Primary Aldosteronism
Most common cause of secondary hypertension. Screen: ARR (aldosterone-to-renin ratio). Confirm: salt loading. Localize: adrenal CT + adrenal vein sampling. Cause: adenoma (Conn's) vs bilateral hyperplasia.
🔍 Overview
Overview
Primary aldosteronism (PA) is autonomous aldosterone production independent of the renin-angiotensin system. It is the most common cause of secondary hypertension, affecting 5-13% of all hypertensive patients and up to 20% of resistant HTN. Two main subtypes: bilateral adrenal hyperplasia (BAH, ~60%) and aldosterone-producing adenoma (APA / Conn's syndrome, ~35%). The distinction matters because APA is surgically curable while BAH is treated medically. Classic lab triad: hypertension + hypokalemia + metabolic alkalosis, but most patients are normokalemic (hypokalemia is present in only 30-50%). PA causes cardiovascular damage disproportionate to BP -higher rates of stroke, MI, AF, and HF than essential HTN at the same BP level, because aldosterone drives myocardial and vascular fibrosis directly, not just through the blood pressure. That is why finding it matters even when the BP looks controlled.
🧪 Workup
Workup
📋 What changed in the 2025 Endocrine Society guideline (a complete update of the 2016 guideline)
- Screen every patient with hypertension CHANGED 2025 -not only the high-risk groups below. 2016 restricted screening to resistant HTN, hypokalemia, adrenal incidentaloma, and early-onset or severe HTN. The rationale is that PA affects 5 to 14% of hypertensives in primary care and up to 30% in referral centers, and was being detected in almost nobody.
- Confirmatory testing is now selective CHANGED 2025 -reserved for an intermediate-probability screen in a patient who actually wants to pursue surgery. If the plan is medical therapy regardless, a suppression test rarely changes management.
- Spironolactone is preferred over other MRAs on cost and availability, and MRAs are preferred over ENaC inhibitors such as amiloride and triamterene NEW 2025.
- Add a dexamethasone suppression test when an adenoma is found NEW 2025, to detect co-secreted cortisol, which changes peri-operative steroid cover.
- Step 1 -Screening (ARR): Plasma aldosterone concentration (PAC) / plasma renin activity (PRA) = aldosterone-to-renin ratio. ARR > 30 with PAC ≥ 10-15 ng/dL = positive screen. Draw morning, seated, K⁺-repleted. Hold interfering medications: spironolactone × 6 weeks, eplerenone × 6 weeks, ACEi/ARB acceptable (may cause false negatives). Endocrine Society, 2016
- Who to screen: 2025: every patient with hypertension CHANGED. The highest-yield groups remain resistant HTN (≥ 3 drugs), HTN + hypokalemia (spontaneous or diuretic-induced), HTN + adrenal incidentaloma, HTN onset < 40, severe HTN (≥ 160/100), obstructive sleep apnea, atrial fibrillation out of proportion to risk factors, and a family history of early stroke or PA -so start there if you cannot screen everyone at once.
- Step 2 -Confirmatory test (suppress aldosterone), now selective: skip it entirely when there is spontaneous hypokalemia + undetectable renin + PAC > 20 ng/dL, which is diagnostic on its own, and skip it when the patient is going to be treated medically regardless. Reserve it for an intermediate screen in a surgical candidate.
- IV saline infusion test: 2L NS over 4h → measure PAC. If PAC > 10 ng/dL post-infusion = confirmed (aldosterone should suppress but doesn't).
- Oral salt loading: High-sodium diet × 3 days → 24h urine aldosterone. > 12 mcg/24h = confirmed.
- Fludrocortisone suppression test: Fludrocortisone 0.1 mg q6h × 4 days → PAC remains > 6. Most specific but rarely used (cumbersome, risk of hypokalemia).
- Step 3 -Subtype differentiation + localization:
- CT adrenals -look for unilateral adenoma (> 1 cm). BUT: CT is wrong 38% of the time (nonfunctioning incidentaloma mimics APA, or microadenoma is missed).
- Adrenal vein sampling (AVS) -gold standard to lateralize aldosterone production. Lateralization ratio ≥ 4:1 = unilateral source → surgery. Essential for ALL surgical candidates unless: age < 35 with clear > 1 cm unilateral adenoma + normal contralateral.
🚨 Management
Management
- Unilateral APA (Conn's): Laparoscopic adrenalectomy -biochemical cure in 94%, but only 37% become normotensive off all antihypertensives; another 47% improve PASO, 2017. Counsel the patient before surgery that the operation cures the hormone problem far more reliably than it cures the blood pressure. Pre-op: control BP and K⁺ with MRA (spironolactone or eplerenone). Post-op: monitor K⁺ (contralateral zona glomerulosa may be suppressed → transient hypoaldosteronism).
- Bilateral adrenal hyperplasia: Medical therapy with mineralocorticoid receptor antagonists (MRA):
- Spironolactone 25-100 mg daily -most effective MRA. Anti-androgenic side effects: gynecomastia (up to 50% in men), menstrual irregularity, decreased libido. PATHWAY-2, 2015
- Eplerenone 25-50 mg BID -selective MRA with far fewer anti-androgenic effects, so it is the switch when gynecomastia appears. Roughly half as potent per mg, and it must be dosed twice daily because of its shorter half-life.
- Adjunct: Sodium restriction (< 2g/day), additional antihypertensives as needed (CCB, thiazide)
- Monitoring K⁺ on MRA: Hyperkalemia risk, especially with CKD or ACEi/ARB combo. Check K⁺ + Cr at 1 week, 4 weeks, then q3-6 months.
Monitoring
| Setting | What to check, and when | Why |
|---|---|---|
| Starting or uptitrating an MRA | K⁺ and creatinine at 1 week and 4 weeks, then every 3 to 6 months once stable | MRAs cause hyperkalemia, and the risk multiplies with CKD or a concurrent ACE inhibitor or ARB. A creatinine rise of up to 30% is expected as the hyperfiltration comes off. |
| After adrenalectomy | K⁺ and BP within the first week; stop or halve the MRA and potassium supplements on the day of surgery | The contralateral zona glomerulosa has been chronically suppressed, so transient hypoaldosteronism with hyperkalemia is common in the first weeks. Continuing the MRA into that window is the classic post-op error. |
| Cure assessment | Renin and aldosterone at 3 months, with BP and drug count | Use the PASO definitions: biochemical cure is the rule, clinical cure is not. A persistently suppressed renin suggests residual disease. |
| On long-term medical therapy | Renin should become detectable, plus BP and K⁺ | An unsuppressed renin indicates adequate mineralocorticoid receptor blockade. If renin stays suppressed the dose is too low, and the cardiovascular risk of aldosterone excess persists even with a normal BP. |
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Spironolactone (Aldactone) | 25-100 mg daily | PO | First-line MRA. Most effective for PA. Anti-androgenic SE (gynecomastia 50%, sexual dysfunction). Monitor K⁺. PATHWAY-2, 2015 |
| Eplerenone (Inspra) | 50-100 mg BID | PO | Selective MRA. Fewer hormonal SE. More expensive. May need higher doses than spironolactone. |
| Amiloride | 5-10 mg daily | PO | Alternative for K⁺-sparing if MRA intolerance. Less effective for BP lowering than spironolactone. |
| Nifedipine (Procardia) | 30-60 mg daily | PO | Add-on antihypertensive. Does not interfere with ARR screening. |
🏥 Rounds
Pimp Questions
❓ Why can't you rely on CT alone to decide on surgery for primary aldosteronism?
CT is wrong in up to 38% of cases. Reasons: (1) Nonfunctioning adrenal incidentalomas are common (5-10% of adults have them) -a visible nodule may NOT be the aldosterone source. (2) Microadenomas (< 1 cm) may be the true source but invisible on CT. (3) Bilateral hyperplasia can have an asymmetric appearance mimicking a unilateral adenoma. Adrenal vein sampling (AVS) is the gold standard -it directly measures aldosterone from each adrenal vein. Endocrine Society, 2016
❓ What medications must you hold before ARR screening and for how long?
Spironolactone and eplerenone: hold × 6 weeks (major interference). Diuretics: hold × 4 weeks (cause hypokalemia → suppress aldosterone; stimulate renin). Beta-blockers: suppress renin → false positive ARR. ACEi/ARBs: may cause false negatives (stimulate renin) but are ACCEPTABLE to continue if needed for BP control. Safe alternatives: verapamil, hydralazine, doxazosin (alpha-blocker). Always ensure K⁺ is repleted before testing.
❓ Why does primary aldosteronism cause hypokalemia and metabolic alkalosis?
Aldosterone acts on the principal cells of the collecting duct → activates ENaC → Na⁺ reabsorption creates a negative lumen potential → drives K⁺ and H⁺ secretion. Result: (1) Na⁺ retention → volume expansion → HTN, (2) K⁺ secretion → hypokalemia, (3) H⁺ secretion → metabolic alkalosis. However, only 30-50% of PA patients are hypokalemic at diagnosis -most are normokalemic.
❓ Why does PA cause more cardiovascular damage than essential HTN at the same BP?
Aldosterone has direct mineralocorticoid receptor-mediated effects on the heart, vasculature, and kidneys independent of BP: (1) myocardial fibrosis → LVH and diastolic dysfunction, (2) vascular inflammation and stiffness, (3) glomerular damage → proteinuria, (4) increased AF risk. PA patients have 2-4× higher rates of stroke, MI, and AF compared to BP-matched essential HTN. This is why MRA therapy improves outcomes beyond BP lowering alone, and why the target on medical therapy is a detectable renin rather than simply a normal blood pressure.
Clinical Examples
📋 Case 1, Classic Primary Aldosteronism with Adenoma
Patient: 44M with resistant HTN (BP 162/98 on 3 drugs) and recurrent hypokalemia (K⁺ 2.8 despite 80 mEq KCl daily). PAC 32 ng/dL, PRA 0.2, ARR 160. Saline infusion: PAC 22 (failed suppression). CT: 1.8 cm left adrenal adenoma.
Key findings: Confirmed primary aldosteronism, positive screen (ARR > 30) and positive confirmatory test (saline-suppressed PAC > 10). CT shows unilateral adenoma but CT is wrong 38% of the time.
Management:
- Adrenal vein sampling (AVS), mandatory before surgery (CT misidentifies lateralization in 38%)
- Start spironolactone 50 mg daily while awaiting AVS (treats HTN + replaces K⁺)
- If AVS lateralizes left → laparoscopic left adrenalectomy (cure rate 50-60% for HTN, ~100% for hypokalemia)
- Hold ACEi/ARB 4 weeks before AVS (interfere with renin/aldo ratio)
- Post-op: monitor for hyperkalemia (suppressed contralateral zona glomerulosa takes weeks to recover)
Teaching point: Never skip AVS based on CT alone. A 1.8 cm "adenoma" may be a non-functioning incidentaloma, with the real source being bilateral hyperplasia. AVS changes management in 38% of cases.
📋 Case 2, Bilateral Adrenal Hyperplasia
Patient: 56F with resistant HTN (4 drugs), K⁺ 3.2 on supplementation. PAC 24, PRA 0.4, ARR 60. Saline infusion: PAC 14. CT: bilateral adrenal limb thickening. AVS: no lateralization (bilateral aldosterone excess).
Key findings: Bilateral idiopathic hyperaldosteronism (IHA), accounts for ~60% of PA. Surgery not curative (bilateral process). Medical management is definitive therapy.
Management:
- Spironolactone 25-50 mg daily, titrate to BP and K⁺ (first-line MRA for PA)
- If gynecomastia/breast tenderness → switch to eplerenone 50 mg BID (selective MRA, fewer anti-androgenic effects)
- Target BP < 130/80, K⁺ 4.0-5.0
- Low-sodium diet (< 2g Na/day), amplifies MRA efficacy
- Monitor Cr and K⁺ at 1 week, 4 weeks, then q3-6 months (MRA can cause hyperkalemia especially with CKD)
Teaching point: Bilateral hyperplasia is more common than adenoma. These patients are managed medically for life. Spironolactone is preferred (more potent) but eplerenone avoids anti-androgen side effects in men.
📋 Case 3, Normokalemic Primary Aldosteronism
Patient: 52M with resistant HTN (BP 154/92 on amlodipine, losartan, chlorthalidone). K⁺ consistently 3.8-4.0 (normal). Screened because of resistant HTN. PAC 18 ng/dL, PRA 0.3, ARR 60.
Key findings: Normokalemic PA, up to 50% of PA patients are normokalemic. Hypokalemia is neither sensitive nor specific for PA. Endocrine Society recommends screening all patients with resistant HTN.
Management:
- Confirm with saline infusion test or fludrocortisone suppression test
- Hold interfering medications before testing: spironolactone (6 weeks), ACEi/ARB (2 weeks), dihydropyridine CCB and alpha-blockers are allowed during testing
- If confirmed: CT adrenals → AVS if surgical candidate
- Start MRA therapy, many "resistant HTN" patients become controlled once PA is treated
- PA may explain 5-10% of all HTN and 20% of resistant HTN
Teaching point: Normal potassium does NOT rule out PA. The classic teaching "hypokalemia = think aldosteronism" misses half of cases. Screen based on resistant HTN, not potassium level.
Sample Presentation
Mr. Kim is a 48-year-old man with resistant hypertension (amlodipine 10, lisinopril 40, HCTZ 25 -BP 158/96) and persistent hypokalemia (K⁺ 3.0 despite supplementation). BMI 28. No secondary HTN features on exam. Labs: PAC 28 ng/dL, PRA 0.3 ng/mL/hr, ARR 93. Confirmatory: saline infusion PAC 18 ng/dL (failed suppression). CT adrenals: 1.4 cm left adrenal adenoma.
Key Points: Confirmed primary aldosteronism -positive ARR, failed saline suppression. CT shows left adenoma, BUT must do adrenal vein sampling before committing to surgery (CT is wrong 38% of the time). Start spironolactone 50 mg while awaiting AVS. Replace K⁺. If AVS lateralizes left → laparoscopic left adrenalectomy.
- K⁺ + Cr at 1 week, 4 weeks, then q3-6 months on MRA -hyperkalemia risk (especially with CKD, ACEi/ARB)
- BP -target < 130/80. Most patients need additional antihypertensives besides MRA.
- ARR is NOT useful for monitoring -it's only a screening test. Follow clinical endpoints (BP, K⁺).
- Post-adrenalectomy: Check K⁺ and aldosterone at 1 month. Expect transient hyperkalemia (suppressed contralateral adrenal). Hold MRA. Resume antihypertensives only if BP remains elevated.
- Annual cardiovascular risk assessment -PA causes disproportionate end-organ damage. Screen for AF, LVH (echo), proteinuria.
📋 Summary
Summary
Screen Much More Widely Than You Think
The 2025 Endocrine Society guideline recommends screening every hypertensive patient, a change from 2016, which restricted screening to resistant hypertension, hypertension with hypokalemia, an adrenal incidentaloma, early-onset hypertension or a family history of early stroke. Primary aldosteronism is the commonest cause of secondary hypertension and is heavily under-diagnosed.
Hypokalemia Is the Exception, Not the Rule
Most patients with primary aldosteronism are normokalemic. Waiting for a low potassium before screening is the single biggest reason the diagnosis is missed. When it is present, it is a strong clue, often with a metabolic alkalosis.
Screen With the Aldosterone-to-Renin Ratio
A high aldosterone with a suppressed renin is the pattern. Correct the potassium before drawing it, since hypokalemia suppresses aldosterone and produces a false negative. Mineralocorticoid receptor antagonists must be stopped for 4 to 6 weeks; beta blockers falsely raise the ratio and ACE inhibitors, ARBs and diuretics falsely lower it. Verapamil, hydralazine and doxazosin are the interference-free agents to control blood pressure meanwhile.
Confirm Before Localizing
A confirmatory test showing failure to suppress aldosterone with salt loading, by oral sodium loading, saline infusion, fludrocortisone suppression or captopril challenge. Skip confirmation only when the picture is unambiguous: spontaneous hypokalemia with undetectable renin and a clearly raised aldosterone.
Adrenal Vein Sampling Decides the Treatment
CT alone is not enough: non-functioning adenomas are common in older patients and a small aldosterone-producing adenoma can be invisible. Adrenal vein sampling distinguishes a unilateral adenoma, which surgery cures, from bilateral hyperplasia, which it does not. It can be skipped in a patient under 35 with spontaneous hypokalemia and a clear unilateral adenoma on CT.
Unilateral Disease: Operate
Laparoscopic adrenalectomy normalizes the potassium in essentially everyone and cures or greatly improves the blood pressure in most. Check potassium and blood pressure within the first week and stop or halve the MRA and any potassium supplement, because the contralateral gland has been chronically suppressed and transient hyperkalemia is expected.
Bilateral Disease: Block the Receptor
Spironolactone 25 to 100 mg daily is first line. Eplerenone when the anti-androgenic effects (gynecomastia, erectile dysfunction, menstrual irregularity) are not tolerated, at the cost of being less potent and twice-daily. Check potassium and creatinine at 1 week and 4 weeks, then every 3 to 6 months, and remember the hyperkalemia risk multiplies with CKD or a concurrent ACE inhibitor or ARB.
Treat It Even When the Blood Pressure Is Controlled
Aldosterone excess causes cardiac fibrosis, atrial fibrillation, stroke and renal injury out of proportion to the blood pressure, so the target is the hormone, not just the number. On medical therapy, renin should become detectable, which is the marker of adequate receptor blockade; a still-suppressed renin means the dose is too low.
📄 One Pager
Text version
One-Pager
Primary Aldosteronism
Screen → Confirm → Localize
3-Step Workup
Screen: ARR > 30 + PAC ≥ 10. Confirm: saline infusion (PAC > 10 post). Localize: CT adrenals + AVS (gold standard, CT wrong 38%). Lateralization ≥ 4:1 → surgery.
Trials
Endocrine Society PA Guidelines 2016 · PATHWAY-2 2015 (spironolactone best add-on for resistant HTN) · PASO 2017 (PA cardiovascular outcomes)
Related Topics
Adrenal CrisisCushing's SyndromeDiabetes InsipidusHypercalcemiaHyperosmolar Hyperglycemic State (HHS)Hyperthyroidism / Graves' Disease