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Jayne A. Franklyn, MD, PhD; Michael C. Sheppard, PhD, FRCP; Patrick Maisonneuve, PhD

JAMA. 2005;294:71-80.

Context  Hyperthyroidism has been reported to cause excess all-cause and circulatory mortality. Whether this can be reversed is unknown, as is the influence of mild persisting thyroid dysfunction and treatment-induced hypothyroidism.

Objectives  To determine whether radioiodine treatment is associated with increased mortality and to determine the influences of mild thyroid dysfunction and the development of overt hypothyroidism treated with thyroxine (T₄).

Design, Setting, and Participants  A population-based study of 2668 individuals aged 40 years or older treated for overt hyperthyroidism with radioiodine in the West Midlands region of England from 1984-2002.

Main Outcome Measures  Cause of death compared with age- and period-specific mortality in England and Wales and assessment of the influence of T₄ therapy for radioiodine-induced hypothyroidism and subclinical thyroid dysfunction on mortality.

Results  In 15 968 person-years of follow-up, 554 died vs 487 expected deaths (standardized mortality ratio [SMR], 1.14; 95% confidence interval [CI], 1.04-1.24, P=.002). Increased risks of all-cause and circulatory deaths vs age- and period-specific mortality were observed in follow-up in those not requiring, or prior to, T₄ therapy. These increased risks were not observed during follow-up on T₄ therapy (circulatory disease SMR prior to T₄, 1.33; 95% CI, 1.14-1.53 vs SMR, 0.91; 95% CI, 0.70-1.17 during T₄). Patients receiving T₄ had decreased risk of mortality vs risk in the period not requiring, or prior to, T₄ therapy (all-cause mortality hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; circulatory mortality HR, 0.65; 95% CI, 0.48-0.87). Increased all-cause mortality vs the background population was observed in the period prior to T₄ therapy in follow-up associated with low, normal, and high serum thyrotropin. The SMR for ischemic heart disease increased slightly when analyzed by serum thyrotropin, high serum thyrotropin being the highest SMR (low thyrotropin SMR, 1.06; 95% CI, 0.75-1.45; normal thyrotropin SMR, 1.17; 95% CI, 0.76-1.71; high thyrotropin SMR, 1.48; 95% CI, 0.86-2.37). Comparison within the cohort showed that mild hypothyroidism prior to T₄ therapy was associated with increased risk of mortality from ischemic heart disease vs biochemical euthyroidism (HR, 2.08; 95% CI, 1.04-4.19).

Conclusions  Patients treated with radioiodine for hyperthyroidism had increased mortality vs age- and period-specific mortality in England and Wales, a finding no longer evident during T₄ therapy. This supports treating hyperthyroidism with doses of radioiodine sufficient to induce overt hypothyroidism. The association within the cohort of mortality from ischemic heart disease with subclinical hypothyroidism suggests T₄ replacement should be considered should this biochemical abnormality develop after radioiodine therapy.

Author Affiliations: Division of Medical Sciences, University of Birmingham, England (Drs Franklyn and Sheppard) and the Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy (Dr Maisonneuve).

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