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By Roger Bertholf, PhD, DABCC, FACB
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If one were to compile a list of terms that ought to be eliminated from the laboratory medicine lexicon, “pseudohyponatremia” (PHN) would certainly be on it (and, by the way, such a list would be very long!). The problem with the term PHN is that it is used in reference to two completely different phenomena, and it misleadingly implies that sodium behaves differently from other water-soluble components in blood.

Clinicians use the term PHN in situations where blood hyperosmolality, usually due to severe hyperglycemia, results in movement of water from the intracellular fluid (ICF) to the extracellular fluid (ECF), diluting all of the solutes in ECF to restore osmotic balance. When that happens, the plasma sodium concentration decreases, along with the concentration of any other plasma constituents that do not freely equilibrate across cell membranes (this is sometimes called “hypertonic hyponatremia”). The reason this is considered “pseudo“ (or “false”) hyponatremia  is that it does not reflect a deficiency in total body sodium stores, such as occurs in renal sodium  loss. However, the term “hyponatremia” means, literally, low blood sodium concentration, and in cases of hypertonic hyponatremia, the blood sodium is, in fact, low, so the “pseudo” modifier seems inappropriate. The hyponatremia may be clinically benign, but the measurement is accurate. In 1973, Katz reported a formula that increases sodium by 1.6 mmol/L for every 100 mg/dL glucose concentration above 100 mg/dL (e.g., for a patient with a glucose of 200 mg/dL, the sodium would be adjusted upward by 1.6 mmol/L. The “1.6” correction factor is based on a number of assumptions relating to the movement of various solutes between the ECF and ICF, and has been shown to vary across glucose concentrations, so it is an approximation from which deviation will be observed at extremes of hyperglycemia.

To laboratorians, PHN refers to the falsely low sodium concentrations measured in plasma when significant hyperproteinemia or hyperlipidemia is present. Proteins and lipoproteins are in micromolar concentrations in plasma, and therefore have minimal effect on osmolality, but they do occupy a volume from which the aqueous fraction of plasma (and all of its dissolved constituents) are excluded. Ordinarily, the volume of plasma occupied by proteins and lipoproteins is a small fraction (<5%) of total plasma volume, but in severe hyperproteinemia or hyperlipidemia, the excluded volume is sufficient to bias the apparent concentrations of plasma constituents that exist almost exclusively in the aqueous fraction, such as sodium. In an analytical method that depends on a precisely measured volume of specimen (the vast majority of analytical methods do), this volume exclusion effect is equivalent to short-sampling, since the volume of the aqueous, sodium-containing fraction is less than what is delivered by the sampling apparatus. Some analytical methods, however, do not require the volume of sample to be known, and an example is direct potentiometry (e.g., a pH meter). Direct potentiometry measures the activity of an analyte at the surface of an electrode exposed to undiluted specimen. The total volume of the specimen is irrelevant, as is any volume excluded by hyperproteinemia or hyperlipidemia. In this case, “pseudo-“ is more appropriate, since the measured sodium concentration (except by direct potentiometry) does not reflect the true sodium concentration in the aqueous phase, which is the physiologically relevant parameter.

But why does the term PHN imply that only sodium is affected? Sodium is one of many plasma components that exist almost exclusively in the aqueous phase, and all of these components are affected equally by volume displacement. Why is there never a reference to “pseudohypokalemia,” “pseudohypochloremia,” or “pseudohypomagnesemia”? A 10% reduction (or apparent reduction) in sodium due to volume exclusion would be accompanied by a 10% reduction in potassium, chloride, bicarbonate, magnesium, inorganic phosphate, etc. The only difference is that a 10% reduction in sodium concentration typically will exceed the reference limits, whereas a 10% reduction in most other components in the aqueous phase of plasma would not be clinically relevant. So the decrease in sodium gets more attention, even though many other aqueous components in plasma are equally affected.

 

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Posted by
On 3/3/2011

To Roger and all, Would not the use of an osmometer reading in conjunction with an electrolyte panel a be of any value in the assessment of PHN? After all the osmolality test measures the total concentration of the solution and is not affected by the volume of the sample. I would be interested in hearing your poinion on this topic? This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

Posted by
On 3/3/2011

To Roger and Commentator, I agree with both of you, and please let me add a few details. As stated, the conversion from plasma sodium by direct ISE to plasma concentration assumes normal plasma with mass concentration of water of 0.93 kg/L (due to dissolved protein, lipid, salt etc). A physiological saline concentration calibrator has a mass concentration of water of 0.99 kg/L. From these figures, a positive bias of 6 % might be expected. However, liquid junction potential differences, binding of sodium in plasma, and perhaps activity coefficient differences will lower the direct ISE result, so the observed historical difference before conversion - instead of 6 per cent - was rather about 4 per cent. Submitted by Niels Fogh-Anderasen, MD, FACB

Posted by
On 3/3/2011

This topic is by no means trivial, thanks for putting in in the spotligth. On the knowledgesite www.acutecaretesting.org there is two educational articles daeling with the same topic: - "Pseudohyponatremia" by Chris Higgins, Jan 2007 - "Understanding different electrolyte values" by Carl Holbel Oct 2002 Enjoy the reading Anne Skurup

Posted by
On 3/3/2011

The last post in this thread states that the concentration of protein in blood is 7 g/dl (=7 gram%). The author uses this as confirmation that the percentage "non-water volume" of plasma is 7%. However, the author mixes up two different units. In the discussion about pseudohyponatremia we are talking units of volume vs volume: the volume of plasma occupied by water vs the volume of plasma occupied by solutes and non-dissolved matter. The 7 g/dl of proteins is expressed in units of mass vs volume of plasma. It is totally coincidental that the mass of dissolved protein in plasma expressed in mass/volume units is approximately equal tho the percentage of solutes and non-dissolved matter in plasma expressed in volume/volume. Huub van Ingen Department of Clinical Chemistry Ruwaard van Putten Hospital, Spijkenisse The Netherlands

Posted by
On 2/24/2011

Roger, A very nice discussion of this obscure topic. It would be appropriate to point out that direct potentiometry is typically used in whole blood analyzers, and in the Vitros analyzers. In fact, when these were first introduced, they reported significantly higher sodium concentrations, before calibration was used to make them agree with other (indirect) methods such as flame photometry and indirect (diluted) ISE methods in more widespread use. However, since the calibration factor is unaffected by the presence of increased protein or lipids, the sodium concentration is not falsely low. I believe that the actual normal amount of protein and lipid is more like 7% than < 5%., however. Since a normal total protein is about 7 g/dL and 100 dL of plasma weigh about 100 g, that is the 7% right there. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

About the Author
Roger Bertholf, PhD, DABCC, FACB
Roger Bertholf, PhD, DABCC, FACB 
 

Additional Resources

 

Tzamaloukas AH, Ing TS, Siamopoulos KC, Rohrsheib M, Elisaf MS, Raj DSC, Murata GH. Body fluid abnormalities in severe hyperglycemia in patients on chronic dialysis: review of published reports. Journal of Diabetes and Its Complications 2008;22:29-37.

 

Katz MA. Hyperglycemia-induced hyponatremia: Calculation of the expected serum sodium depression. New England Journal of Medicine 1973;289:843-4.

 

Robin AP, Ing TS, Lancaster GA, Soung LS, Sparagana M, Geis WP, Hano JE. Hyperglycemia-induced hyponatremia: a fresh look. Clinical Chemistry 1979;25(3):496-7.

 

Elisaf M, Papagalanis ND, Siamopoulos KC. The importance of serum sodium in the symptomatology of hyperglycemic-induced hypertonicity. Journal of Nephrology 1993; 6:202-5.

 

Diabetes and Laboratory Medicine

 

Special Issue of Clinical Chemistry on Diabetes