Mineralocorticoid Deficiency
Mineralocorticoid Hormone Action
Aldosterone is the principal mineralocorticoid secreted from the outer zona glomerulosa of the adrenal cortex. The daily production rate is approximately 100 to 150 µg/day, compared to the production of cortisol, the principal glucocorticoid, which is 10 to 15 mg/day. Aldosterone biosynthesis is facilitated through the functional zonation of the adrenal cortex, that is, the zonal-specific expression of key steroidogenic enzymes, principally the expression of the product of the CYP11B2 gene, aldosterone synthase, in the zona glomerulosa. Conversely, the absence of CYP17 in the zona glomerulosa explains why glucocorticoids are not synthesized in this layer. Synthesis is regulated by three principal secretagogues, adrenocorticotropic hormone (ACTH), potassium, and angiotensin II, but of these, angiotensin II plays a dominant role, principally by stimulating aldosterone synthase expression and activity via second messenger pathways that include increased intracellular calcium and induction of calcium/calmodulin-dependent protein kinase.1
Mineralocorticoid Receptor
The mineralocorticoid receptor (MR) is a ligand-activated transcription factor of the steroid/thyroid/retinoid superfamily of intracellular receptors. The MR gene contains 10 exons, spans over 400 kb, encodes a protein of 984 amino acids and is located on chromosome 4q31.1-4q31.2.2 Exon 2 contains the translation start site. Alternative transcription of two 5′-untranslated exons (exons 1α and 1β) produces two mRNA isoforms, MRα and MRβ, which are coexpressed in aldosterone target tissues. The MR is expressed mainly in epithelial cells of the distal tubules and collecting duct of the kidney, the distal colon, and the ducts of salivary and sweat glands, as well as in nonepithelial tissues such as the heart, the vasculature, and certain regions of the central nervous system, particularly the hippocampus. The MR is composed of an amino-terminal region that harbors a ligand-independent transactivation function, a centrally located, highly conserved DNA-binding domain, and a complex C-terminal domain responsible for ligand binding and ligand-dependent transactivation. In the absence of ligand, the MR is located mainly in the cytoplasm, associated with chaperone proteins. Upon hormone binding, the MR dissociates from chaperone proteins such as heat shock protein hsp90, hsp70, p23, and p48 proteins, undergoes nuclear translocation in response to localization signals (NLS0, NSL1, and NSL2) and interacts with coactivators (e.g., steroid receptor coactivator 1 [SRC-1]) or corepressors (e.g., SMRT and PIAS1) at the mineralocorticoid response elements. Several MR target genes have been identified so far, such as the amiloride-sensitive epithelial sodium channel in the apical membrane, basolateral Na+,K+-ATPase pump, serum and glucocorticoid–regulated kinase 1 (sgk1), K-ras2-gene, elongation factor ELL, ERK cascade inhibitor GILZ (glucocorticoid-induced leucine zipper protein), plasminogen activator inhibitor 1 (PAI-1), endothelin 1 (ET-1), ubiquitin-specific protease 2-45 (Usp2-45), and channel-inducing factor (CHIF).3,4 Several down-regulated genes have also been identified.
One paradox was that the cloned MR had a similar affinity for aldosterone and cortisol. At a pre-receptor level, the autocrine expression of the type 2 isozyme of 11β-hydroxysteroid dehydrogenase ensures the inactivation of the higher concentrations of cortisol, thereby permitting aldosterone to bind to the MR in vivo.5,6
The classical action of aldosterone is to stimulate epithelial sodium transport. This involves early and late pathways, both of which are mediated via the MR. The principal effector pathway in mediating this sodium transport is the epithelial sodium channel (ENaC), a highly selective sodium channel found at the apical surface of tight epithelia of salt-reabsorbing tissues, including the distal nephron, the distal colon, salivary and sweat glands, lung, and taste buds.7 It plays a critical role in the control of sodium balance, extracellular fluid volume, and blood pressure, since the ENaC-mediated entry of sodium into the cell in these epithelial tissues represents the rate-limiting step for the movement of sodium from the mucosal side to the serosal side. These channels allow the transport of sodium into the cell by diffusion without coupling to the flow of other solutes and without the direct input of metabolic energy. ENaCs are often referred to as “amiloride-sensitive” because of their high sensitivity to the potassium-sparing diuretic amiloride and its analogues. These channels are stimulated by aldosterone and inhibited by amiloride.7
ENaCs are composed of three subunits: α, β, and γ. These three subunits are 35% homologous at the amino acid level and are conserved throughout evolution.8 Moreover, the three subunits are similar in structure and share the following characteristics: short intracellular proline-rich C-termini, two transmembrane-spanning domains, and a large extracellular loop.9 The α subunit has been localized to chromosome 12p13.1-pter, and the β and γ subunits have been localized to 16p12.2-13.11.10 For optimal sodium conductance, the stoichiometry of the channel is 2α : 1β : 1γ subunits. It is not clear yet how such a two-α subunit stoichiometry of ENaC can be reconciled with the trimeric nature of the channel as suggested by the ASIC crystal structure.11 Mutations in the C-terminal domains of the β and γ subunits of ENaC explain an autosomal-dominant form of low renin hypertension, Liddle’s syndrome.12–14 Here the ENaC is constitutively active, subsequently shown to occur because of loss of the C-terminal proline-rich sites that target the ENaC subunits for degradation through a ubiquitin ligase known as Nedd-4.15
The late-response actions of aldosterone upon sodium conductance (6 to 24 hours) involve direct induction of transcription of the α subunit. However, the early effects (<6 hours), although still operating through the MR, are not mediated directly through ENaC gene transcription. Instead, two separate groups16,17 identified the rapid induction of sgk-1, which directly phosphorylates the Nedd4 protein that blocks the interaction with the C-terminal domains of the ENaC subunits and hence ubiquitination and degradation of the ENaC channels. This increases surface expression of ENaC and sodium conductance.
In summary, therefore, recent years have seen considerable advances in our understanding of the molecular mechanisms underpinning aldosterone-regulated epithelial sodium transport. Defining normality has uncovered the basis for clinical disorders causing mineralocorticoid deficiency (Fig. 13-1).
FIGURE 13-1 Genetic causes of mineralocorticoid deficiency. The schematic cell represents a renal cell from the distal tubule/collecting duct segment, which expresses the mineralocorticoid receptor (MR), is aldosterone (A) sensitive, and expresses 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), serum and glucocorticoid–regulated kinase 1 (sgk1), and the epithelial sodium channel (ENaC). CHIF, Channel-inducing factor; ERK, extracellular signal-regulated kinase; GILZ, glucocorticoid-induced leucine zipper protein.
Failure of Aldosterone Biosynthesis: Hypoaldosteronism
Combined Glucocorticoid and Mineralocorticoid Deficiencies: Adrenal Failure
The causes of primary adrenal failure and its clinical features are described elsewhere. Aldosterone deficiency occurs in congenital adrenal hyperplasia due to 21-hydroxylase and 3β-hydroxysteroid dehydrogenase deficiencies. Patients with 11β-hydroxylase or 17α-hydroxylase deficiency also have hypoaldosteronism but have mineralocorticoid excess because of excess secretion of the mineralocorticoid deoxycorticosterone (DOC) proximal to the enzymatic block. At presentation, most patients with primary autoimmune adrenal failure have evidence of both glucocorticoid and mineralocorticoid deficiency. However, as adrenal failure evolves, selective aldosterone deficiency can occur in the presence of preserved zona fasciculata function. While glucocorticoid responsiveness to ACTH, metyrapone, or insulin-induced hypoglycemia may be normal, plasma renin activity (PRA) is elevated, and plasma aldosterone levels are low or undetectable. This is accompanied by mild metabolic acidosis and, occasionally, hyponatremia. With time, progression to “panadrenal” insufficiency can occur. A year or more can separate the onset of the mineralocorticoid and glucocorticoid deficiencies.18–20
Primary adrenal hypoplasia often affects the zona glomerulosa, causing mineralocorticoid insufficiency and salt loss, as well as impaired glucocorticoid synthesis and release. Mutations in DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenita–critical region on the X chromosome gene 1) cause X-linked adrenal hypoplasia congenita (AHC).21 The patients are characterized by primary adrenal failure (combined glucocorticoid and mineralocorticoid deficiency), testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Mild DAX1 mutations, such as the missense mutation (W105C) in the amino-terminal region of the DAX1 gene, are associated with more variable clinical phenotypes and may be a cause of isolated mineralocorticoid deficiency.22 Aldosterone deficiency also occurs in 10% to 15% of individuals who have ACTH resistance as part of the triple A (Allgrove) syndrome (AAAS, ALADIN), with isolated adrenal failure, alacrima, or upper-gastrointestinal abnormalities such as achalasia of the esophagus.23 Severe loss-of-function mutations in the MC2R (ACTH-receptor) gene, which is expressed also in the zona glomerulosa, may be found in a significant proportion of children with primary adrenal insufficiency, e.g., familial glucocorticoid deficiency type 1 (FGD1) and who have been diagnosed as having salt-losing forms of adrenal hypoplasia. These findings may suggest a supportive role for ACTH in mineralocorticoid synthesis and release, especially in times of stress (e.g., infection), salt-restriction, heat, or relative mineralocorticoid insensitivity.24 Mineralocorticoid requirements often decrease with age, as evidenced by the fall in normal mineralocorticoid secretion rates after infancy.
Isolated Hypoaldosteronism
Primary Isolated Hypoaldosteronism
Prior to the characterization of the CYP11B2 gene, which is located on chromosome 8q24,25,26 the disease was termed corticosterone methyl oxidase type I (CMO I) deficiency and corticosterone methyl oxidase type II (CMO II) deficiency. Subsequently, both variants were shown to be secondary to mutations in aldosterone synthase and are now termed type 1 and type 2 aldosterone synthase deficiency. Aldosterone synthase catalyses the three terminal steps of aldosterone biosynthesis, 11β-hydroxylation of deoxycorticosterone to corticosterone, 18-hydroxylation to 18-hydroxycorticosterone, and 18-oxidation to aldosterone. Patients with type 1 aldosterone synthase deficiency have low to normal levels of 18-hydroxycorticosterone but undetectable levels of aldosterone (or urinary tetrahydroaldosterone), whereas patients with the type 2 variant have high levels of 18-hydroxycorticosterone and only subnormal or even normal levels of aldosterone. This suggests blockade of only the terminal 18-oxidation step, with some residual aldosterone synthase activity. The explanation for the variable biochemical phenotype is unknown, particularly now that the same mutation in the CYP11B2 gene has been uncovered in both variants (Fig. 13-2, Table 13-1). It is possible that this may reflect polymorphic variants in the residual and normal product of the CYP11B1 gene, 11β-hydroxylase.
FIGURE 13-2 Schematic representation of identified mutations in the CYP11B2 gene. The CYP11B2 gene is represented with its intron/exon structure. Mutations found for aldosterone synthase deficiency (ASD) type 1 are shown above the gene structure; those responsible for ASD type 2 are presented below the gene structure.
At variance with the MR knockout mouse model, the aldosterone synthase knockout mouse model is not lethal. As expected, ionic homeostasis is altered in the absence of aldosterone, but high levels of corticosterone and angiotensin II seem to partially rescue sodium balance,27 underscoring the importance of the MR over its ligand, aldosterone.
Both variants of aldosterone synthase deficiency are rare and inherited as autosomal-recessive traits (see Table 13-1). The type 2 deficiency is found most frequently among Jews of Iranian origin.
Secondary Isolated Hypoaldosteronism
Hyperreninemic hypoaldosteronism can occur in critically ill patients with disorders such as sepsis, cardiogenic shock, or liver cirrhosis.47,48 Cortisol levels in these patients are elevated and commensurate with the level of stress. In normal subjects, aldosterone, corticosterone, and 18-hydroxycorticosterone levels can be suppressed in 48 to 96 hours with continuous ACTH stimulation.49–51 Prolonged ACTH secretion is thought to impair aldosterone synthase activity and explain the underlying mechanism of this syndrome. These patients have an increased ratio of plasma 18-hydroxycorticosterone to aldosterone, and the aldosterone response to angiotensin II infusion is impaired. Hypoxia and proinflammatory cytokines may be additional mechanisms that inhibit aldosterone synthesis from the zona glomerulosa, as may elevated circulating levels of atrial natriuretic peptide (ANP).52 Additionally, many critically ill patients are taking medications that can interfere with aldosterone production (see later). Hyperreninemic hypoaldosteronism is also reported in patients with tumors that have metastasized to the adrenals.
Syndrome of Hyporeninemic Hypoaldosteronism
The syndrome of hyporeninemic hypoaldosteronism (SHH), also referred to as type 4 distal renal tubular acidosis (RTA), is not uncommon and usually occurs in late middle age (median age 68 years) in males more than females. Underlying diabetes mellitus is present in 50% of cases and chronic renal insufficiency in 80% of cases. It is frequent in patients with tubulointerstitial forms of renal disease but has been described in virtually every type of renal abnormality.53–56 SHH accounts for 50% to 70% of patients with unexplained hyperkalemia and renal disease in patients with relatively preserved glomerular filtration rate (GFR).53,55,56
Patients have low PRA and aldosterone levels that cannot be stimulated by provocative tests. Hyperchloremic metabolic acidosis occurs in about 70%, and mild to moderate hyponatremia is seen in about 50% of affected patients. Hyperkalemia that is out of proportion to the degree of renal insufficiency is observed in all patients.55,56 The pathogenesis is unknown, but proposed mechanisms include hyporeninemia due to damaged juxtaglomerular apparatus, sympathetic insufficiency, altered renal prostaglandin production, and impaired conversion of prorenin to renin.57,58 Low renin production does not appear to be the sole factor, since PRA can be normal in some patients. It is possible that some cases can be explained by sodium retention leading to volume expansion, with secondary suppression of renin and aldosterone.
The leading causes of interstitial nephritis, in which hyperkalemia occurs early and before chronic renal failure, are anatomic genitourinary abnormalities, analgesic abuse with aspirin or phenacetin, hyperuricemia, nephrocalcinosis, nephrolithiasis, and sickle cell disease. Diabetic patients are predisposed to hyperkalemia because of insulin deficiency and hyperglycemia, and this may be exacerbated by autonomic neuropathy. IgM monoclonal gammopathy has been associated with nodular glomerulosclerosis, a concentrating defect, and hyporeninemic hypoaldosteronism.59 Patients with acquired immunodeficiency syndrome (AIDS) can have persistent hyperkalemia secondary to adrenal insufficiency or, less frequently, hyporeninemic hypoaldosteronism.
There is no ideal medical therapy for SHH. The majority of patients with mild selective hypoaldosteronism require no therapy. Treatment may be indicated in patients with severe hyperkalemia. Reducing the extracellular potassium load is the single most effective measure in controlling hyperkalemia. Reducing dietary intake of potassium is helpful. The long-term control of glucose homeostasis in diabetes mellitus may reduce the risk of developing SHH, and autonomic insufficiency is probably avoidable in well-controlled diabetes. Since many medications can interfere with the renin-aldosterone axis, avoidance of these drugs is of major importance. β-Adrenergic receptor blockers, prostaglandin synthetase inhibitors, and potassium-sparing diuretics should be avoided in patients with SHH and in diabetic patients with latent hypoaldosteronism. Calcium channel blockers, antidopaminergic agents, and drugs that impair adrenal function must be used with caution. Patients taking angiotensin-converting enzyme (ACE) inhibitors must be monitored carefully for hyperkalemia. The prolonged administration of heparin can worsen hypoaldosteronism60 and has been associated with lethal hyperkalemia. Fludrocortisone 0.2 mg/day for 2 weeks usually normalizes potassium levels in patients with SHH,61,62 but there is a risk of salt retention and hypertension. In severe SHH, fludrocortisone acetate, in doses of 0.1 to 1.0 mg/day (equivalent to 200 to 2000 µg aldosterone daily), can be required. Diuretics may be the optimal therapy for patients with SHH and coexisting diseases associated with sodium retention. Older patients with hypertension, mild renal impairment, and congestive heart failure respond better to diuretic therapy than to mineralocorticoid replacement. Since kaliuresis is the goal of diuretic therapy, the diuretic employed should have a potent kaliuretic activity; thiazide diuretics are more effective than loop diuretics and induce less natriuresis.
