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Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1

Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1
Literature review current through: Sep 2023.
This topic last updated: Jan 03, 2023.

INTRODUCTION — Liddle syndrome and autosomal recessive pseudohypoaldosteronism type 1 are rare genetic disorders associated with abnormalities in the function of the collecting tubule sodium channel, also called the epithelial sodium channel (ENaC) or the amiloride-sensitive sodium channel:

ENaC function is increased in Liddle syndrome, leading to manifestations similar to those caused by mineralocorticoid excess, such as hypertension and, in some patients, hypokalemia and metabolic alkalosis. Presentation at a young age, which occurs in most patients, suggests the possibility of a genetic disorder rather than an adrenal adenoma. In addition, plasma and urinary aldosterone levels are reduced, not increased as in primary aldosteronism.

ENaC function is decreased in autosomal recessive pseudohypoaldosteronism type 1, resulting in aldosterone resistance. Affected patients present in infancy with sodium wasting, hypovolemia, and hyperkalemia. These findings are similar to those in other forms of hypoaldosteronism in children, except that plasma aldosterone levels are elevated, not reduced.

The clinical presentation, genetics, and management of Liddle syndrome and pseudohypoaldosteronism will be reviewed here. Other causes of hypertension and hypokalemia, and of hypoaldosteronism are reviewed separately:

(See "Diagnosis of primary aldosteronism".)

(See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

COLLECTING TUBULE SODIUM CHANNEL — The cortical collecting tubule contains two cell types with different functions: principal cells (approximately 65 percent) and intercalated cells:

The principal cells have sodium and potassium channels in the luminal (apical) membrane and, as in all sodium reabsorbing cells, Na-K-ATPase pumps in the basolateral membrane (figure 1) [1-3]. Aldosterone-sensitive sodium channels, also called epithelial sodium channels (ENaCs), are present in the colon and sweat glands as well as the collecting tubule.

The intercalated cells are primarily involved in hydrogen, bicarbonate, and potassium handling (figure 2). They do not reabsorb sodium, since they have a lower level of Na-K-ATPase activity and few, if any, apical membrane sodium channels [3,4].

The principal cells contribute to net sodium reabsorption and are the primary site of potassium secretion. The entry of sodium into these cells primarily occurs down a concentration gradient through the luminal sodium channels (figure 1) [1-3].

Aldosterone plays a central role in these processes, mainly by increasing the number of open luminal sodium channels [5,6]. As an example, going from a high- to a low-sodium diet (which is associated with enhanced aldosterone release and increased sodium reabsorption in the cortical collecting tubule) can increase the number of open sodium channels per cell from less than 100 to approximately 3000 [2]. There is also a later increase in Na-K-ATPase activity and open luminal potassium channels.

Although increased intracellular sodium concentrations downregulate the activity of the luminal sodium channels, increased export of cell sodium via increased Na-K-ATPase activity assures that increased numbers of sodium channels remain open [7].

Amiloride blocks the collecting tubule sodium channels, leading to natriuresis and potassium retention [1]. Data derived from cloned sodium channel genes indicate that the site of amiloride binding is distinct from the channel pore [1,8]. Within the kidney, the sodium channel is primarily expressed in the late distal tubule and cortical and outer medullary portions of the collecting tubule [9].

LIDDLE SYNDROME

Clinical presentation — Liddle syndrome is a rare autosomal dominant condition in which there is a primary increase in collecting tubule sodium reabsorption and, in most cases, potassium secretion [10-13]. Affected patients typically present with hypertension, hypokalemia, and metabolic alkalosis, findings that are similar to those seen in other disorders caused by mineralocorticoid excess [14]. Most patients present at a young age, but some are not detected until well into adulthood [15].

However, some patients with Liddle syndrome are not hypokalemic at presentation [10,16]. In one kindred, for example, the average serum potassium of 18 affected family members was 3.6 mEq/L [10]. In the absence of hypokalemia, the positive family history of early onset hypertension and, in some members, hypokalemia would be the major findings suggesting possible Liddle syndrome. Absence of hypokalemia has also been demonstrated in the majority of patients with primary aldosteronism. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'Hypokalemia: An inconsistent finding'.)

Pathogenesis — Correction of the hypokalemia and hypertension in one patient with Liddle syndrome by kidney transplantation suggested that enhanced activity of the luminal membrane sodium channels, not increased secretion of a non-aldosterone mineralocorticoid, was the underlying defect [10].

This hypothesis was confirmed by the demonstration that the genetic abnormality in Liddle syndrome involves gain-of-function pathogenic variants in SCNN1A, SCNN1B, and SCNN1G, which encode the alpha, beta, and gamma subunits of the epithelial sodium channel (ENaC), respectively [12,17-20]. Deletions or substitutions in a short proline-rich segment of the intracytoplasmic C-terminus cause an inability of these subunits to bind with an intracellular ubiquitin protein ligase (Nedd4) that normally removes the luminal sodium channel from the cell surface [21,22]. Liddle syndrome is classified into three types: type 1 (beta subunit, OMIM #177200), type 2 (gamma subunit, OMIM #618114), and type 3 (alpha subunit, OMIM #618126). In one systematic review, 31 different causative pathogenic variants in 72 families from four continents were identified [14].

Failure to remove sodium channels results in an inability to reduce their number in response to low levels of aldosterone that result from the volume expansion-mediated suppression of renin secretion. These pathogenic variants result in a "gain-of-function" that mimics the effects of hyperaldosteronism [16,17,19,23-26].

Expression of these abnormal genes in the Xenopus oocyte is associated with a marked increase in sodium transport and loss of inhibition of channel activity by elevated intracellular sodium concentrations [7,24,26,27]. On the other hand, the ability to respond to aldosterone is maintained [28].

Diagnosis — Patients with Liddle syndrome classically present with the triad of hypertension, hypokalemia, and metabolic alkalosis at a relatively young age. The consistent findings among such individuals are low plasma renin activity and, in contrast to primary aldosteronism, reductions in both the plasma aldosterone concentration and urinary excretion of aldosterone [10].

The differential diagnosis of this constellation of abnormalities includes some forms of congenital adrenal hyperplasia, familial cortisol resistance, the syndrome of apparent mineralocorticoid excess, licorice ingestion, Cushing's syndrome, and a DOC-producing adrenal tumor. (See appropriate topic reviews.)

A positive family history of hypertension at a young age with some members being hypokalemic should lead to the suspicion of a genetic disorder. However, sporadic cases of Liddle syndrome have been described [29]. As a result, the absence of a family history does not preclude the diagnosis.

Genetic testing of the genes encoding the three subunits of ENaC, SCNN1A, SCNN1B, and SCNN1G, provides definitive confirmation of Liddle syndrome [12,14,30]. Nearly all pathogenic variants are nonsense, frameshift, or missense mutations that delete or alter the proline-rich PY motif of a subunit.

Therapy — Therapy in Liddle syndrome consists of prescribing amiloride or triamterene, potassium-sparing diuretics that directly block the collecting tubule sodium channels and can correct both the hypertension and, if present, the hypokalemia [23,26,31-34]. The mineralocorticoid antagonist spironolactone is ineffective since the increase in sodium channel activity in Liddle syndrome is not mediated by aldosterone [10,34,35].

PSEUDOHYPOALDOSTERONISM TYPE 1 — Pseudohypoaldosteronism type 1 is a rare hereditary disorder characterized by generalized resistance to the actions of aldosterone. It typically presents in infancy with sodium wasting, hypovolemia, and hyperkalemia. These features are similar to other forms of hypoaldosteronism in children except that plasma aldosterone levels are markedly elevated. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Two different modes of inheritance of pseudohypoaldosteronism type 1 have been described with somewhat different clinical features [36-39]:

Autosomal recessive pseudohypoaldosteronism type 1 (MIM #264350), involving the epithelial sodium channel (ENaC), in which the defect is permanent and affects all aldosterone target organs (including the kidney, colon, and sweat glands).

Autosomal dominant or sporadic pseudohypoaldosteronism type 1 (MIM #177735), which is due to heterozygous pathogenic variants in the NR3C2 gene coding for the mineralocorticoid receptor, in which the defect is limited to the kidney. This renal variant has an estimated prevalence of 1 in 80,000 newborns [39], and is associated with milder salt wasting than autosomal recessive disease, and often improves with age. This disorder and pseudohypoaldosteronism type 2 (also called Gordon's syndrome), which also does not involve the sodium channel, are discussed elsewhere. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Pseudohypoaldosteronism type 2 (Gordon's syndrome)' and "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Autosomal recessive disease — The genetic defect in the autosomal recessive form of pseudohypoaldosteronism type 1 involves the alpha, beta, or gamma subunits (SCNN1A, SCNN1B, SCNN1G) of the sodium channel, resulting in resistance to the stimulatory effect of aldosterone [38,40]:

The majority of reported pathogenic variants are in the alpha subunit, most commonly frameshift or premature stop codon defects. Studies in the Xenopus oocyte expression system suggest that, although these abnormalities frequently result in marked reductions in channel activity, even a mild defect can cause salt wasting, hyponatremia, hyperkalemia, acidosis, and volume depletion.

Beta and gamma pathogenic variants, due to frameshift and premature stop codon defects, are less common. Given the paucity of data relating to these abnormalities, an accurate correlation between genotype and clinical phenotype has not been performed.

In addition to the typically severe fluid and electrolyte disturbances [41], sodium channel activity is also impaired in the lung, often leading to frequent lower respiratory tract infections and excess airway liquid [38,42,43]. This manifestation plus associated increases in sweat sodium and chloride concentrations results in a clinical picture that can mimic cystic fibrosis, including recurrent episodes of chest congestion, coughing, and wheezing [43]. Two features different from cystic fibrosis are a reduction in respiratory symptoms after age five years and the absence of an increase in lung infections due to Pseudomonas aeruginosa [43]. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

"Knockout" mice lacking the alpha subunit of the ENaC die in the neonatal period because of defective lung liquid clearance, while mice without either the beta or gamma subunit die of hyperkalemia but not defective lungs [38,44,45]. These findings suggest that only the alpha subunit is required for an air-filled lung, while all three subunits are required for an adequate response to aldosterone.

Treatment — Initial therapy of autosomal recessive pseudohypoaldosteronism type 1 consists of a high-salt diet, which prevents volume depletion and, by enhancing sodium delivery to the potassium secretory site in the collecting tubules, increases potassium excretion and lowers the plasma potassium concentration. High-dose fludrocortisone (1 to 2 mg/day [versus 0.05 to 0.1 mg/day in adrenal insufficiency]) or carbenoxolone can be added if a high-salt intake is ineffective or not well tolerated [46].

The efficacy of carbenoxolone in autosomal recessive pseudohypoaldosteronism type 1 is presumably related to its antagonism of cortisol metabolism, thereby allowing cortisol (which circulates in much higher concentrations than aldosterone) to activate mineralocorticoid receptors. Indirect proof for this mechanism, which is the same as that seen with the active ingredient in licorice, was shown by the response to the administration of dexamethasone, a potent glucocorticoid with minimal mineralocorticoid activity. Dexamethasone abolished the effect of carbenoxolone, presumably by diminishing endogenous cortisol secretion [46]. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

Liddle syndrome and autosomal recessive pseudohypoaldosteronism type 1 are rare genetic disorders associated with abnormalities in the function of the collecting tubule sodium channel: increased function in Liddle syndrome; and decreased function and resistance to aldosterone in pseudohypoaldosteronism. (See 'Introduction' above.)

Patients with Liddle syndrome typically present at a relatively young age with hypertension and, in most cases, hypokalemia and metabolic alkalosis. These findings are similar to those caused by primary aldosteronism, except that both the plasma aldosterone concentration and urinary excretion of aldosterone are reduced (see 'Liddle syndrome' above):

A positive family history of hypertension at a young age with some members being hypokalemic should lead to the suspicion of a genetic disorder. The diagnosis of Liddle syndrome is established by genetic testing. (See 'Diagnosis' above.)

We recommend treatment with amiloride or triamterene (Grade 1B). These potassium-sparing diuretics directly treat the primary defect in this disorder by blocking the collecting tubule sodium channels. The mineralocorticoid antagonist spironolactone is ineffective since the increase in sodium channel activity is not mediated by aldosterone. (See 'Therapy' above.)

Patients with autosomal recessive pseudohypoaldosteronism type 1 typically present in infancy with sodium wasting, hypovolemia, and hyperkalemia. These features are similar to other forms of hypoaldosteronism in children, except that both the plasma aldosterone concentration and urinary excretion of aldosterone are markedly increased. (See 'Pseudohypoaldosteronism type 1' above.)

Sodium channel activity is also impaired in the lung and sweat glands, often leading to frequent lower respiratory tract infections and increased sweat sodium and chloride concentrations that mimic those in cystic fibrosis (see 'Autosomal recessive disease' above). In patients with autosomal recessive pseudohypoaldosteronism type 1:

We recommend treatment with a high-salt diet (Grade 1C), which prevents volume depletion and, by enhancing sodium delivery to the potassium secretory site in the collecting tubules, increases potassium excretion and lowers the plasma potassium concentration. (See 'Treatment' above.)

If a high-salt diet is not sufficiently effective or not well tolerated, we recommend high-dose fludrocortisone (1 to 2 mg/day [versus 0.05 to 0.1 mg/day in adrenal insufficiency]) or carbenoxolone (Grade 1C). (See 'Treatment' above.)

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