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Results of the Screening of Thyroids: Because of the March 2011 nuclear accident in Fukushima, Japan, the Fukushima Prefecture initiated a thyroid ultrasound examination program. The first cycle of examinations on all children (more than 300,000) of the Fukushima Prefecture identified 116 patients as having malignant or suspected malignant thyroid nodules, and in the second cycle 59 new cases were identified. According to the available data, the thyroid cancers found by the screening are unlikely to be due to radiation, but the possibility cannot be excluded., Urgent Measures: The current thyroid ultrasound examination program has been detecting thyroid cancers, regardless of the cause, in all children in the Fukushima Prefecture. Fukushima Prefecture is already taking measures against thyroid cancer, even if an increase occurs in radiation-induced thyroid cancer in Fukushima Prefecture. Therefore, the urgent challenge is how to treat children with thyroid cancer found by the screening., Future Directions of the Measures: At the end of each cycle, the findings must be carefully discussed with experts around the world and among stakeholders in Fukushima, and a consensus must be reached regarding whether the current program will be continued or needs improvement. In addition, the survey should be improved as an epidemiological follow-up research program. Before starting this, a consensus must be reached with the inhabitants with regard to carrying out epidemiological research for several decades. Dialogue absolutely must continue among all stakeholders to determine how best to formulate a program to deal with urgent matters and to determine the next stage of any epidemiological research.

Background: Methimazole (MMI) is usually used at an initial dose of 30 mg/day for severe Graves' disease (GD) hyperthyroidism, but adverse effects are more frequent at this dose than at MMI 15 mg/day., Objectives: We designed a regimen to address the lack of a primary therapeutic effect of the MMI 15 mg/day by combining it with inorganic iodine at 38.2 mg/day. Our aim was to compare the two regimens (MMI 15 mg+inorganic iodine at 38.2 mg/day (M15+I) vs. MMI 30 mg/day (M30)) in terms of therapeutic effect, adverse effects, and remission rate., Design and Patients: In a prospective study, 310 patients with untreated GD (serum free thyroxine (fT4) ≥5 ng/dL) were assigned to one of the two regimens. Potassium iodide was discontinued in the M15+I group as soon as the serum fT4 level was within the reference range (0.8-1.6 ng/dL)., Results: Percentages of patients achieving an fT4 level within reference range in ≤30, ≤60, or 90 days on the study treatment regimens were 45.3%, 73.9%, and 82.0% respectively for the M15+I group, and 24.8%, 63.1%, and 75.2% respectively for the M30 group. Hence, the proportions of patients achieving this goal in ≤30 or ≤60 days were significantly larger in the M15+I group. Adverse effects that required discontinuation of MMI were more frequent in the M30-treated than in the M15+I-treated group (14.8% vs. 7.5%; p=0.0387). The remission rates in the M15+I and M30 groups were 19.9% and 14.8%-higher in the former, but the difference did not reach statistical significance., Conclusion: The results of this study raise the possibility that M15+I is superior to M30 as a primary treatment for moderate to severe hyperthyroidism caused by GD.

Purpose of Review: This is a summary of the nuclear accident at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Stations (FDNPS) on 11 March 2011 to be used as a review of the radiation effects to the thyroid and strategies of prevention., Recent Findings: The amount of radioiodine released to the environment following the Fukushima accident was 120 Peta Becquerel, which is approximately one-tenth of that in the Chernobyl accident. Residents near the FDNPS were evacuated within a few days and foodstuffs were controlled within 1 or 2 weeks. Therefore, thyroid radiation doses were less than 100 mSv (intervention levels for stable iodine administration) in the majority of children, including less than 1 year olds, living in the evacuation areas. Because the incidence of childhood thyroid cancer increased in those residing near the site following the Chernobyl accident, thyroid screening of all children (0-18 years old) in the Fukushima Prefecture was started. To date, screening of more than 280 000 children has resulted in the diagnosis of thyroid cancer in 90 children (approximate incidence, 313 per million). Thus, although the dose of radiation was much lower, the incidence of thyroid cancer appears to be much higher than that following the Chernobyl accident., Summary: A comparison of the thyroidal consequences following the Fukushima and Chernobyl nuclear reactor accidents is discussed. We also summarize the recent increased incidence in thyroid cancer in the Fukushima area following the accident in relation to increased thyroid ultrasound screening and the use of advanced ultrasound techniques., Video Abstract: http://links.lww.com/COE/A8.

At the outset of the accident at Fukushima Daiichi Nuclear Power Plant in March 2011, the radiation doses experienced by residents were calculated from the readings at monitoring posts, with several assumptions being made from the point of view of protection and safety. However, health effects should also be estimated by obtaining measurements of the individual radiation doses. The individual external radiation doses, determined by a behavior survey in the "evacuation and deliberate evacuation area" in the first 4 months, were <5 mSv in 97.4% of residents (maximum: 15 mSv). Doses in Fukushima Prefecture were <3 mSv in 99.3% of 386,572 residents analyzed. External doses in Fukushima City determined by personal dosimeters were <1 mSv/3 months (September-November, 2011) in 99.7% of residents (maximum: 2.7 mSv). Thyroid radiation doses, determined in March using a NaI (TI) scintillation survey meter in children in the evacuation and deliberate evacuation area, were <10 mSv in 95.7% of children (maximum: 35 mSv). Therefore, all doses were less than the intervention level of 50 mSv proposed by international organizations. Internal radiation doses determined by cesium-134 ((134)C) and cesium-137 ((137)C) whole-body counters (WBCs) were <1 mSv in 99% of the residents, and the maximum thyroid equivalent dose by iodine-131 WBCs was 20 mSv. The exploratory committee of the Fukushima Health Management Survey mentions on its website that radiation from the accident is unlikely to be a cause of adverse health effects in the future. In any event, sincere scientific efforts must continue to obtain individual radiation doses that are as accurate as possible. However, observation of the health effects of the radiation doses described above will require reevaluation of the protocol used for determining adverse health effects. The dose-response relationship is crucial, and the aim of the survey should be to collect sufficient data to confirm the presence or absence of radiation health effects. In particular, the schedule of decontamination needs reconsideration. The decontamination map is determined based on the results of airborne monitoring and the radiation dose calculated from readings taken at the monitoring posts at the initial period of the accident. The decontamination protocol should be reevaluated based on the individual doses of the people who desire to live in those areas.

Background: A special report, 'The Fukushima Accident', was delivered at the 35th Annual Meeting of the European Thyroid Association in Krakow on September 11, 2011, and this study is the follow-up of the special report., Objectives: To present a preliminary review of potential thyroid consequences of the 2011 Fukushima nuclear reactor accident., Methods: Numerous new data have been presented in Japanese, and most of them are available on the website from each research institute and/or from each municipality. The review was made using these data from the website., Results: When individual radiation doses were expressed as values in more than 99% of residents, radiation doses by behavior survey in evacuation and deliberate evacuation areas were less than 10 mSv in the first 4 months, and internal radiation doses measured by whole body counters were less than 1 mSv/year. Individual thyroid radiation doses were less than 50 mSv (intervention levels) even in evacuation areas. As for health consequences, no one died and no one suffered from acute effects. The thyroid ultrasound examination is in progress and following examination of almost 40,000 children, 35% of them have nodules and/or cysts but no cancers., Conclusions: Countermeasures against radiation must consider current individual measured values, although every effort must be taken to reconstruct radiation doses as precisely as possible. At present, the difference of thyroid radiation dose between Chernobyl and Fukushima appears to be due to the strict control of milk started within a week after the accident in Fukushima. Since the iodine-131 plume moved around in wide areas and for a long time, the method of thyroid protection must be reconsidered.

Background: Few population-based studies report the changes with time in thyroid function tests in patients with subclinical hypothyroidism. We compared the risk for developing overt hypothyroidism in patients with subclinical hypothyroidism and euthyroid controls from the same population of elderly Japanese. We also sought associations of selected parameters with the development of overt hypothyroidism in the subclinical hypothyroid and euthyroid groups., Methods: We measured thyrotropin (TSH) and free thyroxine (T4) levels at baseline examinations performed from 2000 to 2003 in the cohort of Japanese atomic-bomb survivors and identified 71 patients with spontaneous subclinical hypothyroidism (normal free T4 and TSH >4.5 mIU/L without a history of thyroid treatment, mean age 70 year) and 562 euthyroid controls. We re-examined TSH and free T4 levels an average of 4.2 years later (range, 1.9-6.9)., Results: The risk for progression to overt hypothyroidism was significantly increased in subclinical hypothyroid patients (7.0%) compared with control subjects (1.6%) after adjusting for age and sex (odds ratio, 4.56; p=0.009). Higher baseline TSH levels were associated with progression from subclinical to overt hypothyroidism (p=0.02) in the multivariate analysis, including age, sex, antithyroid peroxidase antibody, and ultrasonography (US) findings. The analysis using binary TSH data suggested that a TSH level >8 mIU/L was a predictive value for development of overt hypothyroidism (p=0.005). On the other hand, serum TSH levels spontaneously normalized in 38 (53.5%) of the patients with subclinical hypothyroidism. In the multivariate analysis, normalization of TSH levels was associated with lower baseline TSH levels (p=0.004) and normal and homogenous thyroid US findings (p=0.04). Atomic-bomb radiation dose was not associated with subclinical hypothyroidism or its course., Conclusions: Subclinical hypothyroidism was four times more likely to be associated with development of overt hypothyroidism than euthyroid controls in the sample population of Japanese elderly. TSH levels in half of the patients normalized spontaneously when assessed after an average follow-up period of 4.2 years. Baseline TSH level and thyroid US findings are potential predictors of future thyroid function in subclinical hypothyroidism.

Objective: A possible association between subclinical hypothyroidism and cardiovascular disease (CVD) has been reported. Monitoring of atomic-bomb survivors for late effects of radiation exposure at the Radiation Effects Research Foundation has provided the opportunity to examine associations between subclinical hypothyroidism and metabolic CVD risk factors. The objective of the study was to evaluate associations between subclinical hypothyroidism and metabolic CVD risk factors, and a cluster of these factors., Design and Participants: This was a cross-sectional study of 3549 subjects (mean age 70 years; 1221 men and 2328 women) between 2000 and 2003 comprising 306 subjects with subclinical hypothyroidism and 3243 control euthyroid subjects in Japan., Measurements: We investigated associations between subclinical hypothyroidism and metabolic CVD risk factors such as hypertension, diabetes mellitus, dyslipidaemia and hyperuricaemia, and a cluster of these factors., Results: Subclinical hypothyroidism was not significantly associated with either hypertension, diabetes mellitus or hyperuricaemia defined by taking into account the use of medications in both men and women, but in men it was associated with dyslipidaemia (P = 0.02). We observed a significantly increased odds ratio (OR) for the presence of three or more metabolic CVD risk factors in men with subclinical hypothyroidism after adjusting for age, body mass index (BMI), and smoking status [OR: 1.83, 95% confidence interval (CI): 1.13-2.94, P = 0.01]. The significant associations remained after an additional adjustment for atomic-bomb radiation dose., Conclusions: There appears to be a significant increase in a cluster of metabolic CVD risk factors among people with subclinical hypothyroidism.

Objective: The objective of the study was to evaluate the association of thyroid disease with radiation dose in atomic bomb survivors exposed in utero., Design: This was a cross-sectional study., Setting: The study was conducted in atomic bomb survivors in Hiroshima and Nagasaki, Japan., Participants: Participants included 328 atomic bomb survivors exposed in utero (mean age 55.2 yr, 162 males) who participated in the thyroid study at the Radiation Effects Research Foundation. Examinations were conducted between March 2000 and February 2003., Main Outcome Measures: The relationships of various thyroid conditions to atomic bomb radiation dose were measured., Results: Among the 319 participants excluding nine participants whose exposure radiation dose was not estimated, the mean maternal uterine radiation dose was 0.256 Gy. We observed no significant dose-response relationship for the prevalence of solid thyroid nodules (odds ratio at 1 Gy, 2.78; 95% confidence interval 0.50-11.80, P = 0.22), but the risk estimate was similar to the estimate for childhood exposures. The prevalence of cysts and autoimmune thyroid diseases was not associated with radiation dose (P > 0.30). We could not evaluate the dose response for malignant tumors or benign nodules due to the small number of cases., Conclusions: We did not observe a statistically significant linear dose response to radiation for thyroid nodules or autoimmune thyroid diseases 55-58 yr after participants' in utero exposure. However, the risk estimate for solid thyroid nodules was similar for those exposed in utero and those exposed in childhood. Because the study had limited statistical power to detect moderately sized effects, further studies are needed for a definitive conclusion.

Context: Effects of irradiation on thyroid diseases such as thyroid nodules and autoimmune thyroid diseases have not been evaluated among people exposed to radiation more than 50 years in the past., Objective: To evaluate the prevalence of thyroid diseases and their radiation-dose responses in atomic bomb survivors., Design, Setting, and Participants: Survey study comprising 4091 cohort members (mean age, 70 [SD, 9] years; 1352 men and 2739 women) who participated in the thyroid study at the Radiation Effects Research Foundation. Thyroid examinations were conducted between March 2000 and February 2003., Main Outcome Measures: Prevalence of thyroid diseases, including thyroid nodules (malignant and benign) and autoimmune thyroid diseases, and the dose-response relationship of atomic bomb radiation in each thyroid disease., Results: Thyroid diseases were identified in 1833 (44.8%) of the total participants (436 men [32.2% of men] and 1397 women [51.0% of women]) (P<.001). In 3185 participants, excluding persons exposed in utero, not in the city at the time of the atomic bombings, or with unknown radiation dose, the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts was 14.6%, 2.2%, 4.9%, and 7.7%, respectively. The prevalence of positive thyroid antibodies, antithyroid antibody-positive hypothyroidism, and Graves disease was 28.2%, 3.2%, and 1.2%, respectively. A significant linear dose-response relationship was observed for the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts (P<.001). We estimate that about 28% of all solid nodules, 37% of malignant tumors, 31% of benign nodules, and 25% of cysts are associated with radiation exposure at a mean and median thyroid radiation dose of 0.449 Sv and 0.087 Sv, respectively. No significant dose-response relationship was observed for positive antithyroid antibodies (P = .20), antithyroid antibody-positive hypothyroidism (P = .92), or Graves disease (P = .10)., Conclusions: A significant linear radiation dose response for thyroid nodules, including malignant tumors and benign nodules, exists in atomic bomb survivors. However, there is no significant dose response for autoimmune thyroid diseases.

Context: Radiation exposure is associated with development of thyroid nodules. The long-term risk of thyroid cancer development in irradiated people with thyroid nodules, however, has not been clarified., Objective: The objective of this study was to assess the long-term risk of cancer development in irradiated individuals with thyroid nodules., Design, Setting, and Participants: This prospective study comprised 2637 atomic bomb survivors (mean age, 59 yr; 1071 men and 1566 women) who participated in the baseline thyroid study of the Nagasaki Radiation Effects Research Foundation from 1984 through 1987. The participants were divided into three groups at baseline by ultrasound findings: 82 cases of solid thyroid nodules other than cancer, 121 cases of thyroid cysts, and 2434 thyroid nodule-free controls. Both the solid nodule and the cyst groups included postoperative cases. In the solid nodule group, 68 cases had ultrasound-detected solid nodules, including 31 cases diagnosed as benign by cytological or histological examination. They were followed for an average of 13.3 yr., Main Outcome Measure: Incident thyroid cancer was measured during an average 13.3-yr follow-up period., Results: During the follow-up period, six thyroid cancer cases (7.3%) were found in the solid nodule group, seven cases in the controls (0.3%), and one case (0.8%) in the cyst group. In 31 cases with solid nodules diagnosed as benign, three cases (9.7%) developed thyroid cancer. The hazard ratio (HR) for cancer development was significantly high at 23.6 [95% confidence interval (CI), 7.6-72.8] in the solid nodule group (HR, 40.2; 95% CI, 9.4-173.0 in 31 people with solid nodules diagnosed as benign) but not in the cyst group (HR, 2.7; 95% CI, 0.3-22.2), after controlling for age and sex. Sex, age, TSH level, thyroglobulin level, radiation dose, nodule volume, and increase in nodule volume did not predict cancer development in the solid nodule group., Conclusions: Risk of thyroid cancer development is high in atomic bomb survivors with solid thyroid nodules, suggesting the need for careful observation of irradiated individuals with such nodules.

We investigated possible associations between subclinical hypothyroidism and atherosclerotic diseases (ischemic heart disease and cerebrovascular disease) and mortality. Of 2856 participants (mean age 58.5 yr) in a thyroid disease screening between 1984 and 1987, 257 subjects with subclinical hypothyroidism (TSH > 5.0 mU/liter) and 2293 control subjects (TSH range 0.6-5.0 mU/liter) were analyzed. In the baseline cross-sectional analysis, subclinical hypothyroidism was associated with ischemic heart disease independent of age, systolic blood pressure, body mass index, cholesterol, smoking, erythrocyte sedimentation rate, or presence of diabetes mellitus [odds ratio (OR), 2.5; 95% confidence interval (95% CI), 1.1-5.4 in total subjects and OR, 4.0; 95% CI, 1.4-11.5 in men] but not in women. However, there was no association with cerebrovascular disease (OR, 0.9; 95% CI, 0.4-2.4). We were unable to detect an influence of thyroid antibody presence on the association between subclinical hypothyroidism and ischemic heart disease. In a 10-yr follow-up study until 1998, increased mortalities from all causes in yr 3-6 after baseline measurement were apparent in men with subclinical hypothyroidism (hazard ratio, 1.9-2.1) but not in women, although specific causes of death were not determined. Our results indicate that subclinical hypothyroidism is associated with ischemic heart disease and might affect all-cause mortality in men.

Two-dimensional cDNA electrophoresis was used to analyze gene expressions in papillary carcinoma and normal tissue of thyroid glands. Pooled thyroid tissues were used to extract mRNA. Complementary DNAs, synthesized with NotI anchor primers, were digested with three restriction enzymes, NotI, EcoRV, and PvuII. The protruding NotI ends were filled in with (32)P deoxynucleotide triphosphates, and the radiolabeled cDNA fragments were separated in two dimensions. Approximately 500 cDNA fragments were visualized as discrete spots without probes. A total of 20 spots, 9 up-regulated and 11 down-regulated cDNAs in papillary carcinoma, were selected and cloned for sequencing. This experiment lent itself to a novel discovery of up-regulated human epididymal protein 1 (HE-1) and down-regulated CL-100 genes in thyroid papillary carcinomas confirmed by Northern blot analysis. Immunohistochemical stains showed abundant HE-1 protein in the papillary carcinoma, whereas little or no HE-1 protein was detected in other types of thyroid cancers and normal thyroid tissues. The restricted localization of HE-1 protein to the portions of papillary projections suggests an involvement of HE-1 protein for forming papillary shape. Our study showed that two-dimensional cDNA electrophoresis is a useful method of detecting differentially expressed genes in human diseases as demonstrated for HE-1 and CL-100 in papillary carcinoma.

The purpose of this review is to provide an account of our present knowledge about the epidemiology of nonmedullary thyroid carcinoma, to discuss the effects of environment, lifestyle and radiation on the risk of developing thyroid cancer, and to discuss aspects on primary prevention of the disease. In areas not associated with nuclear fallout, the annual incidence of thyroid cancer ranges between 2.0-3.8 cases per 100,000 in women and 1.2-2.6 per 100,000 in men, women of childbearing age being at highest risk. Low figures are found in some European countries (Denmark, Holland, Slovakia) and high figures are found in Iceland and Hawaii. Differences in iodine intake may be one factor explaining the geographic variation, high iodine intake being associated with a slightly increased risk of developing thyroid cancer. In general, lifestyle factors have only a small effect on the risk of thyroid cancer, a possible protective effect of tobacco smoking has been recently reported. Because of the (small) increase in risk of thyroid cancer associated with iodination programs, these should be supervised, so that the population does not receive excess iodine. The thyroid gland is highly sensitive to radiation-induced oncogenesis. This is verified by numerous reports from survivors after Hiroshima and Nagasaki, the Nevada, Novaja Semlja and Marshal Island atmospheric tests, and the Chernobyl plant accident, as well as by investigations of earlier medical use of radiation for benign diseases in childhood. These reports are summarized in the review. There appears to be a dose-response relation for the risk of developing cancer after exposure to radioactive radioiodine. The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. Thus, the incidence of thyroid cancer in children in the Belarus area was less than 1 case per million per year before the Chernobyl accident, increasing to a peak exceeding 100 per million per year in certain areas after the accident. It is a social obligation of scientists to inform the public and politicians of these risks. All nuclear power plants should have a program in operation for stockpiling potassium iodide for distribution within 1-2 days after an accident.

Two different phases in disease activity are observed during the clinical course of thyroid-associated ophthalmopathy (TAO). The assessment of disease activity is important for predicting the outcome of medical management because medical treatment can be effective in the active stage. The aim of this study was to investigate whether magnetic resonance imaging (MRI) could assess the disease activity in TAO. To investigate the relation between MRI-T2 signal intensity (SI) and extraocular muscle (EOM) size, 11 patients with TAO were evaluated. EOM sizes (enlargement, volume) were measured by MRI-T1 image. T2-SI of EOM was expressed as a percentage of temporal muscle. The reduction in T2-SI was significantly positively correlated with that of EOM enlargement after treatment. Additionally, T2-SI in pretreatment showed a significant correlation with reduction in EOM volume for therapeutic effect, which indicates T2-SI in pretreatment can be one of the reliable parameters for predicting the therapeutic outcome of treatment. To investigate whether MRI-T2 pattern could predict the reversibility of diplopia, 28 patients with Graves' disease with or without ophthalmopathy were evaluated. Patients with TAO with reversible diplopia showed an uniform T2 pattern in enlarged EOM. However, in patients with irreversible diplopia caused by the mechanical limitation of EOM, MRI-T2 image showed no uniformity with a partial appearance of low T2-SI. The partial low T2-SI may indicate the progress of inactive (fibrotic) change in EOM after active (inflammatory) change. In conclusion, MRI is a useful tool for detection not only of EOM enlargement, but also disease activity in TAO. MRI-T2 SI and pattern can predict the outcome of medical management in TAO.