What is the difference between Liddle syndrome and Conn's (Primary Aldosteronism) syndrome in terms of diagnosis and treatment in a patient presenting with hypertension?

Distinguishing Liddle Syndrome from Conn's Syndrome (Primary Aldosteronism)

The critical difference is aldosterone levels: Conn's syndrome has elevated aldosterone with suppressed renin, while Liddle syndrome has suppressed aldosterone AND suppressed renin—both conditions present with hypertension and hypokalemia, but measuring aldosterone is essential to distinguish them. 1

Pathophysiology

Conn's syndrome results from autonomous aldosterone overproduction from either an adrenal adenoma or bilateral adrenal hyperplasia, causing sodium retention and potassium excretion in the distal nephron 1.

Liddle syndrome stems from genetic mutations in epithelial sodium channel (ENaC) subunits (SCNN1A, SCNN1B, or SCNN1G genes), causing excessive sodium channels to remain in the cell membrane and increasing sodium reabsorption independent of aldosterone 1, 2.

Clinical Presentation Differences

Age of Onset

• Liddle syndrome: Typically presents in childhood or adolescence 1
• Conn's syndrome: Presents in the fourth to fifth decade of life 1

Common Features (Both Conditions)

• Hypertension, hypokalemia, and metabolic alkalosis 1
• Low plasma renin activity 1, 2

Diagnostic Biochemical Profiles

Conn's Syndrome (Primary Aldosteronism)

• Elevated plasma aldosterone concentration 1
• Suppressed plasma renin activity 1
• Aldosterone-to-renin ratio (ARR) typically >30 1, 3
• Plasma aldosterone should be at least 10 ng/dL for positive ARR 3

Liddle Syndrome

• Suppressed plasma aldosterone levels 1, 2
• Suppressed plasma renin activity 1, 2
• Both aldosterone AND renin are low (distinguishing feature) 1, 4
• Normal or elevated serum sodium with hypokalemia 2

Critical Diagnostic Pitfall

Measuring both aldosterone and renin is crucial when evaluating mineralocorticoid hypertension—measuring only one can lead to misdiagnosis. 1 A case report documented a 17-year-old initially misdiagnosed with primary aldosteronism because high aldosterone levels were noted, but genetic testing ultimately revealed Liddle syndrome with a SCNN1B mutation 5.

Confirmatory Testing

For Suspected Conn's Syndrome

• Confirmatory testing with intravenous saline suppression test or oral salt-loading test 3
• Adrenal venous sampling to distinguish unilateral versus bilateral disease before surgery 3
• CT imaging of adrenals 3

For Suspected Liddle Syndrome

• Genetic testing is the gold standard for diagnosis 5, 2
• Test for mutations in SCNN1A, SCNN1B, and SCNN1G genes 2
• Consider genetic testing in young patients with hypertension, suppressed renin and aldosterone, and family history 1
• 31 different causative mutations have been reported in 72 families 2

Treatment Approaches

Conn's Syndrome

• Unilateral disease: Laparoscopic adrenalectomy is treatment of choice 1, 3
• Bilateral disease or non-surgical candidates: Spironolactone (first-line) or eplerenone (if spironolactone side effects occur) 1, 3
• Mineralocorticoid receptor antagonists are the mainstay for bilateral hyperplasia 3

Liddle Syndrome

• Amiloride or triamterene to directly block ENaC channels 1, 4, 6
• Low sodium diet is essential 1, 2
• Spironolactone is ineffective because the defect is downstream of aldosterone action 4, 5
• Blood pressure and potassium normalize within 5-7 days of appropriate ENaC blocker therapy 6, 7

Key Clinical Clues for Liddle Syndrome

• Young age at presentation (childhood/adolescence) 1
• Family history of early-onset hypertension (autosomal dominant inheritance) 2, 7
• Failure to respond to spironolactone should raise suspicion 5
• Severe hypertension despite multi-drug therapy 6
• May occur in all ethnic populations including Black individuals 6