Liddle Syndrome
The most likely diagnosis is Liddle syndrome (Option D). This patient presents with the pathognomonic triad of refractory hypertension, hypokalemia with metabolic alkalosis, and suppressed levels of both renin and aldosterone—a pattern that distinguishes Liddle syndrome from all other mineralocorticoid excess states.
Diagnostic Reasoning
Key Distinguishing Features
The critical diagnostic clue is the combination of low aldosterone AND low renin in the setting of hypertension and hypokalemia 1, 2, 3. This biochemical signature immediately narrows the differential:
- Low urinary sodium indicates avid sodium retention at the distal tubule level, consistent with inappropriate activation of the epithelial sodium channel (ENaC) 1
- Metabolic alkalosis (pH 7.50, HCO₃⁻ 36 mmol/L) results from enhanced distal tubular hydrogen ion secretion coupled with potassium wasting 1, 3
- Absence of family history does not exclude Liddle syndrome, as sporadic mutations occur 1
Why Not the Other Options?
Conn syndrome (primary aldosteronism) is definitively excluded because aldosterone is LOW, not elevated 4, 5. Primary aldosteronism characteristically shows elevated aldosterone with suppressed renin (aldosterone-to-renin ratio ≥30 with aldosterone ≥10 ng/dL) 4, 5.
Pheochromocytoma presents with episodic hypertension, headaches, sweating, and palpitations—not the sustained hypertension with electrolyte derangements seen here 4. It does not cause hypokalemia or suppress both renin and aldosterone 4.
Gitelman syndrome causes hypokalemia and metabolic alkalosis but presents with hypotension or normal blood pressure, not hypertension 5. This is a loss-of-function tubular defect, opposite to Liddle syndrome's gain-of-function.
Renal artery stenosis causes secondary hyperaldosteronism with elevated renin AND elevated aldosterone, not suppressed levels of both 4, 5. The renin-angiotensin-aldosterone axis is activated, not suppressed 5.
Pathophysiology of Liddle Syndrome
Liddle syndrome results from gain-of-function mutations in the β or γ subunits of ENaC 1. These mutations:
- Prevent normal ubiquitination of ENaC subunits, slowing their internalization from the apical membrane 1
- Increase channel open probability in some cases, further amplifying sodium reabsorption 1
- Mimic hyperaldosteronism at the tubular level despite suppressed aldosterone, causing volume expansion that suppresses both renin and aldosterone 1, 2, 3
The disorder affects not only renal tubular cells but also erythrocyte sodium transport, with increased intracellular sodium and membrane permeability 2.
Clinical Confirmation and Management
Diagnostic Approach
Genetic testing for ENaC mutations (SCNN1B and SCNN1G genes) provides definitive confirmation 1. The clinical phenotype—hypertension with hypokalemic alkalosis, suppressed renin and aldosterone—is highly specific and often sufficient for diagnosis 1, 3.
Treatment Strategy
Amiloride or triamterene are the treatments of choice, as they directly block ENaC activity 1, 2, 3. Key management principles:
- Sodium restriction is essential and must be combined with potassium-sparing diuretics 2, 3
- Blood pressure is extremely sensitive to salt intake during treatment—high sodium intake can overcome the therapeutic effect of triamterene 2
- Spironolactone is ineffective because the defect is downstream of aldosterone action 2, 3
- Treatment normalizes blood pressure, corrects hypokalemia, and restores plasma renin to normal levels when combined with adequate sodium restriction 2, 3
Common Pitfall
Do not mistake this for primary aldosteronism based solely on the hypertension-hypokalemia presentation 4, 5. The low aldosterone level is the critical distinguishing feature that points away from Conn syndrome and toward a primary tubular defect like Liddle syndrome 1, 2, 3.