1.gif (1892 bytes)

Brief Reports

Indian Pediatrics 2005; 42:913-918 

Effect of Carbamazepine on Serum Lipids and Liver Function Tests

 

Anju Aggarwal, Manish Kumar and M.M.A Faridi

From the Department of Pediatrics, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi 110 095, India.

Correspondence to: Dr. Anju Aggarwal, Flat No.3C, Block C2B, Janakpuri,
New Delhi 110 058, India. E-mail - [email protected]

Manuscript received: October 25, 2004, Initial review completed: December 14, 2004;
Revision accepted: March 18, 2005.

Abstract:

We prospectively studied the effect of carbamazepine (CBZ) therapy on serum lipids and liver function tests in 28 patients and 28 age and sex matched controls. The mean age of patients was 8.29 years, duration of therapy with CBZ 10.3 months and dose of CBZ 13.1 mg/dL. The patients and controls were comparable in weight, height and BMI. Mean + SD of cholesterol 162 ± 25.8 mg/dL in patients was significantly more (P<0.001) than controls 131±25.2 mg/dL. Mean LDL cholesterol and HDL cholesterol were also significantly raised in patients. Values of mean VLDL, triglycerides, ratio of LDL/HDL, TC/HDL-C bilirubin and SGPT were not significantly different in two groups. Blood Levels of alkaline phosphatase were significantly more in patients compared to controls. The long term implications of these findings need to be studied.

Key words: Alkaline phosphatase, Carbamazepine, Cholesterol, Lipids.

Epidemiological, clinical and experimental investigations have shown that alteration in serum lipids predisposes to atherosclerosis(1,2). There are contradictory reports on the influence of antiepileptic drugs on serum lipids and their influence on atherosclerosis(3-9). Risk of atherosclerosis is directly related to increase in serum concentration of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C); and inversely related to increase in high-density lipoprotein cholesterol (HDL-C)(10,11). Alteration in lipid profile may vary in different populations. This is one of the first studies on Indian children that aimed to evaluate the effect of carbamazepine (CBZ) on serum lipids and liver function tests.

Subjects and Methods

This prospective study was conducted in Pediatric outpatients department of a tertiary care hospital. The patients who were on CBZ monotherapy for at least three months were included in the study. Patients who had received any other anticonvulsant before CBZ therapy or were receiving two or more anticonvulsants or had a family history of atherosclerosis or metabolic disease or any other hepatic, renal or cardiac disease requiring long term therapy were excluded from the study. Patients with gross developmental delay or congenital abnormalities were also excluded from the study. Detailed family and developmental history and history regarding type of seizure, diagnosis, dose, dosing schedule was recorded. Weight and height were recorded as per standard techniques and body mass index (BMI) was calculated. The control group consisted of 28 healthy age and sex-matched children. Those who fulfilled these criteria were enrolled for this study after written consent from their parents.

Venous blood sample (2 mL) was drawn from antecubital vein and serum was separated stored at 2ºC-8ºC. Sample was collected in the morning after a fasting period of 8-12 hours in both cases and controls. Serum was analyzed for lipid profile by autoanalyzer using colorimetric method for triglycerides and total cholesterol (ENZOKIT Ranbaxy). High-density lipoprotein was determined using AutoZyme HDL-choles-terol precipitating reagent (Accurex Bio-medical). Very low density lipoproteins (VLDL) and LDL-C were calculated using Friedewald formula i.e., LDL cholesterol = Total cholesterol–(HDL cholesterol × 0.2 Triglycerides).

Statistical analysis

Based on previous study(8) a sample size of 27 was calculated to detect a difference of 22 mg/dL in mean total cholesterol with a power of 80% and a of 0.05. Data was analyzed using SPSS version 6.0. Unpaired (2-tailed) Student t test was applied to difference in means of various parameters in the two groups (significance of P <0.05). Number of patients with higher than normal blood levels were compared in patients and controls using Chi-square test. Fisher test was applied for values <5. Effect of diet, dose and duration of treatment on various parameters were analyzed using Anova test within as well as between groups using multiple comparisons.

Results

A total of 56 subjects were included (28 cases and 28 controls). Mean age was 8.3 ± 2.8 years in patients and 8.4 ± 2.6 years in controls (range 3-12 years). There were 18 females and 10 males in each group. Mean duration of therapy was 10.3 ± 6.9 months. Mean dose of CBZ was 13.1 ± 3.5 mg/kg/day. Type of seizure was partial with secondary generalization in 43% (n = 12), complex partial seizure in 46% (n = 13) and simple partial seizure in 11% (n = 3). Clinical characteristics of the two groups are shown in Table I. There was no difference in weight, height, BMI, and type of diet among the two groups. Table II depicts mean levels of lipid profile and liver function tests in cases and controls. There was significant increase in TC, LDL-C and HDL-C level in cases in comparison to controls (P <0.001). There was also significant increase in serum alkaline phosphatase in cases (P <0.03) in comparison to controls. However levels of VLDL, triglycerides (TG), LDL/HDL, TC/HDL, total bilirubin and SGPT were not altered significantly. Diet, duration of therapy, doses and dosing schedule did not alter the lipid profile and liver function test (P >0.05).

TABLE

Clinical Characteristics of Cases and Controls.

Parameter Cases (n=28) Controls (n=28)
Age (yr) 8.29 ± 2.8 8.36 ± 2.64
Sex    
     Male 10 10
     Female 18 18
Weight (kg) 21.7 ± 8.0 20.9 ± 5.6
Height (cm) 120.3 ± 18.0 118.0 ± 13.2
Body mass index 14.5 ± 2.0 14.8 ± 2.0
Diet    
     Vegetarian 15 18
     Nonvegertarian 13 10

 

TABLE II

Lipid Profile and Liver Function Tests.
Parameter
Cases (n = 28) 
Controls (n = 28) 
P value
Cholesterol (TC)
162.8 +  25.8
131 ± 25.2
0.001
HDL
49.0 +  9.16
32.9  +  11.5
<0.001
VLDL
17.0 +  7.2
21.8 +  10.6
0.5
LDL
96.7 +  22
72.5 +  21.4
<0.001
Triglycerides
84.8 +  36.3
108.7 +  52.3
0.5
Bilirubin  
0.52 +  0.13
0.66 +  0.7
0.3
SGPT
31.1 +  28.9
30.6  +  11.1
0.4
Alkaline phosphatase
398.7 +  242.1
219.7 +  175.3
0.003
TC/HDL-C
3.41 +  0.74
3.74 +  1.0
0.2
LDL-C/HDL-C
2.04 +  0.6
2.07 +  0.7
0.9
*  Values represent mean ± SD

Patients were divided in groups according to lipid levels above or below a clinically significant level (Table III). There were significantly more children with HDL >35 mg/dL and alkaline phosphatase >300 IU/L among those receiving carbamazepine compared to controls (P<0.05). Children with VLDL >30 mg/dL, TG >100 mg/dL, Cholesterol >170 mg/dL, LDL >110 mg/dL, SGPT >40 IU/L and serum bilirubin >1 mg/dL were not significantly different in two groups. If TC of >150 mg/dL or more was compared with 150 mg/dL in the two groups there was a significant difference ( P <0.001).

TABLE III

Subjects with Abnormal Lipids and Liver Function Tests.
Parameters Cases n (%) Controls n (%) P value
LDL (mg/dL)      
<110 20 (71.5%) 26(92%) 0.08
110 8 (28.5%) 2(8%)  
Cholesterol (mg/dL)      
<170   17 (60.71) 25 (89.28) 0.1
170 11 (39.28) 3 (10.71)  
VLDL (mg/dL)      
<30   27 (96) 24 (86) 0.2
30 1 (4) 4 (14)  
HDL (mg/dL)      
<35 2 (7) 13 (46.5) 0.001*
35 26 (93) 15 (53.5)  
TG (mg/dL)      
<100   18 (64) 11 (39) 0.06
100 10 (36) 17 (61)  
Bilirubin  (mg/dL)      
<1 28 (100) 27 (96) 0.3
1 0 1 (4)  
SGPT (IU/L)      
<40   22 (78.5) 23 (82) 0.7
40 6 (21.5) 5 (18)  
Alkaline phosphatase (IU/L)      
<300 13 (46.5) 25 (89) 0.001
300 15 (43.5) 3 (11)  
Discussion

CBZ is a commonly used antiepileptic drug in children. It also induces liver microsomal enzymes, thereby altering the metabolism of lipids, bile acids and bilirubin(12). This leads to alteration in serum lipid levels and thus affects the development of atherosclerosis. Some serum lipids and apoproteins are atherogenic while others seem to have an anti-atherogenic effect. Subjects with high serum HDL-C levels have a low risk of coronary heart disease, whereas those with high serum TC and LDL-C have increased risk. However the ratio between the cholesterol fractions (TC/HDL-C; HDL-C/LDL-C) is a better predictor for the development of atherosclerosis(6). Increased HDL-C/TC and HDL-C/LDL-C is a powerful protective factor against atherosclerosis while the reverse increases the risk.

There are contradictory reports on the relationship of antiepileptic drugs to serum lipids. CBZ therapy leads to increased serum HDL-C levels, and HDL-C/TC ratio also tends to be increased(6). Muuronen, et al. reported that the mortality related to athero-sclerotic heart disease was lower among patients treated with antiepileptic drugs than in the general population. They related this finding to the increased levels of HDL-C in these patients(2). Some studies have failed to demonstrate a significant change in serum lipids in patients receiving CBZ mono-therapy(6,13). However most workers have shown significant increase in TC and other lipid fractions in epileptic children receiving CBZ(7-10,14). This fact matches with the results of our study as well where we have found significantly increased levels of TC, HDL-C and LDL-C. Franzoni, et al. showed that rise in TC was a result of increased LDL-C levels only(10). Others have suggested that the increase in TC is due to increase in both LDL-C and HDL-C(11), as seen in the present study. Similarly, there are contradictory reports on the effects of anticonvulsants on atherogenic ratio (TC/HDL and LDL/HDL ratio). Increased TC/HDL and LDL/HDL ratio indicate a higher risk of atherosclerosis. It is suggested that an increase in this ratio, following CBZ therapy might increase the risk of atherosclerosis(5). The present study does not show a significant alteration in TC/HDL and LDL/HDL ratio. This result matches with the results of others(7), showing no significant difference in TC/HDL-C and LDL-C/HDL-C ratio in children receiving CBZ. In our study LDL-C levels were 33.3% higher in cases compared to controls whereas HDL-C levels were 53.3% higher. Since HDL-C levels are supposed to be protective, significance of these changes needs to be studied further.

The Committee on Nutrition of American Academy of Pediatrics (AAP) has classified serum cholesterol levels in the range of 170 to 199 mg/dL as "borderline" and levels in excess of 200 mg/dL "high"(15). Nine (32%) patients on CBZ in its study showed serum TC level in the range of 170 to 199 mg/dL as opposed to 3 (10%) in control group (P not significant). Only 2 cases (7%) had TC in excess of 200 mg/dL, compared to none in controls. The AAP defines LDL-C level in the range of 110 to 129 mg/dL "borderline" and in excess of 129 mg/dL "high". Eight (28.5%) patients on CBZ showed LDL-C in the range of 110 to 129mg/dL, compared to one in control group.

Results of liver function tests did not differ significantly in patients except for raised alkaline phosphatase. CBZ is considered to increase vitamin D metabolism, and risk of bone disease. Decreased vitamin D levels in subjects on CBZ might result in increased blood levels of alkaline phosphatase(16) as seen in this study.

This study shows that blood level of TC, LDL-C, HDL-C and alkaline phosphatase were increased during CBZ treatment. Further studies are required to examine the implication of these changes and the need for preventive measures. Long term prospective studies are required to evaluate the risk of atherosclerosis caused by alteration in serum lipid levels in children receiving therapy with CBZ.

Contributors: AA and MMAF were involved in concept and design of the study. MK collected the data. AA, MK and MMAF analyzed the data. AA and MK drafted the manuscript and MMA critically reviewed the manuscript. AA will act as guarantor.

Funding: None.

Competing Interest: None.

 

Key Messages


• Carbamazepine alters lipid levels in children.

• Long-term implication of such alterations in terms of atherosclerosis and dietary intervention needs to be studied
 

 

 References

 

1. Newman WP, Friedman DS, Voors AW. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis: the Bogalusa Heart Study. New Engl J Med 1986, 314: 138-144.

2. Muuronen A, Kaste M, Nikkila EA, Tolppanen EM. Mortality from ischemic heart disease among the patients using anticonvulsant drugs: A case control study. BMJ 1985; 291: 1481-1483.

3. Miller GJ. The epidemiology of plasma lipoproteins and atherosclerotic disease. In: Miller NE, Lewis B (eds). Lipoproteins, atherosclerosis and coronary heart disease. Elsevier, Amsterdam, pp 59-71.

4. Luoma PV. Microsomal enzyme induction lipoprotein and atherosclerosis. Pharmacol Toxicol 1988; 62: 243-249.

5. Demircioglu S, Soylu A, Diric E. Carbamazepine and valproic acid: Effects on the serum lipids and liver functions in children. Pediatr Neurol 2000, 23: 142-146.

6. Zeilthoper S, Doppelbauer A, Tribl G, Leitha T, Deecke L. Changes in serum lipid pattern during long term anticonvulsant treatment. Clin Invest 1993; 71: 574-578.

7. Eris JM, Lojo S, Del Rio MC, Novo I. Effect of long term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995; 45: 1155-1157.

8. Yilmaz E, Dosan Y, Gurgoze MK, Gungor S. Serum lipid changes during anticonvulsive treatment in epileptic children. Acta Neurol Belg 2001; 101: 217-220.

9. Nikolaos T, Stylianos G, Chryssoula N, Irini P, Christos M, Dimitrios T, et al. The effect of long-term antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherepy. Med Sci Monit 2004; 10: MT50- MT52.

10. Franzoni E, Govoni M, D’Addato S, Gualandi S, Sangiorgi Z, Descovich GC, et al. Total cholesterol, high density lipoprotein cholesterol and Triglycerides in children receiving antiepileptic drugs. Epilepsia 1992; 33: 932-935.

11. Eiris JM, Rodriguez IN, Rio MD, Mesegaer P, Rio MC, Gago MC. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and pheno-barbital therapy in children with epilepsy. Epilepsy Research 2000: 41: 1-7.

12. Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins. In: Secriver CR, Beaudet AL, Sly WS, Valle D (eds). The Metabolic and Molecular Basis of Inherited Disease, 7th edn, vol II. New York, McGraw-Hill, 1995; pp 1841-1851.

13. Dada G, Caksen H, Icagasioglu D. Effect of long term carbamazepine therepy on serum lipids, vitamin B12 and folic acid level in children. J Pediatr Endocrinol Metab 2003; 16: 193-196.

14. Bramswig S, Sudhop T, Luers C, Von Bergman K, Berthhold HK. Lipoprotein A concentration increases during treatment with carbamaze-pine. Epilepsia 2003; 44: 457-460.

15. American Academy of Pediatrics, Committee on Nutrition. Statement on cholesterol. Pediatrics 1992; 90: 469-473.

16. Tjellesen L, Christiansen C. Serum vitamin D metabolites in epileptic patients treated with two different anticonvulsants. Acta Neurol Scand 1982, 66: 335-341.

Home

Past Issue

About IP

About IAP

Feedback

Links

 Author Info.

  Subscription