Patients may present to medical attention with symptoms related to low serum sodium concentrations. However, many patients present due to manifestations of other medical comorbidities, with hyponatremia being recognized only secondarily. For many people, therefore, the recognition is entirely incidental. Patients may develop clinical symptoms due to the cause of hyponatremia or the hyponatremia itself.
Many medical illnesses, such as congestive heart failure, liver failure, renal failure, or pneumonia, may be associated with hyponatremia. These patients frequently present because of primary disease symptomatology (eg, dyspnea, jaundice, uremia, and cough). 
Symptoms range from nausea and malaise, with mild reduction in the serum sodium, to lethargy, decreased level of consciousness, headache, and (if severe) seizures and coma. Overt neurologic symptoms most often are due to very low serum sodium levels (usually <115 mEq/L), resulting in intracerebral osmotic fluid shifts and brain edema. This neurologic symptom complex can lead to tentorial herniation with subsequent brain stem compression and respiratory arrest, resulting in death in the most severe cases.
The severity of neurologic symptoms correlates well with the rate and degree of the drop in serum sodium. A gradual drop in serum sodium, even to very low levels, may be tolerated well if it occurs over several days or weeks, because of neuronal adaptation. The presence of an underlying neurologic disease, like a seizure disorder, or nonneurologic metabolic abnormalities, like hypoxia, hypercapnia, or acidosis, also affects the severity of neurologic symptoms.
In interviewing the patient, obtaining a detailed medication history, including information on over-the-counter (OTC) drugs the patient has been using, is important because many medications may precipitate hyponatremia (eg, antipsychotic medications, diuretics). A dietary history with reference to salt, protein, and water intake is useful as well. For patients who are hospitalized, reviewing the records of parenteral fluids administered is crucial.
Examination should include orthostatic vital signs and an accurate assessment of volume status. This determination (ie, hypervolemic, euvolemic, hypovolemic) often guides treatment decisions.
A full assessment for medical comorbidities is also essential, with particular attention paid to cardiopulmonary and neurologic components of the examination.
Although the differential diagnosis is quite broad, most hyponatremia can be divided into hypertonc, normotonic, or hypotonic in origin. Miscellaneous causes account for the remainder of cases.
Patients with hypertonic hyponatremia have normal total body sodium and a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum, which causes a water shift from the intracellular compartment to the extracellular compartment.
Glucose produces a drop in the serum sodium level of 1.6 mEq/L for each 100 mg/dL of serum glucose greater than 100 mg/dL. This relationship is nonlinear, with greater reduction in plasma sodium concentrations with glucose concentrations over 400 mg/dL, making 2.4 mEq/L for each 100 mg/dL increase in glucose over 100 mg/dL a more accurate correction factor when the glucose is greater than 400 mg/dL. 
Other examples of osmotically active molecules include mannitol (often used to treat brain edema) or maltose (used with intravenous immunoglobulin administration).
Severe hyperlipidemia and paraproteinemia can lead to low measured serum sodium concentrations with normal serum osmolality. Normally, the plasma water comprises 92-94% of plasma volume. The plasma water fraction falls with an increase in fats and proteins. The measured sodium concentration in the total plasma volume is respectively reduced, although the plasma water sodium concentration and plasma osmolality are unchanged. This artifactual low sodium (so-called pseudohyponatremia) is secondary to measurement by flame photometry. It can be avoided by direct ion-selective electrode measurement.
Hyponatremia after transurethral resection of the prostate (TURP) or hysteroscopy is caused by absorption of irrigants, glycine, sorbitol, or mannitol, contained in nonconductive flushing solutions used for those procedures. The degree of hyponatremia is related to the quantity and rate of fluid absorbed. The plasma osmolality is also variable and changes over time.
The presence of a relatively large osmolal gap due to excess organic solute is diagnostic in the appropriate clinical setting. Symptomatic patients are treated depending on plasma osmolality and volume status, with hypertonic saline for patients in hypoosmolar state or a loop diuretic in volume-overloaded patients with normal renal function.
Hemodialysis, which will correct the hyponatremia and remove glycine and its toxic metabolites, can be used in patients with end-stage renal disease. Use of isotonic saline as an irrigant instead of glycine with the new bipolar resectoscope for TURP in high-risk patients (with large prostates that require lengthy resection) could avoid this complication, making this disorder a diagnosis of the past. 
Hypotonic hyponatremia always reflects the inability of the kidneys to handle the excretion of free water to match intake. It can be divided pathophysiologically into the following categories, according to the effective intravascular volume: hypovolemic, hypervolemic, and euvolemic. These clinically relevant groupings aid in determination of likely underlying etiology and guide treatment.
Hypovolemic hypotonic hyponatremia
This usually indicates concomitant solute depletion, with patients presenting with orthostatic symptoms. The pathophysiology underlying hypovolemic hypotonic hyponatremia is complex and involves the interplay of carotid baroreceptors, the sympathetic nervous system, the renin-angiotensin system, antidiuretic hormone (ADH; vasopressin) secretion, and renal tubular function. In the setting of decreased intravascular volume (eg, severe hemorrhage or severe volume depletion secondary to GI or renal loss, or diuretic use) owing to a decreased stretch on the baroreceptors in the great veins, aortic arch, and carotid bodies, an increased sympathetic tone to maintain systemic blood pressure generally occurs.
This increased sympathetic tone, along with decreased renal perfusion secondary to intravascular volume depletion, results in increased renin and angiotensin excretion. This, in turn, results in increased sodium absorption in the proximal tubules of the kidney and consequent decreased delivery of solutes to distal diluting segments, causing an impairment of renal free water excretion. There also is a concomitant increase in serum ADH production that further impairs free water excretion. Because angiotensin is also a very potent stimulant of thirst, free water intake is increased, and, at the same time, water excretion is limited. Together, these changes lead to hyponatremia.
Cerebral salt wasting (CSW) is seen with intracranial disorders, such as subarachnoid hemorrhage, carcinomatous or infectious meningitis, and metastatic carcinoma, but especially after neurologic procedures. Disruption of sympathetic neural input into the kidney, which normally promotes salt and water reabsorption in the proximal nephron segment through various indirect and direct mechanisms, might cause renal salt wasting, resulting in reduced plasma volume. Plasma renin and aldosterone levels fail to rise appropriately in patients with CSW despite a reduced plasma volume because of disruption of the sympathetic nervous system. In addition, the release of 1 or more natriuretic factors could also play a role in the renal salt wasting seen in CSW. Volume depletion leads to an elevation of plasma vasopressin levels and impaired free water excretion.
Distinguishing between CSW and syndrome of inappropriate ADH secretion (SIADH) can be challenging, because there is considerable overlap in the clinical presentation. Vigorous salt replacement is required in patients with CSW, whereas fluid restriction is the treatment of choice in patients with SIADH. Infusion of isotonic saline to correct the volume depletion is usually effective in reversing the hyponatremia in cerebral salt wasting, since euvolemia will suppress the release of ADH. The disorder is usually transient, with resolution occurring within 3-4 weeks of disease onset. [14, 15]
Salt-wasting nephropathy causing hypovolemic hyponatremia may rarely develop in a range of renal disorders (eg, interstitial nephropathy, medullary cystic disease, polycystic kidney disease, partial urinary obstruction) with low salt intake.
Diuretics may induce hypovolemic hyponatremia. Note that thiazide diuretics, in contrast to loop diuretics, impair the diluting mechanism without limiting the concentrating mechanism, thereby impairing the ability to excrete a free water load. Thus, thiazides are more prone to causing hyponatremia than are loop diuretics. This is particularly so in elderly persons, who already have impaired diluting ability.
Hypervolemic hypotonic hyponatremia
This is characterized by clinically detectable edema or ascites that signifies an increase in total body water and sodium. Paradoxically, however, a decrease in the effective circulating volume, critical for tissue perfusion, stimulates the same pathophysiologic mechanism of impaired water excretion by the kidney that is observed in hypovolemic hypotonic hyponatremia. Commonly encountered examples include liver cirrhosis, congestive heart failure, nephrotic syndrome, and severe hypoproteinemia (albumin level <1.5-2 g/dL).
Normovolemic (euvolemic) hypotonic hyponatremia
This is a very common cause of hyponatremia in patients who are hospitalized. It is associated with nonosmotic and non–volume-related ADH secretion (ie, SIADH) secondary to a variety of clinical conditions, including the following:
CNS disturbances (eg, hypopituitarism  )
Common medications associated with SIADH are as follows: chlorpropamide (potentiating renal action of ADH), carbamazepine (possesses antidiuretic property), cyclophosphamide (marked water retention secondary to SIADH and potentially fatal hyponatremia may ensue in selected cases; use of isotonic saline rather than free water to maintain a high urine output to prevent hemorrhagic cystitis can minimize the risk), vincristine, vinblastine, amitriptyline, haloperidol, selective serotonin reuptake inhibitors (particularly in elderly patients), and monoamine oxidase (MAO) antidepressants. In these circumstances, the ability of the kidney to dilute urine in the setting of serum hypotonicity is reduced.
Hyponatremia is a relatively common adverse effect of desmopressin, a vasopressin analogue that acts as a pure V2 agonist. Its common use in the treatment of central diabetes insipidus, von Willebrand disease, and nocturia in adults and of enuresis in children requires regular monitoring of serum sodium levels.
The diagnostic criteria for SIADH are as follows:
Normal hepatic, renal, and cardiac function - clinical euvolemia (absence of intravascular volume depletion)
Normal thyroid and adrenal function
Urine osmolality greater than 100 mOsm/kg, generally greater than 400-500 mOsm/kg with normal renal function
Urinary sodium concentrations are also typically greater than 20 mEq/L on a normal salt diet as sodium excretion will reflect dietary sodium intake. Serum uric acid levels are generally reduced; this is due to reduced tubular uric acid reabsorption, which parallels the decrease in proximal tubular sodium reabsorption associated with central volume expansion. These findings are also found in a renal salt wasting process. This similarity makes the differentiation between salt wasting and SIADH difficult except that in renal wasting, one would expect to find a hypovolemic state.
Reset osmostat is another important cause of normovolemic hypotonic hyponatremia. This may occur in elderly patients and during pregnancy. These patients regulate their serum osmolality around a reduced set point; however, in contrast to patients with SIADH (who also have a downward resetting of the osmotic threshold for thirst),  they are able to dilute their urine in response to a water load to keep the serum osmolality around the preset low point.
Severe hypothyroidism (unknown mechanism, possibly secondary to low cardiac output and glomerular filtration rate) and adrenal insufficiency are also associated with nonosmotic vasopressin release and impaired sodium reabsorption, leading to hypotonic hyponatremia. Hyponatremia associated with cortisol deficiency, such as primary or secondary hypoadrenalism, commonly presents subtly and may go undiagnosed. A random cortisol level check, especially in acute illness, can be misleading if the level is normal (when it should be high). Testing for adrenal insufficiency and hypothyroidism should be part of the hyponatremic workup, as the disorders respond promptly to hormone replacement. Depending on the etiology, mineralocorticoid will also need replacement.
Hospitalized patients who are infected with human immunodeficiency virus (HIV) have a high incidence of hyponatremia. In these cases, hyponatremia is usually due to at least one of the following three disorders associated with an increased ADH level:
Increased release of ADH due to malignancy, to occult or symptomatic infection of the central nervous system, or to pneumonia resulting from infection with Pneumocystis jiroveci or other organisms.
Effective volume depletion secondary to fluid loss from the gastrointestinal tract, due primarily to infectious diarrhea.
Adrenal insufficiency often due to an adrenalitis, an abnormality that may be infectious in origin, perhaps being induced by cytomegalovirus, Mycobacterium avium-intracellulare, or HIV itself. Affected patients have a high risk of morbidity and mortality.
There are other causes that do not fit neatly in any of the above categories and may or may not be associated with elevated levels of ADH or simply overwhelm the capacity of the kidneys to properly excrete excess water.
The most common precipitant of hyponatremia in patients after surgery  is the iatrogenic infusion of hypotonic fluids. Inappropriate administration of hypotonic intravenous fluids after surgery increases the risk of developing hyponatremia in these vulnerable patients, who retain water due to nonosmotic release of ADH, which is typically elevated for a few days after most surgical procedures. Hospital-acquired acute hyponatremia is disturbingly common also among hospitalized children and adults.
Severe malnutrition seen in weight-conscious women (low protein, high water intake diet) is a special condition in which a markedly decreased intake of solutes occurs, which limits the ability of the kidney to handle the free water. Because a mandatory solute loss of 50-100 mOsm/kg of urine exists, free water intake in excess of solute needs can produce hyponatremia.  Another example is beer drinker's potomania, because a diet consisting primarily of beer is rich in free water but solute poor.
Compulsive intake of large amounts of free water exceeding the diluting capacity of the kidneys (>20 L/d), even with a normal solute intake of 600-900 mOsm/d, may also result in hyponatremia, but in contrast to SIADH, the urine is maximally dilute. In addition to a central defect in thirst regulation, which plays an important role in the pathogenesis of primary polydipsia, different abnormalities in ADH regulation have been identified in psychotic patients, all impairing free water excretion. Transient stimulation of ADH release during acute psychotic episodes, an increase in the net renal response to ADH, downward resetting of the osmostat, and antipsychotic medication may contribute. Limiting water intake will rapidly raise the plasma sodium concentration as the excess water is readily excreted in dilute urine 
Acute hyponatremia is associated with ultra-endurance athletes and marathon runners.  With women making up a higher percentage, the strongest single predictor is weight gain during the race correlating with excessive fluid intake. Longer racing time and body mass index extremes are also associated with hyponatremia, whereas the composition of fluids consumed (plain water rather than sports drinks containing electrolytes) is not. Oxidization of glycogen and triglyceride during a race is associated with the production of "bound" water, which then becomes an endogenous, electrolyte-free water infusion contributing to hyponatremia induced by water ingestion in excess of water losses.
It should be noted that some collapsed runners are normonatremic or even hypernatremic,  making blanket recommendations difficult. However, fluid intake to the point of weight gain should be avoided. [22, 23] Athletes should rely on thirst as their guide for fluid replacement and avoid fixed, global recommendations for water intake. Symptomatic hyponatremic patients should receive 100 mL of 3% sodium chloride over 10 minutes in the field before transportation to hospital. This maneuver should raise the plasma sodium concentration an average of 2-3 mEq/L. 
Nonsteroidal anti-inflammatory drug (NSAID) use may increase the risk of development of hyponatremia by strenuous exercise by inhibiting prostaglandin formation. Prostaglandins have a natriuretic effect. Prostaglandin depletion increases NaCl reabsorption in the thick ascending limb of Henle (ultimately increasing medullary tonicity) and ADH action in the collecting duct, leading to impaired free water excretion. 
Symptomatic and potentially fatal hyponatremia can develop with rapid onset after ingestion of the designer drug ecstasy (methylenedioxymethamphetamine, or MDMA), an amphetamine. A marked increase in water intake via direct thirst stimulation, as well as inappropriate secretion of ADH, contributes to the hyponatremia seen with even small amount of drug intake.
Nephrogenic syndrome of inappropriate antidiuresis (or NSIAD) is an SIADH-like clinical and laboratory picture seen in male infants who present with neurologic symptoms secondary to hyponatremia but who have undetectable plasma arginine vasopressin (AVP) levels. This hereditary disorder is secondary to mutations in the V2 vasopressin receptor, resulting in constitutive activation of the receptor with elevated cAMP production in the collecting duct principle cells. Treatment of NSIAD poses a challenge. Water restriction improves serum sodium levels and osmolality in infants, but it limits calorie intake in these formula-fed infants. The use of demeclocycline or lithium is potentially limited because of adverse effects. The current therapy of choice is fluid restriction and the use of oral urea to induce an osmotic diuresis. 
Hyponatremic hypertensive syndrome, a rare condition, consists of severe hypertension associated with renal artery stenosis, hyponatremia, hypokalemia, severe thirst, and renal dysfunction characterized by natriuresis, hypercalciuria, renal glycosuria, and proteinuria. Angiotensin-mediated thirst coupled with nonosmotic release of vasopressin provoked by angiotensin II and/or hypertensive encephalopathy are likely mechanisms for this syndrome. Sodium depletion due to pressure natriuresis and potassium depletion due to hyperaldosteronism with high plasma renin activity are also likely to play a role in the pathogenesis of hyponatremia. The abnormalities resolve with correction of the renal artery stenosis. 
Using a retrospective case note analysis, an Irish study examined the incidence of hyponatremia in a variety of neurologic conditions.  The investigators found that the occurrence of hyponatremia was greater in persons with subarachnoid hemorrhage (62 out of 316 patients, or 19.6%; P <0.001), intracranial neoplasm (56 out of 355 patients, or 15.8%; P <0.001), traumatic brain injury (44 out of 457 patients, or 9.6%; P <0.001), and pituitary disorders (5 out of 81 patients, or 6.25%; P = 0.004) than it was in patients with spinal disorders (4 out of 489 patients, or 0.81%).
The investigators also determined that the median hospital stay for patients with hyponatremia was 19 days, compared with a median stay of 12 days for the study's other patients.
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