Scand J. clin. Lab. Invest. 38, 731-736, 1978.
Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans K . R O O T W E L T , T. G A N E S' & S . I. J O H A N N E S S E N t Department of Clinical Chemistry, Rikshospitalet, * Department of Neurology, UllevHl sykehus, and tNational Hospital for Epilepsy, Sandvika, Norway
Rootwelt, K., Ganes, T. & Johannessen, S.I. Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans. Scand. J. clin. Lab. Invest. 38, 731-736, 1978. Patients on long-term treatment with either of the stereochemically related antiepileptic drugs phenytoin (DPH) or carbamazepine (CBZ) had similar changes in serum thyroid hormone concentrations. T4, FT4, FT4 index, T3, FT3, FT3 index and rT3 were reduced, whereas T3U and TSH were not significantly different from the reference group levels. Long-term phenobarbitone treatment had no convincing effect on the investigated parameters when used alone, but possibly potentiated the effect of CBZ. In patients starting on CBZ, T4 fell to a stable 70% of the basal level after 1-2 weeks. T3 decreased transitorily to 85% of the basal level. TSH showed a complementary but somewhat delayed transitory increase. T3U and TBG did not change significantly. The effect of CBZ and DPH can be explained by interference with thyroid hormone binding to TBG combined with enzyme-induced increased metabolic clearance rate of thyroid hormones without homeostatic maintenance of premedication levels of FT4 and FT3. We suggest that the regulated factor maintaining euthyroidism in these patients is the total quantity of thyroid hormones being degraded in the tissues per unit time. We conclude that serum concentrations of FT4 and FT3 do not reflect thyroid status adequately under all circumstances. Key-words: carbamazepine; phenobarbital; phenytoin; thyroid hormones; thyrotropin ; thyroxine binding protein K . Rootwelt, M.D., Section of Nuclear Medicine, Department of Clinical Chemistry, Rikshospitalet, Oslo 1, Norway
Since 1961 it has been known that phenytoin (DPH) has a significant effect on the levels of thyroid hormones in the plasma [5, 9, 13, 14, 16, 21, 241. In 1977 Fichsel & Knopfle and ourselves independently reported that carbamazepine (CBZ) has a similar effect [6-81. This presentation is an extended and more 0036-5513/78/1200-0731 $02.00 0 1978 Medisinsk Fysiologisk Forenings Forlag
detailed account of our findings. The effect of the drug on serum levels of thyroxine (T4), free thyroxine (FT4), triidothyronine (T3), free triiodothyronine (FT3), reverse triiodothyronine (rT3), thyroxine binding globulin (TBG) and thyrotropin (TSH) is reported, as is also the results of triiodothyronine uptake tests (T3U) and calculations of free thyroxine and free triiodothyronine indices (FT4 index and FT3
132
K . Rootwelt, T. Caries & S. I . Johannesseri
index). For comparative purposes the results of less extensive studies of DPH and phenobarbitone (PB) influence on the same serum parameters are given. MATERIAL A N D METHODS
Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Clinical material Six groups of adult patients with epilepsy using one or two antiepileptic drugs were studied. The antiepileptic medication was well adjusted so that drug concentrations in serum were at therapeutic level in all patients. The patients were not suspected to suffer from thyroid dysfunction. Group A (thirteen patients) used CBZ only. Group B (fourteen patients) used CBZ and PB. Group C (ten patients) used DPH only. Group D (ten patients) used PB only. Patients in groups A-D had all received their antiepileptic medication for several months at the onset of the investigation. Group E comprised seven patients in whom the epilepsy was diagnosed and treatment with CBZ started at the beginning of the study period. Drug and hormone levels were determined before treatment, daily the first 4 days of treatment, and thereafter less frequently for 1 month. Group F consisted of only one patient. Longterm CBZ was discontinued, and she was followed up for 2 weeks. As controls were used eighty-three adult euthyroid patients referred to thyroid function studies. They used no drugs, had no clinical evidence of goitre and revealed no history of thyroid or pituitaryihypothalamic disease. As reference group for some of the tests twentythree healthy persons belonging to the laboratory staff were used. The controls and the reference groups were not matched to the patient population with respect to age and sex distribution.
determined with ‘KIT reverse T3 peg’ from Hypolab, Coinsins, Switzerland, CV 15 :
Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans K . R O O T W E L T , T. G A N E S' & S . I. J O H A N N E S S E N t Department of Clinical Chemistry, Rikshospitalet, * Department of Neurology, UllevHl sykehus, and tNational Hospital for Epilepsy, Sandvika, Norway
Rootwelt, K., Ganes, T. & Johannessen, S.I. Effect of carbamazepine, phenytoin and phenobarbitone on serum levels of thyroid hormones and thyrotropin in humans. Scand. J. clin. Lab. Invest. 38, 731-736, 1978. Patients on long-term treatment with either of the stereochemically related antiepileptic drugs phenytoin (DPH) or carbamazepine (CBZ) had similar changes in serum thyroid hormone concentrations. T4, FT4, FT4 index, T3, FT3, FT3 index and rT3 were reduced, whereas T3U and TSH were not significantly different from the reference group levels. Long-term phenobarbitone treatment had no convincing effect on the investigated parameters when used alone, but possibly potentiated the effect of CBZ. In patients starting on CBZ, T4 fell to a stable 70% of the basal level after 1-2 weeks. T3 decreased transitorily to 85% of the basal level. TSH showed a complementary but somewhat delayed transitory increase. T3U and TBG did not change significantly. The effect of CBZ and DPH can be explained by interference with thyroid hormone binding to TBG combined with enzyme-induced increased metabolic clearance rate of thyroid hormones without homeostatic maintenance of premedication levels of FT4 and FT3. We suggest that the regulated factor maintaining euthyroidism in these patients is the total quantity of thyroid hormones being degraded in the tissues per unit time. We conclude that serum concentrations of FT4 and FT3 do not reflect thyroid status adequately under all circumstances. Key-words: carbamazepine; phenobarbital; phenytoin; thyroid hormones; thyrotropin ; thyroxine binding protein K . Rootwelt, M.D., Section of Nuclear Medicine, Department of Clinical Chemistry, Rikshospitalet, Oslo 1, Norway
Since 1961 it has been known that phenytoin (DPH) has a significant effect on the levels of thyroid hormones in the plasma [5, 9, 13, 14, 16, 21, 241. In 1977 Fichsel & Knopfle and ourselves independently reported that carbamazepine (CBZ) has a similar effect [6-81. This presentation is an extended and more 0036-5513/78/1200-0731 $02.00 0 1978 Medisinsk Fysiologisk Forenings Forlag
detailed account of our findings. The effect of the drug on serum levels of thyroxine (T4), free thyroxine (FT4), triidothyronine (T3), free triiodothyronine (FT3), reverse triiodothyronine (rT3), thyroxine binding globulin (TBG) and thyrotropin (TSH) is reported, as is also the results of triiodothyronine uptake tests (T3U) and calculations of free thyroxine and free triiodothyronine indices (FT4 index and FT3
132
K . Rootwelt, T. Caries & S. I . Johannesseri
index). For comparative purposes the results of less extensive studies of DPH and phenobarbitone (PB) influence on the same serum parameters are given. MATERIAL A N D METHODS
Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14 For personal use only.
Clinical material Six groups of adult patients with epilepsy using one or two antiepileptic drugs were studied. The antiepileptic medication was well adjusted so that drug concentrations in serum were at therapeutic level in all patients. The patients were not suspected to suffer from thyroid dysfunction. Group A (thirteen patients) used CBZ only. Group B (fourteen patients) used CBZ and PB. Group C (ten patients) used DPH only. Group D (ten patients) used PB only. Patients in groups A-D had all received their antiepileptic medication for several months at the onset of the investigation. Group E comprised seven patients in whom the epilepsy was diagnosed and treatment with CBZ started at the beginning of the study period. Drug and hormone levels were determined before treatment, daily the first 4 days of treatment, and thereafter less frequently for 1 month. Group F consisted of only one patient. Longterm CBZ was discontinued, and she was followed up for 2 weeks. As controls were used eighty-three adult euthyroid patients referred to thyroid function studies. They used no drugs, had no clinical evidence of goitre and revealed no history of thyroid or pituitaryihypothalamic disease. As reference group for some of the tests twentythree healthy persons belonging to the laboratory staff were used. The controls and the reference groups were not matched to the patient population with respect to age and sex distribution.
determined with ‘KIT reverse T3 peg’ from Hypolab, Coinsins, Switzerland, CV 15 :
