Journal http://jcn.sagepub.com/ of Child Neurology
Evaluation of Thyroid Hormones in Children Receiving Carbamazepine or Valproate: A Prospective Study Ihsan Kafadar, Betül Aydin Kiliç, Mujde Arapoglu, Koray Yalçin and Nazan Dalgiç J Child Neurol published online 15 April 2014 DOI: 10.1177/0883073814529822 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/04/14/0883073814529822
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Original Article
Evaluation of Thyroid Hormones in Children Receiving Carbamazepine or Valproate: A Prospective Study
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814529822 jcn.sagepub.com
_ Ihsan Kafadar, MD1, Betu¨l Aydın Kılıc¸, MD2, Mujde Arapoglu, MD3, Koray Yalc¸ın, MD4, and Nazan Dalgıc¸, MD2
Abstract The aim of this study was to determine the alterations in thyroid function during carbamazepine or valproate monotherapy in a prospective study. Forty patients treated with valproate, 33 patients treated with carbamazepine, and 36 control patients, all aged between 2 and 18 years, were enrolled in our study. Serum levels of thyroid hormones were measured before the beginning of the antiepileptic therapy and at 6 and 12 months of treatment. Carbamazepine-treated patients showed mean serum thyroid hormone levels significantly lower than baseline evaluation and the control group. Thyroid-stimulating hormone levels at 6 and 12 months were not significantly different in carbamazepine treated patients. Serum hormone levels did not change during valproate treatment. Thyroid-stimulating hormone levels were significantly higher at the 12th month of valproate treatment. Our data suggest that although carbamazepine causes significant alterations in thyroid hormone levels, these changes do not lead to clinical symptoms at the follow-up period of 12 months. Keywords carbamazepine, valproate, children, epilepsy, thyroid functions Received December 01, 2013. Received revised February 21, 2014. Accepted for publication March 05, 2014.
Carbamazepine and valproic acid are the most commonly used antiepileptic drugs in children with partial or generalized epilepsy. Although they are well tolerated, they have subtle effects on thyroid function.1,2 Majority of the studies about the effects of antiepileptic drugs on thyroid function have been performed in adult patients. Different thyroid dysfunctions and subclinical hypothyroidism have been reported in the literature in adults.3,4 There are few studies in children based on the long- and short-term effects of antiepileptic drugs on thyroid functions.2,5 Most of these are retrospective studies.1,6 This is one of the few prospective studies including a control group about the effects of antiepileptic treatment on thyroid function in children. In our study, changes in serum thyroid hormone levels during carbamazepine or valproic acid monotherapy were analyzed.
findings. Seizure type was classified according to the criteria of the International League Against Epilepsy.7 We studied 36 sex- and age-matched controls. Control group consisted of patients admitted to the department of Pediatric Neurology outpatient clinic of the same hospital during the same period for reasons other than convulsions. Their physical and laboratory examination findings were all normal. The main criteria for exclusion from the study were abnormal neurologic and/or physical examination, abnormal cerebral computed tomography and/or magnetic resonance imaging (MRI) scan, any systemic disease, and poor seizure control. Patients who were on other medication or had history of previous antiepileptic drug use, who had severe mental retardation or other combined neurologic disorders, and
1
Methods A total of 40 newly diagnosed patients who were planned to receive valproic acid and a total of 33 newly diagnosed patients who were planned to receive carbamazepine treatment were enrolled in our study. Our patients were admitted to the Pediatric Neurology outpatient clinic of our hospital in Istanbul with the diagnosis of partial or generalized epilepsy between March 2012 and February 2013. Patients were aged between 2 and 18 years. They were diagnosed as epilepsy with the history, clinical, and electroencephalographical
Department of Pediatrics, Division of Pediatric Neurology, Sisli Etfal Training & Research Hospital, Istanbul, Turkey 2 Department of Pediatrics, Sisli Etfal Training & Research Hospital, Istanbul, Turkey 3 Department of Pediatrics, Acibadem University, Istanbul, Turkey 4 Department of Pediatrics, Okmeydanı Training & Research Hospital, Istanbul, Turkey Corresponding Author: Mujde Arapoglu, MD, Maslak Acibadem Hospital, Bu¨yu¨kdere Cad. No: 40, Maslak, 34457, Istanbul, Turkey. Email: [email protected]
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who had abnormal thyroid hormone levels or other biochemical findings before treatment were also excluded from the study. Age, sex, epilepsy type, electroencephalographic (EEG) changes, number of seizures and seizure control, dosage of the antiepileptic drugs used, and serum levels of carbamazepine and valproic acid at 6 and 12 months of treatment were evaluated. Serum thyroxine (T4), triiodothyronine (T3), free thyroxine (fT4), free triiodothyronine (fT3), and thyroidstimulating hormone were measured before the beginning of the antiepileptic therapy and at 6 and 12 months of treatment. Thyroid hormone levels were compared in carbamazepine- and valproic acid–treated patients and with the control group. Thyroid glands were carefully palpated and presence of palpitation, fatigue, sweating, weight change, constipation, and nervousness were recorded in each patient. Carbamazepine and valproic acid were prescribed at the normal dosages: carbamazepine 20 to 30 mg/kg per day and valproic acid 20 to 30 mg/kg per day. Both were administered in 2 doses. Therapeutic ranges of serum levels were accepted between 50 and 100 mg/mL for valproic acid and 4 and 12 mg/mL for carbamazepine. All patients had serum levels of antiepileptic drugs within these limits. Reference ranges for the serum concentrations of triiodothyronine was 0.80 to 1.7 ng/mL, thyroxine was 5.5 to 13 mg/dL, free triiodothyronine was 2 to 5 pg/mL, free thyroxine was 0.8 to 2.3 ng/dL, and thyroid-stimulating hormone was 0.7 to 5 mIU/mL. Serum thyroxine, triiodothyronine, free thyroxine, free triiodothyronine, and thyroid-stimulating hormone levels were performed by chemiluminescent immunoassay (ADVIA Centaur XP device, Siemens Healthcare Firm). Serum level of valproic acid was measured with chemiluminescent immunoassay using the IMMULITE 2000 system (Siemens Medical Solutions, USA). Serum level of carbamazepine was measured with florescence polarization immunoassay using the INTEGRA 400 system (Roche Diagnostics, USA).
Statistical Analysis SPSS software (version 13.0; SPSS, Chicago, IL) was used to analyze the data. One-way analysis of variance was used for the comparison of the averages of more than 2 groups. Tukey and Tamhane tests were applied for the multiple comparisons. Pearson chi-square and Fisher exact tests were used for the comparison of categorical variables. Repeated measures analyses of general linear models were performed for the relationship between the measurements at the beginning of the treatment, at 6 and 12 months of treatment, and for the relationship between the 2 patient groups. Benforroni test was used for the paired comparison with Pillai’s Trace test. Pearson and Spearman correlation tests were performed at the analysis of the relationship of the variables of patient groups in itself. A P value lower than .05 was considered significant.
Results Mean age of the carbamazepine-treated patients was 10.3 + 3.70 years. Mean age of the valproic acid–treated patients was 9.7 + 4.16 years and mean age of the control group was 10.1 + 3.17 years. Thirty-three patients were treated with carbamazepine, of whom 11 were girls (33.3%) and 22 were boys (66.7%). Forty patients were treated with valproic acid, of whom 14 were girls (35%) and 26 were boys (65%). The control group consisted of 36 patients, of whom 16 (44.4%) were girls and 20 (55.6%) were boys. Mean age and sex were similar in all groups (P > .05).
Carbamazepine-treated patients were followed up 31.5 (+7.4) months. Valproic acid–treated patients were followed up 34 (+9.5) months. Follow-up period was similar in both groups (P > .05). At baseline evaluation, thyroid hormones were normal in all epileptic children and the control group. Baseline hormone levels were not statistically different in all groups (P > .05). Carbamazepine-treated patients showed mean serum thyroxine, free thyroxine, triiodothyronine, and free triiodothyronine levels significantly lower than baseline evaluation (6- and 12-month serum level of thyroxine compared to baseline was P < .01 and P < .001, respectively; 6-month serum level of free thyroxine compared to baseline was P < .001; 6- and 12-month serum level of triiodothyronine compared to baseline was P < .05 and P < .01, respectively; 12-month serum level of free triiodothyronine compared to baseline was P .05) (Table 1). Serum thyroxine, free thyroxine, triiodothyronine, and free triiodothyronine levels were not significantly different compared to baseline and the control group in valproic acid–treated patients (P > .05). Mean thyroid-stimulating hormone levels were within normal limits in both groups. Thyroid-stimulating hormone levels were significantly higher at the 12th month of valproic acid treatment compared to baseline levels and the control group (P < .05). (Table 2) Correlation between serum levels of carbamazepine and valproic acid and thyroid hormones and thyroid-stimulating hormone levels at 6 and 12 months of treatment were not significantly different in between groups (P > .05) (Tables 3 and 4). Electroencephalographic changes were mostly focal sharp or spike waves, and generalized spike-waves activity in both groups. Background activity was normal. None of the patients showed continuous spike waves during sleep, electrical status epilepticus in sleep or burst suppression pattern. Mean number of seizures until the beginning of the treatment was 3.1 + 1.72 in the carbamazepine group and 2.95 + 0.95 in the valproic acid group. In 78.8% of patients (n ¼ 26), seizures were under control by 12 months of carbamazepine treatment, whereas in 21.2% of patients (n ¼ 7), seizures were not under control. In the first 12 months of treatment, patients on carbamazepine who did not respond to treatment had 1.75 + 0.7 seizures. In the valproic acid group, seizures were under control in 80% (n ¼ 32) of patients, and 20% of patients (n ¼ 8) still had convulsions (1.57 + 0.53) by 12 months. Seizure control was not statistically different in
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Table 1. Mean Hormone Levels of the Patients Receiving Carbamazepinea Control group
Before treatment
6th mo of treatment
12th mo of treatment
T4
8.51 (1.62)
8.38 (1.85)
7.06 (2.14)
6.94 (2.04)
fT4
1.36 (0.14)
1.38 (0.23)
1.24 (0.28)
1.26 (0.31)
T3
1.37 (0.21)
1.32 (0.19)
1.26 (0.19)
1.24 (0.22)
fT3
3.15 (0.38)
3.07 (0.46)
2.91 (0.59)
2.85 (0.54)
TSH
2.46 (0.99)
2.48 (1.17)
2.48 (0.97)
2.49 (1.99)
P value P0 > P1 < P10 < P2 < P20 < P3 > P0 > P1 < P10 < P2 > P20 > P3 > P0 > P1 < P10 < P2 < P20 < P3 > P0 > P1 > P10 > P2 < P20 < P3 > P0 > P1 > P10 > P2 > P20 > P3 >
0.05 0.01* 0.001* 0.001* 0.001* 0.05 0.05 0.001* 0.01* 0.05 0.05 0.05 0.05 0.05* 0.001* 0.01* 0.001* 0.05 0.05 0.05 0.05 0.05* 0.01* 0.05 0.05 0.05 0.05 0.05 0.05 0.05
Abbreviations: P0, baseline levels compared with the control group; P1, 6-month levels compared with the baseline; P10, 6-month levels compared with the control group; P2, 12-month levels compared with the baseline; P20, 12-month levels compared with the control group; P3, 12-month levels compared with the 6-month levels; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine; fT4, free thyroxine; fT3, free triiodothyronine. a Values are mean (standard deviation). *Statistically significant value.
between groups (P > .05). Triiodothyronine and thyroxine levels were not statistically different in both groups (P > .05). When seizure control was compared to the antiepileptic drugs used, triiodothyronine and thyroxine levels were not significantly different in between groups (P > .05). Serum free triiodothyronine and free thyroxine levels were significantly lower in the group of patients whose seizures were not under control (P < .001). When seizure control was compared to the antiepileptic drugs used, free triiodothyronine and free thyroxine levels were not significantly different in between groups (P > .05). Thyroidstimulating hormone levels were not significantly different in between groups (P > .05). When seizure control was compared to the antiepileptic drugs used, thyroid-stimulating hormone levels were not significantly different in between groups (P > .05).
Discussion Antiepileptic treatment, especially valproate and carbamazepine, is known to affect thyroid hormone levels. The exact
mechanism of these alterations is unclear. Some studies postulate that epilepsy itself might cause changes in hormone levels with an effect on the hypothalamus-hypophysis-thyroid axis.8 In our study, blood tests were performed after the patients had their first convulsions and before the beginning of the treatment. Since our baseline evaluations for thyroid functions compared with the healthy control group were normal; we suppose that thyroid changes are not the result of the convulsive disorder itself (P > .05). Our follow-up study demonstrated that carbamazepinetreated patients had mean serum thyroxine, free thyroxine, triiodothyronine, and free triiodothyronine levels significantly lower than the baseline evaluation and the control group. Thyroid-stimulating hormone levels in this group did not change over the follow-up period of 12 months. Some studies report similar findings, whereas in some studies triiodothyronine and free triiodothyronine levels remain unchanged. Most of these studies with carbamazepine are retrospective studies.3,5,9
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Table 2. Mean Hormone Levels of the Patients Receiving Valproic Acida Control group
Before treatment
6th mo of treatment
12th mo of treatment
T4
8.51 (1.62)
8.72 (2.03)
8.25 (1.76)
8.32 (1.81)
fT4
1.36 (0.14)
1.37 (0.21)
1.29 (0.2)
1.29 (0.25)
T3
1.37 (0.21)
1.40 (0.29)
1.32 (0.25)
1.31 (0.38)
fT3
3.15 (0.38)
3.29 (0.69)
3.21 (0.78)
3.16 (0.74)
TSH
2.46 (0.99)
2.46 (1.07)
2.98 (1.38)
3.17 (1.5)
P value P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 < P20 < P3 >
0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05* 0.05* 0.05
Abbreviations: fT4, free thyroxine; fT3, free triiodothyronine; P0, baseline levels compared with the control group; P1, 6-month levels compared with the baseline; P10, 6-month levels compared with the control group; P2, 12-month levels compared with the baseline; P20, 12-month levels compared with the control group; P3, 12-month levels compared with the 6-month levels; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine. a Values are mean (standard deviation). *Statistically significant value.
Table 3. Correlation Between Drug Serum Levels and Thyroid Hormones at 6 Months of Treatment.
Serum CBZ levels at 6 mo Serum VPA levels at 6 mo
T4 r value at 6 mo
fT4 r value at 6 mo
T3 r value at 6 mo
fT3 r value at 6 mo
TSH r value at 6 mo
0.25 (P < .05) 0.184 (P < .05)
0.20 (P < .05) 0.204 (P < .05)
0.051 (P < .05) 0.182 (P < .05)
0.126 (P < .05) 0.12 (P < .05)
0.21 (P < .05) 0.278 (P < .05)
Abbreviations: CBZ, carbamazepine; fT4, free thyroxine; fT3, free triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine; VPA, valproic acid.
Table 4. Correlation Between Drug Serum Levels and Thyroid Hormones at 12 Months of Treatment. T4 r value at 12 mo fT4 r value at 12 mo T3 r value at 12 mo fT3 r value at 12 mo TSH r value at 12 mo Serum CBZ levels at 12 mo Serum VPA levels at 12 mo
0.303 (P < .05) 0.20 (P < .05)
0.12 (P < .05) 0.227 (P < .05)
0.134 (P < .05) 0.245 (P < .05)
0.162 (P < .05) 0.067 (P < .05)
0.211 (P < .05) 0.234 (P < .05)
Abbreviations: CBZ, carbamazepine; fT4, free thyroxine; fT3, free triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine; VPA, valproic acid.
Aggarwal et al9 found that both valproic acid and carbamazepine alter thyroid functions by decreasing free thyroxine levels-more with carbamazepine in their retrospective study.
Verrotti et al10 evaluated thyroid hormone levels at 0, 3, 6, and 12 months of carbamazepine therapy and demonstrated that free thyroxine levels were significantly lower than baseline at
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3, 6, and 12 months, whereas thyroid-stimulating hormone remained unchanged. These findings were similar to ours, whereas in some studies carbamazepine treatment is found to increase thyroid-stimulating hormone levels.1,2,11 A decrease in serum thyroid hormone levels can already be detected in patients receiving carbamazepine as early as 1 or 2 months after the initiation of the treatment in a few studies that were planned prospectively.12 Thyroid hormone levels were already lower at 6 months of carbamazepine treatment in most studies, and this decrease persisted at 12 months as in our study.4 A decrease in serum concentrations of thyroid hormones may be due to induction of the hepatic P450 enzyme system, resulting in an increase in the metabolism of thyroid hormones.13 Positive feedback mechanism of the hypothalamic– pituitary–thyroid axis may not be activated by this decrease in free thyroxine and free triiodothyronine levels. Thus, thyroid-stimulating hormone levels in these patients remain normal.10 Another effect of carbamazepine on thyroid hormones may be due to interference with the competitive binding of thyroid hormone to thyroxine-binding globulin.12 Peripheral conversion of thyroxine to active triiodothyronine also increases, leading to significantly low levels of free thyroxine compared to control groups. Our patients receiving valproic acid did not show any significant abnormalities of thyroid hormones compared to baseline levels and the control group (P > .05). Thyroid-stimulating hormone levels at 12 months of valproic acid treatment were significantly high compared to baseline levels and the control group (P < .05). The effect of valproic acid on thyroid hormones is different in various studies. Most of the previous reports showed no change of thyroid function.1,3,5,10 Both low and unchanged serum thyroxine and free thyroxine levels with normal thyroid-stimulating hormone levels have been found in patients receiving valproic acid monotherapy,1 whereas other studies documented high thyroid-stimulating hormone levels.6,14-16 In another study, out of 143 patients receiving valproic acid, 36 had thyroid-stimulating hormone >5 mIU/L (index level for subclinical hypothyroidism) and 10 had low levels of free thyroxine. Out of 36 patients with high thyroid-stimulating hormone levels, 9 had symptoms of hypothyroidism.14 On the other hand, a study by Verrotti et al10 demonstrated no alteration in children receiving valproate monotherapy. These different results seem partly due to different study methods in mostly retrospective studies. Thyroidstimulating hormone levels also seem to vary widely among different populations. Therefore, prospective studies with a control group would be more reliable about the effects of antiepileptic drugs as our study. Increase in thyroid-stimulating hormone with valproic acid treatment might be due to g-aminobutyric acid (GABA)–stimulating properties of valproic acid. GABA inhibits release of somatostatin, which inhibits thyroid-stimulating hormone secretion.17,18 Valproic acid treatment might also lead to zinc and selenium deficiencies which are important enzymes in thyroid hormone synthesis, but the evidence is insufficient.18
Extra thyroidal pathways other than hypothalamic-pituitaryaxis alterations might also be involved in thyroid hormone metabolism. Decrease in the concentration of serum thyroxine-binding globulin and displacement from proteinbinding sites are also other possible explanations.2,16 Although our patients on carbamazepine treatment had lower thyroid hormone levels during the follow-up period, these changes were all within normal reference ranges. Their thyroid-stimulating hormone levels also did not change and none of these hormonal changes led to any clinical symptoms in the follow-up period of 12 months. Therefore, clinical significance of low serum thyroid hormone concentrations is unclear. More long-term studies are needed to detect any subtle changes in asymptomatic individuals. When epileptic activity was compared in both groups as number of seizures and severity of EEG changes, we did not find a correlation between hormone levels and epileptic activity. There might be an association between the development of low serum thyroid hormone levels and serum antiepileptic drugs concentrations.16 High daily antiepileptic drug dose might be proportional to high serum antiepileptic drugs levels. Serum antiepileptic drug levels did not change in our follow-up period of 12 months. We did not find a correlation between thyroid hormone levels and daily antiepileptic drug dosage and serum antiepileptic drug levels. Verrotti et al10 also did not find a similar correlation. A limitation of our study is that we could not study the effect on thyroid function after discontinuation of the therapy. Some studies show that high thyroid hormone levels return to normal after discontinuation of antiepileptic drugs.6,10,16 In conclusion, our data suggest that although carbamazepine causes significant alterations in thyroid hormone levels, these changes do not lead to clinical symptoms. Valproic acid does not alter serum levels of thyroid hormones. Although subclinical changes induced by these drugs seem to be transient and reversible, clinicians should be aware of these changes. Further prospective and long-term studies are required to monitor the effects of antiepileptic treatment on thyroid function. Acknowledgment All work occured in Pediatric Neurology Clinic of Sisli Etfal Government Hospital.
Author Contributions _ wrote the first draft of the article. MA reviewed and edited the artiIK cle. BAK and ND acquired the data. KY was responsible for analysis and interpretation of data and stastistical work.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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Ethical Approval The informed consent of this study has been signed by the parents. The study was approved by the Ethical Committee of the Sisli Etfal Training & Research Hospital (201171).
References 1. Verrotti A, Basciani F, Morrresi S, et al. Thyroid hormones in epileptic children receiving carbamazepine and valproic acid. Pediatr Neurol. 2001;25:43-46. 2. Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, et al. Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia. 1999;40:1761-1766. 3. Isoja¨rvi JIT, Turkka J, Pakarinen AJ, et al. Thyroid function in men taking carbamazepine, oxcarbazepine or valproate for epilepsy. Epilepsia. 2001;42:930-934. 4. Lossius MI, Taubøll E, Mowinckel P, Gjerstad L. Reversible effects of antiepileptic drugs on thyroid hormones in men and women with epilepsy: a prospective randomized double-blind withdrawal study. Epilepsy Behav. 2009;16:64-68. 5. Hirfanog˘lu T, Serdarog˘lu A, C ¸ amurdan O, et al. Thyroid function and volume in epileptic children using carbamazepine, oxcarbamazepine and valproat. Pediatr Int. 2007;49:822-826. 6. Vainionpa¨a¨ LK, Mikkonen K, Ra¨ttya¨ J, et al. Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication. Epilepsia. 2004;45:197-203. 7. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-685. 8. Timiras PS, Hill HF. Hormones and epilepsy. Adv Neurol. 1980; 27:655-666.
9. Aggarwal A, Rastogi N, Mittal H, et al. Thyroid hormone levels in children receiving carbamazepine or valproate. Pediatr Neurol. 2011;45:159-162. 10. Verrotti A, Laus M, Scardapane A, et al. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol. 2009;160:81-86. 11. Attilakos A, Garoufi A, Voudris K, et al. Thyroid dysfunction associated with increased low-density lipoprotein cholesterol in epileptic children treated with carbamazepine monotherapy: a causal relationship? Eur J Paediatr Neurol. 2007;11: 358-361. 12. Isoja¨rvi JI, Pakarinen AJ, Myllyla¨ VV. Thyroid function in epileptic patients treated with carbamazepine. Arch Neurol. 1989; 46:1175-1178. 13. Connell JM, Rapeport WG, Gordon S, Brodie MJ. Changes in circulating thyroid hormones during short-term hepatic enzyme induction with carbamazepine. Eur J Clin Pharmacol. 1984;26: 453-456. 14. Mikati MA, Tarabay H, Khalil A, et al. Risk factors for development of subclinical hypothyroidism during valproic acid therapy. J Pediatr. 2007;151:178-181. 15. Attilakos A, Katsarou E, Prassouli A, et al. Thyroid function in children with epilepsy treated with sodium valproate monotherapy: a prospective study. Clin Neuropharmacol. 2009;32: 32-34. 16. Kim SH, Chung HR, Kim SH, et al. Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy. Neuropediatrics. 2012;43:135-139. 17. Lo¨scher W, Schmidt D. Increase of human plasma GABA by sodium valproate. Epilepsia. 1980;21:611-615. 18. Castro-Gago M, Novo-Rodrı´guez MI, Go´mez-Lado C, et al. Evolution of subclinical hypothyroidism in children treated with antiepileptic drugs. Pediatr Neurol. 2007;37:426-430.
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Evaluation of Thyroid Hormones in Children Receiving Carbamazepine or Valproate: A Prospective Study Ihsan Kafadar, Betül Aydin Kiliç, Mujde Arapoglu, Koray Yalçin and Nazan Dalgiç J Child Neurol published online 15 April 2014 DOI: 10.1177/0883073814529822 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/04/14/0883073814529822
Published by: http://www.sagepublications.com
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>> OnlineFirst Version of Record - Apr 15, 2014 What is This?
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Original Article
Evaluation of Thyroid Hormones in Children Receiving Carbamazepine or Valproate: A Prospective Study
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814529822 jcn.sagepub.com
_ Ihsan Kafadar, MD1, Betu¨l Aydın Kılıc¸, MD2, Mujde Arapoglu, MD3, Koray Yalc¸ın, MD4, and Nazan Dalgıc¸, MD2
Abstract The aim of this study was to determine the alterations in thyroid function during carbamazepine or valproate monotherapy in a prospective study. Forty patients treated with valproate, 33 patients treated with carbamazepine, and 36 control patients, all aged between 2 and 18 years, were enrolled in our study. Serum levels of thyroid hormones were measured before the beginning of the antiepileptic therapy and at 6 and 12 months of treatment. Carbamazepine-treated patients showed mean serum thyroid hormone levels significantly lower than baseline evaluation and the control group. Thyroid-stimulating hormone levels at 6 and 12 months were not significantly different in carbamazepine treated patients. Serum hormone levels did not change during valproate treatment. Thyroid-stimulating hormone levels were significantly higher at the 12th month of valproate treatment. Our data suggest that although carbamazepine causes significant alterations in thyroid hormone levels, these changes do not lead to clinical symptoms at the follow-up period of 12 months. Keywords carbamazepine, valproate, children, epilepsy, thyroid functions Received December 01, 2013. Received revised February 21, 2014. Accepted for publication March 05, 2014.
Carbamazepine and valproic acid are the most commonly used antiepileptic drugs in children with partial or generalized epilepsy. Although they are well tolerated, they have subtle effects on thyroid function.1,2 Majority of the studies about the effects of antiepileptic drugs on thyroid function have been performed in adult patients. Different thyroid dysfunctions and subclinical hypothyroidism have been reported in the literature in adults.3,4 There are few studies in children based on the long- and short-term effects of antiepileptic drugs on thyroid functions.2,5 Most of these are retrospective studies.1,6 This is one of the few prospective studies including a control group about the effects of antiepileptic treatment on thyroid function in children. In our study, changes in serum thyroid hormone levels during carbamazepine or valproic acid monotherapy were analyzed.
findings. Seizure type was classified according to the criteria of the International League Against Epilepsy.7 We studied 36 sex- and age-matched controls. Control group consisted of patients admitted to the department of Pediatric Neurology outpatient clinic of the same hospital during the same period for reasons other than convulsions. Their physical and laboratory examination findings were all normal. The main criteria for exclusion from the study were abnormal neurologic and/or physical examination, abnormal cerebral computed tomography and/or magnetic resonance imaging (MRI) scan, any systemic disease, and poor seizure control. Patients who were on other medication or had history of previous antiepileptic drug use, who had severe mental retardation or other combined neurologic disorders, and
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Methods A total of 40 newly diagnosed patients who were planned to receive valproic acid and a total of 33 newly diagnosed patients who were planned to receive carbamazepine treatment were enrolled in our study. Our patients were admitted to the Pediatric Neurology outpatient clinic of our hospital in Istanbul with the diagnosis of partial or generalized epilepsy between March 2012 and February 2013. Patients were aged between 2 and 18 years. They were diagnosed as epilepsy with the history, clinical, and electroencephalographical
Department of Pediatrics, Division of Pediatric Neurology, Sisli Etfal Training & Research Hospital, Istanbul, Turkey 2 Department of Pediatrics, Sisli Etfal Training & Research Hospital, Istanbul, Turkey 3 Department of Pediatrics, Acibadem University, Istanbul, Turkey 4 Department of Pediatrics, Okmeydanı Training & Research Hospital, Istanbul, Turkey Corresponding Author: Mujde Arapoglu, MD, Maslak Acibadem Hospital, Bu¨yu¨kdere Cad. No: 40, Maslak, 34457, Istanbul, Turkey. Email: [email protected]
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who had abnormal thyroid hormone levels or other biochemical findings before treatment were also excluded from the study. Age, sex, epilepsy type, electroencephalographic (EEG) changes, number of seizures and seizure control, dosage of the antiepileptic drugs used, and serum levels of carbamazepine and valproic acid at 6 and 12 months of treatment were evaluated. Serum thyroxine (T4), triiodothyronine (T3), free thyroxine (fT4), free triiodothyronine (fT3), and thyroidstimulating hormone were measured before the beginning of the antiepileptic therapy and at 6 and 12 months of treatment. Thyroid hormone levels were compared in carbamazepine- and valproic acid–treated patients and with the control group. Thyroid glands were carefully palpated and presence of palpitation, fatigue, sweating, weight change, constipation, and nervousness were recorded in each patient. Carbamazepine and valproic acid were prescribed at the normal dosages: carbamazepine 20 to 30 mg/kg per day and valproic acid 20 to 30 mg/kg per day. Both were administered in 2 doses. Therapeutic ranges of serum levels were accepted between 50 and 100 mg/mL for valproic acid and 4 and 12 mg/mL for carbamazepine. All patients had serum levels of antiepileptic drugs within these limits. Reference ranges for the serum concentrations of triiodothyronine was 0.80 to 1.7 ng/mL, thyroxine was 5.5 to 13 mg/dL, free triiodothyronine was 2 to 5 pg/mL, free thyroxine was 0.8 to 2.3 ng/dL, and thyroid-stimulating hormone was 0.7 to 5 mIU/mL. Serum thyroxine, triiodothyronine, free thyroxine, free triiodothyronine, and thyroid-stimulating hormone levels were performed by chemiluminescent immunoassay (ADVIA Centaur XP device, Siemens Healthcare Firm). Serum level of valproic acid was measured with chemiluminescent immunoassay using the IMMULITE 2000 system (Siemens Medical Solutions, USA). Serum level of carbamazepine was measured with florescence polarization immunoassay using the INTEGRA 400 system (Roche Diagnostics, USA).
Statistical Analysis SPSS software (version 13.0; SPSS, Chicago, IL) was used to analyze the data. One-way analysis of variance was used for the comparison of the averages of more than 2 groups. Tukey and Tamhane tests were applied for the multiple comparisons. Pearson chi-square and Fisher exact tests were used for the comparison of categorical variables. Repeated measures analyses of general linear models were performed for the relationship between the measurements at the beginning of the treatment, at 6 and 12 months of treatment, and for the relationship between the 2 patient groups. Benforroni test was used for the paired comparison with Pillai’s Trace test. Pearson and Spearman correlation tests were performed at the analysis of the relationship of the variables of patient groups in itself. A P value lower than .05 was considered significant.
Results Mean age of the carbamazepine-treated patients was 10.3 + 3.70 years. Mean age of the valproic acid–treated patients was 9.7 + 4.16 years and mean age of the control group was 10.1 + 3.17 years. Thirty-three patients were treated with carbamazepine, of whom 11 were girls (33.3%) and 22 were boys (66.7%). Forty patients were treated with valproic acid, of whom 14 were girls (35%) and 26 were boys (65%). The control group consisted of 36 patients, of whom 16 (44.4%) were girls and 20 (55.6%) were boys. Mean age and sex were similar in all groups (P > .05).
Carbamazepine-treated patients were followed up 31.5 (+7.4) months. Valproic acid–treated patients were followed up 34 (+9.5) months. Follow-up period was similar in both groups (P > .05). At baseline evaluation, thyroid hormones were normal in all epileptic children and the control group. Baseline hormone levels were not statistically different in all groups (P > .05). Carbamazepine-treated patients showed mean serum thyroxine, free thyroxine, triiodothyronine, and free triiodothyronine levels significantly lower than baseline evaluation (6- and 12-month serum level of thyroxine compared to baseline was P < .01 and P < .001, respectively; 6-month serum level of free thyroxine compared to baseline was P < .001; 6- and 12-month serum level of triiodothyronine compared to baseline was P < .05 and P < .01, respectively; 12-month serum level of free triiodothyronine compared to baseline was P .05) (Table 1). Serum thyroxine, free thyroxine, triiodothyronine, and free triiodothyronine levels were not significantly different compared to baseline and the control group in valproic acid–treated patients (P > .05). Mean thyroid-stimulating hormone levels were within normal limits in both groups. Thyroid-stimulating hormone levels were significantly higher at the 12th month of valproic acid treatment compared to baseline levels and the control group (P < .05). (Table 2) Correlation between serum levels of carbamazepine and valproic acid and thyroid hormones and thyroid-stimulating hormone levels at 6 and 12 months of treatment were not significantly different in between groups (P > .05) (Tables 3 and 4). Electroencephalographic changes were mostly focal sharp or spike waves, and generalized spike-waves activity in both groups. Background activity was normal. None of the patients showed continuous spike waves during sleep, electrical status epilepticus in sleep or burst suppression pattern. Mean number of seizures until the beginning of the treatment was 3.1 + 1.72 in the carbamazepine group and 2.95 + 0.95 in the valproic acid group. In 78.8% of patients (n ¼ 26), seizures were under control by 12 months of carbamazepine treatment, whereas in 21.2% of patients (n ¼ 7), seizures were not under control. In the first 12 months of treatment, patients on carbamazepine who did not respond to treatment had 1.75 + 0.7 seizures. In the valproic acid group, seizures were under control in 80% (n ¼ 32) of patients, and 20% of patients (n ¼ 8) still had convulsions (1.57 + 0.53) by 12 months. Seizure control was not statistically different in
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Table 1. Mean Hormone Levels of the Patients Receiving Carbamazepinea Control group
Before treatment
6th mo of treatment
12th mo of treatment
T4
8.51 (1.62)
8.38 (1.85)
7.06 (2.14)
6.94 (2.04)
fT4
1.36 (0.14)
1.38 (0.23)
1.24 (0.28)
1.26 (0.31)
T3
1.37 (0.21)
1.32 (0.19)
1.26 (0.19)
1.24 (0.22)
fT3
3.15 (0.38)
3.07 (0.46)
2.91 (0.59)
2.85 (0.54)
TSH
2.46 (0.99)
2.48 (1.17)
2.48 (0.97)
2.49 (1.99)
P value P0 > P1 < P10 < P2 < P20 < P3 > P0 > P1 < P10 < P2 > P20 > P3 > P0 > P1 < P10 < P2 < P20 < P3 > P0 > P1 > P10 > P2 < P20 < P3 > P0 > P1 > P10 > P2 > P20 > P3 >
0.05 0.01* 0.001* 0.001* 0.001* 0.05 0.05 0.001* 0.01* 0.05 0.05 0.05 0.05 0.05* 0.001* 0.01* 0.001* 0.05 0.05 0.05 0.05 0.05* 0.01* 0.05 0.05 0.05 0.05 0.05 0.05 0.05
Abbreviations: P0, baseline levels compared with the control group; P1, 6-month levels compared with the baseline; P10, 6-month levels compared with the control group; P2, 12-month levels compared with the baseline; P20, 12-month levels compared with the control group; P3, 12-month levels compared with the 6-month levels; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine; fT4, free thyroxine; fT3, free triiodothyronine. a Values are mean (standard deviation). *Statistically significant value.
between groups (P > .05). Triiodothyronine and thyroxine levels were not statistically different in both groups (P > .05). When seizure control was compared to the antiepileptic drugs used, triiodothyronine and thyroxine levels were not significantly different in between groups (P > .05). Serum free triiodothyronine and free thyroxine levels were significantly lower in the group of patients whose seizures were not under control (P < .001). When seizure control was compared to the antiepileptic drugs used, free triiodothyronine and free thyroxine levels were not significantly different in between groups (P > .05). Thyroidstimulating hormone levels were not significantly different in between groups (P > .05). When seizure control was compared to the antiepileptic drugs used, thyroid-stimulating hormone levels were not significantly different in between groups (P > .05).
Discussion Antiepileptic treatment, especially valproate and carbamazepine, is known to affect thyroid hormone levels. The exact
mechanism of these alterations is unclear. Some studies postulate that epilepsy itself might cause changes in hormone levels with an effect on the hypothalamus-hypophysis-thyroid axis.8 In our study, blood tests were performed after the patients had their first convulsions and before the beginning of the treatment. Since our baseline evaluations for thyroid functions compared with the healthy control group were normal; we suppose that thyroid changes are not the result of the convulsive disorder itself (P > .05). Our follow-up study demonstrated that carbamazepinetreated patients had mean serum thyroxine, free thyroxine, triiodothyronine, and free triiodothyronine levels significantly lower than the baseline evaluation and the control group. Thyroid-stimulating hormone levels in this group did not change over the follow-up period of 12 months. Some studies report similar findings, whereas in some studies triiodothyronine and free triiodothyronine levels remain unchanged. Most of these studies with carbamazepine are retrospective studies.3,5,9
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Table 2. Mean Hormone Levels of the Patients Receiving Valproic Acida Control group
Before treatment
6th mo of treatment
12th mo of treatment
T4
8.51 (1.62)
8.72 (2.03)
8.25 (1.76)
8.32 (1.81)
fT4
1.36 (0.14)
1.37 (0.21)
1.29 (0.2)
1.29 (0.25)
T3
1.37 (0.21)
1.40 (0.29)
1.32 (0.25)
1.31 (0.38)
fT3
3.15 (0.38)
3.29 (0.69)
3.21 (0.78)
3.16 (0.74)
TSH
2.46 (0.99)
2.46 (1.07)
2.98 (1.38)
3.17 (1.5)
P value P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 > P20 > P3 > P0 > P1 > P10 > P2 < P20 < P3 >
0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05* 0.05* 0.05
Abbreviations: fT4, free thyroxine; fT3, free triiodothyronine; P0, baseline levels compared with the control group; P1, 6-month levels compared with the baseline; P10, 6-month levels compared with the control group; P2, 12-month levels compared with the baseline; P20, 12-month levels compared with the control group; P3, 12-month levels compared with the 6-month levels; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine. a Values are mean (standard deviation). *Statistically significant value.
Table 3. Correlation Between Drug Serum Levels and Thyroid Hormones at 6 Months of Treatment.
Serum CBZ levels at 6 mo Serum VPA levels at 6 mo
T4 r value at 6 mo
fT4 r value at 6 mo
T3 r value at 6 mo
fT3 r value at 6 mo
TSH r value at 6 mo
0.25 (P < .05) 0.184 (P < .05)
0.20 (P < .05) 0.204 (P < .05)
0.051 (P < .05) 0.182 (P < .05)
0.126 (P < .05) 0.12 (P < .05)
0.21 (P < .05) 0.278 (P < .05)
Abbreviations: CBZ, carbamazepine; fT4, free thyroxine; fT3, free triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine; VPA, valproic acid.
Table 4. Correlation Between Drug Serum Levels and Thyroid Hormones at 12 Months of Treatment. T4 r value at 12 mo fT4 r value at 12 mo T3 r value at 12 mo fT3 r value at 12 mo TSH r value at 12 mo Serum CBZ levels at 12 mo Serum VPA levels at 12 mo
0.303 (P < .05) 0.20 (P < .05)
0.12 (P < .05) 0.227 (P < .05)
0.134 (P < .05) 0.245 (P < .05)
0.162 (P < .05) 0.067 (P < .05)
0.211 (P < .05) 0.234 (P < .05)
Abbreviations: CBZ, carbamazepine; fT4, free thyroxine; fT3, free triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; T3, triiodothyronine; VPA, valproic acid.
Aggarwal et al9 found that both valproic acid and carbamazepine alter thyroid functions by decreasing free thyroxine levels-more with carbamazepine in their retrospective study.
Verrotti et al10 evaluated thyroid hormone levels at 0, 3, 6, and 12 months of carbamazepine therapy and demonstrated that free thyroxine levels were significantly lower than baseline at
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3, 6, and 12 months, whereas thyroid-stimulating hormone remained unchanged. These findings were similar to ours, whereas in some studies carbamazepine treatment is found to increase thyroid-stimulating hormone levels.1,2,11 A decrease in serum thyroid hormone levels can already be detected in patients receiving carbamazepine as early as 1 or 2 months after the initiation of the treatment in a few studies that were planned prospectively.12 Thyroid hormone levels were already lower at 6 months of carbamazepine treatment in most studies, and this decrease persisted at 12 months as in our study.4 A decrease in serum concentrations of thyroid hormones may be due to induction of the hepatic P450 enzyme system, resulting in an increase in the metabolism of thyroid hormones.13 Positive feedback mechanism of the hypothalamic– pituitary–thyroid axis may not be activated by this decrease in free thyroxine and free triiodothyronine levels. Thus, thyroid-stimulating hormone levels in these patients remain normal.10 Another effect of carbamazepine on thyroid hormones may be due to interference with the competitive binding of thyroid hormone to thyroxine-binding globulin.12 Peripheral conversion of thyroxine to active triiodothyronine also increases, leading to significantly low levels of free thyroxine compared to control groups. Our patients receiving valproic acid did not show any significant abnormalities of thyroid hormones compared to baseline levels and the control group (P > .05). Thyroid-stimulating hormone levels at 12 months of valproic acid treatment were significantly high compared to baseline levels and the control group (P < .05). The effect of valproic acid on thyroid hormones is different in various studies. Most of the previous reports showed no change of thyroid function.1,3,5,10 Both low and unchanged serum thyroxine and free thyroxine levels with normal thyroid-stimulating hormone levels have been found in patients receiving valproic acid monotherapy,1 whereas other studies documented high thyroid-stimulating hormone levels.6,14-16 In another study, out of 143 patients receiving valproic acid, 36 had thyroid-stimulating hormone >5 mIU/L (index level for subclinical hypothyroidism) and 10 had low levels of free thyroxine. Out of 36 patients with high thyroid-stimulating hormone levels, 9 had symptoms of hypothyroidism.14 On the other hand, a study by Verrotti et al10 demonstrated no alteration in children receiving valproate monotherapy. These different results seem partly due to different study methods in mostly retrospective studies. Thyroidstimulating hormone levels also seem to vary widely among different populations. Therefore, prospective studies with a control group would be more reliable about the effects of antiepileptic drugs as our study. Increase in thyroid-stimulating hormone with valproic acid treatment might be due to g-aminobutyric acid (GABA)–stimulating properties of valproic acid. GABA inhibits release of somatostatin, which inhibits thyroid-stimulating hormone secretion.17,18 Valproic acid treatment might also lead to zinc and selenium deficiencies which are important enzymes in thyroid hormone synthesis, but the evidence is insufficient.18
Extra thyroidal pathways other than hypothalamic-pituitaryaxis alterations might also be involved in thyroid hormone metabolism. Decrease in the concentration of serum thyroxine-binding globulin and displacement from proteinbinding sites are also other possible explanations.2,16 Although our patients on carbamazepine treatment had lower thyroid hormone levels during the follow-up period, these changes were all within normal reference ranges. Their thyroid-stimulating hormone levels also did not change and none of these hormonal changes led to any clinical symptoms in the follow-up period of 12 months. Therefore, clinical significance of low serum thyroid hormone concentrations is unclear. More long-term studies are needed to detect any subtle changes in asymptomatic individuals. When epileptic activity was compared in both groups as number of seizures and severity of EEG changes, we did not find a correlation between hormone levels and epileptic activity. There might be an association between the development of low serum thyroid hormone levels and serum antiepileptic drugs concentrations.16 High daily antiepileptic drug dose might be proportional to high serum antiepileptic drugs levels. Serum antiepileptic drug levels did not change in our follow-up period of 12 months. We did not find a correlation between thyroid hormone levels and daily antiepileptic drug dosage and serum antiepileptic drug levels. Verrotti et al10 also did not find a similar correlation. A limitation of our study is that we could not study the effect on thyroid function after discontinuation of the therapy. Some studies show that high thyroid hormone levels return to normal after discontinuation of antiepileptic drugs.6,10,16 In conclusion, our data suggest that although carbamazepine causes significant alterations in thyroid hormone levels, these changes do not lead to clinical symptoms. Valproic acid does not alter serum levels of thyroid hormones. Although subclinical changes induced by these drugs seem to be transient and reversible, clinicians should be aware of these changes. Further prospective and long-term studies are required to monitor the effects of antiepileptic treatment on thyroid function. Acknowledgment All work occured in Pediatric Neurology Clinic of Sisli Etfal Government Hospital.
Author Contributions _ wrote the first draft of the article. MA reviewed and edited the artiIK cle. BAK and ND acquired the data. KY was responsible for analysis and interpretation of data and stastistical work.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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Ethical Approval The informed consent of this study has been signed by the parents. The study was approved by the Ethical Committee of the Sisli Etfal Training & Research Hospital (201171).
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