Continuing Education Activity

Pseudohyponatremia is a rare laboratory abnormality characterized by a serum sodium concentration below 135 mEq/L in the setting of a normal serum osmolality (280 to 300 mOsm/kg), thereby posing a risk of severe morbidity and mortality if not recognized promptly. Pseudohyponatremia, unlike true hyponatremia associated with low serum osmolality, is an artifact resulting from blood sample processing for sodium measurement. Failure to promptly recognize this can lead to severe complications, necessitating prompt evaluation for additional abnormal solutes affecting the laboratory assessment. 

Osmotically active solutes such as mannitol or hyperglycemia can contribute to pseudohyponatremia, but a severe elevation of cholesterol stands out as the primary cause. Management primarily targets treating the underlying condition responsible for elevated cholesterol levels. Accurate interpretation of serum sodium values is essential for distinguishing pseudohyponatremia from other forms of hyponatremia, and consultation with a nephrologist may be necessary for proper differentiation. This activity reviews the evaluation and management of pseudohyponatremia while emphasizing the collaborative role of the interprofessional team in patient care. This activity provides clinicians from primary care, emergency medicine, internal medicine, and related subspecialties with the skills necessary to distinguish this common electrolyte imbalance in their patients. In addition, this activity also improves prompt recognition and effective management by clinicians, which is crucial in preventing morbidity and mortality associated with pseudohyponatremia.

Objectives:

• Differentiate between pseudohyponatremia and true hyponatremia, recognizing the artifact resulting from blood sample processing for sodium measurement.

• Implement appropriate management strategies targeting the underlying condition responsible for elevated cholesterol levels in cases of pseudohyponatremia.

• Select appropriate diagnostic tests, such as serum osmolality measurement, to aid in the differentiation of pseudohyponatremia from other electrolyte imbalances.

• Collaborate with interprofessional healthcare teams to ensure comprehensive evaluation and management of pseudohyponatremia cases, thereby optimizing patient outcomes.

Introduction

Pseudohyponatremia is a rare laboratory abnormality characterized by a serum sodium concentration below 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 necessitates prompt evaluation for additional abnormal solutes affecting the laboratory assessment.[1] Pseudohyponatremia is an artifact resulting from blood sample processing for sodium measurement, and failure to promptly recognize this can lead to severe complications.

Osmotically active solutes such as mannitol or hyperglycemia can contribute to pseudohyponatremia, but a severe elevation of cholesterol stands out as the primary cause. Identifying pseudohyponatremia based on false laboratory analysis is preferred. 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 some cases, is truly low. For this reason, one should not include hyperosmolar hyponatremia as a potential classification of pseudohyponatremia. Accurate interpretation of serum sodium values is essential for distinguishing pseudohyponatremia from other forms of hyponatremia, such as hyponatremia and hyperosmolar hyponatremia. Management primarily involves accurately interpreting serum sodium values and addressing the underlying condition responsible for elevated cholesterol levels, which may necessitate consultation with a nephrologist for proper differentiation.

Etiology

Many disease states and conditions contribute to the development of pseudohyponatremia, with severely elevated levels of cholesterol being the most prevalent cause.[2] In serum blood samples from patients with severe hypertriglyceridemia, the sample may exhibit overt lipemia, hyperviscosity, or discoloration due to the high concentration of insoluble triglycerides. However, soluble cholesterols in blood may not induce changes in viscosity or color under these circumstances.[3][4][5][6]

Pseudohyponatremia that results from the accumulation of cholesterol components include hypertriglyceridemia,[7] hyperlipidemia,[8] lipoprotein X accumulation (typically secondary to biliary obstruction or cholestasis such as primary biliary cirrhosis), and familial hypercholesterolemia.

Abnormally high protein levels, including native or exogenous immunoglobulins, may lead to pseudohyponatremia, with various medical conditions contributing to protein accumulation. Notable examples include [9] chronic infectious disease states, such as the hepatitis C virus (HCV) or HIV, malignant monoclonal gammopathies, such as multiple myeloma, POEMS syndrome, and Waldenstrom macroglobulinemia,[10] malignancy, particularly malignant lymphoproliferative disorders,[11][8] myelodysplastic syndromes, heavy- and light-chain diseases, immunoglobulin deposition diseases, such as amyloidosis, and intravenous immunoglobulin therapy.[12]

Epidemiology

Reports of falsely low serum sodium levels due to lipemic serum date back to as early as the 1950s.[13] Although the precise incidence of pseudohyponatremia remains unclear, it appears to be more prevalent in patients with predisposing conditions, including hyperlipidemia, plasma cell dyscrasias, malignancy, and chronic infections such as HCV and HIV.[9]

Pathophysiology

Approximately 93% of plasma is water; the remaining 7% is solutes.[9] Most electrolytes, including sodium ions, are nearly completely dissociated in the water component of plasma. To measure the serum sodium level, technicians typically dilute the serum sample, requiring a correction factor of 0.93. These indirect methods of serum sodium measurement are accurate and valid under standard physiological conditions. However, in cases of abnormally high levels of additional solute, the ratio of solid to water in plasma becomes unpredictably altered, resulting in inaccurate readings when measuring sodium ions.

Serum sodium measurement is most commonly obtained by one of 3 laboratory processes, as mentioned below.[14]

Flame emission spectrophotometry: In the early 1950s, serum sodium was measured by a process known as flame emission spectrophotometry, in which a diluted sample of serum was sprayed across a flame. A spectrophotometer then measures the light intensity 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 transitioning to a new method called indirect ion-selective electrode potentiometry. This laboratory method provides an advantage over flame emission spectrophotometry in that only the aqueous components of the solution are measured. However, the serum in the indirect ion-selective electrode is again diluted, which, in turn, requires a corrective factor. Thus, the indirect ion-selective electrode method of sodium measurement is also prone to error in the presence of excess solute in the serum 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: Similar to the indirect ion-selective electrode, the direct ion-selective electrode potentiometry method also utilizes potentiometry to precisely detect sodium levels in a given serum sample. However, the direct method does not require serum dilution before testing. The reported serum sodium level does not require a correction factor and is therefore not susceptible to an artifactual error by excess solute in serum. Direct ion-selective electrode potentiometry is the most frequently used method in arterial blood gas analysis.[15]

History and Physical

A thorough history and physical examination are essential for suspected pseudohyponatremia. A comprehensive review of systems should be obtained, and a careful review of the patient’s medical history is required to identify 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; no direct physical examination findings are attributable to pseudohyponatremia. However, a focused physical examination is necessary to help rule out pathologic hyponatremia, which, if not recognized promptly, could potentially lead to severe morbidity and mortality. Clinicians should evaluate neuropsychiatric abnormalities with a complete neurological examination and psychiatric screening at the initial encounter. The initial neurocognitive and psychiatric evaluation helps establish a baseline to reference at subsequent encounters. A focused cardiovascular and respiratory examination is also part of the standard evaluation.

Pseudohyponatremia does not produce specific physical examination findings. However, evidence of the underlying disorder may guide further investigation:

• Hypercholesterolemia: Obesity, peripheral arterial disease, cardiovascular disease, and xanthomas.
• Hyperproteinemia/hypergammaglobulinemia: A history of malignancy, evidence of metastasis, bone lesions, abnormal electrolyte or hematology studies, pain, and evidence of immunodeficiency.
• Lipoprotein X accumulation: Abdominal pain, pancreatitis, pruritis, jaundice, and xanthomas.[16]

Evaluation

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 death.[3][6][17] 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, defined as a value of less than 280 mOsm/kg.[18] 

Calculated serum osmolality should also be obtained, as a significant discrepancy between measured and calculated serum osmolality suggests confounding factors. When 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.

Most cases of pseudohyponatremia do not require the use of direct ion-selective electrode potentiometry to confirm the diagnosis, with few exceptions. Direct ion-selective electrode potentiometry is worth considering when the diagnosis is uncertain and confirmation of pseudohyponatremia is anticipated to alter management significantly. However, without these criteria, direct ion-selective electrode potentiometry will likely offer limited diagnostic or prognostic value.

In cases where multiple confounding factors, especially osmotically active solutes, are present, direct ion-selective electrode potentiometry should be considered to differentiate between hyperosmolar hyponatremia and pseudohyponatremia.[19][3][5] Some suggest measuring a direct serum sodium level using this method under the following circumstances:

• The blood sample appears grossly lipemic.
• The measured serum osmolality is significantly different from the calculated serum osmolality.
• Hyponatremia occurs concurrently with diabetes mellitus and hyperglycemia.[20]

Treatment / Management

Management of pseudohyponatremia focuses on the treatment of the underlying cause:

• Hypercholesterolemia: Appropriate management involves lowering the causative lipoprotein with lifestyle modification and/or medication. In most cases, this can occur in the ambulatory setting over an extended period.

• Hyperproteinemias and hypergammaglobulinemias: The causative protein or antibody determines appropriate management. For further recommendations, consultation with the appropriate subspecialty may be necessary.

• Lipoprotein X: Pseudohyponatremia resulting from lipoprotein X accumulation is an extremely rare disorder, with nearly all cases associated with some level of cholestasis.[5] Therefore, effective management of this condition primarily revolves around resolving the underlying cholestasis.

• Graft-versus-host disease: Clinicians address suspected pseudohyponatremia associated with cholestasis and subsequent dyslipidemia related to gastrointestinal manifestations of graft-versus-host disease by regulating the immune response.[21] Treatment may involve steroid therapy and/or octreotide, with specialist consultation recommended.

Differential Diagnosis

The differential diagnosis of pseudohyponatremia should include the entire spectrum of hyponatremia-related diseases. Notably, 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 may occur due to an exogenous infusion of 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, and pseudohypoaldosteronism.

After ruling out other causes of hyponatremia, the potential differential diagnosis of pseudohyponatremia may involve hypercholesterolemia, hyperproteinemia, hypergammaglobulinemia, and cholestasis leading to the accumulation of lipoprotein X.

Prognosis

The outcomes in pseudohyponatremia are significantly influenced by the underlying cause. Clinicians are advised to review the corresponding literature for further information regarding the prognosis of the underlying condition associated with the etiology of pseudohyponatremia.

Complications

Due to the broad and complex management of hyponatremic disorders, failure to recognize and accurately diagnose pseudohyponatremia can result in severe morbidity and death.[6][14][22] Therefore, clinicians are advised to maintain a broad differential in approaching hyponatremia, with serum osmolality crucial in ruling in or ruling out pseudohyponatremia.[5][9] A thorough review of the patient’s medical record, laboratory workup, and past medical history can also help identify conditions potentially associated with pseudohyponatremia.

Consultations

In most cases, acute management of pseudohyponatremia with a known etiology typically does not necessitate consultation. Instead, consultation requests should prioritize treating the underlying disorder. Clinicians' comfort in managing disorders related to sodium homeostasis should be considered and may involve collaboration with nephrologists.

Deterrence and Patient Education

Patients should be aware of the diagnosis and the related implications. For hospitalized patients, 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

Some of the standard pearls to treat pseudohyponatremia are as follows:

• Hyponatremia is defined as a serum sodium level of less than 135 mEq/L.

• When considering pseudohyponatremia, a careful review of the history of the present illness, past medical history, medications, and a physical examination to exclude true hyponatremia should occur.

• Serum osmolality is necessary to further characterize the low sodium level in hyponatremia. Pseudohyponatremia is associated with normal serum osmolality, defined as a value between 280 and 300 mOsm/kg.

• Hyponatremia treatment varies significantly based on serum osmolality and evaluation of volume status, and misdiagnosis can result in improper management with potentially fatal outcomes. Hence, before diagnosing pseudohyponatremia, it is essential to exclude true hyponatremia or hyponatremia caused by the presence of an osmotically active solute.

• After establishing the diagnosis of pseudohyponatremia, one must construct a broad differential for possible etiology. The most common etiologies are disease states predisposing the patient to abnormal cholesterol components or protein accumulation in the blood.

• Management of pseudohyponatremia focuses on the treatment of the underlying disorder.

• Pseudohyponatremia, although a laboratory error, does not inherently pose an increased risk of morbidity or mortality. However, many conditions associated with pseudohyponatremia correlate with elevated health risks.

• In many cases, direct measurement of serum sodium level with direct potentiometry is unnecessary.

• Patient education should involve discussing the diagnosis and emphasizing the proper treatment of the underlying medical condition.

Enhancing Healthcare Team Outcomes

Pseudohyponatremia is an uncommon and often overlooked spurious laboratory abnormality. In the absence of true hyponatremia, pseudohyponatremia itself is not directly linked to increased morbidity or mortality. However, it necessitates recognition as an abnormal laboratory finding that warrants further evaluation to identify a potential underlying cause. Depending on the likely etiology, consultation with nephrology is advised.

Serial follow-up in the outpatient primary care setting is also recommended to ensure the resolution of abnormal lab values and compliance with further therapy. An interprofessional healthcare team comprising clinicians, mid-level practitioners, nurses, and pharmacists should maintain open communication and coordinate activities to comprehensively assess and address all potential etiologies, thereby optimizing patient care.