(See also Overview of Adrenal Function Overview of Adrenal Function The adrenal glands, located on the cephalad portion of each kidney (see figure ), consist of a Cortex Medulla The adrenal cortex and adrenal medulla each have separate endocrine functions. The... read more .)
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 Primary Aldosteronism 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 Hyponatremia Hyponatremia is decrease in serum sodium concentration < 136 mEq/L (< 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure... read more 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 Overview of Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is a group of genetic disorders, each characterized by inadequate synthesis of cortisol, aldosterone, or both. In the most common forms, accumulated hormone precursors... read more (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 Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more even when serum potassium levels are normal.
Symptoms and Signs of Primary Aldosteronism
Diastolic hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more and hypokalemic nephropathy with polyuria and polydipsia are common.
Hypernatremia Hypernatremia Hypernatremia is a serum sodium concentration > 145 mEq/L (> 145 mmol/L). It implies a deficit of total body water relative to total body sodium, caused by water intake being less than water... read more , 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
Plasma renin activity (PRA)
Bilateral adrenal vein catheterization (for cortisol and aldosterone levels)
Primary aldosteronism is suspected in patients with hypertension and hypokalemia Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more 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 Cushing Syndrome Cushing syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing disease is Cushing syndrome that results from... read more , or Liddle syndrome Liddle Syndrome Liddle syndrome is a rare hereditary disorder involving increased activity of the epithelial sodium channel (ENaC), which causes the kidneys to excrete potassium but retain too much sodium and... read more ). High levels of both plasma renin activity and aldosterone suggest secondary hyperaldosteronism Secondary Aldosteronism Secondary aldosteronism is increased adrenal production of aldosterone in response to nonpituitary, extra-adrenal stimuli such as renal hypoperfusion. Symptoms are similar to those of primary... read more . The principal differences between primary and secondary aldosteronism are shown in the table . In children, Bartter syndrome Bartter Syndrome and Gitelman Syndrome Bartter syndrome and Gitelman syndrome are autosomal recessive renal disorders characterized by fluid, electrolyte, urinary, and hormonal abnormalities, including renal potassium, sodium, chloride... read more 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.
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
Spironolactone or eplerenone for hyperplasia
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 Treatment Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more occurs in 50 to 70% of patients (1 Treatment references Primary aldosteronism is a disorder caused by autonomous production of aldosterone by the adrenal cortex (due to hyperplasia, adenoma, or carcinoma). Symptoms and signs include episodic weakness... read more ).
Among patients with adrenal hyperplasia, 70% remain hypertensive after bilateral adrenalectomy (2 Treatment references Primary aldosteronism is a disorder caused by autonomous production of aldosterone by the adrenal cortex (due to hyperplasia, adenoma, or carcinoma). Symptoms and signs include episodic weakness... read more ); thus, surgery is not recommended. Hyperaldosteronism in these patients can usually be controlled by a selective aldosterone blocker such as spironolactone, starting with 50 mg orally once a day and increasing over 1 to 3 months to a maintenance dose, usually around 50 to 100 mg once a day; or by amiloride 5 to 10 mg orally once a day; or another potassium-sparing diuretic. The more specific drug eplerenone 50 mg orally once a day to 200 mg orally twice a day may be used because, unlike spironolactone, it does not block the androgen receptor (which can cause gynecomastia Gynecomastia This photo shows enlarged breast tissue in a male patient. Gynecomastia is hypertrophy of breast glandular tissue in males. It must be differentiated from pseudogynecomastia, which is increased... read more 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 Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more .
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
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.
Tumors are removed, and patients with adrenal hyperplasia are treated with aldosterone blockers such as spironolactone or eplerenone.
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
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