Aetiology

Hypernatraemia, defined as a plasma sodium concentration of >145 mmol/L (145 mEq/L), results from the loss of water in most cases.[6][9]​​​ However, there are other causes, such as free water intake deficit, sodium gain, and mineralocorticoid excess, which should also be considered. Pseudohypernatraemia can develop in patients with hypoalbuminaemia.​[10][11]

Free water loss

Renal losses

Regarded as the most common cause of hypernatraemia; occurs through either osmotic diuresis or as a consequence of diabetes insipidus.[6]​​

  • Due to osmotic diuresis

    • Typically the patient will present in a hypovolaemic state.

    • The most frequent cause of an osmotic diuresis is hyperglycaemia and glucosuria in poorly controlled diabetes mellitus. Hyperosmolar hyperglycaemic state (HHS) usually occurs in older patients with type 2 diabetes mellitus and carries a mortality rate of between 5% and 16%.[12]​​ The disease state includes hyperglycaemia, dehydration, and hyperosmolarity without ketoacidosis.

    • Loop diuretics, such as furosemide and torsemide, can cause renal losses of sodium; they produce an iso-osmotic solute diuresis resulting in impaired renal concentrating ability, which reduces the re-absorption of water.

    • Increased production of urea (e.g., from a high-protein diet) and intravenous mannitol can also result in an osmotic diuresis.[6]​​

    • Any urinary output obstruction (e.g., due to benign prostatic hypertrophy, prostatitis, prostate cancer, nephrolithiasis, bladder tumours, urethral strictures) often leads to a post-obstructive diuresis once corrected. Consequently, there is free water loss that may result in hypernatraemia.

  • Due to diabetes insipidus

    • Typically the patient will present in a euvolaemic state.

    • Hypernatraemia secondary to non-osmotic renal water loss is usually caused by central diabetes insipidus, characterised by impaired vasopressin secretion, or by nephrogenic diabetes insipidus, resulting from resistance to the actions of vasopressin.[13]

    • Central diabetes insipidus is most commonly caused by destruction of the neurohypophysis due to trauma, neurosurgery, neoplasm, vascular accidents, granulomatous diseases, or infection.[14]​ Idiopathic cases have been reported, as well as hereditary cases where the familial form of the disease is inherited in an autosomal-dominant fashion and has been attributed to mutations in the propressophysin (AVP precursor) gene. Ingested agents that decrease central ADH secretion include phenytoin and ethanol.[15]​​​

    • Nephrogenic diabetes insipidus may be inherited or acquired.[14]

    • Congenital nephrogenic diabetes insipidus is an X-linked recessive trait due to mutations in the V2 receptor gene. Nephrogenic diabetes insipidus may also be caused by mutations in the aquaporin-2 gene that encodes the water channel protein whose membrane insertion is stimulated by arginine vasopressin (AVP).

    • Sporadic causes of nephrogenic diabetes insipidus are numerous and include lithium, hypercalcaemia, hypokalaemia, and conditions that impair medullary hypertonicity, such as papillary necrosis.

    • Pregnant women, in the second or third trimester, may develop nephrogenic diabetes insipidus (gestational diabetes insipidus) as a result of excessive secretion of vasopressinase by the placenta.[14]

    • Other renal diseases that may result in acquired nephrogenic diabetes insipidus include sickle cell disease, polycystic kidney disease, and obstructive uropathy.[14] Ingested agents that may induce nephrogenic diabetes insipidus and cause hypernatraemia include colchicine, gentamicin, lithium, rifampin (rifampicin), and propoxyphene (dextropropoxyphene).[15]​​

Non-renal losses

May be due to insensible water losses such as evaporation from the skin. In cases of severe burns, patients are usually euvolaemic in the first 48 hours and become hypovolaemic thereafter. Insensible water losses can also occur as a result of losses from the gastrointestinal (GI) tract. These patients usually present in a hypovolaemic state.[1]

  • Insensible losses are increased with fever, exercise, heat exposure, and severe burns. Severe burns, usually thermal in origin, cause increased capillary permeability and third-spacing of fluids in the first 24 hours after the burn (patient euvolaemic). Thereafter, the skin damage allows greater evaporation, increasing insensible water losses (patient becomes hypovolaemic). With regards to heat and sweating, the sodium concentration of sweat decreases with continued profuse perspiration, thereby increasing solute-free water loss.

  • Severe diarrhoea is the most common GI cause of hypernatraemia, and the patient usually presents in a hypovolaemic state. Osmotic diarrhoea induced by lactulose or sorbitol ingestion, carbohydrate malabsorption (most commonly as a result of tropical sprue, bowel resection, lactose intolerance, or pancreatitis), and viral gastroenteritides, results in water loss that exceeds sodium and potassium loss. This is in contrast to secretory diarrhoea, which has a faecal osmolality similar to plasma and presents as volume contraction with normal or low plasma sodium concentration.[6]​​

  • A patient with prolonged vomiting regardless of the cause may lose more water than sodium leading to volume depletion and hypernatraemia.

  • Enteric fistulae (fistulae are tracts that connect 2 epithelial-lined organs) can also result in insensible GI losses; these may occur as a complication of Crohn's disease.

Free water intake deficit

Usually the result of limited access to water, or an impaired thirst mechanism. The patient may present in a hypovolaemic state.

  • Those who may have limited access to water include infants, disabled people, people with impaired mental status, postoperative patients, nursing home patients, and intubated patients.

  • An impaired thirst mechanism as a result of primary hypodipsia is rare, and caused by damage to the hypothalamic osmoreceptors that control thirst. This may be due to a variety of pathological changes, including vascular occlusion, tumours, congenital hypothalamic lesions, and granulomatous disease (e.g., sarcoidosis).[6]​​

  • Inadequate breastfeeding without supplementation may lead to severe and potentially life-threatening hypernatraemia in the infant.[16]

Sodium gain

Hypernatraemia due to sodium gain is uncommon. Exogenous sodium overload is often associated with marked hypernatraemia (plasma sodium concentration may be >170 mmol/L [170 mEq/L]).[17]​ The patient usually presents in a hypervolaemic state.[6]​ Causes include:

  • Inadvertent administration of hypertonic sodium chloride (e.g., irrigation of hydatid cysts) or sodium bicarbonate (e.g., severe metabolic acidosis)[18]

  • Administration of isotonic sodium chloride (saline) to a patient who has diabetic ketoacidosis (DKA) with an osmotic diuresis

  • Replacement of sugar with salt in infant formula (accidental or intentional)​[17]​​

  • Massive salt ingestion (e.g., using Epsom salts as an emetic agent or gargle).

Mineralocorticoid excess

These patients may present in a hypervolaemic state.

  • Cushing's syndrome, whether by primary or secondary aetiology, produces a marked increase in cortisol, thereby increasing serum glucose, often leading to uncontrolled diabetes and hypernatraemia (due to sodium retention as a consequence of water retention).

  • Primary aldosteronism, which produces hyperaldosteronism, leads to increased sodium re-absorption, resulting in volume expansion. The persistent mild volume expansion resets the osmostat regulating ADH release and thirst upwards by several millimoles per litre (mEq/L). As a result, patients with primary aldosteronism usually have a stable plasma sodium concentration between 143 mmol/L (143 mEq/L) and 147 mmol/L (147 mEq/L) (mild hypernatraemia).[19]​​

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