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May 15, 1996, Vol 275, No. 19 >
ARTICLE | May 15, 1996

Normal Serum Free Thyroid Hormone Concentrations in Patients Treated With Phenytoin or Carbamazepine: Title and subTitle BreakA Paradox Resolved FREE

Martin I. Surks, MD; Charles R. DeFesi, PhD
[+] Author Affiliations

Reprints: Martin I. Surks, MD, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467 (e-mail: surks@aecom.yu.edu).


JAMA. 1996;275(19):1495-1498. doi:10.1001/jama.1996.03530430039036
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References

Objective.  —To address the paradox that phenytoin- and carbamazepine-treated patients have decreased serum free thyroxine (T4) and triiodothyronine (T3) concentrations but appear clinically euthyroid and have normal serum thyroid-stimulating hormone (TSH) concentrations.

Design.  —In vitro studies comparing measurements of total and free T4 and T3 by ultrafiltration assay (undiluted serum) and a commercial free T4 estimate kit in control serum samples or serum samples containing added therapeutic levels of phenytoin or carbamazepine. These measurements were made in serum samples diluted 1:5 with either identical serum or phosphate buffer, pH 7.4, and in serum samples from patients with seizure disorders who were treated with phenytoin or carbamazepine.

Setting.  —A 650-bed teaching hospital.

Patients.  —Selected patients (n=19) who were in good health except for seizure disorder, with stable anticonvulsant drug levels in the upper half of the therapeutic range, and were not taking any other drugs that could affect thyroid parameters.

Main Outcome Measure.  —Serum concentrations of free T4 and free T3 in patients taking phenytoin or carbamazepine vs normal controls.

Results.  —Addition of phenytoin or carbamazepine to normal human serum in vitro resulted in a significant increase in free T4 fraction and free T4 (P<.001). In patients taking phenytoin or carbamazepine, serum total T4 decreased significantly to 60% and 74%, respectively, of the control serum concentration (P<.001 for both phenytoin and carbamazepine); free T4 fraction (by ultrafiltration assay) increased 65% and 44%, respectively (P<.001 for phenytoin, P<.01 for carbamazepine); and free T4 remained unchanged. Free T4 concentration measured by a commercial kit (1:5 serum dilution) was significantly lower than the control concentration in both phenytoin- and carbamazepine-treated patients. Serum free T3 and serum TSH were also normal in phenytoin- and carbamazepine-treated patients.

Conclusions.  —Therapeutic levels of phenytoin and carbamazepine displace T4 and T3 from serum binding proteins. When added to serum, the drugs effect an increase in free hormone fractions and free T4 and T3. In drug-treated patients, increased free T4 and free T3 fractions offset the significant decrease in serum T4 and T3, resulting in normal free T4 and free T3 concentrations. Since currently available clinical tests will continue to show decreased free T4 concentrations in patients taking phenytoin or carbamazepine, clinicians should rely on serum TSH measurements to confirm the euthyroid status of these patients.(JAMA. 1996;275:1495-1498)

REFERENCES

1 +
Oppenheimer JH, Fisher LV, Nelson KM, Jailer JW.  Depression of the serum protein-bound iodine level by diphenylhydantoin. J Clin Endocrinol Metab . 1961;;21:252-259.
2 +
Oppenheimer JH, Tavernett RR.  Studies on the thyroxine-diphenylhydantoin interaction: effect of 5,5′-diphenylhydantoin on the displacement of L-thyroxine from thyroxine-binding globulin (TBG). Endocrinology . 1962;;71:496-504.
3 +
Chin W, Schussler GC.  Decreased serum free thyroxine concentration in patients treated with diphenylhydantoin. J Clin Endocrinol . 1968;;28:181-186.
4 +
Larsen PR, Atkinson AJ Jr, Wellman HN, Goldsmith RE.  The effect of diphenylhydantoin on thyroxine metabolism in man. J Clin Invest . 1970;; 49:1266-1279.
5 +
Hansen JM, Skovsted L, Lauridsen UB, Kirkegaard C, Siersbaek-Nielsen K.  The effect of diphenylhydantoin on thyroid function. J Clin Endocrinol Metab . 1974;;39:785-789.
6 +
Stjernholm MR, Alsever RN, Rudolph MC.  Thyroid function tests in diphenylhydantoin-treated patients. Clin Chem . 1975;;21:1388-1392.
7 +
Liewendahl K, Majuri H.  Thyroxine, triiodothyronine and thyrotropin in serum during long-term diphenylhydantoin therapy. Scand J Clin Lab Invest . 1976;;36:141-144.
8 +
Heyma P, Larkins RG, Perry-Keene DP, Peter CT, Ross D, Sloman JG.  Thyroid hormone levels and protein binding in patients on long term diphenylhydantoin treatment. Clin Endocrinol (Oxf) . 1977;;6:369-376.
9 +
Liewendahl K, Majuri H, Helenius T.  Thyroid function tests in patients on long-term treatment with various anticonvulsant drugs. Clin Endocrinol (Oxf) . 1978;;8:185-191.
10 +
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.
11 +
Fichsel H, Knopfle G.  Effects of anticonvulsant drugs on thyroid hormones in epileptic children. Epilepsia . 1978;;19:323-336.
12 +
Yeo PPB, Bates D, Howe JG, et al.  Anticonvulsants and thyroid function. BMJ . 1978;;1:1581-1583.
13 +
Cavalieri RR, Gavin LA, Wallace A, Hammond ME, Cruse K.  Serum thyroxine, free T4, triiodothyronine, and reverse T3 in diphenylhydantoin-treated patients. Metabolism . 1979;;28:1161-1165.
14 +
Bentsen KD, Gram L, Veje A.  Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. Acta Neurol Scand . 1983;;67:235-241.
15 +
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.
16 +
Franklyn JA, Sheppard MC, Ramsden DB.  Measurement of free thyroid hormones in patients on long-term phenytoin therapy. Eur J Clin Pharmacol . 1984;;26:633-634.
17 +
Hegedus L, Hansen JM, Luhdorf K, Perriold H, Feldt-Rasmussen U, Kampmann JP.  Increased frequency of goiter in epileptic patients on long term phenytoin or carbamazepine treatment. Clin Endocrinol (Oxf) . 1985;;23:423-429.
18 +
Liewendahl K, Tikanoja S, Helenius T, Majuri H.  Free thyroxine and free triiodothyronine as measured by equilibrium dialysis and analog radioimmunoassay in serum of patients taking phenytoin and carbamazepine. Clin Chem . 1985;;31:1993-1996.
19 +
Isojarvi JIT, Pakarinen AJ, Myllyla VV.  Thyroid function in epileptic patients treated with carbamazepine. Arch Neurol . 1989;;46:1175-1178.
20 +
Isojarvi JIT, Pakarinen AJ, Ylipalosaari PJ, Myllyla VV.  Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol . 1990;;47:670-676.
21 +
Herman R, Obarzanek E, Mikalauskas KM, Post RM, Jimerson DC.  The effects of carbamazepine on resting metabolic rate and thyroid function in depressed patients. Biol Psychiatry . 1991;;29:779-788.
22 +
Isojarvi JIT, Airaksinen KEJ, Repo M, Pakarinen AJ, Salmela P, Myllyla VV.  Carbamazepine, serum thyroid hormones and myocardial function in epileptic patients. J Neurol Neurosurg Psychiatry . 1993;;56:710-712.
23 +
Smith PJ, Surks MI.  Multiple effects of 5,5′-diphenylhydantoin on the thyroid hormone system. Endocr Rev . 1984;;5:514-523.
24 +
Mann DN, Surks MI.  5,5′-Diphenylhydantoin decreases specific 3,5,3′-triiodothyronine T3 binding by rat hepatic nuclear T3 receptors. Endocrinology . 1983;;112:1723-1724.
25 +
Franklyn JA, Davis JRE, Ramsden DB, Sheppard MC.  Phenytoin and thyroid hormone action. J Endocrinol . 1985;;104:201-204.
26 +
Surks MI, Hupart KH, Pan C, Shapiro LE.  Normal free thyroxine in critical nonthyroidal illnesses measured by ultrafiltration of undiluted serum and equilibrium dialysis. J Clin Endocrinol Metab . 1988;;67:1031-1039.
27 +
Snedecor GW, Cochran WG. Statistical Methods . Ames: Iowa State University Press; 1967;.
28 +
Ekins R.  Measurement of free hormones in blood. Endocr Rev . 1990;;11:5-46.
29 +
Lim CF, Bai Y, Topliss DJ, Barlow JW, Stockigt JR.  Drug and fatty acid effects on serum thyroid hormone binding. J Clin Endocrinol Metab . 1988;; 67:682-688.
30 +
Blackshear JL, Schultz AL, Napier JS, Stuart DD.  Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med . 1983;;99:341-342.

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1 +
Oppenheimer JH, Fisher LV, Nelson KM, Jailer JW.  Depression of the serum protein-bound iodine level by diphenylhydantoin. J Clin Endocrinol Metab . 1961;;21:252-259.
2 +
Oppenheimer JH, Tavernett RR.  Studies on the thyroxine-diphenylhydantoin interaction: effect of 5,5′-diphenylhydantoin on the displacement of L-thyroxine from thyroxine-binding globulin (TBG). Endocrinology . 1962;;71:496-504.
3 +
Chin W, Schussler GC.  Decreased serum free thyroxine concentration in patients treated with diphenylhydantoin. J Clin Endocrinol . 1968;;28:181-186.
4 +
Larsen PR, Atkinson AJ Jr, Wellman HN, Goldsmith RE.  The effect of diphenylhydantoin on thyroxine metabolism in man. J Clin Invest . 1970;; 49:1266-1279.
5 +
Hansen JM, Skovsted L, Lauridsen UB, Kirkegaard C, Siersbaek-Nielsen K.  The effect of diphenylhydantoin on thyroid function. J Clin Endocrinol Metab . 1974;;39:785-789.
6 +
Stjernholm MR, Alsever RN, Rudolph MC.  Thyroid function tests in diphenylhydantoin-treated patients. Clin Chem . 1975;;21:1388-1392.
7 +
Liewendahl K, Majuri H.  Thyroxine, triiodothyronine and thyrotropin in serum during long-term diphenylhydantoin therapy. Scand J Clin Lab Invest . 1976;;36:141-144.
8 +
Heyma P, Larkins RG, Perry-Keene DP, Peter CT, Ross D, Sloman JG.  Thyroid hormone levels and protein binding in patients on long term diphenylhydantoin treatment. Clin Endocrinol (Oxf) . 1977;;6:369-376.
9 +
Liewendahl K, Majuri H, Helenius T.  Thyroid function tests in patients on long-term treatment with various anticonvulsant drugs. Clin Endocrinol (Oxf) . 1978;;8:185-191.
10 +
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.
11 +
Fichsel H, Knopfle G.  Effects of anticonvulsant drugs on thyroid hormones in epileptic children. Epilepsia . 1978;;19:323-336.
12 +
Yeo PPB, Bates D, Howe JG, et al.  Anticonvulsants and thyroid function. BMJ . 1978;;1:1581-1583.
13 +
Cavalieri RR, Gavin LA, Wallace A, Hammond ME, Cruse K.  Serum thyroxine, free T4, triiodothyronine, and reverse T3 in diphenylhydantoin-treated patients. Metabolism . 1979;;28:1161-1165.
14 +
Bentsen KD, Gram L, Veje A.  Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. Acta Neurol Scand . 1983;;67:235-241.
15 +
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.
16 +
Franklyn JA, Sheppard MC, Ramsden DB.  Measurement of free thyroid hormones in patients on long-term phenytoin therapy. Eur J Clin Pharmacol . 1984;;26:633-634.
17 +
Hegedus L, Hansen JM, Luhdorf K, Perriold H, Feldt-Rasmussen U, Kampmann JP.  Increased frequency of goiter in epileptic patients on long term phenytoin or carbamazepine treatment. Clin Endocrinol (Oxf) . 1985;;23:423-429.
18 +
Liewendahl K, Tikanoja S, Helenius T, Majuri H.  Free thyroxine and free triiodothyronine as measured by equilibrium dialysis and analog radioimmunoassay in serum of patients taking phenytoin and carbamazepine. Clin Chem . 1985;;31:1993-1996.
19 +
Isojarvi JIT, Pakarinen AJ, Myllyla VV.  Thyroid function in epileptic patients treated with carbamazepine. Arch Neurol . 1989;;46:1175-1178.
20 +
Isojarvi JIT, Pakarinen AJ, Ylipalosaari PJ, Myllyla VV.  Serum hormones in male epileptic patients receiving anticonvulsant medication. Arch Neurol . 1990;;47:670-676.
21 +
Herman R, Obarzanek E, Mikalauskas KM, Post RM, Jimerson DC.  The effects of carbamazepine on resting metabolic rate and thyroid function in depressed patients. Biol Psychiatry . 1991;;29:779-788.
22 +
Isojarvi JIT, Airaksinen KEJ, Repo M, Pakarinen AJ, Salmela P, Myllyla VV.  Carbamazepine, serum thyroid hormones and myocardial function in epileptic patients. J Neurol Neurosurg Psychiatry . 1993;;56:710-712.
23 +
Smith PJ, Surks MI.  Multiple effects of 5,5′-diphenylhydantoin on the thyroid hormone system. Endocr Rev . 1984;;5:514-523.
24 +
Mann DN, Surks MI.  5,5′-Diphenylhydantoin decreases specific 3,5,3′-triiodothyronine T3 binding by rat hepatic nuclear T3 receptors. Endocrinology . 1983;;112:1723-1724.
25 +
Franklyn JA, Davis JRE, Ramsden DB, Sheppard MC.  Phenytoin and thyroid hormone action. J Endocrinol . 1985;;104:201-204.
26 +
Surks MI, Hupart KH, Pan C, Shapiro LE.  Normal free thyroxine in critical nonthyroidal illnesses measured by ultrafiltration of undiluted serum and equilibrium dialysis. J Clin Endocrinol Metab . 1988;;67:1031-1039.
27 +
Snedecor GW, Cochran WG. Statistical Methods . Ames: Iowa State University Press; 1967;.
28 +
Ekins R.  Measurement of free hormones in blood. Endocr Rev . 1990;;11:5-46.
29 +
Lim CF, Bai Y, Topliss DJ, Barlow JW, Stockigt JR.  Drug and fatty acid effects on serum thyroid hormone binding. J Clin Endocrinol Metab . 1988;; 67:682-688.
30 +
Blackshear JL, Schultz AL, Napier JS, Stuart DD.  Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med . 1983;;99:341-342.

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