Pseudohyponatremia is an uncommonly encountered laboratory abnormality that is 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 is the result of 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. We prefer to make the distinction of 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 are truly low. For this reason, we do 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. It is important to note, however, 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:
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:
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 methods of laboratory evaluation 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.
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 should be performed 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; as such, there are no direct physical examination findings that are attributable to pseudohyponatremia. However, a focused physical examination is necessary to aid in ruling out pathologic hyponatremia, which can lead 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:
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:
Management of pseudohyponatremia focuses on the treatment of the underlying cause:
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:
Following the exclusion of other causes of hyponatremia are excluded, the differential diagnosis of pseudohyponatremia may include the following:
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 assist in identifying conditions that may associate 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.
Patients should be made aware of the diagnosis and the related implications. For hospitalized patients, close follow up should be established 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 focus on addressing the health issues that surround the spurious lab value.
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.
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