What is Conn’s syndrome and how do we manage primary hyperaldosteronism in a hypertensive patient with hypokalemia, metabolic alkalosis, and possible volume depletion?

Conn's Syndrome and Management of Primary Hyperaldosteronism

What is Conn's Syndrome?

Conn's syndrome is primary hyperaldosteronism caused by autonomous, excessive aldosterone production from the adrenal glands—most commonly from a unilateral aldosterone-producing adenoma—resulting in hypertension, suppressed renin, and often (but not always) hypokalemia and metabolic alkalosis. 1

Key Pathophysiology

• Autonomous aldosterone secretion occurs independent of the renin-angiotensin system, causing sodium retention, volume expansion, potassium wasting, and suppression of plasma renin activity 2
• Approximately 50% of cases are unilateral (aldosterone-producing adenoma or unilateral hyperplasia), which are surgically curable, while the other 50% are bilateral adrenal hyperplasia requiring lifelong medical therapy 2, 3
• Hypokalemia is present in only ~50% of patients—normal potassium does NOT exclude the diagnosis, making it a poor screening criterion 4, 5
• Metabolic alkalosis develops from renal hydrogen ion loss in exchange for sodium reabsorption in the distal tubule 4

Cardiovascular Risk Profile

Primary aldosteronism carries dramatically higher cardiovascular risk than essential hypertension at equivalent blood pressure levels 4:

• 12.1-fold increase in atrial fibrillation
• 6.5-fold increase in myocardial infarction
• 4.2-fold increase in stroke
• 3.7-fold increase in heart failure 4

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Diagnostic Approach

Step 1: Screen High-Risk Patients

Screen ALL patients with: 1, 4

• Resistant hypertension (BP uncontrolled on ≥3 drugs including a diuretic)—prevalence up to 20% 4
• Severe hypertension (BP >180/110 mmHg)—prevalence up to 12% 4
• Spontaneous or diuretic-induced hypokalemia (even though absent in 50% of cases) 4, 5
• Adrenal incidentaloma on imaging 4, 3
• Family history of early-onset hypertension or stroke <40 years 4, 3
• Young-onset hypertension (<30-40 years without traditional risk factors) 4

Step 2: Initial Screening Test—Aldosterone-to-Renin Ratio (ARR)

Patient Preparation: 4

• Correct hypokalemia first—target serum K+ 4.0-5.0 mEq/L, as hypokalemia suppresses aldosterone and causes false-negatives 4
• Medication adjustments (when clinically feasible):
  • Stop beta-blockers, centrally acting drugs, and diuretics (suppress renin → false-positive ARR) 4
  • Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) ≥4 weeks before testing 4
  • Safe alternatives: long-acting calcium channel blockers and alpha-receptor antagonists minimally interfere with ARR 4
  • If medications cannot be stopped, test on current regimen and interpret in context 4
• Ensure unrestricted salt intake before testing 4

Blood Collection: 4

• Draw blood in the morning (0800-1000 hours) 4
• Patient should be out of bed for ≥2 hours and seated for 5-15 minutes immediately before collection 4

Positive Screening Criteria: 4, 2

• ARR ≥20-30 (when aldosterone in ng/dL and renin activity in ng/mL/h) AND
• Plasma aldosterone concentration ≥10-15 ng/dL 4, 2
• Specificity improves if minimum plasma renin activity ≥0.5 ng/mL/h is used 4

Step 3: Confirmatory Testing

All positive ARR screens require confirmatory testing to demonstrate autonomous aldosterone secretion that cannot be suppressed with sodium loading. 1, 4

Options: 1, 4

• Intravenous saline suppression test: Infuse 2L normal saline over 4 hours; failure to suppress plasma aldosterone <5 ng/dL confirms diagnosis 4
• Oral sodium loading test: Administer high-salt diet (>200 mEq/day) for 3 days with 24-hour urine aldosterone measurement on day 3 1, 4
• Fludrocortisone suppression test 1

Critical: Perform confirmatory testing with unrestricted salt intake and normal serum potassium 1, 4

Step 4: Subtype Determination—Unilateral vs. Bilateral Disease

This distinction is MANDATORY because it determines surgical candidacy versus lifelong medical therapy. 1

Initial Imaging: 3

• Non-contrast CT scan of adrenal glands to identify adenoma vs. hyperplasia 3
• CT findings alone are INSUFFICIENT for treatment decisions—up to 25% of patients would undergo unnecessary adrenalectomy based on imaging alone 4, 3

Gold Standard—Adrenal Venous Sampling (AVS): 1, 4, 3

• AVS is mandatory before offering adrenalectomy to definitively distinguish unilateral from bilateral disease 4, 3
• Sensitivity 95%, specificity 100% 4
• Exception: Patients <40 years with single adenoma on imaging (bilateral hyperplasia rare in this age group) 4
• Must be performed at experienced centers due to technical complexity 1

Genetic Testing: 1

• Exclude Familial Hyperaldosteronism Type 1 (glucocorticoid-remediable) in patients with family history—requires genetic testing or dexamethasone suppression test 1, 6

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Management Algorithm

For Unilateral Disease (Aldosterone-Producing Adenoma or Unilateral Hyperplasia)

Laparoscopic unilateral adrenalectomy is the treatment of choice. 1, 2, 3

Outcomes: 2, 3

• 100% of patients experience improvement in blood pressure 2
• ~50% achieve complete cure of hypertension 2, 3
• 100% normalization of hypokalemia 1
• Improves cardiac and kidney function parameters 2

Surgical Considerations: 1

• Consider surgery cautiously in older patients or those with significant comorbidities 1
• Multidisciplinary review recommended before proceeding 4

For Bilateral Disease (Idiopathic Hyperaldosteronism)

Medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of lifelong treatment. 1, 2, 3

First-Line: Spironolactone 1, 7

• Starting dose: 25-50 mg once daily 4, 3
• Effective dose: Usually 50-100 mg once daily 1
• Maximum dose: Can titrate up to 300-400 mg once daily if necessary 1, 7
• FDA-approved dosing for primary hyperaldosteronism: 100-400 mg daily 7
• Take consistently with or without food 7

Alternative: Eplerenone 1, 3

• Dose: 50-100 mg daily in 1-2 divided doses 3
• Advantages: Less gynecomastia and erectile dysfunction in men compared to spironolactone 1, 3
• Disadvantages: Less potent than spironolactone, requires twice-daily dosing 1

Newer Agents (Under Investigation): 1

• Non-steroidal MRAs (finerenone, exarenone) and aldosterone synthase inhibitor (baxdrostat) are being tested for primary aldosteronism 1

For Familial Hyperaldosteronism Type 1 (Glucocorticoid-Remediable)

Low-dose dexamethasone corrects the condition without glucocorticoid side effects and is safe during pregnancy 1, 3, 6

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Critical Safety Considerations for MRA Therapy

Pre-Treatment Requirements 3

• Verify serum potassium ≤5.0 mEq/L 3
• Confirm serum creatinine <2.0-2.5 mg/dL or eGFR >30 mL/min 3
• Discontinue potassium supplements before starting MRAs 3

Monitoring Protocol 3

• Check potassium and creatinine at 3 days, 1 week, then monthly for first 3 months 3
• Subsequently monitor every 3 months if stable 3

Drug Interactions and Contraindications 3

Avoid combining MRAs with: 3

• Potassium supplements or potassium-sparing diuretics
• ACE inhibitors or ARBs (without close monitoring)—dramatically increases hyperkalemia risk 4, 3
• NSAIDs or COX-2 inhibitors (increases hyperkalemia and renal dysfunction risk) 3

Use with caution: 3

• Significant renal dysfunction (eGFR <45 mL/min) 3
• In heart failure patients with eGFR 30-50 mL/min, consider initiating spironolactone at 25 mg every other day 7

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Common Diagnostic Pitfalls to Avoid

• Do NOT rely on hypokalemia alone—it is absent in 50% of cases and has low negative predictive value 4, 3, 5
• Do NOT proceed to surgery based on CT findings alone—AVS is mandatory to prevent unnecessary adrenalectomy 4, 3
• Do NOT test patients on interfering medications without context—beta-blockers and diuretics cause false-positives; ACE inhibitors/ARBs cause false-negatives 4
• Do NOT forget to correct hypokalemia before testing—it suppresses aldosterone and causes false-negatives 4
• Do NOT forget the 4-week MRA washout—spironolactone/eplerenone must be withdrawn ≥4 weeks before any testing 4

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Prognosis and Long-Term Considerations

• Early diagnosis is critical—delayed diagnosis leads to irreversible vascular remodeling, resulting in residual hypertension even after appropriate treatment 1, 3
• The rate of cure is higher when diagnosis is made early in the disease course 1
• Target-organ damage is often reversible with appropriate treatment (surgery or MRAs), reducing the excess cardiovascular risk 2
• Refer all confirmed cases to a hypertension specialist or endocrinologist for subtype determination and treatment planning 4, 3