To the Editor: In his Clinical Practice article on Graves' disease,Brent (June 12 issue)1 comments on the combined use of antithyroiddrugs and radioiodine and refers to the results of our trial,2 showing no effects of antithyroid drugs on radioiodine therapyafter a 3-day-withdrawal. However, in a subsequent meta-analysis,3 we found that antithyroid drugs significantly reduced thesuccess of radioiodine therapy, even when the drugs were discontinuedfor a week. This conclusion contradicted those of most of theincluded trials (including our own), which were most likelyunderpowered to detect significant differences. We now discontinueantithyroid drugs for more than a week before radioiodine therapy,if clinically feasible. Adequately powered trials are neededto better inform this issue.
Martin A. Walter, M.D. Mirjam Christ-Crain, M.D. Beat Muller, M.D. University Hospital CH-4031 Basel, Switzerland m.a.walter{at}gmx.net
References
Brent GA. Graves' disease. N Engl J Med 2008;358:2594-2605. [Free Full Text]
Walter MA, Christ-Crain M, Schindler C, Müller-Brand J, Müller B. Outcome of radioiodine therapy without, on or 3 days off carbimazole: a prospective interventional three-group comparison. Eur J Nucl Med Mol Imaging 2006;33:730-737. [CrossRef][Web of Science][Medline]
Walter MA, Briel M, Christ-Crain M, et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 2007;334:514-514. [Free Full Text]
To the Editor: As noted by Brent and others,1 thyroid volume,circulating titers of thyrotropin-receptor antibodies, sex,and age are predictors of remission in Graves' disease and arecommonly used as indicators for choosing the best therapeuticoption. However, several studies2,3,4 have shown that an olderage at presentation and not the contrary, as stated by Brent,characterizes patients with Graves' disease who are most likelyto undergo a prolonged remission after treatment with antithyroiddrugs. Thus, especially in patients with Graves' disease whoare older than 40 years, a full course of antithyroid drugsis a reasonable therapeutic option, which could avoid unnecessarythyroid surgery, radioiodine ablation, or both, with the subsequentneed for lifelong levothyroxine treatment.
Mario Rotondi, M.D., Ph.D. Rodolfo Fonte, M.D. Luca Chiovato, M.D., Ph.D. Fondazione S. Maugeri IRCCS 27100 Pavia, Italy
References
Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905-917. [Free Full Text]
Yamada T, Aizawa T, Koizumi Y, Komiya I, Ichikawa K, Hashizume K. Age-related therapeutic response to antithyroid drug in patients with hyperthyroid Graves' disease. J Am Geriatr Soc 1994;42:513-516. [Web of Science][Medline]
Vitti P, Rago T, Chiovato L, et al. Clinical features of patients with Graves' disease undergoing remission after antithyroid drug treatment. Thyroid 1997;7:369-375. [Web of Science][Medline]
Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038-1042. [Free Full Text]
To the Editor: Brent does not discuss the adverse effects ofcigarette smoking in patients with Graves' disease. Researchfindings support associations between cigarette smoking andboth Graves' disease and Graves' ophthalmopathy. For example,a meta-analysis showed an odds ratio for Graves' disease of3.30 (95% confidence interval [CI], 2.09 to 5.22, based on datafrom eight studies) among current smokers as compared with personswho had never smoked.1 The meta-analysis also showed that theodds ratio for Graves' ophthalmopathy among persons who hadever smoked was 4.40 (95% CI, 2.88 to 6.73, based on data fromsix studies). Among current smokers, the hazard ratio for Graves'disease increases with the intensity of smoking.2
Cigarette smoking is also associated with a higher degree ofseverity in Graves' ophthalmopathy and a lower effectivenessof medical treatment.3 Cigarette smoking increases the riskof progression of ophthalmopathy after radioiodine therapy anddecreases the efficacy of orbital radiation therapy and glucocorticoidtherapy.4
Therefore, clinicians treating patients with Graves' disease,including those with Graves' ophthalmopathy, should stronglyadvise these patients not to smoke cigarettes and, whereverpossible, to avoid exposure to environmental tobacco smoke.
Barry S. Levy, M.D., M.P.H. Tufts University School of Medicine Boston, MA 02111 blevy{at}igc.org
References
Vestergaard P. Smoking and thyroid disorders -- a meta-analysis. Eur J Endocrinol 2002;146:153-161. [Abstract]
Holm IA, Manson JE, Michels KB, Alexander EK, Willett WC, Utiger RD. Smoking and other lifestyle factors and the risk of Graves' hyperthyroidism. Arch Intern Med 2005;165:1606-1611. [Free Full Text]
Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves' ophthalmopathy. Thyroid 2002;11:855-860.
Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med 1998;129:632-635. [Free Full Text]
To the Editor: Brent refers to a study we performed to supportthe claim that no increased risk of cancer has been reportedafter treatment with radioactive iodine in patients with Graves'disease. On the contrary, we have reported an increased riskof cancer both among patients with Graves' disease and amongthose with toxic multinodular goiter.1 The incidence of cancersof the stomach, kidney, and breast was increased. However, theincrease in overall and cancer-related mortality was seen onlyamong the patients with toxic multinodular goiter, who wereolder than the patients with Graves' disease.2 We recommendthat the small but significant risk of cancer should be consideredin planning the treatment for hyperthyroidism, at least in childrenand young adults.
Saara Metso, M.D. Tampere University Hospital 33520 Tampere, Finland saara.metso{at}uta.fi
Pia Jaatinen, M.D., Ph.D. University of Tampere 33014 Tampere, Finland
Jorma Salmi, M.D., Ph.D. Tampere University Hospital 33520 Tampere, Finland
References
Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, Jaatinen P. Increased cancer incidence after radioiodine treatment for hyperthyroidism. Cancer 2007;109:1972-1979. [Erratum, Cancer 2007;110:1875.] [CrossRef][Web of Science][Medline]
Metso S, Jaatinen P, Huhtala H, Auvinen A, Oksala H, Salmi J. Increased cardiovascular and cancer mortality after radioiodine treatment for hyperthyroidism. J Clin Endocrinol Metab 2007;92:2190-2196. [Erratum, J Endocrinol Metab 2007;92:4008.] [Free Full Text]
The author replies: Walter and colleagues detected an influenceof antithyroid-drug treatment on the effectiveness of radioiodinetherapy in their meta-analysis,1 although half the studies includeddid not discontinue the antithyroid drug before radioiodinetherapy; the effectiveness of radioiodine therapy was also improvedwith higher doses of radioiodine.1 Their practice of discontinuingantithyroid drugs for more than 1 week before administeringradioiodine is at the limit of the range of 3 to 7 days recommendedin the review and by most clinical guidelines. The risk of aprolonged interval of antithyroid-drug cessation is worseninghyperthyroidism, which is clinically relevant primarily forpatients with more severe hyperthyroidism or increased susceptibility,such as those with active cardiac disease. I concur with therecommendation for an adequately powered trial.
Rotondi and colleagues correctly state that younger patientswith Graves' disease are less likely to have a remission withantithyroid-drug therapy; I regret the error. The study citedin the review2 showed that patients with Graves' disease whowere less than 40 years old had a lower remission rate afterlong-term antithyroid-drug treatment (32.6%) than patients whowere 40 years or older (47.8%). Younger patients, as comparedwith older patients, have higher levels of thyrotropin-receptorantibodies and the associated manifestations of increased thyroidvolume and increased thyroid hormone levels, especially serumtriiodothyronine.
Levy emphasizes the important role of cigarette smoking in Graves'disease, especially Graves' ophthalmopathy. Patients shouldbe informed that cigarette smoking is likely to worsen ophthalmopathyand reduce the response to treatment. Most studies have showna cigarette dose effect, so a reduction in the number of cigarettessmoked may also be beneficial. Smoking is also associated witha larger goiter at presentation among patients with Graves'disease and a reduced likelihood of remission with antithyroiddrugs.3
Metso and colleagues refer to the association of cancer withradioiodine therapy for hyperthyroidism. The references citedin the review from their group and others focused on cancer-relatedmortality after radioiodine therapy, and this should have beenclarified in the discussion. Metso and colleagues report a smallbut significant dose-related increase in the incidence of stomach,kidney, and breast cancers in long-term follow-up of patientswith hyperthyroidism who received treatment with radioiodine.4 A larger series5 showed an overall reduction in the incidenceof cancer among patients treated with radioiodine for hyperthyroidismbut an increase in the incidence of a few cancers. The finding,from several long-term studies, of no increase in cancer-relatedmortality after radioiodine treatment for Graves' disease isreassuring. The small increase in the incidence of some cancers,including several potentially linked to direct exposure to oruptake of iodine, may be relevant for treatment decisions.
Gregory A. Brent, M.D. Veterans Affairs Greater Los Angeles Healthcare System Los Angeles, CA 90073 gbrent{at}ucla.edu
References
Walter MA, Briel M, Christ-Crain M, et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 2007;334:514-514. [Free Full Text]
Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038-1042. [Free Full Text]
Glinoer D, de Nayer P, Bex M. Effects of L-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study. Eur J Endocrinol 2001;144:475-483. [Abstract]
Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, Jaatinen P. Increased cancer incidence after radioiodine treatment for hyperthyroidism. Cancer 2007;109:1972-1979. [Erratum, Cancer 2007;110:1875.] [CrossRef][Web of Science][Medline]
Franklyn JA, Maisonneuve P, Sheppard M, Betteridge J, Boyle P. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet 1999;353:2111-2115. [CrossRef][Web of Science][Medline]
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