Etiology

The serum sodium concentration is a measure of water status rather than total body salt content and a low serum sodium concentration indicates dilute body fluids or an excess of water over sodium.

Hyponatremia may be classified according to the serum tonicity as being hypertonic, isotonic, or hypotonic:

  • Hypertonic hyponatremia, also known as redistributive hyponatremia, occurs when the presence of excess levels of an osmolyte such as glucose or mannitol causes water to shift from the intracellular to the extracellular compartment, diluting extracellular sodium.

  • Isotonic hyponatremia is an artifact caused by high lipid or protein levels and is usually called pseudohyponatremia.

  • Hypotonic, or true, hyponatremia encompasses all other causes of hyponatremia and is classified as hypovolemic, euvolemic, or hypervolemic.

Patients who develop hyponatremia as a result of head injury, intracranial surgery, subarachnoid hemorrhage, stroke, or brain tumors may have cerebral salt-wasting syndrome or syndrome of inappropriate antidiuretic hormone secretion (SIADH). These conditions are difficult to distinguish, and controversy exists as to whether the distinction is clinically important.[11] Cerebral salt-wasting syndrome tends to produce hypovolemic hyponatremia with hyposmolar or normosmolar urine and a high urine output, whereas SIADH produces euvolemic hyponatremia with hyperosmolar urine and a low urine output. Urinary sodium levels are similar with both conditions.

Hypovolemic hyponatremia (hypotonic)

Gastrointestinal fluid loss

  • Severe diarrhea may cause gastrointestinal sodium loss.

  • Severe vomiting may also cause metabolic alkalosis, which further increases sodium loss via the renal excretion of sodium with bicarbonate.[9]

Third spacing of fluids

  • Loss of fluid to the extravascular space occurs in: for example, acute pancreatitis, major surgery, intestinal obstruction.

Salt-wasting nephropathy

  • Due to intrinsic renal diseases that produce excessive sodium loss to the point of causing hypotension. It is most often seen with tubular and interstitial kidney diseases. Examples include interstitial nephritis, partial urinary tract obstruction, and polycystic kidney disease.

Cerebral salt-wasting syndrome

  • Produced by a range of intracranial pathologies including head injury, intracranial surgery, subarachnoid hemorrhage, stroke, and brain tumors.

  • The intracranial pathology causes excessive urinary sodium loss. The mechanism of the effect is uncertain, but elevated brain natriuretic peptide has been implicated.[12][13]

Mineralocorticoid deficiency

  • Due to autoimmune destruction of the adrenal cortex (Addison disease) and/or 21-hydroxylase deficiency producing a decrease in the production of cortisol, aldosterone, and dehydroepiandrosterone.

  • The decrease in aldosterone production causes increased sodium loss from the kidney.

Euvolemic hyponatremia (hypotonic)

Medications

  • The most common are thiazide diuretics and antidepressants.[7]

  • Mechanisms include vasopressin (ADH) analogs (desmopressin, oxytocin) and medications that stimulate ADH release or potentiate its effects (e.g., selective serotonin reuptake inhibitors and most other antidepressants,morphine and other opioids).

  • The precise mechanism of thiazide-associated hyponatremia is unknown but it includes excessive fluid intake, sodium depletion, and impaired excretion of free water.[14]

SIADH secretion

  • Defined as hyponatremia with an inappropriately elevated urine osmolality (>100 mOsm/kg H₂O), excessive urine sodium excretion (>20 mEq/L, but is often >40 mEq/L), and decreased serum osmolality in the absence of diuretic therapy. It is a diagnosis of exclusion. Inappropriate secretion is produced either by dysregulation of the cells that produce ADH or by secretion of ADH from an ectopic source. ADH, in turn, causes increased resorption of water by the kidney.

  • Central nervous system causes include head injury, intracranial surgery, subarachnoid hemorrhage, meningitis, brain abscess, and stroke.

  • ADH may be secreted by tumors. The most common source is small cell lung cancer; other cancers are rare causes. These include cervical cancer, lymphoma, leukemia, and pancreatic cancer.

  • Lung diseases such as pneumonia, lung abscess, COPD, cystic fibrosis, or positive-pressure ventilation can cause SIADH by stimulating ectopic secretion of ADH.

  • Idiopathic SIADH refers to patients with SIADH in whom no underlying cause is identified.

Iatrogenic

  • Almost all patients who undergo surgery have impaired water excretion that lasts 2 to 3 days. This is due to a transient increase in ADH secretion. Administration of hypotonic fluids during the postoperative period can therefore cause severe hyponatremia.

  • During transurethral resection of prostate or hysteroscopy, the operative field is often irrigated with large volumes of hypertonic fluids (glycine, mannitol, or sorbitol). Absorption of the fluid without the solute can cause severe acute euvolemic hyponatremia. However, if the solute is also absorbed, the result is a severe acute hypertonic (redistributive) hyponatremia.

  • During endometrial ablation, the operative field is often irrigated with large volumes of hypotonic fluids, which, if absorbed, can cause severe euvolemic hyponatremia. The risk can be reduced by the use of isotonic mannitol.

Intense/prolonged physical activity

  • High fluid intake during intense or prolonged physical activity (e.g., marathon running, military training, wilderness exploration) may cause euvolemic hyponatremia due to impaired renal free water excretion, especially if solute intake is relatively low.

Psychogenic polydipsia

  • Also known as primary polydipsia

  • Defined as excessive oral fluid intake due to the persistent sensation of a dry mouth. Excess water intake overwhelms the capacity of the kidney to excrete free water.

  • Frequently seen in psychiatric patients, and may be related to the underlying disorder or as a result of medications.

Potomania

  • This condition occurs because salt and protein intake is inadequate.

  • It can occur in association with heavy beer drinking, inadequate diets (i.e., very low-calorie diets with high fluid intake), or crash diets.

  • Urea and electrolyte levels in the urine fall as a result and the ability of the kidney to excrete free water is therefore limited.

Hypervolemic hyponatremia (hypotonic)

Acute kidney injury or chronic kidney disease

  • Patients with acute kidney injury or chronic kidney disease who are unable to excrete sodium will have sodium retention and an expansion in total body water volume.​[15]

Congestive cardiac failure

  • Systemic hypoperfusion stimulates the renin-angiotensin-aldosterone system, ADH, and norepinephrine, all of which act on the kidney to reduce water and sodium excretion. Patients are unable to excrete ingested water, leading to hyponatremia, with total body water volume expansion.

Liver cirrhosis

  • Hyponatremia is a common finding in cirrhotic patients with associated ascites, and worsens as the liver disease progresses.[15]​​ Low circulatory volume, caused by splanchnic vasodilation, results in hyponatremia via a similar mechanism to that in congestive cardiac failure. Water retention, and therefore hyponatremia, increases if ADH secretion becomes persistent (nonosmotic).[16]

Nephrotic syndrome

  • Increased protein loss through the kidneys leads to a loss of colloid osmotic pressure and leakage of fluid from the intravascular compartment. The fluid loss may rarely be severe enough to stimulate persistent ADH secretion sufficient to cause hyponatremia and an expansion of the total body water volume.

Redistributive hyponatremia (hypertonic)

May be due to hyperglycemia or the absorption or administration of a hypertonic fluid (e.g., mannitol, glycine, or sorbitol).

Hyperglycemia is usually caused by diabetes but can also be caused by medications (corticosteroids, niacin, pentamidine, protease inhibitors, some antipsychotics) or by stress from a recent stroke, myocardial infarction, trauma, infection, or inflammation.

Mannitol, glycine, or sorbitol fluids administered intravenously, or used to irrigate the operative field during transurethral resection of prostate or hysteroscopy, may cause hypertonic hyponatremia.

Pseudohyponatremia (isotonic)

An artifact produced by high serum lipid or protein levels. The lipid or protein fraction of the plasma is increased relative to the nonlipid or nonprotein fraction. This leads to a falsely low reading of the sodium concentration because conventional electrodes measure only sodium in the nonlipid fraction. Newer electrodes measure sodium directly and the measured sodium concentration will be normal if these electrodes are used. The most common cause of high protein levels is multiple myeloma; this diagnosis is already known in the majority of patients.

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