Liddle Syndrome

Overview

Definition

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

Epidemiology

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

Etiology

Gene mutations change the structure of the respective epithelial sodium channel (ENaC) subunit and also affect the region of the protein involved in signaling for its breakdown.

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

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 owing to structural changes in the respective subunits:
  • Location of ENaC channels: surface of epithelial cells of 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 the 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 the placement of the sodium channels → decrease in their degradation → hyperaldosteronism-like state

Clinical Presentation and Diagnosis

Clinical presentation

Liddle syndrome is rare and has a presentation similar to many syndromes associated with mineralocorticoid excess. The syndrome is, therefore, 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.

Lab testing:

• 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 patients with a family history and suspected Liddle syndrome.

Management

Treatment

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

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

Complications

Because of its rare occurrence and the symptoms similar to 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 to the prognosis in Liddle syndrome.
• Adequate treatment → good prognosis
• Delayed detection → delay in therapy → manifesting as major cardiovascular and renal complications

Differential Diagnosis

• Primary hyperaldosteronism: also known as Conn’s syndrome. Primary hyperaldosteronism is the excess production of aldosterone, which results in low renin levels and high aldosterone levels. The condition is caused by primary adrenal hyperplasia or adrenal adenoma and presents with hypertension, muscle weakness, muscle spasms, polyuria, and headaches. Diagnosis is by clinical history and examination as well as lab testing. Management includes adrenalectomy and spironolactone.
• Mineralocorticoid excess: autosomal recessive disorder that results from mutations in the HSD11B2 gene that encodes the kidney isozyme 11β-hydroxysteroid dehydrogenase type 2. Mineralocorticoid excess 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 patients. Management includes aldosterone antagonists like spironolactone and renal transplantation.
• Glucocorticoid resistance: familial disease characterized by reduced cortisol effects due to a glucocorticoid receptor defect countered by hyperactivity of the hypothalamic–pituitary–adrenal axis. Patients present with signs of adrenal overproduction of mineralocorticoids—hypertension, hypokalemic alkalosis, hirsutism in females, male-pattern baldness, and menstrual irregularities. Diagnosis is based on a high cortisol level and normal to high adrenocorticotrophic hormone (ACTH) level. Management is by administration of mineralocorticoid-sparing synthetic glucocorticoids to suppress ACTH secretion.
• Renovascular hypertension: caused by vasoconstriction of renal arteries due to abnormal hormone response. The clinical presentation of renovascular hypertension includes hypertension, kidney dysfunction, and pulmonary edema caused by renal artery stenosis. Diagnosis is made by blood and urine analysis; the lipid profile is also important. Management is by surgical intervention.