# Primary Aldosteronism

## Overview and Significance

### Definition

Primary aldosteronism (PA) is defined as autonomous aldosterone production from the adrenal gland, independent of the renin-angiotensin system, resulting in hypertension and often hypokalemia. It is recognized as the most common cause of secondary hypertension, a distinction that underscores the importance of systematic screening in appropriate patient populations.

### Epidemiology

The prevalence of primary aldosteronism is substantially higher than historically appreciated. Current estimates indicate that PA affects 5-13% of hypertensive patients and up to 20% of those with resistant hypertension. Previously, PA was considered rare, with prevalence estimates of approximately 1%, largely because screening was limited to patients presenting with the classic combination of hypertension and hypokalemia. It is now well established that the majority of PA patients are normokalemic, with 50-70% maintaining normal serum potassium levels. This recognition has fundamentally changed screening practices and significantly increased diagnostic yield.

### Cardiovascular Consequences

The clinical significance of primary aldosteronism extends far beyond blood pressure elevation. Aldosterone excess causes end-organ damage that is independent of blood pressure, meaning that patients with PA sustain greater cardiovascular injury than patients with essential hypertension matched for blood pressure levels. Cardiac fibrosis and left ventricular hypertrophy are more pronounced than in BP-matched essential hypertension. The risk of atrial fibrillation is increased with an odds ratio of 12-fold, stroke risk is elevated 4-fold, and myocardial infarction risk is increased 6-fold. Additional consequences include proteinuria with CKD progression and metabolic syndrome, as aldosterone impairs insulin signaling. Critically, targeted treatment through either adrenalectomy or mineralocorticoid receptor antagonist therapy reverses this excess cardiovascular risk, making accurate diagnosis of PA a clinically impactful intervention.

## Pathophysiology

### Normal RAAS Physiology

Understanding the normal renin-angiotensin-aldosterone system is essential for comprehending the pathophysiology of PA. Renin is released from juxtaglomerular cells in response to three stimuli: decreased renal perfusion pressure, decreased sodium chloride delivery to the macula densa, and sympathetic nervous system stimulation. Renin cleaves angiotensinogen (produced by the liver) to generate angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme, predominantly in the pulmonary vasculature. Angiotensin II stimulates the zona glomerulosa of the adrenal cortex to secrete aldosterone. Aldosterone acts on the mineralocorticoid receptor in the distal nephron, increasing sodium reabsorption through epithelial sodium channels (ENaC) while promoting potassium and hydrogen ion secretion. The resulting volume expansion provides negative feedback by suppressing further renin release.

### Subtypes of PA

Aldosterone-producing adenoma (APA, also known as Conn syndrome) accounts for 30-40% of PA cases. These are unilateral lesions, and molecular characterization has revealed somatic mutations in several ion channel and ATPase genes. KCNJ5 mutations are the most common, particularly in women and in larger adenomas. Other identified mutations include ATP1A1, ATP2B3, CACNA1D, and CLCN2.

Bilateral adrenal hyperplasia (BAH), also termed idiopathic hyperaldosteronism (IHA), is the most common subtype, accounting for 60-70% of cases. It involves bilateral zona glomerulosa hyperplasia without a discrete adenoma. Unilateral adrenal hyperplasia constitutes 2-5% of cases and is characterized by unilateral zona glomerulosa hyperplasia that lateralizes on adrenal venous sampling despite the absence of a discrete adenoma.

Familial hyperaldosteronism encompasses several rare genetic forms. FH type I, or glucocorticoid-remediable aldosteronism (GRA), results from a chimeric CYP11B1/CYP11B2 gene that places aldosterone synthesis under ACTH control, rendering it suppressible by dexamethasone. It characteristically presents with early-onset hypertension and a family history of hemorrhagic stroke. FH type II is caused by CLCN2 mutations and is not glucocorticoid-suppressible. FH type III involves germline KCNJ5 mutations causing severe bilateral hyperplasia that may require bilateral adrenalectomy. FH type IV is associated with CACNA1H mutations. Aldosterone-producing carcinoma is exceedingly rare but should be suspected when a large adrenal mass exceeding 4 cm is associated with PA biochemistry.

<image>A pathophysiology diagram comparing normal RAAS regulation with primary aldosteronism. Left panel (Normal): show the RAAS cascade with renin from JG cells, angiotensinogen from liver, ACE from lung, angiotensin II stimulating zona glomerulosa to produce aldosterone, acting on collecting duct MR to increase Na reabsorption and K secretion, with negative feedback loop from volume expansion suppressing renin. Right panel (Primary Aldosteronism): show autonomous aldosterone production from either an adenoma (APA) or bilateral hyperplasia (BAH) bypassing the RAAS; suppressed renin (shown as crossed out or diminished); aldosterone excess causing Na retention, K wasting, volume expansion, and direct cardiac/vascular fibrosis independent of BP. Use arrows and feedback loops with clear labeling.</image>

## Screening and Diagnosis

### Who to Screen (Endocrine Society 2016 Guidelines)

The Endocrine Society recommends screening for PA in several clinical scenarios: sustained hypertension above 150/100 mmHg or any drug-resistant hypertension; hypertension requiring three or more drugs including a diuretic, or controlled on four or more drugs; hypertension with spontaneous or diuretic-induced hypokalemia; hypertension with an adrenal incidentaloma; hypertension with sleep apnea; hypertension with a family history of early-onset hypertension or cerebrovascular accident at young age; first-degree relatives of PA patients; and hypertension with atrial fibrillation.

### Aldosterone-to-Renin Ratio (ARR) - Screening Test

The screening test for PA involves simultaneous measurement of morning (sitting) plasma aldosterone concentration (PAC) and plasma renin activity (PRA) or direct renin concentration (DRC). Using PAC in ng/dL and PRA in ng/mL/h, an ARR of 30 or greater with a PAC of at least 15 ng/dL suggests PA. When using DRC measured in mU/L, an ARR of 3.7 or greater (ng/dL per mU/L) or laboratory-specific cut-offs should be applied. The test has sensitivity of approximately 90% with specificity ranging from 70-90% depending on the cut-offs used and testing conditions.

### Medications Affecting ARR (Must Know)

| Medication | Effect on Renin | Effect on Aldosterone | Net ARR Effect | Recommendation |
|---|---|---|---|---|
| Beta-blockers | Suppressed ↓↓ | Mildly suppressed ↓ | **False positive** ↑ | Withdraw ≥2 weeks before testing |
| Spironolactone/Eplerenone | Increased ↑ | Increased ↑ | **False negative** ↓ | Withdraw ≥4-6 weeks before testing |
| Amiloride | Increased ↑ | Variable | **False negative** ↓ | Withdraw ≥2 weeks |
| ACE inhibitors/ARBs | Increased ↑↑ | Mildly decreased ↓ | **False negative** ↓ | Ideally withdraw ≥2 weeks (some guidelines allow testing) |
| Clonidine | Suppressed ↓ | Variable | **False positive** ↑ | Withdraw ≥2 weeks |
| NSAIDs | Suppressed ↓ | Variable | **False positive** ↑ | Withdraw if possible |
| DHP CCBs (amlodipine) | Mildly increased ↑ | Minimal effect | Minimal | Acceptable during testing |
| Verapamil SR | Minimal effect | Minimal effect | Minimal | **Preferred** agent during testing |
| Alpha-blockers (doxazosin) | Minimal effect | Minimal effect | Minimal | **Preferred** agent during testing |

Understanding the effects of commonly prescribed medications on the ARR is critical for accurate interpretation. Medications that can cause false-negative results by suppressing aldosterone or stimulating renin include spironolactone and eplerenone (which should be withdrawn at least 4-6 weeks before testing), amiloride (withdraw at least 2 weeks), and ACE inhibitors and ARBs (which raise renin and may normalize the ARR; ideally withdrawn 2 weeks before testing, though some guidelines permit testing with appropriate interpretive adjustments). Dihydropyridine calcium channel blockers mildly raise renin but are considered acceptable during testing.

Medications that can cause false-positive results by raising aldosterone or suppressing renin present an equally important consideration. Beta-blockers are the most common cause of false-positive ARR because they suppress renin to a greater degree than they suppress aldosterone; they should be withdrawn at least 2 weeks before testing. Central alpha-2 agonists such as clonidine and NSAIDs also suppress renin and can produce false-positive results.

Medications acceptable for use during ARR testing include verapamil (slow-release) and hydralazine, which have the least interference with the assay, and alpha-blockers such as doxazosin and prazosin. It is also essential that hypokalemia be corrected before testing, as low potassium suppresses aldosterone secretion and can produce a false-negative result.

### Confirmatory Testing (At Least One Required After Positive ARR)

A positive screening ARR requires at least one confirmatory test before a definitive diagnosis of PA can be established. The oral sodium loading test involves consuming a high-sodium diet (>200 mEq Na/day) for 3 days, with a 24-hour urine aldosterone collected on day 3. PA is confirmed when urinary aldosterone exceeds 12 mcg per 24 hours (some centers use 14 mcg), provided urinary sodium exceeds 200 mEq, confirming adequate sodium loading.

The intravenous saline infusion test involves infusing 2 liters of 0.9% NaCl over 4 hours, beginning in the morning with the patient seated or supine. A PAC above 10 ng/dL (>277 pmol/L) at 4 hours confirms PA, while a value below 5 ng/dL excludes it; intermediate values are indeterminate. Caution is required in patients with heart failure or uncontrolled hypertension.

The fludrocortisone suppression test, involving fludrocortisone 0.1 mg every 6 hours for 4 days with NaCl supplementation, confirms PA when the upright PAC remains above 6 ng/dL on day 5 at 10 AM with suppressed PRA. This test is cumbersome and rarely used in practice. The captopril challenge test, using captopril 25-50 mg orally with PAC measured at baseline and 2 hours, is the least accurate confirmatory test but is useful when saline loading is contraindicated. PA is suggested when PAC fails to suppress by more than 30% from baseline.

### Subtype Differentiation

#### Adrenal CT

Adrenal CT is obtained as the initial imaging study after biochemical confirmation. It may reveal a unilateral adenoma, bilateral nodularity, or normal-appearing adrenals. However, CT has significant limitations that clinicians must appreciate. Non-functioning adrenal incidentalomas are common, especially in patients over 40, meaning a unilateral nodule may represent a non-functioning incidentaloma alongside contralateral micronodular disease that is the true aldosterone source. Small APAs under 1 cm may be missed entirely. The SPARTACUS trial demonstrated that CT alone misallocates surgical candidates in 38% of cases. While CT reliably identifies large aldosteronomas or macronodular disease, it is insufficient for surgical decision-making in most cases.

#### Adrenal Venous Sampling (AVS) - Gold Standard for Lateralization

Adrenal venous sampling remains the gold standard for determining whether aldosterone excess is unilateral or bilateral, and it is required in most patients before considering surgery. The one exception is young patients under 35 years with spontaneous hypokalemia, marked PA biochemistry, and a unilateral adenoma exceeding 1 cm on CT, who may proceed directly to surgery.

AVS involves bilateral simultaneous catheterization of the adrenal veins with measurement of aldosterone and cortisol in both adrenal veins and a peripheral vein. The selectivity index, calculated as the ratio of adrenal vein cortisol to peripheral cortisol, must be 3 or greater unstimulated or 5 or greater with cosyntropin stimulation to confirm successful catheterization. The lateralization index, calculated as the aldosterone-to-cortisol ratio of the dominant side divided by that of the non-dominant side, must reach 4 or greater to indicate a unilateral source. The contralateral suppression index, in which the aldosterone-to-cortisol ratio of the non-dominant side falls below the peripheral ratio, provides further confirmation of unilateral disease.

Cosyntropin stimulation during AVS, administered as a continuous infusion at 50 mcg/h or as a bolus of 250 mcg, maximizes cortisol secretion and improves selectivity, though protocols vary by institution. Success rates range from 74-96% depending on institutional experience. The right adrenal vein is technically more challenging to cannulate because it is shorter and drains directly into the IVC, unlike the left adrenal vein, which drains into the left renal vein. An experienced interventional radiologist is essential.

<image>An anatomical and procedural diagram of adrenal venous sampling (AVS). Show a frontal view of the abdomen with kidneys, adrenal glands, IVC, and aorta. Illustrate bilateral femoral vein catheter access with catheters advanced to adrenal veins. Left panel: show the left adrenal vein draining into the left renal vein (easier to cannulate). Right panel: show the right adrenal vein draining directly into the IVC (more technically challenging, shorter). Include sampling sites with labeled blood collection points: right adrenal vein, left adrenal vein, and peripheral (IVC or iliac). Inset table showing calculation of selectivity index (adrenal cortisol / peripheral cortisol ≥3) and lateralization index (dominant aldosterone/cortisol ratio / non-dominant ratio ≥4). Use clean anatomical illustration with labeled structures.</image>

## Management

### Unilateral PA (APA or Unilateral Hyperplasia)

#### Laparoscopic Adrenalectomy

Laparoscopic adrenalectomy is the preferred treatment for unilateral PA, curing hyperaldosteronism in more than 95% of cases. Hypertension cure, defined as achieving target blood pressure off all antihypertensive medications, occurs in 30-60% of patients, with significant improvement in the remainder. Predictors of blood pressure cure include younger age, shorter duration of hypertension, fewer antihypertensive medications, female sex, lower BMI, and absence of a family history of hypertension.

Preoperative MRA therapy with spironolactone for 4-6 weeks before surgery corrects hypokalemia and volume status, reducing operative complications. Postoperatively, patients must be monitored for hyperkalemia resulting from suppression of the contralateral adrenal's renin-aldosterone axis, which may take weeks to months to recover. MRA and potassium supplementation should be discontinued postoperatively, and potassium should be monitored closely.

### Bilateral PA (BAH/IHA)

#### Medical Therapy (Lifelong)

| Agent | Dose | Mechanism | Key Side Effects | Notes |
|---|---|---|---|---|
| Spironolactone | 12.5-100 mg daily (max 400 mg) | Non-selective MRA | Gynecomastia (30-50%), breast tenderness, menstrual irregularity | First-line for bilateral PA |
| Eplerenone | 50-200 mg daily (usually BID) | Selective MRA | Fewer anti-androgenic effects; no gynecomastia | 40-70% potency of spironolactone; higher doses needed |
| Amiloride | 5-20 mg daily | ENaC blocker | Hyperkalemia | No direct aldosterone blockade; does not prevent end-organ damage |

Spironolactone is the first-line mineralocorticoid receptor antagonist, started at 12.5-25 mg daily and titrated to 25-100 mg daily (maximum 400 mg), targeting normalization of potassium and blood pressure. Its side effects are dose-dependent and include gynecomastia (30-50%), breast tenderness, erectile dysfunction, and menstrual irregularities, all resulting from its anti-androgenic effects through progesterone receptor and androgen receptor binding.

Eplerenone is the selective MRA alternative, dosed at 50-200 mg daily (usually twice daily), with significantly fewer anti-androgenic side effects (no gynecomastia) but approximately 40-70% the potency of spironolactone. Higher doses are typically needed, often 100-200 mg daily, and it is preferred in men experiencing androgen-related side effects from spironolactone.

Amiloride, an ENaC blocker at 5-20 mg daily, serves as an alternative for patients intolerant of MRAs. However, because it provides no direct aldosterone blockade, it does not address the aldosterone-mediated end-organ damage that occurs independent of blood pressure and potassium.

Adjunctive antihypertensive agents are often required, with calcium channel blockers (amlodipine) and ACE inhibitors or ARBs preferred as add-on therapy.

#### Monitoring

Serum potassium and renal function should be checked at 1 week, 4 weeks, and then every 3-6 months. Blood pressure targets follow standard guidelines (less than 130/80 mmHg). Hyperkalemia requires vigilance, particularly with concomitant ACE inhibitor or ARB therapy, renal impairment, or continued potassium supplementation. Plasma renin activity should be monitored, with a target of renin rising into the detectable or normal range, which confirms adequate MRA dosing.

### Medical Therapy Endpoints

The goals of medical therapy are to normalize potassium without supplementation, achieve target blood pressure with minimal medications, and restore renin from its fully suppressed state. An emerging concept is targeting normalization of the aldosterone-to-renin ratio rather than simply controlling blood pressure and potassium, reflecting a growing appreciation for the importance of directly addressing aldosterone-mediated tissue damage.

## Emerging Concepts

### Aldosterone Synthase Inhibitors

A new class of drugs targeting CYP11B2 (aldosterone synthase) represents an exciting therapeutic development. Baxdrostat (CIN-107) is a selective CYP11B2 inhibitor whose Phase 2 data from the BrigHTN trial demonstrated dose-dependent blood pressure reduction in resistant hypertension, with Phase 3 trials ongoing. Lorundrostat, another selective CYP11B2 inhibitor, showed significant blood pressure reduction in the Phase 2 TARGET trial in patients with resistant hypertension and suppressed renin. These agents offer the advantage of direct aldosterone lowering without the side effects of mineralocorticoid receptor blockade, and they avoid the hyperkalemia associated with MRA therapy, though adrenal insufficiency is theoretically possible.

### Primary Aldosteronism Resolution Score (PASO)

The PASO system provides standardized outcomes reporting for PA surgery, categorizing results as complete clinical success (normotensive off all medications), partial clinical success (blood pressure improved), or absent clinical success (no blood pressure improvement), along with parallel biochemical success categories based on normalization of ARR, potassium, and aldosterone.

### Autonomous Aldosterone Production in Normotensives

Emerging data suggest that mild autonomous aldosterone production may exist on a continuum, contributing to what has traditionally been classified as "essential" hypertension and increasing cardiovascular risk in the broader population. Aldosterone-renin ratio screening may identify subclinical PA before overt hypertension develops, with implications for earlier intervention with MRA therapy extending beyond classic PA.

## Glucocorticoid-Remediable Aldosteronism (FH Type I)

### Pathophysiology

Glucocorticoid-remediable aldosteronism results from an unequal crossing-over of the CYP11B1 (11-beta-hydroxylase) and CYP11B2 (aldosterone synthase) genes on chromosome 8q. This creates a chimeric gene in which the aldosterone synthase coding region is placed under the ACTH-responsive 11-beta-hydroxylase promoter, causing aldosterone production to be regulated by ACTH rather than the renin-angiotensin-aldosterone system. Consequently, aldosterone secretion becomes suppressible by exogenous glucocorticoids.

### Diagnosis

GRA should be suspected in patients with early-onset PA before age 20 or those with a family history of early-onset hypertension or hemorrhagic stroke before age 40. Definitive diagnosis is achieved through genetic testing using long-range PCR for the chimeric CYP11B1/CYP11B2 gene, which is recommended in all PA patients under 20 years or with a suggestive family history. Urinary elevations of 18-oxocortisol and 18-hydroxycortisol, which are hybrid steroids produced by the chimeric enzyme, provide biochemical support for the diagnosis.

### Treatment

Treatment involves low-dose dexamethasone (0.125-0.25 mg nightly) or prednisolone (2.5-5 mg nightly) to suppress ACTH-driven aldosterone production. Care must be taken to avoid glucocorticoid over-replacement, which can produce iatrogenic Cushing syndrome; the goal is normalization of blood pressure and potassium rather than complete ACTH suppression. MRA therapy serves as an adjunct or alternative when the required glucocorticoid dose is too high. All first-degree relatives should be tested genetically.

## Key Clinical Pearls

- Most patients with primary aldosteronism are normokalemic; screening should not be limited to those with hypokalemia; the ARR should be checked in all patients with resistant hypertension
- Beta-blockers are the most common cause of false-positive ARR (suppress renin more than aldosterone); ideally switch to verapamil SR and/or doxazosin 2 weeks before testing
- Adrenal CT alone misclassifies the source of PA in ~38% of cases; adrenal venous sampling remains the gold standard for lateralization in most patients over age 35
- Spironolactone is first-line medical therapy for bilateral PA, but gynecomastia in men is common at effective doses (30-50%); eplerenone at higher doses (100-200 mg/day) is the main alternative
- Aldosterone causes cardiovascular damage (LVH, fibrosis, stroke, MI) independent of blood pressure; targeted treatment of PA reduces this excess risk, making correct diagnosis clinically impactful
- All patients with PA diagnosed before age 20 (or with family history of early-onset hypertension or hemorrhagic stroke) should be tested for glucocorticoid-remediable aldosteronism (FH type I)

## References

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3. Monticone S, et al. "Cardiovascular Events and Target Organ Damage in Primary Aldosteronism Compared with Essential Hypertension." Eur Heart J. 2018;39(7):2569-2580.
4. Williams TA, et al. "Outcomes after Adrenalectomy for Unilateral Primary Aldosteronism: PASO Study." Lancet Diabetes Endocrinol. 2017;5(9):689-699.
5. Freeman MW, et al. "Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension." N Engl J Med. 2023;388(5):446-456.