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Hyponatremia (American English) or hyponatraemia (British English) is an electrolyte disturbance in which the sodium ion concentration in the plasma is lower than normal. Sodium is the dominant extracellular cation (positive ion) and cannot freely cross from the interstitial space into the cell, because charged sodium ions attract up to 25 water molecules around them, creating a large polar structure that is too large to pass through the cell membrane. Its homeostasis (stability of concentration) inside the cell is vital to the normal function of any cell. Normal serum sodium levels are between approximately 135 and 145 mEq/L (135 - 145 mmol/L). Hyponatremia is generally defined as a serum level of less than 135 mEq/L and is considered severe when the serum level is below 125 mEq/L.
Many conditions including congestive heart failure, liver failure, kidney failure and pneumonia can have an associated hyponatremia. It can also be caused by overhydration from drinking too much water (polydipsia).
In the vast majority of cases, hyponatremia occurs as a result of a proportional excess of water relative to the plasma sodium (salt level in the blood). Lack of sodium (salt) alone is very rarely the cause of hyponatremia, although it can promote hyponatremia indirectly. In particular, sodium loss can lead to a state of volume depletion (loss of blood volume in the body), with volume depletion serving as a signal for the release of ADH (anti-diuretic hormone). As a result of ADH-stimulated water retention (too much water in the body), blood sodium becomes diluted and hyponatremia results.
Exercise-associated hyponatremia (EAH), however, is common at marathons and other endurance events. Researchers found, for instance, that 13% of the athletes who finished the 2002 Boston Marathon were in a clinically hyponatremic condition, i.e. their salt levels in their blood had fallen below an acceptable level. Tim Noakes' 2012 book "Waterlogged" addresses this phenomenon clearly.
Signs and symptoms
Symptoms of hyponatremia include nausea and vomiting, headache, confusion, lethargy, fatigue, loss of appetite, restlessness and irritability, muscle weakness, spasms, or cramps, seizures, and decreased consciousness or coma. The presence and severity of symptoms are associated with the level of plasma sodium (salt level in the blood), with the lowest levels of plasma sodium associated with the more prominent and serious symptoms (the less the salt the more severe the symptoms). However, emerging data suggest that mild hyponatremia (plasma sodium levels at 131 mEq/L or above) is associated with numerous complications or subtle, presently unrecognized symptoms (e.g., increased falls, altered posture and gait, reduced attention).
Neurological (brain) symptoms typically occur with very low levels of plasma sodium (usually <115 mEq/L). When sodium levels in the blood become excessively low, excess water enters the brain cells and the cells swell. This is called hyponatremic encephalopathy. This is very dangerous because the soft brain is confined by the rigid skull. As the brain expands tentorial herniation can occur which is a squeezing of the brain across the internal structures of the skull.
This can lead to headache, nausea, vomiting and confusion, seizures, brain stem compression and respiratory arrest (stopping breathing), and non-cardiogenic pulmonary edema (fluid in the lungs). This can be fatal if not treated promptly.
The severity of symptoms depends on how fast and how severe the drop in blood salt level. A gradual drop, even to very low levels, may be tolerated well if it occurs over several days or weeks, because of neuronal adaptation. The presence of underlying neurological disease, like a seizure disorder, or non-neurological metabolic abnormalities, also affects the severity of neurologic symptoms.
Based on the above classification, some of the many specific causes of hyponatremia can be listed as follows:
Hypervolemic hyponatremia — Both sodium & water content increase: Increase in sodium content leads to hypervolemia and water content to hyponatremia. Total body water and sodium are regulated independently
- cirrhosis of the liver
- congestive heart failure
- nephrotic syndrome in the kidneys
- massive edema of any cause
Euvolemic hyponatremia — total body water increases, but the body's sodium content stays the same
- states of severe pain or nausea
- in the setting of trauma or other damage to the brain
- SIADH (and its many causes)
- Glucocorticoid (steroid) deficiency
Hypovolemic hyponatremia — The hypovolemia (extracellular volume loss) is consequent on total body sodium loss but, overall, total body water is decreased and is the aetiology of the hyponatremia
- any cause of hypovolemia such as prolonged vomiting, decreased oral intake, severe diarrhea
- diuretic use (due to the diuretic causing a volume depleted state and thence ADH release, and not a direct result of diuretic-induced urine sodium loss)
- Addison's disease in which the adrenal glands do not produce sufficient steroid hormones (combined glucocorticoid and mineralocorticoid deficiency)
Miscellaneous causes of hyponatremia that are not included under the above classification scheme include:
- factitious hyponatremia (due to massive increases in blood triglyceride levels, extreme elevation of immunoglobulins as may occur in multiple myeloma, and extreme hyperglycemia)
- hypothyroidism and adrenal insufficiency (both thyroid hormone and cortisol are required to excrete free water)
- beer potomania and other malnourished states where poor dietary protein intake leads to inadequate urine solute formation thereby impeding the kidney's ability to excrete free water
- primary polydipsia (where the amount of urine solute required to excrete huge quantities of ingested water exceeds the body's ability to produce it; this typically occurs when 12 or more litres of water are ingested per day)
Examination includes taking vital signs when lying, sitting, and standing, and an assessment of how much blood is in the body. This determination (i.e. hypervolemic, euvolemic, hypovolemic) helps guide treatment decisions. A full assessment of other medical conditions (comorbidity) is also taken, because heart and brain conditions affect the results and the treatment decisions.
The hyponatremia can be spurious (false) and/or artifactual hyponatremia in which case there is no hypotonicity. Hypertonic hyponatremia, caused by resorption of water drawn by molecules such as glucose (hyperglycemia or diabetes) or mannitol (hypertonic infusion). Isotonic hyponatremia, more commonly called "pseudohyponatremia," is caused by measurement error due to hypertriglyceridemia (most common) or paraproteinemia. It occurs when using techniques that measure the amount of sodium in a specified volume of serum/plasma, or that dilute the sample before analysis.
True hyponatremia is Hypotonic hyponatremia and is by far the most common type, and is often simply referred to as "hyponatremia." Hypotonic hyponatremia is categorized in 3 ways based on the patient's blood volume status. Each category represents a different underlying reason for the increase in ADH that led to the water retention and thence hyponatremia:
- Hypervolemic hyponatremia, wherein there is decreased effective circulating volume (less blood flowing in the body) even though total body volume is increased (by the presence of edema or swelling, especially in the ankles). The decreased effective circulating volume stimulates the release of anti-diurectic hormone(ADH), which in turn leads to water retention. Hypervolemic hyponatremia is most commonly the result of congestive heart failure, liver failure (cirrhosis), or kidney disease (nephrotic syndrome).
- Euvolemic hyponatremia, wherein the increase in ADH is secondary to either physiologic but excessive ADH release (as occurs with nausea or severe pain) or inappropriate and non-physiologic secretion of ADH, i.e. syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). Often categorized under euvolemic is hyponatremia due to inadequate urine solute (not enough chemicals or electrolytes to produce urine) as occurs in beer potomania or "tea and toast" hyponatremia, hyponatremia due to hypothyroidism or central adrenal insufficiency, and those rare instances of hyponatremia that are truly secondary to excess water intake (i.e., extreme psychogenic polydipsia)
- Hypovolemic hyponatremia, wherein ADH secretion is stimulated by or associated with volume depletion (not enough water in the body).
The volemic classification fails to include spurious (fake) and/or artifactual hyponatremia, which is addressed in the osmolar classification. This includes hyponatremia that occurs in the presence of massive hypertriglyceridemia, severe hyperglycemia, and extreme elevation of immunoglobulin levels.
In chronic hyponatremia, sodium (salt) levels drop gradually over several days or weeks and symptoms and complications are typically moderate. Chronic hyponatremia is often called asymptomatic hyponatremia in clinical settings because it is thought to have no symptoms; however, emerging data suggests that "asymptomatic" hyponatremia is not actually asymptomatic.
In acute hyponatremia sodium (salt) levels drop rapidly, resulting in potentially dangerous effects, such as rapid brain swelling, which can result in coma and death.
The treatment of hyponatremia depends on the underlying cause and whether the patient's blood volume status is hypervolemic, euvolemic, or hypovolemic. In the setting of hypovolemia, intravenous administration of normal saline (salt) is usual, careful care taken not to raise the serum sodium level (salt level in the blood) too quickly (see below). Euvolemic hyponatremia is usually managed by fluid restriction and treatment to abolish any stimuli for ADH secretion such as nausea. Likewise, drugs causing SIADH are discontinued if possible. Patients with euvolemic hyponatremia that persists despite those measures may be candidates for a so-called vaptan drug as discussed below. Hypervolemic hyponatremia is usually treated by addressing the underlying heart or liver failure. If it is not be possible to do so, the treatment becomes the same as that for euvolemic hyponatremia (i.e. fluid restriction and/or use of a vaptan drug).
Hyponatremia is corrected slowly in order to lessen the chance of the development of central pontine myelinolysis (CPM), a severe neurological disease involving a breakdown of the myelin sheaths covering parts of nerve cells. In fact, overly rapid correction of hyponatremia is the most common cause of that potentially devastating disorder. During treatment of hyponatremia, the serum sodium (salt level in the blood) is not allowed to rise by more than 8 mmol/l over 24 hours (i.e. 0.33 mmol/l/h rate of rise). In practice, too rapid correction of hyponatremia and thence CPM is most likely to occur during the treatment of hypovolemic hyponatremia. In particular, once the hypovolemic state has been corrected, the signal for ADH release disappears. At that point, there will be an abrupt water diuresis (an increase in urination since there is no longer any ADH acting to retain the water). A rapid and profound rise in serum sodium (salt level in the blood) can then occur. Should the rate of rise of serum sodium exceed 0.33 mmol/l/h over several hours, vasopressin may be administered to prevent ongoing rapid water diuresis (excessive urination).
Pharmaceutically, vasopressin receptor antagonists can be used in the treatment of hyponatremia, especially in patients with SIADH, congestive heart failure or liver cirrhosis. A vasopressin receptor antagonist is an agent that interferes with the action at the vasopressin receptors. A new class of medication, the "vaptan" drugs has been specifically developed to inhibit the action of vasopressin on its receptors (V1A, V1B, and V2). These receptors have a variety of functions, with the V1A and V2 receptors are expressed peripherally and involved in the modulation of blood pressure and kidney function respectively, while the V1A and V1B receptors are expressed in the central nervous system. V1A is expressed in many regions of the brain, and has been linked to a variety of social behaviors in humans and animals.
The “vaptan” class of drugs contains a number of compounds with varying selectivity, several of which are either already in clinical use or in clinical trials as of 2010.
Unselective (mixed V1A, V2)
The V2-receptor antagonists tolvaptan and conivaptan allow excretion of electrolyte free water and are effective in increasing serum sodium in euvolemic and hypervolemic hyponatremia.
Chronic hyponatremia can lead to such complications as neurological impairments. These neurological impairments most often affect gait (walking) and attention, and can lead to falls, osteoporosis, and decreased reaction time.
Complications for chronic hyponatremia are most dangerous for geriatric patients. Falls are the leading cause of deaths related to injury among people 65 years or older. In a recent study the incidence of hyponatremia in elderly patients with large-bone fractures was more than double that of non-fracture patients. Recent work by Verbalis et al. suggests that hyponatremia induces osteoporosis and found the adjusted odds ratio for developing osteoporosis to be 2.87 times higher among adults with mild hyponatremia compared to those without.
Hyponatremia is the most common electrolyte disorder. Electrolytes are sodium (salt), potassium, calcium, magnesium, chloride, hydrogen phosphate, and hydrogen carbonate. The disorder is more frequent in females, the elderly, and in patients who are hospitalized. The incidence of hyponatremia depends largely on the patient population. A hospital incidence of 15–20% is common, while only 3–5% of patients who are hospitalized have a serum sodium level (salt blood level) of less than 130 mEq/L. Hyponatremia has been reported in up to 30% of elderly patients in nursing homes and is also present in approximately 30% of depressed patients on selective serotonin reuptake inhibitors.
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