Normal Serum Free Thyroid Hormone Concentrations in Patients Treated With Phenytoin or Carbamazepine: A Paradox Resolved
Abstract
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 phospate 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 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.
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A similar phenomenon (normal TSH and low FT4) has been attributed to a measurement artifact in the case of free thyroid hormone concentrations.
“A similar phenomenon (normal TSH and low FT4) has been attributed to a measurement artifact in the case of free thyroid hormone concentrations (182).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [182]
Therapeutic levels of phenytoin, carbamazepine, salsalate, salicylate, furosemide, fenclofenac, ethacrynic acid, and heparin induce displacement of T4 from binding proteins in vitro.
“Firstly, therapeutic levels of phenytoin, carbamazepine, salsalate, salicylate, furosemide, fenclofenac, ethacrynic acid, and heparin induce the displacement of T4 from the binding proteins in vitro [ 87 , 88 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [87]
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“A similar phenomenon (normal TSH and low FT4) has been attributed to a measurement artifact in the case of free thyroid hormone concentrations (182).”
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- Authors
- Surks, M. I.
- Corresponding author
- Surks, Martin I.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 1996-05-15
- Volume
- 275
- Issue
- 19
- Pages
- 1495
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W133522358
- Cited by
- 8
- References
- 5
- Citations by year
- 2024: 1 · 2021: 3 · 2020: 1 · 2016: 1 · 2015: 1
- FWCI
- 0.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- free thyroxine, serum thyroid hormones, phenytoin, carbamazepine, antiepileptic drugs, drug effects on thyroid function
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