Pseudohyponatremia: is that a thing?

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As most stories do, this one begins with a case. I was on call over the weekend, it was busy, and I was called by the neuro ICU for a new consult. Their patient had been hyponatremic for days and everything they tried had failed. They had treated the patient as having cerebral salt wasting with normal saline, sodium chloride tablets, furosemide, fluid restriction, and fludrocortisone, to no avail. The consult call was for consideration of hypertonic saline. As I began to look through the chart, I noticed something startling. At the time of admission, when the serum sodium was 124 mmol/L, the serum osmolarity was within the normal range at 272 mosm/L. The patient was not azotemic and thusly I knew that tonicity was similar to osmolarity and I suspected that we were dealing with was pseudohyponatremia.

Pseudohyponatremia (not to be confused with isotonic or hypertonic true hyponatremia) occurs when there exists a larger than normal solid state in plasma. A common question posed is why is it that normal saline is “normal” when it is in fact hypertonic to plasma? This is because we need to differentiate plasma and plasma water. Plasma is the liquid component of blood not consisting of blood cells and platelets. The percentage of plasma in whole blood is calculated by 1-hct. Components of plasma include water (typically ~93%) with suspended proteins, lipids, glucose, clotting factors, and hormones. If the percent of proteins or lipids are elevated, the solid phase of plasma will take up a higher concentration and will affect the measurement of serum sodium by artificially lowering the plasma water percentage. For a visual explanation of this phenomenon, please see the image below excerpted from Joel Topf’s Fluid, Electrolyte, and Acid-Base Companion (posted with permission).

The sodium measurement technique is particularly important in the determination of true vs pseudohyponatremia. The gold standard is measurement with direct ion specific electrode potentiometry. However, more common methods utilized in most hospital laboratories include indirect ion specific electrode (ISE) potentiometry and the older technique, flame emission spectrophotometry. Typically, most basic metabolic panel analyzers use indirect ISE and blood gas analyzers use direct potentiometry. Indirect ISE involves a premeasurement dilution of plasma and due to this an assumption is made during measurement that the percentage of plasma water is 93 percent. Thusly, when this assumption is not true, measurement of the sodium concentration from an ABG can help clarify true vs pseudohyponatremia.

There exist a few conditions that can classically cause pseudohyponatremia.

  • Hyperproteinemia – Any cause of hyperproteinemia can result in an increase in the solid phase of plasma. This is classically described in multiple myeloma patients but can occur as an effect of IVIG or be seen in the hyper gammaglobulinemic state of chronic infection. Typically, serum protein levels are greater than 10 g/dL. 
  • Hypertriglyceridemia – An elevated level of triglycerides can also increase the solid phase of plasma, this is typically seen in extreme elevations with triglyceride levels of greater than 1,000 mg/dl. At these levels the blood will have a milky appearance and may even be noted to be frankly lipemic limiting evaluation. 
  • HypercholesterolemiaRecent case reports have highlighted that in liver failure, particularly in obstructive jaundice, that there can be a non-lipemic hypercholesterolemia resulting in pseudohyponatremia. Lipoprotein analysis has shown that the primary lipoprotein responsible for this is Lipoprotein X. The pathogenesis of lipoprotein-X in cholestasis is not completely understood. Interestingly, reviews of LCAT deficiency (in which lipoprotein X also accumulates) do not typically describe hyponatremia or pseudohyponatremia as part of that diseases milieu. 

A controversial issue is the proper terminology of the hypertonic hyperosmolar hyponatremia from hyperglycemia. It has been described both as pseudohyponatremia and true dilutional hyponatremia. Glucose is tonically active and is dissolved in plasma water. In the patient with hyperglycemia induced hyponatremia glucose can be a large component of osmolarity. Water leaves the intracellular space and equilibrates the osmolarity of the ICF to the ECF in patients with hyperglycemia. Hence, while some may call this as pseudohyponatremia (noting that the hyponatremia in this case does not mean hypo-osmolarity), I would argue that the better designation is dilutional hyponatremia. Menchine et al evaluated the accuracy of blood gas vs biochemistry testing in Emergency Room patients presenting with diabetic ketoacidosis (DKA). They found excellent correlation between the blood gas (direct ISE) and biochemistry (indirect ISE) sodium measurements, supporting the designation of dilutional hyponatremia over pseudohyponatremia.

To conclude, it is oft quoted that the first step in the workup of hyponatremia is to confirm that it is in fact true, hypotonic hyponatremia. In our patient referenced earlier, I wrote my consult note and recommended checking sodium by direct ISE and it was 134 mmol/L compared to indirect of 126 mmol/L. We then measured triglycerides and the result was greater than 1,000 mg/dl. All sodium directed therapies were held without adverse effect. Once again, nephrology saves the day!

Ankur Shah 
Nephrology Fellow
University of Pennsylvania
NSMC Intern, Class of 2018

1 comment

  1. Although the text above states Normal saline hypertonic to plasma, it's actually isotonic.
    Explanation: the osmotic coefficient of NS is ~93%)

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