Continuing Education Activity
Pseudohyponatremia is an uncommon laboratory artifact finding that can lead to severe morbidity and mortality if not recognized promptly. This activity reviews the evaluation and management of pseudohyponatremia and highlights the role of the interprofessional team in managing patients with this finding.
- Describe the laboratory modalities that can result in pseudohyponatremia.
- Identify the typical presentation of a patient with pseudohyponatremia.
- Summarize the evaluation and workup considerations for pseudohyponatremia.
- Review how the interprofessional team should work together to treat a patient with pseudohyponatremia.
Pseudohyponatremia is an uncommonly encountered laboratory abnormality defined by a serum sodium concentration of less than 135 mEq/L in the setting of a normal serum osmolality (280 to 300 mOsm/kg). Conversely, true hyponatremia is associated with low serum osmolality and should prompt evaluation for the presence of an additional abnormal solute that may be affecting the laboratory assessment. The finding of pseudohyponatremia is an artifact that results from the way a blood sample is processed for serum sodium measurement.
Some sources cite the presence of osmotically-active solutes, such as mannitol or hyperglycemia, as an additional etiology of pseudohyponatremia. It is preferable to identify pseudohyponatremia based on false laboratory analysis, in which the laboratory result does not match the actual sodium level. Due to the hyperosmolality and resultant fluid shifts invoked by the presence of osmotically-active solutes, the serum sodium, as reported by laboratory assessment in these cases, is truly low. For this reason, one should not include hyperosmolar hyponatremia as a potential classification of pseudohyponatremia.
There are many disease states and conditions attributable to the development of pseudohyponatremia. The most common cause of pseudohyponatremia is due to severely elevated levels of cholesterol. In serum blood samples taken from patients with severe hypertriglyceridemia, the sample may appear overtly lipemic, hyper viscous, or discolored from the overwhelming presence of insoluble triglycerides. However, it is important to note that some cholesterols are soluble in blood; hence, changes in blood viscosity or color may not occur in these circumstances. Examples of pseudohyponatremia due to accumulation of cholesterol components include:
- Lipoprotein X accumulation (typically secondary to biliary obstruction or cholestasis such as primary biliary cirrhosis)
- Familial hypercholesterolemia
Abnormally high levels of protein, including native or exogenous immunoglobulins, may also result in pseudohyponatremia. There are a wide variety of medical conditions that can result in such accumulation of protein; notable examples include:
- Chronic infectious disease states, such as the hepatitis C virus or HIV
- Malignant monoclonal gammopathies, such as multiple myeloma, POEMS syndrome, and Waldenstrom macroglobulinemia
- Malignancy, particularly malignant lymphoproliferative disorders
- Myelodysplastic syndromes
- Heavy chain disease
- Light chain disease
- Immunoglobulin deposition diseases, such as amyloidosis
- Intravenous immunoglobulin therapy (IVIG)
Falsely low serum sodium levels due to lipemic serum have been reported as early as the 1950s. The incidence of pseudohyponatremia is unclear, though it is more common in patients with a predisposing condition, such as hyperlipidemia, plasma cell dyscrasias, malignancy, and chronic infections such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV).
Approximately 93% of plasma is composed of water, and the remaining 7% is composed of solutes. Most electrolytes, including sodium ions, are almost entirely dissociated in the water component of plasma. To measure the serum sodium level, most laboratory evaluation methods require the technician first to dilute the serum sample, thus necessitating a correction factor of 0.93. These indirect methods of serum sodium measurement have proven to be accurate and valid under standard physiologic conditions. However, in the presence of an abnormally excessive level of additional solute, the ratio of solid to water in plasma is altered unpredictably, leading to inaccurate readings when sodium ions are measured indirectly.
Laboratory Assessment of Serum Sodium
Serum sodium measurement is most commonly obtained by one of three laboratory processes: flame emission spectrophotometry, indirect ion-selective electrode potentiometry, and direct-ion-selective electrode potentiometry.
- Flame Emission Spectrophotometry: In the early 1950s, serum sodium was measured by a process known as flame emission spectrophotometry (FES), in which a diluted sample of serum was sprayed across a flame. A spectrophotometer then measures the intensity of light generated at the specific wavelength corresponding to sodium. From this data, the serum sodium level is extrapolated with efficiency with the necessary application of a correction factor.
- Indirect Ion-Selective Electrode Potentiometry: In the 1980s, laboratories began to transition to a new method called Indirect ion-selective electrode (IISE) potentiometry. This laboratory method provides an advantage over FES in that only the aqueous components of the solution are measured. However, the serum in IISE is again diluted, which, in turn, requires a corrective factor to be applied. Thus, the IISE method of sodium measurement is also prone to error in the presence of excess solute in the serum, even when considering the percentage of the aqueous component. According to a recent participant summary report conducted by the College of American Pathologists, approximately two-thirds of laboratories in the United States currently utilize this method.
- Direct Ion-Selective Electrode Potentiometry (DISE): like IISE, the DISE method also utilizes potentiometry to precisely detect sodium levels in a given serum sample; however, the direct method does not require dilution of the serum before testing. The serum sodium level reported does not require a correction factor and is therefore not susceptible to an artifactual error by the presence of excess solute in serum. DISE is the most frequently used method in arterial blood gas analysis.
History and Physical
A thorough history and physical examination are essential for suspected pseudohyponatremia. A comprehensive review of systems should be obtained, in addition to a careful review of the patient’s past medical history to search for a potential etiology. Symptoms that suggest true hyponatremia, such as fatigue, muscle cramps, altered mentation, headaches, and seizure, should be excluded before considering the spurious elevation of serum sodium. Comprehensive medication reconciliation is necessary at the initial encounter to exclude exogenous factors that may alter normal sodium homeostasis.
A false interpretation of laboratory technology identifies the diagnosis of pseudohyponatremia; thus, there are no direct physical examination findings attributable to pseudohyponatremia. However, a focused physical examination is necessary to help rule out pathologic hyponatremia, potentially leading to severe morbidity and mortality if not recognized promptly. The clinician should evaluate for neuropsychiatric abnormalities with a complete neurological examination and psychiatric screening at the initial encounter. The initial neurocognitive and psychiatric evaluation also helps to establish a baseline to reference at subsequent encounters. Additionally, a cardiovascular and respiratory examination is a requirement to evaluate for any abnormalities that require attention.
While there are no specific physical examination findings that are caused by pseudohyponatremia, evidence of the underlying disorder may be present that can help to direct further workup:
- Hypercholesterolemia: obesity, peripheral arterial disease, presence of cardiovascular disease, xanthomas.
- Hyperproteinemia/hypergammaglobulinemia: a history of malignancy, evidence of metastasis, bone lesions, abnormal electrolyte or hematology studies, pain, evidence of immunodeficiency.
- Accumulation of lipoprotein X: abdominal pain, pancreatitis, pruritis, jaundice, xanthomas.
The most important step in the initial evaluation of suspected pseudohyponatremia is to exclude true hyponatremia; failure to accurately diagnose true hyponatremia can result in severe iatrogenic complications and even death. Evaluation of hyponatremia should always include a thorough history and physical examination, with specific attention to the history of present illness, past medical history, medications, and assessment of volume status. Serum osmolality should also be obtained, as true hyponatremia is more likely to be associated with low serum osmolality, which is defined as a value of less than 280 mOsm/kg. Calculated serum osmolality should also be obtained, as a significant discrepancy between measured and calculated serum osmolality suggests confounding factors. Once a diagnosis of pseudohyponatremia is confirmed, the clinician should construct a differential diagnosis of potential etiologies—the likely etiologies under consideration direct further laboratory workup of pseudohyponatremia.
When to Consider Direct Ion-Selective Electrode Potentiometry (DISE)
Most cases of pseudohyponatremia do not require the use of DISE to confirm the diagnosis, with few exceptions. In general, DISE merits consideration in situations where the diagnosis is uncertain, and confirmation of pseudohyponatremia is likely to change management significantly; in the absence of these criteria, DISE is likely to be of little diagnostic or prognostic value. If multiple confounders are present, particularly the presence of osmotically active solutes, one should consider DISE to discriminate between hyperosmolar hyponatremia and pseudohyponatremia. We recommend measuring a direct serum sodium level with DISE in the following circumstances:
- The blood sample is grossly lipemic.
- Measured serum osmolality is significantly different from calculated serum osmolality.
- Hyponatremia in the setting of diabetes mellitus and hyperglycemia
Treatment / Management
Management of pseudohyponatremia focuses on the treatment of the underlying cause:
- Hypercholesterolemia: appropriate management involves lowering of the causative lipoprotein with lifestyle modification and/or medication. In most cases, this can take place in the ambulatory setting over an extended period.
- Hyperproteinemias and hypergammaglobulinemias: the causative protein or antibody determines appropriate management. Consultation with the appropriate subspecialty may be necessary for further recommendations.
- Lipoprotein X: pseudohyponatremia due to the accumulation of lipoprotein X is an exceedingly rare disorder; nearly all cases have involved some degree of cholestasis. Hence, appropriate management of this condition focuses on the resolution of cholestasis.
- Graft-versus-host disease (GVHD): clinicians direct the management of suspected pseudohyponatremia related to cholestasis and subsequent dyslipidemia related to gastrointestinal manifestations of GVHD by controlling the immune response. Treatment may include steroid therapy and/or octreotide; specialist consultation is recommended.
The differential diagnosis of pseudohyponatremia should include the entire spectrum of disease associated with hyponatremia. Likewise, it is essential to note that the diagnosis of pseudohyponatremia does not exclude the possibility of additional disorders of sodium homeostasis that may be masked by laboratory error.
Disorders to consider in the differential of a low sodium level include the following:
- Hypertonic or isotonic hyponatremia due to exogenous infusion: mannitol, glucose, glycine, sorbitol, or ethanol
- Hypertonic hyponatremia due to hyperglycemia
- Hypovolemic hypotonic hyponatremia due to gastrointestinal, renal injury, or skin loss of free water
- Hypovolemic hypotonic hyponatremia due to adrenal insufficiency
- Euvolemic hypotonic hyponatremia due to psychogenic polydipsia, renal injury, chronic urinary obstruction, hypothyroidism, beer potomania, excess pain, or syndrome of inappropriate diuretic hormone release (SIADH)
- Hypervolemic hypotonic hyponatremia due to chronic renal injury, heart failure, or liver disease
- Congenital or acquired metabolic derangements of sodium, such as renal tubular acidosis, Liddle syndrome, Bartter syndrome, Gitelman syndrome, pseudohypoaldosteronism, etc.
Following the exclusion of other causes of hyponatremia are excluded, the differential diagnosis of pseudohyponatremia may include the following:
- Cholestasis (resulting in accumulation of lipoprotein X)
Outcomes in pseudohyponatremia strongly correlate with the causative etiology. Once establishing the etiology of pseudohyponatremia, clinicians are encouraged to review the corresponding literature for further information regarding the prognosis of the underlying condition.
Due to the broad and complex management of hyponatremic disorders, failure to recognize and accurately diagnose pseudohyponatremia can result in serious morbidity and death. As such, the recommendation is that clinicians always maintain a broad differential in the approach to hyponatremia; serum osmolality, in particular, can help to rule in or rule out pseudohyponatremia. A thorough review of the patient’s medical record, laboratory workup, and past medical history can also help identify conditions potentially associated with pseudohyponatremia.
In most cases, acute management of pseudohyponatremia in the setting of a known etiology rarely requires consultation. Rather, requests for consultation should focus on the treatment of the underlying disorder. Clinician comfort regarding the management of disorders in sodium hemostasis should be considered and can guide potential specialist involvement.
Deterrence and Patient Education
Patients should be made aware of the diagnosis and the related implications. For hospitalized patients, discharge staff should establish close follow-up before discharge to facilitate continuity of care. Repeat assessment of serum sodium and other laboratory studies related to the causative etiology are reasonable to ensure resolution or improvement. Patients should understand that pseudohyponatremia does not appear to connect to an increased risk of morbidity or mortality; however, future treatment should address the health issues surrounding the spurious lab value.
Pearls and Other Issues
- Hyponatremia is defined as a serum sodium level of less than 135 mEq/L
- When considering pseudohyponatremia, a careful review of the history of present illness, past medical history, medications, and a physical examination to exclude true hyponatremia should take place.
- For hyponatremia, serum osmolality is necessary to characterize the low sodium level further. Pseudohyponatremia is associated with normal serum osmolality, which is defined as a value between 280 and 300 mOsm/kg.
- Hyponatremia treatment varies considerably depending on serum osmolality and assessment of volume status; misdiagnosis can lead to improper management with potentially fatal outcomes. Therefore, before diagnosing pseudohyponatremia, true hyponatremia, or hyponatremia due to the presence of an osmotically active solute should be excluded.
- After establishing the diagnosis of pseudohyponatremia, one must construct a broad differential for possible etiology. The most common etiologies are disease states that predispose the patient to abnormal accumulation of cholesterol components or proteins in the blood.
- Management of pseudohyponatremia focuses on the treatment of the underlying disorder.
- Pseudohyponatremia is a lab error that by itself does not carry an increased risk of morbidity or mortality; however, many conditions that result in pseudohyponatremia correlate with increased health risk.
- In many cases, direct measurement of serum sodium level with direct potentiometry is not necessary.
- Patient education should involve discussing the diagnosis and specific emphasis on the proper treatment of the underlying medical condition.
Enhancing Healthcare Team Outcomes
Pseudohyponatremia is an uncommon, underrecognized spurious lab abnormality. In the absence of true hyponatremia, pseudohyponatremia is not independently associated with increased morbidity or mortality. Pseudohyponatremia requires recognition as an inappropriately abnormal lab finding that warrants further evaluation to assess for a potential explanation. Consultation with the appropriate specialist, based on the likely etiology, is recommended. Serial follow-up in the outpatient primary care setting is also the recommended approach to ensure the resolution of abnormal lab value and compliance with further therapy. An interprofessional healthcare team comprised of clinicians, mid-level practitioners, nurses, and pharmacists, exercising open communication and coordinated activity can assess and address all the potential etiologies and optimally drive patient care. [Level 5]