What is the difference between Conn's (primary aldosteronism) syndrome and Liddle syndrome in terms of underlying causes, symptoms, and treatment options?

Conn's Syndrome vs. Liddle Syndrome: Key Differences

Conn's syndrome (primary aldosteronism) and Liddle syndrome are fundamentally different conditions: Conn's involves excessive aldosterone production from the adrenal glands, while Liddle syndrome results from a genetic defect in kidney sodium channels that mimics aldosterone excess without any aldosterone elevation. 1, 2

Underlying Pathophysiology

Conn's Syndrome (Primary Aldosteronism)

• Caused by autonomous aldosterone overproduction from either an adrenal adenoma (30% of cases) or bilateral adrenal hyperplasia (70% of cases) 1
• The excess aldosterone drives sodium retention and potassium excretion in the distal nephron 1
• Represents the most common form of secondary hypertension, affecting approximately 3% of hypertensive patients 1, 3

Liddle Syndrome

• Results from genetic mutations in the epithelial sodium channel (ENaC) subunits (β or γ subunits) that prevent normal channel degradation 1, 2
• These mutations prevent ubiquitination of ENaC subunits, causing excessive sodium channels to remain in the cell membrane and increasing sodium reabsorption 2
• This creates a state of aldosterone-independent sodium retention—the kidneys act as if aldosterone is present when it is not 3, 4
• Inherited in an autosomal dominant pattern and typically presents early in life, often in childhood 1, 5

Clinical Presentation

Shared Features (Both Conditions)

• Hypertension (often severe and early-onset) 1, 5, 3
• Hypokalemia with metabolic alkalosis 1, 5, 2
• Muscle weakness, fatigue, polyuria, and polydipsia 5, 3

Distinguishing Clinical Features

• Liddle syndrome often presents in childhood or adolescence, whereas Conn's syndrome typically presents in the fourth to fifth decade 1, 5
• Liddle syndrome may be associated with nephrocalcinosis and progressive renal failure from long-standing hypertension 5

Diagnostic Biochemical Profile

Conn's Syndrome

• Elevated plasma aldosterone concentration 1
• Suppressed plasma renin activity (PRA) 1
• Aldosterone-to-renin ratio typically >30 1
• Urinary potassium excretion >30 mmol/24h despite hypokalemia 3
• Confirmatory testing with saline suppression test or salt loading test shows failure to suppress aldosterone 1

Liddle Syndrome

• Suppressed plasma aldosterone levels 1, 5, 4, 2
• Suppressed plasma renin activity 5, 4, 2
• Both aldosterone AND renin are low—this is the critical distinguishing feature 3, 4
• Hypokalemia may be present but can sometimes be normal 3
• Genetic testing confirms mutations in SCNN1B or SCNN1G genes (encoding ENaC β or γ subunits) 1, 2

The key diagnostic distinction: In Conn's syndrome, aldosterone is HIGH with low renin; in Liddle syndrome, BOTH aldosterone and renin are LOW. 3, 4, 2

Treatment Approaches

Conn's Syndrome Treatment Algorithm

For unilateral disease (adenoma):

• Laparoscopic adrenalectomy is the treatment of choice and potentially curative 1, 6
• Adrenal vein sampling should be performed to confirm lateralization before surgery 1

For bilateral disease (hyperplasia) or non-surgical candidates:

• Spironolactone 50-100 mg daily, titrated up to 300-400 mg daily as needed 1, 6
• Eplerenone can be used as an alternative for patients intolerant of spironolactone side effects 1, 7, 6
• Monitor potassium and creatinine within 2-3 days and at 7 days after initiation, then monthly for 3 months 6

Liddle Syndrome Treatment Algorithm

Spironolactone and other aldosterone antagonists are INEFFECTIVE in Liddle syndrome because the problem is not aldosterone excess 5, 4, 2

First-line treatment:

• Amiloride (5-30 mg daily) or triamterene to directly block ENaC channels 5, 3, 4, 2
• Low sodium diet (<2.4 g sodium/day) is essential 5, 4, 2
• This combination can restore normotension and correct electrolyte abnormalities 4, 2

Definitive treatment:

• Kidney transplantation completely corrects hypertension and hypokalemia, confirming the tubular origin of the disease 5

Critical Pitfalls to Avoid

• Do not treat Liddle syndrome with spironolactone—it will fail because aldosterone is already suppressed 5, 4
• Do not assume hypokalemia must be present in either condition; normokalaemic forms exist and are increasingly recognized 1, 8
• Always measure BOTH aldosterone AND renin when evaluating mineralocorticoid hypertension—measuring only one can lead to misdiagnosis 1, 3
• Consider genetic testing for Liddle syndrome in young patients with hypertension, suppressed renin and aldosterone, especially with family history 1, 2
• Screen for familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism) in Conn's syndrome patients, as it requires different treatment with dexamethasone 1, 3, 8