Pseudohyponatremia: Mechanism, Diagnosis, Clinical Associations and Management: Comparison
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Pseudohyponatremia remains a problem for clinical laboratories. The two methods involved assess the serum sodium concentration ([Na]S) using sodium ion-specific electrodes: (a) a direct ion-specific electrode (ISE), and (b) an indirect ISE. A direct ISE does not require dilution of a sample prior to its measurement, whereas an indirect ISE needs pre-measurement sample dilution. [Na]S measurements using an indirect ISE are influenced by abnormal concentrations of serum proteins or lipids.

  • hyponatremia
  • pseudohyponatremia
  • pseudonormonatremia
  • pseudohypernatremia

1. Mechanisms of Pseudohyponatremia

The relation between the SSC and the SWC is traditionally expressed as SSC + SWC = 1, indicating that the SWC changes in the opposite direction and by the same magnitude when the SSC changes [31][1]. The actual SWC is slightly lower than the value of 1—SSC, because the SWC value includes the molecular volumes of crystalloids dissolved in serum water, in addition to the volume of water. These molecular volumes are too small to affect the accuracy of calculations involving the SWC, amounting to about 0.9% of the expression 1—SSC [12][2].
The proposed mechanisms of pseudohyponatremia when the [Na]S is measured via the indirect ISE or FES, which require pre-measurement dilution of the serum specimen, include the following: (a) the electrolyte exclusion effect; (b) the dilution effect; and (c) the hyperviscosity effect. None of these three mechanisms operates when the [Na]S is measured using the direct ISE. In addition, pseudohyponatremia has been reported as a result of mechanisms specific to certain medical conditions.

1.1. Sodium Concentration Lowering by the Electrolyte Exclusion Effect

The electrolyte exclusion effect, also known as the volume displacement effect, can be defined as a decrease in the concentrations of electrolytes in whole serum because these electrolytes are contained only in the SWC [27,32][3][4]. 
The indirect ISE method, which measures sodium concentration in the water fraction of a diluted serum sample, is subject to the electrolyte dilution effect, as will be shown in the next subsection. In contrast, the direct ISE approach, which measures sodium concentration in the water fraction of undiluted serum, is not affected by the electrolyte exclusion effect. The direct ISE values will be the same at all SWC values when the [Na]SW is the same. For example, at a [Na]SW of 151 mmol/L, the direct ISE will report a [Na]S of 0.93 × 151 = 140.4 mmol/L at both an SWC = 0.93 and an SWC = 0.79.
Several studies have documented that the direct ISE method is not influenced by electrolyte exclusion. The [Na]S measured by the direct ISE method was the same before and after removal of excess lipids from a hyperlipemic serum in one study [33][5]. In a second study, [Na]S values measured with FES were substantially lower than the corresponding values measured by a direct ISE in hyperlipemic sera, while after removal of the lipids, the [Na]S values measured via FES rose substantially and became almost identical to the values measured with a direct ISE [34][6]. In another study, progressively increasing the protein concentration in aqueous solutions had minimal effects on the concentrations of sodium and potassium measured by the direct ISE, but produced a progressive decrease in the concentrations of both cations measured with FES [23][7].

1.2. Sodium Concentration Lowering by the Dilution Effect

Dilution of a serum sample with high SSC prior to measurement of its [Na]S combined with the electrolyte exclusion effect results in pseudohyponatremia [32][4]. The dilution factor for serum water (DFSW) is calculated as (volume of fluid added plus serum water volume)/(serum water volume) [32][4]. This factor increases progressively at progressively lower SWC values with use of the same volume of diluent [32][4].
Table 1 shows an example of the effect of dilution on the measurement of [Na]S with an indirect ISE in a serum sample with normal SSC and two serum samples with high SSC values. The [Na]SW was 151 mmol/L in all three samples. Note that the true values of the [Na]S computed directly from the [Na]SW and the SWC differed only slightly from the corresponding values of [Na]S computed after measurement of the sodium concentration in the water of the diluted serum specimens when the [Na]SW and the [Na]S were computed assuming an SWC of 0.93 (Table 1). Therefore, the effect of dilution consists only in expressing the exclusion effect when the auto-analyzer algorithms for an indirect ISE compute the [Na]S using an SWC of 0.93 and its corresponding DFSW.
Table 1. Dilution effect. Measured [Na]S after 1:31 (serum volume: diluent plus serum volume) pre-measurement dilution in sera with three different solid contents and the same [Na]SW (151 mmol/L).
Component SSC = 0.07

SWC = 0.93		 SSC = 0.14

SWC = 0.86		 SSC = 0.21

SWC = 0.79
Diluent, L 0.3 0.3 0.3
Serum, L 0.01 0.01 0.01
Serum sample water, L 0.0093 0.0086 0.0079
Total sample

water, L		 0.3093

(0.3 + 0.0093)		 0.3086

(0.3 + 0.0086)		 0.3079

(0.3 + 0.0079)
Dilution factor serum water (38) 33.2581

(0.3093/0.0093)		 35.8837

(0.3086/0.0086)		 38.9747

(0.3079/0.0079)
Sodium content

of sample, mmoL		 1.4043

(0.0093 × 151)		 1.2986

(0.0086 × 151)		 1.1929

(0.0079 × 151)
[Na]DSW, mmol/L 4.540

(1.4043/0.3093)		 4.2080

(1.2986/0.3086)		 3.8743

(1.1929/0.3079)
[Na]SW 1, mmol/L 151.0

(4.540 × 33.2581)		 140.0

(4.2080 × 33.2581)		 128.9

(3.8743 × 33.2581)
[Na]S 1, mmol/L 140.4

(151 × 0.93)		 130.2

(140 × 0.93)		 119.8

(128.9 × 0.93)
To recapitulate, in sera with the same [Na]SW values, the electrolyte exclusion effect is responsible for the progressively lower [Na]S values reported via an indirect ISE at progressively higher SSC values. Pre-measurement dilution allows expression of the electrolyte exclusion effect.

1.3. Sodium Concentration Lowering by the Hyperviscosity Effect

The hyperviscosity effect becomes apparent when highly viscous serum specimens are diluted prior to measuring their sodium concentrations [35][8]. Pronounced hyperproteinemia, e.g., in multiple myeloma or Waldenstrom’s macroglobulinemia [36][9], causes serum hyperviscosity. When using pumps, e.g., roller ones, in apportioning serum and diluent to deliver the required volume of diluted serum to an automatic dilution device, hyperviscosity can cause a decrease in the delivered serum to the device that assays the sodium activity while the delivery of the non-viscous diluent is unimpeded, thus augmenting the electrolyte exclusion effect. A low temperature of a measured sample can increase this hyperviscosity effect [37][10]. This device-related decrease in serum sample delivery (hence, in sodium delivery) to a sodium analysis device causes pseudohyponatremia [38,39,40][11][12][13].
Overlack and coauthors reported that hyperviscosity accounted for the largest proportion of pseudohyponatremia cases in patients with multiple myeloma and hyperproteinemia [41][14]. Hyperviscosity contributed to pseudohyponatremia that was observed after immunoglobulin infusion [42][15], and in the hypercholesterolemic plasma of a patient with primary biliary cirrhosis [43][16]. In conclusion, the impaired delivery of serum with hyperviscosity to the sodium-measuring apparatus after pre-measurement dilution is purely a mechanical problem, and is unrelated to the electrolyte exclusion effect. Hyperviscosity does not influence the [Na]S measured by placing a drop of serum on a microslide in an apparatus that uses a direct ISE [23][7].

2. Diagnosis of Pseudohyponatremia

One approach used to calculate the [Na]SW, and consequently to diagnose pseudohyponatremia, consists of dividing the [Na]S reported by a method using pre-measurement dilution by the SWC [44][17]. Waugh developed the following empirical formula expressing SWC in 100 mL of serum [12][2]:
100   ×   SWC = 99.1 − 0.73 × S P − 1.03 × S L
where 99.1 is the volume of water contained in 100 mL of a crystalloid solution having the composition and concentrations of crystalloids in serum water; [SP] is the concentration of proteins in g/dL of serum; and [SL] is the concentration of lipids in g/dL of serum. Various other methods for estimating the SWC and [Na]SW have been proposed [45,46,47,48,49,50,51,52][18][19][20][21][22][23][24][25]. SSC values lower than 0.07 may result in pseudonormonatremia in cases of hypotonic hyponatremia, or in pseudohypernatremia in cases of true normonatremia. Formula 1 suggests that a low plasma protein [PP] is the main cause of spurious hypernatremia or spurious normonatremia, since the normal values of plasma lipid [PL] are around 0.3 g/100 mL and the normal values of [PP] are around 8 g/100 mL.
Musso and Bargman proposed that the first step in evaluating hyponatremia in asymptomatic patients on peritoneal dialysis consists of checking for pseudohyponatremia [55][26]. Pseudohyponatremia should be considered in all low [Na]S values measured using an indirect ISE. Pseudohyponatremia is diagnosed directly in this case by measuring the [Na]S with a direct ISE [56][27]. However, detecting whether a low [Na]S value was caused by hypotonic hyponatremia, hypertonic hyponatremia, or pseudohyponatremia [57][28], and particularly whether there are combinations of pseudohyponatremia with other dysnatremic states when a low [Na]S value is reported via the indirect ISE method, is based on measuring serum osmolality, and computing the osmol gap [58][29]. The osmol gap represents the difference between the measured serum osmolality and serum osmolarity, calculated as the sum 2 × [Na]S + serum urea + serum glucose, where both the serum glucose and urea concentrations are in mmol/L [17,59][30][31].
Figure 1 shows a “based on the osmol gap” scheme for the diagnosis of pseudohyponatremia and other dysnatremias potentially associated with it in cases of a low [Na]S measured with the indirect ISE approach. Combinations of dysnatremias should be suspected in every case with an osmol gap that is larger than 10 mmol/L. Pseudohyponatremia is confirmed when the [Na]S measured a direct ISE exceeds the corresponding indirect ISE value. In all instances of pseudohyponatremia, the osmol gap should be recalculated using the [Na]S measured with a direct ISE. If the new osmol gap is within the normal range, pseudohyponatremia was the sole cause of the original gap. If the new osmol gap is less than the original, but still above the normal range, this means that pseudohyponatremia is combined with excesses of solutes other than sodium, glucose, or urea. Combinations of pseudohyponatremia with other dysnatremias that can be detected by large osmol gaps are encountered clinically.
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Figure 1. Diagnosis of pseudohyponatremia and accompanying dysnatremias. Osmol gaps that are calculated using the direct instead of the indirect [Na]S value and are still enlarged indicate the presence in serum of a solute other than sodium salts, glucose, or urea. [Na]S values < 135 mmol/L reported by direct ISE result from either hypotonic or hypertonic hyponatremia. Hyperglycemic states by far represent the most frequent cause of hypertonic hyponatremia. * Hypertonic hyponatremia masked by a mechanism causing hypernatremia, e.g., osmotic diuresis caused by hyperglycemia.
In addition to pseudohyponatremia, large osmol gaps are encountered in situations where there is a gain of solutes other than sodium, glucose, and urea in the serum [60][32]. Examples of endogenous solute gains include advanced chronic kidney disease [61][33] and the sick cell syndrome [62][34]. A large osmol gap from the gain in exogenous solutes distributed in total body water, e.g., ethanol [63][35], may be associated with both hypotonic hyponatremia and pseudohyponatremia (through hyperlipidemia). Gains in solutes with extracellular distribution cause hypertonic hyponatremia.

3. Clinical Conditions Associated with Pseudohyponatremia

3.1. Hyperproteinemia

Hyperproteinemic diseases may produce multiple mechanisms for hyponatremia. In multiple myeloma, hyperproteinemia is the usual cause of pseudohyponatremia. Serum cholesterol levels are routinely low in patients with multiple myeloma because of increased low-density lipoprotein (LDL) clearance and the uptake of cholesterol by tumor cells [115][36]. However, pseudohyponatremia results from a combination of hyperproteinemia and hypercholesterolemia in patients with multiple myeloma who exhibit hypercholesterolemia [116][37]. Low [Na]S values in multiple myeloma patients may represent combinations of pseudohyponatremia with other dysnatremias. Combinations of pseudohyponatremia and hypotonic hyponatremia are encountered when there are manifestations of myeloma that cause a relative excess of body water, e.g., the syndrome of inappropriate antidiuretic hormone secretion [117,118,119][38][39][40]. Hyponatremia is also encountered when paraproteins in sera have positive charges [120][41].
Monoclonal gammopathies may cause hyperproteinemia and hyperviscosity [121][42]. An infusion of immunoglobulins may cause pure pseudohyponatremia or a combination of pseudohyponatremia and hypertonic hyponatremia. Immunoglobulin preparations for intravenous infusion frequently contain 10% maltose solutions [122][43]. Maltose is metabolized by maltase contained in the brush border of renal proximal tubular cells [123][44]. In patients with renal dysfunction, the infusion of immunoglobulin solutions has been found to cause combinations of pseudohyponatremia due to hyperproteinemia and hypertonic hyponatremia that is secondary to maltose accumulation in the extracellular compartment [124,125][45][46]. Maltose present in the serum increases the osmol gap. Combinations of pseudohyponatremia and hypertonic hyponatremia have also been reported after infusions of sucrose-containing immunoglobulin preparations [126][47].

3.2. Hyperlipidemia

Severe hypertriglyceridemia may cause both pancreatitis and pseudohyponatremia [81,82,83,84][48][49][50][51]. The lipoprotein lipase, an enzyme of endothelial cells, catabolizes triglyceride-containing compounds including chylomicrons and very-low-density lipoprotein (VLDL). Asparaginase, a drug used for the treatment of hematologic malignancies and other malignant diseases, inhibits lipoprotein lipase activities [127][52]. The concentration of triglycerides in serum becomes elevated transiently after asparaginase administration [128][53]. In some instances, both serum cholesterol and serum triglyceride levels are elevated after asparaginase treatment [87][54].

3.3. Diabetic Ketoacidosis

As in immunoglobulin infusion, diabetic ketoacidosis (DKA) with elevated serum lipid levels may cause combined pseudohyponatremia and hypertonic hyponatremia. In addition, osmotic diuresis in combination with thirst and fluid intake may cause combinations of pseudohyponatremia, hypertonic hyponatremia and hypernatremia or hypotonic hyponatremia in hyperglycemic emergencies [65,129][55][56]. The presence and degree of dysnatremias masked by combined pseudohyponatremia and hypertonic hyponatremia can be detected by measuring the [Na]S with a direct ISE and computing the [Na]S that results from correcting the hyperglycemia [65][55]; monitoring the [Na]S during treatment remains imperative [65][55].
Pseudohyponatremia in DKA may be encountered in the absence of an elevated SSC [96][57]. In this case, a low blood pH or other unknown conditions are thought to affect [Na]S measurement with an indirect ISE [94][58]. The effect of very high glucose concentrations on the measurement of sodium concentration with ISE methods need further studies. In samples with extremely high glucose concentrations, one study reported finding spuriously high sodium concentrations when the [Na]S was measured using a direct ISE, but not for an indirect ISE [130][59], while a second study reported spuriously high sodium concentrations measured with an indirect ISE, but not with a direct ISE [131][60].

3.4. Enzyme Mutations Causing Hypertriglyceridemia

Enzyme mutations, mainly of the lipoprotein lipase, may cause profound hypertriglyceridemia, and consequently pseudohyponatremia [132][61]. Several enzyme mutations causing hypertriglyceridemia have been reported [133,134,135,136,137,138,139][62][63][64][65][66][67][68].

3.5. Hypercholesterolemia Caused by Cholestasis

Liver diseases that are associated with cholestasis have been linked to pseudohyponatremia associated with hypercholesterolemia. Cholesterol is transported in the blood by VLDL and lipoprotein X. The blood levels of lipoprotein X are elevated in cases of hypercholesterolemia, due to cholestasis [140,141][69][70]. Pseudohyponatremia that is secondary to severe hypercholesterolemia associated with use of certain drugs has also been reported [106,107][71][72]. Hepatitis with cholestasis has been observed as a complication of these medications, which include the antipsychotic quetiapine [142][73], trimethoprim-sulfamethoxazole [143][74], and the antiviral agent valacyclovir [144][75]. Alagille syndrome, an autosomal dominant disorder caused by mutations in genes JaG1 or NOTCH2 of the Notch signaling pathway, causes cholestasis and severe clinical manifestations from other organ systems [145][76].

3.6. Pseudohyponatremia in the Absence of Elevated Serum Solids Content

In addition to DKA, other conditions can cause pseudohyponatremia in the absence of an elevated SSC. Pseudohyponatremia associated with pseudohyperkalemia has been reported in heparinized plasma samples from patients with non-Hodgkin’s lymphoma [146][77] and acute lymphoblastic leukemia [147][78]. Some of the proposed mechanisms affecting the collected blood sample include the following: (a) lysis of white blood cells in heparinized blood samples with the release of potassium and ATP into the plasma, causing sodium influx into lymphocytes and pseudohyponatremia [147][78]; and (b) a defect in the cell membranes of red blood cells causing potassium to exit from red cells and sodium to enter these cells [148][79].
The combination of pseudohyperkalemia and pseudohyponatremia has also been observed in serum samples that were separated with some delay after blood sample collection in a patient with hereditary stomatocytosis; this is an autosomal dominant condition in which a defect in the red cell membrane leads to increased sodium influx into the red cells, which is counteracted in vivo by a large increase in sodium/potassium ATPase activity of the red cell membrane. After blood collection, the activity of the ATPase is diminished as a consequence of a decrease in the blood sample temperature and the reduced supply of ATP due to a decrease in glucose concentration of the serum sample, leading to the development of pseudohyperkalemia and pseudohyponatremia [149][80].

3.7. Differences in [Na]

S

Values Measured by Different Direct ISE Apparatuses

When the degree of pseudohyponatremia is considered, differences between [Na]S values measured with a direct ISE in a “point-of-care” (POC) setting in an intensive care unit using the blood gas apparatus and in the main hospital laboratory should be considered. The frequencies of discrepancies found in paired measurements between the two direct ISE apparatuses reported by Weld and co-investigators were 4.1% for a ≥4 mmol/L disagreement, 13.4% for a ≥3 mmol/L disagreement, and 36.2% for a ≥2 mmol/L disagreement; these authors identified the level of serum proteins as one source of disagreement, with measurements in the central laboratory being lower than the corresponding POC measurements at low serum protein levels, and higher than the POC measurements at high serum protein levels; the authors concluded that these disagreements were sufficient to affect conditions in which an accurate measurement of the [Na]S is required, e.g., in the treatment of hyponatremia [150][81].
Other potential sources of discrepancies between the two direct ISE methods include differences in bicarbonate and glucose concentrations between the blood sample measured in the blood gas POC apparatus and the serum sample measured in the apparatus of the main hospital laboratory, and a high level of blood hemoglobin resulting in a spurious decrease in the [Na]S measured in whole blood with the direct ISE [151][82]. Finally, influences of hypernatremia and blood pH values on the measurement of [Na]S by different ISE technologies have been reported [152][83].

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