Pseudohyponatremia: Is This Sodium Really Low?

Periodically I get a call from a clinician saying, “What’s wrong with your sodiums?” In general, this call is triggered by a sodium <125 mmol/L. My first response question is always: What are the child’s protein and/or lipid levels?

At issue here is the type of ion-selective electrode (ISE) used to measure the electrolytes. There are two basic types, indirect and direct, and knowing which one your chemistry analyzer uses is important. Direct ISEs are exactly that. They measure the ion activity in the sample directly, in whatever fluid volume is present in the sample, and are basically not affected by other constituents in the sample. The activity is then converted to concentration and a result is produced. Indirect ISE’s do not do a direct measurement. They dilute the sample first and measure the concentration of electrolytes in the diluted sample. This usually works well, but becomes problematic when the sample happens to have a high concentration of proteins or lipids. The reason for that is this: systems using indirect ISE measurement assume that the sample is all water. In reality, normal plasma/serum is roughly 93% water with 7% solids present (proteins and lipids). If the sample being analyzed has less than 93% water, for example when either protein or lipid makes up more than 7% of the volume, the resulting measurement will be falsely low, as you can see from this table. A normal, 7% solids sample that an indirect ISE measurement would give you a value of 135 mmol/L; if the solids are 20%, that sample will give you a value of 116 mmol/L.

True concentration % water Direct ISE measurement Indirect ISE measurement
145 mmol/L 93 145 mmol/L 135 mmol/L (145/0.93L)
145 mmol/L 80 145 mmol/L 116 mmol/L (145/0.8 L)

This is called pseudohyponatremia. The sodium is not really low; it’s perfectly normal. The instrument is giving you a falsely low value. The vast majority of wet chemistry analyzers measure electrolytes by indirect ISE. Only a few big chemistry analyzers measure electrolytes using direct ISEs, and those usually have a correction factor so that the directly measured results are more in line with the big majority of indirect ISE measurements.

What can you do about falsely low sodiums caused by hyperproteinemia or hyperlipidemia? If it’s related to lipids, you may be able to clarify the sample by centrifugation or chemicals and get a real result. Alternatively, blood gas analyzers and some POC analyzers, like the i-STAT, measure electrolytes by direct ISE. If you have or can get a whole blood sample, you can use these analyzers to give you a real result. Otherwise you may be explaining pseudohyponatremia to a concerned physician.



-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

3 thoughts on “Pseudohyponatremia: Is This Sodium Really Low?”

  1. I’m curious about the effect on the anion gap. If it only affects sodium, wouldn’t this be a tip-off to the performing lab and the physician? I’ve mentally calculated the anion gap for my entire career and am now wondering if I was lulling myself into a false sense of security.

    1. Good question! This effect will be the same for all electrolytes measured this way, so it will also affect potassium and chloride. CO2 will only be effected if it’s measured by ion-selective electrode (ISE). Thus, if all your electrolytes are ISE, probably the anion gap would not be affected since all four electrolytes should equally be affected. If your CO2 is enzymatic, the anomaly may be reflected in the anion gap. I honestly have not paid attention to it!

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