaloma
- Hypertension and sleep apnea
- Hypertension and a family history of early onset hypertension or cerebrovascular accident before the age of 40
- All hypertensive first-degree relatives of patients with primary aldosteronism
Aldosterone reference range is 3-24 ng/dL.
Specimen requirement is 0.5 mL of serum collected in a gold or red top tube.
Reference
Kolar MJ et al. Weakness and Low Potassium in a 47-Year Old Male. Clinical Chemistry 2021;67:941-946.
