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Thyroid-Stimulating Hormone–Receptor Antibody and Thyroid Hormone Concentrations in Smokers vs Nonsmokers With Graves Disease Treated With Carbimazole
To the Editor: Cigarette smoking increases the risk of complications of Graves disease, such as ophthalmopathy and relapse after treatment with antithyroid drugs.1 Anecdotally, patients with Graves disease who smoke appear to respond more slowly to treatment with carbimazole. We therefore retrospectively compared the decline in concentrations of thyroid-stimulating hormone (TSH)–receptor antibody and thyroid hormones in smokers and nonsmokers during carbimazole therapy.
Methods
We studied 59 consecutive patients (25 smokers and 34 nonsmokers) meeting inclusion criteria who attended the Endocrine Clinic, Royal Infirmary, Edinburgh, United Kingdom, between January and April 2007 during the first 12 months of carbimazole therapy for Graves disease (TABLE). Carbimazole was used in an initial maximum dose of 40 mg/d and at review reduced according to thyroid hormone and TSH concentrations. TSH-receptor antibody, free thyroxine (FT4), and total triiodothyronine (T3) concentrations were measured every 4 to 6 weeks. TSH-receptor antibodies were measured using the TRAK human luminescence immunoassay (Brahms, Hennigsdorf, Germany), which is a competitive-binding assay. Values greater than 1.5 IU/L were regarded as positive. Levels of TSH, FT4, and T3 were measured using an Architect automated immunoassay platform (Abbott Diagnostics, Dartford, United Kingdom). Patients who were pregnant, allergic to carbimazole, former smokers, irregular attenders, and those who reported poor medication adherence were excluded. The project was approved by the local ethics committee, and all patients provided oral consent.
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Table. Clinical Characteristics and Response of TSH-Receptor Antibodies and Thyroid Hormones During Treatment With Carbimazole for Graves Disease
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Power calculations revealed that 16 participants were needed in each group to have a 90% chance of detecting at least a 25% difference in each outcome at a 2-sided  level of .05. Data collected over the 12 months of carbimazole therapy were analyzed by summary measure analysis2 using the area under the curve (AUC) as calculated by the trapezoid rule. Groups were compared using the Mann-Whitney test. All statistical tests were performed using GraphPad Prism version 4 (GraphPad Software Inc, La Jolla, California).
Results
All 59 patients completed the study. Smokers and nonsmokers had similar concentrations of TSH-receptor antibodies and thyroid hormones at diagnosis (Table). With carbimazole treatment, smokers compared with nonsmokers showed a much slower reduction in concentrations of TSH-receptor antibody (AUC, 107.5 vs 59.0 IU/L; P = .02), FT4 (AUC, 17.4 vs 12.5 ng/dL; P = .01), and T3 (AUC, 2078 vs 1526 ng/dL; P = .003) (Figure and Table). After 12 months the concentrations of TSH-receptor antibody, FT4, and T3 were not significantly different between smokers and nonsmokers. Smokers required higher doses of carbimazole than nonsmokers (median, 17.8 mg/d vs 10.4 mg/d; P = .04) (Table).
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Figure. Thyroid-Stimulating Hormone (TSH)–Receptor Antibody and Thyroid Hormone Concentrations in Smokers and Nonsmokers With Graves Disease During Treatment With Carbimazole
Means at each time point are shown for serum concentrations of TSH-receptor antibodies (A), free thyroxine (FT4 ) (B), and total triiodothyronine (T3) (C) in smokers (n = 25) and nonsmokers (n = 34) during the first 12 months of carbimazole therapy. Area under the curve comparisons yielded P = .02 for TSH-receptor antibodies, P = .01 for FT4, and P = .003 for T3. Error bars represent 95% confidence intervals. To convert FT4 to pmol/L, multiply by 12.871; to convert T3 to nmol/L, multiply by 0.0154.
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Comment
These findings suggest an association between smoking and the rates of decline of TSH-receptor antibody and thyroid hormones with carbimazole use. The mechanism for such differences is unclear. There is no evidence that smokers were less adherent with carbimazole use than nonsmokers. Aside from inhibiting thyroid hormone synthesis, antithyroid drugs have immunomodulatory effects that attenuate TSH-receptor antibody concentrations, which may contribute to their efficacy3; cigarette smoking might inhibit this immunosuppressive action. The rate of decrease in TSH-receptor antibody concentrations during the early phase of antithyroid drug treatment may reliably predict remission of Graves hyperthyroidism.4 Thus, protracted elevation of TSH-receptor antibody concentrations might explain why smoking increases the risk of treatment failure.1
lnterindividual differences in the response to antithyroid therapy in patients with hyperthyroidism may reflect kinetic variability.5 It is also possible that smoking affects carbimazole absorption, concentration in the thyroid gland, or metabolism. Smoking is thought to affect expression of microsomal enzymes, which may influence the concentration of carbimazole or its metabolites.6
Study limitations include small patient sample size from a single site, retrospective data collection, and the possibility of confounders such as sex and drug interactions. These results require confirmation in a larger prospective study.
Author Contributions: Dr Nyirenda had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Toft.
Acquisition of data: Nyirenda, Stoddart, Taylor.
Analysis and interpretation: Nyirenda, Taylor, Toft.
Drafting of the manuscript: Nyirenda, Beckett, Stoddart, Taylor, Toft.
Critical revision of the manuscript for important intellectual content: Toft, Beckett, Nyirenda.
Statistical analysis: Nyirenda, Beckett, Taylor.
Administrative, technical, or material support: Beckett, Stoddart.
Study supervision: Toft.
Financial Disclosures: None reported.
Funding/Support: None.
Moffat J. Nyirenda, MRCP
Endocrinology Unit
Queen's Medical Research Institute
University of Edinburgh
Edinburgh, United Kingdom
Peter N. Taylor, MRCP
Endocrine Clinic
The Royal Infirmary of Edinburgh
Mary Stoddart, MIBMS;
Geoffrey J. Beckett, PhD, FRCPath
Clinical Biochemistry
University of Edinburgh
Anthony D. Toft, MD
anthony.toft{at}luht.scot.nhs.uk
Endocrine Clinic
The Royal Infirmary of Edinburgh
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2009;301(2):162-164.
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