Liddle Syndrome

LS is a genetic disorder and renal regulation of serum levels of sodium and potassium is disturbed from an early age. However, hypokalemia, metabolic alkalosis and hypertension may not cause any symptoms in pediatric or adolescent patients and unless there is a familial history of LS - which frequently is the case - affected individuals may not seek medical attention. Of note, de novo mutations of genes encoding for ENaC subunits have been reported and thus, lack of a familial history of LS does not rule out this syndrome [7] [8]. Here, either symptoms induced by electrolyte imbalances or dysregulation of blood pressure (e.g., fatigue and weakness) prompt patients to consult their physician or the former are detected during routine examinations.

None of the aforementioned symptoms should be considered an exclusion criterion; also, electrolyte imbalances and hypertension may be very mild. In such atypical cases, a family history of early-onset hypertension and severe cardiovascular events may be required to bring about the suspicion of LS.

It is not uncommon that a tentative diagnosis of LS is only made after hypertension cannot be reduced with standard medication.

The symptom triad of hypokalemia, metabolic alkalosis and hypertension in a child or adolescent is highly suspicious of LS. Consequently, patients (or their parents) should be queried for similar pathologies that may have been diagnosed in family members. Also, additional laboratory analyses of blood samples should be carried out. They may reveal hypernatremia and reduced levels of renin and aldosterone. The latter is of diagnostic importance since the main differential diagnoses are distinct forms of hyperaldosteronism. In primary aldosteronism or Conn syndrome, an increased production of adrenal aldosterone causes renin concentrations to diminish; in secondary aldosteronism, restriction of renal blood flow induces augmented renin and aldosterone levels. Furthermore, hypokalemia and metabolic alkalosis may be triggered by genetic disorders like Bartter syndrome and Gitelman syndrome, but hypertension is not characteristic for these diseases [9].

Urine samples may be analyzed and should confirm the aforementioned electrolyte imbalances, i.e., LS patients excrete a lot of potassium, but reduced quantities of sodium and aldosterone.

Definitive diagnosis of LS requires a genetic screen and identification of the underlying gene mutation. Both SCNN1B and SCNN1G should be examined and sequencing results should be revised for any of those gene defects known to induce LS. However, gene variants that have not yet been related to this disease should also be considered as possible sources of ENaC malfunction [8].

Diagnosis of LS should prompt the physical examination of the patient's relatives, of those family members pertaining to previous as well as to following generations [10].

Dietary adaptions, mainly salt restriction, and inhibition of mutated sodium channels by potassium-sparing diuretics are the mainstays of LS therapy. Although this therapeutic approach is symptomatic rather than causative, it counteracts the effects of increased sodium reabsorption at the level of the channelopathy and thus prevents consequent serum electrolyte imbalances and hypertension. Amiloride and triamterene are the drugs of choice and are administered at doses of up to 20 and 300 mg per day, respectively. Lower doses may suffice; the individual dose should be adjusted to the patient's response to treatment.

If patients follow dietary recommendations and comply with drug intake, serum electrolyte levels and blood pressure should normalize. Regular follow-ups including measurement of blood pressure, serum potassium and assessment of acid-base balance are strongly recommended.

Of note, spironolactone and eplerenone are not effective against LS-associated hypertension, since ENaC activity does not depend on aldosterone and patients do indeed present reduced serum aldosterone concentrations.

An early diagnosis and timely initiation of an adequate treatment largely contributes to avoid severe complications resulting from hypertension. Indeed, dietary adjustments and life-long administration of potassium sparing diuretics is generally sufficient to reestablish physiological serum electrolyte concentrations and blood pressure. Life expectancy of LS patients receiving the aforementioned treatment is normal or near to normal.

In contrast, untreated LS may be associated with severe cardiovascular sequelae and even sudden death before the age of 40 [3].

Constitutive activation of the epithelial sodium channel ENaC accounts for electrolyte imbalances and hypertension in LS patients.

Three distinct subunits - an α, β, γ subunit, respectively - form this heterotrimeric channel. Every subunit consists of intracellular NH2- and COOH-termini, two transmembrane helices and an extracellular loop. According to current knowledge, both β and γ subunits may negatively regulate channel activity by targeting the receptor for ubiquitination and induction of degradation [4]. This hypothesis is supported by the fact that mutations of those genes encoding for these subunits have been related with LS [5]; these genes are designated SCNN1B and SCNN1G. All gene defects associated with this pathology are gain-of-function mutations.

Gene mutations associated with LS are inherited with an autosomal dominant trait.

LS is a very rare disease, although familial prevalence may be high due to dominant inheritance. To date, gene defects associated with this syndrome have only been reported for a few dozen families and even less isolated cases.

As has been indicated above, LS is associated with mutations of the β or γ subunit of ENaC, an ion channel that is expressed in distinct parts of the renal tubule system. It is located on the apical surface of epithelial cells lining the respective tubules and allows for reabsorption of sodium ions along the electrochemical gradient. Lateral and basal sodium efflux and return to the circulation is mediated by Na+/K+-ATPase pumps expressed on the respective surfaces of the epithelial cell. Here, three sodium ions are exchanged for two potassium ions.

In LS, β or γ subunits of ENaC lose their affinity for Nedd4, an ubiquitin ligase that marks the ion channel for ubiquitination, endocytotic uptake and degradation. Presumably, this alteration of binding properties is provoked by mutations affecting conserved proline-rich regions in COOH-termini of the respective subunits. If Nedd4 binding cannot occur, ion channel internalization is not induced and the cell-surface half-life is significantly prolonged [6]. This results in a net-overexpression of ENaC.

Epithelial sodium channels constitute the rate-limiting step in sodium reabsorption. According to the aforementioned mechanisms, constitutive activity of excess amounts of ENaC leads to enhanced luminal absorption and basal efflux of sodium as well as elevated intracellular potassium concentrations. Moreover, lumen-negative electrical potentials caused by the aforementioned ion movements induces release of cations into the lumen of the renal tubule. Potassium and hydrogen ions account for the majority of these cations and thus, LS patients present with hypokalemia and metabolic alkalosis. Hypernatremia may be observed in affected individuals. Because elevated sodium concentrations provoke an increased osmotic pressure in extracellular fluids, passive reabsorption of water augments and volume-mediated hypertension results from those pathophysiological events described above. Because hyponatremia and hypovolemia are the main stimulants for secretion of renin and aldosterone, plasma levels of these hormones are typically diminished in LS patients.

ENaC can be blocked with distinct compounds, e.g., with amiloride or triamterene. Thus, such potassium sparing diuretics are the treatment of choice for LS patients.

Affected families may benefit from genetic counseling, particularly because inheritance of one mutated gene suffices to induce LS.

Early diagnosis assures initiation of treatment in a timely manner and helps to prevent cardiovascular complications. Furthermore, patients diagnosed with LS can increase the efficacy of their medication by keeping a diet low in sodium.

Liddle syndrome (LS) is a rare genetic disorder that is inherited with an autosomal dominant trait. To date, several mutations of genes encoding for subunits of the amiloride-sensitive epithelial sodium channel ENaC have been related to LS. This ion channel is mainly expressed in renal collecting tubules, but it can also be found in more proximal parts of the tubule system as well as in the respiratory and gastrointestinal tract [1]. Thus, LS pertains to the large group of channelopathies.

The disease has first been described by Grant W. Liddle and colleagues who referred to it as "ectopic ACTH syndrome" [2]. And indeed, increased serum levels of ACTH that may be seen in patients suffering from primary hyperaldosteronism or Conn syndrome, for instance, cause symptoms similar to those observed in LS: decreased serum concentrations of renin and aldosterone, hypokalemia and metabolic alkalosis as well as hypertension. Therefore, the term pseudohyperaldosteronism is sometimes used as an alternative designation for LS, although the former comprises additional etiologic factors and pathogenetic mechanisms.

LS patients present with the above mentioned symptoms at an early age, typically in childhood or adolescence [3]. Because young LS patients may feel just fine, the disease may also remain undetected until adulthood if pathological alterations of blood pressure or blood biochemistry are not encountered during routine screens. The latter are thus indicated in patients with a family history of early-onset hypertension and possibly sudden death in young adulthood. If left untreated, such severe cardiovascular complications are very common.

Therapy consists in administration of potassium-sparing diuretics like amiloride or triamterene. These drugs block ENaC and thus counteract the effects of gain-of-function mutations that cause LS. Both electrolyte imbalances and hypertension can be corrected. Life expectancy of adequately treated LS patients is near normal.

Liddle syndrome (LS) is a rare genetic disorder associated with early-onset hypertension, electrolyte imbalances and possibly severe cardiovascular complications if not adequately treated.

Causes

LS patients suffer from malfunction of an ion channel expressed in their kidneys. In simple terms, the kidneys' function is to produce primary urine (in great amounts, since this is merely filtrated blood) and to reabsorb the vast majority of electrolytes and water before passing it on to ureters and urinary bladder.

Many different proteins are involved in this process, one of them being the sodium channel ENaC that is expressed in epithelial cells lining the distal parts of the renal tubule system. In LS, gene defects lead to an abnormally high activity of ENaC. Here, epithelial cells reabsorb great amounts of sodium through ENaC, transport those ions through the cell and exchange them on their basal side for potassium. However, the exchange rate slightly favors sodium, i.e., more sodium ends up in the patient's circulation than potassium in their urine. Water passively diffuses to the site of higher ion concentrations, i.e., to the blood. Additionally, the aforedescribed ion movements are associated with loss of hydrogen ions into the lumen of renal tubules.

Symptoms

According to those mechanisms mentioned before, LS patients present with hypertension (due to increased renal absorption of water and subsequent increment of fluid volume), hypokalemia (loss of potassium), metabolic alkalosis (loss of hydrogen) and possibly hypernatremia (enhanced reabsorption of sodium).

Because LS is a genetic disorder, those conditions manifest at an early age, most frequently in adolescence. They are commonly detected during routine screens. Also, a familial history of early-onset hypertension may (and should) prompt parents to have their child checked.

Diagnosis

Even in the absence of a familial history of LS, the symptom triad of hypokalemia, metabolic alkalosis and hypertension in a child or adolescent is highly suspicious of LS. Additional laboratory analyses of blood samples will reveal low renin and aldosterone levels and thus support this tentative diagnose. Definitive diagnosis does require identification of the underlying gene mutation, though.

Diagnosis of LS should lead to physical examination of the patient's relatives, of those family members pertaining to previous as well as to following generations.

Treatment

The overactive ion channel ENaC can be blocked by administration of potassium-sparing diuretics like amiloride or triamterene. This medication has to be used throughout life and needs to be combined with a low-sodium diet. Following these recommendations, hypertension and electrolyte imbalances can be corrected. Thus, adequately treated LS patients have a normal life expectancy.

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