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Liddle Syndrome (Pseudoaldosteronism)

Liddle Syndrome (Pseudoaldosteronism) is a topic covered in the 5-Minute Clinical Consult.

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Basics

Description

  • Autosomal dominant (AD) disorder characterized by early-onset hypertension associated with hypokalemia, metabolic alkalosis, suppressed plasma renin activity, and aldosterone levels
  • Mutation of β- or γ-subunit of epithelial sodium channel (ENaC) located in the distal nephron results in gain of function mutation of ENaC and the following:
    • Excess sodium reabsorption
    • Increased urinary potassium excretion
    • Suppressed renin and aldosterone levels
    • Secondary hypertension
  • Resistant to conventional treatment including mineralocorticoid receptor antagonist (spironolactone, eplerenone) but responsive to ENaC inhibitor (amiloride, triamterene)

Epidemiology

Incidence
Unknown


Prevalence
  • Unknown, rare
  • May be underrecognized due to variable expressivity
  • Described in populations worldwide

Etiology and Pathophysiology

  • The ENaC is a cell membrane–bound ion channel that is permeable to sodium (Na+) ion. In the kidney, it is expressed in the apical membrane of principal cells and controls sodium reabsorption at the cortical collecting duct (CCD) and is regulated by aldosterone.
  • ENaC is composed of three subunits: α, β, and γ.
  • Under normal condition, ENaC is degraded by ubiquitin proteasome or NEDD4.
  • Mutations in β- or γ-subunit make ENaC unrecognizable by NEDD4 and result in decreased degradation and removal of ENaC from the cell membrane, causing an overactivity of ENaC (gain of function mutation).
  • Net result: excessive reabsorption of sodium, which leads to volume expanded hypertension, and suppression of renin and aldosterone
  • Mineralocorticoid antagonists are therefore ineffective.
  • Hypokalemia and metabolic alkalosis develop in response to reabsorption of sodium in exchange for potassium and hydrogen ions secretion. These findings are however variable.

Genetics
  • Monogenic AD inheritance with high penetrance but variable expressivity
  • Children of affected parents have a 50% chance of inheriting disease allele.
  • Mutation in SCNN1B or SCNN1G genes encoding for β- or γ-subunit of ENaC located on chromosome 16p12

Risk Factors

Family history of first-degree relative with onset of hypertension at young age. Sporadic cases have also been reported.

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Citation

Stephens, Mark B., et al., editors. "Liddle Syndrome (Pseudoaldosteronism)." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816194/all/Liddle_Syndrome__Pseudoaldosteronism_.
Liddle Syndrome (Pseudoaldosteronism). In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816194/all/Liddle_Syndrome__Pseudoaldosteronism_. Accessed March 26, 2019.
Liddle Syndrome (Pseudoaldosteronism). (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816194/all/Liddle_Syndrome__Pseudoaldosteronism_
Liddle Syndrome (Pseudoaldosteronism) [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 March 26]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816194/all/Liddle_Syndrome__Pseudoaldosteronism_.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Liddle Syndrome (Pseudoaldosteronism) ID - 816194 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816194/all/Liddle_Syndrome__Pseudoaldosteronism_ PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -