Valproate use and thyroid dysfunction in children with idiopathic epilepsy
Abstract
Background Long-term administration of valproic acid (VPA) has side effects, including thyroid dysfunction. Subclinical hypothyroidism (SCH) identified by elevated serum thyroid stimulating hormone (TSH) concentrations with normal thyroxine (T4) and triiodothyronine (T3), or normal free thyroxine (fT4) and free triiodothyronine (fT3) has been demonstrated in idiopathic epilepsy patients receiving VPA.
Objective To evaluate for associations between age at initiation of VPA treatment and duration of treatment with thyroid dysfunction.
Methods A cross-sectional study was conducted from October 2012 to May 2013 in Haji Adam Malik and Pirngadi Hospitals, Medan, North Sumatera. Subjects were children ranging from 0 and below 18 years who had been diagnosed with idiopathic epilepsy. Blood specimens were taken to evaluate serum T3, T4, and TSH levels in all subjects. Data were analyzed using bivariate and multivariate analyses.
Results A total of 49 subjects were included in the study. Age of ≤ 4 years at initiation of VPA was found to be a significant risk factor for SCH in the bivariate analysis (OR 6.67; 95%CI 1.215 to 36.594, P=0.036). Three factors had P values <0.25 in the bivariate analysis and were subsequently analyzed by stepwise multivariate regression test: age at initiation of VPA, duration of treatment, and drug dosage. The VPA initiation at age <4 years had 6.67 times the risk of SCH than the age of >4 years (95%CI 1.215 to 36.594; P=0.029). Duration of treatment and VPA dosage were not significantly associated with SCH on multivariate analysis
Conclusion Age ≤ 4 years old at the initiation of VPA is associated with thyroid dysfunction. However, no significant association was found between duration of treatment as well as drug dosage with thyroid dysfunction.
References
Stafstrom CE. The epilepsies. In: David RB, Bodensteiner JB, Mandelbaum DE, Olson B, editors. Clinical pediatric neurology. 3rd ed. New York: Demos Medical; 2009. p. 151-86.
Panayiotopolous CP. Clinical aspects of the diagnosis of epileptic seizures and epileptic syndromes. In: Panayiotopolous CP, editor. The epilepsies seizures, syndromes and management. 1st ed. Oxfordshire: Bladon Medical Publishing; 2005.p.1-25.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, 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;51:676–85.
George J, Joshi SR. Drugs and thyroid. J Assoc Physicians India. 2007;55:215-23.
Benedetti MS, Whomsley R, Baltes E, Tonner F. Alteration of thyroid hormone homeostasis by antiepileptic drugs in humans: involvement of glucuronyltransferase induction. Eur J Clin Pharmacol. 2005;61:863-72.
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;49:822-6.
Sahu JK, Gulati S, Kabra M, Arya R, Sharma R, Gupta N, et al. Evaluation of subclinical hypothyroidism in ambulatory children with controlled epilepsy on valproate monotherapy. J Child Neurol. 2012;27:594-7.
McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001;86:4585-90.
Kim SH, Chung HR, Kim H, Lim BC, Chae JH, Kim KJ, et al. Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy. Neuropediatrics. 2012;43:135-9.
Susanto R, Madarina J. Gangguan kelenjar tiroid. In: Batubara J, Tridjaja B, Pulungan AB, editors. Buku ajar endokrinologi anak. 1st ed. Jakarta: Badan Penerbit IDAI; 2010. p. 205-50.
Center For Disease Control and Prevention. 2000 CDC growth charts for the United States : Methods and development. Vital Health Stat 11. 2002;246:1-190.
WHO. WHO multicentre Growth and reference Study Group. WHO child growth standards; length/height-for-age, weight forage, weight-for-length, weight-for-height, and body mass index-for-age: Methods and development. Geneva, 2006.
Manescu ML, Pakai RM. The influence of the treatment with valproic acid in the thyroid function in children and adolescents diagnosticated with epilepsy. Jurnalul Pediatrului. 2010;13:66-9.
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;151:178-81.
Amirsalari S, Kayhanidost ZT, Kavemanesh Z, Torkman M, Beiraghdar F, Teimoori M, et al. Thyroid function in epileptic children who receive carbamazepine, primidone, phenobarbital and valproic acid. Iranian J Child Neurology. 2011;5:15-20.
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;160:81-6.
Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29:76-131
Donerat H, Kara IS, Karakoc A, Tan H, Orbak Z. Serum thyroid hormone profile and trace elements in children receiving valproic acid therapy: a longitudinal and controlled study. J Trace Elem Med Biol. 2012;26:243-7
Cansu A, Serdaroglu AG, Camurdan O, Hırfanoglu T, Bideci A, Gucuyener 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;47:1855-9.
Adlin V. Subclinical hypothyroidism: deciding when to treat. Am Fam Physician. 1998;57:776-80.
Kaplowitz PB. Subclinical hypothyroidism in children: normal variation or sign of a failing thyroid gland? Int J Pediatr Endocrinol. 2010;2010:281453.
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Accepted 2018-08-23
Published 2018-08-30
