Causes of Hyponatremia: Does This Patient Have Pseudo-Hyponatremia ?

1.Does a  patient with the following lab values have pseudo-hyponatremia?

Anion gap = 14, glucose = 247 mg percent, sodium = 109 mEq per liter, potassium is 4 mEq per liter bicarbonate = 16 mg/L, chloride 100 mg/L, BUN is = 7 mg percent, creatinine < 0.4 mg percent

Total protein 5.7 g percent, albumin 4.3 g percent

Total cholesterol = 994 mg percent, HDL = 21 mg percent, LDL less than 3 mg percent, triglycerides 7889 mg percent

2.Are all follow-up sodium levels subjective pseudohyponatremia and values dependent on ongoing insulin therapy?

The answer : 1.NO and 2.NO

The differential diagnosis for pseudohyponatremia includes hyperglycemia with elevated glucose levels typically greater than 400 mg percent, hyperlipidemia and or hypertriglyceridemia and hyper proteinemia seen in multiple myeloma.

There have been many reports in the past of pseudohyponatremia with hypertriglyceridemia and or hyperlipidemia.  So why in this example does the patient does not have pseudohyponatremia.It is critical to understand how electrolyte levels are measured in the current laboratory setting and how handling of a lipemic specimen is handled differently currently then has been in the past.

The two different technologies used for the measurement of electrolytes are named in various ways in the literature; however, the most frequently used names are direct ISE and indirect ISE. ISE means ion-selective electrodes.

Indirect ISE:

• Measures on a total plasma sample (or serum) that has been diluted with a large volume of diluent.
• Requires that the plasma and erythrocytes are separated by centrifugation.
• Due to the dilution, this method measures the mean concentration in plasma, i.e. the weighted average between the concentration in the electrolyte-containing water part and in the electrolyte-free protein/lipid part. The concentration is calculated by multiplying the result with the dilution factor.
• The results are comparable to flame photometry.
• This technology is typically used in the large so-called chemistry analyzers in the centralized laboratory.
• The reported result depends of the content of solids in the sample.

Direct ISE:

Measures on a non-diluted whole-blood or plasma sample. However, the actual measurement is performed on the plasma water.

• When whole blood is used, it does not involve any sample preparation.
• Direct ISE actually measures the electrolyte activity in the plasma water (mmol/kg H2O) rather than "concentration in the plasma (mmol/L)". The electrochemical activity of the ions in the water is converted to the readout concentration by a fixed (ion-specific) multiplier. This is only accurate for a given ionic strength, usually chosen to equal 160 mmol/L for plasma.
• The use of this fixed factor ensures that direct ISE reflects the actual, clinically relevant activity, irrespective of the level of proteins and/or lipids. This is not changed by the fact that the result traditionally is termed "concentration".
• This conversion is based on recommendations from the IFCC Expert Panel on pH and Blood Gases and is made in order to avoid the confusion of having two types of electrolytes results.
• This technology is typically used in blood gas analyzers and POC electrolyte analyzers, and these may be placed both in the laboratory and in a point-of-care environment.
• The reported result is independent of the content of solids in the sample.

In conclusion, the results from the two different types of analyzer are brought to correlate for samples with a normal content of proteins and lipids. This, of course, requires that all preanalytical and analytical variations are eliminated.

SAMPLES WITH AN ABNORMAL PROTEIN/LIPID CONTENT
The variation of the content of proteins and lipids from the normal situation will cause an error on the reported electrolyte results from the indirect ISE.

In the literature, it is reported that the error is less than 5 % when triglyceride concentration is less than 2500 mg/dL (recommended level is 35-160 mg/dL). The impact of errors on the measurement of electrolytes applies to all electrolytes; however, it is most pronounced on sodium.

Examples of errors on sodium from the literature: An error of 17 mmol/L  is reported with an increased protein content, and an error of 26 mmol/L  due to increased lipid content.

When the solid content deviates from the normal, it is typically increased, and the typical types of error are then:

Electrolyte concentration is reported as normal or low when it is actually dangerously high, or
Electrolyte concentration is reported as too low when it is actually normal.
The latter phenomenon is also called pseudohyponatremia where sodium is concerned.

Increased content of protein and lipids is the case for a long list of common medical conditions such as diabetes, liver and kidney syndromes, alcoholism, etc. Due to its magnitude is may lead the physicians to life-threatening erroneous conclusions and should therefore be taken into consideration when evaluating electrolyte results reported from the indirect ISE technology.

Based on the above explanation the patient should have pseudohyponatremia from hyperlipidemia, however, this is not how present day lipemic specimen's are handled.  After centrifugation of whole blood, the lipid layer is actually dissolved and solids in the sample do not influence result anymore. The samples are pre-treated with LipoClear. Electrolytes are  measured in the clear specimen.  See Image below

Therefore,only significant hyperglycemia and hyperproteinemia are more likely then triglycerides to cause pseudohyponatremia. This patient did not have hyperglycemia nor hyperproteinemia. As triglyceride levels fall with insulin therapy, the reported sodium levels will not alter. If they do then the specimen was not handled properly with LipoClear.

 Ultracentrifugation is the other method if LipoClear is not available to measure electolytes without inference from the lipids .