|Rev Esp Endocrinol Pediatr 2010;1 Suppl(1):33-39 | Doi. 10.3266/RevEspEndocrinologPediatr.pre2010.Nov.10|
|Enviado a Revisar: 6 Nov. 2010 | Accepted: 6 Nov. 2010 | En Publicación: 8 Nov. 2010|
|Felix G. Riepe|
|Division of Paediatric Endocrinology, Department of Paediatrics. Christian Albrechts University, University Hospital Schleswig-Holstein. 24105 Kiel (Germany)|
|Correspondencia para Felix G. Riepe, Division of Paediatric Endocrinology, Department of Paediatrics, Christian Albrechts University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany|
E-mail: : firstname.lastname@example.org
Fluid balance, sodium and potassium homeostasis and blood pressure are regulated through the effect of aldosterone on polarized epithelial cells. Therefore, disturbances of sodium homeostasis can be caused either by insufficient biosynthesis of aldosterone in the adrenal gland or by disturbed aldosterone signalling at the polarized epithelial cells. Aldosterone biosynthesis is disturbed in several form of congenital adrenal hyperplasia. These forms of steroidogenic defects are not discussed here. A small group of patients have an isolated form of aldosterone deficiency, a rare disease first described in the early 1960s causing hyponatremia (1, 2).
Aldosterone is synthetized in the zona glomerulosa of the adrenal cortex by the action of four enzymes (Fig. 1). Cholesterol side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase type 2, 21-hydroxylase and aldosterone synthase. Aldosterone synthase is a cytochrome P450 enzyme which is located in the mitochondria. Aldosterone is a bi-functional enzyme converting 11-deoxycor ticosterone in corticosterone and corticosterone via 18-OH-corticosterone in aldosterone. Aldosterone synthase shows high homology with 11ß-hydroxylase at the protein level(3). Aldosterone synthase needs the redox partner adrenodoxin as well as adrenodoxin reductase as co-factors for its steroidogenic activity.
The MR acts as ligand-dependent transcription factor. MR is coded by the NR3C2 gene. The NR3C2 gene is localized on chromosome 4q31.1(5). The mature MR protein consists of 984 amino acids and can be functionally subdivided in three domains, the N-terminal domain, the DNA-binding domain and the C-terminal ligand-binding domain (LBD). The N-terminal domain contains two distinct activation function (AF) domains, referred to as AF1a and AF1b(6). In addition an inhibitory sequence was characterized. These regions are responsible for the recruitment of co-activators and co-repressors as well as a ligand-dependent interaction with the LBD(7).
The epithelial sodium channel (ENaC) constitutes the rate limiting step in sodium re-absorption in the apical membrane of epithelia(10). It is characterized by a high selectivity for sodium over potassium and a high affinity for the potassium-sparing diuretics amiloride and triamterene. ENaC is a heteromultimeric protein consisting of three subunits, termed α, β and γ ENaC(11). The α, β and γ ENaC subunits are coded by the SCNN1A gene on chromosome 12p13, and the SCNN1B and the SCNN1G genes on chromosome 16p12. As deduced from the crystal structure of the ENaC orthologue ASIC1 channel, ENaC is likely a trimer consisting of three homologous subunits α, β and γ(12). However, good evidence alternatively supports the presence of two α ENaC subunits in the functional channel(13). All three subunits share about 35% homology at the amino acid level and adopt the same topology, with two transmembrane α helices, a short intracellular amino- and carboxyterminal end and a large extracellular loop corresponding to about two thirds of the protein.
Filtrated sodium is reabsorbed from the glomerular filtrate and potassium is secreted through a tight epithelium in the kidney (Fig. 2). Sodium crosses the apical membrane and enters the epithelial cell through the ion selective ENaC. Sodium is actively exchanged against potassium at the basolateral membrane mediated by the Na, K-ATPase(14). This generates a lumen-negative voltage that drives potassium facilitated through a selective potassium channel (ROMK) into the lumen. Aldosterone binds to MR after passively crossing the epithelial membrane.
Aldosterone synthase deficiency is an autosomal recessively inherited disorder. Due to deficient adrenal zona glomerulosa aldosterone synthase activity, 11-deoxycorticosterone is not efficiently converted to aldosterone. Insufficient aldosterone secretion leads to decreased sodium reabsorption from and potassium secretion into the urine. All affected children present with frequent vomiting, failure to thrive, and severe, life-threatening salt-loss in the first weeks of life. The clinical severity of the disease decreases with age(20). Adolescents and adults may show only the abnormal steroid pattern which persists throughout life(21). The typical steroid profile in patients with aldosterone synthase deficiency consists of low to undetectable aldosterone plasma levels and elevated mineralocorticoid precursor levels. Renin secretion is increased because of poor feedback control. Patients can be categorized through the level of 18-hydroxycorticosterone (18- OH-B) into a type I and a type II deficiency. In type I deficiency 18-OH-B is decreased, whereas it is markedly elevated in type II. Treatment of aldosterone synthase deficiency consists of the substitution of 9α-fluorocortisol, a steroid with high mineralocorticoid activity. Continued mineralocorticoid replacement after childhood is not always necessary(20).
PHA is a rare heterogenous syndrome of mineralocorticoid resistance leading to insufficient potassium and hydrogen secretion. The common clinical features are hyperkalemia, metabolic acidosis and elevated plasma aldosterone levels. PHA has been classified into three distinct clinical forms (Table 1) (24). This classification includes primarily salt losing syndromes, such as PHA type 1 and PHA type 3 and the potassium retaining PHA type 2. All forms are caused by a mineralocorticoid resistance due to disturbances in the mineralocorticoid mediated signal transduction. The clinical features and the underlying pathophysiology of PHA type 1 are described in detail in the following. PHA type 2 is characterized by hyperkalemia and hypertension. It has been described by Gordon et al. as heterogenous syndrome with highly variable plasma aldosterone concentrations, suppressed plasma renin activity, various degrees of hyperchloremia and metabolic acidosis(25). Renal and adrenal functions are normal.
PHA1 is characterized by neonatal salt loss resistant to mineralocorticoid treatment(32). Laboratory findings are hyponatremia, hyperkalemia and metabolic acidosis. Plasma renin and aldosterone concentrations are highly elevated, reflecting a peripheral resistance of the kidney and other tissues to mineralocorticoids. The medical treatment of PHA1 consists of sodium supplementation. In addition ion exchange resins may be necessary in order to lower elevated potassium levels. Two forms of PHA1 can be distinguished at the clinical and genetic level (33). The severity of the disease and the phenotype of the two genetically different PHA1 forms vary noticeable.
Isolated renal resistance to aldosterone, leading to renal salt loss, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive, elevated plasma renin and aldosterone concentrations are the characteristics of autosomal dominant PHA1 (adPHA1) (33, 34). The leading clinical sign is insufficient weight gain due to chronic dehydration. Hyperkalemia is generally mild and metabolic acidosis is not always detectable. The patients mainly manifest in early infancy. Medical treatment consists of sodium supplementation what is usually sufficient to lower the elevated potassium levels. Sodium supplementation becomes generally unnecessary by 1 to 3 years of age(32, 35), what is explained by the maturation of the renal salt conservation abilities by the replacement of distal sodium reabsorption through proximal parts of the tubulus. Overall adPHA1 is the milder PHA1 form as the salt-loss is strictly restricted to the kidney. The clinical spectrum ranges from healthy unaffected patients, patients without electrolyte disturbances but elevated plasma renin and aldosterone levels to patients with clinically manifest renal salt loss(36). Elevated aldosterone levels are the only biochemical marker of adPHA1 in adulthood(37). However, reports from several families suggest that adult carriers of causative mutations might also have normal levels of aldosterone(38).
The systemic arPHA1 follows an autosomal recessive trait of inheritance. The clinical manifestation is most often within the neonatal period with severe dehydration and hyponatremia due to systemic salt loss, including kidneys, colon and sweat and salivary glands. Elevated sodium concentration in sweat and absent nasal or rectal transepithelial voltage differences can be used as diagnostic tools.
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