(See also Overview of Adrenal Function.)
Aldosterone is the most potent mineralocorticoid produced by the adrenal cortex. It causes sodium retention and potassium loss. In the kidneys, aldosterone causes transfer of sodium from the lumen of the distal tubule into the tubular cells in exchange for potassium and hydrogen. The same effect occurs in salivary glands, sweat glands, cells of the intestinal mucosa, and in exchanges between intracellular fluid (ICF) and extracellular fluid (ECF).
Aldosterone secretion is regulated by the renin-angiotensin system and, to a lesser extent, by adrenocorticotropic hormone (ACTH). Renin, a proteolytic enzyme, is stored in the juxtaglomerular cells of the kidneys. Reduction in blood volume and flow in the afferent renal arterioles or hyponatremia induces secretion of renin. Renin transforms angiotensinogen from the liver to angiotensin I, which is transformed by angiotensin-converting enzyme (ACE) to angiotensin II, which in turn causes secretion of aldosterone. Sodium retention and water retention resulting from increased aldosterone secretion increase the blood volume and reduce renin secretion.
Primary aldosteronism is caused by an
Adrenal adenoma, usually unilateral, of the glomerulosa or fasciculata cells of the adrenal cortex
Adrenal carcinoma or hyperplasia (rare)
Adenomas are extremely rare in children, but primary aldosteronism sometimes occurs in childhood adrenal carcinoma or hyperplasia.
In adrenal hyperplasia, which is more common among older males, both adrenals are overactive, and no adenoma is present. The clinical picture can also occur with certain forms of congenital adrenal hyperplasia (in which other mineralocorticoids are elevated) and the dominantly inherited dexamethasone-suppressible hyperaldosteronism.
Small aldosterone-secreting adenomas are increasingly recognized as a cause of primary hypertension even when serum potassium levels are normal.
Symptoms and Signs of Primary Aldosteronism
Diastolic hypertension and hypokalemic nephropathy with polyuria and polydipsia are common.
Hypernatremia, hypervolemia, and a hypokalemic alkalosis may occur, causing episodic weakness, paresthesias, transient paralysis, and tetany.
In many cases, the only manifestation is mild to moderate hypertension.
Edema is uncommon.
Diagnosis of Primary Aldosteronism
Electrolytes
Plasma aldosterone
Plasma renin activity (PRA)
Adrenal imaging
Bilateral adrenal vein catheterization (for cortisol and aldosterone levels)
Primary aldosteronism is suspected in patients with hypertension and hypokalemia but increasingly is being diagnosed in patients with normokalemia and resistant hypertension.
Initial laboratory testing consists of plasma aldosterone levels and plasma renin activity (PRA). Ideally, the patient should not take any medications that affect the renin-angiotensin system (eg, thiazide diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], beta-blockers) for 4 to 6 weeks before tests are done. Plasma renin activity is usually measured in the morning with the patient recumbent. Patients with primary aldosteronism typically have plasma aldosterone > 15 ng/dL (> 0.42 nmol/L) and low levels of PRA, with a ratio of plasma aldosterone (in ng/dL) to plasma renin activity (in ng/mL/hour) > 20. However, the diagnostic ratio depends on the type of assay and assay units and should therefore be individualized. After initial measurements are made, a 4-hour saline infusion or 3 days of dietary salt loading is given, and aldosterone is measured again to see whether it can be suppressed. In primary hyperaldosteronism, serum aldosterone production is autonomous and will not fall below a diagnostic value. Some would use 3 days of oral salt loading instead.
Low levels of both plasma renin activity and aldosterone suggest nonaldosterone mineralocorticoid excess (eg, due to licorice ingestion, Cushing syndrome, or Liddle syndrome). High levels of both plasma renin activity and aldosterone suggest secondary hyperaldosteronism. The principal differences between primary and secondary aldosteronism are shown in the table Distinguishing Primary and Secondary Aldosteronism. In children, Bartter syndrome is distinguished from primary hyperaldosteronism by the absence of hypertension and marked elevation of PRA; there is a similar, milder syndrome in adults with Gitelman syndrome.
Distinguishing Primary and Secondary Aldosteronism
Clinical Finding | Primary Aldosteronism | Secondary Aldosteronism | ||
|---|---|---|---|---|
Adenoma | Hyperplasia | Renovascular or Accelerated Hypertension | Edematous Disorders† | |
Blood pressure | ↑↑ | ↑ | ↑↑↑↑ | N or ↑ |
Edema | Rare | Rare | Rare | Present |
Serum sodium | N or ↑ | N or ↑ | N or ↓ | N or ↓ |
Serum potassium | N or ↓ | N or ↓ | ↓ | N or ↓ |
Plasma renin activity* | ↓↓ | ↓↓ | ↑↑ | ↑ |
Aldosterone | ↑ | ↑ | ↑↑ | ↑ |
* When corrected for age; older patients have lower mean plasma renin activity. | ||||
† Secondary to decreased renal blood flow as in heart failure, cirrhosis, nephrotic syndrome. | ||||
↑↑↑↑= very greatly increased; ↑↑= greatly increased; ↑= increased; ↓↓= greatly decreased; ↓= decreased; N = normal. | ||||
Patients with findings suggesting primary hyperaldosteronism should undergo CT or MRI to determine whether the cause is a tumor or hyperplasia. However, imaging tests are relatively insensitive, and most patients require bilateral catheterization of the adrenal veins to measure cortisol and aldosterone levels to confirm whether the aldosterone excess is unilateral (tumor) or bilateral (hyperplasia). It is possible that in the future PET-radionuclide imaging with radiolabeled metomidate may be more helpful, but this is as yet not in routine clinical use.
Treatment of Primary Aldosteronism
Surgical removal of tumors
Tumors should be removed laparoscopically. After removal of an adenoma, serum potassium normalizes and blood pressure decreases in all patients; complete normalization of the blood pressure without the need for antihypertensive treatment occurs in 50 to 70% of patients (1).
Among patients with adrenal hyperplasia, 70% remain hypertensive after bilateral adrenalectomy (2spironolactone, it does not block the androgen receptor (which can cause gynecomastia and sexual dysfunction); it is the drug of choice for long-term treatment in males unless low-dose spironolactone is effective.
Approximately half of patients with hyperplasia need additional antihypertensive treatment.
Treatment references
1. Ekman N, Grossman AB, Dworakowska D. What We Know about and What Is New in Primary Aldosteronism. Int J Mol Sci 2024;25(2):900. Published 2024 Jan 11. doi:10.3390/ijms25020900
2. MacKay D, Nordenstrom A, Falhammar H. Bilateral Adrenalectomy in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 2018;103(5):1767-1778. doi:10.1210/jc.2018-00217
Key Points
Diagnosis should be suspected in hypertensive patients with hypokalemia in the absence of Cushing syndrome.
Initial testing includes measurement of plasma aldosterone levels and plasma renin activity before and after saline infusion.
Adrenal imaging tests are done, but often bilateral adrenal vein catheterization is needed to distinguish tumor from hyperplasia.
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Brown JM, Siddiqui M, Calhoun DA, et al. The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study. Ann Intern Med 2020;173(1):10-20. doi:10.7326/M20-0065
