Causes of hyponatremia without hypotonicity (including pseudohyponatremia)

INTRODUCTION — The serum tonicity is defined as the concentration of solutes that do not easily cross the cell membrane (effective osmoles). These solutes are primarily sodium salts in the extracellular space. As a result, serum sodium is used as a surrogate for assessing tonicity of the extracellular fluid.

The vast majority of patients with hyponatremia have hypotonicity, but there are exceptions. Hyponatremia without hypotonicity can be found in patients with hyperglycemia and in patients who have accumulated exogenous effective osmoles like mannitol, sucrose, maltose, sorbitol, glycine, or radiocontrast. In patients with extreme hyperlipidemia or hyperproteinemia, the serum sodium concentration will be measured as low by autoanalyzers and other analytical instruments that employ a diluting step, a laboratory artifact known as "pseudohyponatremia." However, the sodium concentration will be measured as normal by direct sodium-selective electrodes used by blood gas analyzers and some point-of-care devices.

The causes of hyponatremia without hypotonicity are presented in this topic. The evaluation of adults with hypotonic hyponatremia, the most common presentation of hyponatremia, is discussed elsewhere. (See "Diagnostic evaluation of adults with hyponatremia".)

TONICITY VERSUS OSMOLALITY IN HYPONATREMIA — Serum osmolality, which normally ranges from 275 to 295 mosmol/kg, is usually, but not always, low in patients with hyponatremia who need to be treated (table 1). However, the serum osmolality is not a required part of the diagnostic approach in all patients with hyponatremia; rather, it is measured in specific clinical scenarios. (See "Diagnostic evaluation of adults with hyponatremia".)

Serum tonicity, also called the effective plasma or serum osmolality, is the physical property sensed by osmoreceptors; serum tonicity also determines the transcellular distribution of water. Water can freely cross almost all cell membranes and moves from an area of lower tonicity (higher water content) to an area of higher tonicity (lower water content). Thus, hypotonicity causes cells to swell. Swelling of osmoreceptor cells should suppress antidiuretic hormone (ADH) release from the posterior pituitary and thereby cause excretion of excess water in dilute urine to restore normal serum tonicity [1]. Failure of normal osmoregulation leads to persistent hypotonicity that may, if it develops acutely, result in swelling of brain cells and neurologic consequences.

The main difference between tonicity and osmolality is that tonicity reflects the concentration of solutes that do not easily cross cell membranes (mostly sodium salts with a small contribution from glucose and potassium) and therefore affect the movement of water between cells and the extracellular fluid.

By contrast, osmolality also includes the osmotic contributions of urea and (if present) ethanol or other alcohols or glycols. These solutes are considered "ineffective" osmoles since they can equilibrate across cell membranes and therefore have little effect on water movement.

The measured osmolality should be close to the osmolality calculated from the osmotic contributions of the serum sodium concentration (SNa), glucose, and urea, which are the solutes in the extracellular fluid. Although potassium is also an effective osmole, it is usually not included in the calculated serum osmolality because it is quantitatively less important. If blood glucose (Glu) is reported in mg/dL, its osmotic contribution is calculated by dividing the contribution in mg/dL by 18; if the urea concentration is reported as blood urea nitrogen (BUN) in mg/dL, its osmotic concentration is calculated by dividing the BUN in mg/dL by 2.8:

If urea and glucose concentrations are reported in mmol/L rather than mg/dL, the formula is:

When the BUN is elevated, the measured serum osmolality will exceed the tonicity. If this is not recognized, then hypertonic or isotonic hyponatremia may be suspected in azotemic patients who instead have hypotonic hyponatremia. This most commonly occurs in patients with advanced kidney disease. They may develop hyponatremia because reduced kidney function impairs their ability to excrete excess water [2]. Although the low serum sodium concentration reduces the serum osmolality, this reduction is counterbalanced to a variable degree by azotemia, which increases the osmolality. Thus, the measured osmolality may be normal or elevated.

However, while the high urea concentrations raise the osmolality, they do not increase tonicity. In contrast to sodium and glucose, urea is an ineffective osmole since it can freely cross cell membranes and therefore does not obligate water movement out of cells. Thus, patients with hyponatremia and azotemia have a low effective serum osmolality (ie, a low tonicity). In this setting, tonicity may be calculated by subtracting the theoretical urea contribution to osmolality from measured osmolality:

Dividing the BUN by 2.8 converts mg/dL of urea nitrogen into mmol/L of urea, which is required when calculating osmolality. If blood urea is measured in units of mmol/L, the formula is:

True hypotonic hyponatremia despite a normal or elevated measured serum osmolality is also common in patients with alcohol use disorder [3]. The reduction in the osmotic contribution from a low serum sodium can be offset in such patients by a high plasma ethanol level. Ethanol, like urea, is an ineffective osmole since it can freely cross cell membranes and therefore does not obligate water movement out of cells. Thus, patients with hyponatremia and alcohol use disorder may have a low serum sodium concentration but a markedly higher measured osmolality [4]. The large difference between the calculated and measured serum osmolality becomes apparent when the blood alcohol level is measured. (See "Serum osmolal gap", section on 'Ethanol ingestion'.)

HYPERTONIC OR ISOTONIC HYPONATREMIA

Hypertonic hyponatremia caused by hyperglycemia — In patients with marked hyperglycemia, the increase in serum glucose raises the serum tonicity, which pulls water out of cells, expands the extracellular water space, and thereby lowers the serum sodium concentration (table 1). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum sodium'.)

A common clinical question that arises in hyperglycemic patients is whether a reduced serum sodium concentration is entirely due to the hyperglycemia-induced water shift from the intracellular to the extracellular space. To answer this question, the "corrected" sodium concentration and the effective osmolality can be calculated:

●The corrected serum sodium is the concentration that would result if the glucose level were reduced to the normal range. Calculation of the "corrected" serum sodium can be useful to assess whether hyponatremia can be fully explained by hyperglycemia. If the corrected serum sodium is within the normal range, then the patient does not have hypotonic hyponatremia. However, if the corrected serum sodium is low, then the patient likely does have hypotonic hyponatremia. By contrast, a corrected serum sodium that is elevated above the normal range indicates that hypernatremia exists. Thus, the corrected serum sodium helps predict the expected change in serum sodium during correction of hyperglycemia.

To calculate the "corrected" serum sodium, we recommend the use of the following ratio: The sodium concentration will fall by approximately 2 mEq/L for each 100 mg/dL (5.5 mmol/L) increase in glucose concentration [5].

●Hypertonic, rather than hypotonic, hyponatremia can also be identified by calculating the effective osmolality from the concentration of the measured (not the corrected) serum sodium concentration (SNa) plus the concentration of blood glucose in mmol/L (which is the concentration of blood glucose [Glu] ÷ 18 if glucose is measured in mg/dL). An effective osmolality >290 mosmol/kg excludes a diagnosis of hypotonic hyponatremia.

Hypertonic hyponatremia caused by hyperglycemia does not pose a risk of cerebral edema, because water moves out of cells. However, rapid correction of hyperglycemia without a commensurate rise in serum sodium may cause a precipitous decrease in effective osmolality and cause cerebral edema, particularly in children and young adults with diabetic ketoacidosis [6]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Cerebral edema'.)

Thus, it is useful to monitor effective osmolality during treatment of uncontrolled diabetes mellitus with severe hyperglycemia, aiming for a gradual decrease in effective osmolality.

Hypertonic or isotonic hyponatremia caused by exogenous solutes

Intravenous mannitol — Infusion of hypertonic mannitol can lower the serum sodium concentration in the same way as hyperglycemia (table 1). If mannitol is excreted in the urine, it provokes urinary water losses that raise the serum sodium concentration. However, if mannitol is retained in the extracellular space due to impaired kidney function, it causes hypertonicity, which pulls water out of cells, resulting in hyponatremia.

If hyponatremia occurs in a patient who has received mannitol, the serum osmolality should be measured. A gap between the measured serum osmolality and the calculated osmolality that is greater than 10 mosmol/kg indicates that mannitol has been retained (calculator 1 and calculator 2) [7]. (See "Complications of mannitol therapy".)

Intravenous immune globulins — Intravenous immune globulin (IVIG) therapy can cause hyponatremia without hypoosmolality (table 1). In patients with impaired kidney function, IVIG (which, by itself, can cause acute kidney injury) can produce hypertonic hyponatremia because parenteral formulations of immunoglobulin are usually suspended in hypertonic mannitol, maltose, or sucrose [8-10].

In patients with a low glomerular filtration rate, these sugars, which are normally excreted by the kidney, are retained in the blood. Thus, their concentrations increase and, because they are effective osmoles, serum tonicity increases. This causes water to exit cells and thereby reduces the serum sodium concentration. Hyponatremia in such patients may be severe and prolonged, partly due to shift of water caused by the retained effective osmoles and partly due to positive water balance caused by oliguric kidney injury.

A gap between the measured osmolality and the calculated osmolality indicates that the infused sugar has been retained (calculator 1 and calculator 2). (See "Intravenous immune globulin: Adverse effects".)

Some investigators have attributed the decrease in serum sodium concentration to pseudohyponatremia caused by IVIG-induced hyperproteinemia and hyperviscosity, similar to the cause of pseudohyponatremia in patients with a plasma cell dyscrasia [11]. (See 'Patients with a plasma cell dyscrasia' below.)

However, the proposed diagnosis of pseudohyponatremia was not verified in this study by measuring serum sodium concentrations with a sodium-selective electrode. In addition, the observed increase in serum proteins after IVIG infusion is insufficient to cause more than a trivial reduction in serum sodium concentration [8-10]. (See 'Confirming pseudohyponatremia with direct ion-selective electrodes' below.)

Isotonic hyponatremia due to surgical irrigants — The absorption of nonconductive glycine, sorbitol, or mannitol irrigation solutions during transurethral resection of the prostate or bladder (called the transurethral resection syndrome), hysteroscopy, or laparoscopic surgery can lower the serum sodium by increasing the extracellular fluid volume with these sodium-free solutions (table 1). (See "Hyponatremia following transurethral resection, hysteroscopy, or other procedures involving electrolyte-free irrigation" and "Hysteroscopy: Managing fluid and gas distending media".)

As an example, the most commonly used glycine solution has a glycine concentration of 1.5 percent and an osmolality of 200 mosmol/L. Thus, if a large volume of this solution is absorbed, the serum osmolality will decrease slightly (because the absorbed fluid is somewhat hypotonic compared with serum). However, the serum sodium concentration will decrease markedly because the absorbed fluid is sodium free.

When irrigant solutions containing sorbitol are used, the sorbitol that is not excreted by the kidney is slowly metabolized to carbon dioxide and water. Absorption of large volumes of sorbitol-containing fluid can therefore produce an isotonic hyponatremia and, if the sorbitol is not excreted because of kidney failure, a later-onset hypotonic hyponatremia develops as the sorbitol is metabolized to carbon dioxide and water.

In patients who have undergone surgery in which a glycine, sorbitol, or mannitol irrigation solution was used, a gap between the measured osmolality and the calculated osmolality indicates that these solutes have been retained in the extracellular space (calculator 1 and calculator 2).

Isotonic hyponatremia due to cardioplegia with histidine-tryptophan-ketoglutarate — Histidine-tryptophan-ketoglutarate (HTK) is a slightly hypertonic (ie, 310 mosmol/L), low-sodium solution that is widely used to induce electromechanical cardiac arrest during open heart surgery. In one study, infusion of HTK (median 2 liters) caused a decrease in serum sodium of 15 mmol/L within 30 to 60 minutes; the hyponatremia resolved spontaneously toward the end of surgery [12]. Measured serum osmolality remained normal, suggesting no intervention is required for this specific form of isotonic hyponatremia.

PSEUDOHYPONATREMIA — Hyperlipidemia or hyperproteinemia reduces the water content of a given volume of plasma. Although the sodium concentration in the water phase is not affected, the sodium concentration per unit of plasma is reduced. If the analyzer measures sodium concentration per volume of plasma, the measurement will be reduced (table 1). However, analyzers that directly measure the sodium concentration in the water phase of plasma are not affected by this error. Serum osmolality measurements are also not affected by this artifact [13,14]. This laboratory artifact is called pseudohyponatremia. (See "Causes of hypotonic hyponatremia in adults".)

Causes of pseudohyponatremia — Although rare, it is important to suspect pseudohyponatremia in the following clinical scenarios in order to prevent misdiagnosis of hyponatremia and possible complications from aggressive treatment with isotonic or hypertonic saline [15,16]:

●Patients who have lipemic serum

●Patients who have obstructive jaundice

●Patients who have a plasma cell dyscrasia

Patients with lipemic serum — Hypertriglyceridemia that is severe enough to result in clinically significant pseudohyponatremia has been reported primarily in patients with pancreatitis and diabetic ketoacidosis. In patients with acute pancreatitis, the presence of pseudohyponatremia at presentation increases the likelihood that the pancreatitis is due to hypertriglyceridemia [17].

Patients with obstructive jaundice — Pseudohyponatremia can occur in jaundiced patients with biliary obstruction or cholestasis who have extreme elevations of total serum cholesterol and high levels of lipoprotein X. The lowest reported total serum cholesterol resulting in pseudohyponatremia was 977 mg/dL (the corresponding serum sodium was 129 mmol/L), and the highest was 4091 mg/dL (the corresponding serum sodium was 101 mmol/L) [18]. Lipoprotein X is an insoluble compound that forms when there is reflux of unesterified cholesterol and phospholipids into the circulation. Lipoprotein X does not accumulate in other diseases resulting in severely elevated total serum cholesterol, such as homozygous familial hypercholesterolemia, which is not associated with pseudohyponatremia. In contrast to hypertriglyceridemia, elevated lipoprotein X levels do not cause the serum to appear lipemic.

Patients with a plasma cell dyscrasia — Pseudohyponatremia can occur in patients with myeloma who have severe hyperproteinemia (usually greater than 10 g/dL). In addition to the reduction in plasma water content caused by a high protein concentration, monoclonal proteins may artefactually lower the sodium concentration measured by volume-sensitive devices because of hyperviscosity and other factors that interfere with proper dilution of the plasma sample.

Confirming pseudohyponatremia with direct ion-selective electrodes — Electrolyte concentration units are usually reported as milliequivalents per liter (mEq/L) of plasma or serum. In normal individuals, plasma or serum is approximately 93 percent water and 7 percent solids (mainly fats and proteins). Thus, each liter of plasma contains approximately 930 mL of water, and a normal sodium concentration of 143 mEq/L of plasma or serum is equivalent to a concentration of 154 mEq/L of plasma water (154 x 0.93 = 143).

It is the sodium concentration in plasma water that is physiologically important. In patients with marked hyperlipidemia or hyperproteinemia, a smaller portion of the plasma sample consists of water. If the sodium concentration per liter of plasma water phase remains normal at 154 mEq/L of water, but the percentage of water in plasma falls as a result of hyperlipidemia or hyperproteinemia, then the sodium concentration per liter of plasma or serum will fall. Under these conditions, any measurement requiring an exact volume of serum or plasma (such as with flame photometry or indirect ion-selective electrodes) will be susceptible to a pseudohyponatremia artifact.

Direct ion-selective electrodes, which directly measure the concentration in the water phase of plasma or serum, are not affected by changes in the water percentage and are not susceptible to artefactual lowering of the serum sodium concentration by hyperlipidemia and hyperproteinemia [14,19,20]. Such direct ion-selective electrodes are utilized by most "point-of-care" bedside analyzers and devices used to measure blood gases. Many laboratory autoanalyzers also use ion-selective electrodes to measure sodium; most of these devices utilize indirect potentiometry, which involves a preanalytical dilution step. In healthy individuals, sodium measurements by direct and indirect potentiometry agree fairly closely; one study showed that the indirect measurements were on average 1.9 mEq/L higher [21]. However, the indirect method requires an exact volume of plasma or serum to be diluted, and therefore, in patients with hyperlipidemia or hyperproteinemia, this step creates a water volume error similar to that described above [13,14,20].

In patients with hypertonic or isotonic hyponatremia caused by hyperglycemia or exogenous solutes, the serum sodium concentration will be measured as low by an ion-selective electrode because, in these conditions, the sodium concentration in plasma water and interstitial fluid is truly low. However, in patients with isotonic hyponatremia caused by hyperlipidemia or hyperproteinemia, the serum sodium concentration will be measured as normal because, in these conditions, the sodium concentration in plasma water and interstitial fluid are normal. In both pseudohyponatremia and in hyponatremia caused by an excess of nonsodium solutes, the plasma osmolality will not be low (table 2).

An example illustrates how this artifact occurs with any device utilizing a dilution step, regardless of how the sodium concentration in the diluted sample is measured. Although actual sample sizes used by these instruments are smaller, and although the actual dilution is much less, for the sake of illustration, consider an instrument that aspirates a 1 mL sample of plasma. Consider also that the instrument requires that the aspirated sample to be diluted 1:1000 before performing the actual measurement of the sodium concentration in the water phase of the diluted specimen [13,14]:

●Assume that the plasma water content is normal at 93 percent and the sodium concentration in plasma water is also normal at 154 mEq/L (or 154 microEq/mL). The sodium concentration in the total plasma sample will be (154 mEq/L x 0.93 = 143 mEq/L [or 143 microEq/mL]), and the 1 mL aspirated sample will contain 143 microEq of sodium. If that 1 mL plasma sample is diluted with water to a total volume of 1 L (1:1000 dilution), the sodium concentration in the diluted specimen will be 143 microEq/L. Taking account of the dilution term, the analyzer will report a sodium concentration of 143 mEq/L of plasma.

●However, now assume that severe hyperlipidemia is present and has reduced the water content of the plasma to 80 percent while the sodium concentration in the water phase remains normal at 154 mEq/L of plasma water. The sodium concentration in the initial plasma sample will be (154 mEq/L x 0.8 = 123 mEq/L); the aspirated 1 mL sample will contain 123 microEq of sodium, and, after dilution by 1:1000, the sodium concentration will be 123 microEq/L. Taking account of the dilution term, the analyzer would report a sodium concentration of 123 mEq/L of plasma.

In each of these cases, the sodium concentration in the water phase of the blood is normal at 154 mEq/L, although the laboratory autoanalyzer reports different values for the serum sodium.

As an alternative to using ion-selective electrodes, the water content of plasma in patients with hyperlipidemia or hyperproteinemia can be estimated by the following formula [14]:

where L and P refer to the total lipid and protein concentrations in g/L, respectively. This value is then used to "correct" the sodium concentration so that it is adjusted to the normal value for plasma water content of 93 percent.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia".)

SUMMARY

●Plasma tonicity is defined as the concentration of solutes that do not easily cross the cell membrane (effective osmoles). These solutes are primarily sodium salts in the extracellular space. As a result, serum or plasma sodium is used as a surrogate for assessing tonicity of the extracellular fluid. The vast majority of patients with hyponatremia have hypotonicity, although some hyponatremic patients are not hypotonic. (See 'Introduction' above.)

●The main difference between tonicity and osmolality is that tonicity reflects the concentration of solutes that do not easily cross cell membranes (mostly sodium salts with a small contribution from glucose) and therefore affect the movement of water between cells and the extracellular fluid. By contrast, osmolality also includes the osmotic contributions of urea and (if present) ethanol or other alcohols or glycols. These solutes are considered "ineffective" osmoles since they can equilibrate across cell membranes and therefore have little effect on water movement. The measured serum osmolality can sometimes be misleading, suggesting a diagnosis of hypertonic hyponatremia or isotonic hyponatremia in a patient who instead has hypotonic hyponatremia. This most commonly occurs in patients with advanced kidney disease and in those with alcohol use disorder. (See 'Tonicity versus osmolality in hyponatremia' above.)

●There are three general categories of hyponatremia without hypotonicity:

•Hypertonic hyponatremia caused by hyperglycemia – The increase in serum glucose raises the serum tonicity, pulling water out of cells and expanding the extracellular water space, thereby lowering the serum sodium concentration. Hyponatremia can be attributed to the hyperglycemia if the "corrected" serum sodium is normal (calculated by adding 2 mEq/L to the serum sodium for each 100 mg/100 mL [5.5 mmol/L] increase in glucose concentration) or if the effective osmolality is at least 290 mosmol/kg (calculated by doubling the serum sodium concentration and adding concentration of glucose in mmol/L). (See 'Hypertonic hyponatremia caused by hyperglycemia' above.)

•Hypertonic or isotonic hyponatremia caused by exogenous solutes – Infusion of mannitol or intravenous immune globulin (IVIG; which is suspended in hypertonic mannitol, maltose, or sucrose) can, if kidney function is impaired, lead to retention of these sugars in the blood. This causes water to exit cells and thereby reduces the serum sodium concentration. The absorption of nonconductive glycine, sorbitol, or mannitol irrigation solutions during transurethral resection of the prostate or bladder, during hysteroscopy, or during laparoscopic surgery or the infusion of histidine-tryptophan-ketoglutarate (HTK) during open heart surgery can lower the serum sodium by increasing the extracellular fluid volume with these sodium-free solutions. (See 'Hypertonic or isotonic hyponatremia caused by exogenous solutes' above.)

•Pseudohyponatremia – Hyperlipidemia or hyperproteinemia lowers the serum sodium concentration (and therefore the calculated serum osmolality) when it is measured with certain analyzers, without causing a major change in the sodium concentration in the water phase of serum or the measured serum osmolality. This is a laboratory artifact that is called pseudohyponatremia. Although rare, it is important to suspect pseudohyponatremia in the following clinical scenarios in order to prevent complications from aggressive treatment with isotonic or hypertonic saline (see 'Pseudohyponatremia' above):

-Patients who have lipemic serum

-Patients who have obstructive jaundice

-Patients who have a plasma cell dyscrasia