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Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children
Carbamazepine and Valproic Acid: Effects on the Serum Lipids and Liver Functions in Children Sadiye Demirciog˘lu, MD, Alper Soylu, MD, and Eray Dirik, MD We aimed to determine the effects of carbamazepine, which induces liver microsomal enzymes, and valproic acid on the serum lipids and liver function test results in epileptic children. Thirty-eight epileptic children (18 males, 20 females, mean age 8.6 ⴞ 3.9 years) were evaluated for serum lipids and liver function test results at the onset and the second and sixth months of antiepileptic therapy. The results of the children receiving carbamazepine (n ⴝ 31) and valproic acid (n ⴝ 7) were compared. In addition, the values obtained at different periods of treatment were compared within each group. The differences in the serum lipid levels and liver function test results of the children in the carbamazepine group and the valproic acid group were not statistically significant throughout the study. However, the total cholesterol, low-density lipoprotein, total cholesterol/high-density lipoprotein, and gamma glutamyl transferase levels were significantly increased in the carbamazepine group during treatment (P < 0.05) but not in the valproic acid group. Carbamazepine treatment alters the serum lipid profile of the children in such a way that it facilitates the development of atherosclerosis. Valproic acid does not alter the levels of the serum lipids. © 2000 by Elsevier Science Inc. All rights reserved.
liver, and CBZ induces liver microsomal enzyme (LME) activation, leading to alterations in the metabolism of bile acids, cholesterol, other lipids, bilirubins, and many other endogenous molecules and exogenous drugs that are metabolized by these enzymes [1]. VA, on the other hand, does not induce LME activation. CBZ causes hyperlipidemia because of its stimulatory effect on the LME system [2-4]. Hyperlipidemia is one of the major risk factors of atherosclerosis, the first signs of which can be detected during childhood [5]. In this study, we evaluated the effects of long-term treatment with CBZ and VPA on the liver enzymes and serum lipids in epileptic children by a prospective, selfcontrolled method. Patients and Methods
Introduction
The study was conducted in the Pediatric Neurology Department of Dokuz Eylu¨l University Medical Faculty between September 1996 and March 1998. The patients attending the outpatient department with a history of recent new-onset seizure or those attending the emergency department during the ictal or postictal period of their first seizure were candidates for this study after evaluation of the following additional criteria: a diagnosis of epilepsy; absence of any other disease; absence of liver, kidney, heart, or any other organ system dysfunction; no history of long-term medication to treat any other disease; treatment with only CBZ or VA; and absence of a family history of early atherosclerosis or any other metabolic disease. All the patients were evaluated during the interictal period. Those who fulfilled the previous criteria were enrolled in this study after written consent from their parents was obtained. Venous blood samples of the patients were obtained from the antecubital vein after a fasting period of 8-12 hours before the onset of antiepileptic treatment and at the end of the second and sixth months of therapy. The following parameters were evaluated in these blood samples:
Carbamazepine (CBZ) and valproic acid (VPA) are among the first choice of drugs in the treatment of childhood epilepsy. These drugs are metabolized in the
1. Serum lipid profile: triglycerides (TG) in a Hitachi 747-200 autoanalyzer using the glycerophosphate calorimetric method (Rondox, UK); total cholesterol (TC) in a Hitachi 747-200 autoanalyzer using the enzymatic end-point method (Rondox); high-density lipoprotein
Demirciog˘lu S, Soylu A, Dirik E. Carbamazepine and valproic acid: Effects on the serum lipids and liver functions in children. Pediatr Neurol 2000;23:142-146.
From the Department of Pediatrics; Dokuz Eylu¨l University; Medical Faculty; I˙zmir, Turkey.
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Communications should be addressed to: Dr. Dirik; Mustafa Kemal Sahil Bulvarı; Sahil Apt. No. 255, Kat. 2; Gu¨zelyalı, I˙zmir, Turkey. Received October 19, 1999; accepted March 13, 2000.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(00)00175-2 ● 0887-8994/00/$20.00
Table 1.
Changes in serum lipids and liver function test results during carbamazepine treatment
Serum Lipids
Pretreatment
Triglycerides (mg/dL) TC (mg/dL) HDL (mg/dL) LDL (mg/dL) TC/HDL LDL/HDL Alpha-lipoprotein (%) Pre-beta-lipoprotein (%) Beta-lipoprotein (%) GGT (U/L) ALP (U/L) SGOT (U/L) SGPT (U/L) Total bilirubin (mg/dL) Direct bilirubin (mg/dL)
92.42 ⫾ 40.71 161.58 ⫾ 40 56.52 ⫾ 16.72 94.94 ⫾ 25.48 2.95 ⫾ 0.71 1.82 ⫾ 0.68 30.09 ⫾ 7.88 18.27 ⫾ 10.82 44.12 ⫾ 9.85 12.97 ⫾ 4.79 416.81 ⫾ 147.19 25.03 ⫾ 7.4 16.39 ⫾ 5.39 0.47 ⫾ 0.25 0.15 ⫾ 0.08
During Treatment Second Month Sixth Month 103.87 ⫾ 35.72 194 ⫾ 35.49 57.94 ⫾ 16.17 118 ⫾ 36.38 3.55 ⫾ 1.25 2.25 ⫾ 1.05 29.95 ⫾ 9.33 21.92 ⫾ 12.24 46.63 ⫾ 9.34 20.19 ⫾ 8.7 472.58 ⫾ 8.7 25.03 ⫾ 7.45 17.29 ⫾ 8.11 0.39 ⫾ 0.24 0.16 ⫾ 0.09
93.53 ⫾ 39.89 182.37 ⫾ 24.29 52.03 ⫾ 14.69 114.73 ⫾ 22.12 3.66 ⫾ 1.08 2.4 ⫾ 0.97 32.74 ⫾ 11.18 19.9 ⫾ 12.97 47.44 ⫾ 10.74 19.5 ⫾ 6.93 498.43 ⫾ 171.02 23.9 ⫾ 7.02 14.73 ⫾ 3.82 0.42 ⫾ 0.24 0.17 ⫾ 0.07
P Value 0.292 0.000 0.267 0.002 0.021 0.041 0.402 0.605 0.496 0.000 0.126 0.811 0.338 0.408 0.226
Data presented as the mean ⫾ S.D. Abbreviations: ALP ⫽ Alkaline phosphotase GGT ⫽ Gamma glutamyl transferase HDL ⫽ High-density lipoprotein LDL ⫽ Low-density lipoprotein
SGOT ⫽ Serum glutamic-oxaloacetic transaminase SGPT ⫽ Serum glutamic-pyruvate transaminase TC ⫽ Total cholesterol
(HDL) using the manual precipitation method; low-density lipoprotein (LDL) calculated according to the Friedewald formula; and lipid electrophoresis using the Helene Laboratories Cliniscan-2 cellulose acetate plates in an Cliniscan-2 densitometer 2. Atherogenic ratios: TC/HDL and LDL/HDL 3. Liver function tests in a Hitachi 747-200 autoanalyzer using commercial preparations (Rondox): serum gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and direct bilirubin levels The normal ranges of the parameters evaluated in this study vary in the different age groups. However, since the number of children fulfilling the inclusion criteria was small, we could not categorize the children into age groups. Instead, statistical analyses were performed on the basis of the variation of the serum levels of these parameters in relation to the time during the course of antiepileptic treatment. Statistical Analyses. Data obtained from all the patients (without considering the treatment groups) were analyzed to evaluate the variation at three different periods using analysis of variance with the random block model (significance set point: P ⬍ 0.05). The CBZ and VA groups were evaluated to compare the data obtained at different periods using the paired t test (significance set point: P ⬍ 0.016) and the Friedman two-way analysis of variance test (significance set point: P ⬍ 0.05), respectively. The number of patients with higher than normal levels of serum lipids or liver enzymes at different periods of treatment were compared using the chi-square test. The results of the CBZ and VA groups were compared by the Wilcoxon signed rank test (significance set point: P ⬍ 0.05).
Results Of the 205 patients attending the outpatient department with a history of recent new-onset seizure or those presenting during the ictal or postictal period of their first seizure to the emergency department, 60 patients (age range ⫽ 8 months to 17 years) fulfilling the study criteria
were included in this study. However, 22 of these patients did not return for follow-up visits, and the study was completed with 38 patients (18 males and 20 females, mean age ⫽ 8.6 ⫾ 3.9 years). The CBZ group included 31 patients (14 males and 17 females, mean age ⫽ 8.9 ⫾ 3.8 years). The VA group included seven patients (four males and three females, mean age ⫽ 7.6 ⫾ 4.3 years). The age and sex distributions between the two groups were not significantly different. The changes in the serum lipid levels and liver function test results during the treatment period in the CBZ group are presented in Table 1. The changes in TC, LDL, TC/HDL ratio, LDL/HDL ratio, and GGT were significant (P ⬍ 0.05). TC and LDL increased significantly in the second month of treatment compared with pretreatment levels but stayed at that level thereafter. The TC/HDL ratio increased significantly only in the sixth month of treatment compared with pretreatment values. The LDL/HDL ratio did not increased significantly in the paired t test (P ⬎ 0.016), although the differences were significant in the analysis of variance (P ⫽ 0.041). GGT increased significantly in the second month of treatment compared with the pretreatment levels, but the second and sixth month post-treatment levels were similar. On the other hand, neither serum lipid levels nor liver function test results changed significantly during the treatment period in the VA group (Table 2). The serum lipid levels and liver function test results in the CBZ group were also compared with the upper limits (95th percentile) of the normal ranges for age. Thus the parameters above the 95th percentile for that age were
Demirciog˘lu et al: Carbamazepine and Valproic Acid 143
Table 2.
Changes in serum lipids and liver function test results during valproic acid treatment
Serum Lipids
Pretreatment
Triglycerides (mg/dL) TC (mg/dL) HDL (mg/dL) LDL (mg/dL) TC/HDL LDL/HDL Alpha-lipoprotein (%) Pre-beta-lipoprotein (%) Beta-lipoprotein (%) GGT (U/L) ALP (U/L) SGOT (U/L) SGPT (U/L) Total bilirubin (mg/dL) Direct bilirubin (mg/dL)
85 ⫾ 24.18 171 ⫾ 27 62.43 ⫾ 11.77 104.29 ⫾ 42.5 2.6 ⫾ 0.56 1.67 ⫾ 0.57 27.51 ⫾ 5.95 18.75 ⫾ 6.74 44.44 ⫾ 6.61 15.04 ⫾ 5.29 416.81 ⫾ 147.19 25.03 ⫾ 7.4 16.39 ⫾ 5.39 0.47 ⫾ 0.25 0.15 ⫾ 0.08
During Treatment Second Month Sixth Month 87.14 ⫾ 30.99 177.14 ⫾ 26.91 62.14 ⫾ 12.59 106 ⫾ 17.6 2.93 ⫾ 0.75 1.81 ⫾ 0.68 30.9 ⫾ 7.95 15.18 ⫾ 10.34 49.04 ⫾ 12.02 17.54 ⫾ 7.27 472.58 ⫾ 209.13 25.03 ⫾ 7.45 17.29 ⫾ 8.11 0.39 ⫾ 0.24 0.16 ⫾ 0.09
84.71 ⫾ 31.39 169.43 ⫾ 23.57 50.57 ⫾ 14.19 103.29 ⫾ 27.15 3.53 ⫾ 0.95 2.20 ⫾ 0.83 32.76 ⫾ 13.97 21.35 ⫾ 13.24 48.52 ⫾ 13.76 18.1 ⫾ 7.31 498.43 ⫾ 171.02 23.9 ⫾ 7.02 14.73 ⫾ 3.82 0.42 ⫾ 0.24 0.17 ⫾ 0.07
P Value 0.367 0.564 0.651 0.866 0.409 0.276 0.18 0.866 0.564 0.13 0.846 0.173 0.628 0.507 0.778
Data presented as the mean ⫾ S.D. Abbreviations as in Table 1.
determined at the pretreatment and post-treatment periods (Table 3). Although the number of children with TC and LDL levels greater than the 95th percentile increased with treatment, the number with TG and HDL greater than the 95th percentile decreased. However, these changes were not statistically significant. Lipid electrophoresis revealed that, although insignificant, the amount of alpha-lipoprotein and pre-beta-lipoprotein higher than the upper limit of normal increased, but the amount of beta-lipoprotein that was higher than the upper limit of normal remained unchanged during CBZ treatment. The GGT level, which Table 3. Patients with serum lipid levels and liver function test results over the 95th percentile for age in the carbamazepine group
Serum Lipids
Pretreatment (n)
Triglycerides TC HDL LDL TC/HDL LDL/HDL* Alpha-lipoprotein Pre-beta-lipoprotein Beta-lipoprotein GGT*† ALP† SGOT SGPT Total bilirubin Conjugated bilirubin*‡
8 (25.8) 6 (19.3) 5 (16.1) 3 (9.6) 1 (3.2) 2 (6.4) 2 (6.4) 5 (16.1) 4 (12.9) 0 (0) 12 (38.7) 0 (0) 1 (3.2) 2 (6.4) 7 (22.5)
During Treatment Second Sixth Month (n) month (n) 7 (22.5) 11 (35.4) 4 (12.9) 5 (16.1) 5 (16.1) 5 (16.1) 5 (16.1) 6 (19.3) 5 (16.1) 5 (16.1) 18 (58) 0 (0) 0 (0) 1 (3.2) 3 (9.6)
5 (16.1) 7 (22.5) 3 (9.6) 7 (22.5) 4 (12.9) 8 (25.8) 5 (16.1) 7 (22.5) 4 (12.9) 2 (6.4) 17 (54.8) 0 (0) 0 (0) 1 (3.2) 0 (0)
* Pretreatment and sixth month values significantly different. Pretreatment and second month values significantly different. ‡ Second and sixth month values significantly different. Abbreviations as in Table 1. Numbers in parentheses are percentages. †
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was within normal ranges in all patients before treatment onset, increased to above the upper limit of normal in five and two children at the second and sixth months of treatment, respectively. The increase in the second month was significant (P ⫽ 0.014). Similarly, the number of children with ALP levels above the 95th percentile increased with treatment and was significant in the second month (P ⫽ 0.029). On the other hand, serum glutamicoxaloacetic transaminase, serum glutamic-pyruvate transaminase, and total bilirubin values were within normal ranges in all but one or two patients at all times. The number of children with direct bilirubin levels higher than the 95th percentile was greater before the onset of treatment, and none of the children had levels higher than the normal range at the end of the sixth month (P ⫽ 0.001 and P ⫽ 0.002 compared with the pretreatment and second month values, respectively). When the serum lipid levels and liver function test results of the CBZ and VA groups were compared by the Wilcoxon signed rank test, no difference was observed for any of the three periods between these two groups. Discussion Antiepileptic drugs inducing LME activation have been reported to increase serum HDL levels by some investigators [6]. In addition, Muuronen et al. [7] reported that the mortality related to atherosclerotic heart disease was lower among patients treated with antiepileptic drugs than in the general population. They also related this finding to the increased levels of HDL in these patients [7]. In many other studies evaluating the relationship of antiepileptic drugs to serum lipids, contradictory results have been reported about the lipid fractions affected. No sufficient data in published reports are available related to the effects of antiepileptic drugs on the serum lipid levels in child-
hood, except for one prospective study that evaluated the late changes in the serum lipid levels 2.5 years after the onset of therapy [8]. Our study, on the other hand, was a prospective, self-controlled study that evaluated the early effects of antiepileptic drugs on the serum lipid levels in the pediatric age group. Although TG levels increased slightly in the CBZ group, the TG levels before the onset and after the sixth month of therapy did not differ significantly in either the CBZ or the VA group in our study. Although some studies performed in both adults and children demonstrated that serum TG levels increased significantly during CBZ treatment, all of these studies evaluated the TG levels at least 1 year after treatment onset [4,8]. In addition, some studies have failed to demonstrate any significant elevation in TG levels even after 1 year of CBZ treatment [3,9]. Finally, some studies have observed a decrease in serum TG levels during VA treatment, and other studies have failed to demonstrate any difference, as was the case in the present study [2,3,8,9]. The most apparent change in the serum lipid profile was observed in the TC levels of the CBZ group in this study. The TC levels were significantly higher in both the second and the sixth months of therapy compared with the pretreatment levels. However, because the second and sixth-month values were not different from each other, it seems that the maximum increase in the serum TC levels resulting from liver enzyme induction occurs at the second month of CBZ therapy. Only a few studies failed to demonstrate a significant increase in TC levels during CBZ treatment [3,8]. However, many other studies observed that TC levels increased significantly, as did our study [4,6,8,9]. Serum TC levels did not differ before or during the treatment with VA in the present study. Although some studies indicated a significant decrease in the TC levels in patients receiving VA treatment [3,9], others reported that VA did not affect the TC levels [10]. The effects of antiepileptic drugs on serum lipid levels were studied first with respect to the changes on TC and HDL cholesterol; the changes in LDL cholesterol were not evaluated [6]. LDL was probably not studied because of the low incidence of atherosclerotic heart disease among persons with high levels of HDL cholesterol [11]. Later, it was determined that high LDL cholesterol levels inhibit the protective effects of HDL cholesterol [2]. In the present study, HDL cholesterol levels did not change in the children treated with either CBZ or VA. LDL cholesterol levels, on the other hand, increased significantly in the CBZ group. VA therapy did not affect the LDL cholesterol levels. Although some reports have described an association between increased levels of HDL and antiepileptic drugs that induce microsomal enzyme activation, these studies were performed in adults using control groups [4,6-9]. Some studies, however, have demonstrated an increase in HDL cholesterol with CBZ treatment or have failed to demonstrate any change with treatment [3,12]. LDL cholesterol was reported to be
significantly decreased in some studies evaluating adult patients [3,7]. However, other studies performed in adults and in children revealed increased levels, in accordance with the results of the present study [8,10]. Because 75% of TC is transported in LDL, increased levels of LDL in parallel with an increase in TC levels is expected. Because the hepatic cholesterol synthesis is stimulated by the antiepileptic drugs that induce the microsomal enzymes, this cholesterol load is transported to the plasma by LDL. Excess LDL in the plasma is taken up by the endothelial cells and macrophages by way of a receptor-independent method. This LDL cannot be converted to HDL, and thus foam cells are formed [1]. In this study the maximum elevation of TC and LDL in the CBZ group occurred in the second and sixth months of treatment, respectively. This finding led us to the assumption that some of the increased TC was converted to LDL after the second month of therapy. Thus it is possible that HDL could also increase significantly as the follow-up period of these patients is extended. Atherogenic ratios are more helpful in the diagnosis and follow-up of the atherosclerosis and atherosclerotic heart diseases. The American Academy of Pediatrics considers serum TC levels greater than 200 mg/dL and serum LDL levels greater than 129 mg/dL to be high. The American Academy of Pediatrics also considers the atherogenic ratios and LDL to be more predictive of coronary vascular disease than TC. When the TC is high, LDL and the atherogenic ratios should be determined [13]. Increased TC/HDL and LDL/HDL ratios indicate a higher risk of atherosclerosis [2,4]. Both of these ratios were determined to be increased in the CBZ group in this study. The tendency of the TC/HDL ratio to increase in the second month became statistically significant compared with the pretreatment level in the sixth month. Although the LDL/ HDL ratio also tended to increase with ongoing treatment, the level at the sixth month was not significantly higher than the pretreatment level (Table 1). Increased TC/HDL and LDL/HDL ratios were attributed to an increase in the levels of the TC and LDL, respectively. Published data related to the effects of the antiepileptic drugs on the atherogenic ratios are contradictory. Some investigators reported a significant decrease in TC/HDL ratios during the CBZ treatment [7], and some reported a slight increase during the first year of treatment followed by an insignificant decrease [4]. This ratio was reported to be increased 18 and 6 months after the onset of CBZ treatment in two studies performed in adult and pediatric patients, respectively [3,12]. Similarly, there are contradictory reports on the LDL/HDL ratio in the studies performed in adults [10]. However, the results of the studies performed in the children revealed an increase in this ratio, similar to the results in our CBZ group [12]. In the CBZ group, TC/HDL and LDL/HDL ratios greater than the upper limit of normal were more frequent in the second and sixth months, respectively, as were the levels of TC and LDL (Table 3).
Demirciog˘lu et al: Carbamazepine and Valproic Acid 145
The atherogenic ratios did not change significantly in the patients treated with VA in this study (Table 2). However, the TC/HDL and LDL/HDL ratios increased 35% and 31%, respectively, at the end of the sixth post-treatment month compared with the pretreatment levels. The CBZ group also revealed a similar degree of increase in these ratios. Thus the insignificance of the statistical analyses in VA group might be the consequence of the small number. The published data related to the effects of VA on the atherogenic ratios are also contradictory. Increased, decreased, and unchanged levels have been reported [3,9,12]. The changes in the serum alpha-lipoprotein and betalipoprotein fractions observed in the lipid electrophoresis were similar to those of HDL and LDL in the CBZ group (Table 1). However, the results of lipid electrophoresis were distributed over a wide range and were statistically insignificant. This insignificance could also be caused by the use of a semiquantitative method and low patient numbers. The level of GGT increased during CBZ treatment (P ⫽ 0, Table 1). The pattern of elevation of GGT, which peaks in the second month of treatment, is similar to those of TC and LDL. ALP is another excretion enzyme like GGT, and its mean level increased during CBZ treatment, although insignificantly (Table 1). Antiepileptic drugs causing enzyme induction were reported to lead to rickets by way of acceleration of vitamin D metabolism [14]. Thus the elevation of ALP during CBZ treatment could be caused by decreased vitamin D levels. Conjugated bilirubin levels were above the normal levels before CBZ treatment in 22.5% of the patients. However, this rate decreased to 0 in the sixth month of CBZ treatment (Table 3). This decrease could be the result of the increased excretion rate of the bilirubins along with the elevated levels of the excretory enzymes (GGT, ALP) [15]. Gough et al. [16] also observed that the serum bilirubin levels were lower in patients treated with CBZ than those of a control group. In conclusion, this study demonstrated that TC, LDL, and the atherogenic ratios increase during treatment with CBZ. In addition, the increase in the level of GGT is thought to be related to the inductive effect of CBZ. The National Child Education Program in the United States dictates that some preventive measures should be taken in childhood to prevent premature atherosclerosis [8]. Furthermore, some investigators have recommended avoiding a diet with high cholesterol levels in children treated with CBZ [8,17]. This study presents the changes in the serum lipid levels during the early period of antiepileptic treatment. The results
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of this study, in the context of the published data related to the alterations of serum lipids resulting from antiepileptic treatment inducing microsomal enzyme activation, suggest that the changes in the serum lipids beyond 6 months of treatment could be more significant. However, longer treatment periods in larger populations are needed to assess the relative risk of atherosclerosis caused by the alterations observed during treatment with CBZ.
References [1] Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 7th ed, vol II. New York: McGraw-Hill, 1995:1841-51. [2] Luoma PV. Microsomal enzyme induction, lipoproteins and atherosclerosis. Pharmacol Toxicol 1988;62:243-9. [3] Zeilthofer J, Doppelbauer A, Tribl G, Leitha T, Deecke L. Changes in serum lipid pattern during long-term anticonvulsive treatment. Clin Invest 1993;71:574-8. [4] Isojarvi JIT, Pakarinen AJ, Myllyla VV. Serum lipid levels during carbamazepine medication: A prospective study. Arch Neurol 1993;50:590-3. [5] Rationale for attention to cholesterol levels in children and adolescent. Pediatrics 1992;89(Suppl):S528-36. [6] Luoma PV, Sotanlemi EA, Pelkonen RD, Myllyla VV. Plasma high density lipoprotein cholesterol and hepatic cytochrome P-450 concentrations in epileptics undergoing anticonvulsant treatment. Scand J Clin Lab Invest 1980;40:163-7. [7] Muuronen A, Kaste M, Nikkila EA, Tolppanen EM. Mortality from ischemic heart disease among the patients using anticonvulsive drugs: A case-control study. BMJ 1985;291:1481-3. [8] Verotti A, Domizio S, Angelozzi B, Sabatino G, Morgese G, Chiarelli F. Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants. J Pediatr Child Health 1997;33:242-5. [9] Eiris JM, Lojo S, Del Rio MC, Novo I. Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995;45:1155-7. [10] Heldenberg D, Harel S, Holtzman M, Levtow O, Tamir I. The effect of chronic anticonvulsant therapy on serum lipids and lipoproteins in epileptic children. Neurology 1983;33:510-3. [11] Miller GJ, Miller NE. Plasma high-density lipoprotein concentrations and development of ischemic heart disease. Lancet 1975;1:16-9. [12] So¨zu¨er DT, Ataklı D, Dog˘u O, Baybas S, Arpacı B. Serum lipids in epileptic children treated with carbamazepine and valproate. Eur J Pediatr 1997;186:565-7. [13] American Academy of Pediatrics, Committee on Nutrition. Statement on cholesterol. Pediatrics 1992;90:469-73. [14] Tjellesen L, Christiansen C. Serum vitamin D metabolites in epileptic patients treated with two different anticonvulsants. Acta Neurol Scand 1982;66:335-41. [15] Dreifuss FE, Langer DH. Hepatic considerations in the use of antiepileptic drugs. Epilepsia 1987;28(Suppl 2):S23-9. [16] Gough HT, Goggin T, Crowley M, Callaghan N. Serum bilirubin levels with antiepileptic drugs. Epilepsia 1988;30:597-602. [17] 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.
liver, and CBZ induces liver microsomal enzyme (LME) activation, leading to alterations in the metabolism of bile acids, cholesterol, other lipids, bilirubins, and many other endogenous molecules and exogenous drugs that are metabolized by these enzymes [1]. VA, on the other hand, does not induce LME activation. CBZ causes hyperlipidemia because of its stimulatory effect on the LME system [2-4]. Hyperlipidemia is one of the major risk factors of atherosclerosis, the first signs of which can be detected during childhood [5]. In this study, we evaluated the effects of long-term treatment with CBZ and VPA on the liver enzymes and serum lipids in epileptic children by a prospective, selfcontrolled method. Patients and Methods
Introduction
The study was conducted in the Pediatric Neurology Department of Dokuz Eylu¨l University Medical Faculty between September 1996 and March 1998. The patients attending the outpatient department with a history of recent new-onset seizure or those attending the emergency department during the ictal or postictal period of their first seizure were candidates for this study after evaluation of the following additional criteria: a diagnosis of epilepsy; absence of any other disease; absence of liver, kidney, heart, or any other organ system dysfunction; no history of long-term medication to treat any other disease; treatment with only CBZ or VA; and absence of a family history of early atherosclerosis or any other metabolic disease. All the patients were evaluated during the interictal period. Those who fulfilled the previous criteria were enrolled in this study after written consent from their parents was obtained. Venous blood samples of the patients were obtained from the antecubital vein after a fasting period of 8-12 hours before the onset of antiepileptic treatment and at the end of the second and sixth months of therapy. The following parameters were evaluated in these blood samples:
Carbamazepine (CBZ) and valproic acid (VPA) are among the first choice of drugs in the treatment of childhood epilepsy. These drugs are metabolized in the
1. Serum lipid profile: triglycerides (TG) in a Hitachi 747-200 autoanalyzer using the glycerophosphate calorimetric method (Rondox, UK); total cholesterol (TC) in a Hitachi 747-200 autoanalyzer using the enzymatic end-point method (Rondox); high-density lipoprotein
Demirciog˘lu S, Soylu A, Dirik E. Carbamazepine and valproic acid: Effects on the serum lipids and liver functions in children. Pediatr Neurol 2000;23:142-146.
From the Department of Pediatrics; Dokuz Eylu¨l University; Medical Faculty; I˙zmir, Turkey.
142
PEDIATRIC NEUROLOGY
Vol. 23 No. 3
Communications should be addressed to: Dr. Dirik; Mustafa Kemal Sahil Bulvarı; Sahil Apt. No. 255, Kat. 2; Gu¨zelyalı, I˙zmir, Turkey. Received October 19, 1999; accepted March 13, 2000.
© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(00)00175-2 ● 0887-8994/00/$20.00
Table 1.
Changes in serum lipids and liver function test results during carbamazepine treatment
Serum Lipids
Pretreatment
Triglycerides (mg/dL) TC (mg/dL) HDL (mg/dL) LDL (mg/dL) TC/HDL LDL/HDL Alpha-lipoprotein (%) Pre-beta-lipoprotein (%) Beta-lipoprotein (%) GGT (U/L) ALP (U/L) SGOT (U/L) SGPT (U/L) Total bilirubin (mg/dL) Direct bilirubin (mg/dL)
92.42 ⫾ 40.71 161.58 ⫾ 40 56.52 ⫾ 16.72 94.94 ⫾ 25.48 2.95 ⫾ 0.71 1.82 ⫾ 0.68 30.09 ⫾ 7.88 18.27 ⫾ 10.82 44.12 ⫾ 9.85 12.97 ⫾ 4.79 416.81 ⫾ 147.19 25.03 ⫾ 7.4 16.39 ⫾ 5.39 0.47 ⫾ 0.25 0.15 ⫾ 0.08
During Treatment Second Month Sixth Month 103.87 ⫾ 35.72 194 ⫾ 35.49 57.94 ⫾ 16.17 118 ⫾ 36.38 3.55 ⫾ 1.25 2.25 ⫾ 1.05 29.95 ⫾ 9.33 21.92 ⫾ 12.24 46.63 ⫾ 9.34 20.19 ⫾ 8.7 472.58 ⫾ 8.7 25.03 ⫾ 7.45 17.29 ⫾ 8.11 0.39 ⫾ 0.24 0.16 ⫾ 0.09
93.53 ⫾ 39.89 182.37 ⫾ 24.29 52.03 ⫾ 14.69 114.73 ⫾ 22.12 3.66 ⫾ 1.08 2.4 ⫾ 0.97 32.74 ⫾ 11.18 19.9 ⫾ 12.97 47.44 ⫾ 10.74 19.5 ⫾ 6.93 498.43 ⫾ 171.02 23.9 ⫾ 7.02 14.73 ⫾ 3.82 0.42 ⫾ 0.24 0.17 ⫾ 0.07
P Value 0.292 0.000 0.267 0.002 0.021 0.041 0.402 0.605 0.496 0.000 0.126 0.811 0.338 0.408 0.226
Data presented as the mean ⫾ S.D. Abbreviations: ALP ⫽ Alkaline phosphotase GGT ⫽ Gamma glutamyl transferase HDL ⫽ High-density lipoprotein LDL ⫽ Low-density lipoprotein
SGOT ⫽ Serum glutamic-oxaloacetic transaminase SGPT ⫽ Serum glutamic-pyruvate transaminase TC ⫽ Total cholesterol
(HDL) using the manual precipitation method; low-density lipoprotein (LDL) calculated according to the Friedewald formula; and lipid electrophoresis using the Helene Laboratories Cliniscan-2 cellulose acetate plates in an Cliniscan-2 densitometer 2. Atherogenic ratios: TC/HDL and LDL/HDL 3. Liver function tests in a Hitachi 747-200 autoanalyzer using commercial preparations (Rondox): serum gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and direct bilirubin levels The normal ranges of the parameters evaluated in this study vary in the different age groups. However, since the number of children fulfilling the inclusion criteria was small, we could not categorize the children into age groups. Instead, statistical analyses were performed on the basis of the variation of the serum levels of these parameters in relation to the time during the course of antiepileptic treatment. Statistical Analyses. Data obtained from all the patients (without considering the treatment groups) were analyzed to evaluate the variation at three different periods using analysis of variance with the random block model (significance set point: P ⬍ 0.05). The CBZ and VA groups were evaluated to compare the data obtained at different periods using the paired t test (significance set point: P ⬍ 0.016) and the Friedman two-way analysis of variance test (significance set point: P ⬍ 0.05), respectively. The number of patients with higher than normal levels of serum lipids or liver enzymes at different periods of treatment were compared using the chi-square test. The results of the CBZ and VA groups were compared by the Wilcoxon signed rank test (significance set point: P ⬍ 0.05).
Results Of the 205 patients attending the outpatient department with a history of recent new-onset seizure or those presenting during the ictal or postictal period of their first seizure to the emergency department, 60 patients (age range ⫽ 8 months to 17 years) fulfilling the study criteria
were included in this study. However, 22 of these patients did not return for follow-up visits, and the study was completed with 38 patients (18 males and 20 females, mean age ⫽ 8.6 ⫾ 3.9 years). The CBZ group included 31 patients (14 males and 17 females, mean age ⫽ 8.9 ⫾ 3.8 years). The VA group included seven patients (four males and three females, mean age ⫽ 7.6 ⫾ 4.3 years). The age and sex distributions between the two groups were not significantly different. The changes in the serum lipid levels and liver function test results during the treatment period in the CBZ group are presented in Table 1. The changes in TC, LDL, TC/HDL ratio, LDL/HDL ratio, and GGT were significant (P ⬍ 0.05). TC and LDL increased significantly in the second month of treatment compared with pretreatment levels but stayed at that level thereafter. The TC/HDL ratio increased significantly only in the sixth month of treatment compared with pretreatment values. The LDL/HDL ratio did not increased significantly in the paired t test (P ⬎ 0.016), although the differences were significant in the analysis of variance (P ⫽ 0.041). GGT increased significantly in the second month of treatment compared with the pretreatment levels, but the second and sixth month post-treatment levels were similar. On the other hand, neither serum lipid levels nor liver function test results changed significantly during the treatment period in the VA group (Table 2). The serum lipid levels and liver function test results in the CBZ group were also compared with the upper limits (95th percentile) of the normal ranges for age. Thus the parameters above the 95th percentile for that age were
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Table 2.
Changes in serum lipids and liver function test results during valproic acid treatment
Serum Lipids
Pretreatment
Triglycerides (mg/dL) TC (mg/dL) HDL (mg/dL) LDL (mg/dL) TC/HDL LDL/HDL Alpha-lipoprotein (%) Pre-beta-lipoprotein (%) Beta-lipoprotein (%) GGT (U/L) ALP (U/L) SGOT (U/L) SGPT (U/L) Total bilirubin (mg/dL) Direct bilirubin (mg/dL)
85 ⫾ 24.18 171 ⫾ 27 62.43 ⫾ 11.77 104.29 ⫾ 42.5 2.6 ⫾ 0.56 1.67 ⫾ 0.57 27.51 ⫾ 5.95 18.75 ⫾ 6.74 44.44 ⫾ 6.61 15.04 ⫾ 5.29 416.81 ⫾ 147.19 25.03 ⫾ 7.4 16.39 ⫾ 5.39 0.47 ⫾ 0.25 0.15 ⫾ 0.08
During Treatment Second Month Sixth Month 87.14 ⫾ 30.99 177.14 ⫾ 26.91 62.14 ⫾ 12.59 106 ⫾ 17.6 2.93 ⫾ 0.75 1.81 ⫾ 0.68 30.9 ⫾ 7.95 15.18 ⫾ 10.34 49.04 ⫾ 12.02 17.54 ⫾ 7.27 472.58 ⫾ 209.13 25.03 ⫾ 7.45 17.29 ⫾ 8.11 0.39 ⫾ 0.24 0.16 ⫾ 0.09
84.71 ⫾ 31.39 169.43 ⫾ 23.57 50.57 ⫾ 14.19 103.29 ⫾ 27.15 3.53 ⫾ 0.95 2.20 ⫾ 0.83 32.76 ⫾ 13.97 21.35 ⫾ 13.24 48.52 ⫾ 13.76 18.1 ⫾ 7.31 498.43 ⫾ 171.02 23.9 ⫾ 7.02 14.73 ⫾ 3.82 0.42 ⫾ 0.24 0.17 ⫾ 0.07
P Value 0.367 0.564 0.651 0.866 0.409 0.276 0.18 0.866 0.564 0.13 0.846 0.173 0.628 0.507 0.778
Data presented as the mean ⫾ S.D. Abbreviations as in Table 1.
determined at the pretreatment and post-treatment periods (Table 3). Although the number of children with TC and LDL levels greater than the 95th percentile increased with treatment, the number with TG and HDL greater than the 95th percentile decreased. However, these changes were not statistically significant. Lipid electrophoresis revealed that, although insignificant, the amount of alpha-lipoprotein and pre-beta-lipoprotein higher than the upper limit of normal increased, but the amount of beta-lipoprotein that was higher than the upper limit of normal remained unchanged during CBZ treatment. The GGT level, which Table 3. Patients with serum lipid levels and liver function test results over the 95th percentile for age in the carbamazepine group
Serum Lipids
Pretreatment (n)
Triglycerides TC HDL LDL TC/HDL LDL/HDL* Alpha-lipoprotein Pre-beta-lipoprotein Beta-lipoprotein GGT*† ALP† SGOT SGPT Total bilirubin Conjugated bilirubin*‡
8 (25.8) 6 (19.3) 5 (16.1) 3 (9.6) 1 (3.2) 2 (6.4) 2 (6.4) 5 (16.1) 4 (12.9) 0 (0) 12 (38.7) 0 (0) 1 (3.2) 2 (6.4) 7 (22.5)
During Treatment Second Sixth Month (n) month (n) 7 (22.5) 11 (35.4) 4 (12.9) 5 (16.1) 5 (16.1) 5 (16.1) 5 (16.1) 6 (19.3) 5 (16.1) 5 (16.1) 18 (58) 0 (0) 0 (0) 1 (3.2) 3 (9.6)
5 (16.1) 7 (22.5) 3 (9.6) 7 (22.5) 4 (12.9) 8 (25.8) 5 (16.1) 7 (22.5) 4 (12.9) 2 (6.4) 17 (54.8) 0 (0) 0 (0) 1 (3.2) 0 (0)
* Pretreatment and sixth month values significantly different. Pretreatment and second month values significantly different. ‡ Second and sixth month values significantly different. Abbreviations as in Table 1. Numbers in parentheses are percentages. †
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was within normal ranges in all patients before treatment onset, increased to above the upper limit of normal in five and two children at the second and sixth months of treatment, respectively. The increase in the second month was significant (P ⫽ 0.014). Similarly, the number of children with ALP levels above the 95th percentile increased with treatment and was significant in the second month (P ⫽ 0.029). On the other hand, serum glutamicoxaloacetic transaminase, serum glutamic-pyruvate transaminase, and total bilirubin values were within normal ranges in all but one or two patients at all times. The number of children with direct bilirubin levels higher than the 95th percentile was greater before the onset of treatment, and none of the children had levels higher than the normal range at the end of the sixth month (P ⫽ 0.001 and P ⫽ 0.002 compared with the pretreatment and second month values, respectively). When the serum lipid levels and liver function test results of the CBZ and VA groups were compared by the Wilcoxon signed rank test, no difference was observed for any of the three periods between these two groups. Discussion Antiepileptic drugs inducing LME activation have been reported to increase serum HDL levels by some investigators [6]. In addition, Muuronen et al. [7] reported that the mortality related to atherosclerotic heart disease was lower among patients treated with antiepileptic drugs than in the general population. They also related this finding to the increased levels of HDL in these patients [7]. In many other studies evaluating the relationship of antiepileptic drugs to serum lipids, contradictory results have been reported about the lipid fractions affected. No sufficient data in published reports are available related to the effects of antiepileptic drugs on the serum lipid levels in child-
hood, except for one prospective study that evaluated the late changes in the serum lipid levels 2.5 years after the onset of therapy [8]. Our study, on the other hand, was a prospective, self-controlled study that evaluated the early effects of antiepileptic drugs on the serum lipid levels in the pediatric age group. Although TG levels increased slightly in the CBZ group, the TG levels before the onset and after the sixth month of therapy did not differ significantly in either the CBZ or the VA group in our study. Although some studies performed in both adults and children demonstrated that serum TG levels increased significantly during CBZ treatment, all of these studies evaluated the TG levels at least 1 year after treatment onset [4,8]. In addition, some studies have failed to demonstrate any significant elevation in TG levels even after 1 year of CBZ treatment [3,9]. Finally, some studies have observed a decrease in serum TG levels during VA treatment, and other studies have failed to demonstrate any difference, as was the case in the present study [2,3,8,9]. The most apparent change in the serum lipid profile was observed in the TC levels of the CBZ group in this study. The TC levels were significantly higher in both the second and the sixth months of therapy compared with the pretreatment levels. However, because the second and sixth-month values were not different from each other, it seems that the maximum increase in the serum TC levels resulting from liver enzyme induction occurs at the second month of CBZ therapy. Only a few studies failed to demonstrate a significant increase in TC levels during CBZ treatment [3,8]. However, many other studies observed that TC levels increased significantly, as did our study [4,6,8,9]. Serum TC levels did not differ before or during the treatment with VA in the present study. Although some studies indicated a significant decrease in the TC levels in patients receiving VA treatment [3,9], others reported that VA did not affect the TC levels [10]. The effects of antiepileptic drugs on serum lipid levels were studied first with respect to the changes on TC and HDL cholesterol; the changes in LDL cholesterol were not evaluated [6]. LDL was probably not studied because of the low incidence of atherosclerotic heart disease among persons with high levels of HDL cholesterol [11]. Later, it was determined that high LDL cholesterol levels inhibit the protective effects of HDL cholesterol [2]. In the present study, HDL cholesterol levels did not change in the children treated with either CBZ or VA. LDL cholesterol levels, on the other hand, increased significantly in the CBZ group. VA therapy did not affect the LDL cholesterol levels. Although some reports have described an association between increased levels of HDL and antiepileptic drugs that induce microsomal enzyme activation, these studies were performed in adults using control groups [4,6-9]. Some studies, however, have demonstrated an increase in HDL cholesterol with CBZ treatment or have failed to demonstrate any change with treatment [3,12]. LDL cholesterol was reported to be
significantly decreased in some studies evaluating adult patients [3,7]. However, other studies performed in adults and in children revealed increased levels, in accordance with the results of the present study [8,10]. Because 75% of TC is transported in LDL, increased levels of LDL in parallel with an increase in TC levels is expected. Because the hepatic cholesterol synthesis is stimulated by the antiepileptic drugs that induce the microsomal enzymes, this cholesterol load is transported to the plasma by LDL. Excess LDL in the plasma is taken up by the endothelial cells and macrophages by way of a receptor-independent method. This LDL cannot be converted to HDL, and thus foam cells are formed [1]. In this study the maximum elevation of TC and LDL in the CBZ group occurred in the second and sixth months of treatment, respectively. This finding led us to the assumption that some of the increased TC was converted to LDL after the second month of therapy. Thus it is possible that HDL could also increase significantly as the follow-up period of these patients is extended. Atherogenic ratios are more helpful in the diagnosis and follow-up of the atherosclerosis and atherosclerotic heart diseases. The American Academy of Pediatrics considers serum TC levels greater than 200 mg/dL and serum LDL levels greater than 129 mg/dL to be high. The American Academy of Pediatrics also considers the atherogenic ratios and LDL to be more predictive of coronary vascular disease than TC. When the TC is high, LDL and the atherogenic ratios should be determined [13]. Increased TC/HDL and LDL/HDL ratios indicate a higher risk of atherosclerosis [2,4]. Both of these ratios were determined to be increased in the CBZ group in this study. The tendency of the TC/HDL ratio to increase in the second month became statistically significant compared with the pretreatment level in the sixth month. Although the LDL/ HDL ratio also tended to increase with ongoing treatment, the level at the sixth month was not significantly higher than the pretreatment level (Table 1). Increased TC/HDL and LDL/HDL ratios were attributed to an increase in the levels of the TC and LDL, respectively. Published data related to the effects of the antiepileptic drugs on the atherogenic ratios are contradictory. Some investigators reported a significant decrease in TC/HDL ratios during the CBZ treatment [7], and some reported a slight increase during the first year of treatment followed by an insignificant decrease [4]. This ratio was reported to be increased 18 and 6 months after the onset of CBZ treatment in two studies performed in adult and pediatric patients, respectively [3,12]. Similarly, there are contradictory reports on the LDL/HDL ratio in the studies performed in adults [10]. However, the results of the studies performed in the children revealed an increase in this ratio, similar to the results in our CBZ group [12]. In the CBZ group, TC/HDL and LDL/HDL ratios greater than the upper limit of normal were more frequent in the second and sixth months, respectively, as were the levels of TC and LDL (Table 3).
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The atherogenic ratios did not change significantly in the patients treated with VA in this study (Table 2). However, the TC/HDL and LDL/HDL ratios increased 35% and 31%, respectively, at the end of the sixth post-treatment month compared with the pretreatment levels. The CBZ group also revealed a similar degree of increase in these ratios. Thus the insignificance of the statistical analyses in VA group might be the consequence of the small number. The published data related to the effects of VA on the atherogenic ratios are also contradictory. Increased, decreased, and unchanged levels have been reported [3,9,12]. The changes in the serum alpha-lipoprotein and betalipoprotein fractions observed in the lipid electrophoresis were similar to those of HDL and LDL in the CBZ group (Table 1). However, the results of lipid electrophoresis were distributed over a wide range and were statistically insignificant. This insignificance could also be caused by the use of a semiquantitative method and low patient numbers. The level of GGT increased during CBZ treatment (P ⫽ 0, Table 1). The pattern of elevation of GGT, which peaks in the second month of treatment, is similar to those of TC and LDL. ALP is another excretion enzyme like GGT, and its mean level increased during CBZ treatment, although insignificantly (Table 1). Antiepileptic drugs causing enzyme induction were reported to lead to rickets by way of acceleration of vitamin D metabolism [14]. Thus the elevation of ALP during CBZ treatment could be caused by decreased vitamin D levels. Conjugated bilirubin levels were above the normal levels before CBZ treatment in 22.5% of the patients. However, this rate decreased to 0 in the sixth month of CBZ treatment (Table 3). This decrease could be the result of the increased excretion rate of the bilirubins along with the elevated levels of the excretory enzymes (GGT, ALP) [15]. Gough et al. [16] also observed that the serum bilirubin levels were lower in patients treated with CBZ than those of a control group. In conclusion, this study demonstrated that TC, LDL, and the atherogenic ratios increase during treatment with CBZ. In addition, the increase in the level of GGT is thought to be related to the inductive effect of CBZ. The National Child Education Program in the United States dictates that some preventive measures should be taken in childhood to prevent premature atherosclerosis [8]. Furthermore, some investigators have recommended avoiding a diet with high cholesterol levels in children treated with CBZ [8,17]. This study presents the changes in the serum lipid levels during the early period of antiepileptic treatment. The results
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of this study, in the context of the published data related to the alterations of serum lipids resulting from antiepileptic treatment inducing microsomal enzyme activation, suggest that the changes in the serum lipids beyond 6 months of treatment could be more significant. However, longer treatment periods in larger populations are needed to assess the relative risk of atherosclerosis caused by the alterations observed during treatment with CBZ.
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