✅ Model Answer:
• Diagnosis: Liddle syndrome (ENaC gain-of-function mutation – SCNN1B or SCNN1G).
• Evidence: Hypertension, hypokalemia, metabolic alkalosis, low plasma renin and aldosterone (low-renin hypertension), family history of early-onset hypertension.
• Next step: Genetic testing (SCNN1B, SCNN1G). Start amiloride or triamterene (ENaC blockers). Avoid spironolactone (ineffective). Monitor BP and potassium. Screen family members.

✅ Model Answer:
• Genes: SCNN1B (β-subunit) and SCNN1G (γ-subunit) of the epithelial sodium channel (ENaC) – located on chromosome 16p12.
• Inheritance: Autosomal dominant.
• Pathophysiology: Gain-of-function mutations in ENaC (usually in the C-terminus, affecting the PY motif that mediates ubiquitination and degradation) → increased Na reabsorption in the distal nephron → volume expansion, hypertension, and suppression of renin and aldosterone. Increased Na reabsorption also drives K and H+ excretion → hypokalemia and metabolic alkalosis.
• Why spironolactone is ineffective: Spironolactone is an aldosterone receptor antagonist. In Liddle syndrome, the defect is downstream of aldosterone (direct ENaC overactivity). Aldosterone levels are low, and the receptor is normal, so blocking it has no effect.
• Effective treatment: Amiloride or triamterene directly block ENaC.

✅ Model Answer:
• Classic features:
- Early-onset hypertension: Often severe, diagnosed in childhood or adolescence.
- Hypokalemia: Usually mild to moderate (K 2.8-3.5 mEq/L).
- Metabolic alkalosis.
- Suppressed plasma renin and aldosterone (low-renin hypertension).
- No edema (despite Na retention – due to "aldosterone escape").
- Family history of early-onset hypertension or stroke.
- No response to spironolactone (aldosterone antagonist).
- Response to amiloride/triamterene (ENaC blockers).
• Other: Headache, palpitations (if severe hypertension), rarely hypokalemic paralysis.

✅ Model Answer:
• Biochemical:
- Serum K: Low (<3.5 mEq/L).
- HCO3: Elevated (>30 mEq/L) – metabolic alkalosis.
- Plasma renin: Low (suppressed).
- Plasma aldosterone: Low (suppressed).
- Serum Na: Normal.
- Serum Mg: Normal.
- Urine K: Elevated (>20 mEq/L) despite hypokalemia.
• Family history: Autosomal dominant pattern.
• Drug trial: Amiloride/triamterene lowers BP and corrects hypokalemia; spironolactone has no effect.
• Genetic testing: SCNN1B and SCNN1G gene sequencing (confirmatory).
• Exclude other causes: Primary aldosteronism (elevated aldosterone), GRA (elevated aldosterone, 18-OH-cortisol), renal artery stenosis (elevated renin).

✅ Model Answer:
• ENaC blockers (first-line):
- Amiloride: 5-20 mg/day (in 1-2 divided doses).
- Triamterene: 50-300 mg/day.
- Mechanism: Directly block ENaC, reducing Na reabsorption, lowering BP, and correcting hypokalemia.
• Dietary salt restriction: Reduce Na intake to <2 g/day.
• Avoid: Spironolactone (ineffective – aldosterone receptor antagonist, not ENaC blocker).
• Avoid: NSAIDs (may worsen renal function).
• Monitor: BP, serum K, creatinine.
• Family screening: Screen first-degree relatives.
• Genetic counseling.

✅ Model Answer:
• Hypertension: Severe, early-onset → target organ damage (LVH, stroke, chronic kidney disease, retinopathy).
• Hypokalemia: Muscle weakness, cramps, arrhythmias (prolonged QT), paralysis.
• Metabolic alkalosis: Can worsen hypokalemia.
• Cardiovascular: Increased risk of stroke, MI, heart failure.
• Renal: Chronic kidney disease (if hypertension is uncontrolled).
• Psychosocial: Impact of lifelong hypertension and treatment.
• Family screening: High risk for family members.

✅ Model Answer:
• Prognosis:
- Good with early diagnosis and treatment (amiloride).
- BP control: Usually achieved with ENaC blockers.
- Quality of life: Good with treatment.
- Life expectancy: Normal if BP is controlled.
- Complications: Prevented with adequate treatment.
• Long-term follow-up:
- Monitor BP, serum K, creatinine.
- Monitor for target organ damage (echocardiogram, renal function).
- Family screening.
- Genetic counseling.

✅ Model Answer:
• Liddle syndrome:
- Renin: Low.
- Aldosterone: Low.
- Mechanism: ENaC gain-of-function.
- Treatment: Amiloride/triamterene.
- Spironolactone: Ineffective.
- Genetics: SCNN1B/SCNN1G.
- Family history: Autosomal dominant, early-onset HTN.
• Glucocorticoid-remediable aldosteronism (GRA):
- Renin: Low.
- Aldosterone: Elevated.
- Mechanism: Chimeric gene (CYP11B1/CYP11B2) → ACTH-dependent aldosterone excess.
- Treatment: Dexamethasone (suppresses ACTH) or spironolactone.
- Spironolactone: Effective.
- Genetics: CYP11B1/CYP11B2 fusion gene.
- Family history: Autosomal dominant, early-onset HTN and strokes.