Neuropediatrics 2014; 45(01): 016-021
DOI: 10.1055/s-0033-1349226
Original Article
Georg Thieme Verlag KG Stuttgart · New York

An Examination of the Mutual Effects of Valproic Acid, Carbamazepine, and Phenobarbital on 25-Hydroxyvitamin D Levels and Thyroid Function Tests

Mehmet Ibrahim Turan
1   Department of Pediatric Neurology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
,
Atilla Cayir
2   Department of Pediatric Endocrinology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
,
Omer Ozden
1   Department of Pediatric Neurology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
,
Huseyin Tan
1   Department of Pediatric Neurology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
› Institutsangaben
Weitere Informationen

Publikationsverlauf

11. November 2012

06. Mai 2013

Publikationsdatum:
25. Juli 2013 (online)

Abstract

Background The effects of antiepileptic drugs (AEDs) on bone metabolism and the endocrine system are not fully known, and publications on the subject are inconsistent.

Objective The study aimed to examine the mutual effects of valproic acid (VPA), carbamazepine (CBZ), and phenobarbital (PB)—AEDs frequently used in childhood—on bone mineral metabolism and thyroid function tests.

Patients and Methods Children monitored with a diagnosis of idiopathic epilepsy by the pediatric neurology clinic, using AEDs for at least 6 months and with episodes under control, were included in the study. Patients were divided into groups on the basis of the drugs used. Thyroid function tests and 25-hydroxyvitamin D or 25(OH)D levels were measured from blood specimens. The data obtained were then compared with those of the control group.

Results A significantly high level of subclinical hypothyroidism was seen in patients using VPA (p < 0.001). There was no significant difference between any of the three study groups and the control group in terms of 25(OH)D (p > 0.05).

Conclusions Pediatric patients using AEDs, particularly VPA, should be monitored for subclinical hypothyroidism. VPA, CBZ, and PB have no effect on vitamin D levels.

 
  • References

  • 1 Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol 2003; 16 (2) 165-170
  • 2 de Silva M, MacArdle B, McGowan M , et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996; 347 (9003) 709-713
  • 3 Guerrini R, Zaccara G, la Marca G, Rosati A. Safety and tolerability of antiepileptic drug treatment in children with epilepsy. Drug Saf 2012; 35 (7) 519-533
  • 4 Landmark CJ, Fossmark H, Larsson PG, Rytter E, Johannessen SI. Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population. Epilepsy Res 2011; 95 (1-2) 51-59
  • 5 Isojärvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllylä VV. Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol 1990; 47 (6) 670-676
  • 6 Pack A. Effects of treatment on endocrine function in patients with epilepsy. Curr Treat Options Neurol 2005; 7 (4) 273-280
  • 7 Sahu JK, Gulati S, Kabra M , et al. Evaluation of subclinical hypothyroidism in ambulatory children with controlled epilepsy on valproate monotherapy. J Child Neurol 2012; 27 (5) 594-597
  • 8 Cansu A. Antiepileptic drugs and hormones in children. Epilepsy Res 2010; 89 (1) 89-95
  • 9 Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58 (6) 1003-1009
  • 10 Nilsson OS, Lindholm TS, Elmstedt E, Lindback A, Lindholm TC. Fracture incidence and bone disease in epileptics receiving long-term anticonvulsant drug treatment. Archives of orthopaedic and traumatic surgery. Arch Orthop Unfallchir 1986; 105: 146-149
  • 11 Pack AM. The association between antiepileptic drugs and bone disease. Epilepsy Curr 2003; 3 (3) 91-95
  • 12 Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994; 16 (5) 382-385
  • 13 Välimäki MJ, Tiihonen M, Laitinen K , et al. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994; 9 (5) 631-637
  • 14 O'Hare JA, Duggan B, O'Driscoll D, Callaghan N. Biochemical evidence for osteomalacia with carbamazepine therapy. Acta Neurol Scand 1980; 62 (5) 282-286
  • 15 Vrzal R, Doricakova A, Novotna A , et al. Valproic acid augments vitamin D receptor-mediated induction of CYP24 by vitamin D3: a possible cause of valproic acid-induced osteomalacia?. Toxicol Lett 2011; 200 (3) 146-153
  • 16 Rousso I, Pharmakiotis A, Gatzola M, Karatza E, Tourkantonis A, Sklavounou-Tsouroutsoglou S. Effects of phenobarbital, diphenylhydantoin and carbamazepine on thyroid function in epileptic children. Acta Endocrinol Suppl (Copenh) 1984; 265: 48-49
  • 17 Hamed SA, Hamed EA, Kandil MR, El-Shereef HK, Abdellah MM, Omar H. Serum thyroid hormone balance and lipid profile in patients with epilepsy. Epilepsy Res 2005; 66 (1-3) 173-183
  • 18 Yüksel A, Kartal A, Cenani A, Yalçin E. Serum thyroid hormones and pituitary response to thyrotropin-releasing hormone in epileptic children receiving anti-epileptic medication. Acta Paediatr Jpn 1993; 35 (2) 108-112
  • 19 Verrotti A, Scardapane A, Manco R, Chiarelli F. Antiepileptic drugs and thyroid function. J Pediatr Endocrinol Metab 2008; 21 (5) 401-408
  • 20 Kim SH, Chung HR, Kim SH , et al. Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy. Neuropediatrics 2012; 43 (3) 135-139
  • 21 Sheth RD, Wesolowski CA, Jacob JC , et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127 (2) 256-262
  • 22 Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and bone. Arch Biochem Biophys 2010; 503 (1) 129-136
  • 23 Williams GR. Actions of thyroid hormones in bone. Endokrynol Pol 2009; 60 (5) 380-388
  • 24 Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008; 122 (2) 398-417
  • 25 Kim SH, Lee JW, Choi KG, Chung HW, Lee HW. A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy. Epilepsy Behav 2007; 10 (2) 291-295
  • 26 Pack AM, Morrell MJ, Randall A, McMahon DJ, Shane E. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 2008; 70 (18) 1586-1593
  • 27 Verrotti A, Basciani F, Morresi S, Morgese G, Chiarelli F. Thyroid hormones in epileptic children receiving carbamazepine and valproic acid. Pediatr Neurol 2001; 25 (1) 43-46
  • 28 Borusiak P, Langer T, Heruth M, Karenfort M, Bettendorf U, Jenke AC. Antiepileptic Drugs and Bone Metabolism in Children: Data from 128 Patients. J Child Neurol 2013; 28 (2) 176-183
  • 29 El-Maouche D, Mehta SH, Sutcliffe CG , et al. Vitamin D Deficiency and its relation to bone mineral density and liver fibrosis in HIV/HCV co-infection. Antivir Ther 2013; 18 (2) 237-242
  • 30 Holick MF, Garabedian M. Vitamin D: photobiology, metabolism, mechanism of action, and clinical applications. In: Favus MJ, , ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006: 129-137
  • 31 White P, Cooke N. The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 2000; 11 (8) 320-327
  • 32 Sato Y, Kondo I, Ishida S , et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001; 57 (3) 445-449
  • 33 Blank DW, Joffe RT. Effect of carbamazepine on thyroid hormone measurement in vitro. Clin Chim Acta 1984; 143 (2) 173-176
  • 34 Joffe RT, Gold PW, Uhde TW, Post RM. The effects of carbamazepine on the thyrotropin response to thyrotropin-releasing hormone. Psychiatry Res 1984; 12 (2) 161-166
  • 35 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) 81-86
  • 36 Park SE, Cho MA, Kim SH , et al. The adaptation and relationship of FGF-23 to changes in mineral metabolism in Graves' disease. Clin Endocrinol (Oxf) 2007; 66 (6) 854-858
  • 37 Tanaka E. Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther 1999; 24 (2) 87-92
  • 38 Hahn TJ, Birge SJ, Scharp CR, Avioli LV. Phenobarbital-induced alterations in vitamin D metabolism. J Clin Invest 1972; 51 (4) 741-748
  • 39 Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Q J Med 1986; 59 (230) 569-577
  • 40 Fong CY, Riney CJ, Vitamin D. Vitamin D deficiency among children with epilepsy in South Queensland. J Child Neurol 2013;
  • 41 Huang MJ, Liaw YF. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 1995; 10 (3) 344-350
  • 42 Loria P, Carulli L, Bertolotti M, Lonardo A. Endocrine and liver interaction: the role of endocrine pathways in NASH. Nature reviews. Gastroenterol Hepatol 2009; 6: 236-247
  • 43 Fernandez V, Llesuy S, Solari L, Kipreos K, Videla LA, Boveris A. Chemiluminescent and respiratory responses related to thyroid hormone-induced liver oxidative stress. Free Radic Res Commun 1988; 5 (2) 77-84
  • 44 Messarah M, Boumendjel A, Chouabia A , et al. Influence of thyroid dysfunction on liver lipid peroxidation and antioxidant status in experimental rats. Exp Toxicol Pathol 2010; 62 (3) 301-310
  • 45 Chung GE, Kim D, Kim W , et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol 2012; 57 (1) 150-156
  • 46 Pagadala MR, Zein CO, Dasarathy S, Yerian LM, Lopez R, McCullough AJ. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci 2012; 57 (2) 528-534
  • 47 Silva MF, Ruiter JP, Overmars H , et al. Complete beta-oxidation of valproate: cleavage of 3-oxovalproyl-CoA by a mitochondrial 3-oxoacyl-CoA thiolase. Biochem J 2002; 362 (Pt 3) 755-760
  • 48 Silva MF, Ruiter JP, IJlst L , et al. Differential effect of valproate and its Delta2- and Delta4-unsaturated metabolites, on the beta-oxidation rate of long-chain and medium-chain fatty acids. Chem Biol Interact 2001; 137 (3) 203-212
  • 49 Aires CC, Ijlst L, Stet F , et al. Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis. Biochem Pharmacol 2010; 79 (5) 792-799
  • 50 Ferrajolo C, Capuano A, Verhamme KM , et al. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70 (5) 721-728
  • 51 Biton V. Effect of antiepileptic drugs on bodyweight: overview and clinical implications for the treatment of epilepsy. CNS Drugs 2003; 17 (11) 781-791
  • 52 Tomita S, Ohnishi J, Nakano M, Ichikawa Y. The effects of anticonvulsant drugs on vitamin D3-activating cytochrome P-450-linked monooxygenase systems. J Steroid Biochem Mol Biol 1991; 39 (4A) 479-485