Secondary hypertension (HTN)

Liddle syndrome

• Very rare, but estimates of prevalence vary

• Typically presents in childhood with early-onset hypertension, but sometimes not identified until adulthood

• Pathophysiology: overactivity of the epithelial sodium channel (ENaC) on the luminal surface of the principal cells in the collecting duct

  • Gain of function mutation results in ↑ number (and thereby ↑ of activity) of ENaCs

    • ENaC regulation involves a balance of the insertion and removal of channels in the cell membrane

    • A mutation results in structural alteration of one of the channel's three subunits (α, β or γ), preventing the subunits from being recognized for retrieval and degradation (ubiquitination) by intracellular ubiquitin protein ligase (Nedd4-2)

    • The impairment of retrieval of ENaC from the cell membrane results in an overabundance, and thus an overactivity, of ENaC in the principal cells of the collecting duct

  • ↑ ENaC activity → ↑ Na⁺ reabsorption from the tubular lumen → ↑ water reabsorption (volume expansion and hypertension) and ↑ K⁺ secretion

    • ↑ Na⁺ reabsorption → ↓ charge in the tubular lumen → ↑ K⁺ and H⁺ secretion → hypokalemia and metabolic alkalosis

      • The hypokalemic state itself contributes to the metabolic alkalosis, as it causes increased acid (H⁺) secretion into the renal tubule and drives hydrogen (H⁺) intracellularly in exchange for potassium

    • ↑ Na⁺ reabsorption → ↑ water retention → volume expansion → suppression of renin → suppression of aldosterone

• Clinical findings:

  • Given the variable penetrance of the disease, not all features are necessarily present in all patients (even in the same family)

  • Hypertension, mild to severe (when severe, can be resistant to multiple antihypertensives)

  • Low potassium (hypokalemia)

  • High bicarbonate (metabolic alkalosis)

  • Normal or high sodium (hypernatremia)

  • Low renin and low aldosterone

• Diagnosis:

1. Clinical identification of a Liddle syndrome phenotype

2. Evaluate treatment response to amiloride

3. Confirm with genetic testing

• • • Note: SCNN1A is not included in some genetic panels since most cases of Liddle syndrome are caused by mutations in SCNN1B or SCNN1G

    • Given the autosomal dominant inheritance pattern and variable penetrance of the disease, testing 1st-degree family members (parents, siblings, children) is recommended

    • Not all genetic mutations are known, so patients with a strong clinical suspicion and expected treatment response may still be considered as having Liddle syndrome (sometimes referred to as having "Liddle-like syndrome" or "Liddle-like phenotype" to distinguish from patients with known pathogenic mutations).

• Inheritance: Autosomal dominant

  • Almost all cases involve SCNN1B (beta) or SCNN1G (gamma) on chromosome 16, but cases involving SCNN1A (alpha) on chromosome 12 have been reported

    • Note: these same genes are affected in pseudohypoaldosteronism type 1, although in PHA1 there is a loss of function mutation

  • Over 30 mutations have been identified

• Treatment:

  • Amiloride is first-line therapy

    • Superior efficacy compared to triamterene

    • Mechanism: targets and blocks ENaC directly

      • While also "potassium sparing diuretics," eplerenone, spironolactone, finerenone are ineffective in Liddle syndrome because they act via a different mechanism: antagonizing the mineralocorticoid receptor has little effect given that aldosterone levels are already suppressed.

  • A low salt diet is recommended

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• Triad of HTN, hypokalemia, metabolic alkalosis

• Genetic testing available: SCNN1A, SCNN1B, SCNN1G

• Treatment: low salt diet, amiloride/triamterene

  • MR antagonists do not work, because the channel itself has a gain of function mutation (ie., it is not a problem of MR upregulation)

• Prognosis: high risk for cardiovascular morbidity and mortality

• Angiotensin II promoter is stimulating ACTH to make aldosterone

• Chimeric gene: unequal crossing over during mitosis so promoter and regulatory areas are swapped

  • Angiotensin II promoter ends up stimulating aldo syntehesis

• Glucocorticoid remediable aldosteronism: FHA type 1

• AD inheritance

• There are different crossover patterns

• Has not been identified in African American patients

• Early hypertension

• Associated with cerebral aneurysms and intracranial bleeding

• Once diagnosed, MRA screening is recommended starting at puberty

• Hypertension from volume expansion, hypokalemia, alkalosis

• Dexamethasone suppression test would work but is rarely done

• Low PRA

• Urine steroid profiles (increased 18-hydroxy and 18-oxocortisol)

• Treatment

  • Glucocorticoids to suppress ACTH-stimulated mineralocorticoid production

    • Long-term treatment is needed but can use a low dose of steroids

  • MR antagonists

  • ENaC antagonists (amiloride or triamterene): adjunctive therapy to control HTN, but can be discontinued once in a steady state on steroids