Risk for progression to overt hypothyroidism in an elderly Japanese population with subclinical hypothyroidism.

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.

Metabolic cardiovascular disease risk factors and their clustering 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.

Thyroid diseases in atomic bomb survivors exposed in utero.

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.

Basic characteristics of chronic hypotension cases: a longitudinal follow-up study from 1958 through 1999.

Few epidemiological studies have been conducted on the prevalence, blood pressure trends by age, and basic characteristics of chronic hypotension. Among 13,370 subjects (5,094 men and 8,276 women) examined from 1958 to 1999 in Japan, 92 were identified as chronic hypotensives (11 men and 81 women) whose systolic blood pressure (SBP, mmHg) was lower than 100 mmHg for 8 or more years. Trends of SBP and body mass index (BMI, kg/m2) were determined over a 16-year period in this group of chronic hypotensives and 276 age- and sex-matched controls (33 men and 243 women); during this 16-year period, the chronic hypotensives and controls ranged in age from 19 to 75 years. BMI, heart rate (HR, bpm), body temperature (degrees C), Hb (g/dl), and creatinine (Cre, mg/dl) were compared between the chronic hypotensives and the controls at the last examination. The chronic hypotensives had a female preponderance (0.2% in men and 1.0% in women, p=0.001), and their SBP and BMI increased little with increasing age. BMI (20.2+/-3.4), BMI-adjusted SBP (101+/-19), HR (63+/-10), body temperature (36.7+/-0.3), Hb (12.5+/-1.1), and Cre (0.81+/-0.13) were lower in the chronic hypotensives than those (22.9+/-3.4, 126+/-20, 68+/-10, 36.8+/-0.3, 12.9+/-1.1, and 0.86+/-0.12, respectively) in controls (p<0.05). The present results clearly show that chronic hypotensives have a female preponderance and low BMI, HR, body temperature, Hb, and Cre in addition to low SBP that does not increase with age.

Radiation dose-response relationships for thyroid nodules and autoimmune thyroid diseases in Hiroshima and Nagasaki atomic bomb survivors 55-58 years after radiation exposure.

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.

Do glucose and lipid metabolism affect cancer development in Nagasaki atomic bomb survivors?

The relationship between lipid or glucose metabolism and cancer has not yet been elucidated. We conducted 75-g oral glucose tolerance tests (75-g OGTTs) and lipid measurements between 1983 and 1985 in 516 Nagasaki atomic bomb survivors. Excluding those who already had cancer at the baseline examinations and those who developed cancers or died of any cause within 5 yr after the baseline examinations, we determined incident cancer cases until 2000 in the remaining 451 subjects (214 males and 237 females) and evaluated, by means of the Cox proportional hazard model, whether glucose or lipid metabolism predicts cancer development. The age- and sex-adjusted relative risk (RR) for incident cancer was 0.903 (95% confidence interval, CI = 0.842-0.968), 1.740 (95% CI = 1.238-2.446), 1.653 (95% CI = 0.922-2.965), and 1.024 (95% CI = 0.996-1.053) for total cholesterol (10 mg/dl), radiation dose (1 Sv), smoking, and 1-h blood glucose (1-h BG; 10 mg/dl) in 75-g OGTTs, respectively. Multiple regression analysis of age, sex, smoking, body mass index, 1-h BG, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and radiation dose also showed that total cholesterol was negatively (RR = 0.872; 95% CI = 0.793-0.958) and radiation dose positively (RR = 1.809; 95% CI = 1.252-2.613) related to incident cancer. Cholesterol could be negatively and radiation dose positively associated with cancer development independently.

Long-term prognosis of thyroid nodule cases compared with nodule-free controls in atomic bomb survivors.

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.

Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism.

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.

Effects of radiation on fatty liver and metabolic coronary risk factors among atomic bomb survivors in Nagasaki.

In order to clarify the basic mechanism(s) linking radiation exposure and coronary heart disease (CHD), we here collected ultrasonographic data on fatty liver and measured levels of metabolic CHD risk factors from November 1990 through October 1992 in 1,517 Nagasaki atomic bomb survivors (575 men and 942 women). Using a cross-sectional study design, we examined the effects of radiation dose on fatty liver and CHD risk factors by means of a multiple logistic regression model. Fatty liver was related to the metabolic CHD risk factors associated with insulin resistance syndrome: obesity, hypertension, hypercholesterolemia, low high density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, and abnormal glucose metabolism. Radiation dose was positively related to fatty liver, low HDL-cholesterol, and hypertriglyceridemia, whereas it had no effects on obesity, hypertension, hypercholesterolemia, or abnormal glucose metabolism. The present results suggested that radiation dose was related to 1) fatty liver, which clustered the metabolic CHD risk factors associated with insulin resistance syndrome and 2) atherogenic lipid profiles. It is suggested that these associations are involved in the basic mechanism(s) linking radiation exposure and CHD.