Causes of hyponatremia in adults

Author
Richard H Sterns, MD
Section Editor
Michael Emmett, MD
Deputy Editor
John P Forman, MD, MSc
Disclosures: Richard H Sterns, MD Nothing to disclose. Michael Emmett, MD Consultant/Advisory Boards: ZS
Pharma [treatment of hyperkalemia (potassium binder, zirconium silicate)]. John P Forman, MD, MSc Nothing to
disclose.
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2015. | This topic last updated: Aug 12, 2014.
INTRODUCTION Hyponatremia is commonly defined as a serum sodium concentration below
135 meq/L but can vary to a small degree in different clinical laboratories [1,2]. The dilutional fall in
serum sodium is in most patients associated with a proportional reduction in the serum osmolality
(ie, to a level below 275 mosmol/kg), but there are some exceptions. (See 'Hyponatremia with a
high or normal serum osmolality' below.)
In virtually all patients, hyponatremia results from the intake (either oral or intravenous) and
subsequent retention of water [3]. A water load will, in normal individuals, be rapidly excreted as the
dilutional fall in serum osmolality suppresses the release of antidiuretic hormone (ADH, also called
vasopressin) (figure 1), thereby allowing excretion of the excess water in a dilute urine. The
maximum attainable urine volume in normal individuals on a regular diet is over 10 L/day. This
provides an enormous range of protection against the development of hyponatremia since the daily
fluid intake in most healthy individuals is less than 2 to 2.5 L/day.
In contrast to the response in normal individuals, patients who develop hyponatremia typically have
an impairment in renal water excretion, most often due to an inability to suppress ADH secretion. An
uncommon exception occurs in patients with primary polydipsia who can become hyponatremic
because they rapidly drink such large quantities of fluid that they overwhelm the excretory capacity
of the kidney even though ADH release is appropriately suppressed.
An overview of the causes of hyponatremia will be presented here (table 1). Most of the individual
causes of hyponatremia are discussed in detail separately, as are issues related to the diagnosis
and treatment of hyponatremia [3,4]. (See "Evaluation of adults with hyponatremia" and "Overview
of the treatment of hyponatremia in adults".)
DETERMINANTS OF THE SERUM SODIUM CONCENTRATION Understanding the factors that
determine the serum sodium concentration is required to appreciate the factors that promote the
development of hyponatremia and what the composition of intravenous fluids must be to correct the
hyponatremia.

In the following discussion, the term "tonicity" (also called the effective plasma osmolality) refers to
the osmotic activity of solutes that do not easily cross cell membranes and therefore determine the
transcellular distribution of water.
The extracellular and intracellular fluids are in osmotic equilibrium since water moves freely across
most cell membranes. As a result, plasma tonicity is equal to the effective intracellular osmolality
and to the effective osmolality of the total body water (TBW). These relationships can be
summarized by the following equation:
Plasma tonicity = (Extracellular solute + Intracellular solute)

TBW
Exchangeable sodium salts (Nae) are the primary effective extracellular solute and exchangeable
potassium (Ke) and its associated intracellular anions are the primary intracellular solutes; these
solutes are the major determinants of the effective plasma osmolality. Glucose, the other major
extracellular solute is, in the absence of marked hyperglycemia, present in a much lower molar
concentration than sodium (eg, 5 mmol/L [90 mg/dL] versus 140 mmol/L).
Approximately 30 percent of total body sodium and a smaller fraction of total body potassium are
bound in areas such as bone where they are "nonexchangeable" and therefore not osmotically
active. In addition, urea is considered an ineffective osmole since it freely equilibrates across the
cell membranes. When the plasma concentration of an ineffective osmole changes, the solute
rapidly moves into or out of cells to equalize the concentrations. Thus, there is little or no water shift
into or out of the cells as occurs with changes in the plasma sodium concentration.
Thus, plasma tonicity (effective plasma osmolality) can be expressed as:
Plasma tonicity (2 x Nae + 2 x Ke)

TBW
The multiplier 2 accounts for the osmotic contributions of the anions accompanying sodium and
potassium. In the absence of marked hyperglycemia or the administration of mannitol, the above
equation can be simplified to:
2 x plasma Na (2 x Nae + 2 x Ke)

TBW
and then to:
Plasma Na (Nae + Ke)

TBW
As shown in the figure, this relationship applies over a wide range of plasma or serum sodium
concentrations (figure 2) [5].

Application to hyponatremia The importance of considering the effect of potassium on the

plasma sodium concentration in patients with hyponatremia can be illustrated by the following
examples:
In patients with hyponatremia induced by thiazide diuretics, the sodium plus potassium
concentration in the urine may exceed that in the plasma, which will directly lower the plasma
sodium concentration independent of fluid intake. (See 'Diuretic-induced
hyponatremia' below.)
In a patient who has both severe hyponatremia and severe hypokalemia (due, for example,
to diuretic therapy or vomiting), treatment with large amounts of potassium in addition to
isotonic or hypertonic saline may lead to overly rapid correction of the hyponatremia and
possible brain injury due to osmotic demyelination syndrome. (See "Overview of the treatment
of hyponatremia in adults", section on 'Risk of osmotic demyelination'.)
CLASSIFICATION At least two classification systems have been used for the etiology of
hyponatremia with a low serum osmolality (defined as a serum osmolality less than
275 mosmol/kg): one stratifies patients according to whether circulating antidiuretic hormone (ADH)
levels are inappropriately elevated or appropriately suppressed [3], and the other stratifies patients
according to volume status (hypovolemia, normovolemia, or hypervolemia) [6,7]. In either case, the
development of hyponatremia requires the intake of water that cannot be excreted.
The individual causes of hyponatremia are described below in the appropriate sections.
According to serum ADH levels Urinary excretion of a water load requires the suppression of
ADH release, which is mediated by the reduction in serum osmolality (figure 1). An inability to
suppress ADH release is the most common cause of hyponatremia and can be seen in the following
settings:
True volume depletion, which can be due to gastrointestinal losses (eg, vomiting or diarrhea)
or renal losses (most often thiazide rather than loop diuretics)
Decreased tissue perfusion (also called effective arterial volume depletion) due to reduced
cardiac output in heart failure or to systemic vasodilation in cirrhosis
A primary (ie, not hypovolemic) increase in ADH release in the syndrome of inappropriate
ADH secretion (SIADH), including an infrequent variant characterized by resetting of the
osmostat
There are also disorders in which hyponatremia occurs despite appropriate suppression of ADH
secretion. These include primary polydipsia, a low dietary solute intake, and advanced renal failure.
According to volume status The causes of hyponatremia can also be stratified by volume
status [6,7]:
Hypovolemia due to gastrointestinal losses (eg, vomiting or diarrhea) or renal losses (most
often thiazide rather than loop diuretics)
Normovolemia, which is most often associated with the SIADH but can also be seen with
primary polydipsia and a low dietary solute intake
Hypervolemia due to heart failure or cirrhosis

Hyponatremia can also occur in patients with advanced renal failure. These patients may appear
either euvolemic or, if they also retain salt and develop edema, hypervolemic.
HYPONATREMIA WITH A LOW SERUM OSMOLALITY The serum osmolality (Sosm) can be
calculated by the concentration in millimoles per liter of the major serum solutes according to the
following equation:
Sosm (mmol/kg) = (2 x serum [Na]) + (serum [glucose]/18) + (blood urea nitrogen/2.8)
The serum sodium concentration is multiplied by two to account for the accompanying anions
(mostly chloride and bicarbonate) that provide electroneutrality, and the corrections in the glucose
concentration and blood urea nitrogen (BUN) are to convert mg/dL into mmol/L. These corrections
in glucose and BUN do not need to be made when standard units are used.
The contributions of glucose and BUN to the serum osmolality are normally small, except in
conditions such as diabetes mellitus and renal failure. Thus, the serum osmolality can be estimated
in most patients by doubling the serum sodium concentration. (See "General principles of disorders
of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and
edema)", section on 'Plasma osmolality'.)
The two most common causes of hyponatremia with a low serum osmolality are effective arterial
blood volume depletion and the syndrome of inappropriate antidiuretic hormone (ADH) secretion,
both of which are associated with persistent ADH release [6-8].
Most patients with hyponatremia have a single cause but, in some patients, multiple factors
contribute to the fall in serum sodium. Symptomatic infection with human immunodeficiency virus
(HIV) is an example of this phenomenon, as volume depletion, the syndrome of inappropriate ADH
secretion, and adrenal insufficiency all may be present. (See "Electrolyte disturbances with HIV
infection".)
Effective arterial blood volume depletion The term "effective arterial blood volume" (also
called effective circulating volume) refers to the volume of arterial blood that is perfusing the tissues.
Effective arterial blood volume depletion can occur by two mechanisms: true volume depletion; and
edematous patients with heart failure or cirrhosis in whom tissue perfusion is reduced because of a
low cardiac output or arterial vasodilation, respectively. The reduction in tissue perfusion is sensed
by baroreceptors at three sites: in the carotid sinus and aortic arch that regulate sympathetic activity
and, with significant volume depletion, the release of antidiuretic hormone; in the glomerular afferent
arterioles that regulate the activity of the renin-angiotensin system; and in the atria and ventricles
that regulate the release of natriuretic peptides. (See "General principles of disorders of water
balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)",
section on 'Effective arterial blood volume'.)
Regardless of the mechanism, significantly decreased tissue perfusion is a potent stimulus to the
secretion of ADH (figure 3). This response is mediated by baroreceptors in the carotid sinus, which
sense a reduction in pressure or stretch, and can overcome the inhibitory effect of hyponatremia on
ADH secretion. Thus, water retention and hyponatremia can develop in patients with any disorder
causing effective arterial blood volume depletion.
True volume depletion True volume depletion can be caused by the loss of sodium and water
from the gastrointestinal tract (eg, vomiting or diarrhea), in the urine (most often due to diuretic

therapy), or bleeding. Such patients may also have hypokalemia and, if enough fluid is lost,
azotemia due to decreased renal perfusion.
The replacement of severe diarrhea losses due to cholera (which is associated with a sodium
concentration in stool of 120 to 140 meq/L) with an oral rehydration solution with reduced osmolality
(ie, more free water) may result in an increased incidence of hyponatremia as compared to
replacement with standard oral rehydration therapy, which has a higher sodium concentration [9].
(See "Oral rehydration therapy".)
Diuretic-induced hyponatremia Hyponatremia, which can be severe, is an occasional
complication of therapy with thiazide diuretics. It typically begins soon after the onset of thiazide
therapy. In contrast, hyponatremia is only rarely induced by loop diuretics since the inhibition of
sodium chloride transport in the loop of Henle prevents the generation of the countercurrent
gradient and therefore limits the ability of ADH to promote water retention.
The following discussion will briefly review the mechanisms involved in thiazide-induced
hyponatremia. A more complete discussion is presented elsewhere. (See "Diuretic-induced
hyponatremia", section on 'Pathogenesis'.)
Although hypovolemia can contribute to thiazide-induced hyponatremia, most patients appear
clinically euvolemic and several other factors appear to play a role in the development of
hyponatremia:
An underlying tendency to increased water intake.
A reduction in diluting ability and therefore impaired water excretion, which is a direct effect
of reduced sodium chloride reabsorption without water in the distal tubule.
The sodium plus potassium concentration in the urine may exceed that in the plasma, which
will directly lower the plasma sodium concentration (see'Determinants of the serum sodium
concentration' above). As an example, in a study of five patients with recent onset of severe
thiazide-induced hyponatremia (mean serum sodium 105 meq/L), the urine sodium plus
potassium concentration was 156 meq/L [10].
Heart failure and cirrhosis Even though the plasma and extracellular volumes may be
markedly increased in heart failure and cirrhosis, the pressure sensed at the carotid sinus
baroreceptors is generally reduced due to the fall in cardiac output in heart failure and to arterial
vasodilatation in cirrhosis [3,11]. Thus, serum ADH levels tend to reflect the severity of the
underlying disease, making the development of hyponatremia an important prognostic sign. A stable
serum sodium below 130 meq/L is a marker of near end-stage liver or heart disease (figure 4).
(See "Hyponatremia in patients with heart failure" and "Hyponatremia in patients with cirrhosis".)
In contrast, hyponatremia is an uncommon finding in patients with the nephrotic syndrome in the
absence of concurrent renal failure. Most such patients have relatively normal tissue perfusion and
effective arterial volume and therefore do not have a clinically important stimulus to ADH secretion.
(See"Pathophysiology and treatment of edema in patients with the nephrotic syndrome", section on
'Volume regulatory hormones'.)
Syndrome of inappropriate ADH secretion Persistent ADH release and water retention can be
seen in a variety of disorders that are not associated with hypovolemia, a condition called syndrome
of inappropriate ADH secretion (SIADH). Major causes include central nervous system disease,

malignancy, certain drugs, and recent surgery. (See "Pathophysiology and etiology of the syndrome
of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Etiology'.)
Endocrine disorders The original definition of SIADH excluded patients with glucocorticoid
deficiency or hypothyroidism [12,13]. However, hyponatremia with features that are identical to
those found in patients meeting the classical definition of SIADH (ie, euvolemia with a high urine
osmolality and urine sodium) can also occur in patients with hypothyroidism or secondary adrenal
insufficiency (not primary adrenal insufficiency, in which hyponatremia is associated with
hypovolemia). Because these endocrine disorders are not always clinically apparent when patients
first present with unexplained hyponatremia, some authors include endocrine disorders in the
differential diagnosis of SIADH.
Hypothyroidism Hyponatremia is sometimes associated with moderate to severe
hypothyroidism, particularly in patients with primary hypothyroidism and myxedema [14-18]. Thus,
thyroid function should be evaluated in any patient with an otherwise unexplained reduction in the
plasma sodium concentration. However, because hypothyroidism and hyponatremia are common
findings in hospitalized patients, their coexistence may not necessarily be causal; other
explanations for hyponatremia should still be sought unless hypothyroidism is severe.
The mechanism by which hypothyroidism induces hyponatremia is incompletely understood.
Patients with hypothyroidism have a diminished ability to excrete free water and fail to achieve
maximally dilute urine after a water load. Some but not all studies have reported elevated levels of
ADH in patients who have hyponatremia associated with hypothyroidism [14-16]. This may be due
in part to a reduced cardiac output, which can lead to the release of ADH via the carotid sinus
baroreceptors [15,16,19]. However, some patients fulfill criteria for SIADH since the urine sodium is
not low as would be expected if a reduced cardiac output were responsible [20].
The glomerular filtration rate is also decreased in hypothyroidism. This can directly diminish free
water excretion by diminishing water delivery to the diluting segments [17,18]. Decreased delivery
may be particularly important in those cases in which hyponatremia develops despite appropriate
suppression of ADH release [21,22]. Regardless of the mechanism, the net effect of the impairment
in water excretion is the retention of ingested water and a reduction in the plasma sodium
concentration by dilution.
Some have questioned whether hypothyroidism deserves its traditional listing as a cause of
hyponatremia [23]. As an example, a study that compared 999 ambulatory patients with newly
diagnosed hypothyroidism with 4875 euthyroid controls found no difference in serum sodium
concentrations [24]. In addition, none of the hypothyroid patients had a serum sodium concentration
<120 mmol/L, while two controls had hyponatremia of this severity. Although there was a statistical
correlation between higher TSH levels and lower serum sodium concentrations, the slope of the
relationship was clinically negligible. In contrast, symptomatic hyponatremia (with serum sodium
concentrations ranging from 121 to 110 meq/L) was reported in five patients with metastatic thyroid
carcinoma after withdrawal of thyroid hormone replacement (withdrawn prior to administration of
radioactive iodine) [25]. The serum sodium returned to normal after thyroid replacement was
restarted. However, four of the five patients had known lung or cerebral metastases, which may
have contributed to hyponatremia.

Adrenal insufficiency The hypersecretion of ADH seen with cortisol deficiency may be in part
due to the reductions in systemic blood pressure and cardiac output (via an unknown mechanism)
and the interruption of a negative feedback loop in which cortisol suppresses ADH release. In
primary adrenal insufficiency (Addison disease), hypovolemia-induced ADH secretion resulting from
aldosterone deficiency also contributes. Secondary adrenal insufficiency (hypopituitarism), presents
with euvolemic hyponatremia with biochemical features of SIADH. These issues are discussed in
detail elsewhere. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)
Pregnancy The release of human chorionic gonadotropin during pregnancy may be responsible
for a mild resetting of the osmostat downward that is responsible for a fall in the serum sodium
concentration of about 5 meq/L [26]. (See "Renal and urinary tract physiology in normal
pregnancy".)
Ectopic ANP Although SIADH is more common, ectopic atrial natriuretic peptide production may
be rarely associated with hyponatremia in some patients with small cell lung cancer [27-29].
Exercise-associated hyponatremia Marathon and ultramarathon runners can develop
potentially severe hyponatremia that is primarily due to excessive water intake combined, in many
cases, with impaired water excretion due to persistent ADH secretion. A similar sequence can occur
during military operations and desert hikes. (See "Exercise-associated hyponatremia".)
Ecstasy (MDMA) intoxication Symptomatic and potentially fatal hyponatremia has been
described after ingestion of the designer amphetamine ecstasy (methylenedioxymethamphetamine
or MDMA) [30-40]. Two factors appear to be of primary importance in the development of
hyponatremia: a marked increase in water intake [30,31,34], as occurs with primary polydipsia; and
drug-induced inappropriate secretion of ADH, which limits water excretion [30,31,33-36,38].
(See 'Primary polydipsia' below.)
Hyponatremia is a major cause of death related to ecstasy use [40]. As with other causes of
hyponatremia [41], young women with ecstasy-induced hyponatremia are more likely than men to
develop severe neurologic complications such as coma and death [37,39]. Women are also more
likely than men to develop ecstasy-induced hyponatremia [42,43]. In a study of 63 ecstasy users
and 44 non-users attending a commercial "rave" party, mild hyponatremia (defined as a serum
sodium less than 136 meq/L) was significantly more common among ecstasy users (14 versus 0
percent), and among female as opposed to male ecstasy users (27 versus 3 percent) [42]. No
cases of symptomatic hyponatremia were identified in this small series, and those with
hyponatremia had serum sodium concentrations ranging between 133 and 135 meq/L.
(See "Manifestations of hyponatremia and hypernatremia", section on 'Susceptibility of
premenopausal women' and "MDMA (ecstasy) intoxication".)
Hyponatremia despite appropriate suppression of ADH There are several conditions in which
hyponatremia can occur despite suppression of ADH release: advanced renal failure, primary
polydipsia, and low dietary solute intake.
Advanced renal failure The relative ability to excrete free water (free water excretion divided by
the glomerular filtration rate) is not significantly impaired in patients with mild to moderate renal
failure [44]. Thus, normonatremia is usually maintained.

In contrast, in advanced renal failure, the minimum urine osmolality rises to as high as 200 to
250 mosmol/kg despite the appropriate suppression of ADH [45]. The osmotic diuresis induced by
increased solute excretion per functioning nephron is thought to be responsible for the inability to
dilute the urine.
The impairment in free water excretion in advanced renal failure can lead to the retention of
ingested water and the development of hyponatremia. Although the water retention will also lower
the serum osmolality, this will be offset at least in part by the elevation in blood urea nitrogen (BUN).
As a result, the measured serum osmolality may be normal or even increased, a finding that can
also be seen in some other disorders. (See 'Hyponatremia with a high or normal serum
osmolality' below.)
However, there is a difference between the measured serum osmolality and the effective serum
osmolality. Urea is an ineffective osmole since it can freely cross cell membranes and therefore
does not obligate water movement out of the cells. Thus, patients with hyponatremia and renal
failure have a low effective serum osmolality (Sosm) that becomes apparent if the measured Sosm
is corrected for the effect of urea:
Corrected Sosm = Measured Sosm - (BUN 2.8)
Dividing the BUN by 2.8 converts mg/dL into mmol/L, which is required when estimating its
contribution to osmolality. If the blood urea is measured in units of mmol/L, the formula is:
Corrected Sosm = Measured Sosm - blood urea concentration
Primary polydipsia Primary polydipsia, a disorder in which there is a primary increase in thirst,
is most often seen in patients with psychiatric illnesses [46-51]. As an example, one study of 239
hospitalized patients with mental illness found that 6.6 percent had a history compatible with
compulsive water drinking and that one-half of these had intermittent symptoms of hyponatremia
due to transient water retention [52].
It is presumed that a central defect in thirst regulation plays an important role in the pathogenesis of
polydipsia [49,53]. In some cases, for example, the osmotic threshold for thirst is reduced below the
threshold for the release of ADH [54]. In contrast to normal subjects in whom the thirst threshold is
roughly equal to or a few mosmol/kg higher than the threshold for ADH [55], these patients will
continue to drink until the plasma osmolality is less than the threshold level. This may be difficult to
achieve, however, since ADH secretion will be suppressed by the fall in plasma osmolality, resulting
in rapid excretion of the excess water and continued stimulation of thirst. The mechanism
responsible for abnormal thirst regulation in patients with primary polydipsia is unclear.
Normal subjects can excrete more than 400 to 600 mL of urine per hour, a response that is
mediated by suppression of ADH secretion and the subsequent formation of a dilute urine with a
minimum osmolality between 40 and 100 mosmol/kg. If ADH regulation were intact, primary
polydipsia should not lead to clinically important disturbances in the plasma sodium concentration
unless intake were massively increased. Thus, the serum sodium concentration is usually normal or
only slightly reduced in primary polydipsia since the excess water is readily excreted [47]. These
patients may be asymptomatic or present with complaints of polydipsia and polyuria.
(See "Diagnosis of polyuria and diabetes insipidus".)

Water intake may occasionally exceed 400 to 600 mL per hour, particularly in institutionalized
patients with severe psychosis [51], and may produce fatal hyponatremia even though the urine is
maximally dilute with an osmolality below 100 mosmol/kg [56,57]. Symptomatic hyponatremia can
also be induced with an acute 3- to 4-liter water load. This is sometimes seen in anxious patients
preparing for a radiologic examination or in those attempting to dilute their urine to avoid a positive
urine drug test [58].
However, some patients with polydipsia who become hyponatremic have a higher urine osmolality
than polydipsic patients who remain normonatremic, indicating a concurrent increase in ADH
release and/or response [46,53,59,60]. A number of different abnormalities in ADH regulation have
been identified in psychotic patients, each of which can impair water excretion. Studies in patients
who have had at least one episode of hyponatremia have revealed the following defects [53]:
Transient stimulation of ADH release during acute psychotic episodes, producing the
syndrome of inappropriate ADH secretion (SIADH) [59,61].
An increase in the net renal response to ADH so that, at the same plasma ADH levels,
psychotic patients have a higher urine osmolality and therefore a lower rate of free water
excretion than healthy controls [53]. How this occurs is not known.
Antipsychotic or antidepressant drugs (such as fluoxetine) may also produce SIADH in a few
patients. As examples, carbamazepine and fluoxetine can produce hyponatremia with a
SIADH-like clinical picture [62,63].
A downward resetting of the osmostat regulating ADH release. As a result, a lower-thannormal plasma sodium concentration is required to completely suppress ADH release and
excrete a water load. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic
hormone secretion (SIADH) and reset osmostat".)
Transient ADH release due to nausea [51].
The net effect is that some modestly hyponatremic patients with primary polydipsia do not have a
maximally dilute urine as would be expected if ADH were appropriately suppressed by the fall in
plasma osmolality and there were not increased sensitivity to ADH [53]. The likelihood of developing
hyponatremia will be increased further if some other cause for enhanced ADH release is present,
such as nausea, stress, or concurrent diuretic therapy [58,64].
Primary polydipsia can also occur with hypothalamic lesions that affect the thirst center, as can be
seen with infiltrative diseases such as sarcoidosis [65]. Low dietary solute intake can contribute to
the development of hyponatremia by limiting water excretion even if the secretion of ADH is
appropriately suppressed. (See 'Low dietary solute intake' below.)
As in any patient with polydipsia and polyuria, the possibility of diabetes insipidus should be
considered in patients with psychiatric illness who present with these symptoms in the absence of
hyponatremia. If compliance is possible, we recommend a water restriction test. An alternative in
the uncooperative patient is to increase the plasma osmolality via a slow infusion of hypertonic
saline. (See "Diagnosis of polyuria and diabetes insipidus".)
Measuring the urine osmolality is also important in polydipsic patients who are hyponatremic. Pure
primary polydipsia should be associated with appropriate suppression of ADH release and a urine
osmolality below 100 mosmol/kg. A higher urine osmolality, which is often present, suggests at least

a contributory role for increased ADH release or responsiveness [46,53,60]. (See "Evaluation of
adults with hyponatremia".)
There is no proven specific therapy for primary polydipsia with or without hyponatremia in psychotic
patients. Acutely, limiting water intake will rapidly raise the plasma sodium concentration as the
excess water is readily excreted in a dilute urine. The risk of inducing osmotic demyelination in this
setting is unclear [66,67].
Over the long term, limiting the use of drugs that cause dry mouth, restricting fluid intake, and
frequent weighing (to detect water retention) all may be helpful. Some clinicians have tried
the tetracycline derivative demeclocycline, which induces reversible ADH resistance; however, this
agent has not generally been effective [68]. (See "Treatment of hyponatremia: Syndrome of
inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)
Low dietary solute intake Beer drinkers or other malnourished patients (including those with
low-protein, high water intake diets; ie, the "tea and toast syndrome") may have a marked reduction
in water excretory capacity that is directly mediated by poor dietary intake [69-71]. Ingestion of a
normal diet results in the generation and excretion of 600 to 900 mosmol of solute per day (primarily
sodium and potassium salts and urea). Thus, if the minimum urine osmolality is 60 mosmol/kg, the
maximum urine output will be 10 to 15 L/day (eg, 900 mosmol/day 60 mosmol/kg = 15 L).
In contrast, beer contains little or no sodium, potassium, or protein to generate solutes for excretion.
In addition, the alcohol and carbohydrate load from beer will suppress endogenous protein
breakdown and therefore urea excretion. As a result, daily solute excretion may fall below 250
mosmol, leading to a reduction in the maximum urine output to below 4 L/day even though the urine
is maximally dilute. Hyponatremia will ensue if more than this amount of fluid is taken in.
HYPONATREMIA WITH A HIGH OR NORMAL SERUM OSMOLALITY Although hyponatremia
is typically associated with a proportional reduction in serum osmolality (to a level below
275 mosmol/kg), some patients have a high (ie, greater than 295 mosmol/kg) or normal serum
osmolality. One example, advanced renal failure, was described above. In that disorder, the
associated elevation in blood urea nitrogen can counteract the fall in serum osmolality induced by
hyponatremia. However, the effective serum osmolality is reduced in proportion to the hyponatremia
in this setting since urea is an ineffective osmole. (See 'Advanced renal failure' above.)
In the following sections on high and normal serum osmolality, the development of hyponatremia
may be linked to the factor that affects the serum osmolality. It is also possible that the factor that
raises the serum osmolality is independent of the development of hyponatremia. One example of
such an effect is alcohol ingestion [72]. Alcohol is an ineffective osmole (like urea) and will therefore
not cause hyponatremia; however, alcohol will increase osmolality. Thus, in patients who are
hyponatremic, significant alcohol ingestion can raise the serum osmolality to normal or high values.
(See "Serum osmolal gap", section on 'Ethanol intoxication'.)
High serum osmolality Hyponatremia with a high serum osmolality is most often due to marked
hyperglycemia in patients with diabetic ketoacidosis or hyperosmolar hyperglycemic state (also
known as nonketotic hyperglycemia). Less common causes include the administration and
subsequent retention of hypertonic mannitol or of maltose or sucrose when intravenous immune
globulin is given in a maltose or sucrose solution to patients with renal failure. (See"Complications
of mannitol therapy" and "General principles in the use of immune globulin".)

The rise in serum osmolality induced by hyperglycemia, mannitol, maltose, or sucrose pulls water
out of the cells, thereby lowering the serum sodium concentration by dilution.
Marked hyperglycemia The changes that can occur in patients with marked hyperglycemia are
discussed in detail elsewhere but will be briefly reviewed here. (See "Diabetic ketoacidosis and
hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on
'Serum sodium'.)
Physiologic calculations suggest that the serum sodium concentration should fall by 1.6 meq/L for
every 100 mg/dL (5.5 mmol/L) rise in the serum glucose concentration [73]. However, this standard
correction factor was not verified experimentally.
In an attempt to address this issue, hyperglycemia was induced in six healthy subjects by the
administration of both somatostatin (to block endogenous insulin secretion) and a hypertonic
dextrose solution [74]. A nonlinear relationship was observed between the changes in the glucose
and sodium concentrations:
The 1.6:100 ratio applied when the serum glucose concentration was less than
400 mg/dL (22.2 mmol/L)
At higher glucose concentrations, there was a greater reduction in the serum sodium
concentration (1:25 ratio, ie, a 4 meq/L reduction in serum sodium per 100 mg/dL further
increase in serum glucose)
These calculations are idealized since they do not account for the osmotic diuresis typically induced
by glucose excretion in the urine. The loss of water in excess of sodium and potassium will raise the
serum sodium concentration. Some patients with uncontrolled diabetes have such a marked
osmotic diuresis that, at presentation, the serum sodium concentration is increased and the serum
osmolality is markedly elevated.
The calculations are best used to estimate how much the serum sodium concentration will rise as
the hyperglycemia is corrected. The administration of insulin drives glucose and water into the cells,
reversing the initial direction of water movement and raising the serum sodium concentration.
Normal serum osmolality
Nonconductive irrigation solutions Isosmotic hyponatremia can be produced by the addition
of an isosmotic (or near isosmotic) but non-sodium-containing fluid to the extracellular space. This
problem primarily results from the absorption of variable quantities of nonconductive glycine
or sorbitolirrigation solutions during transurethral resection of the prostate or bladder (called the
transurethral resection syndrome) or during hysteroscopy or laparoscopic surgery.
These patients may develop marked hyponatremia (below 110 meq/L) and neurologic symptoms.
Multiple factors can contribute to the neurologic symptoms, including the very low serum sodium
concentration itself, glycine toxicity, and the accumulation of ammonia, serine, or glyoxylate from
the metabolism of glycine. (See "Hyponatremia following transurethral resection or hysteroscopy",
section on 'Pathogenesis of neurologic symptoms' and"Hysteroscopy: Managing fluid and gas
distending media".)
Pseudohyponatremia Pseudohyponatremia, which is associated with a normal serum
osmolality, refers to those disorders in which marked elevations in serum lipids or proteins result in

a reduction in the fraction of serum that is water and an artificially low serum sodium concentration
[3,75,76]. In normal subjects, the plasma water is approximately 93 percent of the plasma volume,
with fats and proteins accounting for the remaining 7 percent. Thus, a normal plasma sodium
concentration of 142 meq/L (measured per liter of plasma) actually represents a concentration in
the physiologically important plasma water of 153 meq/L (142 0.93 = 153).
However, the plasma water fraction may fall below 80 percent in patients with marked
hyperlipidemia (as with lactescent serum in uncontrolled diabetes mellitus) or hyperproteinemia (as
in multiple myeloma). In these settings, the plasma water sodium concentration and plasma
osmolality are unchanged, but the measured sodium concentration in the total plasma volume will
be reduced since the specimen contains less plasma water. This specific artifact is dependent upon
the method used for electrolyte measurement. Thus, it is a prominent artifact when flame
photometry or indirect potentiometry is utilized but does not occur when with direct potentiometry.
The diagnosis and impact of pseudohyponatremia is discussed separately. (See "Evaluation of
adults with hyponatremia", section on 'Serum osmolality'.)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10 th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
Basics topics (see "Patient information: Hyponatremia (The Basics)")
SUMMARY
Although the definition may vary slightly among clinical laboratories, hyponatremia is
commonly defined as a serum sodium concentration below 135meq/L. In virtually all patients,
hyponatremia is due to the intake (either oral or intravenous) of water that cannot be excreted.
This is usually accompanied by a proportional fall in serum osmolality (to a level below
275 mosmol/kg) but there are settings in the which the serum osmolality is high (greater than
295 mosmol/kg) or normal. (See 'Introduction' above.)
At least two classification systems have been used for the etiology of hyponatremia with a
low serum osmolality: one stratifies patients according to whether circulating antidiuretic
hormone (ADH) levels are inappropriately elevated or appropriately suppressed, and the other
stratifies patients according to volume status (hypovolemia, normovolemia, or hypervolemia).
(See 'Classification' above.)
There are two major causes of hyponatremia with a low serum osmolality, both of which are
associated with elevated serum ADH levels (see'Hyponatremia with a low serum
osmolality' above):

Effective arterial blood volume depletion, which may be associated with true volume
depletion (due, for example, to gastrointestinal or renal losses, as with thiazide diuretics)
or with hypervolemia in patients with heart failure or cirrhosis. (See 'Effective arterial
blood volume depletion'above.)
Heart failure and cirrhosis cause hyponatremia despite increased plasma volume
because the pressure sensed at the carotid sinus baroreceptors is reduced due to the
fall in cardiac output in heart failure and to peripheral vasodilatation in cirrhosis. The rise
in serum ADH levels varies with the severity of the disease, making the development of
hyponatremia an important adverse prognostic sign. (See 'Heart failure and
cirrhosis' above.)
Normovolemia in the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
(See 'Syndrome of inappropriate ADH secretion'above.)
Hyponatremia with a low serum osmolality can also occur in a number of other settings:
In association with hormonal changes, such adrenal insufficiency, hypothyroidism, the
release of human chorionic gonadotropin during pregnancy, and ectopic production of
atrial natriuretic peptide. (See 'Endocrine disorders' above.)
In marathon and ultramarathon runners due to excessive water intake combined with
impaired water excretion due to persistent ADH secretion. A similar sequence can occur
during military operations and desert hikes. (See 'Exercise-associated
hyponatremia' above.)
Despite appropriate suppression of ADH release in patients with advanced renal failure,
primary polydipsia, and low dietary solute intake. (See'Hyponatremia despite appropriate
suppression of ADH' above.)
Hyponatremia can also occur in patients with a high or normal serum osmolality; in addition
to the following disorders which cause both hyponatremia and a high or normal serum
osmolality, ethanol ingestion can raise the serum osmolality in patients who are hyponatremic
for some other reason (see'Hyponatremia with a high or normal serum osmolality' above):
Hyponatremia with a high serum osmolality can be seen with hyperglycemia, advanced
renal failure, or, less often, in association with the administration of
hypertonic mannitol or maltose. In advanced renal failure, the associated elevation in
blood urea nitrogen can counteract the fall in serum osmolality induced by hyponatremia.
However, the effective serum osmolality is appropriately reduced in this setting since
urea is an ineffective osmole. (See 'Advanced renal failure' above.)
Hyponatremia with a normal (or near-normal) serum osmolality can result from the addition of
an isosmotic but non-sodium-containing fluid to the extracellular space, as occurs with the use
of nonconductive glycine or sorbitol flushing solutions during transurethral resection of the
prostate or bladder. (See 'Nonconductive irrigation solutions' above.)
Pseudohyponatremia is defined as an artificially low serum sodium concentration associated
with a normal serum osmolality due to marked elevations in lipids or proteins, resulting in a
reduction in the water-containing fraction of serum. (See 'Pseudohyponatremia' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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