What is pseudohyponatremia?

The following post was written several years ago. Although more recent developments have changed the field of clinical laboratory science since the original posting, the information contained was deemed to be of historical interest.

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.