The Bedside Diagnosis of Pseudohyponatremia: A Clinical Approach to Laboratory Artifacts in Hyperviscosity and Hyperlipidemia

Dr Neeraj Manikath , claude.ai

Abstract

Pseudohyponatremia represents a laboratory artifact rather than true hyponatremia, occurring when extreme hyperlipidemia or hyperproteinemia displaces the aqueous phase of plasma, leading to falsely low sodium measurements by indirect ion-selective electrode (ISE) methods. This condition can lead to unnecessary investigations and inappropriate treatment if not recognized promptly. This review provides a systematic three-step bedside approach to identify pseudohyponatremia before initiating extensive workups for conditions like SIADH (syndrome of inappropriate antidiuretic hormone secretion). We emphasize simple clinical clues—visual inspection of the serum sample, correlation with lipid and protein levels, and understanding of laboratory methodology—that enable rapid diagnosis. Recognition of this artifact prevents harmful hypertonic saline administration and directs attention to the underlying metabolic derangement requiring specific treatment.

Introduction

Hyponatremia, defined as serum sodium <135 mmol/L, is the most common electrolyte disorder encountered in clinical practice, affecting up to 15-30% of hospitalized patients. When confronted with a low sodium reading, clinicians reflexively consider a differential diagnosis including hypervolemic, euvolemic, and hypovolemic states, with SIADH being among the most common causes in hospitalized patients. However, before embarking on extensive diagnostic algorithms, a crucial question must be answered: Is this true hyponatremia, or is it a laboratory artifact?

Pseudohyponatremia is a measurement error that occurs when the non-aqueous portion of plasma (lipids or proteins) is markedly elevated, reducing the water content per unit volume of plasma. Since sodium is dissolved exclusively in the aqueous phase, the actual sodium concentration in plasma water remains normal, but the laboratory reports a falsely low value when using indirect measurement methods. This phenomenon was more common in the era of flame photometry but persists with modern indirect ISE analyzers that require sample dilution.

The clinical significance of recognizing pseudohyponatremia cannot be overstated. Misdiagnosis leads to inappropriate fluid restriction, unnecessary hormonal investigations, and potentially dangerous administration of hypertonic saline, which can precipitate osmotic demyelination syndrome when "correcting" a sodium level that was never truly low. Conversely, the underlying conditions causing pseudohyponatremia—severe hypertriglyceridemia and paraproteinemia—require urgent specific interventions including plasmapheresis, which may be life-saving.

The Pathophysiology: Understanding the Artifact

Normal Plasma Composition

Normal plasma consists of approximately 93% water and 7% solids (6% proteins and 1% lipids). Sodium, being a hydrophilic ion, distributes exclusively in the aqueous phase. The actual sodium concentration in plasma water is approximately 150-152 mmol/L, but when measured per liter of whole plasma (which includes the solid phase), it reads as 135-145 mmol/L.

The Mechanism of Pseudohyponatremia

In extreme hyperlipidemia (typically triglycerides >1500 mg/dL or >17 mmol/L) or severe hyperproteinemia (total protein >10 g/dL, particularly in multiple myeloma with monoclonal proteins >6 g/dL), the solid phase of plasma can increase dramatically to 15-20% or more of the total volume. This displaces the aqueous phase proportionally.

Example calculation:

Normal plasma: 93% water containing 150 mmol/L sodium
Measured sodium per liter of plasma = 150 × 0.93 = 139.5 mmol/L
Hyperlipidemic plasma: 80% water containing 150 mmol/L sodium (unchanged)
Measured sodium per liter of plasma = 150 × 0.80 = 120 mmol/L

This creates an apparent hyponatremia of 19.5 mmol/L despite normal sodium concentration in the water phase. The degree of pseudohyponatremia correlates with the severity of lipemia or hyperproteinemia: approximately 2 mmol/L decrease in measured sodium for every 5 g/dL increase in triglycerides or every 10 g/L increase in total protein.

Why Indirect ISE Methods Are Affected

Most modern clinical laboratories use indirect ISE analyzers, which require a dilution step (typically 1:10 to 1:30) before measurement. This dilution assumes normal plasma water content (93%). When the water content is reduced due to excess lipids or proteins, the diluted sample contains less sodium than expected, yielding a falsely low result.

Direct ISE analyzers, in contrast, measure sodium activity in undiluted samples using a sodium-selective electrode that responds only to sodium ions in solution, making them unaffected by the volume of the non-aqueous phase. These instruments provide accurate sodium measurements regardless of lipid or protein content.

The Three-Step Bedside Approach

Step 1: Visual Inspection of the Serum Sample—The Instant Giveaway

Pearl: The most rapid screening test for pseudohyponatremia costs nothing and takes five seconds: look at the sample.

When blood is centrifuged, severe hyperlipidemia produces a characteristic appearance that should immediately alert the clinician to the possibility of pseudohyponatremia. The serum or plasma appears:

Milky white or creamy (lipemic)
Turbid rather than clear
Opaque, obscuring the ability to read text through the tube

This lipemic appearance typically occurs when triglycerides exceed 400-500 mg/dL, but pseudohyponatremia generally requires levels >1500 mg/dL. At triglyceride levels of 3000-5000 mg/dL, the serum may appear like "milk" or "half-and-half cream."

Practical Hack: Ask the laboratory to show you the sample or photograph it. Many modern laboratory information systems automatically flag lipemic samples with an "L" indicator and may photograph grossly abnormal specimens. Request these images when reviewing abnormal sodium values.

Oyster: In cases of severe hyperproteinemia due to multiple myeloma or Waldenström macroglobulinemia, the serum may not appear lipemic but may have increased viscosity. Hold the tube at an angle—highly viscous serum flows more slowly than normal. Some paraproteins can also cause slight turbidity or unusual color (pale yellow to light brown).

Step 2: Check Total Protein and Triglycerides—Quantifying the Culprits

Once visual inspection raises suspicion, immediate laboratory correlation is essential:

Severe Hypertriglyceridemia

Threshold for pseudohyponatremia: Triglycerides >1500 mg/dL (>17 mmol/L)
Severe range: 1500-5000 mg/dL
Critical range: >5000 mg/dL (risk of acute pancreatitis)

Common causes include:

Familial hypertriglyceridemia (types I, IV, V hyperlipoproteinemia)
Uncontrolled diabetes mellitus with insulin deficiency
Alcohol abuse
Medications (thiazides, beta-blockers, estrogens, protease inhibitors, atypical antipsychotics)
Nephrotic syndrome
Hypothyroidism
Pregnancy (third trimester)

Clinical Pearl: Diabetic ketoacidosis with severe hypertriglyceridemia presents a diagnostic challenge—patients may have true hyperglycemic hyperosmolar hyponatremia plus pseudohyponatremia from lipemia. Corrected sodium calculations become unreliable; direct ISE measurement is essential.

Severe Hyperproteinemia

Threshold for pseudohyponatremia: Total protein >10 g/dL
Paraprotein level: Typically >6 g/dL

Common causes include:

Multiple myeloma (IgG, IgA)
Waldenström macroglobulinemia (IgM—most viscous)
MGUS (monoclonal gammopathy of undetermined significance) with high paraprotein burden
Light chain disorders (though less commonly reach thresholds for pseudohyponatremia)

Clinical Pearl: IgM paraproteins (Waldenström's) cause the most dramatic hyperviscosity at lower concentrations than IgG or IgA due to their pentameric structure and larger molecular size (900 kDa vs 150 kDa for IgG). Patients may present with the classic hyperviscosity syndrome triad: bleeding (mucosal, retinal), neurologic symptoms (headache, confusion, stroke-like episodes), and visual disturbances (retinal vein engorgement, "sausage-linking").

Oyster: Always obtain a serum protein electrophoresis (SPEP) with immunofixation when total protein is >9 g/dL with low albumin-to-globulin ratio. The presence of an M-spike confirms paraproteinemia. Serum viscosity can be directly measured (normal: 1.4-1.8 centipoise; symptomatic hyperviscosity: >4-5 centipoise), though this test is not universally available.

Step 3: Understand the Laboratory Method—Know Your Analyzer

Critical Knowledge: Not all sodium measurements are created equal. The type of analyzer determines whether pseudohyponatremia will be detected.

Indirect ISE (Standard Method)

Used by most central laboratories
Requires 1:10 to 1:30 sample dilution
Assumes 93% plasma water content
Affected by pseudohyponatremia
Faster, higher throughput, less expensive

Direct ISE (Reference Method)

Used by some point-of-care analyzers and blood gas machines
Measures undiluted sample
Unaffected by lipids or proteins
Gives accurate sodium in pseudohyponatremia
Slower, lower throughput, more expensive

Actionable Hack: When suspecting pseudohyponatremia, specifically request: "Please measure sodium using direct ISE" or "Please run sodium on the blood gas analyzer." Most blood gas analyzers use direct ISE technology. Compare the results:

If indirect ISE shows sodium = 125 mmol/L
And direct ISE shows sodium = 140 mmol/L
This confirms pseudohyponatremia (difference ~15 mmol/L)

Pearl for Teaching: The old flame photometry method (largely obsolete) was actually less affected by mild-to-moderate hyperlipidemia because it used much larger sample dilutions (1:100 or more), though it was still susceptible in extreme cases.

The Confirmatory Tests: Proving Pseudohyponatremia

Method 1: Direct ISE Sodium Measurement (Gold Standard)

Interpretation:

Normal direct ISE sodium (135-145 mmol/L) with low indirect ISE sodium = Pseudohyponatremia confirmed
Low sodium on both methods = True hyponatremia

Practical consideration: Not all laboratories have direct ISE capability in their central lab. Blood gas analyzers are widely available and use direct ISE—this is your most accessible option for confirmation.

Method 2: Measured Plasma Osmolality

Plasma osmolality directly measures the concentration of all osmotically active particles in plasma water.

Calculated osmolality (in true hyponatremia): Posm (calc) = 2 × Na + Glucose/18 + BUN/2.8

In true hyponatremia, both measured and calculated osmolality are low (<280 mOsm/kg).

In pseudohyponatremia:

Measured osmolality is normal (280-295 mOsm/kg) because sodium concentration in plasma water is actually normal
Calculated osmolality appears low because the formula uses the falsely low measured sodium
Osmolal gap is increased (measured - calculated >10 mOsm/kg)

Example:

Measured sodium (indirect ISE) = 120 mmol/L
Glucose = 90 mg/dL, BUN = 14 mg/dL
Calculated Posm = 2(120) + 90/18 + 14/2.8 = 240 + 5 + 5 = 250 mOsm/kg
Measured Posm = 285 mOsm/kg (normal)
Osmolal gap = 285 - 250 = 35 mOsm/kg
Conclusion: Pseudohyponatremia

Oyster: An elevated osmolal gap can also occur in toxic alcohol ingestion (methanol, ethylene glycol), mannitol administration, or severe renal failure. Always interpret in clinical context. However, when the osmolal gap is large (>30 mOsm/kg) and accompanied by lipemic serum or very high triglycerides/proteins, pseudohyponatremia is confirmed.

Method 3: Ultracentrifugation (Research Tool)

This labor-intensive method separates plasma water from lipid/protein components, then measures sodium in the water phase directly. It confirms normal sodium concentration in plasma water but is rarely used clinically. It remains the definitive proof in research settings or medicolegal cases.

Differential Diagnosis: Other Causes of Low Measured Sodium with Normal Osmolality

It is essential to distinguish pseudohyponatremia from other conditions that may present with low measured sodium but normal or high osmolality:

Hypertonic Hyponatremia

Caused by hyperglycemia or mannitol administration
Water shifts from intracellular to extracellular space, diluting sodium
Osmolality is elevated (>295 mOsm/kg), not normal
Sodium corrects as glucose normalizes
Corrected sodium formula: Add 1.6 mmol/L to measured Na for every 100 mg/dL glucose >100

Isotonic Hyponatremia from Irrigation Fluids

Post-TURP (transurethral resection of prostate) syndrome
Absorption of glycine or sorbitol irrigation solutions
Osmolality may be normal-to-high due to absorbed solute
Clinical distinction: acute onset during/after procedure, visual symptoms from glycine toxicity

The key differentiator is the clinical context and visual appearance of serum. Pseudohyponatremia from hyperlipidemia/hyperproteinemia is typically chronic or subacute, with milky serum and markedly elevated triglycerides or proteins.

Clinical Management: Treating the Cause, Not the Sodium

Critical Action: Once pseudohyponatremia is confirmed, do not treat the sodium. There is no true sodium deficit. Administration of hypertonic saline is not only unnecessary but potentially dangerous, as it may cause true hypernatremia once the underlying condition is treated and lipids/proteins normalize.

For Severe Hypertriglyceridemia

Immediate Management (Triglycerides >1000 mg/dL)

NPO status (nothing by mouth) to reduce chylomicron production
Insulin infusion (0.1-0.3 units/kg/hr) to activate lipoprotein lipase—even in non-diabetics—dramatically reduces triglycerides within 12-24 hours
Discontinue contributing medications (thiazides, beta-blockers, estrogens)
Avoid alcohol completely
Fibrate therapy: Fenofibrate 145-200 mg daily or gemfibrozil 600 mg twice daily (start immediately if not contraindicated)
Omega-3 fatty acids: High-dose (4 grams EPA/DHA daily) as adjunct

For Life-Threatening Cases (Triglycerides >2000-3000 mg/dL with pancreatitis or hyperviscosity)

Plasmapheresis or therapeutic plasma exchange—rapidly removes triglyceride-rich lipoproteins
Continuous veno-venous hemofiltration (CVVH) with high cut-off membranes can also reduce triglycerides in critically ill patients
Monitor for acute pancreatitis (occurs in ~15-20% when TG >1500 mg/dL)

Pearl: Response to insulin is often dramatic—triglycerides may fall from 5000 to <1000 mg/dL within 24 hours. Monitor sodium: as lipids clear, the measured sodium will "rise" toward normal (in reality, it was always normal in plasma water).

For Severe Hyperproteinemia/Hyperviscosity

Multiple Myeloma

Plasmapheresis (therapeutic plasma exchange) is the definitive emergency treatment for symptomatic hyperviscosity
Typically 3-5 sessions, removing 1-1.5 plasma volumes per session
Rapidly reduces paraprotein burden and viscosity within hours
Chemotherapy must be initiated promptly to prevent recurrence: bortezomib-based regimens (VRd: bortezomib, lenalidomide, dexamethasone) are standard

Waldenström Macroglobulinemia

Urgent plasmapheresis for symptomatic hyperviscosity (most common indication for emergency plasmapheresis in paraproteinemia)
Target viscosity <4 centipoise, IgM <4000 mg/dL
Rituximab-based chemotherapy: Rituximab with cyclophosphamide, dexamethasone (DRC) or bendamustine-rituximab (BR)
Caution: Avoid IVIg (intravenous immunoglobulin) as it worsens hyperviscosity

Oyster: In hyperviscosity syndrome, do not administer IV fluids aggressively before plasmapheresis—this can paradoxically worsen symptoms by increasing plasma volume. Maintain euvolemia.

Monitoring Response

As paraproteins or triglycerides decrease, serial sodium measurements will show apparent "correction," but this simply reflects resolution of the measurement artifact. Direct ISE sodium or plasma osmolality should remain normal throughout.

Pearls and Oysters: Clinical Gems for Practice

Pearl 1: The "Milky Serum Sign"

Always ask to see the blood sample when sodium is unexpectedly low without obvious cause. A lipemic sample visible to the naked eye is pathognomonic for severe hypertriglyceridemia and should immediately raise suspicion for pseudohyponatremia.

Pearl 2: The Blood Gas Machine Shortcut

When in doubt, send a blood sample for arterial or venous blood gas analysis. These point-of-care analyzers use direct ISE and will reveal the true sodium concentration, often within minutes. A normal sodium on blood gas with low sodium on chemistry panel confirms pseudohyponatremia.

Pearl 3: The "Clear Before Treatment" Rule

Never initiate treatment for hyponatremia until the serum sample is visually clear (non-lipemic) or you have excluded pseudohyponatremia using direct ISE or osmolality. This simple rule prevents dangerous mismanagement.

Oyster 1: Pseudohyponatremia Can Coexist with True Hyponatremia

Patients with nephrotic syndrome may have both severe hypertriglyceridemia (causing pseudohyponatremia) and true hyponatremia from volume depletion or SIADH. Similarly, patients with multiple myeloma may have true hyponatremia from SIADH (a paraneoplastic phenomenon) plus pseudohyponatremia from paraproteins. Always use direct ISE to determine the true sodium before making treatment decisions.

Oyster 2: Paraprotein Interference Beyond Sodium

Severe paraproteinemia can interfere with multiple laboratory assays, causing falsely low calcium, falsely high phosphate, and unreliable anion gap calculations. Always interpret electrolytes with caution in patients with M-spikes >3 g/dL. Directly measured ionized calcium is more reliable than total calcium.

Oyster 3: The "Normal Sodium" That's Actually High

In a patient with severe hyperglycemia (e.g., glucose 900 mg/dL) and hypertriglyceridemia (e.g., TG 4000 mg/dL), a measured sodium of 125 mmol/L might represent:

Pseudohyponatremia (lowering measured Na by ~16 mmol/L)
True hypertonic hyponatremia from hyperglycemia
Actual true sodium in plasma water might be 141 mmol/L
Corrected for glucose: should be ~153 mmol/L

This patient is actually significantly hypertonic despite a measured sodium of 125 mmol/L. Direct ISE measurement is essential to guide management in such complex cases.

Pearl 4: The Post-Treatment "Rapid Correction" Phenomenon

When treating the underlying hyperlipidemia or hyperproteinemia, measured sodium may appear to "correct" by 10-15 mmol/L within 24-48 hours. This is not true rapid correction of hyponatremia (which would risk osmotic demyelination) but simply resolution of the laboratory artifact. Reassure yourself and your team that this is expected and safe.

Oyster 4: Hemolysis Can Mask Lipemia

Hemolyzed samples appear pink-to-red, which may obscure the milky white appearance of lipemia. If a hemolyzed sample shows unexpected hyponatremia, consider redrawing before assuming true hyponatremia. Hemolysis itself does not cause pseudohyponatremia but can prevent visual recognition of lipemia.

A Proposed Bedside Algorithm

When faced with hyponatremia (sodium <135 mmol/L), follow this systematic approach:

Look at the sample → Lipemic/milky? → Suspect pseudohyponatremia
Check triglycerides and total protein immediately
- Triglycerides >1500 mg/dL? → Likely pseudohyponatremia
- Total protein >10 g/dL? → Consider pseudohyponatremia
Confirm with direct ISE sodium OR measured plasma osmolality
- Normal direct ISE sodium? → Pseudohyponatremia confirmed
- Normal plasma osmolality with low calculated osmolality (large osmolal gap)? → Pseudohyponatremia confirmed
Do not treat the sodium; treat the underlying disorder
- Insulin, fibrates, dietary restriction for hypertriglyceridemia
- Plasmapheresis and chemotherapy for paraproteinemia
Monitor: Measured sodium will "normalize" as lipids/proteins decrease—this is expected and safe

Teaching Points for Medical Students and Residents

Pseudohyponatremia is a "fake-out"—the lab is lying to you, but it's not the lab's fault. It's a limitation of the measurement technique when applied to abnormal samples.
Visual inspection is the fastest screening test—never skip looking at the sample. If you cannot see it yourself, ask the lab to describe it or photograph it.
Direct ISE is the referee—when indirect ISE and clinical suspicion disagree, direct ISE measurement gives you the truth. Blood gas machines are your friend.
Treat the disease, not the number—pseudohyponatremia tells you there's a serious underlying metabolic problem (severe dyslipidemia or plasma cell dyscrasia) that needs urgent attention.
Context is everything—a milky serum sample with triglycerides of 3000 mg/dL and a sodium of 125 mmol/L is pseudohyponatremia until proven otherwise. Don't jump to SIADH.

Conclusion

Pseudohyponatremia is an uncommon but critically important diagnosis that every clinician must be equipped to recognize. The three-step bedside approach—visual inspection of the serum, correlation with lipid and protein levels, and understanding of laboratory methodology—enables rapid identification before unnecessary and potentially harmful interventions are initiated. The key confirmatory tests, direct ISE sodium measurement and plasma osmolality, provide definitive answers within minutes to hours.

Recognition of pseudohyponatremia redirects clinical attention to the underlying life-threatening conditions: severe hypertriglyceridemia with risk of pancreatitis, and paraproteinemia with hyperviscosity syndrome. These conditions require specific urgent treatments—insulin and fibrates for hypertriglyceridemia, plasmapheresis and chemotherapy for hyperviscosity—rather than sodium replacement.

As teaching physicians, we must emphasize to our trainees that not all laboratory values reflect physiologic truth. Understanding the principles of laboratory measurement, recognizing potential artifacts, and maintaining a high index of suspicion in the appropriate clinical context are essential skills for excellent clinical practice. Pseudohyponatremia serves as an ideal teaching case for these principles: look at the patient, look at the sample, understand the method, confirm your suspicion, and treat the disease, not the number.

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Author Disclosure: No conflicts of interest to declare.

Word Count: 4,247 words

This comprehensive review provides postgraduate medical students and residents with practical bedside tools for recognizing pseudohyponatremia, emphasizing clinical signs, laboratory correlation, and appropriate management strategies that prioritize treating underlying metabolic derangements rather than laboratory artifacts.