Adrenal disorders
Primary Aldosteronism (Conn Syndrome): The Renin-Suppressed Hypertension
Roughly 5–10% of all hypertensive patients — and up to 20% of those with resistant hypertension — harbor an autonomous adrenal source of aldosterone, making primary aldosteronism the single most common curable secondary cause of high blood pressure. Yet fewer than 1% are ever screened, and the average patient waits years for a diagnosis.
Primary aldosteronism (PA) is aldosterone secretion that is inappropriate for, and independent of, the renin–angiotensin system. Because the aldosterone drives sodium retention and volume expansion, it feeds back to suppress renin — the biochemical fingerprint of the disease. Its most famous form, an aldosterone-producing adenoma, is Conn syndrome, described by Jerome Conn in 1955.
- MechanismAutonomous aldosterone → renal Na+ retention, K+/H+ loss, suppressed renin
- Classic clueHypertension + spontaneous or diuretic-induced hypokalemia (though most are normokalemic)
- Screening testAldosterone-to-renin ratio (ARR), typically ≥20–30 ng/dL per ng/mL/h with aldosterone >15 ng/dL
- Confirmatory testFailure to suppress aldosterone after saline load or oral sodium/fludrocortisone
- First-line treatmentAdrenalectomy (unilateral disease) or MR antagonist — spironolactone/eplerenone (bilateral)
- Main complicationsExcess CV and renal damage: LVH, AF, stroke, CKD — beyond that explained by BP alone
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What It Is and Why It Matters
Primary aldosteronism is a state of autonomous, renin-independent aldosterone excess arising from one or both adrenal glands. It is not a rare zebra: contemporary series place its prevalence at 5–10% of unselected hypertensives, climbing toward 20% in resistant hypertension and higher still in hypertension with spontaneous hypokalemia.
Why it matters clinically:
- It is potentially curable. A unilateral aldosterone-producing adenoma removed by laparoscopic adrenalectomy can normalize or dramatically improve blood pressure.
- Aldosterone is directly toxic. Independent of blood pressure, mineralocorticoid receptor (MR) activation causes cardiac fibrosis, left ventricular hypertrophy, atrial fibrillation, stroke, albuminuria, and CKD. PA patients have higher cardiovascular event rates than blood-pressure-matched essential hypertensives.
- Targeted therapy exists. MR antagonists specifically block the pathologic pathway.
The tragedy is under-recognition: the majority of cases are missed because clinicians anchor on "essential" hypertension and never check the aldosterone-to-renin ratio.
The Mechanism, Step by Step
Aldosterone is the terminal mineralocorticoid of the zona glomerulosa, normally released only when angiotensin II or hyperkalemia demands it. In PA that regulation is uncoupled.
- Autonomous secretion: A somatic mutation in an adrenal cell — most often in the potassium channel gene KCNJ5 (also CACNA1D, ATP1A1, ATP2B3) — causes membrane depolarization, calcium influx, and constitutive CYP11B2 (aldosterone synthase) activity.
- Receptor action: Aldosterone enters the principal cell and binds the cytosolic mineralocorticoid receptor. The complex translocates to the nucleus and upregulates the epithelial sodium channel (ENaC), the Na⁺/K⁺-ATPase, and serum/glucocorticoid-regulated kinase (SGK1).
- Downstream physiology: Sodium is reabsorbed in the distal nephron; water follows, expanding plasma volume. The electrogenic Na⁺ uptake creates a lumen-negative gradient driving K⁺ and H⁺ secretion — hence hypokalemia and metabolic alkalosis.
- Feedback loop: Volume expansion suppresses juxtaglomerular renin release → the hallmark low/suppressed plasma renin. "Aldosterone escape" from atrial natriuretic peptide limits edema, so patients are hypertensive but not classically edematous.
Clinical Presentation and Classic Signs
The stereotyped teaching triad is hypertension, hypokalemia, and metabolic alkalosis — but modern data have overturned the assumption that potassium is usually low.
- Hypertension: Often moderate-to-severe, resistant to two or three agents, or of early onset. This is the near-universal feature.
- Hypokalemia: Present in only about 9–37% of cases; most patients are normokalemic. When present it may be spontaneous or unmasked by a thiazide/loop diuretic. Symptoms include muscle weakness, cramps, polyuria/polydipsia (from hypokalemic nephrogenic diabetes insipidus), and even flaccid paralysis or tetany.
- Metabolic alkalosis from renal H⁺ loss; the alkalosis plus low potassium can lower ionized calcium and produce paresthesias or a positive Trousseau/Chvostek sign.
- Notably absent: significant edema (aldosterone escape) and, importantly, few specific symptoms — which is exactly why screening is so often skipped.
End-organ signs — LVH on ECG/echo, atrial fibrillation, and microalbuminuria — may already be present at diagnosis.
Diagnosis: Tests, Cutoffs, and Imaging
Endocrine Society guidelines define a three-step pathway: screen → confirm → subtype.
- 1. Screen with the aldosterone-to-renin ratio (ARR). Draw morning, seated plasma aldosterone concentration (PAC) and renin. A positive screen typically requires an ARR ≥20–30 (ng/dL per ng/mL/h) plus a PAC that is elevated (commonly >15 ng/dL). Correct hypokalemia first, and account for interfering drugs — MR antagonists must be stopped ~4–6 weeks beforehand; ACE-inhibitors/ARBs and beta-blockers can shift the ratio.
- 2. Confirm autonomy. Show that aldosterone fails to suppress with a saline infusion test (2 L over 4 h; PAC >10 ng/dL confirms), oral sodium loading with 24-h urine aldosterone, the fludrocortisone suppression test, or captopril challenge. GRA is excluded/confirmed with genetic testing or dexamethasone suppression.
- 3. Subtype (unilateral vs bilateral). Adrenal CT localizes, but small adenomas and nonfunctioning "incidentalomas" mislead. In candidates for surgery, adrenal vein sampling (AVS) is the gold standard for lateralization; a lateralization index >4 (cortisol-corrected) indicates a unilateral source.
Management: Why Each Treatment Works
Therapy follows the subtype, and each option maps directly onto the mechanism.
- Unilateral disease (adenoma / unilateral hyperplasia) → laparoscopic adrenalectomy. Removing the autonomous source eliminates the aldosterone excess. Roughly half achieve cure of hypertension and nearly all improve; hypokalemia resolves. Post-op, watch for transient hyperkalemia as the chronically suppressed contralateral gland recovers.
- Bilateral disease, or non-surgical patients → mineralocorticoid receptor antagonists. Spironolactone competitively blocks the MR, halting ENaC-driven Na⁺ retention and K⁺ wasting; its anti-androgen/progesterone effects cause gynecomastia and menstrual irregularity. Eplerenone is MR-selective with fewer sex-hormone side effects but less potent. Newer agents like esaxerenone/finerenone extend the class.
- Glucocorticoid-remediable aldosteronism → low-dose glucocorticoid (e.g., dexamethasone) to suppress the ACTH-driven chimeric aldosterone synthase.
Crucially, MR blockade also mitigates the blood-pressure-independent cardiac and renal fibrosis, so treating aldosterone is more than treating a number.
Mimics, Pitfalls, and Significance
The most dangerous error is treating PA as ordinary hypertension and never checking the ARR. Key distinctions and traps:
- Low-renin, low-aldosterone mimics: When renin is suppressed but aldosterone is also low, think apparent mineralocorticoid excess (11β-HSD2 deficiency or licorice/glycyrrhizin, letting cortisol activate the MR), Liddle syndrome (gain-of-function ENaC mutation — treated with amiloride, not spironolactone), or exogenous mineralocorticoid.
- Secondary hyperaldosteronism (renovascular disease, renin-secreting tumor, diuretic use, heart failure/cirrhosis) has high renin — the opposite pattern.
- Drug interference is the classic false-negative/positive trap: MR antagonists and high-dose diuretics raise renin and mask PA; NSAIDs and beta-blockers lower it.
- CT-only subtyping misassigns surgery in up to a third of cases; skipping AVS in patients over ~35 risks removing a non-functioning nodule while leaving the true culprit.
Recognized and treated, PA is one of hypertension's genuine cures — a reminder that a suppressed renin should never be ignored.
| Entity | Renin | Aldosterone | Distinguishing feature / treatment |
|---|---|---|---|
| Aldosterone-producing adenoma (APA / Conn) | Suppressed (low) | High | Unilateral source; often KCNJ5/CACNA1D/ATP1A1 somatic mutation → unilateral adrenalectomy is curative |
| Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) | Suppressed (low) | High (often milder) | No unilateral lateralization on AVS → lifelong MR antagonist |
| Glucocorticoid-remediable aldosteronism (FH-I) | Suppressed (low) | High | CYP11B1/CYP11B2 chimeric gene; ACTH-driven; suppresses with low-dose dexamethasone |
| Apparent mineralocorticoid excess / Liddle / licorice | Suppressed (low) | LOW | Aldosterone is low — non-aldosterone MR activation (11βHSD2 loss, ENaC gain) |
| Essential (primary) hypertension | Normal/variable | Normal | Normal ARR; most common cause overall — rule PA in only when ratio is elevated |
Frequently asked questions
Do I need to have low potassium to have primary aldosteronism?
No — this is the biggest myth about the disease. Only roughly 9–37% of patients have hypokalemia; the majority are normokalemic. Waiting for low potassium before screening misses most cases. The disease is defined biochemically by inappropriately high aldosterone with suppressed renin, not by the potassium level.
What is the aldosterone-to-renin ratio and why is it the screening test?
The ARR compares plasma aldosterone to plasma renin. In primary aldosteronism, aldosterone is high while renin is suppressed by volume expansion, so the ratio is markedly elevated — typically flagged at ≥20–30 (ng/dL per ng/mL/h) with an aldosterone above about 15 ng/dL. It's a screen, not a diagnosis: a positive ratio must be followed by a confirmatory suppression test.
Why does aldosterone cause high blood pressure but not swelling?
Aldosterone drives sodium and water retention in the distal nephron, expanding blood volume and raising blood pressure. However, a compensatory phenomenon called 'aldosterone escape' — driven by atrial natriuretic peptide and pressure natriuresis — allows the kidney to shed the extra sodium once volume rises, so patients stay hypertensive but typically do not develop overt edema.
When is surgery the right answer versus lifelong medication?
Surgery (unilateral laparoscopic adrenalectomy) is appropriate when the aldosterone excess comes from one gland — an adenoma or unilateral hyperplasia — confirmed by adrenal vein sampling showing lateralization. Bilateral adrenal hyperplasia cannot be cured by removing one gland, so those patients are managed with lifelong mineralocorticoid receptor antagonists like spironolactone or eplerenone.
How does spironolactone actually work, and why does it cause breast tenderness?
Spironolactone competitively blocks the mineralocorticoid receptor, preventing aldosterone from upregulating the ENaC sodium channel, which restores potassium and lowers blood pressure. Because spironolactone is non-selective, it also antagonizes androgen and progesterone receptors, causing gynecomastia, breast tenderness, and menstrual irregularities. Eplerenone is MR-selective and avoids most of these effects.
Why is primary aldosteronism considered more dangerous than ordinary high blood pressure?
Aldosterone is directly toxic to the heart, blood vessels, and kidneys beyond its effect on blood pressure — it promotes fibrosis, left ventricular hypertrophy, atrial fibrillation, stroke, and chronic kidney disease. Studies show primary aldosteronism patients suffer more cardiovascular events than essential hypertensives with the same blood pressure, which is why targeting aldosterone specifically matters.