Hypoaldosteronism  -   Mineralocorticoid Deficiency

Aldosterone deficiency syndromes    [REF: Scientific American Medicine 2000]

Occasionally, aldosterone deficiency is the only, or predominant, sign of adrenal insufficiency. Isolated defects of aldosterone biosynthesis are rare, but partial defects are an aspect of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. Symptoms attributable to aldosterone deficiency may provide the principal early diagnostic clues to hypoadrenalism; for example, postural hypotension may occur before anorexia, weight loss, asthenia, and hyperpigmentation.

Two syndromes of isolated aldosterone deficiency,

  1. Idiopathic hypoaldosteronism
    The rare condition idiopathic hypoaldosteronism presents as heart block, secondary to hyperkalemia, or as postural hypotension, secondary to hypovolemia with or without significant hyponatremia. Patients would be expected to demonstrate low plasma and urinary aldosterone levels combined with increased plasma renin activity, although few reports are available.
    RX:  fludrocortisone 0.05 to 0. 10 mg daily, combined with liberal salt intake, is effective.
  2. Hyporeninemic hypoaldosteronism
    Hyporeninemic hypoaldosteronism is much more common than idiopathic hypoaldosteronism. In mild forms, the former condition is perhaps still underdiagnosed. Typical patients are older than 45 years and have chronic renal disease. The kidney disorder affects the tubular and interstitial tissue more than it does the glomeruli. Diabetes mellitus is a common finding. The hallmark of hyporeninemic hypoaldosteronism is mild to marked chronic hyperkalemia, which is sometimes worsened abruptly by hyperglycemia. A hyperchloremic metabolic acidosis, with a normal or low sodium level, is usually present. Restricting sodium intake aggravates the clinical manifestations. The underlying physiologic derangement is a plasma renin level that is low despite hyperkalemia, volume contraction, and hyponatremia. Although the cause of the low renin level is disputed, it is usually attributed to a defect in the juxtaglomerular apparatus. Prostaglandin deficiency induced by nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to be a reversible cause of the syndrome. In other cases, the disorder has been aggravated by heparin, calcium channel blockers, or beta-adrenergic blockers.
    RX: includes correction of acidosis, liberalization of sodium intake, and judicious use of fludrocortisone as required for controlling the potassium elevation without inducing congestive heart failure.


The clinical manifestations
usually include hyperkalemia and metabolic acidosis, attributed to a reduction in renin secretion also (hyporeninemic hypoaldosteronism).


  • unexplained hyperkalemia with or without a mild nonanion gap metabolic acidosis.
  • low plasma aldosterone concentration (PAC) despite the ambient hyperkalemia, and the PAC-to-PRA (renin assay) ratio will tend to be in the normal range. Oral or intravenous furosemide and upright posture will not provoke a significant increase in PRA or aldosterone.
  • an attenuated aldosterone response to ACTH, with a peak response of less than 16 ng/dL despite prevailing hyperkalemia.

Etiology: - is uncertain.

  1. Renal Cause:
    Because most of these patients have some degree of chronic renal insufficiency, there may be a primary disorder of structure or function of the juxtaglomerular apparatus. This disorder is usually seen in patients with diabetic nephropathy but has also been reported in patients with interstitial nephropathies, glomerulonephritis, and nephropathies associated with multiple myeloma, systemic lupus erythematosus, and analgesic abuse.
  2. Autoimmune disorder Cause:
    Selective hypoaldosteronism has been frequently associated with autoimmune disorders associated with the polyglandular autoimmune endocrine deficiency syndromes, such as isolated ACTH deficiency, hypoparathyroidism, Hashimoto thyroiditis, and vitiligo. Therefore, a primary autoimmune-mediated adrenal defect in the zona glomerulosa secretion of aldosterone may be initially subclinical and only become clinically manifest when superimposed hyporeninemia results in more profound decreases in aldosterone secretion. Hyporeninemic hypoaldosteronism with hyperkalemia has also been observed in patients with AIDS.
  3. Drug Cause:
    Certain drugs may also contribute to the development of hypoaldosteronism and may aggravate or precipitate the syndrome in patients with suboptimal aldosterone secretory reserve. As mentioned, prostaglandin synthesis inhibitors such as indomethacin, ACE inhibitors, and adrenergic b-receptor blockers may all exacerbate this syndrome. Chlorbutol, a preservative used in heparin preparations, has also been shown to be a potent inhibitor of aldosterone production and may explain the inhibition of aldosterone secretion in patients treated with this anticoagulant.


Hyperreninemic hypoaldosteronism may also occur in the presence of adequate cortisol secretion. Hyperreninemic hypoaldosteronism has also been seen in patients with severe illness in the intensive care unit. The dissociation of renin and aldosterone during serious illnesses is poorly understood. These patients usually do not have hyperkalemia, presumably owing to the mineralocorticoid effects of the hypercortisolism that accompanies serious illness. Chronic ACTH secretion, as seen in seriously ill patients, has also been shown to decrease aldosterone secretion from the zona glomerulosa. Many patients with AIDS also have impaired aldosterone secretion despite either normal or elevated PRA levels. Patients with critical illness and AIDS have also been reported to have low levels of DHEA with subnormal responsiveness to ACTH administration. These findings suggest that there is an adrenocortical adaptation to serious illness with a relative shift in the metabolism of adrenal pregnenolone away from mineralocorticoids and adrenal androgens and toward glucocorticoids.

Patients with hyperreninemic hypoaldosteronism can easily be identified by using the PAC-to-PRA ratio. The PRA in these patients is, by definition, greater than 2 ng/mL per hour, and the PAC-to-PRA ratio is less than 2.0.

Another rare cause of selective primary adrenal defect in aldosterone production is a deficiency in corticosterone methyl oxidase (CMO) enzyme (P450aldo). Two forms of this disorder:  

  1. CMO type I reflects a biosynthetic defect at the level of the 18 hydroxylation of corticosterone. Thus, hypoaldosteronism in CMO-1 is characterized by a normal plasma 18-hydroxycorticosterone-to-aldosterone ratio.
  2. CMO type II reflects inability of 18 hydroxycorticosterone to be converted to aldosterone; thus, an elevated 18 hydroxycorticosterone-to-aldosterone ratio is seen. The spectrum of clinical features characterizing this syndrome ranges from salt-wasting crisis in the neonate, to growth impairment in children, and to an asymptomatic presentation in adults.


Severe mineralocorticoid insufficiency with significant hyperkalemia and metabolic acidosis can be managed with Florinef/fludrocortisone, 0.1 - 0.2 mg/d PO.  Because many patients with this syndrome are elderly, fluid status and hypertension may be a problem; a conservative approach, often using a loop diuretic, may be sufficient. It is very important for patients to be educated about avoiding drugs that may aggravate the syndrome, such as ACE inhibitors, prostaglandin synthetase inhibitors (NSAID), beta blockers, and potassium-sparing diuretics.

ACP Library on Disk 2- (c) 1997


REF:  UpToDate 2006


— Patients suspected to have hypoaldosteronism should be questioned about the use of any drug or the presence of a disease that can impair aldosterone release, such as a nonsteroidal antiinflammatory drug, an angiotensin converting enzyme (ACE) inhibitor, cyclosporine, heparin, or the acquired immune deficiency syndrome .

If none of these findings is present, then evaluation for some other form of hypoaldosteronism should be pursued.

The most common causes of hypoaldosteronism are

  1. hyporeninemic hypoaldosteronism or
  2. primary adrenal insufficiency, an adrenal enzyme defect (most often CYP11B2 [aldosterone synthase, P450c11as] deficiency), or
  3. pseudohypoaldosteronism, a rare genetic disorder of aldosterone resistance, the autosomal recessive form of which is due to a mutation in the collecting tubule sodium channel gene.

These disorders can be differentiated by measurement of plasma renin activity (PRA) and serum aldosterone and cortisol. These tests should be performed after the administration of a loop diuretic or three hours in the upright position, which will increase renin and aldosterone release in normals, but not in these disease states.

Hyporeninemic hypoaldosteronism most often occurs in patients 50 to 70 years of age with diabetic nephropathy or chronic interstitial nephritis who have mild to moderate renal insufficiency.

Hyporeninemic hypoaldosteronism is associated with

  1. low PRA (in most but not all cases),
  2. low serum aldosterone concentration, and
  3. normal serum cortisol concentration.

Patients with primary adrenal insufficiency have low serum aldosterone and cortisol concentrations, but high PRA due to volume depletion and hypotension.

Children with an adrenal enzyme deficiency fall into one of two categories. Those with one of the forms of congenital adrenal hyperplasia (ie, CYP21A2 [21-hydroxylase], CYP17 [17-hydroxylase] or 3-beta-hydroxysteroid dehydrogenase deficiency, or congenital lipoid hyperplasia) have a concurrent defect in cortisol synthesis. Thus, their serum values are similar to those in primary adrenal insufficiency, but adrenal androgen synthesis may be increased, leading to virilization [3]. (See "Overview of congenital adrenal hyperplasia due to CYP21A2 (21-hydroxylase) deficiency" and see "Uncommon causes of congenital adrenal hyperplasia" for discussions of the pathogenesis and treatment of these disorders).

In comparison, children with congenital isolated (or primary) hypoaldosteronism have a defect in one of the two steps (both of which are mediated by the same enzyme, CYP11B2, involved in the production of aldosterone: the addition of a hydroxyl group at the 18-carbon position; and the subsequent oxidation of this hydroxyl group to an aldehyde group [4]; however, mutations in CYP11B2 were not found in eight unrelated kindreds, in whom the affected gene is unknown [6].

In either of these conditions, serum aldosterone concentration is low, serum cortisol concentration is normal, and PRA is high.

The diagnosis of congenital isolated hypoaldosteronism can be confirmed by measurement of serum 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, 18-hydroxydeoxycorticosterone, and aldosterone [7]. (See "Etiology and treatment of hypoaldosteronism (type 4 RTA)", section on Congenital adrenal hyperplasia and isolated hypoaldosteronism, which reviews the biosynthetic defects in this disorder).

Children with the rare syndrome of aldosterone resistance (pseudohypoaldosteronism) have high PRA and serum aldosterone concentration [8]. (See "Genetic disorders of the renal sodium channel: Liddle's syndrome and pseudohypoaldosteronism"). Infants with the autosomal variant, in which the epithelial sodium channel is abnormal, may present with a miliaria papular rash, due presumably to high sodium concentration in sweat [9]. In comparison to the above conditions, therapy with conventional doses of a mineralocorticoid is usually ineffective (see below).

Hyperkalemic patients in whom all of these tests are normal and in whom renal function is not markedly impaired probably have a selective potassium secretory defect or the hyperkalemic form of type 1 renal tubular acidosis [1].