Etiology
Hypernatremia, defined as a plasma sodium concentration of >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. Pseudohypernatremia can develop in patients with hypoalbuminemia.[10][11]
Free water loss
Renal losses
Regarded as the most common cause of hypernatremia; occurs through either osmotic diuresis or as a consequence of diabetes insipidus.[6]
Due to osmotic diuresis
Typically the patient will present in a hypovolemic state.
The most frequent cause of an osmotic diuresis is hyperglycemia and glucosuria in poorly controlled diabetes mellitus. Hyperosmolar hyperglycemic 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 hyperglycemia, dehydration, and hyperosmolarity without ketoacidosis.
Loop diuretics, such as furosemide and torsemide, can cause renal losses of sodium; they produce an isoosmotic solute diuresis resulting in impaired renal concentrating ability, which reduces the reabsorption 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 tumors, urethral strictures) often leads to a postobstructive diuresis once corrected. Consequently, there is free water loss that may result in hypernatremia.
Due to diabetes insipidus
Typically the patient will present in a euvolemic state.
Hypernatremia secondary to nonosmotic renal water loss is usually caused by central diabetes insipidus, characterized 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, hypercalcemia, hypokalemia, 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 hypernatremia include colchicine, gentamicin, lithium, rifampin, and propoxyphene.[15]
Nonrenal losses
May be due to insensible water losses such as evaporation from the skin. In cases of severe burns, patients are usually euvolemic in the first 48 hours and become hypovolemic thereafter. Insensible water losses can also occur as a result of losses from the gastrointestinal (GI) tract. These patients usually present in a hypovolemic 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 euvolemic). Thereafter, the skin damage allows greater evaporation, increasing insensible water losses (patient becomes hypovolemic). With regards to heat and sweating, the sodium concentration of sweat decreases with continued profuse perspiration, thereby increasing solute-free water loss.
Severe diarrhea is the most common GI cause of hypernatremia, and the patient usually presents in a hypovolemic state. Osmotic diarrhea 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 diarrhea, which has a fecal 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 hypernatremia.
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 disease.
Free water intake deficit
Usually the result of limited access to water, or an impaired thirst mechanism. The patient may present in a hypovolemic 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 pathologic changes, including vascular occlusion, tumors, congenital hypothalamic lesions, and granulomatous disease (e.g., sarcoidosis).[6]
Inadequate breast-feeding without supplementation may lead to severe and potentially life-threatening hypernatremia in the infant.[16]
Sodium gain
Hypernatremia due to sodium gain is uncommon. Exogenous sodium overload is often associated with marked hypernatremia (plasma sodium concentration may be >170 mEq/L).[17] The patient usually presents in a hypervolemic 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 hypervolemic state.
Cushing syndrome, whether by primary or secondary etiology, produces a marked increase in cortisol, thereby increasing serum glucose, often leading to uncontrolled diabetes and hypernatremia (due to sodium retention as a consequence of water retention).
Primary aldosteronism, which produces hyperaldosteronism, leads to increased sodium reabsorption, resulting in volume expansion. The persistent mild volume expansion resets the osmostat regulating ADH release and thirst upward by several milliequivalents per liter. As a result, patients with primary aldosteronism usually have a stable plasma sodium concentration between 143 and 147 mEq/L (mild hypernatremia).[19]
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