A Sodium of 123 mmol/L With a Normal Measured Osmolality
A 68-year-old man has three weeks of fatigue and weight loss, no vomiting or diarrhoea, and is clinically euvolemic with normal blood pressure and no oedema. Blood is drawn into a lithium heparin tube at 08:00 and analysed at 10:00 on a chemistry analyser that uses indirect (diluted) ion-selective electrodes. Results: sodium 123 mmol/L, potassium 4.1 mmol/L, chloride 88 mmol/L, bicarbonate 24 mmol/L, glucose 5.2 mmol/L, urea 6.0 mmol/L, creatinine 88 µmol/L, total protein 122 g/L, albumin 30 g/L, total calcium 2.05 mmol/L, and measured osmolality 279 mOsm/kg. The sample is clear and not lipemic, and the hemolysis and icterus indices are not raised. His sodium three months earlier was 137 mmol/L. The referring physician has already prescribed 3% saline for "symptomatic hyponatraemia" and asks the laboratory to confirm the result urgently.
1. Calculate and interpret the osmolality gap. Is this true hyponatraemia?
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Calculated osmolality = 2 × 123 + 5.2 + 6.0 = 257 mOsm/kg. Measured osmolality is 279 mOsm/kg, so the osmolal gap is about 22 mOsm/kg, which is abnormally large.
In true hypotonic hyponatraemia, the measured osmolality is low and agrees with the calculated value; a normal measured osmolality in the face of a low measured sodium means either that the sodium result is falsely low or that an unmeasured osmole is present. There is no history of mannitol, glycine or alcohol, the glucose is normal, and the sample is not lipemic. What is present is a total protein of 122 g/L with a low albumin of 30 g/L - a pattern suggesting a paraprotein, and therefore a large non-aqueous phase.
So this is not true hyponatraemia. It is pseudohyponatremia: the sodium concentration per litre of whole plasma is genuinely low because the plasma contains less water per unit volume, but the sodium concentration in the plasma water, which is what the brain and cells see, is normal or near normal. Giving 3% saline to this patient would risk hypernatraemia.
2. Explain the mechanism by which the analyser produced this result, and what test would confirm it.
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Indirect ion-selective electrodes measure sodium in a diluted aliquot and report the result per volume of the original specimen. That calculation assumes a normal plasma water fraction (about 93%). With a total protein of 122 g/L, the aqueous fraction is substantially reduced, so the same amount of sodium per litre of plasma water is reported as a lower concentration per litre of plasma.
The same proportional effect applies to other analytes confined largely to plasma water and measured by dilution - chloride, potassium and calcium are all reported slightly low for the same reason. Sodium is the analyte where it is noticed, because its reference interval is narrow and its physiological range is small. Note also that the anion gap calculated from these numbers (123 − 88 − 24 = 11, or lower once albumin is considered) is not interpretable when both sodium and chloride are affected.
Confirmation is by direct ion-selective electrode on a blood gas analyser, which measures sodium activity in undiluted plasma water and is not affected by the protein content. The direct result should be substantially higher than 123 mmol/L. After the direct sodium is known, the osmolal gap should be recalculated; if it persists, a second osmole should be sought.
3. What should the laboratory do and say right now, and what follow-up testing is indicated?
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The laboratory should telephone the clinician before the 3% saline is given, explain that the measured osmolality is normal and that the result is pseudohyponatremia from hyperproteinaemia, and ask for the order to be reviewed. A direct ISE result on a blood gas sample should be obtained and reported alongside a comment explaining the discrepancy.
The report should state that the sodium was measured by an indirect method, that hyperproteinaemia causes a falsely low result, and that the concentration in plasma water is more reliably reflected by direct ISE. The potassium, chloride and calcium results from the same sample should be interpreted with the same caveat.
Follow-up is directed at the underlying cause: serum protein electrophoresis with immunofixation, serum free light chains, a skeletal survey or whole-body imaging as appropriate, and assessment for hyperviscosity. A full blood count and film, calcium and renal function are relevant to a possible plasma cell disorder. If the direct sodium turns out to be genuinely low, a separate work-up for hyponatraemia is needed - but not before the artefact has been excluded. The teaching point is that the measured osmolality is the laboratory's first-line defence against pseudohyponatraemia, and it should be checked whenever the sodium does not fit the clinical picture.