Liddle, Bartter and Gitelman syndromes

CD - collecting duct
DCT - distal convoluted tubule
ENaC - epithelial sodium channel (antagonised by amiloride and triamterene)
MR - mineralocorticoid receptor
NCCT - sodium chloride cotransporter (antagonised by thiazide diuretics)
NKCC2 - sodium-potassium-chloride cotransporter (antagonised by loop diuretics)
ROMK2 - renal outer medullary potassium channel
TALLH - thick ascending limb of loop of Henle

Liddle syndrome

  • Autosomal dominant gain-of-function mutation in β- and γ-subunits of ENaC
  • Causes hypertension with hypokalaemic alkalosis
  • Low-salt diet is important

Pseudohypoaldosteronism type 1

  • Inverse of Liddle syndrome: salt-wasting with hyperkalaemic acidosis
  • Recessive PHA1 is homozygous loss-of-function mutations, causing severe decompensation with minor illnesses
  • Dominant PHA1 is heterozygous, causing milder disease
Nephron mechanisms in Liddle, Bartter & Gitelman syndromes

Bartter syndrome

  • Dysfunction of NKCC2, hence resembles effect of treatment with loop diuretics
  • Type 1 - defective NKCC2
  • Type 2 - defective ROMK2, which regulates NKCC2 by recycling potassium back into tubule
  • Type 3 - defective CLCKB, which permits NKCC2 by shuttling chloride out of LoH cells
  • Type 4 - defective Barttin, a co-factor of CLCKB in kidney and ear, hence also causes deafness
  • Severe salt-wasting presenting in early infancy - or with prematurity and polyhydramnios
  • Commonly hypercalciuria with normocalcaemia and renal tract calcification, and normomagnesaemia
  • Type 3 often normocalciuric and mildly hypomagnesaemic
  • Treatment with sodium and potassium supplementation
  • Indomethacin helpful in type 2

Gitelman syndrome

  • Much more common than Bartter syndrome
  • Loss of function of NCCT (mutation in SCL12A3), hence resembles effect of thiazides
  • Hypokalaemia, hypocalciuria and hypomagnesaemia, metabolic alkalosis
  • Low blood pressure and secondary hyperreninaemic hyperaldosteronism
  • Usual treatment with sodium, potassium and magnesium supplementation
  • Symptomatic hypokalaemia may be treated with aldosterone antagonists or RAAS blockers, though these may worsen hypotension