|ORIGINAL CONTRIBUTION - CLINICS IN PEDIATRIC NEUROLOGY
|Year : 2017 | Volume
| Issue : 4 | Page : 180-183
Assessment of serum lipid profile and liver function parameters in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond
Muzamil M Mugloo1, Rubeena Akhtar2, Seema Malik3
1 Department of Neonatology, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India
2 Department of Anesthesia and Intensive Care, Sabah Hospital, Kuwait
3 Department of Pediatrics, Vidal Health Care Hospitals, Chennai, Tamil Nadu, India
|Date of Web Publication||7-Jul-2017|
Muzamil M Mugloo
Department of Neonatology, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objectives: The highest incidence of epilepsy in children coupled with the need of long-term antiepileptic treatment could lead to development of metabolic complications at an early age. Phenytoin and valproic acid are commonly used antiepileptic drugs in children. This study aimed to assess the serum lipid profile and liver function tests in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond. Materials and Methods: This prospective descriptive study recruited children from the pediatric outpatient department of a tertiary care GB Pant Children Hospital, Srinagar, Kashmir, India from August 2009 to September 2011. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition aged 3–18 years on phenytoin or valproic acid monotherapy for 6 months or beyond were enrolled. After baseline clinical and anthropometric evaluation (including body mass index [BMI]), the fasting blood samples were analyzed for serum lipid profile and liver enzyme changes. Results: Total of 75 children were enrolled. There were 25 patients each in phenytoin, valproic acid, and control group. We observed statistically significant high mean total cholesterol and alkaline phosphatase levels in group receiving phenytoin when compared with valproic acid or control group. Conclusion: The lipid and liver enzyme abnormalities may be observed in children on phenytoin or valproic acid therapy, which warrants careful screening and monitoring.
Keywords: Anticonvulsants, atherosclerosis, epilepsy, hyperlipidemia, liver enzymes
|How to cite this article:|
Mugloo MM, Akhtar R, Malik S. Assessment of serum lipid profile and liver function parameters in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond. Astrocyte 2017;3:180-3
|How to cite this URL:|
Mugloo MM, Akhtar R, Malik S. Assessment of serum lipid profile and liver function parameters in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond. Astrocyte [serial online] 2017 [cited 2021 Apr 11];3:180-3. Available from: http://www.astrocyte.in/text.asp?2017/3/4/180/209925
| Introduction|| |
Epilepsy is one of the most prevalent noncommunicable neurologic conditions accounting for significant disability and mortality. It is estimated to affect almost 70 million people worldwide. As per World Health Organization, nearly 80% of the people with epilepsy live in low- and middle-income countries. In many parts of the world, people with epilepsy and their families suffer from stigma and discrimination. About 5–10% of population will have at least one seizure with highest incidence occurring in early childhood and late adulthood. The community lifetime incidence of epilepsy is 3% with more than half of the cases beginning in childhood. Treatment of epilepsy often requires lifelong treatment with antiepileptic drugs, thereby increasing the likelihood of adverse effects and toxicity. Adult studies on the effects of various antiepileptic drugs on serum lipid levels and by extrapolation on atherosclerosis have reported contradictory results., Phenytoin and valproic acid are broad spectrum antiepileptic drugs commonly used for most pediatric epilepsies. The lipid abnormalities with phenytoin have been described infrequently., Although many studies have described the lipid abnormalities in children on valproic acid,,,, the results are conflicting with regard to the variable trends observed in the lipid parameters and liver enzymes. Increase in serum concentration of certain lipids and lipoproteins in children such as total cholesterol (TC), elevated triglyceride (TG) concentrations, increased low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) are important risk factors for the development of coronary heart disease in later life. Thus, evaluation for changes in serum lipid levels and liver function tests (LFT) following antiepileptic drugs may be useful to choose the safest drug and prevention of cardiovascular complications in later life. Phenytoin is metabolized in liver by hydroxylation and glucuronide conjugation. The kinetics of metabolism is capacity limited; changes from first order to zero order over therapeutic range, thus small increments in dose, produce disproportionately high plasma concentrations. Valproic acid is completely metabolized in liver by oxidation and glucuronide conjugation. Valproic acid causes a decrease in serum-free carnitine levels by inhibition of plasmalemmal carnitine uptake having concerns particularly in children younger than 2 years for developing an idiosyncratic potentially fatal hepatotoxic syndrome.
With the concerns of hepatotoxicity and derangement of lipid profiles necessitating monitoring, the present study was planned to evaluate and compare the effects of phenytoin and valproic acid on serum lipid levels and LFT in children.
| Materials and Methods|| |
This prospective descriptive study was conducted in an outpatient department in a tertiary care children hospital GB Pant in Srinagar, Kashmir, India from August 2009 to June 2011. An informed written consent was obtained from parent of each child enrolled in the study after explaining the study. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition,, aged 3–18 years on phenytoin or valproic acid monotherapy for 6 months or beyond were enrolled. Age and sex-matched healthy controls were enrolled from the outpatient department. The children who were having chronic liver, heart or renal disease, thyroid disorder or other endocrinopathies, progressive neurological or psychiatric illness, on drugs which may alter the lipid profile or liver enzymes such as steroids, insulin, statins, and those whose parents refused consent were excluded. Based on the sample size of study by Dewan et al. considering probability of type 1 error (α) of 0.05, desired power (β) of 0.8, a sample size of 25 was achieved in each group. The information on the age, sex, weight (kg), BMI, type of seizures, duration of the antiepileptic drug monotherapy, and dose of the antiepileptic drug was collected followed by detailed systemic examination.
A venous blood sample (5 ml) was drawn after an overnight fast of at least 10 hours from morning 9 am to 11 am. Serum samples were kept at −20°C until analyzed. Serum TG and TC were estimated by enzyme colorimetric assay. VLDL-C and LDL-C were calculated using Friedewald formula (LDL-C = TC-HDL + 0.2 TG). Serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetate (SGOT), and alkaline phosphatase (ALP) were estimated by a spectrophotometer. The laboratory personnel was blinded to the group of the enrolled study participant. Descriptive statistics was expressed as mean with standard deviation (mean ± SD). Analysis of variance (ANOVA) test was applied to compare lipid levels and LFT in the three groups followed by independent t-test for comparison between valproic aid and control group. P < 0.05 were considered to indicate significance in all the statistical analyses, which were performed using Statistical Package for the Social Sciences (SPSS) version 15.0.
| Results|| |
A total of 75 children were enrolled. There were 25 patients each in phenytoin, valproic acid, and control group. In this study doses of phenytoin and valproic acid were used in the ranges of 3–8 mg/kg (5.8 ± 1.3) and 10–40 mg/kg (26 ± 8.2), respectively. Statistically significant high mean TC and ALP in group receiving phenytoin for 6 months or beyond was observed when compared with valproic acid or control group. However, there was no statistically significant difference among mean TC, HDL-C, LDL-C, TG, and LFT levels in the group receiving valproic acid when compared with control group. The results of baseline, clinical, and biochemical characteristics of the three groups are shown in [Table 1].
| Discussion|| |
The present study was designed to investigate the effects of phenytoin and valproic acid on lipid profile and liver function parameters in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond.
In this study significant increase in TC and ALP levels in phenytoin group was observed when compared with valproic acid or control group. The results in this study are similar to Berlit et al., Pelkonen et al. and Luoma et al., i.e., an increase in TC and TG in epileptic patients on long-term treatment with phenytoin and to Kazamatsuri , Aldenhövel  who found an increase in ALP with long-term phenytoin treatment.
Long-term treatment with phenytoin is often accompanied by various metabolic and endocrine abnormalities. Particular attention has been paid to effects on pancreatic β-cells, where it inhibits the release of insulin and suppresses the response of plasma insulin to various stimuli, thereby increasing the serum lipid levels.
The effect of phenytoin may also be due to the induction of CYP enzyme. They are the inducers of CYP51 enzyme. CYP51 is a housekeeping gene of the cytochrome P450 super family, which is involved in cholesterol biosynthesis in humans. The CYP450 enzyme system is involved in the synthesis and metabolism of cholesterol. In particular; CYP51A1 plays a key role in cholesterol synthesis.
The results of previous studies exploring the effects of valproic acid on lipid metabolism are inconsistent. The studies have shown either increased, decreased,,, or no change ,, in the levels of serum cholesterol or triglycerides in children on valproic acid monotherapy. In this study the patients who were on valproic acid showed no significant changes in TC, HDL-C, LDL-C, and TG levels when compared with control group. Investigations by Demircioğlu et al. and Yilmaz et al. showed the similar effect of valproic acid on serum lipid profile. This study showed no significant effect of valproic acid on liver enzymes ALP, aspartate transaminase, and alanine transaminase. Investigations by Hauser et al. have found the comparable results with valproic acid.
The risk of atherosclerosis has been the main point of discussion. The Expert Panel on Blood Cholesterol Levels on Children and Adolescent of National Educational Cholesterol Program (NCEP, 1992) suggests that prevention of premature atherosclerosis should begin early in the childhood. Children are likely to be more vulnerable to any potential factor unfavorably affecting their metabolic status. As the lipid abnormalities may be encountered in children on phenytoin or valproic acid therapy, periodic monitoring and counseling for lifestyle modifications may be warranted. These should be used cautiously in those with preexisting risk factors for metabolic syndrome such as family history, obesity, dyslipidemia, hypertension, or insulin resistance.
The limitations of this study included lack of serial measurements, the unavailability of dietary habits, and long-term follow-up of the enrolled children. Despite the need for more prospective studies, this study showed need for monitoring in children on long-term phenytoin or valproic acid therapy.
| Conclusion|| |
The lipid and liver enzyme abnormalities may be observed in children on phenytoin or valproic acid therapy. Whenever these antiepileptic drugs are used, the children should be periodically screened for serum lipids.
The authors would like to thank the children and their parents for participation in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Epilepsy GC. Epilepsy in the WHO African Region: Bridging the gap. Brazzaville. World Health Organization Regional Office for Africa. 2004.
Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: A meta-analytic approach. Epilepsia 2010;51:883-90.
O'Neill B, Callaghan N, Stapleton M, Molloy W. Serum elevation of high density lipoprotein (HDL) cholesterol in epileptic patients taking carbamazepine or phenytoin. Acta Neurol Scand 1982;65:104-9.
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;33:932-5.
Dewan P, Aggarwal A, Faridi MM. Effect of phenytoin and valproic acid therapy on serum lipid levels and liver function tests. Indian Pediatr 2008;45:855.
Phabphal K, Geater A, Limapichart K, Sathirapanya P, Setthawatcharawanich S. Role of CYP2C9 polymorphism in phenytoin-related metabolic abnormalities and subclinical atherosclerosis in young adult epileptic patients. Seizure 2013;22:103-8.
Eiris JM, Lojo S, Del Rio MC, Novo I, Bravo M, Pavon P, et al
. Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995;45:1155-7.
Demircioğlu 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.
Rauchenzauner M, Haberlandt E, Scholl-Bürgi S, Karall D, Schoenherr E, Tatarczyk T, et al
. Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children. Epilepsy Res 2008;80:142-9.
Abaci A, Saygi M, Yis U, Demir K, Dirik E, Bober E. Metabolic alterations during valproic acid treatment: A prospective study. Pediatr Neurol 2009;41:435-9.
Yilmaz E, Dosan Y, Gurgoze MK, Gungor S. Serum lipid changes during anticonvulsive treatment. Serum lipids in epileptic children. Acta Neurol Belg 2001;101:217-20.
Fisher RS, Boas WV, Blume W, Elger C, Genton P, Lee P, et al
. Epileptic seizures and epilepsy: Definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470-2.
Berg AT, Scheffer IE. New concepts in classification of the epilepsies: Entering the 21st
century. Epilepsia 2011;52:1058-62.
Berlit P, Krause KH, Heuck CC, Schellenberg B. Serum lipids and anticonvulsants. Acta Neurol Scand 1982;66:328-34.
Pelkonen R, Fogelholm R, Nikkilä EA. Increase in serum cholesterol during phenytoin treatment. Br Med J 1975;4:85.
Luoma PV, Reunanen MI, Sotaniemi EA. Changes in Serum Triglyceride and Cholesterol Levels during Long-Term Phenytoin Treatment for Epilepsy. Acta Med Scand 1979;206:229-31.
Kazamatsuri H. Elevated serum alkaline phosphatase levels in epilepsy during diphenylhydantoin therapy. N Engl J Med 1970;283:1411-2.
Aldenhövel HG. The influence of long-term anticonvulsant therapy with diphenylhydantoin and carbamazepine on serum gamma-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. Eur Arch Psychiatry Neurol Sci 1988;237:312-6.
Kizer JS, Vargas-Cordon M, Brendel K, Bressler R. The in vitro
inhibition of insulin secretion by diphenylhydantoin. J Clin Invest 1970;49:1942-8.
Gibbons GF. The role of cytochrome P450 in the regulation of cholesterol biosynthesis. Lipids 2002;37:1163-70.
Verrotti A, Domizio S, Angelozzi BE, Sabatino G, Morgese G, Chiarelli F. Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants. J Paediatr Child Health 1997;33:242-5.
Tekgul H, Demir N, Gokben S. Serum lipid profile in children receiving anti-epileptic drug monotherapy: Is it atherogenic?. J Pediatr Endocrinol Metab 2006;19:1151-5.
Sonmez FM, Demir E, Orem A, Yildirmis S, Orhan F, Aslan A, et al
. Effect of antiepileptic drugs on plasma lipids, lipoprotein (a), and liver enzymes. J Child Neurol 2006;21:70-4.
Hauser E, Seidl R, Freilinger M, Male C, Herkner K. Hematologic manifestations and impaired liver synthetic function during valproic acid monotherapy. Brain Dev 1996;18:105-9.