Effects of valproic acid, levetiracetam, carbamazepine, and oxcarbazepine on thyroid function tests in childrenSUMMARY
OBJECTIVE: The aim of the study was to evaluate the effects of commonly used medications for epilepsy on thyroid function tests in children.
METHODS: Epileptic children treated with valproic acid, levetiracetam, carbamazepine, and oxcarbazepine were retrospectively examined along with a healthy control group. Levels of free thyroxine 4 and thyroid-stimulating hormone were compared.
RESULTS: In patients receiving valproic acid monotherapy, thyroid-stimulating hormone levels increased compared to both the control group and pre-treatment levels, while free thyroxine 4 levels remained unchanged. In those receiving carbamazepine or oxcarbazepine monotherapy, average free thyroxine 4 levels were found to be lower compared to the control group and pre-treatment levels, with no difference in thyroid-stimulating hormone levels. For patients receiving levetiracetam monotherapy, there was no difference in free thyroxine 4 and thyroid-stimulating hormone levels compared to the control group and pre-treatment levels.
CONCLUSION: Despite significant changes in thyroid hormone levels with valproic acid, carbamazepine, and oxcarbazepine treatment, no significant clinical findings were observed. Additionally, no effect of levetiracetam on thyroid function tests was detected.
KEYWORDS:
Anticonvulsants; Children; Thyroid hormone
INTRODUCTION
Epilepsy is a common neurological disorder in childhood and is usually treated with antiepileptic drugs (AEDs). AEDs can be associated with certain side effects, one of the lesser-known being subclinical hypothyroidism. Subclinical hypothyroidism is characterized by an increase in serum thyroid-stimulating hormone (TSH) levels, while fT4 levels remain within the normal range. Antiepileptic drugs can affect thyroid function through various mechanisms. For instance, drugs such as valproate and carbamazepine can influence the peripheral conversion of thyroid hormones, the levels of thyroid hormone-binding globulin, and the functions of the thyroid gland. Specifically, carbamazepine and oxcarbazepine affect thyroid function in children by inducing hepatic enzymes, while valproic acid (VPA) impacts thyroid function through various mechanisms (e.g., gamma aminobutyric acid (GABA) effects, zinc deficiency, etc.). The effects of levetiracetam (LEV) on thyroid function remain unclear1,2. These drugs can cause an increase in serum TSH levels, which may lead to the development of subclinical hypothyroidism. Subclinical hypothyroidism is usually asymptomatic and is diagnosed through laboratory tests. Diagnosing subclinical hypothyroidism in children requires consideration of age-specific TSH and T4 reference ranges. In this study, we aimed to investigate the effects of LEV, VPA, carbamazepine (CBZ), and oxcarbazepine (OCX) monotherapy on thyroid hormones in children with epilepsy.
METHODS
We retrospectively reviewed the records of patients aged 3–18 years who were seen at the Pediatric Neurology Clinic of Pamukkale University Medical School Hospital between January 2019 and 2024. The study included 237 patients who were on monotherapy: 75 on VPA, 80 on LEV, 48 on CBZ, and 34 on OXC, as well as 200 individuals in the control group. Idiopathic epileptic children who had been on VPA, LEV, CBZ, or OXC monotherapy for at least 12 months and had been seizure-free for at least 6 months were included in the study. Patients were treated with VPA monotherapy at doses ranging from 10 to 40 mg/kg/day, LEV at 20 to 45 mg/kg/day, CBZ at 10 to 20 mg/kg/day, or OXC at 10 to 35 mg/kg/day. The diagnosis of epilepsy was made according to the definition and classification of the International League Against Epilepsy (ILAE)3. All children had normal neurological examination and cranial imaging findings. Thyroid functions of patients on monotherapy and healthy children (control group) were compared at 0, 6, and 12 months. Serum VPA and CBZ levels were measured. LEV and OXC levels were not measured. The chemiluminescence immunoassay method was used to measure TSH and fT4 levels (Abbott Architect i200SR, USA). Laboratory reference values were considered normal, with fT4 levels between 0.7 and 1.5 ng/dL and TSH levels between 0.5 and 5 uIU/mL. Subclinical hypothyroidism was characterized by a TSH level exceeding 5 uIU/mL while maintaining a normal fT4 level4. Patients with chronic disease, mental retardation, and those using multiple AEDs were excluded from the study. Ethical approval was obtained.
Statıstıcal analysıs
Data were analyzed using the Statistical Package for the Social Sciences (SPSS) software (version 13.0). One-way ANOVA was used for comparing means across multiple groups, with Turkey and Tamhane tests for multiple comparisons. Pearson chi-square and Fisher exact tests were used for categorical variables. Repeated measures analyses with general linear models were conducted for treatment measurements at baseline, 6 months, and 12 months, and between patient groups. The Bonferroni test was applied for paired comparisons along with Pillai's Trace test. Pearson and Spearman correlations assessed relationships within patient groups. A p<0.05 was considered significant.
RESULTS
The study included 241 children with epilepsy and 200 children in the control group. Demographic information is provided in Table 1. There was no difference in age and gender when the patient and control groups were compared. At the initial evaluation, thyroid hormone levels were within normal ranges for both the epileptic children and the control group. The baseline hormone levels did not show any statistically significant variation across the groups (p>0.05). In patients taking VPA, TSH levels were markedly elevated at both the 6-month and 12-month marks compared to the control group and baseline measurements (p<0.001), while fT4 levels remained unchanged (p>0.05). In patients on CBZ and OXC, fT4 levels were lower at the 6th and 12th months compared to the control group and baseline values (p<0.001), but they remained within the normal reference range. TSH levels did not change (p>0.05). In patients treated with LEV, fT4 and TSH levels remained stable at both 6 and 12 months compared to the control group and initial measurements (p>0.05) (see Table 2). Before treatment, there were no significant differences in thyroid hormone levels and body mass index (BMI) between the control group and the medication groups. Subclinical hypothyroidism was observed in 12 patients (16%) from the VPA group, 2 patients (1%) from the CBZ group, and 1 patient (0.7%) from the OXC group. No hypothyroidism was detected in the LEV group. There were no clinical symptoms that would suggest hypothyroidism in our cases. There was no relationship found between the dosage or length of medication and the levels of fT4 and TSH.
DISCUSSION
We observed thyroid hormone abnormalities in epileptic patients using VPA, CBZ, and OXC, but not in those using LEV. This suggests that some antiepileptic drugs may affect thyroid function. The relationship between thyroid hormones and epilepsy is complex, with some suggesting epilepsy or AEDs might impact thyroid function1,2. Since thyroid hormone levels were normal before treatment and after the first convulsions, we assume that the observed changes were not due to the convulsive disorder itself.
In our patients using VPA therapy, despite an increase in TSH levels compared to pre-treatment and control groups, there was no change in fT4 levels, and they were clinically euthyroid. A meta-analysis reported significantly higher TSH levels in 12–52% of patients on VPA monotherapy2. In a study of 45 cases over 6 months, TSH increased, fT4 decreased, and fT3 increased5. However, few studies have reported no changes in thyroid function tests6,7, and severe hypothyroidism is rare8. Our study found subclinical hypothyroidism in 18% of children on VPA therapy, consistent with Karatoprak et al. (16%)9 and Alhyan et al. (17.7%)5. The literature indicates that changes in thyroid hormone levels with valproic acid are not permanent and normalize after discontinuation of the drug2,8.
There are multiple mechanisms through which valproic acid affects thyroid hormones. Valproic acid can increase TSH levels due to its effects on GABA. It inhibits somatostatin, which suppresses TSH secretion; it can cause zinc and selenium deficiencies, disrupting thyroid hormone synthesis; and it can lead to magnesium deficiency, which reduces iodine uptake and T4 synthesis, resulting in increased TSH secretion. Additionally, magnesium deficiency can impair the effects of thyroid hormones2.
In our study, although there was a reduction in serum fT4 levels at both 6 and 12 months in patients receiving CBZ compared to the control group and baseline levels, these levels remained within the normal reference range. We found no change in TSH levels. Our findings are consistent with a previous meta-analysis that reported an association between CBZ use and low serum fT4 levels without changes in TSH levels in children10. According to the literature, 28–33% of patients using CBZ had a reduction in fT4 levels2. Most studies have found decreases in T4, fT4, T3, and fT3 even after just 1 month of treatment2,11–13. Some studies also reported elevated TSH levels in 10–25% of patients after 12 months of treatment2,13.
Another study reported a significant decrease in serum fT4 at 1 and 6 months in eight CBZ-treated cases, with no change in TSH levels11. The strengths of this study are its longer follow-up and larger sample size. The clinical significance of low serum thyroid hormone levels remains unclear, and long-term, multicenter studies are needed to assess the impact on asymptomatic individuals.
The decrease in serum thyroid hormones may be due to the hepatic P450 enzyme complex of carbamazepine, which accelerates the metabolism of thyroid hormones. The positive feedback mechanism of the hypothalamic-pituitary-thyroid axis may not respond to these decreases in fT4 and fT3 levels, and TSH levels may remain normal. Carbamazepine's blocking of thyroid hormone binding to thyroxine-binding globulin and increasing peripheral conversion of triiodothyronine lead to lower fT4 levels compared to the control group1,14. However, the clinical significance of low serum thyroid hormones is unclear. Long-term, multicenter studies are needed to determine the impact of these changes in asymptomatic individuals.
In our study, despite a decrease in serum fT4 levels in children treated with OXC at 6 and 12 months compared to the control group and pre-treatment levels, the values remained within the normal reference range. We found no change in TSH levels. Both retrospective and prospective studies have shown that patients using oxcarbazepine often experience decreased serum T4 and fT4 levels without changes in TSH levels13,15–18. This suggests that OXC can alter thyroid function in epileptic children within a short period. Unlike carbamazepine, oxcarbazepine does not induce similar enzyme activity despite its structural similarity. fT4 levels normalize when oxcarbazepine is discontinued. As a result, the effect of oxcarbazepine on thyroid function is not permanent and is well tolerated compared to carbamazepine13. Our data show that although OXC affects thyroid hormone levels, it does not cause clinical findings.
synaptic vesicle glycoprotein 2A (SV2A), present in the central nervous system (CNS) and endocrine tissues, is the target of LEV, suggesting that it might influence endocrine functions19. However, our study found no changes in thyroid hormone levels with LEV monotherapy over 6 and 12 months compared to controls and pre-treatment values. These findings align with other studies, both short and long terms, and may be due to LEV's unique antiepileptic mechanism9,11,15,20. The lack of thyroid hormone abnormalities in many studies could be related to LEV's distinct mode of action.
The relationship between thyroid hormone levels, duration, or dose of treatment is unclear; some studies found a relationship between doses of OXC or VPA and TSH levels21,22, while others did not14. Our study found no relationship between the daily doses of VPA and CBZ and the levels of TSH. The limitations of the study include its retrospective design, the inability to assess the impact on thyroid function after discontinuation of treatment, and the small sample sizes in the OXC and CBZ groups.
CONCLUSION
It should be noted that valproic acid does not affect thyroid hormones significantly, but subclinical hypothyroidism may develop, necessitating close monitoring of symptoms. Although CBZ leads to significant changes in thyroid hormone levels, these changes do not appear to cause clinical symptoms. Routine monitoring of thyroid hormone levels in patients on LEV is generally not required. Longer-term studies are needed to better understand antiepileptic treatment's impact on thyroid function.
Funding:
ETHICS APPROVAL
REFERENCES
-
1 Burakgazi Dalkilic E. Effects of antiepileptic drugs on hormones. Neurosci Lett. 2021;754:135800. https://doi.org/10.1016/j.neulet.2021.135800
» https://doi.org/10.1016/j.neulet.2021.135800 -
2 Rochtus AM, Herijgers D, Jansen K, Decallonne B. Antiseizure medications and thyroid hormone homeostasis: literature review and practical recommendations. Epilepsia. 2022;63(2):259-70. https://doi.org/10.1111/epi.17117
» https://doi.org/10.1111/epi.17117 -
3 Beniczky S, Tatum WO, Blumenfeld H, Stefan H, Mani J, Maillard L, et al. Seizure semiology: ILAE glossary of terms and their significance. Epileptic Disord. 2022;24(3):447-95. https://doi.org/10.1684/epd.2022.1430
» https://doi.org/10.1684/epd.2022.1430 -
4 Murillo-Vallés M, Martinez S, Aguilar-Riera C, Garcia-Martin MA, Bel-Comós J, Ybern MLG. Subclinical hypothyroidism in childhood, treatment or only follow-up? BMC Pediatr. 2020;20(1):282. https://doi.org/10.1186/s12887-020-02177-8
» https://doi.org/10.1186/s12887-020-02177-8 -
5 Alhyan P, Aggarwal A, Chhillar N, Sharma S, Narang M, Malhotra RK. Effect of valproate monotherapy on thyroid function tests and magnesium levels in children with epilepsy. Cureus. 2023;15(5):e39712. https://doi.org/10.7759/cureus.39712
» https://doi.org/10.7759/cureus.39712 -
6 Verrotti A, Laus M, Scardapane A, Franzoni E, Chiarelli F. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol. 2009;160(1):81-6. https://doi.org/10.1530/EJE-08-0325
» https://doi.org/10.1530/EJE-08-0325 -
7 Hirfanoglu T, Serdaroglu A, Camurdan O, Cansu A, Bideci A, Cinaz P, et al. Thyroid function and volume in epileptic children using carbamazepine, oxcarbazepine and valproate. Pediatr Int. 2007;49(6):822-6. https://doi.org/10.1111/j.1442-200X.2007.02456.x
» https://doi.org/10.1111/j.1442-200X.2007.02456.x -
8 Mikati MA, Tarabay H, Khalil A, Rahi AC, El Banna D, Najjar S. Risk factors for development of subclinical hypothyroidism during valproic acid therapy. J Pediatr. 2007;151(2):178-81. https://doi.org/10.1016/j.jpeds.2007.02.046
» https://doi.org/10.1016/j.jpeds.2007.02.046 -
9 Karatoprak E, Paksoy S. Thyroid functions in children on levetiracetam or valproic acid therapy. J Pediatr Epilepsy. 2021;10(01):022-6. https://doi.org/10.1055/s-0040-1716916
» https://doi.org/10.1055/s-0040-1716916 -
10 Zhang YX, Shen CH, Lai QL, Fang GL, Ming WJ, Lu RY, et al. Effects of antiepileptic drug on thyroid hormones in patients with epilepsy: a meta-analysis. Seizure. 2016;35:72-9. https://doi.org/10.1016/j.seizure.2016.01.010
» https://doi.org/10.1016/j.seizure.2016.01.010 -
11 Nishiyama M, Takami Y, Ishida Y, Tomioka K, Tanaka T, Nagase H, et al. Lipid and thyroid hormone levels in children with epilepsy treated with levetiracetam or carbamazepine: a prospective observational study. Epilepsy Behav. 2019;90:15-9. https://doi.org/10.1016/j.yebeh.2018.11.003
» https://doi.org/10.1016/j.yebeh.2018.11.003 -
12 Attilakos A, Garoufi A, Voudris K, Mastroyianni S, Fotinou A, Papadimitriou DT, 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(6):358-61. https://doi.org/10.1016/j.ejpn.2007.03.002
» https://doi.org/10.1016/j.ejpn.2007.03.002 -
13 Yılmaz U, Yılmaz TS, Akıncı G, Korkmaz HA, Tekgül H. The effect of antiepileptic drugs on thyroid function in children. Seizure. 2014;23(1):29-35. https://doi.org/10.1016/j.seizure.2013.09.006
» https://doi.org/10.1016/j.seizure.2013.09.006 -
14 Kafadar İ, Kılıç BA, Arapoglu M, Yalçın K, Dalgıç N. Evaluation of thyroid hormones in children receiving carbamazepine or valproate: a prospective study. J Child Neurol. 2015;30(1):63-8. https://doi.org/10.1177/0883073814529822
» https://doi.org/10.1177/0883073814529822 -
15 Shi KL, Guo JX, Zhao HM, Hong H, Yang CZ, Wu YH, et al. The effect of levetiracetam and oxcarbazepine monotherapy on thyroid hormones and bone metabolism in children with epilepsy: a prospective study. Epilepsy Behav. 2020;113:107555. https://doi.org/10.1016/j.yebeh.2020.107555
» https://doi.org/10.1016/j.yebeh.2020.107555 -
16 Cansu A, Serdaroğlu A, Camurdan O, Hirfanoğlu T, Bideci A, Gücüyener K. The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate. Epilepsia. 2006;47(11):1855-9. https://doi.org/10.1111/j.1528-1167.2006.00821.x
» https://doi.org/10.1111/j.1528-1167.2006.00821.x -
17 Garoufi A, Koemtzidou E, Katsarou E, Dinopoulos A, Kalimeraki I, Fotinou A, et al. Lipid profile and thyroid hormone concentrations in children with epilepsy treated with oxcarbazepine monotherapy: a prospective long-term study. Eur J Neurol. 2014;21(1):118-23. https://doi.org/10.1111/ene.12262
» https://doi.org/10.1111/ene.12262 -
18 Park H, Heo J, Kim MJ, Lee JH, Kim MS, Jin DK, et al. The longitudinal effect of oxcarbazepine on thyroid function in children and adolescents with epilepsy. Epilepsia. 2022;63(12):3148-55. https://doi.org/10.1111/epi.17407
» https://doi.org/10.1111/epi.17407 -
19 Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs. 2011;71(4):489-514. https://doi.org/10.2165/11204490-000000000-00000
» https://doi.org/10.2165/11204490-000000000-00000 -
20 Attilakos A, Dinopoulos A, Tsirouda M, Paschalidou M, Prasouli A, Stamati A, et al. Effect of levetiracetam monotherapy on lipid profiles and thyroid hormones in children with epilepsy: a prospective study. Epilepsy Res. 2019;155:106162. https://doi.org/10.1016/j.eplepsyres.2019.106162
» https://doi.org/10.1016/j.eplepsyres.2019.106162 -
21 Kim SH, Chung HR, Kim SH, Kim H, Lim BC, Chae JH, et al. Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy. Neuropediatrics. 2012;43(3):135-9. https://doi.org/10.1055/s-0032-1313913
» https://doi.org/10.1055/s-0032-1313913 -
22 Schweiger BM, Lao AJ, Tavyev J. A case series of patients with central hypothyroidism from oxcarbazepine therapy. J Child Neurol. 2021;36(3):237-42. https://doi.org/10.1177/0883073820962926
» https://doi.org/10.1177/0883073820962926
