What is pseudohyponatremia, how can it be distinguished from true hyponatremia, and what is the appropriate management?

Pseudohyponatremia

Definition and Mechanism

Pseudohyponatremia is a laboratory artifact where serum sodium appears falsely low despite normal plasma tonicity, occurring when indirect ion-selective electrode (I-ISE) methods are used in patients with severe hyperlipidemia or hyperproteinemia. 1, 2

The mechanism involves the electrolyte exclusion effect: normally, plasma is 93% water and 7% solids (proteins and lipids). When solid content increases (e.g., severe hyperlipidemia >1,500 mg/dL or hyperproteinemia >10 g/dL), the water fraction decreases proportionally. Since sodium exists only in the aqueous phase, the actual sodium concentration in plasma water remains normal, but I-ISE methods—which dilute samples before measurement assuming 93% water content—report falsely low values 1, 2, 3.

Distinguishing Pseudohyponatremia from True Hyponatremia

Key Diagnostic Features

The critical distinguishing feature is normal or elevated serum osmolality (>275 mOsm/kg) in the presence of low measured sodium 4, 5. True hyponatremia always presents with low serum osmolality (<275 mOsm/kg) 4, 5.

Diagnostic Algorithm

1. Measure serum osmolality immediately when hyponatremia is detected 4, 5

   • If osmolality is normal (275-290 mOsm/kg) or elevated: suspect pseudohyponatremia 4, 2
   • If osmolality is low (<275 mOsm/kg): true hyponatremia 4, 5

2. Calculate osmolal gap: Measured osmolality - Calculated osmolality 6

   • Calculated osmolality = 2 × Na + BUN/2.8 + glucose/18 4
   • Elevated osmolal gap (>10 mOsm/kg) suggests pseudohyponatremia, as the falsely low sodium creates an artificially low calculated osmolality 6

3. Assess for causative conditions 1, 2:

   • Severe hyperlipidemia: triglycerides >1,500 mg/dL (visible lipemic serum)
   • Severe hyperproteinemia: total protein >10 g/dL
     • Multiple myeloma with paraproteinemia
     • HIV/HCV coinfection with hypergammaglobulinemia 6
     • Waldenstrom's macroglobulinemia

4. Confirm with direct ion-selective electrode (D-ISE) measurement 1, 2, 3

   • D-ISE measures sodium directly in undiluted plasma water
   • D-ISE will show normal sodium (135-145 mmol/L) in pseudohyponatremia 2, 3
   • The difference between I-ISE and D-ISE measurements quantifies the degree of pseudohyponatremia 3

5. Alternative confirmation: measure plasma water content 3, 7

   • Normal plasma water = 93%
   • Pseudohyponatremia occurs when plasma water <93% 3
   • Can be measured by osmometry before/after dilution or chloride measurement before/after ultrafiltration 7

Clinical Clues

Patients with pseudohyponatremia are asymptomatic from the "hyponatremia" itself because plasma tonicity is normal—there is no osmotic gradient driving water into cells 2. If a patient with measured hyponatremia has confusion, seizures, or other hyponatremic symptoms, it is not pseudohyponatremia 2.

Common Pitfalls

• Treating pseudohyponatremia with hypertonic saline or fluid restriction is dangerous and unnecessary, as the true sodium is normal 2. Inadvertent "correction" can cause iatrogenic hypernatremia 2.

• Relying solely on physical examination to determine volume status has poor accuracy (sensitivity 41%, specificity 80%) and cannot distinguish pseudohyponatremia from true hyponatremia 4, 5.

• Failing to recognize that your laboratory uses I-ISE methodology is the most common error 1. Clinicians must know which method their laboratory employs—most automated analyzers use I-ISE, making pseudohyponatremia a persistent clinical problem 1, 2.

• Pseudohyponatremia is likely underdiagnosed in HIV/HCV coinfected patients due to frequent hypergammaglobulinemia in this population 6.

Appropriate Management

No treatment is required for the sodium level itself 2. Management focuses on the underlying condition causing hyperlipidemia or hyperproteinemia 1, 2:

• For severe hypertriglyceridemia: insulin, fibrates, plasmapheresis if triglycerides >2,000 mg/dL
• For paraproteinemia: treat underlying multiple myeloma or lymphoproliferative disorder
• For hypergammaglobulinemia in HIV/HCV: optimize antiretroviral and antiviral therapy 6

Request D-ISE measurement or plasma water content determination to document true sodium status and prevent inappropriate treatment 2, 3, 7.