What is the management approach for a patient with suspected pseudohyponatremia, particularly those with elevated lipid or protein levels, such as in multiple myeloma or hypertriglyceridemia?

Pseudohyponatremia: Recognition and Management

What is Pseudohyponatremia?

Pseudohyponatremia is a laboratory artifact where serum sodium appears falsely low despite normal plasma osmolality, occurring when extreme hyperlipidemia or hyperproteinemia interferes with certain sodium measurement methods. 1 This is not true hyponatremia and requires no sodium correction—only treatment of the underlying lipid or protein disorder 2.

Mechanism and Laboratory Considerations

Pseudohyponatremia occurs specifically with indirect ion-selective electrode (I-ISE) methods, which dilute plasma before measurement and assume plasma is 93% water 3. When lipids or proteins occupy excessive plasma volume (reducing plasma water content below 93%), the calculated sodium concentration becomes artificially low 1, 3.

Direct ion-selective electrode (D-ISE) methods measure sodium activity directly in plasma water without dilution and are unaffected by lipid or protein content 3. Modern laboratories increasingly use D-ISE, making pseudohyponatremia less common than in previous decades 1.

Clinical Scenarios Where Pseudohyponatremia Occurs

Severe Hypertriglyceridemia

• Triglyceride levels typically >1,500 mg/dL cause clinically significant pseudohyponatremia 2
• Often associated with uncontrolled diabetes, metabolic syndrome, or genetic lipid disorders 2

Hyperproteinemia

• Multiple myeloma with markedly elevated immunoglobulins (particularly IgG or IgA) is the classic cause 4
• Serum protein levels >10 g/dL can produce pseudohyponatremia 1
• May also cause negative anion gap due to unmeasured cationic proteins 4

Hyperglycemia

• Severe hyperglycemia (>400 mg/dL) causes true hyponatremia (not pseudohyponatremia) through osmotic water shift 5
• Corrected sodium = measured sodium + 1.6 mEq/L for each 100 mg/dL glucose above 100 mg/dL 5

Diagnostic Approach

Step 1: Measure Plasma Osmolality

• Normal or elevated plasma osmolality (>280 mOsm/kg) with low sodium indicates pseudohyponatremia 1, 5
• True hyponatremia always presents with low plasma osmolality (<280 mOsm/kg) 5

Step 2: Identify the Laboratory Method

• Contact your laboratory to determine if they use I-ISE or D-ISE 1
• If I-ISE is used and hyperlipidemia/hyperproteinemia is present, request D-ISE measurement 1, 3

Step 3: Calculate Plasma Water Content

• PWC can be determined using the formula: PWC = (I-ISE sodium / D-ISE sodium) × 93% 3
• Normal PWC is 93%; values <93% confirm pseudohyponatremia 3

Step 4: Screen for Underlying Causes

• Lipid panel: Look for triglycerides >1,500 mg/dL 2
• Serum protein electrophoresis: Identify monoclonal gammopathy in suspected multiple myeloma 4
• Total protein and albumin: Elevated total protein (>10 g/dL) with normal albumin suggests paraproteinemia 1

Management Strategy

Primary Principle: Do Not Treat the Sodium

The most dangerous error is treating pseudohyponatremia as true hyponatremia with hypertonic saline or fluid restriction 1. This can lead to:

• Iatrogenic hypernatremia if sodium is "corrected"
• Delayed treatment of the actual underlying disorder
• Unnecessary ICU admission and monitoring

Address the Underlying Condition

For Hypertriglyceridemia:

• Initiate fibrate therapy (fenofibrate 145 mg daily) or high-intensity statin 2
• Optimize glycemic control if diabetic (target HbA1c <7%) 2
• Implement dietary fat restriction (<15% of total calories from fat) 2

For Multiple Myeloma:

• Urgent hematology consultation for chemotherapy initiation 4
• Sodium levels normalize as paraprotein burden decreases with treatment 4
• Monitor for true hyponatremia during chemotherapy (tumor lysis syndrome risk)

For Hyperglycemia-Related Osmotic Shift:

• This represents true hyponatremia, not pseudohyponatremia 5
• Treat hyperglycemia with insulin; sodium will correct as glucose normalizes 2
• Use corrected sodium formula to guide management 5

Critical Pitfalls to Avoid

• Never administer hypertonic saline for pseudohyponatremia—this creates true hypernatremia 1
• Do not implement fluid restriction—the patient is not volume overloaded from hyponatremia 5
• Failing to verify the laboratory method can lead to misdiagnosis; always confirm I-ISE vs D-ISE 1
• Assuming all low sodium with high lipids is pseudohyponatremia—patients can have concurrent true hyponatremia requiring separate evaluation 5

Monitoring and Follow-Up

• Recheck sodium using D-ISE method within 24-48 hours if available 1, 3
• Monitor lipid panel or serum protein electrophoresis weekly during treatment of underlying cause 2, 4
• Once triglycerides fall below 500 mg/dL or paraprotein normalizes, sodium measurements by I-ISE become reliable again 1, 4