Liddle Syndrome

Liddle syndrome, a type of pseudohyperaldosteronism, is a rare cause of secondary hypertension. Liddle syndrome results from autosomal dominant gain-of-function mutations in the genes that encode the epithelial sodium channel (ENaC) subunits, also known as the “collecting tubule sodium channel” or “amiloride-sensitive sodium channel.” The activity of ENAC is increased, leading to sodium and water retention. Liddle syndrome presents with the classic triad of resistant hypertension at an early age, hypokalemia, and metabolic alkalosis, which mimics the symptoms of primary aldosteronism; however, this syndrome is associated with low plasma aldosterone levels. Diagnosis is based on history and physical examination, blood and urine analysis, and genetic testing. Management is by using potassium-sparing diuretics and restricting dietary sodium. Treatment delay can lead to serious cardiovascular and renal complications. The prognosis is good if Liddle syndrome is treated early.

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Overview

Definition

Liddle syndrome is a rare autosomal dominant genetic disorder associated with abnormal functioning of the sodium channels in the collecting tubules. Liddle syndrome is clinically characterized by hypertension, low plasma renin activity, metabolic alkalosis, hypokalemia, and low aldosterone levels.

Epidemiology

  • Extremely rare disorder reported in < 80 families
  • Overall population prevalence is unknown.
  • Individuals may remain asymptomatic for up to 40 years, but Liddle syndrome can also be diagnosed as early as 12 years in a majority of cases.
  • Often remains undiagnosed

Etiology

Gain-of-function gene mutations change the structure of the epithelial sodium channel (ENaC) subunit and also affect the region of the protein involved in signaling for its breakdown, which is normally controlled by aldosterone.

  • SCNN1A: encodes the alpha subunit of the ENaC
  • SCNN1B: encodes the beta subunit of the ENaC
  • SCNN1G: encodes the gamma subunit of the ENaC
Inheritance of liddle syndrome

Inheritance of Liddle syndrome

Image: “Liddle” by Dra marina. License: CC0 1.0

Pathophysiology

Liddle syndrome is inherited in an autosomal dominant pattern (i.e., a single copy of the gene is sufficient for the syndrome to occur).

  • Mutation occurs in the SCNN1A, SCNN1B, and SCNN1G genes that encode the alpha, beta, and gamma subunits of the ENaC.
  • Dysregulation of the ENaC follows due to structural changes in the respective subunits:
    • Location of ENaCs: epithelial cell surface of the kidneys, lungs, and sweat glands
    • Function of the channels: sodium transport into cells, sodium reabsorption in the distal renal tubules
  • Domain change in the channel → no degradation of sodium channels (by the ubiquitin-proteasome pathway)
  • Inability to degrade the channels → chronic presence of the channel in the collecting duct → increased sodium reabsorption
  • Increased sodium reabsorption → increased water reabsorption and hypertension
  • Aldosterone is responsible for controlling the number of sodium channels. Loss of this ability in Liddle syndrome → decrease in channel degradation → hyperaldosteronism-like state

Clinical Presentation and Diagnosis

Clinical presentation

Liddle syndrome is rare and has a presentation similar to many other syndromes associated with mineralocorticoid excess. Thus, Liddle syndrome is often misdiagnosed or remains undetected.

The classic triad of the presentation includes:

  1. Hypertension:
    • Early onset
    • Long standing
    • Often severe or resistant
    • Associated features:
      • Intermittent headaches
      • Fatigue
      • Dizziness
      • Changes in vision
  2. Hypokalemia symptoms:
    • Weakness
    • Fatigue
    • Palpitations
    • Myalgia
    • Constipation
    • Exercise intolerance
  3. Metabolic alkalosis

Diagnosis

The preliminary diagnosis of Liddle syndrome is based mainly on suspicion resulting from the clinical presentation. It is also important to:

  • Consider family history of early-onset hypertension with or without hypokalemia.
  • Rule out other causes of hypertension, hypokalemia, and metabolic alkalosis.

Laboratory findings:

  • Plasma renin level is low.
  • Plasma aldosterone level is normal to low.
  • Urine sodium and aldosterone levels are low.
  • Serum electrolytes:
    • Increased sodium
    • Decreased potassium
    • Increased bicarbonate

Genetic testing should be considered in individuals with a family history of Liddle syndrome and in those in whom this condition is suspected.

Management

Treatment

Early diagnosis of Liddle syndrome leads to resolution or control of the disorder, enabling the affected individual to lead a normal life.

  • Potassium-sparing diuretics:
    • Act by blocking ENaC activity:
      • Amiloride
      • Triamterene
    • Used to treat hypertension while resolving hypokalemia and metabolic alkalosis
  • Salt restriction: < 2 g sodium/day
  • Conventional hypertensive therapies are ineffective.
  • Renal transplantation resolves the disorder completely.

Complications

Owing to its rare occurrence and similarity of symptoms to those of other disorders associated with mineralocorticoid excess, Liddle syndrome is often misdiagnosed, which may cause an increase in the occurrence of complications:

  • Resistant hypertension
  • Left ventricular hypertrophy
  • Hypertensive retinopathy
  • Nephrosclerosis
  • Cerebral ischemia leading to cerebrovascular accidents
  • Chronic renal failure
  • Hypertensive encephalopathy
  • Pulmonary edema

Prognosis

  • Early diagnosis and treatment are key in the prognosis of Liddle syndrome.
  • Adequate treatment → good prognosis
  • Delayed detection → delay in therapy → manifestation as major cardiovascular and renal complications

Differential Diagnosis

  • Primary hyperaldosteronism: also known as Conn’s syndrome. Primary hyperaldosteronism is characterized by the excess production of aldosterone, which results in low renin levels. Primary hyperaldosteronism is caused by primary adrenal hyperplasia or adrenal adenoma and presents with hypertension, muscle weakness, muscle spasms, polyuria, and headaches. Diagnosis is based on clinical history, examination, and laboratory testing. Management includes adrenalectomy and therapy with spironolactone.
  • Apparent mineralocorticoid excess: a rare autosomal recessive disorder that presents with hypertension, hypokalemia, metabolic alkalosis, and low plasma renin. Diagnosis is made by calculating the ratio of free urinary cortisol to free urinary cortisone, which is higher in affected individuals. Management includes aldosterone antagonists, such as spironolactone, and renal transplantation.
  • Glucocorticoid resistance: a familial disease characterized by reduced cortisol effects due to a glucocorticoid receptor defect countered by hyperactivity of the hypothalamic–pituitary–adrenal axis. Affected individuals present with signs of adrenal overproduction of mineralocorticoids—hypertension, hypokalemic alkalosis, hirsutism in women, male-pattern baldness, and menstrual irregularities. Diagnosis is based on high cortisol levels and normal-to-high adrenocorticotrophic hormone (ACTH) levels. Management is using mineralocorticoid-sparing synthetic glucocorticoids to suppress ACTH secretion.
  • Renovascular hypertension: a condition caused by vasoconstriction of the renal arteries due to abnormal hormone response. The clinical presentation of renovascular hypertension includes hypertension, renal dysfunction, and pulmonary edema caused by renal artery stenosis. Diagnosis is based on blood and urine analysis, and obtaining a lipid profile is also important. Management is by surgical intervention.

References

  1. Young, W.F. (2019). Genetic disorders of the collecting tubule sodium channel: Liddle’s syndrome and pseudohypoaldosteronism type 1. UpToDate. Retrieved June 7, 2021, from https://www.uptodate.com/contents/genetic-disorders-of-the-collecting-tubule-sodium-channel-liddles-syndrome-and-pseudohypoaldosteronism-type-1
  2. Liddle syndrome. (2016). Genetic and Rare Diseases Information Center. Retrieved June 7, 2021, from https://rarediseases.info.nih.gov/diseases/7381/liddle-syndrome
  3. Enslow, B.T., et al. (2019). Liddle’s syndrome mechanisms, diagnosis, and management. Integrated Blood Pressure Control 12:13–22.
  4. Hechanova, L.A. (2020). Liddle syndrome. MSD Manual Professional Version. https://www.msdmanuals.com/en-in/professional/genitourinary-disorders/renal-transport-abnormalities/liddle-syndrome
  5. Mubarik, A. et al. (2020). Liddle syndrome. Stat Pearls. https://www.statpearls.com/ArticleLibrary/viewarticle/42871

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