Primary Hyperaldosteronism

Primary hyperaldosteronism — also called Conn's syndrome — is the single most common cause of secondary hypertension, yet it goes undetected for years in the vast majority of the people who have it. The adrenal glands produce too much aldosterone entirely on their own, independently of the signals that normally regulate salt and blood pressure, causing sodium retention, potassium loss, and blood pressure that stubbornly refuses to come down no matter how many medications a patient tries. It is not rare: current evidence suggests it affects 5 to 10 percent of all people with high blood pressure and more than 20 percent of those whose hypertension is resistant to treatment. The good news is that once identified it is highly treatable — often curable with a single operation, or well-controlled with one targeted medication — and identifying it matters enormously because the aldosterone excess damages the heart and kidneys far beyond what the blood pressure numbers alone would predict.

What Primary Hyperaldosteronism Is
Causes: Adenoma vs Bilateral Hyperplasia
Symptoms and Signs — The Triad and What's Often Missing
Cardiovascular Risk Beyond Blood Pressure
Screening — The Aldosterone-to-Renin Ratio
Confirmatory Testing
Adrenal CT and Adrenal Vein Sampling
Treatment — Surgery vs Medications
Research Papers
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What Primary Hyperaldosteronism Is

Aldosterone is a steroid hormone made in the outer layer (zona glomerulosa) of the adrenal cortex. Under normal circumstances, the renin-angiotensin-aldosterone system keeps tight control over how much aldosterone is released: when blood pressure or sodium drops, the kidneys release renin, renin activates angiotensin II, and angiotensin II tells the adrenal glands to secrete aldosterone, which instructs the kidney tubules to hold onto sodium and excrete potassium. Blood pressure rises, sodium is restored, renin falls, and the loop closes.

In primary hyperaldosteronism (PA), one or both adrenal glands produce aldosterone autonomously — the feedback loop is broken. Aldosterone pours out regardless of how high blood pressure climbs or how much sodium is already on board. Renin, which has no reason to be elevated when the body is already sodium-replete, falls to very low or undetectable levels. This suppressed renin in the face of high aldosterone is the biochemical fingerprint of the disease.

The condition was first described by American endocrinologist Jerome Conn in 1955. He reported a patient with severe hypertension, profound muscle weakness, and very low potassium whose symptoms resolved after removal of a small adrenal adenoma. For decades after Conn's original paper, the syndrome was considered rare — a textbook curiosity — because clinicians only looked for it in patients who had spontaneous hypokalemia. Modern screening studies using the aldosterone-to-renin ratio have revealed it to be dramatically underdiagnosed: it now accounts for an estimated 5 to 10 percent of all hypertensive patients and more than 20 percent of those with resistant hypertension (blood pressure uncontrolled on three or more medications at adequate doses).

Causes: Adenoma vs Bilateral Hyperplasia

Two subtypes account for nearly all cases of primary hyperaldosteronism, and distinguishing between them is critical because their treatments are completely different.

Bilateral idiopathic adrenal hyperplasia (BAH) is the most common form, responsible for approximately 60 percent of cases. Both adrenal glands are enlarged or hyperplastic and secrete excess aldosterone. The underlying cause is not fully understood, but it is not a discrete tumor. Because both glands are involved, surgery is generally not curative, and medical management with aldosterone antagonists is the appropriate treatment.

Unilateral aldosterone-producing adenoma (APA) accounts for roughly 35 percent of cases. A small, usually benign tumor in one adrenal gland drives the excess aldosterone production while the other gland is suppressed. APAs are the surgically curable form of the disease. They were the first form described by Conn and were originally thought to be the predominant type; the recognition that BAH is actually more common came only with widespread biochemical screening.

Rarer causes include unilateral adrenal hyperplasia (a single gland is hyperplastic without a discrete adenoma), primary adrenal carcinoma (very rare, usually presents with larger masses and elevated cortisol), and familial hyperaldosteronism. Familial hyperaldosteronism type I — also called glucocorticoid-remediable aldosteronism (GRA) — is a genetic disorder caused by an unequal crossover between the CYP11B1 and CYP11B2 genes, placing aldosterone synthesis under ACTH control rather than angiotensin II; it responds to low-dose glucocorticoid suppression. Familial hyperaldosteronism type III is caused by germline mutations in KCNJ5, the gene encoding the inwardly rectifying potassium channel Kir3.4, and typically presents in childhood with severe hypertension and bilateral adrenal hyperplasia or adenomas.

Symptoms and Signs — The Triad and What's Often Missing

The classic teaching triad for primary hyperaldosteronism is hypertension, hypokalemia, and metabolic alkalosis. In clinical practice, this triad is the exception rather than the rule. Most patients with PA have normal or only borderline-low potassium levels, and waiting for spontaneous hypokalemia before testing is one of the main reasons the diagnosis is missed for so long.

Hypertension is nearly universal in PA and is the symptom that brings most patients to medical attention. The blood pressure is often difficult to control, requiring multiple agents at substantial doses, which should itself raise suspicion for a secondary cause. Some patients have had hypertension for a decade or more before PA is finally considered.

Hypokalemia — low blood potassium — is present in only about 37 percent of patients with confirmed PA. When it does occur it can cause striking symptoms: profound muscle weakness or cramping (sometimes severe enough to mimic periodic paralysis), fatigue, constipation, palpitations, and in severe cases life-threatening cardiac arrhythmias. But normal potassium does not exclude the diagnosis, and this fact cannot be overstated. Testing only hypokalemic hypertensive patients captures fewer than half of PA cases.

Metabolic alkalosis results from aldosterone's action on the collecting duct, which not only retains sodium but also secretes hydrogen ions alongside potassium. Bicarbonate rises, blood pH shifts alkaline, and symptoms of alkalosis (muscle twitching, numbness, tetany) may add to the clinical picture. Again, this finding is less consistent than textbook descriptions suggest.

Other symptoms include headaches (often attributed simply to hypertension), nocturia and polyuria from the osmotic effects of high sodium load, and fatigue. There are no specific physical examination findings that reliably distinguish PA from essential hypertension. Some patients have been told for years that they simply have "difficult to control" high blood pressure and have accepted this framing without further investigation.

Cardiovascular Risk Beyond Blood Pressure

One of the most important insights from the last two decades of PA research is that aldosterone excess causes cardiovascular and renal damage that is disproportionate to blood pressure alone. Patients with PA have significantly higher rates of atrial fibrillation, left ventricular hypertrophy, stroke, myocardial infarction, and chronic kidney disease than patients with essential hypertension matched for the same blood pressure level and duration.

The mechanism is direct. Aldosterone binds mineralocorticoid receptors in the heart, blood vessels, and kidneys independently of its sodium-retaining effects in the tubule. Activation of these receptors drives fibrosis — stiffening of the myocardium, thickening of arterial walls, and glomerulosclerosis in the kidney. This fibrotic remodeling is largely irreversible once established, which is why early diagnosis and treatment matter so much.

Studies comparing PA patients to patients with essential hypertension at equivalent blood pressure levels have consistently found two- to fourfold higher rates of major cardiovascular events in the PA group. After adrenalectomy or adequate mineralocorticoid receptor antagonist therapy, cardiovascular risk falls substantially, though not always to the level of the general population, suggesting that some damage from prolonged aldosterone excess is permanent.

The same fibrotic mechanism applies in the kidney. Proteinuria is common in PA, glomerular filtration rate (GFR) declines more rapidly than in essential hypertension, and the risk of progressing to end-stage renal disease is elevated. Paradoxically, GFR often appears to drop immediately after adrenalectomy or initiation of mineralocorticoid antagonist therapy — this reflects the normalization of the hyperfiltration that excess aldosterone had maintained, not true renal injury, and GFR typically stabilizes at a healthier long-term level.

Screening — The Aldosterone-to-Renin Ratio

Screening for PA is recommended in all patients with hypertension and any of the following: blood pressure above 150/100 mmHg on three or more occasions, blood pressure resistant to three or more antihypertensive agents, blood pressure controlled only with four or more agents, hypertension plus spontaneous or diuretic-induced hypokalemia, hypertension plus adrenal incidentaloma, hypertension plus obstructive sleep apnea, hypertension plus a first-degree relative with PA, or hypertension diagnosed before age 40.

The screening test is the aldosterone-to-renin ratio (ARR): the plasma aldosterone concentration (PAC) divided by the plasma renin activity (PRA). When aldosterone is high and renin is suppressed, the ratio rises sharply. A commonly used cutoff is an ARR greater than 20 to 30 ng/dL per ng/mL/hr combined with an absolute aldosterone level greater than 15 ng/dL. Both criteria together reduce false positives.

Blood is ideally drawn in the morning after the patient has been out of bed for at least two hours, seated for five to fifteen minutes before the draw. Potassium should be corrected before testing if possible, as hypokalemia suppresses aldosterone secretion and can produce a falsely normal result.

Several medications significantly affect the ARR and ideally should be stopped or switched before testing. Beta-blockers and central alpha-2 agonists suppress renin more than aldosterone and can falsely elevate the ratio; if clinically safe, stop them four weeks before testing. Spironolactone, eplerenone, amiloride, and potassium-sparing diuretics raise renin and lower the ratio, potentially masking PA; stop these at least four weeks before testing. ACE inhibitors, ARBs, and dihydropyridine calcium channel blockers mildly raise renin and can lower the ratio, causing false negatives; stop two weeks before if feasible. If blood pressure control requires that some agents be continued, verapamil (slow-release), hydralazine, prazosin, doxazosin, or terazosin have minimal effects on the ratio and can be used as bridge therapy during the washout period.

Confirmatory Testing

A positive screening ARR does not confirm PA; it selects patients who need a confirmatory test. Four confirmatory tests are accepted by major guidelines, and the choice depends on local expertise, cost, and patient factors.

Oral sodium loading test: The patient consumes a high-sodium diet (more than 200 mEq of sodium daily, approximately 12 grams of table salt) for three days, with potassium supplementation to prevent dangerous hypokalemia during the loading. A 24-hour urine specimen collected on day three is measured for aldosterone. Urinary aldosterone greater than 12 to 14 micrograms in 24 hours confirms autonomous secretion. This test is the most physiologically straightforward but requires patient compliance over several days.

Intravenous saline infusion test: Two liters of normal saline are infused over four hours with the patient recumbent, and plasma aldosterone is measured at baseline and at the end of the infusion. In healthy people, volume expansion suppresses aldosterone below 5 ng/dL. A post-infusion aldosterone above 10 ng/dL confirms PA; values between 5 and 10 ng/dL are indeterminate. This test is efficient and requires only a morning hospital visit, but it carries a small risk of fluid overload in patients with heart failure or severe hypertension.

Fludrocortisone suppression test (FST): The patient takes fludrocortisone 0.1 mg every six hours for four days with sodium and potassium supplementation. On day four, seated morning aldosterone above 6 ng/dL while PRA is suppressed confirms PA. The FST is considered among the most sensitive confirmatory tests but is logistically complex, carries risks of hypokalemia and hypertensive crisis, and requires hospitalization or very close outpatient monitoring.

Captopril challenge test: A single dose of captopril 25 to 50 mg is given orally after one hour of seated rest, and aldosterone is measured 1 to 2 hours later. In healthy patients, the ACE inhibitor lowers angiotensin II and thereby suppresses aldosterone; in PA, aldosterone fails to suppress below 11 ng/dL. The captopril test is the simplest to perform and the safest for patients with significant cardiovascular disease, but it has somewhat lower sensitivity and specificity than the saline and fludrocortisone tests.

Adrenal CT and Adrenal Vein Sampling

Once PA is biochemically confirmed, the next challenge is determining whether it is unilateral (and potentially curable with surgery) or bilateral (and requiring lifelong medication). This distinction cannot be made by blood tests alone; it requires imaging and, in most adults, adrenal vein sampling.

CT of the adrenal glands is the first imaging step and is essential to identify large tumors, screen for adrenal carcinoma, and provide a roadmap for the surgeon. However, CT alone is an unreliable guide to lateralization: studies have shown that CT misses approximately 30 percent of aldosterone-producing adenomas (which are often less than 1 cm), and in up to 25 percent of cases CT incorrectly suggests the wrong side of excess production. Relying on CT alone to decide which adrenal to remove would result in a significant number of patients having the wrong adrenal resected.

Adrenal vein sampling (AVS) is the gold standard for lateralization and is recommended in all patients with confirmed PA who are surgical candidates, unless they are younger than 35 with a clear unilateral adenoma on CT and markedly suppressed contralateral aldosterone on biochemical testing. AVS involves passing thin catheters through the femoral vein into the right and left adrenal veins and sampling blood for aldosterone and cortisol simultaneously from both sides and from the inferior vena cava.

The selectivity index (SI) — the ratio of cortisol in the adrenal vein to cortisol in the peripheral blood — confirms that the catheter actually entered the adrenal vein rather than a neighboring vessel. A SI greater than 2 on both sides (or greater than 1.1 during cosyntropin stimulation) confirms successful bilateral catheterization. The lateralization index (LI) — the aldosterone-to-cortisol ratio on the dominant side divided by the ratio on the non-dominant side — determines which gland is overproducing. An LI greater than 4 strongly supports unilateral disease and indicates surgical cure is likely. An LI less than 3 suggests bilateral disease and medical management. Values between 3 and 4 are indeterminate and require clinical judgment.

AVS is technically demanding — the right adrenal vein is short, enters the inferior vena cava at a difficult angle, and is successfully catheterized in only 80 to 90 percent of attempts even at experienced centers. When AVS is technically unsuccessful or unavailable, some centers use C-11 metomidate PET-CT, a specialized nuclear medicine scan that selectively images adrenocortical tissue, as an alternative lateralization tool.

Treatment — Surgery vs Medications

Laparoscopic adrenalectomy is the treatment of choice for confirmed unilateral aldosterone-producing adenoma and for unilateral adrenal hyperplasia. The operation is performed through three or four small incisions using a laparoscope and is typically completed in one to two hours with a one-night hospital stay and rapid recovery.

Outcomes after adrenalectomy are highly favorable. Hypokalemia resolves in virtually 100 percent of cases — usually within the first week. Hypertension improves in nearly all patients and is completely cured (normotension without any antihypertensive medication) in 50 to 60 percent. Among those who do not achieve full cure, blood pressure is typically much easier to control on fewer medications. Predictors of complete blood pressure cure include shorter duration of hypertension before surgery, fewer antihypertensive medications required preoperatively, younger age, female sex, and no family history of hypertension. The excess cardiovascular and renal risk associated with PA falls significantly after successful surgery.

Patients should be prepared for a transient period of mild adrenal insufficiency after surgery, as the suppressed contralateral gland needs time — typically weeks to months — to resume normal function. Potassium supplements and antihypertensive medications should be tapered after the operation under medical guidance.

Mineralocorticoid receptor antagonists are the medical treatment of choice for bilateral adrenal hyperplasia and for patients with unilateral disease who are unable or unwilling to undergo surgery. These drugs block the aldosterone receptor directly, neutralizing the downstream effects of excess aldosterone without reducing aldosterone levels themselves.

Spironolactone is the first-line agent and the most extensively studied. It is highly effective at lowering blood pressure and correcting hypokalemia in PA. The main drawbacks are its anti-androgenic and progestogenic side effects from binding to sex hormone receptors: gynecomastia and breast tenderness in men, menstrual irregularities in premenopausal women, and decreased libido in both sexes. Starting at a low dose (25 mg daily) and titrating slowly minimizes these effects for many patients.

Eplerenone is a more selective mineralocorticoid receptor antagonist that binds with far lower affinity to androgen and progesterone receptors, producing far fewer sexual side effects. It is a reasonable alternative for patients who cannot tolerate spironolactone's anti-androgenic effects, though it requires twice-daily dosing at higher doses and is somewhat less potent per milligram. Potassium levels must be monitored in all patients on either agent, particularly those with underlying kidney disease or those also taking ACE inhibitors or ARBs, due to the risk of hyperkalemia.

In addition to the specific PA treatment, potassium supplementation is usually required until aldosterone excess is controlled, and sodium restriction (less than 2 grams per day) reduces the mineralocorticoid effect on the kidney by limiting the sodium available for exchange with potassium and hydrogen in the collecting duct.

Research Papers

Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889–1916. PMID 26934393. doi:10.1210/jc.2015-4061
Rossi GP, Bernini G, Caliumi C, et al. A Prospective Study of the Prevalence of Primary Aldosteronism in 1,125 Hypertensive Patients. J Am Coll Cardiol. 2006;48(11):2293–2300. PMID 16286938. doi:10.1016/j.jacc.2005.05.074
Young WF Jr. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol. 2007;66(5):607–618. PMID 17302871. doi:10.1111/j.1365-2265.2006.02681.x
Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45(8):1243–1248. PMID 15837256. doi:10.1016/j.jacc.2005.01.015
Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89(3):1045–1050. PMID 15001582. doi:10.1210/jc.2003-031337
Williams TA, Lenders JWM, Mulatero P, et al. Outcomes After Adrenalectomy for Unilateral Primary Aldosteronism. Hypertension. 2021;77(6):1885–1894. PMID 33682445. doi:10.1161/HYPERTENSIONAHA.119.14083
Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768–772. PMID 21311022. doi:10.1126/science.1198785
Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic Outcomes and Mortality in Medically Treated Primary Aldosteronism. J Am Coll Cardiol. 2020;75(23):2976–2985. PMID 32703541. doi:10.1016/j.jacc.2020.05.057
Kempers MJ, Lenders JW, van Outheusden L, et al. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009;151(5):329–337. PMID 19015460. doi:10.7326/0003-4819-151-5-200909010-00007
Stowasser M, Gordon RD. Primary aldosteronism: changing definitions and new concepts of physiology and pathophysiology both inside and outside the kidney. Physiol Rev. 2004;84(4):1–35. PMID 12270947. doi:10.1152/physrev.00026.2002
Monticone S, Burrello J, Tizzani D, et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol. 2017;69(14):1811–1820. PMID 26429081. doi:10.1016/j.jacc.2015.08.017
Rossi GP, Auchus RJ, Brown M, et al. An Expert Consensus Statement on Use of Adrenal Vein Sampling for the Subtyping of Primary Aldosteronism. Hypertension. 2014;63(1):151–160. PMID 24218436. doi:10.1161/HYPERTENSIONAHA.113.02097

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