Hyperaldosteronism

Core concept: Hyperaldosteronism increases distal nephron sodium retention while promoting potassium and hydrogen loss. Primary aldosteronism is autonomous adrenal aldosterone secretion; secondary aldosteronism is a response to upstream renin–angiotensin activation.

Key clinical distinction: Primary aldosteronism generally combines inappropriate aldosterone activity with suppressed renin. Potassium may remain normal, so hypokalemia is not required for suspicion (Adler et al., 2025).

Clinical priority: The 2025 Endocrine Society guideline conditionally suggests primary-aldosteronism screening for all people with hypertension when feasible, rather than restricting consideration to resistant hypertension or hypokalemia. Assess for severe BP complications and interpret paired aldosterone/renin with sampling conditions, medications, and potassium (Adler et al., 2025).

Etiology and Clinical Context

Primary aldosteronism commonly reflects unilateral aldosterone-producing adrenal disease or bilateral adrenal hyperplasia. Secondary aldosteronism results from increased renin signaling, as in renal artery stenosis, reduced effective arterial filling in heart failure or cirrhosis, and selected volume-depleting states. Aldosterone excess has cardiovascular effects beyond blood-pressure elevation (Else & Hammer, 2019; Penman et al., 2023).

Pathophysiology

Aldosterone binds mineralocorticoid receptors in distal nephron principal cells, increasing epithelial sodium-channel activity and Na/K-ATPase function. Sodium reabsorption expands extracellular fluid volume while luminal negativity favors renal potassium secretion. Increased distal hydrogen secretion can produce metabolic alkalosis.

In primary autonomous secretion, volume expansion suppresses renin despite inappropriate aldosterone activity. In secondary disease, a physiologic or pathologic fall in renal perfusion raises renin and angiotensin II, driving adrenal aldosterone synthesis. Secondary aldosteronism may therefore coexist with edema even when effective arterial blood volume is low.

Aldosterone is not simply a potassium hormone: Sodium retention expands extracellular volume and increases blood pressure, while potassium and proton secretion explain hypokalemia and metabolic alkalosis in some patients. Tissue mineralocorticoid receptor activity also supports inflammation and cardiac/vascular fibrosis, contributing to atrial fibrillation, ventricular remodeling, and kidney injury beyond pressure alone. Because potassium balance depends on diet and renal adaptation, most patients with primary aldosteronism need not be hypokalemic.

Clinical Manifestations

Hypertension may be difficult to control or associated with cardiovascular remodeling. Hypokalemia, when present, can cause fatigue, weakness, cramps, paresthesia, palpitations, and polyuria due to impaired renal concentration. Many patients with primary aldosteronism are normokalemic. Severe hypokalemia may precipitate arrhythmias or muscle dysfunction.

Diagnostic Evaluation

The 2025 screening approach uses paired aldosterone and renin (activity or direct concentration) plus their ratio; interpret absolute hormone concentrations, suppression of renin, posture/sampling conditions, medications, renal function, and potassium. Hypokalemia can falsely lower aldosterone and should be corrected before repeating a negative screen when clinically indicated. A positive ARR is a screening result—not itself a functional lateralization study (Adler et al., 2025).

Screening interpretation is conditional: A high aldosterone-to-renin ratio is most persuasive when renin is suppressed and aldosterone is inappropriately maintained or elevated. A low renin concentration can produce a numerically high ratio even when aldosterone is low, so the ratio must never be read without its components. Hypokalemia may suppress aldosterone and create a false-negative result; mineralocorticoid receptor antagonists, diuretics, ACE inhibitors, ARBs, beta blockers, sodium intake, and kidney function can materially alter testing.

Differential and localization: Primary aldosteronism differs from renal artery stenosis or edematous low-effective-volume states, which typically have renin-driven aldosterone elevation. Hypertension with suppressed renin and suppressed aldosterone suggests other processes, such as Liddle syndrome or apparent mineralocorticoid excess, not classic primary aldosteronism. After biochemical confirmation, adrenal CT evaluates anatomy and possible malignancy, but adrenal vein sampling is often needed to establish unilateral secretion before surgery because incidental nodules are common.

Confirmatory testing and localization are conditional, not automatically sequential for every positive screen. The 2025 guidance emphasizes aldosterone-suppression testing when probability is intermediate and a person wants to pursue surgery; some individuals with overt renin-independent aldosterone excess or those proceeding directly to medical therapy do not require it. CT evaluates anatomy; adrenal venous sampling generally distinguishes unilateral from bilateral secretion when adrenalectomy is being considered, with narrow exceptions for highly convincing young-onset unilateral disease (Adler et al., 2025).

Management Principles

Primary unilateral disease may be treated surgically in selected patients, while bilateral disease and nonsurgical cases are generally treated with mineralocorticoid receptor antagonism. Monitor blood pressure, serum potassium, creatinine, and clinical volume status. Secondary aldosteronism requires treatment of the cause; indiscriminate adrenal surgery would not correct renin-driven secretion.

Clinical Reasoning Priorities

Clinical fork: A patient with difficult hypertension, potassium 4.1 mmol/L, very low renin, and aldosterone that is not appropriately suppressed warrants further primary aldosteronism evaluation. If the ratio is high solely because renin is nearly zero but aldosterone is also low, do not label it autonomous aldosterone excess. A separate patient with cirrhosis, ascites, high renin, and high aldosterone has compensatory signaling to reduced effective arterial filling. Medication exposure, hypokalemia, and preparation conditions may change either interpretation.

High-Yield Distinctions

  • Suppressed renin suggests primary autonomous aldosterone activity; elevated renin suggests a secondary stimulus.
  • Normokalemia does not exclude primary aldosteronism.
  • Aldosterone excess increases cardiovascular and renal risk through more than volume-mediated hypertension.

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References

Adler, G. K., Stowasser, M., Correa, R. R., Khan, N., Kline, G., McGowan, M. J., Mulatero, P., Murad, M. H., Touyz, R. M., Vaidya, A., Williams, T. A., Yang, J., Young, W. F., Zennaro, M.-C., & Brito, J. P. (2025). Primary aldosteronism: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism, 110(9), 2453–2495. https://doi.org/10.1210/clinem/dgaf284

Else, T., & Hammer, G. D. (2019). Disorders of the adrenal cortex. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed., Chapter 21). McGraw-Hill Education.

Penman, I. D., Ralston, S. H., Strachan, M. W. J., & Hobson, R. P. (Eds.). (2023). Davidson’s principles and practice of medicine (24th ed.). Elsevier.