The effect of antiepileptic drugs on thyroid hormone homeostasis

Czech version

Authors: J. Šimko ¹; J. Horáček ²
Authors‘ workplace: Neurologická klinika LF UK a FN, Hradec Králové, Neurologická ambulance, Rychnov nad Kněžnou ¹; II. Interní klinika LF UK a FN, Hradec Králové ²
Published in: Cesk Slov Neurol N 2007; 70/103(5): 488-493
Category: Review Article

Overview

The discussion concerning the effect of antiepileptic drugs (AEDs) on thyroid (TH) hormone homeostasis began as early as in the 1960’s. Hormone levels have been shown to decrease only in the case of AEDs – enzymatic inductors (AEDs-IND), namely phenobarbital, primidone, phenytoin, carbamazepine and oxcarbazepine. Patients who are not treated for a thyroid disease remain euthyroid during AEDs-IND medication and do nor require T4(T3) replacement therapy. Patients with TH hypofunction / non-function are exposed to a considerable (approximately 30 %) risk of hypothyreosis decompensation through the mechanism of pharmacokinetic interaction of AED’s-IND with T4 (T3) replacement therapy after the exposure to AED’s-IND. The maximum of this risk can be expected during the initial 2–5 weeks after the start of AED’s-IND medication; specific traits of clinical approach to such patients are mentioned, too. As for the other antiepileptic drugs, the effect on thyroid hormone homeostasis is but of a minor degree, or there are not enough studies on this topic or the existing ones only have the form of case study communications. There are virtually no studies on correlation between the cognitive functions and the thyroid function parameters in patients taking AED’s-IND.

Key words:
antiepileptic drugs – enzymatic induction – hypothyreosis

Sources

1. LaRoche SM, Helmers SL. The New Antiepileptic Drugs: scientific review. JAMA 2004; 291: 605-614.

2. Bialer M. The pharmacokinetics and interactions of new antiepileptic drugs: an overview.

Ther Drug Monit 2005; 27: 722-726.

3. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol 2003; 2: 473-481.

4. Isojärvi JI, Tauboll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy.CNS Drugs 2005;19: 207-223.

5. Benedetti MS, Whomsley R, Baltes E, Tonner F. Alteration of thyroid hormone homeostasis by antiepileptic drugs in humans: involvement of glucuronosyltransferase induction. Eur J Clin Pharmacol 2005; 61: 863-872.

6. Oppenheimer JH, Tavernetti RR. Studies on thyroxine-diphenylhydantion interaction: effect of 5,5΄-diphenylhydantoin on the displacement of L-thyroxine from thyroxine binding globulin (TGB). Endocrinology 1962; 71: 496-504.

7. Rootwelt K, Ganes T, Johannessen SI. Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans. Scand J Clin Lab Invest 1978; 38:731-736.

8. Faber J, Lumholtz IB, Kirkegaard C et al. The effect of phenytoin (diphenylhydantoin) on the extrathyroidal turnover of thyroxine, 3,5,3´-triiodothyronine, 3,3´,5´- triiodothyronine, and 3´,5´-diiodothyronine in man. J Clin Endocrinol Metab 1985; 61: 1093-1099.

9. Larsen PR, Atkinson AJ, Wellman HN at al. The effect of diphenylhydantoin on thyroxine metabolism in man. J Clin Invest 1970; 49: 1266-1279.

10. Ericsson UB, Bjerre I, Forsgren M et al. Thyroglobulin and thyroid hormones in patients on long-term treatment with phenytoin, carbamazepine, and valproic acid. Epilepsia 1985; 26: 594-596.

11. Kelly GS. Peripheral metabolism of thyroid hormones: a review. Altern Med Rev 2000; 5: 306-333.

12. Premachandra BN, Radparvar A, Burman K at al. Apparent increase in type I 5΄-deiodinase activity induced by antiepileptic medication in mentally retarded subjects. Horm Res 2002; 58: 273-278.

13. Hood A, Klaassen CD. Effects of microsomal enzyme inducers on outer-ri deiodinase activity toward thyroid hormones in various rat tissues. Toxicol Appl Pharmacol 2000; 163: 240-248.

14. Park BK. Assessment of the drug metabolism capacity of the liver. Br J Clin Pharmacol 1982; 14: 631-651.

15. Isojärvi JI, Turkka J, Pakarinen AJ, Kotila M, Rattya J, Myllylä VV. Thyroid function in men taking carbamazepine, oxcarbamazepine, or valproate for epilepsy. Epilepsia 2001; 42: 930-934.

16. Isojärvi JI, Airaksinen KE, Mustonen JN et al. Thyroid and myocardial function after replacement of carbamazepine by oxcarbamazepine. Epilepsia 1995; 36: 810-816.

17. Hood A, Allen ML, Liu J et al. Induction of T(4) UDP-GT activity, serum thyroid stimulating hormone, and thyroid follicular cell proliferation in mice treated with microsomal enzyme inducers. Toxicol Appl Pharmacol 2003; 188: 6-13.

18. Liu J, Liu Y, Barter RA et al. Alteration of thyroid homestasis by UDP-glucuronosyltransferase inducers in rats: a dose-response study. J Pharmacol Exp Ther 1995; 273: 977-985.

19. Hood A, Klaassen CD. Differential effects of microcomal enzyme inducers on in vitro thyroxine(T(4)) and triiodothyronine (T(3)) glucuronidation. Toxicol Sci 2000; 55: 78-84.

20. Connell JMC, 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.

21. Larkin JG, Macphee GJ, Beastall GH, Brodie MJ. Thyroid hormone concentrations in epileptic patients. Eur J Clin Pharmacol 1989; 36: 213-216.

22. Isojärvi JI, Pakarinen AJ, Myllylä VV. Thyroid function with antiepileptic drugs. Epilepsia. 1992; 33: 142-148.

23. Yuksel A, Kartal A, Cenani A, Yalcin E. Serum thyroid hormones and pituitary response to thyrotropin-releasing hormone in epileptic children receiving anti-epileptic medication. Acta Paediatr Jpn 1993; 35: 108-112.

24. Tiihonen-M, Liewendahl-K, Waltimo-O, Ojala-M, Valimaki-M. Thyroid status of patients receiving long-term anticonvulsant therapy assessed by peripheral parameters: a placebo-controlled thyroxine therapy trial. Epilepsia 1995; 36: 1118-1125.

25. Verrotti A, Basciani F, Morresi S, Morgese G, Chiarelli F. Thyroid hormones in epileptic children receiving carbamazepine and valproic acid. Pediatr Neurol 2001; 25: 43-46.

26. Isojärvi JIT, Pakarinen AJ, Myllylä VV. Thyroid function in epileptic patients treated with carbamazepine. Arch Neurol 1989; 46: 1175-1178.

27. Benedetti MS. Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol 2000; 14: 301-319.

28. Strandjord RE, Aanderud S, Myking OL, Johannessen SI. The influence of carbamazepine on serum thyroxine and triiodothyronine in patients with epilepsy. Acta Neurol Scand 1981; 63: 111-121.

29. Zhu SQ, Liu XM, Ruan XZ, Cai Z. Changes of thyroid hormone levels in epileptic patients. J Tongji Med Univ 1994; 14: 119-123.

30. Fichsel H., Knöpfle G. Effects of anticonvulsant drugs on thyroid hormones in epileptic children. Epilepsia 1978; 19: 323-336.

31. Yeo PP, Bates D, Howe JG et al. Anticonvulsants and thyroid function. Br Med J 1978; 1: 1581-1583.

32. Liewendahl K, Majuri H, Helenius T. Thyroid function tests in patients on long-term treatment with various anticonvulsant drugs. Clin Endocr 1978; 8: 185-191.

33. Deda G, Akinci A, Tezic T, Karagol U. Effects of anticonvulsant drugs on thyroid hormones in epileptic children. Turk J Pediatr 1992; 34: 239-244.

34. Tanaka K, Kodama S, Yokoyama S et al. Thyroid function in children with long-term anticonvulsant treatment. Pediatr Neurosci 1987; 13: 90-94.

35. Maheshwari MC, Kouchupillai A, Jailkhani BL, Gupta SK. Effect of carbamazepine & its combinations on thyroid functions in epileptics. Indian J Med 1984; 79: 76-79.

36. Oppenheimer JH, Fischer LV, Nelson KM, Jailer JW. Depression of the serum protein-bound iodine level by diphenylhydantoin. J Clin Endocrinol Metab 1961; 21: 252-262.

37. Cusack BJ, Tesnohlidek DA, Loseke VL, Eggerth RM, Olson RD. Phenytoin pharmacokinetics in the rabbit: evidence of rapid autoinduction. Res Commun Pathol Pharmacol 1987; 58: 269-272.

38. Bertilsson L, Tomson T, Tybring G. Pharmacokinetics: time-dependent changes – autoinduction of carbamazepine epoxidation. J Clin Pharmacol 1986; 26: 459-462.

39. Surks MI, DeFesi CR. Normal serum free thyroid hormone concentrations in patients treated with phenytoin or carbamazepine. JAMA 1996; 275: 1495-1498.

40. Connacher AA, Borsey DQ, Browning MC et al. The effective evaluation of thyroid status in patients on phenytoin, carbamazepine or sodium valproate attending an epilepsy clinic. Postgrad Med J 1987; 63: 841-845.

41. Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, Lojo-Rocamonde S et al. Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia 1999; 40: 1761-1766.

42. Surks MI, Ortiz E, Daniels GH et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and managament. JAMA 2004; 291: 228-238.

43. Aanderud S, Strandjord RE. Hypothyroidism induced by anti-epileptic therapy. Acta Neurol Scand 1980; 61: 330-332.

44. Oppenheimer JH, Fischer LV, Nelson KM, Jailer JW. Depression of the serum protein-bound iodine level by diphenylhydantoin. J Clin Endocrinol Metab 1961; 21: 252-262.

45. Faber J, Lumholtz IB, Kirkegaard C, Poulsen S, Jorgensen PH, Siersbaek-Nielsen K et al. The effect of phenytoin (diphenylhydantoin) on the extrathyroidal turnover of thyroxine, 3,5,3´-triiodothyronine, 3,3´,5´- triiodothyronine, and 3´,5´-diiodothyronine in man. J Clin Endocrinol Metab 1985; 61: 1093-1099.

46. De Luca F, Arrigo T, Pandullo E, Siracusano MF, Benvenga S, Trimarchi F. Changes in thyroid function tests induced by 2 month carbamazepine treatment in L-thyroxine-substituted hypothyroid children. Eur J Pediatr 1986; 145: 77-79.

47. Aanderud S, Myking OL, Stranjord RE. The influence of carbamazepine on thyroid hormones and thyroxine binding globulin in hypothyroid patients substituted with thyroxine. Clin Endocrinol 1981; 15: 247-252.

48. Blackshear JL, Schultz AL, Napier JS, Stuart DD. Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med 1983; 99: 341-342.

49. Simko J, Horacek J, Waberzinek G. Severe hypothyroidism as a complication of anticonvulsant treatment. Epilepsia 2004; 45: 292-293.

50. Schroder EJP, Heide D, Bent C, Kaptein E, Visser TJ, Sefano JJ. Effects of 5,5´-diphenylhydantoin on the thyroid status in rats. Eur J Endocrinol 1996; 134: 221-224.

51. Simko J, Horacek J. Carbamazepine and risk of hypothyroidism: a prospective study. Acta Neurol Scand. 2007; [Epub ahead of print] PMID: 17850408.

52. Vainionpaa LK, Mikkonen K, Rattya 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.

53. Bentsen KD, Gram L, Veje A. Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study. Acta Neurol Scand 1983; 67: 235-241.

54. Cansu A, Serdaroglu A, Camurdan O, Hirfanoglu 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: 1855-1859.

55. Nishiyama S, Matsukura M, Fujimoto S, Matsuda I. Reports of two cases of autoimmune thyroiditis while receiving anticonvulsant therapy. Eur J Pediatr 1983; 140: 116-117.

56. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotropin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol 1991; 34: 77-83.

57. Canaris GJ, Manowitz NR, Mayor G, Ridgway C. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526-534.

58. Vieweg WV, Yank GR, Steckler TL, Clayton MT. Grades 1 and 2 hypothyroidism in a state mental hospital: risk factors and clinical findings. Psychiatr Q 1986-87; 58: 135-143.

59. Johnston AM, Eagles JM. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry 1999; 175: 336-339.

60. Bocchetta A, Bernardi F, Pedditzi M et al. Thyroid abnormalities during lithium treatment. Acta Psychiatr Scand 1991; 83: 193-198.

61. Berberoglu M. Drugs and thyroid interaction. Pediatr Endocrinol Rev 2003; Suppl 2: 251-256.

62. Figg WD, Thibault A, Sartor AO et al. Hypothyroidism associated with aminoglutethimide in patients with prostate cancer. Arch Intern Med 1994; 154: 1023.

63. Witztum JL, Jacobs LS, Schonfeld G. Thyroid hormone and thyrotropin levels in patients placed on colestipol hydrochloride. J Clin Endocrinol Metab 1978; 46: 838-840.

64. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000; 283: 2822-2825.