in the diagnostic approach for the patients with hyponatemia , pseudohyponatremia should always be differentiated during the initial steps1 ) . although many clinicians are familiar with the term " pseduhyponatremia " , they may be aware of the concept and application of pseudohyponatremia only on rare occasions during their practice . pseudohyponatremia is an exaggeration of the physiologic dilution of plasma sodium by nonaqueous material2 ) . high concentrations of intravascular protein ( as in multiple myeloma ) or lipid " dilute " the plasma sodium concentration , but do not alter the solute concentrations of the intracellular or interstitial fluid compartments . because the " diluent " in these conditions is nonaqueous , the sodium concentration of the aqueous portion of a plasma sample , as determined by an ion - selective electrode in undiluted serum or plasma , is normal3 ) . thus hyponatremia associated with hyperlipidemia or hyperproteinemia can be considered artifactual , and is called pseudohyponatremia4 ) . previously , fuisz refered to this pseudohyponatremia as a well - known matter in a very comprehensive study on hyponatremia5 ) . it should be noted that laboratory determinations that depend on a diluting step yield artifactually low sodium concentrations in samples taken from patients with severe hyperlipidemia or plasma cell dyscrasias , even if the instrument uses an ion - selective electrode6 ) . in these disorders , the plasma aliquot obtained for dilution contains less plasma water ( and therefore less sodium ) than normal ; the sodium concentration in the diluted sample is thus artifactually reduced . these notions can hardly be realized in daily clinical practice , and pseudohyponatremia may need to be reappraised from the current clinician 's viewpoint . a 35 year - old black male soldier was admitted due to lower extremity weakness . he was previously healthy until he had upper respiratory infectious symptoms 3 days prior to admission . initial serum electrolyte profile showed na 131 , k 3.4 , cl 96 , and total co2 25.9 meq / l . clinical diagnosis of guillain - barre syndrome was made , and intravenous immunoglobulin therapy was carried out for 5 days . at the end of the intravenous infusion of immunoglobulin , his serum sodium concentration was decreased to 116 meq / l but without any relevant symptoms . hyponatremia is a known complication associated with the administration of intravenous immunoglobulin ( ivig)7 - 11 ) . because ivig therapy results in post - infusional hyperproteinemia or an increase in the nonaqueous phase of plasma , ivig is thought to cause pseudohyponatremia , rather than true hyponatremia . steinberger et al . conducted a prospective observational study to evaluate the incidence of hyperproteinemia occurring after ivig therapy and its relationship to serum sodium , osmolality , and the serum osmolal gap10 ) . eighteen ivig infusions at a standard dose of 2 g / kg administered over 2 - 5 days were evaluated . paired t - testing revealed a statistically significant increase in serum protein and viscosity and decrease in serum sodium and calculated osmolality 24 hr after the completion of ivig therapy ( fig . we suspected that our patient had pseudohyponatremia due to ivig - associated hyperproteinemia . however , measurement of serum osmolality and determination of serum sodium concentrations with both indirect and direct ion - selective electrodes ( ise ) were necessary to exclude the possibility of true hyponatremia . the emergency laboratory of my hospital uses two models of autoanalyzers for measurement of electrolytes . both use ion - selective electrodes in diluted plasma specimens ( indirect ise , 30dilution for hitachi 7170s and 10dilution for dade behring dimension ) for measurement of sodium concentration . ivig therapy can result in true hyponatremia , resulting from sucrose - induced translocation of water from the intracellular compartment to the extracellular compartment , as well as the infusion of a large volume of dilute fluid12 ) . however , this occurs in patients with an underlying defect in urinary free - water excretion such as advanced chronic kidney disease . our patient had no azotemia and seemed to have no defect in free - water excretion . besides , an association of the syndrome of inappropriate secretion of antidiuretic hormone ( siadh ) with guillainbarre syndrome has been clearly documented in a number of previous reports13 - 16 ) . according to hoffmann et al . , 25% of patients with guillain - barre syndrome present with hyponatremia due to siadh17 ) . traditionally , sodium in plasma or serum has been determined by flame photometry . nowadays , most diagnostic laboratories in the hospital use sodium - selective electrodes . the development of electrodes that are selective for sodium opened the possibility of potentiometric determination18 ) , which offers advantages . plasma is normally 93% water , and the sodium ion concentration in " plasma water " is the biological index . meq / l in a sample of whole plasma reflects a sodium concentration of 154 meq / l in plasma water ( 143/0.93=154 ) . physiologic saline solutions ( for example , 0.9% nacl ) were designed to reproduce the sodium concentration in plasma water2 ) . ion - selective electrodes for the analysis of sodium are used via two major approaches ( fig . in one , the sample is diluted before analysis ( indirect potentiometry ) , analogous to flame photometry . in the other , the sample is analyzed without dilution ( direct potentiometry ) , analogous to blood ph measurement . when using indirect potentiometry , if the diluent and dilution ratio are properly selected , the activity coefficient and residual liquid junction potential between standards and samples should be matched and the results should reflect total concentration . therefore , it is not surprising that indirect potentiometry and flame photometry give the same values for sodium in plasma with various instruments . direct - potentiometric sodium values are not expected to be the same as flame photometric values because of the influence of water content as depicted in fig . 319 ) . in clinical conditions such as hyperlipemia or hyperproteinemia , in which the water content of pl asma is decreased , low flame - photometric sodium values have been long noted . under such conditions , direct - potentiometric values are more clinically appropriate . given that the water content of normal serum is 91 - 93% , a technique that utilizes a fixed volume aliquot ( flame photometry or indirect potentiometry ) should give values 7 - 9% lower than a technique that does not involve fixed - volume aliquots ( direct potentiometry ) when both use standardization with nacl . this is because direct potentiometry should measure the activity of sodium only in the water phase . however , sodium values obtained by direct potentiometry and flame photometry show that flame - photometric values are 95.7 to 98.8% of direct - potentiometric values20 ) . indirect potentiometry also can lead to an underestimation of serum sodium even though the sodium activity registered by the sodium - selective electrode is oblivious to the non - aqueous volume . automatic aspirators and dilutors prepare the samples and , in situations with excessive non - aqueous volume in plasma , a smaller than expected plasma volume may be aspirated leading to an underestimation of serum sodium during the back - calculation21 ) . extreme cases of hyperlipemia22 ) and hyperproteinemia23 ) will simulate hyponatremia , i.e. , spuriously low sodium concentrations will be determined in sera that are markedly lactescent or for sera with the extremely high protein values that are typical in multiple myeloma . in these instances then will the indirect method mislead us to confusion in interpreting the serum sodium data ? my hospital uses indirect ise methods ( hitachi and dade behring ) for the measurement of serum sodium concentration . serum chemistry data were retrospectively investigated from 9 patients who were admitted to my hospital and received ivig infusion for 4 to 7 days during the recent 6 months ( table 1 ) . the indications for ivig were variable : neurologic , infectious , autoimmune , and inflammatory disorders . after the ivig infusion , serum total protein was significantly increased from 5.331.02 ( meansd ) to 6.680.71 g / dl . however , serum sodium concentration did not show any significant change between pre- and post - ivig infusion : 1415 meq / l vs. 1382 meq / l . they administered a standard dose of 2 g / kg over 2 or 5 days . after the ivig infusion , serum total protein was significantly increased from 6.32 to 8.15 g / dl . serum sodium concentration showed a " significant " decrease from 136 to 133 meq / l . it is interesting that the mean decrease in serum [ na ] is almost the same ( -3 meq / l ) as ours . table 2 shows serum chemistry data from 5 patients with multiple myeloma and 1 with nephrotic syndrome , and they were also admitted to my hospital during the recent 6 months . all 4 myeloma patients had rather high levels of serum total protein , but their serum sodium concentrations were not notably low . the patient with nephrotic syndrome ( case 6 ) presented with severe hyperlipidemia , but his serum sodium concentration was within normal range . although hyperlipidemia causes errors in indirect ise electrolyte measurements , the decrease in serum [ na ] would be only -1 meq / l for each 10-mmol / l increase in total lipid concentration24 ) . actually , as seen in the table 3 which was proposed by levy25 ) for the correction of errors caused by hyperproteinemia or hyperlipidemia
serum consists of water ( 93% of serum volume ) and nonaqueous components , mainly lipids and proteins ( 7% of serum volume ) . 
 sodium is restricted to serum water . in states of hyperproteinemia or hyperlipidemia 
 , there is an increased mass of the nonaqueous components of serum and a concomitant decrease in the proportion of serum composed of water . 
 thus , pseudohyponatremia results because the flame photometry method measures sodium concentration in whole plasma . 
 a sodium - selective electrode gives the true , physiologically pertinent sodium concentration because it measures sodium activity in serum water . whereas the serum sample is diluted in indirect potentiometry , the sample is not diluted in direct potentiometry . 
 because only direct reading gives an accurate concentration , we suspect that indirect potentiometry which many hospital laboratories are now using may mislead us to confusion in interpreting the serum sodium data . 
 however , it seems that indirect potentiometry very rarely gives us discernibly low serum sodium levels in cases with hyperproteinemia and hyperlipidemia . 
 as long as small margins of errors are kept in mind of clinicians when serum sodium is measured from the patients with hyperproteinemia or hyperlipidemia , the present methods for measuring sodium concentration in serum by indirect sodium - selective electrode potentiometry could be maintained in the clinical practice .