Pseudohyponatremia Nejm Cps

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n engl j med 349;15 www.nejm.org october 9, 2003

The new england journal of

medicine

1465

clinical problem-solving

In this Journal

feature, information about a real patient is presented in stages (boldface type)to an expert clinician, who responds to the information, sharing his or her reasoning with

the reader (regular type). The authors’ commentary follows.

Mind the Gap

Alexander Turchin, M.D., Julian L. Seifter, M.D., and Ellen W. Seely, M.D.

From the Division of Endocrinology, Dia-betes and Hypertension (A.T., E.W.S.), andthe Division of Nephrology (J.L.S.), Depart-ment of Medicine, Brigham and Women’sHospital, Boston. Address reprint requeststo Dr. Turchin at the Division of Endocrinol-ogy, Diabetes and Hypertension, Brighamand Women’s Hospital, 221 Longwood

Ave., Boston, MA 02115, or at [email protected].

N Engl J Med 2003;349:1465-9.

Copyright © 2003 Massachusetts Medical Society.

A 62-year-old woman was admitted to the hospital because of abnormal liver-function

tests. She had a history of acute myelogenous leukemia and had undergone transplan-

tation of T-cell–depleted allogeneic bone marrow two years earlier. The patient had

had mildly increased aminotransferase levels since the transplantation. Four months

before admission, the levels of alkaline phosphatase and bilirubin became elevated,

presumably because of chronic graft-versus-host disease. Findings on computed to-

mography (CT) and ultrasonography of the abdomen were negative for disease in thehepatic parenchyma or biliary tree.

On the day of admission, during a routine appointment, the patient’s total bilirubin

level was found to have increased from 4.9 mg per deciliter (83.8 µmol per liter) the

previous day to 9.0 mg per deciliter (153.9 µmol per liter). The serum sodium level was

124 mmol per liter.

This patient presents with immediate problems of abnormal liver function and hypo-

natremia. I would initially approach the problem of hyponatremia and then attempt to

find connections to her relevant medical history.

Hyponatremia may occur with a high, low, or normal serum osmolality. High osmo-

lality indicates the presence of excessive extracellular osmoles leading to the entry of

intracellular water into the extracellular fluid and the dilution of the sodium in the ex-

tracellular fluid. High glucose levels are a typical cause of this condition, and the patient may be at particular risk for hyperglycemia if she is taking glucocorticoids. Unlike

glucose, solutes that enter cells, such as urea or ethanol, do not cause intracellular-to-

extracellular water shift and thus do not cause hyponatremia.

Hyponatremia with low serum osmolality may be observed in patients with hypo-

volemia, states involving low cardiac output, liver disease, the nephrotic syndrome,

or the syndrome of inappropriate secretion of antidiuretic hormone. Hypoadrenalism

or thyroid deficiency must also be considered. Psychogenic polydipsia can also result

in hypo-osmolal hyponatremia and can be distinguished from the above causes by low

urine osmolality and often on the basis of the history.

When the serum osmolality is normal, the first consideration should be pseudohy-

ponatremia, an artifact of measurement that is most commonly caused by severe degrees

of hypertriglyceridemia or chylomicronemia or by severe paraproteinemia. Hyponatre-

mia with normal osmolality can also occur when more than one disorder is present.For example, hypothyroid-induced hypo-osmolality could be offset by hyperglycemia.

To begin with, I would like to know whether the review of the patient’s systems and

the physical examination suggest extracellular volume depletion or fluid overload

and whether she has any stigmata of chronic liver disease. Levels of blood glucose, urea,

and osmolality, as well as urine osmolality and urine sodium, should be measured.

Copyright © 2003 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org at ALLAN BLAIR CANCER CTR on May 30, 2006 .



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The patient reported a number of symptoms con-

sistent with the presence of hypothyroidism, includ-

ing decreased energy, weight gain, constipation,

dry skin, and new-onset hoarseness. Her medica-

tions included tacrolimus, prednisone (40 mg per

day), mycophenolate mofetil, ursodiol, atovaquone,

acyclovir, and clarithromycin. She was afebrile. Her blood pressure was 130/75 mm Hg, and her heart

rate 80 beats per minute. The patient appeared to

be clinically euvolemic. She spoke slowly, with a

coarse voice. The thyroid was not palpable. The

skin was dry and cool, and the nails were brittle.

The reflexes had a slowed relaxation phase. The

patient had scleral icterus and moon facies. There

was no ascites.

The serum osmolality was 294 mOsm per kilo-

gram, the urine osmolality 434 mOsm per kilo-

gram, and the urinary sodium level 62 mmol per li-

ter. The thyrotropin level was 72 µU per milliliter,

the serum total thyroxine level 0.6 µg per deciliter (7.7 nmol per liter), the blood urea nitrogen level

43 mg per deciliter (15.4 mmol per liter), the serum

creatinine level 1.4 mg per deciliter (123.8 µmol per

liter), and the serum glucose level 85 mg per deci-

liter (4.7 mmol per liter). Levothyroxine treatment

was begun.

It is notable that although the patient’s serum osmo-

lality as measured by the freezing-point depression

was 294 mOsm per kilogram, her calculated osmo-

lality (determined as [2¬the urine sodium level] +

[the blood urea nitrogen level÷2.8] +[the serum

glucose level÷18]) was 268 mOsm per kilogram. Inthe absence of hyperglycemia or azotemia that could

account for the osmolal gap (the difference between

the measured osmolality and the calculated osmo-

lality) of 26 mOsm per kilogram, we must consid-

er another explanation for the patient’s apparent

pseudohyponatremia. I would like to know whether

the blood sample was lipemic; a further laboratory

workup should include the measurement of total

serum protein and a lipid profile in order to rule

out hyperproteinemia and hypertriglyceridemia.

Although hypothyroidism can cause hyponatre-

mia, in this case it is at most a minor contributor,

since the patient does not have low serum osmolal-

ity. I would not expect levothyroxine replacement

to improve her serum sodium levels.

The serum sodium level remained low. The to-

tal serum protein level was 5.1 g per deciliter. No

lipemia was observed. A lipid profile obtained two

years earlier showed a total cholesterol level of

181 mg per deciliter (4.68 mmol per liter) and a tri-

glyceride level of 136 mg per deciliter (1.54 mmol

per liter).

Since the serum is not lipemic, extreme hypertrigly-ceridemia is unlikely. Severe hypercholesterolemia

could cause pseudohyponatremia without lipemic

serum; cholesterol, like triglycerides, is insoluble

and would artifactually lower sodium levels by in-

creasing the solid fraction of plasma. I would like

to know the patient’s current cholesterol and triglyc-

eride levels.

The lipid profile revealed a total cholesterol level

of 1836 mg per deciliter (47.48 mmol per liter), a

high-density lipoprotein (HDL) cholesterol level

of 68 mg per deciliter (1.76 mmol per liter), a very-

low-density lipoprotein (VLDL) cholesterol levelof 42 mg per deciliter (1.09 mmol per liter), a tri-

glyceride level of 208 mg per deciliter (2.35 mmol

per liter), and a calculated low-density lipoprotein

(LDL) cholesterol level of 1726 mg per deciliter

(44.63 mmol per liter). The serum sodium level, as

measured on a blood-gas machine with the use of

direct-ion potentiometry, was 145 mmol per liter.

These findings are diagnostic of pseudohyponatre-

mia caused by severe hypercholesterolemia. Where-

as the instruments for routine chemical analysis

typically use indirect potentiometry (involving the

dilution of samples) to measure sodium levels, inthis case, the equipment for measuring arterial

blood gases, which relies on direct potentiometry,

was used. This latter method confirmed that there

was a normal serum sodium concentration.

It is important to emphasize that the treatment

of hypo-osmolal hyponatremia is very different from

the treatment of pseudohyponatremia, and going

down the wrong management path may harm the

patient. Fluid restriction, which is typically used to

correct hypo-osmolal hyponatremia, could, in a pa-

tient like this one, increase the already elevated se-

rum osmolality. This effect could, in turn, worsen a

state of hyperviscosity, if one were present, or im-

pair the blood flow in the microcirculation and ag-

gravate any underlying hypercoagulability.

To treat this patient successfully, it is important

to determine the source of the unusually high cho-

lesterol levels. Hypothyroidism or tacrolimus can




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raise the cholesterol level, but not to this degree. Al-

though the laboratory reported that most of the

cholesterol was in the form of LDL cholesterol,

the LDL cholesterol levels were not measured di-

rectly, but were calculated. The formula for the cal-

culation of the LDL cholesterol level (total cholester-

ol level¡HDL cholesterol level¡VLDL cholesterollevel [the VLDL cholesterol level is usually calculat-

ed by dividing the fasting triglyceride level by 5])

assumes that the cholesterol consists solely of HDL,

LDL, and VLDL fractions. In a patient with liver dis-

ease, however, another form of cholesterol could be

present: lipoprotein X, which has been described

in patients with severe cholestasis, such as those

with primary biliary cirrhosis or, as in this case, with

chronic graft-versus-host disease. Lipoprotein X is

formed when there is reflux of unesterified choles-

terol and phospholipids into the circulation from

the cholestatic biliary ducts; the particles of this

form of cholesterol are not soluble in plasma waterand thus increase the solid fraction of plasma.

A lipoprotein analysis should be performed. Be-

cause high levels of lipoprotein X could result in a

hyperviscosity syndrome, the patient should be ex-

amined carefully for signs of hyperviscosity, such as

dilated, segmented, and tortuous retinal veins, re-

sulting in a “sausage-link” appearance. The serum

viscosity should be measured, and if it is found to

be high (>3 centipoise), prophylactic lipid aphere-

sis should be considered.

During the rest of her hospitalization, the patient’s

serum sodium levels remained stable, around125 mmol per liter when measured by indirect po-

tentiometry but 135 to 136 mmol per liter when

measured directly. A liver biopsy was performed

and revealed bile-duct degeneration and loss con-

sistent with graft-versus-host disease. Lipoprotein

electrophoresis demonstrated that cholesterol was

predominantly carried by lipoprotein X, a finding

that was attributed to the cholestasis associated

with graft-versus-host disease. The patient had no

symptoms suggestive of hyperviscosity, including

visual changes, vertigo, ataxia, and changes in men-

tal status. A funduscopic examination was unre-

markable. The serum viscosity was 1.9 centipoise

(normal range, 1.4 to 1.8). Lipid apheresis was con-

sidered but, given the absence of symptoms and the

mild elevation of the serum viscosity, was deferred

until a trial of medical therapy had been completed.

Colestipol therapy was initiated, and the patient was

discharged from the hospital.

I agree with the decision to initiate colestipol ther-

apy (particularly given that liver dysfunction is a con-

traindication to the use of most other lipid-lower-

ing agents); in the absence of higher serum viscosity,

the decision to withhold apheresis was reasonable.

Since cholestasis induced by graft-versus-host dis-

ease is the primary cause of the patient’s extremehypercholesterolemia, successful management of

graft-versus-host disease will be crucial in correct-

ing the dyslipidemia.

Ten days later, the patient was readmitted to the

hospital because of new-onset shortness of breath

and dyspnea on exertion. CT of the chest showed

numerous lung nodules, and a sputum culture

grew Aspergillus niger, Nocardia asteroides,

and mu-

cor. The serum sodium level was 126 mmol per liter

as measured by indirect potentiometry on admis-

sion. Therapy with voriconazole, imipenem–cila-

statin, amikacin, and liposomal amphotericin B wasbegun; treatment with mycophenolate mofetil,

colestipol, tacrolimus, atovaquone, ursodiol, pred-

nisone (40 mg daily), and levothyroxine was con-

tinued. A week later, the patient’s clinical condition

deteriorated; she became progressively more dys-

pneic, and her oxygen saturation decreased from

98 percent while she was breathing room air on

admission to 92 percent while she was receiving

6 liters of oxygen per minute by nasal cannula; at

the same time, her serum sodium level decreased

to 115 mmol per liter. On repeated measurement,

the total cholesterol level was 1114 mg per decili-

ter (28.8 mmol per liter). The thyroxine level was2.2 µg per deciliter (28.3 nmol per liter).

Although the measurement of the sodium concen-

tration by indirect potentiometry is not valid, the

worsening of the hyponatremia despite improve-

ment in the serum cholesterol level is a cause of con-

cern. The measurement of serum osmolality or a

direct measure of serum sodium would establish

whether there is now hypo-osmolal hyponatremia

present that is complicating the underlying pseu-

dohyponatremia. Hypo-osmolality could be relat-

ed to increased water retention associated with hy-

poxia, with the pulmonary process itself causing

the syndrome of inappropriate secretion of antidiu-

retic hormone, or to diminished cardiac or renal

function. It is unlikely that there is adrenal insuffi-

ciency, since the patient is taking glucocorticoids. I

would measure the serum and urine osmolality

and the serum creatinine level. The sodium con-




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centration should be remeasured by direct poten-

tiometry.

Given the acute worsening of hyponatremia while

the cholesterol levels were improving, a second

workup was performed. As measured by direct po-

tentiometry, the serum sodium level was 128 mmolper liter. The serum osmolality was 269 mOsm per

kilogram, the serum glucose level was 104 mg per

deciliter (5.8 mmol per liter), the blood urea nitro-

gen level was 29 mg per deciliter (10.4 mmol per li-

ter), the serum creatinine level was 1.5 mg per deci-

liter (132.6 µmol per liter), the urine osmolality was

335 mOsm per kilogram, and the urinary sodium

level was 44 mmol per liter. Oxygenation progres-

sively decreased.

Although there is still an osmolal gap (now de-

creased to 23 mOsm per kilogram), there is now also

true hypo-osmolality. Combined with the inappro-priately high osmolality of the urine, this points to

high levels of vasopressin. The absence of clinical

signs of dehydration and the presence of a relative-

ly high urinary sodium level (particularly if there is

no oliguria) and inappropriately high urinary osmo-

lality make intravascular depletion, congestive heart

failure, or end-stage liver failure unlikely. These find-

ings are, however, consistent with the syndrome of

inappropriate secretion of antidiuretic hormone.

The pulmonary disease is the most likely cause, al-

though stress, nausea, or pain (if these are present)

could also play a part.

The syndrome of inappropriate secretion of anti-

diuretic hormone, presumably caused by the lung

infections, was diagnosed, and fluid intake was

restricted to 1500 ml daily. The serum sodium level

(as determined by direct potentiometry) and the

serum osmolality normalized within several days.

Hyponatremia remains a common problem in hos-

pitalized patients, with a prevalence of up to 12 per-

cent.

1

As the discussant notes, appropriate manage-

ment depends on distinguishing between two maincategories of processes leading to a low laboratory

sodium value: hypo-osmolar (or “true”) hyponatre-

mia versus iso-osmolar or hyperosmolar hyponatre-

mia, or pseudohyponatremia.

Hypo-osmolar hyponatremia is a serious de-

rangement of homeostasis and can lead to life-

threatening complications, such as seizures or alter-

ations in mental status; it requires careful correction.

In contrast, pseudohyponatremia is not, in itself,

dangerous, and the primary treatment is for the un-

derlying cause (in this case, hypercholesterolemia).

There may be more than one cause, as in the case

described above.Pseudohyponatremia secondary to hyperlipide-

mia was originally described in the 1950s,

2

when

electrolytes were measured by flame photometry.

With this technique, the serum sample is diluted be-

fore the actual measurement is obtained. Therefore,

if more than the normal fraction of serum (7 percent

by volume) consists of proteins or lipids, the degree

of dilution is underestimated, resulting in artificial-

ly low sodium levels (Fig. 1).

In the 1980s, flame photometry began to be used

less frequently, as direct potentiometry became more

common.

3

In direct potentiometry, undiluted serum

samples are used to measure the transmembrane

potentials resulting from electrolyte gradients, and

the measurement is therefore not dependent on the

water content of the sample. Consequently, a num-

ber of major medical textbooks state that pseudo-

hyponatremia is rarely encountered with the use of

modern instruments.

4-6

However, more than two

com m en t ary

Figure 1. Artificially Low Ion Levels as Determined by Dilution-Based Methods.

Normally, serum contains 7 percent solids by volume. In order to reduce the

volume of blood needed for analysis, serum is frequently diluted before the

actual measurement is obtained. The same volume of diluent is always used;the degree of dilution is estimated under the assumption that the serum con-

tains 7 percent solid-phase particles. When the fraction of solid-phase particles

is increased, the same amount of diluent results in a greater dilution, unbe-

knownst to the laboratory personnel (right side of figure). Consequently, the

calculation of an ion level with the use of a degree of dilution that is based on

the incorrect fraction of solid-phase particles will lead to an underestimate.

Standard volumeof diluent added

Increased Fractionof Solid-Phase Particles

Normal Fractionof Solid-Phase Particles

Solid phase

Water phase




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thirds of the instruments that are currently in use in

laboratories in the United States use a technique of

indirect ion potentiometry for the measurement of

electrolytes.

7

In fact, since a large number of direct-

potentiometry instruments are used only for the

analysis of blood gases, the proportion of routine

measurements of sodium performed with indirect-potentiometry instruments is likely to be even high-

er. Like flame photometry, this method involves the

dilution of the sample before the actual measure-

ment is obtained, which minimizes the amount of

blood that is needed but renders the method sus-

ceptible to the same error of underestimating the

degree of dilution.

There is also a misconception that only hypertri-

glyceridemia, and not hypercholesterolemia, causes

pseudohyponatremia.

6

Unlike high triglyceride lev-

els, high cholesterol levels do not cause the blood

to be visibly lipemic,

8

which would alert laboratory

personnel and permit the removal of excess lipids.Severe hypercholesterolemia is an important but un-

common cause of pseudohyponatremia, and there

are only a few case reports in the literature,

9-11

all of

them involving pseudohyponatremia secondary to

high levels of lipoprotein X. It has been hypothe-

sized that the reflux of bile lipoproteins into the

bloodstream is a mechanism for the formation of

lipoprotein X, and the incubation of bile lipopro-

teins with serum or albumin in vitro leads to the ap-

pearance of lipoprotein-X–like particles.

12

Levels

of lipoprotein X can be as high as several thousand

milligrams per deciliter of cholesterol. Aside from

interfering with laboratory tests and, in extreme

cases, causing the hyperviscosity syndrome,

13

highlevels of lipoprotein X are not known to lead to any

pathologic consequences.

A systematic approach to hyponatremia that is

based on the serum osmolality, such as that followed

by the discussant, can enable the clinician to avoid

errors in diagnosis and potentially harmful treat-

ment. Deaths have followed the misdiagnosis of

pseudohyponatremia as true hyponatremia with ag-

gressive attempts to increase the sodium level with

the use of fluid restriction and hypertonic saline re-

sulting in severe dehydration and hypernatremia.

14

A careful diagnostic evaluation with attention to ba-

sic physiologic principles and to findings that areinconsistent with the presumed cause is crucial for

the effective management of this common problem.

We are indebted to Mary Paton of the College of American Pa-

thologists for her help in obtaining data on the laboratory instru-

ments used to measure sodium, to Dr. Donald Wiebe for his assist-

ance in measuring lipoprotein X, and to Drs. Frederick Grant,

Robert J. Soiffer, and Elizabeth Rhee for their help in taking care of

the patient.

references

1.

Croal BL, Blake AM, Johnston J, Glen

AC, O’Reilly DS. Absence of relation between

hyponatraemia and hypothyroidism. Lancet

1997;350:1402.

2.

Albrink MJ, Hald PM, Man EB, Peters JP. The displacement of serum water by the

lipids of hyperlipemic serum: a new method

for the rapid determination of serum water.

J Clin Invest 1955;34:1483-8.

3.

Weisberg LS. Pseudohyponatremia: a re-

appraisal. Am J Med 1989;86:315-8.

4.

Robinson AG, Verbalis JG. Posterior pi-

tuitary gland. In: Larsen PR, Kronenberg

HM, Melmed S, Polonsky KS, eds. Williams

textbook of endocrinology. 10th ed. Philadel-

phia: W.B. Saunders, 2003:281-329.

5.

Lewis JL III. Water, electrolyte, mineral,

and acid-base metabolism. In: Beers MH,

Berkow R, eds. The Merck manual of diag-

nosis and therapy. Whitehouse Station, N.J.:

Merck Research Laboratories, 1999:120-

64.

6.

Fukagawa M, Kurokawa K, Papadakis

MA. Fluid & electrolyte disorders. In: Tierney

LM Jr, McPhee SJ, Papadakis MA, eds. Cur-rent medical diagnosis & treatment 2003.

42nd ed. New York: McGraw-Hill, 2003:839-

66.

7.

Participant summary report: surveys

1982-2002. Northfield, Ill.: College of Amer-

ican Pathologists, 1982-2002.

8.

Van Eck WF, Peters JP, Man EB. Signifi-

cance of lactescence in blood serum. Metab-

olism 1952;1:383-95.

9.

Coakley JC, Vervaart PP, McKay MRG.

Factitious hyponatremia in a patient with

cholestatic jaundice following bone marrow

transplantation. Pathology 1986;18:158-9.

10.

Ko GTC, Yeung VTF, Chow CC, Mak TW,

Cockram CS. Pseudohyponatraemia second-

ary to hypercholesterolaemia. Ann Clin Bio-

chem 1997;34:324-5.

11.

Hickman PE, Dwyer KP, Masarei JRL.

Pseudohyponatremia, hypercholesterole-

mia, and primary biliary cirrhosis. J ClinPathol 1989;42:167-71.

12.

Manzato E, Fellin R, Baggio G, Walch S,

Neubeck W, Seidel D. Formation of lipopro-

tein-X: its relationship to bile compounds.

J Clin Invest 1976;57:1248-60.

13.

Rosenson RS, Baker AL, Chow MJ, Hay

RV. Hyperviscosity syndrome in a hypercho-

lesterolemic patient with primary biliary cir-

rhosis. Gastroenterology 1990;98:1351-7.

14.

Frier BM, Steer CR, Baird JD, Bloom-

field S. Misleading plasma electrolytes in di-

abetic children with severe hyperlipidaemia.

Arch Dis Child 1980;55:771-5.

Copyright © 2003 Massachusetts Medical Society.




New England Journal of Medicine

CORRECTION

Mind the Gap

Mind the Gap . On page 1466, in the formula that begins on line 4of the third paragraph in the left-hand column, the first amount should

have read ``2× the serum sodium level,´´ rather than ``2× the urine

sodium level,´´ as printed.

N Engl J Med 2003;349:1880-a




New England Journal of Medicine

CORRECTION

Mind the Gap

Mind the Gap . On page 1466, lines 6 through 8 of the third paragraphin the left-hand column, the sentence beginning, ``In the absence of

hyperglycemia or azotemia that could account for the osmolal gap´´

warrants correction. Neither hyperglycemia nor azotemia could con-

tribute to the osmolal gap. On page 1469, lines 3 through 6 of the

partial paragraph in the right-hand column should have read, ``Levels

of lipoprotein X can be as high as several thousand milligrams per

deciliter of serum,´´ rather than ``Levels of lipoprotein X can be as

high as several thousand milligrams per deciliter of cholesterol,´´ as

printed.

N Engl J Med 2004;350:629


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