Transient Dyslipidemia Mimicking the Plasma Lipid Profile of Tangier Disease in a Diabetic Patient with Gram Negative Sepsis

Home , Dyslipidemia, Hypertriglyceridemia, Tangier disease

Available online at www.annclinlabsci.org 150 Annals of Clinical & Laboratory Science, vol. 41, no. 2, 2011

Carlos Palacio, M.D.,1 Irene Alexandraki, M.D.,1 Roger L. Bertholf, Ph.D.,2 and Arshag D. Mooradian, M.D.1 Department of Medicine1 and the Department of Pathology2, University of Florida - College of Medicine, Jacksonville, FL

Abstract. Tangier disease is a rare genetic disorder of lipid metabolism characterized by low concentrations of plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol with normal or elevated levels of triglycerides. In this case report we describe a patient with diabetes who experienced an episode of urosepsis with a plasma lipid profile resembling Tangier disease. Experimental evidence in the literature suggests that similar lipid changes may occur due to cytokines released during sepsis. Clinicians should be aware of these changes to avoid misdiagnosis of lipid disorders.

Introduction Tangier disease during an episode of urosepsis. Within two weeks post recovery the dyslilpidemia Tangier disease (familial alpha lipoprotein resolved and the plasma lipid profile returned to deficiency) is a rare genetic disorder of lipid baseline values. metabolism characterized principally by a severe deficiency of high density lipoprotein (HDL), Clinical History accompanied by low plasma levels of low density lipoprotein (LDL) cholesterol, normal or elevated The patient was a 58-year-old woman presenting plasma levels of triglycerides, and accumulation of with the chief complaint of generalized abdominal cholesteryl ester in reticuloendothelial tissue [1, 2]. pain with nausea, vomiting, and fever for four Phenotypically, patients with Tangier disease may days. Past medical and surgical history were have enlarged orange tonsils, hepatosplenomegaly, significant for diabetes mellitus, an ovarian cyst, peripheral neuropathy, hemolytic anemia and nephrolithiasis and oophorectomy. Family history bleeding diathesis. These patients often have was negative for coronary disease or diabetes premature cardiovascular disease. Tangier disease mellitus. She denied smoking or alcohol use and is caused by a homozygous mutation of the ATP – she ate an exclusively vegetarian diet. The only binding cassette transporter protein A1 (ABC-A1) prescribed medication was metformin 1,000 mg [2]. It is noteworthy that cytokines, notably orally twice per day. TNF-α, down-regulate the ABC-A1 [3, 4]. Thus it is possible that increased TNF-α production, The physical examination was unremarkable such as in sepsis, may produce lipid abnormalities and the patient was in no acute distress. Blood that resemble those seen in Tangier disease. pressure was 112/75 mm Hg, heart rate was 103 beats/minute, respiratory rate was 16/minute, and We describe a patient with diabetes who her temperature was 98.4° F. Oxygen saturation transiently had a plasma lipid profile resembling was 100% on room air. The tonsils were not enlarged, there was no clouding or opacification Address correspondence and reprint requests to Carlos Palacio, MD, of the cornea, no hepatosplenomegaly, and the MPH, FACP, Department of Medicine, University of Florida, 653-1 neurological examination was unremarkable. West Eighth Street, Jacksonville, FL, 32209; tel 904-244-8846; fax 904-244-8844; e-mail [email protected] 0091-7370/11/0200-150. © 2011 by the Association of Clinical Scientists, Inc. Dyslipidemia in sepsis 151 Laboratory evaluation revealed a normal blood phosphate by glycerol phosphate oxidase, and count with the exception of elevated white blood photometric quantification of the peroxide cell count of 14,400/ml, normal serum electrolytes, byproduct. Cholesterol esters were hydrolyzed creatinine, liver enzymes, amylase, lipase, albumin, with cholesterol esterase prior to oxidation with bilirubin, prothrombin time and thyrotropin. cholesterol oxidase and photometric measurement Urinalysis showed pyuria with 1,514 white blood of the peroxide byproduct. HDL-cholesterol was cells and 139 red cells per high power field. The measured with polyethylene glycol-modified urine and blood cultures grew E. coli. The blood cholesterol esterase and oxidase enzymes (HDL-C glucose and lipid profile of the patient during Plus 3rd Generation, Roche Diagnostics). LDL- hospitalization, 3 months prior, and 10 days after cholesterol was measured as above after selective hospitalization are summarized in Table 1. partitioning into a nonionic detergent (LDL-C Plus 2nd Generation, Roche Diagnostics). The

Table 1: Fasting plasma glucose and lipid profile before, during, and after hospitalization and treatment for urosepsis. The anticoagulant used for plasma collection was lithium heparin. The reference ranges for the analytes are shown in parenthesis.

Baseline: Hospital day 2 Hospital day 3 Hospital day 4 Two weeks Three months prior to after discharge hospitalization

Glucose (71-99 mg/dl) 177 166 189 116 125 Total cholesterol (100-199 mg/dl) 196 136 184 210 211 Triglycerides (< 200 mg/dl) 549 534 651 610 296 LDL cholesterol (< 100 mg/dl) 85 <3 <3 3 123 HDL cholesterol (> 60 mg/dl) 33 7 9 7 29

Lipids were measured on a Roche Modular laboratory does not estimate LDL concentration automated chemistry analyzer using Cobas with the Friedwald equation if the triglyceride reagents (Roche Diagnostics, Indianapolis, IN). concentration exceeds 400 mg/dL. Triglycerides were measured with an enzymatic method involving hydrolysis of triacylglycerides to Lipoprotein electrophoresis was performed at a glycerol by lipoprotein lipase, conversion of glycerol referral laboratory (LabCorp, Burlington, NC) to glycerol-3-phosphate (G-3-P) by glycerol on a specimen collected during the patient’s kinase, oxidation of G-3-P to dihydroxyacetone hospitalization, and the result appears in Figure 1. No chylomicrons were detected, but the pre-beta (VLDL) band was significantly increased while the alpha and beta bands were reduced or absent.

A chest radiograph was normal with no cardiomegaly, and CT imaging of the abdomen revealed no organomegaly. There was mild right hydronephrosis with a 2.1 cm calculus noted in the right renal pelvis, and a 2.6 cm right adnexal cyst for which follow-up was recommended. The patient was treated with intravenous ceftriaxone.

Discussion

Fig. 1. Lipoprotein electrophoresis of the patient’s plasma on the second day of admission when total triglycerides were 534 The baseline lipid profile prior to this mg/dl, total cholesterol was 136 mg/dl, LDL cholesterol was 3 patient’s hospitalization was notable for mg/dl and HDL cholesterol was 7 mg/dl. The dotted line is a hypertriglyceridemia with modestly low HDL normal lipoprotein electrophoresis pattern. 152 Annals of Clinical & Laboratory Science, vol. 41, no. 2, 2011 in HDL and LDL cholesterol were not as extreme as seen in our patient [10]. It is noteworthy that these changes may have prognostic implications. In a study by Barlage, et al., changes in HDL- associated apolipoproteins were associated with mortality, and correlated with monocyte and platelet activation [11].

Multiple biochemical changes are potentially Figure 2: Changes in lipoprotein metabolism and their relation to cytokines. TNF-α: tumor necrosis factor-alpha; IL-1β: responsible for lipid abnormalities. The very interleukin-1beta; IL-10: interleukin 10; ABC-A1: ATP – low HDL cholesterol in this patient during an binding cassette transporter protein A1; SR-B1: scavenger class episode of acute septicemia is probably the result B type I receptor; apoA1: apolipoprotein A1; LDL: low density of down regulation of ABC-A1 transporter, lipoprotein cholesterol; LPL: lipoprotein lipase; LCAT: lecithin- decreased scavenger-class B type I (SR-BI) cholesterol acyltransferase; TG: triglyceride; HDL: high density lipoprotein cholesterol; VLDL: very low density lipoprotein receptor that promotes cholesterol efflux from cholesterol. peripheral cells and mediates selective uptake of cholesteryl ester into hepatocytes [13], and cholesterol, typical of metabolic syndrome and the direct inhibitory effects of cytokines on type 2 diabetes [5-7]. Both HDL and LDL apolipoprotein A1 synthesis, the principal cholesterol concentrations decreased dramatically protein of the HDL [14, 15]. during her hospitalization and subsequently returned towards the baseline values two weeks The mechanism responsible for low LDL after recovery from the acute illness. The lipid cholesterol in Tangier disease is not well profile during hospitalization resembles Tangier understood, but may be due to enhanced disease. However, the patient did not have catabolism of LDL [16]. Total cholesterol is physical stigmata of Tangier disease, and the lipid often low in Tangier disease, but cases of normal abnormalities quickly resolved within two weeks total serum cholesterol can occur in patients of treatment. that are heterozygous with familial combined hyperlipidemia [17]. Another explanation for Acute inflammation has been shown to produce the low LDL cholesterol in this patient may be lipid abnormalities [8, 9]. Injection of TNF-α in that conversion of VLDL to LDL is reduced in cynomolgus monkeys caused a 38% increase in septicemic conditions, since lipopolysaccharide plasma triacylglycerol, a 30% decrease in plasma and TNF-α cause a fall in lipoprotein lipase cholesterol, along with significant decreases activity and in plasma concentration of in apolipoproteins A-I and B. These changes lecithin:cholesterol acyltransferase [9]. were qualitatively similar to those seen after lipopolysaccaride injection [8]. However, the Hypertriglyceridemia in Tangier disease is plasma total cholesterol levels did not change attributed to reduced levels of lipoprotein lipase in the animals fed saturated fat and cholesterol activity, and a lower reactivity of VLDL with because the decrease in cholesterol ester content lipoprotein lipase, which may be the result of of LDL and HDL was offset by an increase in abnormal apolipoprotein composition [18]. very low density lipoprotein (VLDL) [9]. Thus, Additionally, hepatocyte ABC-A1 may regulate it is possible that the lipopolysaccaride produced VLDL triglyceride secretion through nascent during the gram negative E. coli sepsis raised HDL production [19]. Large nascent HDL TNF-α levels, which subsequently lowered HDL particles, assembled by hepatic ABC-A1, generate and LDL cholesterol levels. This biochemical a phosphoinisitol-3 (PI 3) kinase-mediated scenario is highlighted in Figure 2. autocrine signal that attenuates VLDL maturation and triglyceride secretion. This pathway may Similar lipid abnormalities have been described in explain the elevated plasma triglyceride and the patients with severe sepsis, although the reductions Dyslipidemia in sepsis 153 inverse relationship between plasma HDL and 7. Mooradian AD, Haas MJ, Wong NC. Transcriptional control of apolipoprotein A-I gene expression in diabetes. Diabetes triglyceride concentrations in individuals with 2004;53:513-520. compromised ABC-A1 function [19]. Increased 8. Ettinger WH, Miller LA, Smith TK, Parks JS. Effect of exposure to lipopolysaccharides and TNF-α in interleukin-1 alpha on lipoprotein lipids in cynomolgus monkeys: comparison to tumor necrosis factor. Biochim gram negative septicemia may reduce ABCA1 Biophys Acta 1992;1128:186-192. function, increase insulin resistance, and aggravate 9. Ettinger WH, Miller LD, Albers JJ, Smith TK, Parks JS. hypertriglyceridemia. Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin: cholesterol acyltransferase in cynomolgus monkeys. J Lipid Res 1990;31:1099-1107. Conclusion 10. Van Leeuwen HJ, Heezius EC, Dallinga GM, van Strijp JA, Verhoef J, van Kessel KP. Lipoprotein metabolism in patients with severe sepsis. Crit Care Med. 2003 May;31(5):1359-66. This case report highlights an extreme case of 11. Barlage S, Gnewuch C, Liebisch G, Wolf Z, Audebert FX, Glück dyslipidemia resembling Tangier disease possibly T, Fröhlich D, Krämer BK, Rothe G, Schmitz G. 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