Revealing the Unseen: Overlooked Causes of Pseudohyponatremia

One of the challenging cases in nephrology is managing a patient with severe hyponatremia, where each decision seems precarious. Overcorrecting sodium levels increases the risk of osmotic demyelination, while undercorrection leaves patients susceptible to complications. Nephrologists thread the needle carefully, focusing on avoiding overcorrection, typically aiming for a 24-hour correction rate below 6 to 8 mEq/L, or even lower at 4-6 mEq/L in patients with alcoholism, liver disease, or malnourished states. In these situations, it is easy to accept hyponatremia at face value without reassessing whether it correctly reflects the patient’s physiology.

Not all cases of hyponatremia reflect a true disturbance in tonicity. Approximately 1–2% of cases are due to laboratory artifact, though this is likely underreported (1). Pseudohyponatremia refers to a falsely low serum sodium level (<135 mEq/L) without true hypoosmolality, and is a laboratory artifact rather than a true reflection of altered extracellular tonicity. This occurs when sodium is measured using indirect ion-selective electrodes (ISEs), which assume that plasma consists of approximately 93% water and 7% solids (proteins and lipids).

Figure 1. The effect of an increase in solid fraction on the measurement of plasma sodium using the indirect ion-selective electrode method in the lab.

Under normal conditions, the sodium concentration in plasma water is about 150–155 mEq/L, corresponding to approximately 140–145 mEq/L when expressed per liter of plasma volume.

In conditions commonly associated with pseudohyponatremia, such as hyperproteinemia or hypertriglyceridemia, the fraction of plasma water decreases as the proportion of solids increases (Figure 1). Since sodium exists only in plasma water, its concentration remains unchanged. However, indirect ISE methods dilute the sample and assume a fixed plasma water fraction of ~93%. When the true fraction is lower (e.g., ~80% or 75%), sodium is underestimated, resulting in pseudohyponatremia (table 1) (2).

Plasma Water fraction	Solids fraction	Plasma Water Sodium (meq/L)	Plasma Sodium by indirect ISE (meq/L)	Plasma Sodium by direct ISE (meq/L)
0.93	0.07	154	154x0.93 =143	143
0.80	0.20	154	154x0.8 = 131	143
0.75	0.25	154	154x0.75 = 116	143

Table 1. Changes in plasma sodium measurements using direct and indirect ISE methods

Measured serum osmolality can help distinguish true hyponatremia from pseudohyponatremia, though interpretation may be confounded by elevated glucose or an azotemic state, the presence of toxic alcohols or ketoacids, or chronic kidney disease (3). The osmolal gap, defined as the difference between measured and calculated serum osmolality (2 × [Na] + [glucose]/18 + [BUN]/2.8), is usually less than 10 mOsm/kg in true hypotonic hyponatremia but is often greater than 10 mOsm/kg in pseudohyponatremia due to spuriously low sodium (Figure 2). Without attention to the osmolal gap, this distinction can be misleading. In practice, if the osmolal gap exceeds 10 mOsm/kg, particularly in patients with laboratory evidence of hyperlipidemia or hyperproteinemia, pseudohyponatremia should be suspected (4).

Figure 2. Evaluation of pseudohyponatremia (adapted and modified from J. Clin. Med. 2023, 12(12), 4076)

A high degree of clinical suspicion is essential. While classic causes such as hyperproteinemia and hypertriglyceridemia are well recognized, other causes are often overlooked (Table 2). Severe hypercholesterolemia, especially in the setting of acute liver failure, cholestatic jaundice, intravenous lipid emulsions, or, rarely, LCAT deficiency, can also lead to pseudohyponatremia (5). At the bedside, several helpful clues may prompt suspicion. These include visibly lipemic serum in some cases (milky or opalescent appearance), clinical evidence of jaundice (elevated direct bilirubin levels, typically >5-10 mg/dl), elevated alkaline phosphatase, a history of intravenous lipid infusion, or a known diagnosis of multiple myeloma or nephrotic syndrome. Noticing these signs can facilitate early consideration of pseudohyponatremia and help avoid unnecessary or potentially harmful interventions.

Hyperproteinemias	High Triglycerides	High Cholesterol
Plasma Cell Dyscrasias	Familial  Hypertriglyceridemia	Intrahepatic and Extrahepatic Cholestasis due to primary sclerosing cholangitis, Primary biliary cirrhosis, drugs, pregnancy, etc.
Lymphoproliferative Disorders	Alcoholism	Lipid infusion with TPN
Autoimmune Diseases	Diabetes Mellitus	Familial Hypercholesterolemia
Chronic Liver Disease	Prolonged Propofol Infusion	Hepatic Graft vs. Host Disease
Chronic Infections (HIV/Hep C/Hep B)

Table 2. Common etiologies that can be associated with pseudohyponatremia

Severe hypercholesterolemia can cause pseudohyponatremia due to the accumulation of

Lipoprotein X (LpX). This is commonly seen in settings such as intravenous lipid administration or cholestasis. LpX forms when impaired bile flow disrupts cholesterol metabolism and excretion. Inability to excrete cholesterol and phospholipids through the biliary tree causes them to accumulate in hepatocytes and canaliculi and to leak into the bloodstream. These lipids associate with albumin and apolipoproteins C and E to form LpX particles (Figure 3). Because LpX has a density similar to LDL, it is often misidentified as LDL-C on standard assays, leading to falsely elevated LDL-C levels (6).

Figure 3. Lipoprotein X formation and accumulation in patients with cholestatic jaundice

Although LpX may buffer the toxicity of excess free cholesterol, it lacks apolipoprotein B (apoB), which is required for normal receptor-mediated clearance. As a result, LpX persists in circulation. Importantly, the absence of apoB makes LpX nonatherogenic; thus, despite markedly elevated measured LDL-C levels, these patients do not appear to have increased cardiovascular risk.

If pseudohyponatremia is suspected, the next step is point-of-care sodium testing using a direct ISE on a blood gas analyzer. Unlike indirect methods, direct ISE measures sodium activity exclusively in plasma water. It is therefore unaffected by plasma solids (4). If direct ISE testing is unavailable, reviewing clinical and laboratory data, including measured osmolality, osmolal gap, and indicators of hyperlipidemia or hyperproteinemia, can help guide interpretation. The Waugh formula can also be used to estimate a corrected sodium value.

Correct Plasma Sodium = Measured Sodium _mg/dl / 1- (0.00073 x Protein _mg/dL) - (0.00010 x Triglycerides _mg/dL)- (0.00004 x Cholesterol _mg/dL) or in this calculator.

In patients presenting with hyponatremia, the initial evaluation should include confirming the diagnosis by measuring serum osmolality and carefully assessing the clinical context. Calculation of the osmolal gap and, when > 10 mosm/kg, point-of-care sodium measurement helps ensure that management reflects the patient’s true electrolyte status and minimizes the risk of unnecessary or potentially harmful interventions when the apparent hyponatremia is artifactual.

References:

1. Nguyen MK, Ornekian V, Butch AW, Kurtz I. A new method for determining plasma water content: application in pseudohyponatremia. Am J Physiol Renal Physiol. 2007;292(5):F1652-6.

2. Oster JR, Singer I. Hyponatremia, hyposmolality, and hypotonicity: tables and fables: Tables and Fables. Arch Intern Med. 1999;159(4):333-336.

3. Ballard M, Chen L. Pseudohyponatremia: A concise guide to diagnosis and management in clinical practice. J Nurse Pract. 2023;19(10):104800.

4. Aziz F, Sam R, Lew SQ, et al. Pseudohyponatremia: Mechanism, diagnosis, clinical associations, and management. J Clin Med. 2023;12(12):4076.

5. Ashorobi D, Liao H. Lipoprotein X-induced hyperlipidemia. In: StatPearls. StatPearls Publishing; 2026.

6. Lee R, Baum S, Roman T, Joshi-Guske P, Aggarwal M. Lipoprotein X: A cause for misleading levels of low-density lipoprotein. JACC Case Rep. 2025;30(37):105757.