Genetics & pathophysiology
Genes
- SCNN1B (β-ENaC) — commonest
- SCNN1G (γ-ENaC)
- SCNN1A (α-ENaC) — rare
- Gain-of-function mutations affect the cytoplasmic PY motif → reduced Nedd4-2-mediated channel internalisation → more ENaC channels at the apical membrane → continuous sodium reabsorption
- Autosomal dominant; 50% inheritance risk
- NHS National Genomic Test Directory R190 — inherited tubulopathies
Pathophysiology
- Excess Na reabsorption in cortical collecting duct → ECF volume expansion → low renin
- Volume expansion suppresses aldosterone (unlike primary aldosteronism)
- Increased lumen-negative voltage drives K+ secretion → hypokalaemia
- H+ secretion → metabolic alkalosis
- Hypertension often severe and resistant to standard agents
Clinical features & diagnosis
Presentation
- Hypertension in childhood or young adulthood (often < 30 years)
- Frequently severe, resistant to ACE-i / ARB / calcium-channel blockers
- Hypokalaemia: muscle weakness, cramps, polyuria, polydipsia
- Metabolic alkalosis on bloods
- Family history of early hypertension or stroke/MI in young relatives
- End-organ damage at unexpectedly young age — LVH, CKD, retinopathy
Bloods
- K+ low (often 2.5–3.5 mmol/L; some normokalaemic if dietary salt low)
- HCO3 raised (mild metabolic alkalosis)
- Mg variable
- Plasma RENIN — low
- Plasma ALDOSTERONE — low
- Cortisol — normal
Urine
- 24-h urinary aldosterone low
- 24-h urinary K+ inappropriately high for hypokalaemia (renal K wasting)
- 24-h urinary Na variable depending on intake
DIFFERENTIAL DIAGNOSIS (the hypokalaemic, low-renin hypertension group):
- PRIMARY ALDOSTERONISM — high aldosterone (Conn syndrome) — spironolactone works
- GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM (FH-I) — CYP11B1/CYP11B2 chimera — dexamethasone-responsive
- APPARENT MINERALOCORTICOID EXCESS (AME) — 11β-HSD2 deficiency — cortisol acts as a mineralocorticoid; high cortisol:cortisone in urine
- LICORICE INGESTION — phenocopy of AME (glycyrrhetinic acid)
- Cushing's syndrome / ectopic ACTH
- Geller syndrome (activating MR mutation; worsens in pregnancy)
- Gordon syndrome (pseudohypoaldosteronism type II) — hyperkalaemia, NOT hypokalaemia
Genetic Testing
- Definitive — sequence SCNN1A, SCNN1B, SCNN1G
- Predictive testing for first-degree relatives
Management & follow-up
First-line
- AMILORIDE 5 mg daily, titrated to 10–20 mg daily as needed
- Alternative: TRIAMTERENE 50–100 mg BD
- Both directly close ENaC → corrects hypertension, hypokalaemia, alkalosis
- Low-sodium diet (Na < 100 mmol/day; ~ 5 g salt/day) — augments response
- Replace potassium and magnesium as needed initially; usually no longer required once ENaC blocker established
Not Effective
- Spironolactone, eplerenone — defect is downstream of aldosterone
- Indirectly: thiazides, ACE-i / ARB partially helpful but inadequate alone
Adjunctive
- Add calcium-channel blocker or thiazide if BP not controlled on amiloride + salt restriction
- Beta-blocker if tachycardia
- Avoid loop diuretics (worsen K loss)
Monitoring
- Home BP monitoring with kept records
- U&E, eGFR every 3–6 months; aim K+ 3.5–5.0
- Annual ECG, echo (to assess LVH), urinalysis, ACR
- Lifestyle: weight, alcohol < 14 units/week, low salt, exercise
- Pregnancy: amiloride considered safe in pregnancy at standard doses; specialist obstetric input
Family
- Cascade genetic testing of all first-degree relatives
- Screen children from age 5 with BP measurements
- Pre-implantation genetic diagnosis available
- Avoid OTC steroids, NSAIDs, decongestants (raise BP) and liquorice
Prognosis
- Excellent if recognised and treated early
- Untreated: hypertensive emergencies, stroke, MI, CKD — many cases first identified at autopsy of young patients before genetic confirmation became routine
UK CARE PATHWAY: regional adult or paediatric nephrology with renal genetics input; clinical genetics for family counselling.
