Markedly Decreased Serum Sodium Concentration in a Patient With Multiple Myeloma

Zhongxin Yu, MD; K. Michael Parker, PhD; Kenneth E. Blick, PhD

Lab Med. 2005;36(4):224-226. 

Introduction

56-year-old male.

Low back pain, cough, and altered mental status (confusion and disorientation).

Non-contributory.

Non-contributory.

Principal Laboratory Findings

.

  Principal Laboratory Findings

Test Patient's Result "Normal" Reference Range
Hematology
WBC count 13.0 4.0-11.0 x103/mm3
RBC count 2.98 4.70-6.10 x106/mm3
Hemoglobin 10.0 13.0-18.0 g/dL
Hematocrit 28.1 39.0-52.0%
MCV 94.3 82.0-99.0 fL
MCH 33.6 27.0-34.0 pg
MCHC 35.6 32.0-36.0 g/dL
Platelet count 202 140-440 x103/mm3
Neutrophils 69 39-78%
Bands 2 0-12%
Lymphocytes 19 15-56%
Monocytes 5 2-14%
Plasma cells 5 0-1%
Anisocytosis Mild
Rouleaux Marked
Chemistry
Sodium 123 135-145 mmol/L
Potassium 3.6 3.5-5.1 mmol/L
Chloride 102 96-108 mmol/L
Anion gap 2 5-17
BUN 8 7-18 mg/dL
Creatinine 0.7 0.8-1.2 mg/dL
Glucose 130 65-110 mg/dL
Calcium 6.2 8.6-10 mg/dL
Triglycerides 327 40-160 mg/dL
Cholesterol 123 120-200 mg/dL
HDL-cholesterol <10 35-80 mg/dL
LDL-cholesterol 48 <130 mg/dL
Total protein 9.9 6.4-8.4 mg/dL
Albumin 1.4 3.4-5.0 mg/dL
A/G ratio 0.2 1.0-2.2 mg/dL
Phosphate 1.4 2.5-4.5 mg/dL
Magnesium 1.9 1.6-2.6 mg/dL
Random urine sodium 99 (not established) mmol/L
Random urine osmolality 511 300-900 mOsm/kg
IgG 5530 700-1,600 mg/dL
IgA 58 70-400 mg/dL
IgM 39 40-230 mg/dL
SPE pattern IgG kappa monoclonal gammopathy
Arterial Blood Gases
pH 7.48 7.38-7.42
pCO2 34 35-45 mmHg
HCO3 26 24-26 mmol/L

WBC = white blood cell; RBC = red blood cell; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDL = low-density lipoprotein; A/G = albumin/globulin; SPE = serum protein electrophoresis

The patient was admitted to the hospital for additional laboratory (Figure 1) and diagnostic testing. Bone marrow biopsy showed plasmacytosis >30%; chest X-ray demonstrated right lower lobe pneumonia; additional radiologic studies showed lytic bone lesions of the skull, C-5 cervical spine, and an aged compression fracture at L-1 of the lumbar spine; and computed tomography (CT) and magnetic resonance imaging (MRI) scans of the brain were unremarkable.

Patient's serum sodium concentration by A) indirect (Synchron LX20 instrument, Beckman Coulter, Brea, CA) and B) direct ion-selective electrode (ISE) method (i-STAT instrument, i-STAT Corporation, East Windsor, NJ), calculated (OsmoCalc) and measured (OsmoMeas) osmolality, and osmolar gap on hospital days 1 through 7 (A) or 4 through 7 (B). OsmoCalc = 2[Na, mmol/L] + [(Glucose, mg/dL)/18] + [(BUN, mg/dL)/2.8]1; OsmoMeas was determined using the Advanced99 Micro Osmometer, Model 330 (Advanced Instruments Inc., Norwood, MA); Osmolar gap = OsmoMeas - OsmoCalc. Na, sodium ion concentration; BUN, blood urea nitrogen; Osmo, osmolality; Meas, measured; Calc, calculated.

Patient's serum sodium concentration by A) indirect (Synchron LX20 instrument, Beckman Coulter, Brea, CA) and B) direct ion-selective electrode (ISE) method (i-STAT instrument, i-STAT Corporation, East Windsor, NJ), calculated (OsmoCalc) and measured (OsmoMeas) osmolality, and osmolar gap on hospital days 1 through 7 (A) or 4 through 7 (B). OsmoCalc = 2[Na, mmol/L] + [(Glucose, mg/dL)/18] + [(BUN, mg/dL)/2.8]1; OsmoMeas was determined using the Advanced99 Micro Osmometer, Model 330 (Advanced Instruments Inc., Norwood, MA); Osmolar gap = OsmoMeas - OsmoCalc. Na, sodium ion concentration; BUN, blood urea nitrogen; Osmo, osmolality; Meas, measured; Calc, calculated.

Questions

  1. What is (are) this patient's most striking laboratory finding(s)?

  2. How do you explain this patient's most striking laboratory finding(s)?

  3. What is this patient's most likely diagnosis?

  4. How is this patient's condition distinguished from other causes of hyponatremia?

  5. What are the 2 principal methods for quantifying serum sodium concentration used routinely in most clinical laboratories in the United States and how do they differ?

  6. What testing should be performed to confirm pseudohyponatremia as the cause of a markedly decreased serum sodium concentration?

  7. Why was this patient's anion gap markedly decreased?

  8. In patients with pseudohyponatremia, how should the serum sodium concentration be monitored?

  9. How is pseudohyponatremia treated?

Possible Answers

  1. This patient has several abnormal test results for a variety of analytes ( ); however, the most striking are a peripheral blood smear with 5% plasma cells and marked Rouleaux; markedly decreased serum sodium, calcium, and albumin concentrations; markedly decreased calculated anion gap and albumin/globulin (A/G) ratio; increased IgG and total protein concentrations; and IgG kappa monoclonal gammopathy. In addition, after admission to the hospital, this patient's osmolar gap { ie, measured osmolality - calculated osmolality, where calculated osmolality was determined using the equation: 2[Na] + ([Glucose]/18) + ([BUN]/2.8)} was large on several days, but narrowed when the calculated osmolality was determined using serum sodium values obtained by a different method for quantifying the patient's serum sodium concentration than the method used initially (Figure 1).

    Table 1.  Principal Laboratory Findings

    Test Patient's Result "Normal" Reference Range
    Hematology
    WBC count 13.0 4.0-11.0 x103/mm3
    RBC count 2.98 4.70-6.10 x106/mm3
    Hemoglobin 10.0 13.0-18.0 g/dL
    Hematocrit 28.1 39.0-52.0%
    MCV 94.3 82.0-99.0 fL
    MCH 33.6 27.0-34.0 pg
    MCHC 35.6 32.0-36.0 g/dL
    Platelet count 202 140-440 x103/mm3
    Neutrophils 69 39-78%
    Bands 2 0-12%
    Lymphocytes 19 15-56%
    Monocytes 5 2-14%
    Plasma cells 5 0-1%
    Anisocytosis Mild  
    Rouleaux Marked  
    Chemistry
    Sodium 123 135-145 mmol/L
    Potassium 3.6 3.5-5.1 mmol/L
    Chloride 102 96-108 mmol/L
    Anion gap 2 5-17
    BUN 8 7-18 mg/dL
    Creatinine 0.7 0.8-1.2 mg/dL
    Glucose 130 65-110 mg/dL
    Calcium 6.2 8.6-10 mg/dL
    Triglycerides 327 40-160 mg/dL
    Cholesterol 123 120-200 mg/dL
    HDL-cholesterol <10 35-80 mg/dL
    LDL-cholesterol 48 <130 mg/dL
    Total protein 9.9 6.4-8.4 mg/dL
    Albumin 1.4 3.4-5.0 mg/dL
    A/G ratio 0.2 1.0-2.2 mg/dL
    Phosphate 1.4 2.5-4.5 mg/dL
    Magnesium 1.9 1.6-2.6 mg/dL
    Random urine sodium 99 (not established) mmol/L
    Random urine osmolality 511 300-900 mOsm/kg
    IgG 5530 700-1,600 mg/dL
    IgA 58 70-400 mg/dL
    IgM 39 40-230 mg/dL
    SPE pattern IgG kappa monoclonal gammopathy  
    Arterial Blood Gases
    pH 7.48 7.38-7.42
    pCO2 34 35-45 mmHg
    HCO3 26 24-26 mmol/L

     

    WBC = white blood cell; RBC = red blood cell; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDL = low-density lipoprotein; A/G = albumin/globulin; SPE = serum protein electrophoresis

     

    Table 1.  Principal Laboratory Findings

    Test Patient's Result "Normal" Reference Range
    Hematology
    WBC count 13.0 4.0-11.0 x103/mm3
    RBC count 2.98 4.70-6.10 x106/mm3
    Hemoglobin 10.0 13.0-18.0 g/dL
    Hematocrit 28.1 39.0-52.0%
    MCV 94.3 82.0-99.0 fL
    MCH 33.6 27.0-34.0 pg
    MCHC 35.6 32.0-36.0 g/dL
    Platelet count 202 140-440 x103/mm3
    Neutrophils 69 39-78%
    Bands 2 0-12%
    Lymphocytes 19 15-56%
    Monocytes 5 2-14%
    Plasma cells 5 0-1%
    Anisocytosis Mild  
    Rouleaux Marked  
    Chemistry
    Sodium 123 135-145 mmol/L
    Potassium 3.6 3.5-5.1 mmol/L
    Chloride 102 96-108 mmol/L
    Anion gap 2 5-17
    BUN 8 7-18 mg/dL
    Creatinine 0.7 0.8-1.2 mg/dL
    Glucose 130 65-110 mg/dL
    Calcium 6.2 8.6-10 mg/dL
    Triglycerides 327 40-160 mg/dL
    Cholesterol 123 120-200 mg/dL
    HDL-cholesterol <10 35-80 mg/dL
    LDL-cholesterol 48 <130 mg/dL
    Total protein 9.9 6.4-8.4 mg/dL
    Albumin 1.4 3.4-5.0 mg/dL
    A/G ratio 0.2 1.0-2.2 mg/dL
    Phosphate 1.4 2.5-4.5 mg/dL
    Magnesium 1.9 1.6-2.6 mg/dL
    Random urine sodium 99 (not established) mmol/L
    Random urine osmolality 511 300-900 mOsm/kg
    IgG 5530 700-1,600 mg/dL
    IgA 58 70-400 mg/dL
    IgM 39 40-230 mg/dL
    SPE pattern IgG kappa monoclonal gammopathy  
    Arterial Blood Gases
    pH 7.48 7.38-7.42
    pCO2 34 35-45 mmHg
    HCO3 26 24-26 mmol/L

     

    WBC = white blood cell; RBC = red blood cell; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDL = low-density lipoprotein; A/G = albumin/globulin; SPE = serum protein electrophoresis

     

  2. All of this patient's abnormal test results are explained, either directly or indirectly, by the large amounts of paraprotein that are present in the serum of patients with multiple myeloma -- a condition known to cause falsely decreased serum sodium values (ie, pseudohyponatremia) when sodium concentration is measured using an indirect ion-selective electrode (ISE) method.

  3. Most likely diagnosis : pseudohyponatremia in a patient with multiple myeloma due to measurement of serum sodium concentration using an indirect ISE method.

  4. Whenever a markedly low serum sodium concentration is observed on any patient, the first question to ask is: Is this a true hyponatremia? Sodium is the major cation in the extracellular fluid (ECF) and its concentration in plasma is maintained in healthy individuals within the narrow range of 135 to 145 mmol/L. The plasma sodium concentration reflects the balance between sodium intake and output. Hyponatremia is defined as a serum sodium concentration less than 135 mmol/L. The most common causes of true hyponatremia are: 1) depletional due to reduced sodium intake from food; 2) increased sodium loss in urine, feces, or sweat, such as in patients using diuretic agents or with diarrhea or extensive burns; and 3) dilutional, such as in patients with chronic renal insufficiency, nephrotic syndrome, or the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) in which an increased ECF volume with a diluted serum sodium concentration. All of these conditions cause true hyponatremia and require immediate medical attention. Pseudohyponatremia is an artifactual hyponatremia most commonly caused by severe hypertriglyceridemia (usually, >1,500 mg/dL) or, less often, by severe hyperproteinemia (usually, >10 g/dL). Pseudohyponatremia occurs as a consequence of how serum sodium is measured. The most commonly used method for quantifying serum sodium concentration is ion-selective electrode (ISE) potentiometry. Only a small percentage of clinical laboratories use flame emission spectroscopy; however, this method is considered the reference method for sodium measurement.[2] Spectrophotometric methods for sodium measurement based upon the interaction of sodium with chromogenic macrocyclic ionophores that are capable of selectively complexing sodium have also been described.

  5. Indirect and direct ISE potentiometry. Direct ISE methods measure the ion activity in an undiluted sample, whereas indirect ISE methods measure the ion activity in a pre-diluted sample. Sodium is dissolved only in the water portion of serum. In the context of marked hyperparaproteinemia (as occurs in patients with multiple myeloma) and/or hyperlipidemia, protein and/or lipid occupy more space in a given volume of serum, resulting in a decrease in the percentage of water (with its sodium content). Consequently, an artifactually low serum sodium concentration is obtained due to the fact that less sodium is present in a given volume of serum, even though the concentration of sodium present in the water phase may be unaltered. This phenomenon usually occurs with an indirect ISE method in which a pre-diluted sample is used for testing. For example, in a specimen containing 1 gram of sodium dissolved in 0.8 liters of water and 0.2 liters of an insoluble substance, the sodium concentration should be 1 g/0.8 L (or 1.25 g/L). However, if this specimen is diluted 100-fold with water (eg, by adding 99 liters of water to the 1 liter of specimen), then the total volume of 100 liters of solution consists of 99.8 liters of water and 0.2 liters of insoluble substance. Because the volume (0.2 L) of the insoluble substance is small compared to the 99.8 L of water, the volume contributed by this substance to the total volume (ie, approximately 100 L) is negligible. The sodium concentration measured in this specimen is 1 g/100 L or 0.01 g/L. When this value is multiplied by the dilution factor (ie, 100), the final sodium concentration is 1.00 g/L. Thus, an error has occurred because the true sodium concentration should be 1.25 g/L. The falsely low result of 1.00 g/L is caused by ignoring the volume contributed by the insoluble substance after dilution of the specimen.

  6. To confirm pseudohyponatremia, serum osmolality should be measured. Actually, for any hyponatremic patient, the initial approach is to measure the serum osmolality to determine whether the hyponatremia represents a true hypo-osmolar state.[3] Osmolality is a colligative property of solutions that depends only on the number of solute particles present in a given volume of solution. The 3 types of solutes most often encountered in biological fluids are: electrolytes, organic molecules, and colloids. Sodium and its counter ions [eg, chloride (Cl-)] are the major contributors to serum osmolality. The other 2 principal, active osmolar solutes in serum are urea and glucose. The reference interval for serum osmolality in healthy individuals is typically 282-300 mOsm/kg of water (H2O). No sex- or age-related differences in serum osmolality values have been reported.[2] To estimate serum (or plasma) osmolality, several formulas have been proposed.[4,5] The most commonly used formula for estimating serum osmolality is: osmolality (mOsm/kg) = 2[Na, mmol/L] + ([Glucose, mg/dL]/18) + ([BUN, mg/dL]/2.8).[1] Under normal physiologic conditions, the calculated osmolality is similar to the measured osmolality so that the difference between them (ie, the osmolar gap) in healthy individuals is approximately 12 (range: 7-19 mOsm/kg H2O).[6] Thus, in a patient with hyponatremia, an increased osmolar gap suggests the presence of either pseudohyponatremia due to hyperparaproteinemia or hypertriglyceridemia, or an increased concentration of a solute (eg, ethanol, etc) whose concentration is not included in the formula stated above for calculating serum osmolality. During his hospital stay, our patient's osmolar gap ranged from 16 mOsm/kg H2O to 47 mOsm/kg H2O (Figure 1A). High osmolar gap values in this range may be seen in patients with pseudohyponatremia. To further support this conclusion, our patient's serum sodium concentration was measured by a direct ISE method (i-STAT instrument, i-STAT Corporation, East Windsor, NJ). Using the i-STAT instrument, the serum sodium values obtained on our patient were higher than those obtained by an indirect ISE method, resulting in higher values for calculated osmolality and much smaller values for the osmolar gap (Figure 1B). These findings support further the conclusion that the low sodium concentration measured initially in our patient's serum was due to pseudohyponatremia and his myeloma-related hyperproteinemia and his hypertriglyceridemia.

  7. The anion gap is a calculated measurement representing the balance between the concentration of serum anions and cations. If the sum of the principal anions in serum, Cl- and HCO3- , is subtracted from the Na+ value (ie, Na+ - [Cl- + HCO3-]), this difference (or "gap") in serum from healthy individuals is usually approximately 12 (range: 7-16). This "gap" is due to the concentration of unmeasured anions (eg, lactate, proteins, SO4,2- HPO42-) in serum.[1] An increased anion gap is often seen in metabolic acidosis and occurs due to a decrease in the HCO3- concentration along with a concomitant increase in unmeasured anions such as lactate, and beta-hydroxybuterate. In contrast, a reduced anion gap is observed typically as a consequence of hypergammaglobulinemia (positively charged proteins), hypercalcemia, or hypermagnesemia. Moreover, a consistently low (eg, 1-3) anion gap, signifies the presence of high levels of a basic (or positively-charged) protein (eg, a paraprotein).[7]

  8. Because this patient is known to have hyperproteinemia due to multiple myeloma, his serum sodium concentration should be assessed using a direct ISE method.

  9. Hyponatremia is a relatively common electrolyte disturbance. Its high prevalence and potential neurologic sequelae make a logical and rigorous differential diagnosis mandatory before any therapeutic intervention.[3] Recognition of pseudohyponatremia as an explanation for a low serum sodium concentration is important because of the nature of the follow-up treatment in patients with pseudohyponatremia versus "true" hyopnatremia. Pseudohyponatremia does not require treatment; however, if misdiagnosed as "true" hyponatremia and unnecessarily treated with fluid restriction -- the typical treatment to correct true hyponatremia -- dehydration and impairment of the blood flow in the microcirculation can occur.

References

  1. Burtis CA, Ashwood ER. Tietz Fundamentals of Clinical Chemistry, Fifth edition. Philadelphia: W.B.Saunders Company; 2001, 740.

  2. Kaplan LA, Pesce AJ. Clinical Chemistry: Theory, Analysis, Correlation, Third edition. St. Louis: Mosby; 1996, 461-446.

  3. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: A systematic approach to laboratory diagnosis. CMAJ. 2002;166:1056-1062.

  4. Weisberg HF. Osmolality-calculated "delta" and more formulas. Clin Chem. 1975;21:1182-1184.

  5. Holmes JH. Measurement of osmolality in serum, urine, and other biololgic fluids by the freezing point determination. In: Preworkshop manual on urinalysis of renal function studies, Chicago: ASCP, Commission on Continuing Education, 1962.

  6. Garcia-Morales EJ. Osmole gap in neurologic-neurosurgical intensive care unit: its normal value, calculation, and relationship with mannitol serum concentrations. Crit Care Med. 2004;32:986-991.

  7. Pincus MR. Interpreting laboratory results: reference values and decision making. In: Henry JB, Clinical Diagnosis and Management by Laboratory Methods. Philadelphia: WB Saunders Company. 19th edition; 1996, 85.