Hypoaldosteronism

Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Patients are usually older, with underlying renal disease (e.g., diabetic nephropathy). Hypoaldosteronism usually presents as hyperkalemia with a mild hyperchloremic metabolic acidosis (normal anion gap). Most patients are asymptomatic and routine lab evaluation demonstrates hyperkalemia, prompting a further workup. The condition is diagnosed using serum and urine tests that demonstrate reduced aldosterone levels and a reduced transtubular potassium gradient, among other characteristic findings. Patients are managed based on their underlying etiology.

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Overview

Definition

Hypoaldosteronism is defined as decreased secretion of aldosterone from the zona glomerulosa of the adrenal cortex, which may be primary or secondary in nature.

Epidemiology

  • Exact incidence is unknown.
  • Age at diagnosis: 
    • Generally occurs in older adults (> 50 years of age)
    • May occur in children with underlying disorders (e.g., diabetes mellitus, sickle cell anemia)
  • Male = female
  • Racial/ethnic bias: more common in Blacks, Native Americans, and Hispanics

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Etiology and Pathophysiology

Physiology review

  • Aldosterone is stimulated directly by:
    • Angiotensin II
    • Hyperkalemia
  • Renin-angiotensin-aldosterone system (RAAS):
    • Renin (secreted by the macula densa cells within the kidneys) → converts angiotensinogen (secreted by hepatocytes) to angiotensin I
    • ACE (secreted by pulmonary vascular endothelium) → converts angiotensin I to angiotensin II
    • Angiotensin II → stimulates release of aldosterone (secreted by the zona glomerulosa in the adrenal cortex)
  • Factors that normally trigger RAAS (and thus ↑ aldosterone):
    • ↓ Blood pressure or blood volume
    • ↓ Sodium delivery to the kidney
    • ↑ Sympathetic tone
  • Effects of aldosterone: 
    • Stimulates production of the following proteins within the principle cells in the distal renal tubules:
      • Na+/K+ ATPase on the basolateral side
      • ENaC (epithelial sodium channels) on the lumen side: allows Na+ reabsorption from the lumen into the principal cells
      • ROMK (renal outer medullary potassium channel) on the lumen side: allows excretion of K+ into the urine
    • Stimulates Na+ reabsorption from the renal tubules:
      • Water follows the Na+.
      • Creates a negative electrical gradient across the lumen, promoting the secretion of K+ and H+ into the urine
Effects of aldosterone on the principal cells within the distal renal tubules

Effects of aldosterone on the principal cells within the distal renal tubules

Image by Lecturio.

Etiology

The 2 primary mechanisms that cause hypoaldosteronism are reduced aldosterone production (which can be hyporeninemic or hyperreninemic) and aldosterone resistance. Medications are often the cause of both mechanisms.

MechanismEtiology
Reduced aldosterone synthesis due to ↓ stimulation of RAAS:
Hyporeninemic hypoaldosteronism (also referred to as type 4 renal tubular acidosis (RTA))
  • Renal disease:
    • Diabetic nephropathy (most common)
    • Chronic interstitial nephritis
    • Acute glomerulonephritis
  • Volume expansion
  • Autonomic neuropathy
  • Systemic disease:
    • Sickle cell disease
    • Systemic lupus erythematosus (SLE)
    • HIV
  • NSAIDs
Reduced aldosterone synthesis due to direct adrenal issues:
Hyperreninemic hypoaldosteronism
  • Primary adrenal insufficiency (Addison disease)
  • Chronic heparin therapy
  • Severe illness
  • Discontinuation of mineralocorticoid drugs after prolonged use
  • Congenital or genetic anomalies:
    • Congenital adrenal hyperplasia (21-hydroxylase deficiency)
    • Isolated (primary) hypoaldosteronism (CYP11B2 defect)
    • Adrenal hypoplasia
Aldosterone resistance (psudohypoaldosteronism)
  • Genetic anomalies in the mineralocorticoid receptors
  • Obstructive uropathies
  • Calcineurin inhibitors

Pathophysiology

  • End result of ↓ aldosterone: 
    • ↑ Serum K+ (↓ urinary excretion of K+)
    • Metabolic acidosis (↓ urinary excretion of H+): renal tubular acidosis type 4
    • ↓ Serum Na+ (↑ urinary excretion of Na+)
    • Volume depletion and hypotension
  • Type 4 RTA:
    • ↑ K+ → inhibits renal ammonia synthesis and urinary ammonia excretion
    • ↓ In urinary ammonia excretion → mild metabolic acidosis (type 4 RTA)
  • Mechanisms of drug-induced hypoaldosteronism:
    • Drugs that cause a ↓ in aldosterone synthesis or release:
      • ACE inhibitors/ARBs
      • Heparin (direct toxic effect on the adrenal zona glomerulosa cells)
      • NSAIDs/COX-2 inhibitors
      • Beta-blockers
    • Inhibit aldosterone effects: 
      • Aldosterone receptor antagonists: spironolactone, eplerenone
      • ENaC inhibitors: amiloride, trimethoprim, pentamidine
    • Induce aldosterone resistance: calcineurin inhibitors cyclosporine and tacrolimus

Clinical Presentation

  • Usually asymptomatic (discovered on routine lab evaluation)
  • Hyperkalemia (> 5 mEq/L) can present with:
    • Cardiac arrhythmias
    • Muscle weakness
  • Hyponatremia (< 135 mEq/L):
    • More common in children and patients with adrenal insufficiency
    • Can present with: 
      • Polyuria
      • Dehydration
      • Nausea and vomiting
      • Neurologic symptoms: short-term memory loss, confusion, lethargy, seizures
  • Clinical features suggestive of associated conditions (e.g., sickle cell anemia, SLE, adrenal insufficiency)

Diagnosis

The diagnosis of hypoaldosteronism should be considered in any patient with persistent hyperkalemia without an obvious cause, such as renal failure or potassium-sparing diuretics.

  • Aldosterone-specific tests:
    • Serum aldosterone:
      • ↓ In all cases of true hypoaldosteronism
      • ↑ In cases of pseudohypoaldosteronism (aldosterone resistance)
    • Plasma renin activity (PRA):
      • In type 4 RTA (hyporeninemic hypoaldosteronism)
      • ↑ In primary adrenal insufficiency
    • Transtubular potassium gradient (TTKG): estimates the action of aldosterone on cortical collecting tubules
      • TTKG = [urine K ÷ (urine osmolality/serum osmolality)] ÷ serum K
      • ↓ TTKG (< 7) in the presence of hyperkalemia: Hypoaldosteronism is likely.
    • Serum cortisol: to screen for adrenal insufficiency
      • ↓ In adrenal insufficiency
      • Normal in isolated hypoaldosteronism
  • In type 4 RTA (hyporeninemic hypoaldosteronism), laboratory tests will show:
    • Aldosterone-specific test findings:
      • ↓ Serum aldosterone
      • ↓ PRA
      • ↓ TTKG
    • Basic metabolic panel (BMP) findings:
      • Non-anion gap metabolic acidosis
      • ↓ Serum HCO3 (usually mild, 18–22 mEq/L)
      • ↑ K+
      • ↑ Cl
      • Markers of ↓ renal function are common (e.g., ↑ creatinine)
    • Urine findings:
      • ↓ Urinary K+
      • Normal urinary phosphate
      • Normal or ↓ urinary calcium
      • Urine pH < 5.3‒5.5
  • Electrocardiogram (due to ↑ cardiac risks associated with hyperkalemia)
  • Testing to rule out other associated conditions, if suspected:
    • 17-hydroxyprogesterone (congenital adrenal hyperplasia)
    • HIV test

Management

The management depends on the underlying etiology.

  • Medication induced: Adjust/remove medications that may be contributing.
  • Type 4 RTA (hyporeninemic hypoaldosteronism):
    • Low-potassium diet
    • Loop or thiazide diuretics
    • Alkali supplementation (NaHCO3) if acidosis does not improve
    • Mineralocorticoid replacement is not recommended, as many patients have underlying conditions (e.g., edema, hypertension) that would be exacerbated.
  • Primary adrenal insufficiency and congenital adrenal hyperplasia:
    • Mineralocorticoid replacement: fludrocortisone
    • Glucocorticoid replacement: hydrocortisone or prednisone
  • Hyperkalemia with ECG changes: emergency management to ↓ K+

Clinical Relevance

  • Congenital adrenal hyperplasia (CAH): consists of a group of autosomal recessive disorders involving a genetic mutation that results in an enzyme deficiency required for cortisol and/or aldosterone synthesis.
  • Primary Addison disease: also called primary adrenal insufficiency. Defined as the inadequate production of adrenocortical hormones, including glucocorticoids, mineralocorticoids, and adrenal androgens. Primary adrenal insufficiency is caused by afflictions in the gland itself. Classic findings include mucosal and cutaneous hyperpigmentation, hypotension, and GI symptoms.
  • Diabetic nephropathy: Diabetes mellitus describes a group of metabolic diseases that are characterized by chronic hyperglycemia and insulin resistance. Long-standing diabetes mellitus causes vascular changes that eventually result in cardiovascular, renal, retinal, and neurological complications.
  • Hyperkalemia: defined as an elevated serum potassium level (> approximately 5.5mEq/L). The condition is usually an incidental finding in the general population but affects 10% of hospitalized patients. There are many causes, including transcellular shifts, tissue breakdown, inadequate excretion, and drug induced. Patients are usually asymptomatic.
  • Hyponatremia: defined as a decreased plasma sodium concentration (> approximately 135 mEq/L). This condition occurs from either loss of sodium or excess water in the extracellular fluid.
  • RTA: an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. The condition is classified into 4 types.

References

  1. Williams, G. H., Dluhy, R.G. (2008). Disorders of the adrenal cortex. In Fauci, A. S., Braunwald, E., Kasper, D.L., et al. (Eds.). Harrison’s Internal Medicine. 17th Ed., p. 2266.
  2. Rajkumar, V. (2021). Hypoaldosteronism. In Waseem, M. (Ed.). StatPearls. Retrieved March 10, 2021, from https://www.statpearls.com/ArticleLibrary/viewarticle/23254
  3. Sondheimer, J. H. (2020). Hyporeninemic hypoaldosteronism. In Batuman, V. (Ed.). Medscape. Retrieved March 10, 2021, from https://emedicine.medscape.com/article/242494-overview
  4. Young, W. F. (2019). Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA). In Forman, J. P. (Ed.). UpToDate. Retrieved March 10, 2021, from https://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-hypoaldosteronism-type-4-rta 

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