Causes of Hipo Na
Content
Causes of hyponatremia
Burton D Rose, MD
UpToDate performs a continuous review of over 350 journals and other
resources. Updates are added as important new information is published.
The literature review for version 14.2 is current through April 2006; this
topic was last changed on May 02, 2006. The next version of UpToDate
(14.3) will be released in October 2006.
INTRODUCTION — In almost all cases, hyponatremia results from the
intake (either oral or intravenous) and subsequent retention of water [ 1].
A water load will, in normal subjects, be rapidly excreted as the dilutional
fall in plasma osmolality suppresses the release of antidiuretic hormone
(ADH), thereby allowing the excretion of a dilute urine. The maximum
rate of water excretion on a regular diet is over 10 liters per day, thereby
providing an enormous range of protection against the development of
hyponatremia.
Some patients with primary polydipsia retain water and become
hyponatremic because they drink such large quantities of fluid that they
overwhelm the excretory capacity of the kidney. In almost all cases,
however, hyponatremia occurs because there is an impairment in renal
water excretion, due most often to an inability to suppress ADH release.
An overview of the causes of hyponatremia will be presented here ( show
table 1); most of the individual disorders are discussed in detail
separately, as are issues in diagnosis and treatment [ 1]. ( See "Diagnosis
of hyponatremia" and see "Treatment of hyponatremia").
It should also be emphasized that, in selected patients, multiple factors
may contribute to the fall in the plasma sodium concentration.
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").
The presence of hyponatremia, even of relatively mild severity, is
associated with adverse survival. This includes patients with heart and/or
hepatic failure, and/or acute myocardial infarction. ( See "Hyponatremia
in cirrhosis" and see "Hyponatremia in heart failure").
DISORDERS IN WHICH ADH LEVELS ARE ELEVATED — The two most
common causes of hyponatremia are effective circulating volume
depletion and the syndrome of inappropriate ADH secretion, disorders in
which ADH secretion is not suppressed.
Effective circulating volume depletion — Significantly decreased
tissue perfusion is a potent stimulus to ADH release. 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, hyponatremia can develop in
patients with any of the following disorders.
True volume depletion — True volume depletion from gastrointestinal
or urinary losses or bleeding will increase ADH and result in hyponatremia
if there is adequate water intake. Such patients may also have
hypokalemia and azotemia due to decreased renal perfusion. This
constellation of findings in patients with a large villous adenoma has been
called the McKittrick-Wheelock syndrome.
The replacement of severe diarrheal 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 may result in an
increased incidence of hyponatremia as compared to replacement with
standard (and higher sodium concentration) oral rehydration therapy [ 2].
( See "Oral rehydration therapy").
Exercise-induced hyponatremia — Ultramarathon and marathon
runners may replace their dilute, but sodium-containing sweat losses with
excessive amounts of hypotonic solutions, with the net effect being a
reduction in the plasma sodium concentration [ 3-6]. A similar sequence
can occur during military operations and desert hikes. Such individuals
may also be taking NSAIDs, which can impair the excretion of free water [
4]. ( see "NSAIDs: Electrolyte complications", section on hyponatremia).
Excessive hypotonic fluid intake may have a greater role than sodium loss
and increased ADH levels, mimicking some of the findings of primary
polydipsia [ 5-8]. In a prospective study of 488 runners who completed
the Boston marathon (approximately 42.2 kilometers), 13 and 0.6 percent
had post-race plasma sodium concentrations of 135 meq/L and 120
meq/L, respectively [ 5]. The most important factors underlying
hyponatremia were increased weight gain and race time. Of those who
gained 2.0 to 2.9 kg and over 3 kg, approximately 10 and 30 percent had
plasma sodium concentration 130 meq/L. Those patients with a race
time greater than four hours had an odds ratio of 7.4 for hyponatremia
compared to those with a race time below 3.5 hours. Theoretically, those
who take longer to complete a run have a longer time to ingest hypotonic
fluid [ 5].
In contrast, a similar study of New Zealand marathon runners reported no
cases of hyponatremia [ 6]. As observed with the Boston marathon study,
plasma sodium concentrations were directly related to changes in weight.
Possible reasons for the difference in prevalence of hyponatremia in the
two studies is that aggressive hydration was not promoted in New
Zealand, and hydration stations were significantly fewer (one every 5
versus 1.6 km).
We can make the following general recommendations for preventing
hyponatremia related to prolonged exertion:
1. Avoid fixed, global recommendations for water intake, since there are
varying rates of water and sodium loss with different body types,
training regimens and climates.
2. Athletes should rely on thirst as their guide for fluid replacement.
3. Athletes should monitor weight before and after training sessions as a
guide to appropriate fluid consumption, with the goal to avoid weight
gain.
4. Medical personnel should avoid hypotonic intravenous solutions in
individuals with exertion-related collapse, especially if the serum
sodium concentration is not known.
In 2005, a consensus conference published guidelines concerning the
evaluation and management of exercise-induced hyponatremia [ 8]. The
following recommendations were made:
1. Onsite analysis of serum or plasma sodium should be performed at
medical facilities at endurance events.
2. if the medical staff is experienced in treating hyponatremia in the field,
any patient with exercise-induced hyponatremia and respiratory
insufficiency, confusion, obtundation, nausea, and vomiting can be
administered 100 mL of 3 percent sodium chloride over ten minutes.
This maneuver should raise the plasma sodium concentration an
average of 2 to 3 meq/L and should not pose a substantial danger.
This initial strategy is intended to stabilize the athlete prior to transfer to
the hospital. Further treatment of symptomatic patients is the same as for
any cause of symptomatic hyponatremia [ 8]. ( See "Treatment of
hyponatremia").
Heart failure and cirrhosis — Even though the plasma volume may
be markedly increased in these disorders, 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 [ 1,9]. Thus, the
rise in ADH levels tend to vary with the severity of the disease, making
the development of hyponatremia an important prognostic sign. ( See
"Hyponatremia in heart failure" and see "Hyponatremia in cirrhosis").
In comparison, hyponatremia in the nephrotic syndrome is more likely to
be due to the renal disease than to underfilling induced by
hypoalbuminemia (unless the plasma albumin concentration is below 1.5
to 2 g/dL [15 to 20 g/L]). ( See "Mechanism and treatment of edema in
nephrotic syndrome").
Thiazide diuretics — Acute and often severe hyponatremia is an
occasional complication of therapy with a thiazide diuretic. This problem is
only rarely seen with 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 induce
water retention. ( See "Diuretic-induced hyponatremia").
Syndrome of inappropriate ADH secretion — Persistent ADH release
and water retention can also be seen in a variety of disorders that are not
associated with hypovolemia. The pattern of ADH release in these
conditions is variable, with about one-third showing a downward resetting
of the osmostat [ 10]. These patients have a stable plasma sodium
concentration between 125 and 135 meq/L. Treatment of the
hyponatremia in this setting is both unnecessary (since the patients are
asymptomatic) and unlikely to be effective (since the new plasma sodium
concentration is recognized as normal and raising this value will stimulate
thirst). ( See "Causes of the SIADH" and see "Treatment of hyponatremia:
SIADH and reset osmostat").
Hormonal changes — Hyponatremia can occur in patients with adrenal
insufficiency (in which it is lack of cortisol that is responsible for the
hyponatremia) and with hypothyroidism. ( See "Hyponatremia and
hyperkalemia in adrenal insufficiency" and see "Hyponatremia in
hypothyroidism").
On the other hand, the release of human chorionic gonadotropin during
pregnancy may be responsible for the mild resetting of the osmostat
downward, leading to a fall in the plasma sodium concentration of about 5
meq/L [ 11]. ( See "Renal and urinary tract physiology in pregnant
women").
Although SIADH is more common, ectopic atrial natriuretic peptide
production may be rarely associated with hyponatremia in some patients
with small cell lung cancer [ 12-14].
DISORDERS IN WHICH ADH LEVELS MAY BE APPROPRIATELY
SUPPRESSED — There are two disorders in which hyponatremia can
occur despite suppression of ADH release: advanced renal failure and
primary polydipsia.
Advanced renal failure — The relative ability to excrete free water (free
water excretion divided by the glomerular filtration rate) is maintained in
patients with mild to moderate renal failure [ 15]. Thus, normonatremia is
usually maintained in the absence of oliguria or advanced renal failure. In
the latter setting, the minimum urine osmolality rises to as high as 200 to
250 mosmol/kg despite the appropriate suppression of ADH; the osmotic
diuresis induced by increased solute excretion per functioning nephron is
thought to be responsible for the inability to dilute the urine [ 16].
Primary polydipsia — Primary polydipsia is a disorder in which there is a
primary stimulation of thirst. It is most often seen in anxious, middleaged women and in patients with psychiatric illnesses, particularly those
taking antipsychotic drugs in whom the common side effect of a dry
mouth leads to increased water intake [ 17-19]. Polydipsia can also occur
with hypothalamic lesions (as with infiltrative diseases such as
sarcoidosis) which directly affect the thirst centers [ 20]. ( See "Polydipsia
and hyponatremia in patients with mental illness").
The plasma sodium concentration is usually normal or only slightly
reduced in primary polydipsia, since the excess water is readily excreted [
18]. These patients may feel asymptomatic or may present with
complaints of polydipsia and polyuria. ( See "Diagnosis of polyuria and
diabetes insipidus").
In rare cases, however, water intake exceeds 10 to 15 L/day and
potentially fatal hyponatremia may ensue even though the urine is
maximally dilute with an osmolality below 100 mosmol/kg [ 21,22].
Symptomatic hyponatremia can also be induced with an acute 3 to 4 liter
water load (as may rarely be seen in anxious patients preparing for a
radiologic examination or for urinary drug testing) [ 23]. The tendency to
hyponatremia in these settings will be increased if there is also an
impairment in water excretion, as with nausea- or stress-induced ADH
release or concurrent diuretic therapy [ 23,24].
Symptomatic and potentially fatal hyponatremia has also been described
after ingestion of the designer amphetamine ecstasy
(methylenedioxymethamphetamine or MDMA) [ 25-28]. Both a marked
increase in water intake [ 25] and inappropriate secretion of ADH may
contribute [ 27,29].
Low dietary solute intake — Beer drinkers or other malnourished
patients (including those with low-protein, high water intake diets) may
have a marked reduction in water excretory capacity that is directly
mediated by poor dietary intake [ 30-32]. Normal subjects excrete 600 to
900 mosmol/kg 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 (for example, 900
mosmol/day ÷ 60 mosmol/kg = 15 L). However, beer contains little or no
sodium, potassium, or protein, and the carbohydrate load will suppress
endogenous protein breakdown and therefore urea excretion. As a result,
daily solute excretion may fall below 250 mosmol/kg, leading to a
reduction in the maximum urine output to below 4 L/day even though the
urine is appropriately dilute. Hyponatremia will ensue if more than this
amount of fluid is taken in.
HYPONATREMIA WITH A HIGH OR NORMAL PLASMA OSMOLALITY
High plasma osmolality — Hyponatremia with a high plasma osmolality
is most often due to hyperglycemia; a less common cause is the
administration and subsequent retention of hypertonic mannitol. In these
settings, the rise in plasma osmolality induced by glucose or mannitol
pulls water out of the cells, thereby lowering the plasma sodium
concentration by dilution. ( See "Clinical features and diagnosis of diabetic
ketoacidosis and nonketotic hyperglycemia in adults" and see
"Complications of mannitol therapy").
A similar sequence can be induced by maltose retention when intravenous
immune globulin is given in a 10 percent maltose solution to patients with
renal failure. ( See "General principles of the use of intravenous immune
globulin").
Physiologic calculations suggest that the plasma sodium concentration
should fall by 1 meq/L for every 62 mg/dL (3.5 mmol/L) rise in the
plasma concentration of glucose or mannitol (which have the same
molecular weight) [ 33]. 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 somatostatin (to block endogenous insulin secretion) and a hypertonic
dextrose solution [ 34]. A nonlinear relationship was observed between
the changes in the glucose and sodium concentrations. The 1:62 ratio
applied when the plasma glucose concentration was less than 400 mg/dL
(22.2 mmol/L). At higher glucose concentrations, there was a greater
reduction in the plasma sodium concentration. An overall ratio of 1:42 (a
2.4 meq/L reduction in the plasma sodium concentration for every 100
mg/dL [5.5 mmol/L] elevation in the plasma glucose) provided a better
estimate of this association than the usual 1:62 ratio.
These calculations are idealized since they do not account for the osmotic
diuresis typically induced by glucose or mannitol excretion in the urine.
The loss of water in excess of sodium and potassium raises the plasma
sodium concentration. Some patients with uncontrolled diabetes have
such a marked osmotic diuresis that they present with an elevation in the
plasma sodium concentration and marked hyperosmolality. ( See "Clinical
features and diagnosis of diabetic ketoacidosis and nonketotic
hyperglycemia in adults")
The calculations are best used to estimate how much the plasma 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 plasma sodium
concentration.
Normal plasma osmolality — Isosmotic hyponatremia can be produced
by the addition of an isosmotic (or near isosmotic) but non-sodiumcontaining fluid to the extracellular space. This problem primarily occurs
with the use of nonconductive glycine or sorbitol flushing solutions during
transurethral resection of the prostate or bladder or irrigation during
laparoscopic surgery, since variable quantities of this solution are
absorbed. These patients may develop marked hyponatremia (below 110
meq/L) and neurologic symptoms. The pathogenesis of these symptoms is
unclear. ( See "Hyponatremia following transurethral resection or
laparoscopic irrigation").
Pseudohyponatremia — Pseudohyponatremia, which is associated
with a normal plasma osmolality, refers to those disorders in which
marked elevations of substances, such as lipids and proteins, result in a
reduction in the fraction of plasma that is water and an artificially low
sodium concentration [ 1,35]. 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 154 meq/L (142 ÷ 0.93 = 154).
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). Ion-selective electrodes have been used to directly measure the
plasma water sodium concentration in this setting [ 36] but have variable
accuracy [ 35]. ( See "Diagnosis of hyponatremia", section on Plasma
osmolality which also contains a formula for estimating the plasma water
content).
True hyponatremia in renal failure — When hyponatremia develops in
patients with renal failure, the plasma osmolality may be normal or high
because of the retention of urea. However, urea is an ineffective osmole,
since it can freely cross cell membranes and does not obligate water
movement out of the cells. Thus, these patients have true hyponatremia,
which will be evidenced if the measured plasma osmolality is corrected for
the effect of urea:
Corrected Posm = Measured Posm - (BUN ÷ 2.8)
Dividing the BUN by 2.8 converts mg/dL into mmol/L, which is required
when measuring osmolality. In countries in which blood urea is measured
in units of mmol/L, the formula is:
Corrected Posm = Measured Posm - blood urea concentration
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REFERENCES
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16. Tannen, RL, Regal, EM, Dunn, MJ, Schrier, RW. Vasopressin-resistant
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17. Hariprasad, MK, Eisinger, RP, Nadler, IM, et al. Hyponatremia in
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18. Barlow, ED, De Wardener, HE. Compulsive water drinking. Q J Med
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Burton D Rose, MD
UpToDate performs a continuous review of over 350 journals and other
resources. Updates are added as important new information is published.
The literature review for version 14.2 is current through April 2006; this
topic was last changed on May 02, 2006. The next version of UpToDate
(14.3) will be released in October 2006.
INTRODUCTION — In almost all cases, hyponatremia results from the
intake (either oral or intravenous) and subsequent retention of water [ 1].
A water load will, in normal subjects, be rapidly excreted as the dilutional
fall in plasma osmolality suppresses the release of antidiuretic hormone
(ADH), thereby allowing the excretion of a dilute urine. The maximum
rate of water excretion on a regular diet is over 10 liters per day, thereby
providing an enormous range of protection against the development of
hyponatremia.
Some patients with primary polydipsia retain water and become
hyponatremic because they drink such large quantities of fluid that they
overwhelm the excretory capacity of the kidney. In almost all cases,
however, hyponatremia occurs because there is an impairment in renal
water excretion, due most often to an inability to suppress ADH release.
An overview of the causes of hyponatremia will be presented here ( show
table 1); most of the individual disorders are discussed in detail
separately, as are issues in diagnosis and treatment [ 1]. ( See "Diagnosis
of hyponatremia" and see "Treatment of hyponatremia").
It should also be emphasized that, in selected patients, multiple factors
may contribute to the fall in the plasma sodium concentration.
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").
The presence of hyponatremia, even of relatively mild severity, is
associated with adverse survival. This includes patients with heart and/or
hepatic failure, and/or acute myocardial infarction. ( See "Hyponatremia
in cirrhosis" and see "Hyponatremia in heart failure").
DISORDERS IN WHICH ADH LEVELS ARE ELEVATED — The two most
common causes of hyponatremia are effective circulating volume
depletion and the syndrome of inappropriate ADH secretion, disorders in
which ADH secretion is not suppressed.
Effective circulating volume depletion — Significantly decreased
tissue perfusion is a potent stimulus to ADH release. 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, hyponatremia can develop in
patients with any of the following disorders.
True volume depletion — True volume depletion from gastrointestinal
or urinary losses or bleeding will increase ADH and result in hyponatremia
if there is adequate water intake. Such patients may also have
hypokalemia and azotemia due to decreased renal perfusion. This
constellation of findings in patients with a large villous adenoma has been
called the McKittrick-Wheelock syndrome.
The replacement of severe diarrheal 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 may result in an
increased incidence of hyponatremia as compared to replacement with
standard (and higher sodium concentration) oral rehydration therapy [ 2].
( See "Oral rehydration therapy").
Exercise-induced hyponatremia — Ultramarathon and marathon
runners may replace their dilute, but sodium-containing sweat losses with
excessive amounts of hypotonic solutions, with the net effect being a
reduction in the plasma sodium concentration [ 3-6]. A similar sequence
can occur during military operations and desert hikes. Such individuals
may also be taking NSAIDs, which can impair the excretion of free water [
4]. ( see "NSAIDs: Electrolyte complications", section on hyponatremia).
Excessive hypotonic fluid intake may have a greater role than sodium loss
and increased ADH levels, mimicking some of the findings of primary
polydipsia [ 5-8]. In a prospective study of 488 runners who completed
the Boston marathon (approximately 42.2 kilometers), 13 and 0.6 percent
had post-race plasma sodium concentrations of 135 meq/L and 120
meq/L, respectively [ 5]. The most important factors underlying
hyponatremia were increased weight gain and race time. Of those who
gained 2.0 to 2.9 kg and over 3 kg, approximately 10 and 30 percent had
plasma sodium concentration 130 meq/L. Those patients with a race
time greater than four hours had an odds ratio of 7.4 for hyponatremia
compared to those with a race time below 3.5 hours. Theoretically, those
who take longer to complete a run have a longer time to ingest hypotonic
fluid [ 5].
In contrast, a similar study of New Zealand marathon runners reported no
cases of hyponatremia [ 6]. As observed with the Boston marathon study,
plasma sodium concentrations were directly related to changes in weight.
Possible reasons for the difference in prevalence of hyponatremia in the
two studies is that aggressive hydration was not promoted in New
Zealand, and hydration stations were significantly fewer (one every 5
versus 1.6 km).
We can make the following general recommendations for preventing
hyponatremia related to prolonged exertion:
1. Avoid fixed, global recommendations for water intake, since there are
varying rates of water and sodium loss with different body types,
training regimens and climates.
2. Athletes should rely on thirst as their guide for fluid replacement.
3. Athletes should monitor weight before and after training sessions as a
guide to appropriate fluid consumption, with the goal to avoid weight
gain.
4. Medical personnel should avoid hypotonic intravenous solutions in
individuals with exertion-related collapse, especially if the serum
sodium concentration is not known.
In 2005, a consensus conference published guidelines concerning the
evaluation and management of exercise-induced hyponatremia [ 8]. The
following recommendations were made:
1. Onsite analysis of serum or plasma sodium should be performed at
medical facilities at endurance events.
2. if the medical staff is experienced in treating hyponatremia in the field,
any patient with exercise-induced hyponatremia and respiratory
insufficiency, confusion, obtundation, nausea, and vomiting can be
administered 100 mL of 3 percent sodium chloride over ten minutes.
This maneuver should raise the plasma sodium concentration an
average of 2 to 3 meq/L and should not pose a substantial danger.
This initial strategy is intended to stabilize the athlete prior to transfer to
the hospital. Further treatment of symptomatic patients is the same as for
any cause of symptomatic hyponatremia [ 8]. ( See "Treatment of
hyponatremia").
Heart failure and cirrhosis — Even though the plasma volume may
be markedly increased in these disorders, 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 [ 1,9]. Thus, the
rise in ADH levels tend to vary with the severity of the disease, making
the development of hyponatremia an important prognostic sign. ( See
"Hyponatremia in heart failure" and see "Hyponatremia in cirrhosis").
In comparison, hyponatremia in the nephrotic syndrome is more likely to
be due to the renal disease than to underfilling induced by
hypoalbuminemia (unless the plasma albumin concentration is below 1.5
to 2 g/dL [15 to 20 g/L]). ( See "Mechanism and treatment of edema in
nephrotic syndrome").
Thiazide diuretics — Acute and often severe hyponatremia is an
occasional complication of therapy with a thiazide diuretic. This problem is
only rarely seen with 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 induce
water retention. ( See "Diuretic-induced hyponatremia").
Syndrome of inappropriate ADH secretion — Persistent ADH release
and water retention can also be seen in a variety of disorders that are not
associated with hypovolemia. The pattern of ADH release in these
conditions is variable, with about one-third showing a downward resetting
of the osmostat [ 10]. These patients have a stable plasma sodium
concentration between 125 and 135 meq/L. Treatment of the
hyponatremia in this setting is both unnecessary (since the patients are
asymptomatic) and unlikely to be effective (since the new plasma sodium
concentration is recognized as normal and raising this value will stimulate
thirst). ( See "Causes of the SIADH" and see "Treatment of hyponatremia:
SIADH and reset osmostat").
Hormonal changes — Hyponatremia can occur in patients with adrenal
insufficiency (in which it is lack of cortisol that is responsible for the
hyponatremia) and with hypothyroidism. ( See "Hyponatremia and
hyperkalemia in adrenal insufficiency" and see "Hyponatremia in
hypothyroidism").
On the other hand, the release of human chorionic gonadotropin during
pregnancy may be responsible for the mild resetting of the osmostat
downward, leading to a fall in the plasma sodium concentration of about 5
meq/L [ 11]. ( See "Renal and urinary tract physiology in pregnant
women").
Although SIADH is more common, ectopic atrial natriuretic peptide
production may be rarely associated with hyponatremia in some patients
with small cell lung cancer [ 12-14].
DISORDERS IN WHICH ADH LEVELS MAY BE APPROPRIATELY
SUPPRESSED — There are two disorders in which hyponatremia can
occur despite suppression of ADH release: advanced renal failure and
primary polydipsia.
Advanced renal failure — The relative ability to excrete free water (free
water excretion divided by the glomerular filtration rate) is maintained in
patients with mild to moderate renal failure [ 15]. Thus, normonatremia is
usually maintained in the absence of oliguria or advanced renal failure. In
the latter setting, the minimum urine osmolality rises to as high as 200 to
250 mosmol/kg despite the appropriate suppression of ADH; the osmotic
diuresis induced by increased solute excretion per functioning nephron is
thought to be responsible for the inability to dilute the urine [ 16].
Primary polydipsia — Primary polydipsia is a disorder in which there is a
primary stimulation of thirst. It is most often seen in anxious, middleaged women and in patients with psychiatric illnesses, particularly those
taking antipsychotic drugs in whom the common side effect of a dry
mouth leads to increased water intake [ 17-19]. Polydipsia can also occur
with hypothalamic lesions (as with infiltrative diseases such as
sarcoidosis) which directly affect the thirst centers [ 20]. ( See "Polydipsia
and hyponatremia in patients with mental illness").
The plasma sodium concentration is usually normal or only slightly
reduced in primary polydipsia, since the excess water is readily excreted [
18]. These patients may feel asymptomatic or may present with
complaints of polydipsia and polyuria. ( See "Diagnosis of polyuria and
diabetes insipidus").
In rare cases, however, water intake exceeds 10 to 15 L/day and
potentially fatal hyponatremia may ensue even though the urine is
maximally dilute with an osmolality below 100 mosmol/kg [ 21,22].
Symptomatic hyponatremia can also be induced with an acute 3 to 4 liter
water load (as may rarely be seen in anxious patients preparing for a
radiologic examination or for urinary drug testing) [ 23]. The tendency to
hyponatremia in these settings will be increased if there is also an
impairment in water excretion, as with nausea- or stress-induced ADH
release or concurrent diuretic therapy [ 23,24].
Symptomatic and potentially fatal hyponatremia has also been described
after ingestion of the designer amphetamine ecstasy
(methylenedioxymethamphetamine or MDMA) [ 25-28]. Both a marked
increase in water intake [ 25] and inappropriate secretion of ADH may
contribute [ 27,29].
Low dietary solute intake — Beer drinkers or other malnourished
patients (including those with low-protein, high water intake diets) may
have a marked reduction in water excretory capacity that is directly
mediated by poor dietary intake [ 30-32]. Normal subjects excrete 600 to
900 mosmol/kg 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 (for example, 900
mosmol/day ÷ 60 mosmol/kg = 15 L). However, beer contains little or no
sodium, potassium, or protein, and the carbohydrate load will suppress
endogenous protein breakdown and therefore urea excretion. As a result,
daily solute excretion may fall below 250 mosmol/kg, leading to a
reduction in the maximum urine output to below 4 L/day even though the
urine is appropriately dilute. Hyponatremia will ensue if more than this
amount of fluid is taken in.
HYPONATREMIA WITH A HIGH OR NORMAL PLASMA OSMOLALITY
High plasma osmolality — Hyponatremia with a high plasma osmolality
is most often due to hyperglycemia; a less common cause is the
administration and subsequent retention of hypertonic mannitol. In these
settings, the rise in plasma osmolality induced by glucose or mannitol
pulls water out of the cells, thereby lowering the plasma sodium
concentration by dilution. ( See "Clinical features and diagnosis of diabetic
ketoacidosis and nonketotic hyperglycemia in adults" and see
"Complications of mannitol therapy").
A similar sequence can be induced by maltose retention when intravenous
immune globulin is given in a 10 percent maltose solution to patients with
renal failure. ( See "General principles of the use of intravenous immune
globulin").
Physiologic calculations suggest that the plasma sodium concentration
should fall by 1 meq/L for every 62 mg/dL (3.5 mmol/L) rise in the
plasma concentration of glucose or mannitol (which have the same
molecular weight) [ 33]. 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 somatostatin (to block endogenous insulin secretion) and a hypertonic
dextrose solution [ 34]. A nonlinear relationship was observed between
the changes in the glucose and sodium concentrations. The 1:62 ratio
applied when the plasma glucose concentration was less than 400 mg/dL
(22.2 mmol/L). At higher glucose concentrations, there was a greater
reduction in the plasma sodium concentration. An overall ratio of 1:42 (a
2.4 meq/L reduction in the plasma sodium concentration for every 100
mg/dL [5.5 mmol/L] elevation in the plasma glucose) provided a better
estimate of this association than the usual 1:62 ratio.
These calculations are idealized since they do not account for the osmotic
diuresis typically induced by glucose or mannitol excretion in the urine.
The loss of water in excess of sodium and potassium raises the plasma
sodium concentration. Some patients with uncontrolled diabetes have
such a marked osmotic diuresis that they present with an elevation in the
plasma sodium concentration and marked hyperosmolality. ( See "Clinical
features and diagnosis of diabetic ketoacidosis and nonketotic
hyperglycemia in adults")
The calculations are best used to estimate how much the plasma 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 plasma sodium
concentration.
Normal plasma osmolality — Isosmotic hyponatremia can be produced
by the addition of an isosmotic (or near isosmotic) but non-sodiumcontaining fluid to the extracellular space. This problem primarily occurs
with the use of nonconductive glycine or sorbitol flushing solutions during
transurethral resection of the prostate or bladder or irrigation during
laparoscopic surgery, since variable quantities of this solution are
absorbed. These patients may develop marked hyponatremia (below 110
meq/L) and neurologic symptoms. The pathogenesis of these symptoms is
unclear. ( See "Hyponatremia following transurethral resection or
laparoscopic irrigation").
Pseudohyponatremia — Pseudohyponatremia, which is associated
with a normal plasma osmolality, refers to those disorders in which
marked elevations of substances, such as lipids and proteins, result in a
reduction in the fraction of plasma that is water and an artificially low
sodium concentration [ 1,35]. 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 154 meq/L (142 ÷ 0.93 = 154).
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). Ion-selective electrodes have been used to directly measure the
plasma water sodium concentration in this setting [ 36] but have variable
accuracy [ 35]. ( See "Diagnosis of hyponatremia", section on Plasma
osmolality which also contains a formula for estimating the plasma water
content).
True hyponatremia in renal failure — When hyponatremia develops in
patients with renal failure, the plasma osmolality may be normal or high
because of the retention of urea. However, urea is an ineffective osmole,
since it can freely cross cell membranes and does not obligate water
movement out of the cells. Thus, these patients have true hyponatremia,
which will be evidenced if the measured plasma osmolality is corrected for
the effect of urea:
Corrected Posm = Measured Posm - (BUN ÷ 2.8)
Dividing the BUN by 2.8 converts mg/dL into mmol/L, which is required
when measuring osmolality. In countries in which blood urea is measured
in units of mmol/L, the formula is:
Corrected Posm = Measured Posm - blood urea concentration
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