What is Conn’s syndrome, what are its causes, and what is the medical management of primary hyperaldosteronism?

What is Conn's Syndrome

Conn's syndrome is primary aldosteronism caused by a unilateral aldosterone-producing adenoma (APA), representing 35-50% of all primary aldosteronism cases and constituting the most common surgically curable form of secondary hypertension. 1, 2

Definition and Pathophysiology

• Primary aldosteronism is characterized by excessive and autonomous aldosterone production by the adrenal glands that is independent of the renin-angiotensin system, leading to suppressed plasma renin activity. 1

• The autonomous aldosterone excess causes sodium retention, extracellular volume expansion, hypertension, and increased urinary potassium excretion—though hypokalemia occurs in only approximately 50% of cases, making it an unreliable screening marker. 3, 1

• Aldosterone exerts direct toxic effects on cardiovascular and renal tissue independent of blood pressure elevation, producing widespread fibrosis and dramatically increased target-organ damage compared to essential hypertension at equivalent blood pressure levels. 1

Causes and Subtypes

Unilateral Disease (50% of cases)

• Aldosterone-producing adenoma (APA) is the classic Conn's syndrome, typically a solitary benign adrenal cortical tumor. 1, 4

• APAs can be subdivided into two morphological subtypes: fasciculata-like cells (angiotensin II-unresponsive) and glomerulosa-like cells (angiotensin II-responsive), with the latter potentially misdiagnosed as bilateral hyperplasia. 4

• Unilateral adrenal hyperplasia is a rare cause of unilateral aldosterone excess. 1

Bilateral Disease (50% of cases)

• Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) accounts for the remaining half of primary aldosteronism cases. 1, 5

Familial Forms

• Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-remediable aldosteronism) is a dominantly inherited disorder that can cause fatal stroke in young affected individuals and is uniquely treatable with low-dose dexamethasone. 6, 4

Medical Management of Primary Hyperaldosteronism

Diagnostic Algorithm

Step 1: Screening with Aldosterone-Renin Ratio (ARR)

• Screen all patients with resistant hypertension (BP uncontrolled on ≥3 medications including a diuretic), severe hypertension (>180/110 mmHg), spontaneous or diuretic-induced hypokalemia, adrenal incidentaloma, or family history of early-onset hypertension/stroke before age 40. 3, 1

• Ensure potassium repletion (target 4.0-5.0 mEq/L) before testing, as hypokalemia suppresses aldosterone production and causes false-negative results. 3

• Collect blood in the morning (0800-1000 hours) with the patient seated for 5-15 minutes after being out of bed for 2 hours. 3

• A positive screen requires BOTH ARR ≥30 (when aldosterone in ng/dL and renin activity in ng/mL/h) AND plasma aldosterone concentration ≥10-15 ng/dL. 3, 1

Step 2: Confirmatory Testing

• All positive ARR screens require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 3

• Options include intravenous saline suppression test (failure to suppress aldosterone below 5 ng/dL after 2L normal saline over 4 hours) or oral sodium loading with 24-hour urine aldosterone measurement. 3

• Mineralocorticoid receptor antagonists must be withdrawn for at least 4 weeks before any confirmatory testing. 3, 6

Step 3: Subtype Determination

• Obtain non-contrast CT scan of the adrenal glands as initial imaging. 3

• Adrenal venous sampling (AVS) is mandatory before offering adrenalectomy to distinguish unilateral from bilateral disease, as CT findings alone lead to unnecessary adrenalectomy in up to 25% of patients. 3, 4

• The only exception: patients <40 years with imaging showing a single affected gland may proceed without AVS, as bilateral hyperplasia is rare in this population. 3

Treatment Based on Subtype

For Unilateral Disease (Conn's Syndrome)

• Laparoscopic unilateral adrenalectomy is the treatment of choice, improving blood pressure in virtually 100% of patients and achieving complete cure of hypertension in approximately 50%. 3, 1, 6

• Surgery also normalizes hypokalemia, reduces antihypertensive medication requirements, and improves cardiac and kidney function parameters. 3

• Delayed diagnosis may result in irreversible vascular remodeling, leaving residual hypertension even after successful surgery. 6

For Bilateral Disease or Non-Surgical Candidates

• Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of lifelong medical therapy for bilateral hyperplasia or patients unsuitable for surgery. 3, 6

• Spironolactone is the first-line MRA, starting at 12.5-50 mg daily and titrating up to 100-400 mg daily as needed for blood pressure and potassium control. 3, 6, 5

• Eplerenone (50-100 mg daily in 1-2 doses) is an alternative MRA with fewer anti-androgenic side effects (gynecomastia, breast tenderness, sexual dysfunction) compared to spironolactone. 6

For Familial Hyperaldosteronism Type I

• Low-dose dexamethasone treatment corrects the aldosterone excess without producing glucocorticoid side effects, as this form is ACTH-dependent. 6, 4

Safety Monitoring for MRA Therapy

• Verify serum potassium ≤5.0 mEq/L and eGFR >30 mL/min (or creatinine <2.0-2.5 mg/dL) before initiating MRAs. 6

• Discontinue potassium supplements before starting MRAs. 6

• Check potassium and creatinine at 3 days, 1 week, then monthly for the first 3 months, and every 3 months thereafter if stable. 6

• Avoid combining MRAs with potassium supplements, potassium-sparing diuretics, ACE inhibitors/ARBs (without close monitoring), or NSAIDs due to severe hyperkalemia risk. 6

• Use MRAs with extreme caution in patients with eGFR <45 mL/min. 6

Common Pitfalls to Avoid

• Do not rely on the presence or absence of hypokalemia to screen for or exclude primary aldosteronism—it is absent in 50% of confirmed cases. 3, 1

• Do not proceed to adrenalectomy based on CT findings alone—AVS is essential to prevent unnecessary surgery. 3, 4

• Do not test patients on mineralocorticoid receptor antagonists—these must be withdrawn for at least 4 weeks before screening or confirmatory testing. 3, 6

• Recognize that beta-blockers and diuretics cause false-positive ARR (by suppressing renin), while ACE inhibitors and ARBs cause false-negative ARR (by raising renin). 3

Clinical Significance

• Primary aldosteronism affects 5-10% of all hypertensive patients and up to 20% of those with resistant hypertension, making it the most common specifically treatable cause of secondary hypertension. 3, 4

• Patients with primary aldosteronism experience dramatically worse cardiovascular outcomes than those with essential hypertension at equivalent blood pressure levels: 3.7-fold increase in heart failure, 4.2-fold increase in stroke, 6.5-fold increase in myocardial infarction, and 12.1-fold increase in atrial fibrillation. 3

• Early diagnosis and targeted treatment—either surgical or medical—can reverse aldosterone-mediated target-organ damage and mitigate excess cardiovascular risk. 3, 1