Hypertriglyceridemia and Hypercholesterolemia Induced by L-Asparaginase

Abstract

Case ReportsHypertriglyceridemia and Hypercholesterolemia Induced by L-Asparaginase K. Aljabri, MD Dipl. ABIM FRCPC S. Sirrs, and MD, FRCPC S. NantelMD, FRCPC K. Aljabri Correspondence to: Dr. K. Aljabri, P.O. Box 6752, Taif, Saudi Arabia From the Department of Medicine, Prince Mansour Military Hospital, Taif, Saudi Arabia Search for more papers by this author , S. Sirrs From the Department of Medicine, Prince Mansour Military Hospital, Taif, Saudi Arabia Search for more papers by this author , and S. Nantel From the Department of Medicine, Prince Mansour Military Hospital, Taif, Saudi Arabia Search for more papers by this author Published Online::1 May 2003https://doi.org/10.5144/0256-4947.2003.173SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionSerum triglycerides and cholesterol may be affected by many factors, including medications like. L-asparaginase and corticosteroids. L-asparaginase, used for induction chemotherapy in acute lymphoblastic leukemia (ALL), has been associated with hypertriglyceridemia and hypercholestrolemia.1 Lipoprotein lipase (LPL) is the major enzyme responsible for conversion of lipoprotein triglyceride into free fatty acids. LPL is synthesized primarily by adipocytes and myocytes and transferred to the luminal side of capillary endothelial cells, where it interacts with circulating triglyceride-rich lipoproteins such as VLDL and chylomicrons.2 It has been implicated in the hyperlipidemia associated with diabetes and hypothyroidism. Whether the effect of L-asparaginase on serum triglycerides and cholesterol is related to a reduction in LPL activity is unclear. We present a case of hypertriglyceridemia and hypercholesterolemia associated with L-asparaginase therapy and review the literature on this subject.CASE REPORTA 31-year old previously well Caucasian male presented with acute lymphoblastic leukemia (ALL) [L2, Philadelphia chromosome (+)]. He was treated with induction chemotherapy (L-asparaginase 1000 units IV daily from day 17-25, prednisone 55 mg twice daily from day 1-28, then tapered over 2 weeks, vincristine 2 mg IV given on day 1, 8, 15, daunorubicin 110 mg from day 1-3) Prophylactic intrathecal methotrexate was given on two occasions. The family history was negative for dyslipidemia or premature coronary artery disease. He denied alcohol or drug use. His body mass index was 18 and he was normotensive with no goiter, no stigmata of chronic liver disease and no xanthelasma or eruptive xanthomata. The liver edge was palpable 3 cm below the costal margin and the spleen tip was felt. Fundi did not show lipemiaretinalis. Because of the lipemic serum, a post-dose lipid profile was obtained 14 and 25 days and 21 weeks after the last dose of L-asparaginase (Table 1). The patient was clinically asymptomatic when the lipid profiles were obtained.Table 1. Lipid parameters one year prior to therapy and after the last dose of Ll-asparaginase.Table 1. Lipid parameters one year prior to therapy and after the last dose of Ll-asparaginase.Other clinical laboratory results with normal ranges for our laboratory, were as follows: Fasting glucose 5.2 mmol/L (3.9-6.0 mmol/L), amylase 47 U/L (35-90 U/L), AST 59 U/L (19-38 U/L), ALT 260 U/L (25-80 U/L), alkaline phosphatase 235 U/L (50-160 U/L), GGT 673 U/L (15-80 U/L), serum fibrinogen 0.62 g/L (1.5-3.3 g/L) TSH 3.0 munits/L. Urinalysis showed no proteinuria, ApoB 2.26 g/L (<1.25 g/L). The apolipoprotein phenotype was E3/E3. LPL activity assayed 16 days after the last dose of L-asparaginase, using the heparin challenge test, was 220 nmol/min/mL (normal= 100-250 nmol/min/mL). Ultrasound of the abdomen showed no fatty infiltration of the liver.DISCUSSIONParsons et al obtained serial fasting lipids in 38 children diagnosed with ALL who received L-asparaginasetherapy.1 Sixty seven percent had fasting triglyceride levels greater than 2.26 mmol/L, 42 % had levels greater than 4.5 mmol/L, 20 % had levels greater than 11.3 mmol/L Cholesterol levels were >5.17 mmol/L in 20% and HDL levels were low. These findings were confirmed by other investigators.3,4 In our patient, the low level of HDL after starting the L-asparaginase was similar to that found in previous reports.5,6 When the lipid profile in our patient was checked 14 days after the last dose of L-asparaginase, triglycerides and total cholesterol were elevated (Table 1). Tozukaet al found that hypertriglyceridemia was induced 8 to 14 days after the end of the L-asparaginasetherapy.5Asharp decrease in fibrinogen concentrations has been reported with use of L-asparaginase.5 We found that the fibrinogen level was consistently low in our patient, who required a pooled cryoprecipitate transfusion. Acute pancreatitis has also been reported in patients receiving L-asparaginase, at an estimated frequency of 10.5% to 16.5%.1,7 A retrospective study in nonleukemic patients by Fortson et al found that the frequency of hyperlipidemia associated with pancreatitis ranged from 1.3% to 3.5%.6 In contrast, no relationship between acute pancreatitis and serum triglyceride levels was reported in another study.1In contrast to Hoogerbruggeet al,8 we found that the LPL activity was normal 16 days after the last dose of L-asparaginase. This may reflect the delay in measuring LPL activity, such that the effect of the L-asparaginase on the LPL actvity was lost when the test was performed. Alternatively, the drug may have been affecting the triglyceride metabolism by a mechansim other than reduction of LPL activity.Elevated apoB was reported by Haltonetal.4 The elevated apoB in in our patient suggest an underlying familial combined hyperlipidemia or an effect of L-asparaginase, as there was no clinical or biochemical evidence of diabetes, hypothyroidism or nephrotic syndrome. Apo E is associated with triglyceride rich lipoprotein catabolism. In the study by Tozukaet al,5 no clear relationship was confirmed between the apo E phenotype and the extent of hypertriglyceridemia, but the number of patients studied was small. As in our patient, normalization of the lipid profiles has been reported following discontinuation of the drug.1,4,5In summary, L-asparaginase may induce hypertriglyceridemia and increase serum cholesterol level though the mechanism may not be related to a reduction in lipoprotein lipase activity. The fibrinogen concentration andthe HDL-cholesterol level can be low in these cases. These effects can reverse after cessation of the drug. Patients should be screened for dyslipidemia at least once a week after receiving L-asparaginase therapy and warned about the possibility of such adverse effects, including the potential risk of acute pancreatitis.ARTICLE REFERENCES:1. Parsons S, Skapek S, Neufeld E, Kuhlman C, Young M. "Asparaginase associated lipid abnormalities in children with acute lymphoblastic leukemia" . Blood. 1997; 89:1886–95. Google Scholar2. Goldberg I. "Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis" . J Lipid Res. 1996; 37:693–707. Google Scholar3. Steinherz P. "Transient severe hyperlipidemia in patients with acute lymphoblastic leukemia treated with prednisone and asparaginase" . Cancer. 1994; 74:3234–9. Google Scholar4. Halton J, Nazir D, McQueen M, Barr R. "Blood lipid profiles in children with acute lymphoblastic leukemia" . Cancer. 1998; 83:379–84. Google Scholar5. Tozuka M, Yamauchi K, Hidaka H, Nakabayashi T, Okumura N, Kat T. "Characterization of hypertriglyceridemia induced by I-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma" . Ann Clin Lab Sci. 1997; 27:351–7. Google Scholar6. Fortson M, Freedman S, Webster P. "Clinical assessment of hyperlipidemic pancreatitis" . Am J Gastro. 1995; 90:2134–9. Google Scholar7. Weetman R, Baehner R. "Latent onset of clinical pancreatitis in children receiving l-asparaginase therapy" . Cancer. 1974; 34:780–85. Google Scholar8. Hoogerbrugge N, Jansen H, Hoogerbrugge P. "Transient hyperlipidemia during treatment of ALL with l-asparaginase is related to decreased lipoprotein lipase activity" . Leukemia. 1997; 11:1377–9. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 23, Issue 3-4May-July 2003 Metrics History Accepted1 December 2002Published online1 May 2003 InformationCopyright © 2003, Annals of Saudi MedicinePDF download