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Increased Cardiovascular and Cancer Mortality after Radioiodine Treatment for Hyperthyroidism

Department of Internal Medicine (S.M., P.J., H.O., J.S.) and Research Unit (H.H.), Tampere University Hospital, FIN-33521 Tampere, Finland; Medical School (S.M., P.J.) and Tampere School of Public Health (H.H., A.A.), University of Tampere, FIN-33014 Tampere, Finland; and STUK-Radiation and Nuclear Safety Authority (A.A.), Research and Environmental Surveillance, FIN-00881 Helsinki, Finland

Address all correspondence and requests for reprints to: Saara Metso, M.D., Department of Internal Medicine, Tampere University Hospital, P.O. Box 2000, FIN-33521 Tampere, Finland. E-mail: saara.metso{at}pshp.fi.

	Abstract

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Context: Patients treated with radioiodine (RAI) for hyperthyroidism have been reported to be at increased risk for death. It is not clear whether the increased mortality is due to hyperthyroidism itself or the effect of RAI.

Objective: Our objective was to compare the mortality of hyperthyroid patients treated with RAI with that of an age- and gender-matched reference population.

Design: We conducted a population-based cohort study.

Participants: A total of 2793 patients who received RAI treatment for hyperthyroidism in Tampere University Hospital between 1965 and 2002, and 2793 reference subjects were followed for a median of 9 yr.

Results: Record linkage with Statistics Finland identified all-cause mortality of 453 vs. 406 per 10,000 person-years in the patients and controls [rate ratio (RR) 1.12; 95% confidence interval 1.03–1.20]. Cerebrovascular diseases accounted for most of the increased mortality among patients (RR 1.40), and mortality from cancer increased (RR 1.29) as well. The risk of death increased in patients older than 60 yr at treatment. Mortality increased with the dose of RAI and was elevated in patients with nodular thyroid disease, but not in those with Graves’ disease. Previous treatment with partial thyroidectomy decreased, whereas antithyroid medication did not affect mortality. In Cox regression analysis, RAI-treated hyperthyroidism (RR 1.56) and age (RR 1.10/1 yr) increased, and the development of hypothyroidism (RR 0.52) reduced mortality significantly.

Conclusions: Hyperthyroidism per se probably accounts for the increased cerebrovascular mortality after RAI treatment. Our results of increased cerebrovascular and cancer mortality emphasize the need for long-term vigilance concerning patients treated with RAI.

	Introduction

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RADIOIODINE [¹³¹I (RAI)] is commonly used as first-line therapy for hyperthyroidism (1). It has been used for this purpose since the 1940s, although the long-term safety of RAI, especially in children and young adults, has been questioned (2). Mortality studies of hyperthyroid patients treated with RAI are few in number and based on three different patient cohorts: American (3, 4, 5, 6); Swedish (7, 8); and English (9, 10, 11).

Hoffman et al. (3) at the Mayo Clinic reported no difference in overall mortality between 1005 women treated with RAI and 2141 women treated with surgery for hyperthyroidism in a continuation of the United States Public Health Service Cooperative Thyrotoxicosis Therapy Follow-up Study 1946–1964. Goldman et al. (4) observed increased standardized mortality rate for deaths from all causes, and from endocrine, circulatory, and respiratory diseases, but not from malignant tumors in 1762 hyperthyroid women treated with RAI (80%), thyroidectomy, or antithyroid drugs at the Massachusetts General Hospital compared with the U.S. women in another continuation of the Cooperative Thyrotoxicosis Therapy Follow-up Study. In the report of the whole original Cooperative Thyrotoxicosis Therapy Follow-up Study, including 35,593 patients, neither hyperthyroidism nor RAI treatment resulted in significantly increased risk of total cancer mortality (6).

In 10,552 Swedish hyperthyroid patients treated with RAI, a significant excess of overall mortality was observed compared with the expected rates. Moreover, the risk of dying of respiratory, cardiovascular, and endocrine diseases, and cancer, especially cancers of digestive and respiratory organs, was elevated (7, 8). In the study of Franklyn et al. (9, 10), the all-cause mortality and mortality due to cardiovascular, cerebrovascular, and thyroid diseases, and hip fracture was increased, but overall cancer mortality was decreased in a cohort of 7209 subjects with hyperthyroidism treated with RAI in the United Kingdom. In the latest study of 3888 hyperthyroid patients treated with RAI, thyroidectomy, or antithyroid drugs, Flynn et al. (12) reported no increase in all-cause, cardiovascular, or cancer mortality but increased risk of arrhythmias compared with the general population of Scotland.

The excess mortality seen in most previous studies may reflect an adverse influence of hyperthyroidism itself, a specific adverse effect of RAI or of subsequent hypothyroidism and its treatment with thyroxine (11). The purpose of the present study was to analyze the total mortality and specific causes of death in a Finnish population treated with RAI for hyperthyroidism, and to study the effect of the etiology of hyperthyroidism, the dose of RAI, recurrent hyperthyroidism, and the development of hypothyroidism on mortality.

	Subjects and Methods

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Information on the etiology and previous treatment of hyperthyroidism, the dates and doses of RAI treatments, and vital status among 2793 patients (457 men and 2336 women) treated for hyperthyroidism with RAI between January 1965 and June 2002 at Tampere University Hospital were obtained from computerized databases kept in Tampere University Hospital and Finnish Population Register Centre. The follow-up period of the patients started at the end of the year of the first RAI treatment. Choosing an age- and gender-matched control subject for each patient from the Population Register Centre formed a reference group. The control subject had to be alive at the time when the patient received the first RAI treatment. The follow-up period of the control subject started at the same time as that of the corresponding patient. In both patient and control groups, the follow-up ended on the date of death, emigration, or the common closing date (December 2003), whichever was first.

The cause of death data of patients and controls was obtained from the Statistics Finland using a computerized record linkage, with the personal identification number as the key. The dates and causes of death of all Finnish citizens certified by a physician are included in this register since 1971. In the present study, 55 deaths (29 patients and 26 controls) occurred before 1971, when the cause of death was not recorded in the national cause-of-death database. A total of 96 persons (10 patients and 86 controls) died abroad, or their cause of death was otherwise unknown.

In the Finnish Cause of Death Register, the causes of death have been coded according to the eighth revision of the International Classification of Diseases (ICD) between 1971 and1986, the Finnish version of ICD-9 (Tautiluokitus 1987) between 1987 and 1995, and the Finnish version of ICD-10 thereafter. A translation between the different versions was made, and the underlying causes of death were classified into nine groups: infectious diseases, malignant tumors, endocrine diseases, cardiovascular diseases, dementia, respiratory diseases, trauma, other causes of death, and unknown cause of death. The classification used in the present study differed from the ICD in a few details. In the ICD, the infectious diseases are classified according to the origin of infectious disease. In our study the deaths due to all infections of central nervous, respiratory, genitourinary, and gastrointestinal systems were classified as infectious diseases. Because the diseases of the central nervous system consisted mainly of cerebrovascular diseases, infectious diseases, and dementia in the present study, we used these separate classes instead of the crude overall category of central nervous system diseases as in the ICD. We used the underlying cause of death in classification. In addition the mortality due to atrial fibrillation (AF) was analyzed using also the contributory causes of death. Information on prevalent cancer, diabetes, and cardiovascular disease at baseline, i.e. diagnosed before the beginning of follow-up, was obtained from the Finnish Care Register using a computerized record linkage.

Information on the etiology of hyperthyroidism, previous surgical and antithyroid treatment, the dates and doses of RAI treatments, and the follow-up of the patients were recorded in the computerized register kept in the Tampere University Hospital since 1965, as described earlier (13). The etiology of hyperthyroidism was determined by clinical examination. If the cause of hyperthyroidism was not apparent by clinical examination, thyroid antibodies were measured. Furthermore, the etiology was verified by thyroid scintigraphy in 59% of cases. After the RAI treatment, the thyroid status of the patients was monitored by blood samples every 1–3 months during the first year, and subsequently at 1- to 3-yr intervals. In addition the patients completed a questionnaire on the symptoms and medication for the thyroid illness. Patients were classified as hypothyroid when symptoms and biochemical evidence, i.e. low total T₄ or free T₄ associated with an elevation of TSH, suggested hypothyroidism and resulted in the initiation of thyroxine replacement therapy. Patients were classified as having relapsed hyperthyroidism when symptoms and biochemical evidence, i.e. high total T₄ or free T₄ associated with decreased levels of TSH, necessitated repeated RAI therapy or continuous antithyroid medication lasting over 1 yr after the RAI therapy.

The ethics committee of the Pirkanmaa Hospital District approved the study protocol. In addition the National Research and Development Centre for Welfare and Health gave permission to use data from the Population Register Centre and Finnish Care Register, and the Statistics Finland gave permission to use the Cause of Death Register. The study was undertaken in accordance with the Declaration of Helsinki.

Statistical analysis

We used the statistical software Stata for Windows, version 8.2 (StataCorp, College Station, TX) to calculate the mortality rates. Other statistical analyses were performed using SPSS for Windows, version 13.0 (SPSS, Inc., Chicago, IL). Normality of the distribution of the variables studied was assessed by the Kolmogorov-Smirnov test. The distributions of all continuous variables were skewed, and, therefore, nonparametric tests (Mann-Whitney U and Kruskal-Wallis tests) were used to assess the relationship between continuous and categorical variables. The ² test was used to determine whether an association between two categorical variables was statistically significant. A two-sided P value less than 0.05 was considered statistically significant. Overall mortality was illustrated by Kaplan-Meier analysis with the log-rank test. In addition to the analysis of the whole RAI treated population and controls, mortality was also counted in the following subgroups of patients using only the corresponding controls: etiology of hyperthyroidism (Graves’ disease, multinodular goiter, or toxic adenoma); total dose of RAI (55–258MBq, 259–369MBq, 370-2664MBq); recurrence of hyperthyroidism after the first dose of RAI (yes, no); development of hypothyroidism during follow-up (yes, no); previous partial thyroidectomy (yes, no); usage of antithyroid medication before RAI (yes, no); and age at the beginning of follow-up (13–50, 50–59, 60–69, and 70–98 yr). Cox regression analysis was performed to evaluate the significance of different factors in predicting the risk of death.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The median age for the patients at treatment and controls at the beginning of the follow-up was 62 yr (quartile range 50–72 yr for both groups). The median follow-up time was 9.0 yr for the patients and 9.4 yr for the controls (Fig. 1). The patients had higher all-cause mortality than the controls (Table 1). The cumulative survival of patients and controls is illustrated as Kaplan-Meier survival curves in Fig. 2. The risk of death was higher in the patients treated with RAI for hyperthyroidism compared with the controls up to 25 yr of follow-up. The risk of death from malignant tumors, and cardiovascular, endocrine, and respiratory diseases was higher in patients than in controls (Table 1).

View larger version (41K): [in this window] [in a new window]   FIG. 1. Numbers and follow-up times of the RAI-treated patients and the age- and gender-specific control group according to different end points.

View larger version (15K): [in this window] [in a new window]   FIG. 2. Kaplan-Meier survival curves of the hyperthyroid patients treated with RAI and the controls (P < 0.001, log-rank test).

Cerebrovascular diseases accounted for the increased risk of death from cardiovascular diseases in the patients compared with the control group (Table 1). The risk of death from endocardial diseases (chronic rheumatic and nonrheumatic valve diseases) and other cardiovascular diseases (conduction disorders of heart, diseases of pulmonary circulation, and unspecified cardiac arrhythmias) was also significantly higher among the patients, but they accounted only for a small fraction of the cardiovascular mortality. AF was equally common as an underlying cause of death among patients and controls (Table 1). However, when the contributory causes of death were included in the analysis, the patients had increased risk of dying due to AF compared with the controls (mortality 29.3 vs. 17.5 per 10,000 person-years in the patients and controls; RR 1.68; 95% CI 1.20–2.34).

A total of 146 (5%) patients and 91 (3%) controls had diabetes before the beginning of follow-up (P < 0.001). Cardiovascular disease was diagnosed in 1000 (36%) patients and 572 (21%) controls before the beginning of follow-up (P < 0.001). When adjustment for previous diabetes, cardiovascular disease, and age was used in the Cox regression analysis, the risk of cardiovascular death in the patients compared with controls was not materially affected (unadjusted RR 1.19; 95% CI 1.07–1.32; adjusted RR 1.15; 95% CI 1.03–1.27). A total of 117 patients (4%) and 112 controls (4%) had prevalent cerebrovascular disease (P = 0.79). Adjusting for prevalent cerebrovascular disease, diabetes, and age did not change the patients’ risk of death from cerebrovascular disease (unadjusted RR 1.40; 95% CI 1.16–1.69; adjusted RR 1.47; 95% CI 1.22–1.79).

The second most frequent cause of death was malignant tumors. The increase in mortality from cancer in the patients was mainly explained by gastroesophageal tumors (Table 1), of which cancer of esophagus caused death in 7 patients and 2 controls, and that of stomach in 24 patients and 11 controls. A total of 125 (5%) patients and 93 (3%) controls had cancer before the beginning of follow-up (P = 0.03). When adjustment for previous cancer, gender, and age was used in the Cox regression analysis, the risk of cancer death was practically unaffected (unadjusted RR 1.29; 95% CI 1.07–1.57; adjusted RR 1.36; 95% CI 1.12–1.65). The excess mortality due to endocrine diseases in the patients was mainly attributable to hyperthyroidism. All 15 deaths from thyroid disease occurred between 1971 and 1986, and were caused by toxic multinodular goiter or adenoma with thyroid crisis mentioned in the death certificate. The increased risk of death from respiratory diseases was due to asthma and obstructive pulmonary disease. The mortality from unknown causes was significantly lower in the patients than in the control group. When the mortality analysis was repeated with the assumption that deaths from unknown causes were distributed similarly as the known causes of death (i.e. similar proportion from each cause in both known and unknown deaths), the results remained unchanged (data not shown).

Of the patients, 57% had Graves’ disease and 43% nodular thyroid disease (toxic multinodular goiter or toxic adenoma). The overall mortality was elevated in the patients with nodular thyroid disease, but not in those with Graves’ disease, when compared with the corresponding controls (Table 2). The mean total dose of RAI administered was 305 MBq (minimum 55, maximum 2664 MBq). A total of 2243 patients (80.3%) received a single dose of RAI, 435 (15.6%) were given two doses, 76 (2.7%) three doses, and 39 (1.7%) four or more doses. When the patients were divided into three groups according to the cumulative dose of RAI and compared with the corresponding control group, the overall risk of death increased with the cumulative dose of RAI (Table 2). The risk of dying in patients whose hyperthyroidism recurred after the initial treatment with RAI was at the same level as in those whose hyperthyroidism was cured with a single dose of RAI. In patients who were known to develop hypothyroidism during the follow-up, mortality was lower than in the corresponding controls. The risk of death was lower in patients previously treated with partial thyroidectomy than in the nonoperated ones. The antithyroid medication before RAI treatment did not affect the risk of death. The risk of overall and cardiovascular mortality in the RAI-treated patients compared with the controls increased significantly only in the subjects older than 60 yr at treatment (Table 2), while the risk of cancer death increased in the 50–59 (RR 1.49; 95% CI 1.00–2.26) and 70- to 98-yr-old patients (RR 1.21; 95% CI 1.21–2.31).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our finding of a higher overall mortality in patients treated with RAI for hyperthyroidism compared with age- and sex-matched controls is consistent with previous studies (4, 5, 8, 9, 11). The strengths of the present study are the completeness of follow-up through high-quality registers, and the detailed data on the amount of RAI administered, etiology of hyperthyroidism, and development of hypothyroidism. It is not possible to distinguish between the effects of treatment and those of the disease, unless an untreated patient group is used as a reference. Both patient and disease characteristics affect the choice of treatment and may induce confounding by indication. Young patients, women of childbearing age, and patients with Graves’ ophthalmopathy are less likely to receive RAI in our hospital district. Unfortunately, we did not have the mortality data of patients treated with thyroidectomy and long-term antithyroid drug therapy for hyperthyroidism. However, the proportion of these patients is less than 10% of all hyperthyroid patients. Therefore, it is unlikely that selection of patients to RAI treatment would have induced confounding.

Consistent with the results of previous studies (4, 5, 8, 9, 11), the risk of death from cardiovascular diseases was higher among the patients treated with RAI than among controls in the present study. Instead of RAI treatment, the hyperthyroidism is probably the major explanation for the elevated cardiovascular mortality. The prevalent cardiovascular disease did not explain the results. Previously, only Franklyn et al. (9) have specified the cardiovascular diseases. In their study, cerebrovascular diseases and ischemic heart disease explained most of the increased cardiovascular mortality. In our study cerebrovascular diseases accounted for the increased risk of death from cardiovascular diseases among the patients, but ischemic heart disease did not cause any excess deaths. Hyperthyroidism is known to exert direct effects on the myocardium and the autonomic nervous system, thus predisposing the patient to arrhythmia, especially AF (14, 15, 16). Hyperthyroidism may cause cerebral infarction by embolic events. There is some evidence that the rate of embolism in thyrotoxicotic AF exceeds that of nonthyrotoxicotic AF (14, 15). Recently, Flynn et al. (12) reported an increased risk of arrhythmia an average of 5 yr after treatment of hyperthyroidism, suggesting that cardiotoxic effects of hyperthyroidism are not fully reversed by restoring euthyroidism. In the present study, AF was observed more frequently as a contributory cause of death in the hyperthyroid patients than in the controls, although it only accounted for a part of the difference in cardiovascular mortality between the patients and controls. Several assessments of both specific causes and all causes of death have consistently indicated high completeness and reliability of the Finnish causes of death register (17, 18, 19, 20). However, we cannot fully exclude confounding due to other risk factors, although the prevalent diabetes did not explain the difference in cerebrovascular mortality, and there was no difference in mortality from ischemic heart disease between the patients and controls.

Results on cancer mortality on hyperthyroid patients treated with RAI have been conflicting, reporting either increased (5, 7), decreased (10), or similar (4, 6) mortality compared with the general population. In two recent studies, Franklyn et al. (10) reported decreased cancer mortality, whereas Hall et al. (7) found an increased risk of death from cancer in patients treated with RAI compared with the expected rates. Our results are consistent with the latter one. The total dose of RAI did not differ substantially between the present study and that of Franklyn et al. (10). The patients were slightly older in the present study than in the study of Franklyn et al. (10). The conflicting results concerning cancer mortality after RAI treatment for hyperthyroidism in different populations might reflect chance, confounding, or differences in sensitivity to radiation-induced cancer depending on the age at exposure, smoking, diet, and baseline cancer rates.

Our results support those of Hall et al. (7), who concluded that RAI might have contributed to the excess stomach cancer mortality seen in their cohort of RAI-treated hyperthyroid patients. When treating hyperthyroidism with RAI, doses of radiation to nonthyroidal tissues are relatively low, i.e. less than 10 cGy, except for the organs that accumulate iodine, including the stomach (25 cGy) (21, 22). Consequently, the stomach might be particularly vulnerable to radiation-induced cancer (22). Although based on a small number of cases, an elevated risk of digestive tract cancer has been reported in the patients treated with RAI for hyperthyroidism (10, 21, 23). The latency period for solid tumors has been observed to be at least 10 yr after radiation exposure (24). Thus, it is possible that the follow-up in the present study was not long enough to detect an increased mortality from cancers with better survival or longer latency than gastroesophageal tumors. The apparent converging of both the overall and cancer survival curves of the patients and controls seen after 25 yr of follow-up does not necessarily reflect a true disappearance of the excess risk, but a random error, due to the small number of subjects being followed up at 25 yr (214 patients and 229 controls).

The significantly elevated mortality from respiratory diseases in our study was in agreement with previous studies from the United States and United Kingdom (4, 8). Increased mortality from respiratory diseases has been presumed to result mainly from respiratory infections due to the immunosuppressive effect of antithyroid medication and the hyperthyroid state. Respiratory infections were classified as infectious disease in the present study, and respiratory diseases included only asthma and chronic obstructive pulmonary disease. However, susceptibility to infections might have contributed to the exacerbation of pulmonary diseases. Furthermore, hyperthyroidism might have increased the risk of death from pulmonary diseases by increasing the consumption of oxygen (16). Unfortunately, data on smoking habits were not available for our patients.

Hypothyroidism has been suggested to contribute to the elevated risk of death by causing hypercholesterolemia, diastolic hypertension, and left ventricular dysfunction (25). Most previous studies lack the follow-up data on the development of hypothyroidism. In the present study, levothyroxine-treated hypothyroidism after RAI treatment seemed to protect against death instead of predisposing to it, which is consistent with the previous 5-yr follow-up study of Franklyn et al. (11). This might reflect the effective cure of hyperthyroidism and encourages the use of RAI doses high enough, despite the risk of hypothyroidism. Furthermore, the patients developing hypothyroidism after RAI may be more properly examined and treated for other diseases because the permanent levothyroxine treatment requires regular medical follow-up. It is also possible that the younger and healthier live long enough after RAI to develop hypothyroidism, and the development of hypothyroidism is an inevitable consequence of RAI treatment unless one dies before developing it.

Conclusions

The present study of patients treated with RAI for hyperthyroidism reports an increased cerebrovascular mortality in the patients treated with RAI compared with an age- and sex-matched control group, which is probably explained by the hyperthyroidism. Furthermore, cancer mortality increased among the patients. Our results emphasize the need for effective treatment of hyperthyroidism despite the risk of hypothyroidism. Lifelong follow-up with careful screening of cerebrovascular risk factors and malignant diseases is recommended for patients treated with RAI for hyperthyroidism.

	Footnotes

 
This work was supported by the Medical Research Fund of Tampere University Hospital.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 20, 2007

Abbreviations: AF, Atrial fibrillation; CI, confidence interval; ICD, International Classification of Diseases; RAI, radioiodine; RR, rate ratio.

Received October 25, 2006.

Accepted March 8, 2007.

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