Continuing Education Activity

Liddle syndrome is one of the rare causes of resistant hypertension that presents in early childhood. Grant Liddle et al. first explained Liddle syndrome in 1963. It is also known as pseudo aldosteronism. It is a rare cause of secondary hypertension due to a genetic mutation, affecting the function of the collecting tubule sodium channel. This activity reviews the etiology, presentation, evaluation, and management of Liddle syndrome and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Identify the genetic etiology of Liddle syndrome.
• Describe the right workup to help establishing that a patient has Liddle syndrome, including potential differential diagnoses.
• Summarize the pharmaceutical treatment of Liddle syndrome.
• Explain the importance of improving coordination among the interprofessional team to enhance care for patients affected by Liddle syndrome.

Introduction

Liddle syndrome is one of the rare causes of resistant hypertension that usually presents since early childhood, but some are not detected until well into adulthood. First explained by Grant Liddle et al. in 1963, it is characterized by a primary increase in collecting tubule sodium reabsorption and potassium secretion. For this reason, is also known as pseudohyperaldosteronism. It is a rare cause of secondary hypertension due to a genetic mutation, affecting the function of the collecting tubule sodium channel.[1] Affected patients typically present with hypertension, hypokalemia, and metabolic alkalosis, findings that are similar to those seen in other disorders caused by mineralocorticoid excess.

Etiology

Liddle syndrome is a congenital disorder due to a single gene mutation. Patients inherit the disorder in an autosomal dominant with early penetrance. Diverse populations can be affected by the syndrome. Genetic studies showed that this syndrome occurs from a gain of function mutations in the epithelial sodium in the distal nephron. In 1995, Hansson et al. discovered the germline mutation in the SCNN1G gene as a cause of the Liddle syndrome.[2] Later, researchers showed that the epithelial sodium channels (ENaC) comprise of 3 homologous subunits alpha, beta, and gamma coded by SCNN1A, SCNN1B, and SCNN1G genes.[3] Mutation in beta or gamma subunits of the ENaC leads to an amplified activity of this channel, independent of aldosterone activity. While these are the well-described mutations associated with Liddle Syndrome, a systemic review by Tetti et al in 2018 discovered 31 different causative mutations from over 72 different families.[4]

Epidemiology

Researchers have not extensively studied the incidence of Liddle syndrome in the hypertensive population. Lin-Ping Wang et al. and Liu et al. studied the prevalence of Liddle syndrome. They found that among younger Chinese patients with unexplained resistant hypertension, the prevalence of Liddle Syndrome was 1.52% and 1.72%, respectively.[1][5] In the first study by Lin-Ping Wang et al., the only participants who were tested for the genetic mutation had to be hypokalemic. However, Liddle syndrome can be seen in patients with normal potassium levels. Therefore, if different researches studied the prevalence of Liddle syndrome in patients with normal potassium and resistant hypertension, it would likely be higher.[6] There is no gender or race predisposition.

Researchers of one study in US veterans concluded that there was approximately a 6% prevalence of symptomatic Liddle syndrome.[7]

Pathophysiology

ENaC is present in the distal colon, ducts of exocrine glands, lungs, and apical surface of the epithelial surface of the distal nephron.[8] Patients with Liddle syndrome have an abnormality in the ENaC in distal nephrons due to mutations in 1 of the 3 subunits. Due to this mutation, the degradation of the sodium channels has been impaired; therefore, the quantity of these channels on the apical surface of the distal nephron increases inappropriately.[9] The sodium feedback inhibition system is also impaired in patients with Liddle syndrome.[10] Typically, increased intracellular sodium in distal nephron cells inhibits apical epithelial sodium channels, but patients with Liddle syndrome become insensitive to sodium concentration. Increased sodium channels cause increased sodium reabsorption, which results in chronic volume retention with a hypertensive state and suppresses renin and aldosterone levels.[11] In this population, renal biopsy showed atrophy of juxtaglomerular cells due to chronically suppressed renin and aldosterone levels.

Additionally, the increased influx of sodium through the ENaC channel causes several different effects on other channels within the membrane. First, it causes increased activity of the Na+/K+ ATPase at the basolateral membrane resulting in increased potassium influx into the cell from the basolateral side. Second, the depolarization of the apical membrane of the cell secondary to sodium entry causes potassium secretion through apical potassium channels and thus potassium is excreted in the urine resulting in hypokalemia.[12]

History and Physical

Patients with Liddle syndrome can be symptomatic or asymptomatic. It usually presents with early-onset resistant hypertension between the ages of 11 to 31 years old due to sodium reabsorption at the level of the distal nephron. It may take years or even decades for healthcare providers to diagnose it. Providers can often misdiagnose the symptoms. Hypertension due to Liddle syndrome is sensitive to a salt-restricted diet[6], and it can present with headaches, dizziness, retinopathy, chronic kidney disease, left ventricular hypertrophy, and sudden death. Due to resistant hypertension, hypokalemia, and ventricular hypertrophy, a patient can develop lethal arrhythmias, potentially leading to sudden death.

Resistant hypertension can cause muscle weakness, polyuria, and polydipsia due to hypokalemia. Hypokalemia and metabolic alkalosis happen due to excessive potassium loss in the urine at the expense of sodium reabsorption.[13][14]

The incidence of hypertension and hypokalemia in patients with Liddle syndrome is about 92.4% and 71.8%, respectively.[15] A systemic review also found that 58.2% of patients with Liddle syndrome also present with hypoaldosteronism.[4] Healthcare providers can order genetic testing to diagnose patients with Liddle syndrome who do not have hypertension or hypokalemia. In these individuals, genetic testing is usually done because of significant family history.

Evaluation

A patient with Liddle syndrome often presents with secondary or resistant hypertension. Laboratory investigation may reveal hypokalemia and metabolic alkalosis.[15] Hyperaldosteronism can also present with the same features and biochemical abnormalities. Renin and aldosterone levels should be checked to differentiate between true hyperaldosteronism and pseudo-hyperaldosteronism (Liddle syndrome). In patients with Liddle syndrome, renin and aldosterone levels are low in contrast to patients with hyperaldosteronism in whom aldosterone levels are high. Due to low levels of aldosterone, spironolactone does not work for patients with Liddle syndrome.[16]

Once the patients are diagnosed with low-renin and low-aldosterone levels, they should be prescribed aldosterone for two months and stay under close observation by a healthcare provider. Some conditions like glucocorticoid resistance syndrome, apparent mineralocorticoid excess syndrome, and congenital adrenal hyperplasia all respond well to this drug. If the patient does not respond to aldosterone, then the clinician should suspect Liddle syndrome. 

Ultimately the final diagnosis is made by genetic analysis of the gene that regulates the ENaC.

Treatment / Management

As discussed above, low levels of aldosterone render spironolactone ineffective in Liddle syndrome patients. The drug of choice is amiloride and it works well because it directly inhibits ENaC. Amiloride is prescribed daily at a dose that ranges from 5 to 20 mg. Triamterene, another potassium-sparing diuretic similar to amiloride, can also be used to manage this syndrome. A sodium-restricted diet showed a cumulative effect with these drugs.[17] However, excessive sodium accumulation on the receptor makes it unavailable for the medication.[18] If renal function is normal, then the incidence of hyperkalemia is very rare. Avoidance of excessive potassium in the diet is suggested along with the use of potassium-sparing diuretics. Amiloride is safe in pregnancy.[19]

Differential Diagnosis

Low renin hypertension can be classified as follows:[16]

1. Low renin with low aldosterone 
2. Low renin with normal aldosterone 
3. Low renin with elevated aldosterone

Liddle syndrome is classified under low renin with low aldosterone. Others causes of hypertension which are classified under low renin with low aldosterone are as follows:

• Apparent mineralocorticoid excess
• An 11-beta-hydroxyl deficiency
• A 17-alpha-hydroxyl deficiency
• Gordons syndrome
• Mineralocorticoid receptor activation mutation
• Glucocorticoid resistance
• Ectopic ACTH
• Licorice use

Mineralocorticoid excess is an autosomal recessive syndrome due to 11beta-hydroxysteroid dehydrogenase type 2 enzyme deficiency. This enzyme converts cortisol (active) into cortisone (inactive) form and this inactive form is unable to bind to the mineralocorticoid receptor.[20]

Gordon syndrome is an autosomal dominant condition due to a gene mutation responsible for ion transport in the kidney which results in increased reabsorption of sodium and decreased excretion of potassium.[21]

Toxicity and Adverse Effect Management

Potassium-sparing diuretics, including triamterene and amiloride, can cause hyperkalemia if the glomerular filtration rate is not within the normal range. Other significant side effects of amiloride are aplastic anemia and neutropenia.

Triamterene can cause ventricular arrhythmias.

Prognosis

Patients with Liddle syndrome respond well to medical therapy such as potassium-sparing diuretics. There aren't any studies available on the long-term mortality of Liddle syndrome. Clinicians often undertreat and misdiagnose these patients. Further studies are needed to establish mortality in the population suffering from secondary hypertension due to this syndrome.

Complications

Complications of Liddle syndrome include hypokalemia, metabolic alkalosis, and resistant hypertension. The patients with resistant hypertension can develop end-organ damage that includes myocardial infarction, transient ischemic attack or cerebrovascular accident, pulmonary edema and ventricular hypertrophy.

Consultations

Consultations that could manage these patients better should include nephrology, pediatrics, and endocrinology, or cardiology that specializes in hypertension treatment.

Deterrence and Patient Education

Patients should be warned about hazards of resistant hypertension and educated about treatment compliance to minimize the risk of heart attack and stoke. Therefore, they should follow-up on regular basis. Moreover, they are advised to take high potassium diet.

Enhancing Healthcare Team Outcomes

Late diagnosis of the Liddle syndrome carries important adverse clinical outcomes; therefore, early diagnosis is essential. Coordination between pediatricians and pediatric nephrologists is essential. It is highly recommended that genetic counseling is offered to the other family members.

Clinical genetic testing is available through the Genetic Testing Registry (GTR), and the geneticists will sequence exon 13 of SCNN1B and SCNN1G.