- Email: [email protected]
Effect of Carbamazepine Therapy on Serum Lipids in Children With Partial Epilepsy
Effect of Carbamazepine Therapy on Serum Lipids in Children With Partial Epilepsy Anju Aggarwal, MD*, Vivek Singh, MD*, Shweta Batra, MD*, M. M. A. Faridi, MD*, and Sangeeta Sharma, MD† Alteration in serum lipids leads to atherosclerosis. Antiepileptic drugs alter serum lipids. The effect of carbamazepine therapy on serum lipids of children with partial epilepsy and correlation of changes with carbamazepine level was prospectively studied. The study population of 29 children (16 male, 13 female; age range, 3-12 years) diagnosed with partial epilepsy were enrolled within 14 days of starting carbamazepine. Serum lipids were measured at enrollment and at 3 months. Carbamazepine levels were determined at 3 months of therapy. Mean total cholesterol was 130.2 ± 27.3 mg/dL at enrollment, and increased significantly to 144.8 ± 32.9 mg/dL at 3 months (P = 0.018). There was a significant change in mean low and very low density lipoproteins, and in triglycerides (P < 0.05). Both the ratio of total cholesterol to high density lipoprotein and the ratio of low density lipoprotein to high density lipoprotein increased significantly. There was no significant change in levels of high density lipoprotein. At 3 months, mean carbamazepine level was 6.5 ± 1.8 mg/dL. Changes in serum lipids did not correlate with serum carbamazepine level (P > 0.05). Carbamazepine therapy increases levels of lipids that increase the risk of atherosclerosis. Ó 2009 by Elsevier Inc. All rights reserved.
endogenous molecules and endogenous drugs that are metabolized by these enzymes [1]. Hyperlipidemia is one of the major risk factors for atherosclerosis, the first sign of which can be detected in early childhood [2]. Epidemiological clinical and experimental studies have shown that alteration in serum lipids predisposes to atherosclerosis [3]. There are contradictory reports on the influence of antiepileptic drugs on serum lipids and the associated influence on atherosclerosis [4-8]. Data from some studies indicate a significant increase in total cholesterol levels and an increase or no increase in the ratio of total cholesterol to high density lipoproteins (HDL) [4,5,8,9], whereas other studies have shown a decrease in atherosclerotic ratio [1,3]. Findings from a study in an Indian population [9] revealed that mean cholesterol and low density lipoprotein levels were significantly elevated in children on carbamazepine therapy, but that mean very low density lipoprotein (VLDL), triglycerides, and LDL/HDL and total cholesterol/HDL cholesterol ratios were not significantly altered. That was a cross-sectional study, and it did not correlate lipid levels with carbamazepine levels. The present study was conducted to prospectively evaluate change in lipid levels during carbamazepine therapy. Materials and Methods
Aggarwal A, Singh V, Batra S, Faridi MMA, Sharma S. Effect of carbamazepine therapy on serum lipids in children with partial epilepsy. Pediatr Neurol 2009;40:94-97.
This prospective study was conducted in the pediatric and neuropsychopharmacology departments of a tertiary care hospital over a period of 1 year. The sample size of 28 was calculated using standard deviation from a study conducted by Demirciog˘lu et al. [4], with acceptable difference of 25 mg/dL in cholesterol levels, significance at P < 0.05, and a power of 80%.
Introduction
Patients, Characteristics, and Tests
Carbamazepine is a commonly used drug in childhood partial epilepsy. Carbamazepine induces liver microsomal enzymes that lead to alteration in the metabolism of bile acids, cholesterol and other lipids, bilirubins, and many other
Children aged 3-12 years who presented with partial seizures were enrolled within 48 hours of presentation. Carbamazepine monotherapy was started and subjects were followed up monthly for 3 months. Children who had received any anticonvulsant before carbamazepine therapy and those suffering from with any liver, kidney, or heart disease or with gross
From the *Department of Pediatrics, University College of Medical Sciences, Guru Tegh Bahadur Hospital, Delhi, India; and the †Department of Neuropsychopharmacology, Institute of Human Behaviour and Applied Sciences, Delhi, India.
Communications should be addressed to: Dr. Aggarwal; Flat No. 3C, Block C2B; Janakpuri; New Delhi 110058, India. E-mail: [email protected] or [email protected] Received July 9, 2008; accepted October 3, 2008.
94 PEDIATRIC NEUROLOGY Vol. 40 No. 2
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.10.003 0887-8994/09/$—see front matter
developmental delay or congenital abnormalities were excluded. Children with family history of atherosclerosis were also excluded. Detailed history regarding the type of seizure, duration, aura long duration, history of hypertension, developmental history, history of jaundice was taken. Relevant family history was recorded. Weight, height, and body mass index were recorded and the patient was examined for neurological deficit. Investigations of etiology included hemogram, liver function tests, Mantoux test, chest X-ray, electroencephalography, and cranial computed tomography. Patients were started on carbamazepine at a dose of 10 mg/kg per day; if required, the dose was increased by 5 mg/kg per day to a maximum dose of 30 mg/kg/day. Patients were advised against any change in diet after starting carbamazepine therapy. A dietary history was recorded at recruitment and at start of therapy. A written informed consent was obtained from the parents. Venous blood sample for serum lipid levels was taken after 12 hours fasting and stored at 20 C. Patients were monitored monthly, and compliance was determined at all visits. At 3 months, blood sample was obtained for lipid profile and carbamazepine levels. Blood samples were collected after 12 hours fasting and before the morning dose carbamazepine. The serum lipid profile was estimated using an RA50 autoanalyzer (Bayer, Mumbai, India) with colorimetric methods for total cholesterol and full enzymatic procedures for triglycerides (Enzokit Ranbaxy, New Delhi, India). The HDL was determined by using AutoZyme HDL-Cholesterol precipitating reagent (Accurex Biomedical, Mumbai, India). The VLDL and LDL were determined using the Friedewald formula: CholesterolLDL = Cholesteroltotal (CholesterolHDL 0.2 triglycerides). Carbamazepine level was measured at the Institute of Human Behaviour and Applied Sciences neuropsychopharmacology laboratory, using cloned enzyme donor immunoassay, on an autoanalyzer system (ECHO; ISE, Srl, Rome, Italy). The laboratory results were interpreted by a clinical pharmacologist. A written comment and, if necessary, information on dosage adjustment or other remarks were provided for each antiepileptic drug level determination requested. All results within the subtherapeutic or supratherapeutic range were verified as part of the quality assurance program. The inter-run assay precision for antiepileptic drugs studied was <10%.
Statistical Analysis Data were analyzed using SPSS version 10 software (SPSS, Chicago, IL). Paired Student’s t test was used to compare mean of various parameters at enrollment and at 3 months. Correlation of lipid levels with carbamazepine was determined by coefficient of correlation. A P value of <0.05 was taken as significant.
Results Of the 46 children recruited for the study, 29 children (63%) were followed for 3 months. Characteristics of the children studied and those lost to follow-up were not significantly different (P > 0.05). Results for the children studied were analyzed to compare lipid levels and liver function tests. Mean age was 7.3 2.4 years (range, 3-12 years). Of the 29 children, 16 were male (55%) and 13 were female (45%). Type of seizure at presentation was simple partial in 9/29 children (31%) and complex partial in 20/29 (69%). Leftsided partial seizures were seen in 10 patients, and right sided partial seizures in 19. Electroencephalographic abnormalities in the form of slow waves or spike and wave form were observed in 20 children. Computed tomography scan revealed abnormalities in 19 of the patients. Ring enhancing granulomas were seen in 17 patients (14 were single; 3 had two granulomas each). One patient had cortical atrophy, one had evidence of cerebritis. Based on history, clinical
examination, Mantoux test, chest X-ray, and size of granuloma, no child was found to be tubercular. All patients had good seizure control during the 3 months. They did not receive any other anticonvulsant or any other drug other than carbamazepine. There was no change in dietary pattern during the study. Baseline levels were compared with findings at 3 months for lipids and liver function (Table 1). Cholesterol increased by 10% during the study period. Mean total cholesterol was 130.6 27.4 mg/dL and 144.8 32.9 mg/dL at baseline and 3 months respectively. This change was statistically significant. A significant increase was seen also in levels of LDL, VLDL, total cholesterol/HDL ratio, and LDL/ HDL ratio (P < 0.05). There was no significant change in levels of HDL, alkaline phosphate, or serum glutamine transaminase. Mean dose of carbamazepine at 3 months was 10.3 1.1 mg/kg per day. Mean carbamazepine level at 3 months of therapy were 6.5 1.8 m/mL (range 2.3-9.2 m/mL).There was no correlation of carbamazepine level with lipid levels at 3 months (P > 0.05) (Table 2).No correlation was found between the d change in lipids and carbamazepine levels (Table 3). Discussion Carbamazepine is a commonly used antiepileptic drug in children. Its role as an antiepileptic is mediated through sodium channel. Carbamazepine induces liver microsomal enzymes, thereby altering the metabolism of lipids, bile acids, and bilirubin [1]. This leads to alteration in serum lipid levels, and so may effect development of atherosclerosis. According to the American Academy of Pediatrics,
Table 1. Comparison of mean levels of lipids and liver function tests at baseline and 3 months in 29 children treated with carbamazepine as initial monotherapy for partial epilepsy Parameter
Baseline
At 3 months
P value
TC, mg/dL HDL, mg/dL VLDL, mg/dL LDL, mg/dL TC/HDL LDL/HDL TG, mg/dL Alkaline phosphatase, IU/L AST, IU/dL
130.6 27.3 44.3 15.1 15.8 7.3 72.3 24.6 3.1 0.86 1.8 0.7 81.8 38.7 347.8 159.8 30.5 9.3
144.7 32.9 42.2 13.0 22.1 13.1 86.6 30.6 3.7 1.1 2.2 0.9 106.6 60.1 354.2 191.8 45.7 67.1
0.018* 0.243 0.002* 0.016* 0.001* 0.018* 0.024* 0.633 0.202
* Significant at P < 0.05. Abbreviations: AST = Aspartate aminotransaminase HDL = High density lipoproteins LDL = Low density lipoproteins TC = Total cholesterol TG = Triglycerides VLDL = Very low density lipoproteins
Aggarwal et al: Carbamazepine and Serum Lipids 95
Table 2. Correlation of mean lipid level with carbamazepine level
Parameter at 3 months TC HDL VLDL LDL TG TC/HDL LDL/HDL
Correlation with carbamazepine level Pearson’s r P value (2-tailed) 0.265 0.248 0.129 0.250 0.240 0.330 0.247
0.164 0.194 0.505 0.184 0.203 0.080 0.197
Abbreviations: HDL = High density lipoproteins LDL = Low density lipoproteins TC = Total cholesterol TG = Triglycerides VLDL = Very low density lipoproteins
Committee of Nutrition [10] certain lipids such as LDL, total cholesterol, and increased total cholesterol/HDL and LDL/HDL ratios are believed to increase the risk of atherosclerosis. Increase in HDL is protective against atherosclerotic disease. Atherogenic ratios are helpful in the diagnosis and follow-up of atherosclerosis and atherosclerotic heart diseases [1]. In the present study, a significant increase in levels of total cholesterol, VLDL, LDL, and triglycerides were observed 3 months after starting carbamazepine therapy (P < 0.05). The total cholesterol/HDL ratio and LDL/HDL ratio were also increased significantly at 3 months. There was no significant change in HDL levels (P > 0.05). Thus, most of the atherogenic ratios increased on carbamazepine therapy. Long-term implications in terms of increased risk of atherosclerosis needs to be studied. The mechanism of increased lipids and atherosclerosis involves microsomal enzymes. Hepatic cholesterol synthesis is stimulated by antiepileptic drugs that induce microsomal enzymes, and this cholesterol load is transported to the plasma by LDL. Excess LDL in plasma is taken up by endothelial cells and microcytes by way of a receptor-independent method. This LDL cannot be converted to HDL, and thus foam cells are formed [11]. Most of the previous reports of an increase in lipids have been from case-control studies [5,8,9]. A few prospective studies [4,6] have demonstrated a increase in total cholesterol, LDL, and total cholesterol/HDL ratio, in accord with the present findings. Demirciog˘lu et al. [4] studied children 8 months to 17 years of age. Mean pretreatment total cholesterol in their study was 161.6 40, which increased to 194.0 35.5 at the 2nd month, then declined to 182.4 24.3 at 6 months; the total percent increase at 6 months was 13%. This increase is similar to an increase of 10% seen in the present study over 3 months. HDL levels did not change significantly, as previously reported [4]. A longer follow-up period is required to estimate the clinical significance of these changes.
96 PEDIATRIC NEUROLOGY Vol. 40 No. 2
Franzoni et al. [12] demonstrated that a rise in total cholesterol was a result of increased LDL cholesterol levels only. Others, however, have suggested an increase in both LDL and HDL cholesterol causes increase in total cholesterol [8]. In the present study, the elevated total cholesterol was due to increase in LDL. A previous study from an Indian population demonstrated a increase in both LDL and HDL but no significant alteration in LDL/HDL ratio [9]. Total cholesterol, LDL, and HDL were significantly higher in cases than in controls, but total cholesterol/HDL and LDL/HDL ratios were not increased. Variations may be due to the fact that the study included children with 6 months to 2 years of therapy. Preventive measures as alteration in dietary lipids have been suggested to counteract changes in lipid levels [8]. Monitoring of lipids should be advised in high-risk patients on carbamazepine therapy. Some studies have demonstrated no significant change in total cholesterol level [13,14] of children on carbamazepine therapy, compared with controls [13]. In a recent study with children followed for 2 years, there was no significant change in levels of atherosclerotic indices as total cholesterol/HDL cholesterol with carbamazepine, valproate or phenobarbitone therapy [14]. Furthermore, all the previous studies included children with different types of seizures or epilepsy, thus involving possibly varied etiology and other confounding factors. The study was limited to children presenting with partial epilepsy, and without any developmental delay. The reference laboratory value for therapeutic carbamazepine in children is 4-12 mg/mL. Thus, most of the subjects in the present study were within the therapeutic range. None of the previous studies have correlated the lipid levels with drug levels; in the present study, there was no correlation between carbamazepine levels and lipid levels (P > 0.05). This present findings revealed a significant increase in atherogenic lipids (total cholesterol, LDL, total cholesterol/HDL Table 3. Correlation of d change in lipid level with carbamazepine level
Parameter at 3 months TC HDL VLDL LDL TG TC/HDL LDL/HDL
Correlation with carbamazepine level Pearson’s r P value (2-tailed) 0.018 0.056 0.274 0.197 0.069 0.079 0.026
Abbreviations: HDL = High density lipoproteins LDL = Low density lipoproteins TC = Total cholesterol TG = Triglycerides VLDL = Very low density lipoproteins
0.927 0.773 0.150 0.306 0.721 0.682 0.893
ratio, LDL/HDL ratio) at 3 months of carbamazepine therapy. Monitoring of high-risk patients may be useful. Long-term follow-up is required to examine the clinical and preventive implications of these changes. References [1] Luoma PV. Microsomal enzyme induction, lipoproteins and atherosclerosis. Pharmacol Toxicol 1988;62:243-9. [2] American Academy of Pediatrics, National cholesterol education program. Report of expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992;89:525-84. [3] Muuronen A, Kaste M, Nikkila¨ EA, Tolppanen EM. Mortality from ischemic heart disease among patients using anticonvulsant drugs: a case-control study. Br Med J (Clin Res Ed) 1985;291:1481-3. [4] Demirciog˘lu S, Soylu A, Dirik E. Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children. Pediatr Neurol 2000;23:142-6. [5] Eirı´s JM, Lojo S, Del Rı´o MC, et al. Effect of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995;45:1155-7. [6] Yilmaz E, Dos xan Y, Gu¨rgo¨ze MK, Gu¨ngo¨r S. Serum lipid changes during anticonvulsive treatment in epileptic children. Acta Neurol Belg 2001;101:217-20.
[7] Nikolaos T, Stylianos G, Chryssoula N, et al. The effect of longterm antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherapy. Med Sci Monit 2004;10:MT50-2. [8] Eirı´s J, Novo-Rodrı´guez MI, Del Rı´o M, Meseguer P, Del Rı´o MC, Castro-Gago M. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy. Epilepsy Res 2000;41:1-7. [9] Aggarwal A, Kumar M, Faridi MMA. Effect of carbamazepine on serum lipids and liver function tests. Indian Pediatr 2005;42:913-8. [10] American Academy of Pediatrics, Committee on Nutrition. Statement on cholesterol. Pediatrics 1992;90:469-73. [11] Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 2. New York, McGraw-Hill, 1995:1841-51. [12] Franzoni E, Govoni M, D’Addato S, et al. Total cholesterol, high density lipoprotein cholesterol, and triglycerides in children receiving antiepileptic drugs. Epilepsia 1992;33:932-5. [13] Zeitlhofer S, Doppelbauer A, Tribl G, Leitha T, Deecke L. Changes in serum lipid pattern during long term anticonvulsant treatment. Clin Investig 1993;71:574-8. [14] Tekgul H, Demir N, Gokben S. Serum lipid profile in children receiving antiepileptic drug monotherapy: is it atherogenic? J Pediatr Endocrinol Metab 2006;19:1151-5.
Aggarwal et al: Carbamazepine and Serum Lipids 97
endogenous molecules and endogenous drugs that are metabolized by these enzymes [1]. Hyperlipidemia is one of the major risk factors for atherosclerosis, the first sign of which can be detected in early childhood [2]. Epidemiological clinical and experimental studies have shown that alteration in serum lipids predisposes to atherosclerosis [3]. There are contradictory reports on the influence of antiepileptic drugs on serum lipids and the associated influence on atherosclerosis [4-8]. Data from some studies indicate a significant increase in total cholesterol levels and an increase or no increase in the ratio of total cholesterol to high density lipoproteins (HDL) [4,5,8,9], whereas other studies have shown a decrease in atherosclerotic ratio [1,3]. Findings from a study in an Indian population [9] revealed that mean cholesterol and low density lipoprotein levels were significantly elevated in children on carbamazepine therapy, but that mean very low density lipoprotein (VLDL), triglycerides, and LDL/HDL and total cholesterol/HDL cholesterol ratios were not significantly altered. That was a cross-sectional study, and it did not correlate lipid levels with carbamazepine levels. The present study was conducted to prospectively evaluate change in lipid levels during carbamazepine therapy. Materials and Methods
Aggarwal A, Singh V, Batra S, Faridi MMA, Sharma S. Effect of carbamazepine therapy on serum lipids in children with partial epilepsy. Pediatr Neurol 2009;40:94-97.
This prospective study was conducted in the pediatric and neuropsychopharmacology departments of a tertiary care hospital over a period of 1 year. The sample size of 28 was calculated using standard deviation from a study conducted by Demirciog˘lu et al. [4], with acceptable difference of 25 mg/dL in cholesterol levels, significance at P < 0.05, and a power of 80%.
Introduction
Patients, Characteristics, and Tests
Carbamazepine is a commonly used drug in childhood partial epilepsy. Carbamazepine induces liver microsomal enzymes that lead to alteration in the metabolism of bile acids, cholesterol and other lipids, bilirubins, and many other
Children aged 3-12 years who presented with partial seizures were enrolled within 48 hours of presentation. Carbamazepine monotherapy was started and subjects were followed up monthly for 3 months. Children who had received any anticonvulsant before carbamazepine therapy and those suffering from with any liver, kidney, or heart disease or with gross
From the *Department of Pediatrics, University College of Medical Sciences, Guru Tegh Bahadur Hospital, Delhi, India; and the †Department of Neuropsychopharmacology, Institute of Human Behaviour and Applied Sciences, Delhi, India.
Communications should be addressed to: Dr. Aggarwal; Flat No. 3C, Block C2B; Janakpuri; New Delhi 110058, India. E-mail: [email protected] or [email protected] Received July 9, 2008; accepted October 3, 2008.
94 PEDIATRIC NEUROLOGY Vol. 40 No. 2
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.10.003 0887-8994/09/$—see front matter
developmental delay or congenital abnormalities were excluded. Children with family history of atherosclerosis were also excluded. Detailed history regarding the type of seizure, duration, aura long duration, history of hypertension, developmental history, history of jaundice was taken. Relevant family history was recorded. Weight, height, and body mass index were recorded and the patient was examined for neurological deficit. Investigations of etiology included hemogram, liver function tests, Mantoux test, chest X-ray, electroencephalography, and cranial computed tomography. Patients were started on carbamazepine at a dose of 10 mg/kg per day; if required, the dose was increased by 5 mg/kg per day to a maximum dose of 30 mg/kg/day. Patients were advised against any change in diet after starting carbamazepine therapy. A dietary history was recorded at recruitment and at start of therapy. A written informed consent was obtained from the parents. Venous blood sample for serum lipid levels was taken after 12 hours fasting and stored at 20 C. Patients were monitored monthly, and compliance was determined at all visits. At 3 months, blood sample was obtained for lipid profile and carbamazepine levels. Blood samples were collected after 12 hours fasting and before the morning dose carbamazepine. The serum lipid profile was estimated using an RA50 autoanalyzer (Bayer, Mumbai, India) with colorimetric methods for total cholesterol and full enzymatic procedures for triglycerides (Enzokit Ranbaxy, New Delhi, India). The HDL was determined by using AutoZyme HDL-Cholesterol precipitating reagent (Accurex Biomedical, Mumbai, India). The VLDL and LDL were determined using the Friedewald formula: CholesterolLDL = Cholesteroltotal (CholesterolHDL 0.2 triglycerides). Carbamazepine level was measured at the Institute of Human Behaviour and Applied Sciences neuropsychopharmacology laboratory, using cloned enzyme donor immunoassay, on an autoanalyzer system (ECHO; ISE, Srl, Rome, Italy). The laboratory results were interpreted by a clinical pharmacologist. A written comment and, if necessary, information on dosage adjustment or other remarks were provided for each antiepileptic drug level determination requested. All results within the subtherapeutic or supratherapeutic range were verified as part of the quality assurance program. The inter-run assay precision for antiepileptic drugs studied was <10%.
Statistical Analysis Data were analyzed using SPSS version 10 software (SPSS, Chicago, IL). Paired Student’s t test was used to compare mean of various parameters at enrollment and at 3 months. Correlation of lipid levels with carbamazepine was determined by coefficient of correlation. A P value of <0.05 was taken as significant.
Results Of the 46 children recruited for the study, 29 children (63%) were followed for 3 months. Characteristics of the children studied and those lost to follow-up were not significantly different (P > 0.05). Results for the children studied were analyzed to compare lipid levels and liver function tests. Mean age was 7.3 2.4 years (range, 3-12 years). Of the 29 children, 16 were male (55%) and 13 were female (45%). Type of seizure at presentation was simple partial in 9/29 children (31%) and complex partial in 20/29 (69%). Leftsided partial seizures were seen in 10 patients, and right sided partial seizures in 19. Electroencephalographic abnormalities in the form of slow waves or spike and wave form were observed in 20 children. Computed tomography scan revealed abnormalities in 19 of the patients. Ring enhancing granulomas were seen in 17 patients (14 were single; 3 had two granulomas each). One patient had cortical atrophy, one had evidence of cerebritis. Based on history, clinical
examination, Mantoux test, chest X-ray, and size of granuloma, no child was found to be tubercular. All patients had good seizure control during the 3 months. They did not receive any other anticonvulsant or any other drug other than carbamazepine. There was no change in dietary pattern during the study. Baseline levels were compared with findings at 3 months for lipids and liver function (Table 1). Cholesterol increased by 10% during the study period. Mean total cholesterol was 130.6 27.4 mg/dL and 144.8 32.9 mg/dL at baseline and 3 months respectively. This change was statistically significant. A significant increase was seen also in levels of LDL, VLDL, total cholesterol/HDL ratio, and LDL/ HDL ratio (P < 0.05). There was no significant change in levels of HDL, alkaline phosphate, or serum glutamine transaminase. Mean dose of carbamazepine at 3 months was 10.3 1.1 mg/kg per day. Mean carbamazepine level at 3 months of therapy were 6.5 1.8 m/mL (range 2.3-9.2 m/mL).There was no correlation of carbamazepine level with lipid levels at 3 months (P > 0.05) (Table 2).No correlation was found between the d change in lipids and carbamazepine levels (Table 3). Discussion Carbamazepine is a commonly used antiepileptic drug in children. Its role as an antiepileptic is mediated through sodium channel. Carbamazepine induces liver microsomal enzymes, thereby altering the metabolism of lipids, bile acids, and bilirubin [1]. This leads to alteration in serum lipid levels, and so may effect development of atherosclerosis. According to the American Academy of Pediatrics,
Table 1. Comparison of mean levels of lipids and liver function tests at baseline and 3 months in 29 children treated with carbamazepine as initial monotherapy for partial epilepsy Parameter
Baseline
At 3 months
P value
TC, mg/dL HDL, mg/dL VLDL, mg/dL LDL, mg/dL TC/HDL LDL/HDL TG, mg/dL Alkaline phosphatase, IU/L AST, IU/dL
130.6 27.3 44.3 15.1 15.8 7.3 72.3 24.6 3.1 0.86 1.8 0.7 81.8 38.7 347.8 159.8 30.5 9.3
144.7 32.9 42.2 13.0 22.1 13.1 86.6 30.6 3.7 1.1 2.2 0.9 106.6 60.1 354.2 191.8 45.7 67.1
0.018* 0.243 0.002* 0.016* 0.001* 0.018* 0.024* 0.633 0.202
* Significant at P < 0.05. Abbreviations: AST = Aspartate aminotransaminase HDL = High density lipoproteins LDL = Low density lipoproteins TC = Total cholesterol TG = Triglycerides VLDL = Very low density lipoproteins
Aggarwal et al: Carbamazepine and Serum Lipids 95
Table 2. Correlation of mean lipid level with carbamazepine level
Parameter at 3 months TC HDL VLDL LDL TG TC/HDL LDL/HDL
Correlation with carbamazepine level Pearson’s r P value (2-tailed) 0.265 0.248 0.129 0.250 0.240 0.330 0.247
0.164 0.194 0.505 0.184 0.203 0.080 0.197
Abbreviations: HDL = High density lipoproteins LDL = Low density lipoproteins TC = Total cholesterol TG = Triglycerides VLDL = Very low density lipoproteins
Committee of Nutrition [10] certain lipids such as LDL, total cholesterol, and increased total cholesterol/HDL and LDL/HDL ratios are believed to increase the risk of atherosclerosis. Increase in HDL is protective against atherosclerotic disease. Atherogenic ratios are helpful in the diagnosis and follow-up of atherosclerosis and atherosclerotic heart diseases [1]. In the present study, a significant increase in levels of total cholesterol, VLDL, LDL, and triglycerides were observed 3 months after starting carbamazepine therapy (P < 0.05). The total cholesterol/HDL ratio and LDL/HDL ratio were also increased significantly at 3 months. There was no significant change in HDL levels (P > 0.05). Thus, most of the atherogenic ratios increased on carbamazepine therapy. Long-term implications in terms of increased risk of atherosclerosis needs to be studied. The mechanism of increased lipids and atherosclerosis involves microsomal enzymes. Hepatic cholesterol synthesis is stimulated by antiepileptic drugs that induce microsomal enzymes, and this cholesterol load is transported to the plasma by LDL. Excess LDL in plasma is taken up by endothelial cells and microcytes by way of a receptor-independent method. This LDL cannot be converted to HDL, and thus foam cells are formed [11]. Most of the previous reports of an increase in lipids have been from case-control studies [5,8,9]. A few prospective studies [4,6] have demonstrated a increase in total cholesterol, LDL, and total cholesterol/HDL ratio, in accord with the present findings. Demirciog˘lu et al. [4] studied children 8 months to 17 years of age. Mean pretreatment total cholesterol in their study was 161.6 40, which increased to 194.0 35.5 at the 2nd month, then declined to 182.4 24.3 at 6 months; the total percent increase at 6 months was 13%. This increase is similar to an increase of 10% seen in the present study over 3 months. HDL levels did not change significantly, as previously reported [4]. A longer follow-up period is required to estimate the clinical significance of these changes.
96 PEDIATRIC NEUROLOGY Vol. 40 No. 2
Franzoni et al. [12] demonstrated that a rise in total cholesterol was a result of increased LDL cholesterol levels only. Others, however, have suggested an increase in both LDL and HDL cholesterol causes increase in total cholesterol [8]. In the present study, the elevated total cholesterol was due to increase in LDL. A previous study from an Indian population demonstrated a increase in both LDL and HDL but no significant alteration in LDL/HDL ratio [9]. Total cholesterol, LDL, and HDL were significantly higher in cases than in controls, but total cholesterol/HDL and LDL/HDL ratios were not increased. Variations may be due to the fact that the study included children with 6 months to 2 years of therapy. Preventive measures as alteration in dietary lipids have been suggested to counteract changes in lipid levels [8]. Monitoring of lipids should be advised in high-risk patients on carbamazepine therapy. Some studies have demonstrated no significant change in total cholesterol level [13,14] of children on carbamazepine therapy, compared with controls [13]. In a recent study with children followed for 2 years, there was no significant change in levels of atherosclerotic indices as total cholesterol/HDL cholesterol with carbamazepine, valproate or phenobarbitone therapy [14]. Furthermore, all the previous studies included children with different types of seizures or epilepsy, thus involving possibly varied etiology and other confounding factors. The study was limited to children presenting with partial epilepsy, and without any developmental delay. The reference laboratory value for therapeutic carbamazepine in children is 4-12 mg/mL. Thus, most of the subjects in the present study were within the therapeutic range. None of the previous studies have correlated the lipid levels with drug levels; in the present study, there was no correlation between carbamazepine levels and lipid levels (P > 0.05). This present findings revealed a significant increase in atherogenic lipids (total cholesterol, LDL, total cholesterol/HDL Table 3. Correlation of d change in lipid level with carbamazepine level
Parameter at 3 months TC HDL VLDL LDL TG TC/HDL LDL/HDL
Correlation with carbamazepine level Pearson’s r P value (2-tailed) 0.018 0.056 0.274 0.197 0.069 0.079 0.026
Abbreviations: HDL = High density lipoproteins LDL = Low density lipoproteins TC = Total cholesterol TG = Triglycerides VLDL = Very low density lipoproteins
0.927 0.773 0.150 0.306 0.721 0.682 0.893
ratio, LDL/HDL ratio) at 3 months of carbamazepine therapy. Monitoring of high-risk patients may be useful. Long-term follow-up is required to examine the clinical and preventive implications of these changes. References [1] Luoma PV. Microsomal enzyme induction, lipoproteins and atherosclerosis. Pharmacol Toxicol 1988;62:243-9. [2] American Academy of Pediatrics, National cholesterol education program. Report of expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992;89:525-84. [3] Muuronen A, Kaste M, Nikkila¨ EA, Tolppanen EM. Mortality from ischemic heart disease among patients using anticonvulsant drugs: a case-control study. Br Med J (Clin Res Ed) 1985;291:1481-3. [4] Demirciog˘lu S, Soylu A, Dirik E. Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children. Pediatr Neurol 2000;23:142-6. [5] Eirı´s JM, Lojo S, Del Rı´o MC, et al. Effect of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995;45:1155-7. [6] Yilmaz E, Dos xan Y, Gu¨rgo¨ze MK, Gu¨ngo¨r S. Serum lipid changes during anticonvulsive treatment in epileptic children. Acta Neurol Belg 2001;101:217-20.
[7] Nikolaos T, Stylianos G, Chryssoula N, et al. The effect of longterm antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherapy. Med Sci Monit 2004;10:MT50-2. [8] Eirı´s J, Novo-Rodrı´guez MI, Del Rı´o M, Meseguer P, Del Rı´o MC, Castro-Gago M. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy. Epilepsy Res 2000;41:1-7. [9] Aggarwal A, Kumar M, Faridi MMA. Effect of carbamazepine on serum lipids and liver function tests. Indian Pediatr 2005;42:913-8. [10] American Academy of Pediatrics, Committee on Nutrition. Statement on cholesterol. Pediatrics 1992;90:469-73. [11] Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 2. New York, McGraw-Hill, 1995:1841-51. [12] Franzoni E, Govoni M, D’Addato S, et al. Total cholesterol, high density lipoprotein cholesterol, and triglycerides in children receiving antiepileptic drugs. Epilepsia 1992;33:932-5. [13] Zeitlhofer S, Doppelbauer A, Tribl G, Leitha T, Deecke L. Changes in serum lipid pattern during long term anticonvulsant treatment. Clin Investig 1993;71:574-8. [14] Tekgul H, Demir N, Gokben S. Serum lipid profile in children receiving antiepileptic drug monotherapy: is it atherogenic? J Pediatr Endocrinol Metab 2006;19:1151-5.
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