Accepted Manuscript Extreme Hypercholesterolemia Presenting with Pseudohyponatremia – A Case Report and Review of the Literature Iram Hussain , MD, Zahid Ahmad , MD, Abhimanyu Garg , MD PII:
S1933-2874(14)00406-1
DOI:
10.1016/j.jacl.2014.11.007
Reference:
JACL 706
To appear in:
Journal of Clinical Lipidology
Received Date: 25 August 2014 Revised Date:
10 November 2014
Accepted Date: 22 November 2014
Please cite this article as: Hussain I, Ahmad Z, Garg A, Extreme Hypercholesterolemia Presenting with Pseudohyponatremia – A Case Report and Review of the Literature, Journal of Clinical Lipidology (2014), doi: 10.1016/j.jacl.2014.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Review of the Literature.
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Extreme Hypercholesterolemia Presenting with Pseudohyponatremia – A Case Report and
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Iram Hussaina, MD, Zahid Ahmada, MD and Abhimanyu Garga, MD
a
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Division of Nutrition and Metabolic Disease, Department of Internal Medicine, University of
Texas Southwestern Medical Center (5323 Harry Hines Boulevard, Dallas, TX 75390, U.S.A).
Corresponding Author: Abhimanyu Garg, MD.
[email protected]
Postal Address:
5323 Harry Hines Boulevard, Dallas, TX 75390, U.S.A
Phone Number:
+12146482895
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Email:
ACCEPTED MANUSCRIPT 2 Abstract Pseudohyponatremia has been reported in association with severe hypertriglyceridemia and hyperparaproteinemia, but its association with severe hypercholesterolemia is not well known.
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We report a 43-year-old woman with refractory primary biliary cirrhosis who presented with asymptomatic hyponatremia (121 mmol/L; normal range: 135 – 145 mmol/L). She was ultimately found to have a total serum cholesterol level of 2415 mg/dL (normal range: 120 – 199 mg/dL) –
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secondary to accumulation of lipoprotein-X – causing pseudohyponatremia. The diagnosis was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270 – 300
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mOsm/kg H2O) and serum sodium by direct potentiometry (141 mmol/L). Furthermore, following 16 sessions of plasmapheresis over a period of 4 months, there was marked lowering of serum cholesterol to 200 mg/dL and normalization of serum sodium (139 mmol/L) as measured by indirect potentiometry. This case shows that extreme hypercholesterolemia from elevations of lipoprotein-X particles in cholestasis can be a rare cause of pseudohyponatremia. It highlights the
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need to measure serum sodium with direct potentiometry in the setting of extreme
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hypercholesterolemia and consider this possibility prior to initiating treatment of hyponatremia.
Key Words
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Pseudohyponatremia; Lipoprotein-X (LpX); Hypercholesterolemia; Primary Biliary Cirrhosis (PBC); Cholestasis; Hyponatremia, Pseudohypokalemia.
ACCEPTED MANUSCRIPT 3 Introduction Pseudohyponatremia is defined as a spuriously low serum sodium concentration in the setting of normal serum osmolality [1-3]. It is important to distinguish pseudohyponatremia from
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true hyponatremia lest injudicious treatment results in increased morbidity and mortality [4]. Pseudohyponatremia is usually seen in cases with extreme hypertriglyceridemia and
hyperparaproteinemia [1-3, 5-7] when serum sodium is measured using routine laboratory testing
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methods i.e. indirect potentiometry/flame photometry [1, 2, 4, 7, 8]. Pseudohyponatremia in association with severe hypercholesterolemia is extremely rare and is not well-recognized. We
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present an unusual case of a woman with primary biliary cirrhosis who presented with pseudohyponatremia secondary to extreme hypercholesterolemia caused by elevation of lipoprotein-X. This report emphasizes having a high index of suspicion for extreme hypercholesterolemia resulting in pseudohyponatremia.
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Case Report
A 43-year-old African American woman was admitted for evaluation and treatment after routine laboratory testing revealed low serum sodium (121 mmol/L; normal range: 135 – 145
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mmol/L). She complained of increasing fatigue, jaundice and itching for several weeks prior to admission. Review of past laboratory testing showed normal serum sodium levels for the last 3
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years; with slight reductions noted 3 months (133 mmol/L) and 1 month (131 mmol/L) prior to presentation. She had not been drinking excessive amounts of water, urine output was normal and she had no mental status changes. She was taking amlodipine, azathioprine, cholestyramine, fenofibrate, hydroxyzine, losartan, ondansetron, prednisone, prochlorperazine, promethazine, ranitidine, sertraline, trazodone and high doses of ursodiol (24 mg/kg/day). She reported no dose adjustments or changes in medications in the past six months that could explain her new onset hyponatremia.
ACCEPTED MANUSCRIPT 4 She was diagnosed with right-sided invasive ductal breast carcinoma associated with breast cancer 1, early onset (BRCA1) gene mutation one year prior to her current presentation, and was status post partial mastectomy and chemoradiotherapy, with no active disease. During
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evaluation of her breast cancer she was noted to have elevated serum alkaline phosphatase level (503 Units/L; normal range: 35 – 104 Units/L) and was subsequently diagnosed with primary biliary cirrhosis – confirmed by liver biopsy and elevated anti-mitochondrial antibodies (titer ≥
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1:320; normal range: negative) – eight months prior to presentation. Her primary biliary cirrhosis has been refractory to medical therapy.
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On physical examination her vital signs were unremarkable, and her skin turgor appeared normal. She had scleral icterus but had no hepatosplenomegaly, xanthelasmata or xanthomata. Her laboratory results (Table 1) revealed hyponatremia, elevated bilirubin levels (10.2 mg/dL; normal range: 0.2 – 1.3 mg/dL) indicating worsening biliary disease, and very high cholesterol levels (total cholesterol 2415 mg/dL; normal range: 120 – 199 mg/dL). She also had hypokalemia
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(3.0 mmol/L; range 3.6 – 5.0 mmol/L) and hypochloremia (87 mmol/L; range 98 – 109 mmol/L). She was initially thought to have hypovolemic hyponatremia and was given intravenous
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normal saline, however a repeat sodium level was unchanged (121 mmol/L) after five hours. Review of her medical records revealed a much lower total serum cholesterol level of 322
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mg/dL two years ago. The marked increase in serum cholesterol suggested rapid progression of primary biliary cirrhosis resulting in accumulation of lipoprotein-X, and development of pseudohyponatremia secondary to lipoproteinemia. The diagnosis of pseudohyponatremia was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270 – 300 mOsm/kg H2O) and measurement of serum sodium by direct potentiometry (141 mmol/L; normal range: 135 – 145 mmol/L). Lipoprotein electrophoresis confirmed major presence of lipoprotein-X (Figure 1 and Table 2). Serum apolipoprotein B level was 218 mg/dL (normal range: 48 – 124 mg/dL).
ACCEPTED MANUSCRIPT 5 Her serum sodium by indirect potentiometry ranged from 120 – 125 mmol/L for the next two days and she was discharged without any additional lipid-lowering drugs. For intractable itching secondary to elevated bile acids (> 180 µmol/L; normal range: ≤ 10 µmol/L) despite
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maximal medical therapy, plasmapheresis was initiated two months after discharge as the patient was not a candidate for liver transplant. She underwent about 15 sessions of plasmapheresis over a four month period before her lipid panel was rechecked. It showed improvement with pre-
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procedure total serum cholesterol of 662 mg/dL that decreased further to 200 mg/dL after the 16th session of plasmapheresis. Her serum sodium level measured by indirect potentiometry
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normalized (139 mmol/L) with reduction in total serum cholesterol levels; as did serum potassium (3.6 mmol/L) and chloride (104 mmol/L) levels (Figure 1). Discussion
We report a case of extreme hypercholesterolemia – total cholesterol 2415 mg/dL – due
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to accumulation of lipoprotein X. The severe hypercholesterolemia resulted in spuriously low serum sodium levels when measured by indirect potentiometry. Normally, the plasma volume is composed of 93% plasma water and 7% proteins and fats [1, 2, 4, 6, 15]. Sodium is measured per liter of plasma, so a concentration of 142 mmol/L actually represents a concentration of 153
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mmol/L (142 ÷ 0.93 = 153) in the physiologically important plasma water [2, 7, 17]. In marked hyperlipidemia for example, in our case due to accumulation of lipoprotein-X, the plasma water
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fraction may fall below 80%. The physiologically important plasma water sodium concentration and plasma osmolality are unchanged, but the measured sodium concentration in the total plasma volume will be reduced since the specimen contains less plasma water [2]. A similar assumption regarding plasma volume composition is made when calculating serum osmolality, resulting in an osmolar gap – our patient’s measured serum osmolality was 296 mOsm/kg H2O, compared to her calculated value (using the equation: serum osmolality = 2*Sodium + Glucose/18 + Blood Urea Nitrogen/2.8) of 252.2 mOsm/kg H2O.
ACCEPTED MANUSCRIPT 6 Flame photometry (the oldest method of measuring serum sodium) and indirect potentiometry (used in most laboratories for routine serum sodium measurements) both involve sample dilution and give similar results [4, 5]. Diluting the plasma and then correcting for the
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dilution gives misleading results because it does not account for the already decreased amount of plasma water and sodium as a result of the excess lipids [4]. Direct potentiometry measures the concentration of sodium in the plasma water directly with no dilution, therefore giving accurate
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results [2, 4, 5, 7].
Since potassium and chloride are also measured by indirect potentiometry, they may also
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be falsely lowered secondary to extreme hypercholesterolemia. However, pseudohypokalemia has been reported in only two patients and pseudohypochloremia in just one patient with pseudohyponatremia due to extreme hypercholesterolemia [15, 16]. Apart from affecting electrolyte analysis, lipoprotein-X can also falsely increase the laboratory measurement of lipoprotein (a), direct and calculated LDL-cholesterol and falsely decrease HDL-cholesterol [3, 15]
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due to interference with the assay.
Lipoprotein-X, an abnormal lipoprotein containing mainly albumin in the core and apolipoprotein C on the surface [9], is reported in patients with cholestasis either from underlying
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liver pathology or graft-versus-host disease. It is also present in patients with familial lecithin cholesterol acyltransferase deficiency in the absence of cholestasis [3, 10, 11]. It is thought that
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bile lipoprotein is a precursor to lipoprotein-X and it accumulates in cholestatic conditions such as primary biliary cirrhosis by reflux of unesterified cholesterol and phospholipids into the circulation [3, 10, 12]. Although elevated levels of lipoprotein-X can form xanthomata, it does not contain apolipoprotein B and high levels are not considered to be atherogenic [13, 14]. There is a marked discrepancy between our patient’s apolipoprotein B level (corresponding to a total cholesterol level of about 400 mg/dL [15]) and her extremely elevated total cholesterol level, suggesting accumulation of a particle not containing apolipoprotein B – in
ACCEPTED MANUSCRIPT 7 this case – lipoprotein X. Primary biliary cirrhosis can cause abnormal composition of lipoproteins such as triglyceride-rich LDL particles and triglyceride-poor VLDL particles that have a higher proportion of apolipoprotein B and lecithin [16]. The elevated VLDL cholesterol level in our patient
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may partly explain the high apolipoprotein B levels. In addition, the apolipoprotein B levels are reported to be high in primary biliary cirrhosis [17] as other lipoprotein particles are also increased secondary to liver disease.
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Review of literature reveals ten reported cases of pseudohyponatremia associated with extreme elevation of total serum cholesterol (Table 2), with presence of lipoprotein-X confirmed in
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seven reports [3, 10-12, 18-22]. All the patients had cholestasis: four following bone marrow transplants with graft-versus-host disease, two drug-induced, two with primary biliary cirrhosis, one with hepatitis C and one with pancreatic cancer. The lowest reported total serum cholesterol resulting in pseudohyponatremia was 977 mg/dL (associated serum sodium: 129 mmol/L) [22] whereas as the highest was 4091 mg/dL (associated serum sodium: 101 mmol/L) [10]. Such high
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cholesterol levels are usually only seen when lipoprotein-X accumulates in cholestasis. Other diseases resulting in elevated total serum cholesterol such as homozygous familial hypercholesterolemia usually have total cholesterol levels lower than 1000 mg/dL [15], therefore
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have not been reported to be associated with pseudohyponatremia. Most interestingly, we documented correction of serum sodium measured by indirect
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potentiometry when the patient’s total serum cholesterol was lowered by repeated plasmapheresis (Figure 2). Of note, her serum potassium and serum chloride levels also returned to normal after lowering her total serum cholesterol, indicating that they were also falsely lowered. A comparison of cases from literature review show a linear relationship between serum sodium and total cholesterol, with higher total serum cholesterol levels resulting in a greater apparent lowering of sodium (Figure 3). This relationship is further demonstration of the effect elevated
ACCEPTED MANUSCRIPT 8 cholesterol has on measurement of serum electrolytes, and may also be the reason the cholesterol has to be extremely elevated before significant pseudohyponatremia is observed. We conclude that pseudohyponatremia can be caused by extreme hypercholesterolemia
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in addition to hypertriglyceridemia, the lipid abnormality more commonly associated with
spuriously low serum sodium levels. The concomitant presence of low serum potassium and chloride may aid the diagnosis. Our case highlights the need to consider severe
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hypercholesterolemia as a possibility prior to initiating treatment of the supposed hyponatremia that may result in complications [1, 23]. A serum osmolality should be checked in all
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hyponatremic patients with cholestasis, and if an osmolar gap is detected then sodium levels should be measured with direct potentiometry [1, 4].
Acknowledgements
We would like to thank Pei-Yun Tseng, B.S. for illustrations and Beverley Adams-Huet, M.S. for
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statistical analysis.
ACCEPTED MANUSCRIPT 9 References
7. 8. 9. 10.
11.
12. 13. 14. 15.
16. 17.
18. 19. 20. 21. 22. 23.
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Dhatt, G., Z. Talor, and A. Kazory, Direct ion-selective electrode method is useful in diagnosis of pseudohyponatremia. J Emerg Med, 2012. 43(2): p. 348-9. Kim, G.H., Pseudohyponatremia: does it matter in current clinical practice? Electrolyte Blood Press, 2006. 4(2): p. 77-82. le Riche, M., L.J. Burgess, and A.D. Marais, Pseudohyponatraemia in a patient with obstructive jaundice. Clin Chim Acta, 2006. 366(1-2): p. 357-60. Fortgens, P. and T.S. Pillay, Pseudohyponatremia revisited: a modern-day pitfall. Arch Pathol Lab Med, 2011. 135(4): p. 516-9. Aw, T.C. and F.L. Kiechle, Pseudohyponatremia. Am J Emerg Med, 1985. 3(3): p. 236-9. Lippi, G. and R. Aloe, Hyponatremia and pseudohyponatremia: first, do no harm. Am J Med, 2010. 123(9): p. e17. Nguyen, M.K., et al., A new method for determining plasma water content: application in pseudohyponatremia. Am J Physiol Renal Physiol, 2007. 292(5): p. F1652-6. Weisberg, L.S., Pseudohyponatremia: a reappraisal. Am J Med, 1989. 86(3): p. 315-8. Narayanan, S., Biochemistry and clinical relevance of lipoprotein X. Ann Clin Lab Sci, 1984. 14(5): p. 371-4. Inamoto, Y., et al., Severe hypercholesterolemia associated with decreased hepatic triglyceride lipase activity and pseudohyponatremia in patients after allogeneic stem cell transplantation. Int J Hematol, 2005. 82(4): p. 362-6. Sivakumar, T., et al., Multiple lipoprotein and electrolyte laboratory artifacts caused by lipoprotein X in obstructive biliary cholestasis secondary to pancreatic cancer. J Clin Lipidol, 2011. 5(4): p. 3248. Klinke, J.A., et al., Quetiapine-associated cholestasis causing lipoprotein-X and pseudohyponatraemia. J Clin Pathol, 2010. 63(8): p. 741-3. Chang, P.Y., et al., Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation. J Lipid Res, 2004. 45(11): p. 2116-22. Crook, M.A., Lipoprotein X: clinical implications. Ann Clin Biochem, 2013. 50(Pt 2): p. 93-4. Raal, F.J., et al., Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet, 2010. 375(9719): p. 998-1006. Miller, J.P., Dyslipoproteinaemia of liver disease. Baillieres Clin Endocrinol Metab, 1990. 4(4): p. 807-32. Jahn, C.E., et al., Lipoprotein abnormalities in primary biliary cirrhosis. Association with hepatic lipase inhibition as well as altered cholesterol esterification. Gastroenterology, 1985. 89(6): p. 1266-78. Hickman, P.E., K.P. Dwyer, and J.R. Masarei, Pseudohyponatraemia, hypercholesterolaemia, and primary biliary cirrhosis. J Clin Pathol, 1989. 42(2): p. 167-71. Ko, G.T., et al., Pseudohyponatraemia secondary to hypercholesterolaemia. Ann Clin Biochem, 1997. 34 ( Pt 3): p. 324-5. Vo, H., et al., Pseudohyponatremia in acute liver disease. Am J Med Sci, 2013. 345(1): p. 62-4. Coakley, J.C., P.P. Vervaart, and M.R. McKay, Factitious hyponatremia in a patient with cholestatic jaundice following bone marrow transplantation. Pathology, 1986. 18(1): p. 158-9. Turchin, A., et al., Severe hypercholesterolemia mediated by lipoprotein X in patients with chronic graft-versus-host disease of the liver. Bone Marrow Transplant, 2005. 35(1): p. 85-9. Bern, M., Clinically significant pseudohyponatremia. Am J Hematol, 2006. 81(7): p. 558-9.
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ACCEPTED MANUSCRIPT 10
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Figure 1: Lipoprotein electrophoretogram showing broad LpX banding. The bottom fraction after ultracentrifugation, normally containing only LDL, HDL and sometimes Lp (a), was electrophoresed. The atypical pattern of the patient’s sample i.e. the reverse migration from the application point (marked by the red line), indicates the presence of lipoprotein X as opposed to LDL. Figure 2: Serum sodium and total cholesterol trends, with time ‘0’ being time of presentation. This shows the drop in serum sodium levels as measured by indirect potentiometry with the rise in total cholesterol levels; followed by normalization of serum sodium levels upon marked lowering of total cholesterol by repeated plasmapheresis over a four month period.
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Figure 3: The relationship between total serum cholesterol and serum sodium (not measured by direct potentiometry) in cases reported in the literature. Each dot represents a patient reported in the literature including our patient.
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Table 1: Initial laboratory studies showing extreme elevation of cholesterol and low sodium, along with low potassium and chloride. LDL-C not reported because of interference with assay.
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Normal Range 135 – 145 mmol/L 3.6 – 5 mmol/L 98 – 109 mmol/L 22 – 31 mmol/L 6 – 16 6 – 23 mmol/L 0.51 – 0.95 mg/dL 3.5 – 5.2 mg/dL 6.6 – 8.7 mg/dL 10 – 35 U/L 10 – 35 U/L 35 – 104 U/L 0.2 – 1.3 mg/dL 65 – 200 mg/dL 8.4 – 10.2 mg/dL 120 – 199 mg/dL 50 – 150 mg/dL 45 – 65 mg/dL ≤ 99 mg/dL
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Value 121 mmol/L 3 mmol/L 87 mmol/L 23 mmol/L 11 16 mg/dL 0.98 mg/dL 2.6 g/dL 6.7 g/dL 120 U/L 107 U/L 507 U/L 10.2 mg/dL 82 mg/dL 9.5 mg/dL 2415 mg/dL 299 mg/dL 42 mg/dL Not Reported
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Laboratory Test Sodium Potassium Chloride CO2 Anion Gap Blood Urea Nitrogen Creatinine Albumin Protein, total Aspartate Aminotransferase Alanine Aminotransferase Alkaline Phosphatase Bilirubin, total Glucose Calcium Cholesterol, total Triglycerides High Density Lipoprotein Cholesterol Low Density Lipoprotein Cholesterol (Calculated)
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Table 2: Results of lipoprotein electrophoresis showing presence of lipoprotein-X. The report stated that low density lipoprotein cholesterol could not be accurately quantitated because of presence of lipoprotein-X and was therefore not reported.
Triglycerides Low Density Lipoprotein Cholesterol (Direct) Low Density Lipoprotein Triglycerides High Density Lipoprotein Cholesterol Very Low Density Lipoprotein Cholesterol Very Low Density Lipoprotein Triglycerides Beta Very Low Density Lipoprotein Cholesterol Beta Very Low Density Lipoprotein Triglycerides Chylomicron Cholesterol Chylomicron Triglycerides Lipoprotein a Cholesterol Lipoprotein X
318 mg/dL Not Reported 265 mg/dL < 3 mg/dL 99 mg/dL 52 mg/dL Not Detected Not Detected Not Detected Not Detected < 3 mg/dL Present
Normal Range < 200 mg/dL
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Value 2295 mg/dL
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Apolipoprotein B
< 150 mg/dL < 100 mg/dL ≤ 50 mg/dL 40 – 59 mg/dL < 30 mg/dL < 120 mg/dL < 15 mg/dL < 15 mg/dL Undetectable Undetectable < 3 mg/dL Undetectable
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Laboratory Test Total Cholesterol
48 – 124 mg/dL
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Table 3: Literature review of cases of extreme hypercholesterolemia associated with pseudohyponatremia. Lipoprotein Underlying Diagnosis Electropheresis
115 116 119
Total Cholesterol (mg/dL) 3011 2815 1691
Hickman, P. E., et al [9] Le Riche, M., et al [3] Klinke, J. A., et al [10]
62 - F 21 - F 36 - M
Ko, G. T., et al [11] Vo, H., et al [12]
27 - M 41 - F
116 120
1830 2621
Not done LpX present
Coakley, J. C., et al [13]
14 - M
123
1667
Not done
Turchin, A., et al [14]
124 129 108 101
1836 977 1713 4091
LpX present
Sivakumar, T., et al [15] Inamoto, Y., et al [16]
64 - F 37 - M 61 - F 55 - F
Our Case
43 - F
121
2415
LpX present
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LpX present Not done LpX present
Primary Biliary Cirrhosis Drug-induced cholestasis Quetiapine-associated cholestasis Primary Biliary Cirrhosis Intra-hepatic cholestasis with Hepatitis C Bone marrow transplant for graft-vs-host disease Bone marrow transplants for graft-vs-host disease Pancreatic Cancer After bone marrow transplant Primary Biliary Cirrhosis
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Sodium (mmol/L)
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Age Sex
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Author (Reference)
LpX present LpX present
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Highlights
Extremely high cholesterol levels may present as pseudohyponatremia.
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Cholestasis may result in accumulation of lipoprotein-X Total cholesterol levels and routine sodium levels are inversely proportional. Presence of lipoprotein-X is shown by lipoprotein electrophoresis.
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Serum osmolality should be measured when pseudohyponatremia is suspected.
S1933-2874(14)00406-1
DOI:
10.1016/j.jacl.2014.11.007
Reference:
JACL 706
To appear in:
Journal of Clinical Lipidology
Received Date: 25 August 2014 Revised Date:
10 November 2014
Accepted Date: 22 November 2014
Please cite this article as: Hussain I, Ahmad Z, Garg A, Extreme Hypercholesterolemia Presenting with Pseudohyponatremia – A Case Report and Review of the Literature, Journal of Clinical Lipidology (2014), doi: 10.1016/j.jacl.2014.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Review of the Literature.
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Extreme Hypercholesterolemia Presenting with Pseudohyponatremia – A Case Report and
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Iram Hussaina, MD, Zahid Ahmada, MD and Abhimanyu Garga, MD
a
M AN U
Division of Nutrition and Metabolic Disease, Department of Internal Medicine, University of
Texas Southwestern Medical Center (5323 Harry Hines Boulevard, Dallas, TX 75390, U.S.A).
Corresponding Author: Abhimanyu Garg, MD.
[email protected]
Postal Address:
5323 Harry Hines Boulevard, Dallas, TX 75390, U.S.A
Phone Number:
+12146482895
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Email:
ACCEPTED MANUSCRIPT 2 Abstract Pseudohyponatremia has been reported in association with severe hypertriglyceridemia and hyperparaproteinemia, but its association with severe hypercholesterolemia is not well known.
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We report a 43-year-old woman with refractory primary biliary cirrhosis who presented with asymptomatic hyponatremia (121 mmol/L; normal range: 135 – 145 mmol/L). She was ultimately found to have a total serum cholesterol level of 2415 mg/dL (normal range: 120 – 199 mg/dL) –
SC
secondary to accumulation of lipoprotein-X – causing pseudohyponatremia. The diagnosis was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270 – 300
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mOsm/kg H2O) and serum sodium by direct potentiometry (141 mmol/L). Furthermore, following 16 sessions of plasmapheresis over a period of 4 months, there was marked lowering of serum cholesterol to 200 mg/dL and normalization of serum sodium (139 mmol/L) as measured by indirect potentiometry. This case shows that extreme hypercholesterolemia from elevations of lipoprotein-X particles in cholestasis can be a rare cause of pseudohyponatremia. It highlights the
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need to measure serum sodium with direct potentiometry in the setting of extreme
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hypercholesterolemia and consider this possibility prior to initiating treatment of hyponatremia.
Key Words
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Pseudohyponatremia; Lipoprotein-X (LpX); Hypercholesterolemia; Primary Biliary Cirrhosis (PBC); Cholestasis; Hyponatremia, Pseudohypokalemia.
ACCEPTED MANUSCRIPT 3 Introduction Pseudohyponatremia is defined as a spuriously low serum sodium concentration in the setting of normal serum osmolality [1-3]. It is important to distinguish pseudohyponatremia from
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true hyponatremia lest injudicious treatment results in increased morbidity and mortality [4]. Pseudohyponatremia is usually seen in cases with extreme hypertriglyceridemia and
hyperparaproteinemia [1-3, 5-7] when serum sodium is measured using routine laboratory testing
SC
methods i.e. indirect potentiometry/flame photometry [1, 2, 4, 7, 8]. Pseudohyponatremia in association with severe hypercholesterolemia is extremely rare and is not well-recognized. We
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present an unusual case of a woman with primary biliary cirrhosis who presented with pseudohyponatremia secondary to extreme hypercholesterolemia caused by elevation of lipoprotein-X. This report emphasizes having a high index of suspicion for extreme hypercholesterolemia resulting in pseudohyponatremia.
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Case Report
A 43-year-old African American woman was admitted for evaluation and treatment after routine laboratory testing revealed low serum sodium (121 mmol/L; normal range: 135 – 145
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mmol/L). She complained of increasing fatigue, jaundice and itching for several weeks prior to admission. Review of past laboratory testing showed normal serum sodium levels for the last 3
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years; with slight reductions noted 3 months (133 mmol/L) and 1 month (131 mmol/L) prior to presentation. She had not been drinking excessive amounts of water, urine output was normal and she had no mental status changes. She was taking amlodipine, azathioprine, cholestyramine, fenofibrate, hydroxyzine, losartan, ondansetron, prednisone, prochlorperazine, promethazine, ranitidine, sertraline, trazodone and high doses of ursodiol (24 mg/kg/day). She reported no dose adjustments or changes in medications in the past six months that could explain her new onset hyponatremia.
ACCEPTED MANUSCRIPT 4 She was diagnosed with right-sided invasive ductal breast carcinoma associated with breast cancer 1, early onset (BRCA1) gene mutation one year prior to her current presentation, and was status post partial mastectomy and chemoradiotherapy, with no active disease. During
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evaluation of her breast cancer she was noted to have elevated serum alkaline phosphatase level (503 Units/L; normal range: 35 – 104 Units/L) and was subsequently diagnosed with primary biliary cirrhosis – confirmed by liver biopsy and elevated anti-mitochondrial antibodies (titer ≥
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1:320; normal range: negative) – eight months prior to presentation. Her primary biliary cirrhosis has been refractory to medical therapy.
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On physical examination her vital signs were unremarkable, and her skin turgor appeared normal. She had scleral icterus but had no hepatosplenomegaly, xanthelasmata or xanthomata. Her laboratory results (Table 1) revealed hyponatremia, elevated bilirubin levels (10.2 mg/dL; normal range: 0.2 – 1.3 mg/dL) indicating worsening biliary disease, and very high cholesterol levels (total cholesterol 2415 mg/dL; normal range: 120 – 199 mg/dL). She also had hypokalemia
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(3.0 mmol/L; range 3.6 – 5.0 mmol/L) and hypochloremia (87 mmol/L; range 98 – 109 mmol/L). She was initially thought to have hypovolemic hyponatremia and was given intravenous
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normal saline, however a repeat sodium level was unchanged (121 mmol/L) after five hours. Review of her medical records revealed a much lower total serum cholesterol level of 322
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mg/dL two years ago. The marked increase in serum cholesterol suggested rapid progression of primary biliary cirrhosis resulting in accumulation of lipoprotein-X, and development of pseudohyponatremia secondary to lipoproteinemia. The diagnosis of pseudohyponatremia was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270 – 300 mOsm/kg H2O) and measurement of serum sodium by direct potentiometry (141 mmol/L; normal range: 135 – 145 mmol/L). Lipoprotein electrophoresis confirmed major presence of lipoprotein-X (Figure 1 and Table 2). Serum apolipoprotein B level was 218 mg/dL (normal range: 48 – 124 mg/dL).
ACCEPTED MANUSCRIPT 5 Her serum sodium by indirect potentiometry ranged from 120 – 125 mmol/L for the next two days and she was discharged without any additional lipid-lowering drugs. For intractable itching secondary to elevated bile acids (> 180 µmol/L; normal range: ≤ 10 µmol/L) despite
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maximal medical therapy, plasmapheresis was initiated two months after discharge as the patient was not a candidate for liver transplant. She underwent about 15 sessions of plasmapheresis over a four month period before her lipid panel was rechecked. It showed improvement with pre-
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procedure total serum cholesterol of 662 mg/dL that decreased further to 200 mg/dL after the 16th session of plasmapheresis. Her serum sodium level measured by indirect potentiometry
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normalized (139 mmol/L) with reduction in total serum cholesterol levels; as did serum potassium (3.6 mmol/L) and chloride (104 mmol/L) levels (Figure 1). Discussion
We report a case of extreme hypercholesterolemia – total cholesterol 2415 mg/dL – due
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to accumulation of lipoprotein X. The severe hypercholesterolemia resulted in spuriously low serum sodium levels when measured by indirect potentiometry. Normally, the plasma volume is composed of 93% plasma water and 7% proteins and fats [1, 2, 4, 6, 15]. Sodium is measured per liter of plasma, so a concentration of 142 mmol/L actually represents a concentration of 153
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mmol/L (142 ÷ 0.93 = 153) in the physiologically important plasma water [2, 7, 17]. In marked hyperlipidemia for example, in our case due to accumulation of lipoprotein-X, the plasma water
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fraction may fall below 80%. The physiologically important plasma water sodium concentration and plasma osmolality are unchanged, but the measured sodium concentration in the total plasma volume will be reduced since the specimen contains less plasma water [2]. A similar assumption regarding plasma volume composition is made when calculating serum osmolality, resulting in an osmolar gap – our patient’s measured serum osmolality was 296 mOsm/kg H2O, compared to her calculated value (using the equation: serum osmolality = 2*Sodium + Glucose/18 + Blood Urea Nitrogen/2.8) of 252.2 mOsm/kg H2O.
ACCEPTED MANUSCRIPT 6 Flame photometry (the oldest method of measuring serum sodium) and indirect potentiometry (used in most laboratories for routine serum sodium measurements) both involve sample dilution and give similar results [4, 5]. Diluting the plasma and then correcting for the
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dilution gives misleading results because it does not account for the already decreased amount of plasma water and sodium as a result of the excess lipids [4]. Direct potentiometry measures the concentration of sodium in the plasma water directly with no dilution, therefore giving accurate
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results [2, 4, 5, 7].
Since potassium and chloride are also measured by indirect potentiometry, they may also
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be falsely lowered secondary to extreme hypercholesterolemia. However, pseudohypokalemia has been reported in only two patients and pseudohypochloremia in just one patient with pseudohyponatremia due to extreme hypercholesterolemia [15, 16]. Apart from affecting electrolyte analysis, lipoprotein-X can also falsely increase the laboratory measurement of lipoprotein (a), direct and calculated LDL-cholesterol and falsely decrease HDL-cholesterol [3, 15]
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due to interference with the assay.
Lipoprotein-X, an abnormal lipoprotein containing mainly albumin in the core and apolipoprotein C on the surface [9], is reported in patients with cholestasis either from underlying
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liver pathology or graft-versus-host disease. It is also present in patients with familial lecithin cholesterol acyltransferase deficiency in the absence of cholestasis [3, 10, 11]. It is thought that
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bile lipoprotein is a precursor to lipoprotein-X and it accumulates in cholestatic conditions such as primary biliary cirrhosis by reflux of unesterified cholesterol and phospholipids into the circulation [3, 10, 12]. Although elevated levels of lipoprotein-X can form xanthomata, it does not contain apolipoprotein B and high levels are not considered to be atherogenic [13, 14]. There is a marked discrepancy between our patient’s apolipoprotein B level (corresponding to a total cholesterol level of about 400 mg/dL [15]) and her extremely elevated total cholesterol level, suggesting accumulation of a particle not containing apolipoprotein B – in
ACCEPTED MANUSCRIPT 7 this case – lipoprotein X. Primary biliary cirrhosis can cause abnormal composition of lipoproteins such as triglyceride-rich LDL particles and triglyceride-poor VLDL particles that have a higher proportion of apolipoprotein B and lecithin [16]. The elevated VLDL cholesterol level in our patient
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may partly explain the high apolipoprotein B levels. In addition, the apolipoprotein B levels are reported to be high in primary biliary cirrhosis [17] as other lipoprotein particles are also increased secondary to liver disease.
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Review of literature reveals ten reported cases of pseudohyponatremia associated with extreme elevation of total serum cholesterol (Table 2), with presence of lipoprotein-X confirmed in
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seven reports [3, 10-12, 18-22]. All the patients had cholestasis: four following bone marrow transplants with graft-versus-host disease, two drug-induced, two with primary biliary cirrhosis, one with hepatitis C and one with pancreatic cancer. The lowest reported total serum cholesterol resulting in pseudohyponatremia was 977 mg/dL (associated serum sodium: 129 mmol/L) [22] whereas as the highest was 4091 mg/dL (associated serum sodium: 101 mmol/L) [10]. Such high
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cholesterol levels are usually only seen when lipoprotein-X accumulates in cholestasis. Other diseases resulting in elevated total serum cholesterol such as homozygous familial hypercholesterolemia usually have total cholesterol levels lower than 1000 mg/dL [15], therefore
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have not been reported to be associated with pseudohyponatremia. Most interestingly, we documented correction of serum sodium measured by indirect
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potentiometry when the patient’s total serum cholesterol was lowered by repeated plasmapheresis (Figure 2). Of note, her serum potassium and serum chloride levels also returned to normal after lowering her total serum cholesterol, indicating that they were also falsely lowered. A comparison of cases from literature review show a linear relationship between serum sodium and total cholesterol, with higher total serum cholesterol levels resulting in a greater apparent lowering of sodium (Figure 3). This relationship is further demonstration of the effect elevated
ACCEPTED MANUSCRIPT 8 cholesterol has on measurement of serum electrolytes, and may also be the reason the cholesterol has to be extremely elevated before significant pseudohyponatremia is observed. We conclude that pseudohyponatremia can be caused by extreme hypercholesterolemia
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in addition to hypertriglyceridemia, the lipid abnormality more commonly associated with
spuriously low serum sodium levels. The concomitant presence of low serum potassium and chloride may aid the diagnosis. Our case highlights the need to consider severe
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hypercholesterolemia as a possibility prior to initiating treatment of the supposed hyponatremia that may result in complications [1, 23]. A serum osmolality should be checked in all
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hyponatremic patients with cholestasis, and if an osmolar gap is detected then sodium levels should be measured with direct potentiometry [1, 4].
Acknowledgements
We would like to thank Pei-Yun Tseng, B.S. for illustrations and Beverley Adams-Huet, M.S. for
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statistical analysis.
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12. 13. 14. 15.
16. 17.
18. 19. 20. 21. 22. 23.
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Dhatt, G., Z. Talor, and A. Kazory, Direct ion-selective electrode method is useful in diagnosis of pseudohyponatremia. J Emerg Med, 2012. 43(2): p. 348-9. Kim, G.H., Pseudohyponatremia: does it matter in current clinical practice? Electrolyte Blood Press, 2006. 4(2): p. 77-82. le Riche, M., L.J. Burgess, and A.D. Marais, Pseudohyponatraemia in a patient with obstructive jaundice. Clin Chim Acta, 2006. 366(1-2): p. 357-60. Fortgens, P. and T.S. Pillay, Pseudohyponatremia revisited: a modern-day pitfall. Arch Pathol Lab Med, 2011. 135(4): p. 516-9. Aw, T.C. and F.L. Kiechle, Pseudohyponatremia. Am J Emerg Med, 1985. 3(3): p. 236-9. Lippi, G. and R. Aloe, Hyponatremia and pseudohyponatremia: first, do no harm. Am J Med, 2010. 123(9): p. e17. Nguyen, M.K., et al., A new method for determining plasma water content: application in pseudohyponatremia. Am J Physiol Renal Physiol, 2007. 292(5): p. F1652-6. Weisberg, L.S., Pseudohyponatremia: a reappraisal. Am J Med, 1989. 86(3): p. 315-8. Narayanan, S., Biochemistry and clinical relevance of lipoprotein X. Ann Clin Lab Sci, 1984. 14(5): p. 371-4. Inamoto, Y., et al., Severe hypercholesterolemia associated with decreased hepatic triglyceride lipase activity and pseudohyponatremia in patients after allogeneic stem cell transplantation. Int J Hematol, 2005. 82(4): p. 362-6. Sivakumar, T., et al., Multiple lipoprotein and electrolyte laboratory artifacts caused by lipoprotein X in obstructive biliary cholestasis secondary to pancreatic cancer. J Clin Lipidol, 2011. 5(4): p. 3248. Klinke, J.A., et al., Quetiapine-associated cholestasis causing lipoprotein-X and pseudohyponatraemia. J Clin Pathol, 2010. 63(8): p. 741-3. Chang, P.Y., et al., Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation. J Lipid Res, 2004. 45(11): p. 2116-22. Crook, M.A., Lipoprotein X: clinical implications. Ann Clin Biochem, 2013. 50(Pt 2): p. 93-4. Raal, F.J., et al., Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet, 2010. 375(9719): p. 998-1006. Miller, J.P., Dyslipoproteinaemia of liver disease. Baillieres Clin Endocrinol Metab, 1990. 4(4): p. 807-32. Jahn, C.E., et al., Lipoprotein abnormalities in primary biliary cirrhosis. Association with hepatic lipase inhibition as well as altered cholesterol esterification. Gastroenterology, 1985. 89(6): p. 1266-78. Hickman, P.E., K.P. Dwyer, and J.R. Masarei, Pseudohyponatraemia, hypercholesterolaemia, and primary biliary cirrhosis. J Clin Pathol, 1989. 42(2): p. 167-71. Ko, G.T., et al., Pseudohyponatraemia secondary to hypercholesterolaemia. Ann Clin Biochem, 1997. 34 ( Pt 3): p. 324-5. Vo, H., et al., Pseudohyponatremia in acute liver disease. Am J Med Sci, 2013. 345(1): p. 62-4. Coakley, J.C., P.P. Vervaart, and M.R. McKay, Factitious hyponatremia in a patient with cholestatic jaundice following bone marrow transplantation. Pathology, 1986. 18(1): p. 158-9. Turchin, A., et al., Severe hypercholesterolemia mediated by lipoprotein X in patients with chronic graft-versus-host disease of the liver. Bone Marrow Transplant, 2005. 35(1): p. 85-9. Bern, M., Clinically significant pseudohyponatremia. Am J Hematol, 2006. 81(7): p. 558-9.
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Figure 1: Lipoprotein electrophoretogram showing broad LpX banding. The bottom fraction after ultracentrifugation, normally containing only LDL, HDL and sometimes Lp (a), was electrophoresed. The atypical pattern of the patient’s sample i.e. the reverse migration from the application point (marked by the red line), indicates the presence of lipoprotein X as opposed to LDL. Figure 2: Serum sodium and total cholesterol trends, with time ‘0’ being time of presentation. This shows the drop in serum sodium levels as measured by indirect potentiometry with the rise in total cholesterol levels; followed by normalization of serum sodium levels upon marked lowering of total cholesterol by repeated plasmapheresis over a four month period.
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Figure 3: The relationship between total serum cholesterol and serum sodium (not measured by direct potentiometry) in cases reported in the literature. Each dot represents a patient reported in the literature including our patient.
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Table 1: Initial laboratory studies showing extreme elevation of cholesterol and low sodium, along with low potassium and chloride. LDL-C not reported because of interference with assay.
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Normal Range 135 – 145 mmol/L 3.6 – 5 mmol/L 98 – 109 mmol/L 22 – 31 mmol/L 6 – 16 6 – 23 mmol/L 0.51 – 0.95 mg/dL 3.5 – 5.2 mg/dL 6.6 – 8.7 mg/dL 10 – 35 U/L 10 – 35 U/L 35 – 104 U/L 0.2 – 1.3 mg/dL 65 – 200 mg/dL 8.4 – 10.2 mg/dL 120 – 199 mg/dL 50 – 150 mg/dL 45 – 65 mg/dL ≤ 99 mg/dL
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Value 121 mmol/L 3 mmol/L 87 mmol/L 23 mmol/L 11 16 mg/dL 0.98 mg/dL 2.6 g/dL 6.7 g/dL 120 U/L 107 U/L 507 U/L 10.2 mg/dL 82 mg/dL 9.5 mg/dL 2415 mg/dL 299 mg/dL 42 mg/dL Not Reported
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Laboratory Test Sodium Potassium Chloride CO2 Anion Gap Blood Urea Nitrogen Creatinine Albumin Protein, total Aspartate Aminotransferase Alanine Aminotransferase Alkaline Phosphatase Bilirubin, total Glucose Calcium Cholesterol, total Triglycerides High Density Lipoprotein Cholesterol Low Density Lipoprotein Cholesterol (Calculated)
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Table 2: Results of lipoprotein electrophoresis showing presence of lipoprotein-X. The report stated that low density lipoprotein cholesterol could not be accurately quantitated because of presence of lipoprotein-X and was therefore not reported.
Triglycerides Low Density Lipoprotein Cholesterol (Direct) Low Density Lipoprotein Triglycerides High Density Lipoprotein Cholesterol Very Low Density Lipoprotein Cholesterol Very Low Density Lipoprotein Triglycerides Beta Very Low Density Lipoprotein Cholesterol Beta Very Low Density Lipoprotein Triglycerides Chylomicron Cholesterol Chylomicron Triglycerides Lipoprotein a Cholesterol Lipoprotein X
318 mg/dL Not Reported 265 mg/dL < 3 mg/dL 99 mg/dL 52 mg/dL Not Detected Not Detected Not Detected Not Detected < 3 mg/dL Present
Normal Range < 200 mg/dL
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Value 2295 mg/dL
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Apolipoprotein B
< 150 mg/dL < 100 mg/dL ≤ 50 mg/dL 40 – 59 mg/dL < 30 mg/dL < 120 mg/dL < 15 mg/dL < 15 mg/dL Undetectable Undetectable < 3 mg/dL Undetectable
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Laboratory Test Total Cholesterol
48 – 124 mg/dL
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Table 3: Literature review of cases of extreme hypercholesterolemia associated with pseudohyponatremia. Lipoprotein Underlying Diagnosis Electropheresis
115 116 119
Total Cholesterol (mg/dL) 3011 2815 1691
Hickman, P. E., et al [9] Le Riche, M., et al [3] Klinke, J. A., et al [10]
62 - F 21 - F 36 - M
Ko, G. T., et al [11] Vo, H., et al [12]
27 - M 41 - F
116 120
1830 2621
Not done LpX present
Coakley, J. C., et al [13]
14 - M
123
1667
Not done
Turchin, A., et al [14]
124 129 108 101
1836 977 1713 4091
LpX present
Sivakumar, T., et al [15] Inamoto, Y., et al [16]
64 - F 37 - M 61 - F 55 - F
Our Case
43 - F
121
2415
LpX present
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LpX present Not done LpX present
Primary Biliary Cirrhosis Drug-induced cholestasis Quetiapine-associated cholestasis Primary Biliary Cirrhosis Intra-hepatic cholestasis with Hepatitis C Bone marrow transplant for graft-vs-host disease Bone marrow transplants for graft-vs-host disease Pancreatic Cancer After bone marrow transplant Primary Biliary Cirrhosis
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Sodium (mmol/L)
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Age Sex
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Author (Reference)
LpX present LpX present
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Highlights
Extremely high cholesterol levels may present as pseudohyponatremia.
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Cholestasis may result in accumulation of lipoprotein-X Total cholesterol levels and routine sodium levels are inversely proportional. Presence of lipoprotein-X is shown by lipoprotein electrophoresis.
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Serum osmolality should be measured when pseudohyponatremia is suspected.
