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.

Apolipoprotein B and insulin resistance are good markers of carotid atherosclerosis in patients with type 2 diabetes mellitus.

BACKGROUND: It is widely known that low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerosis. However, recent studies reported that serum levels of apolipoprotein B (Apo B) and Apo B to apolipoprotein A-1 (Apo A-1) ratio were better predictors of atherosclerotic vascular disease compared with LDL-C. In this study, we investigated that Apo B concentrations and insulin resistance (HOMA-R) can be good markers of carotid atherosclerosis in patients with type 2 diabetes. METHODS: Sixty-six type 2 diabetic patients with carotid atherosclerosis and 66 age- and sex-matched patients without carotid atherosclerosis were compared. The usefulness in risk assessment of LDL-C, Apo B, and HOMA-R for carotid atherosclerosis were estimated by receiver-operating characteristics (ROC) curve analysis. The percentage of carotid atherosclerosis in combination with two of these markers was calculated. RESULTS: Type 2 diabetic patients with carotid atherosclerosis had significantly higher body mass index, higher blood pressure, higher LDL-C, and Apo B, and higher HOMA-R. The ranking of the area under the ROC curve was Apo B, HOMA-R, and LDL-C (0.70, 0.69, and 0.66, respectively). The percentage of patients with carotid atherosclerosis and high LDL-C was 60.7%, high LDL-C+high HOMA-R was 77.4%, and high Apo B+high HOMA-R was 90.9%, respectively. The usefulness of these combinations was significantly better than that of LDL-C alone (p<0.05 and p<0.01, respectively). CONCLUSIONS: In conclusion, the combination of Apo B and HOMA-R is a superior marker of carotid atherosclerosis compared with LDL-C alone in patients with type 2 diabetes.

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.

Coexistence of insulin resistance and inflammation effectively predicts cardiac disease but not stroke in Japanese patients with type 2 diabetes mellitus.

It is well known that insulin resistance (IR) and inflammation (IF) are associated with macroangiopathy. However, whether IR and IF are related to cardiac disease (myocardial infarction, angina pectoris, and heart failure), stroke or both remains elusive. The present hospital-based prospective study was designed to investigate this issue. The study subjects were 300 Japanese patients with type 2 diabetes mellitus and negative history of cardiac disease and stroke. IR (K index of insulin tolerance test; K(ITT)) and IF (high-sensitivity C-reactive protein [hs-CRP]) were measured in each patient at baseline. Patients were followed-up for a mean period of 5.5 years. The time of first evidenced cardiac disease or stroke was monitored. During the follow-up, 35 patients developed cardiac disease and 26 patients developed stroke. Age, smoking, K(ITT), and hs-CRP were independently related to cardiac disease, while age, systolic blood pressure, low HDL, and anti-platelet drug use were independently related to stroke. When patients were subdivided into IR(-) and IR(+), and IF(-) and IF(+), Kaplan-Meier survival analysis showed that the rate of cardiac disease, but not of stroke, was significantly higher in IR(+)IF(+) than IR(-)IF(-) patients (p < 0.01). In conclusion, coexistence of IR and IF effectively predicted cardiac disease but not stroke in Japanese patients with type 2 diabetes mellitus.

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.

Effects of radiation on the longitudinal trends of hemoglobin levels in the Japanese atomic bomb survivors.

The late effects of radiation on the hematopoietic system have not been fully evaluated. We examined the long-term effects of radiation exposure on hemoglobin levels in the Japanese atomic bomb survivors over a 40-year period from 1958 to 1998. Compared to the unexposed survivors, the mean hemoglobin levels for those exposed to a bone marrow dose of 1 Gy were significantly reduced by 0.10 g/dl (95% CI: 0.04 to 0.16) or 0.67% at 40 years of age (P < 0.0001) and by 0.24 g/dl (95% CI: 0.08 to 0.40) or 1.8% at 80 years of age. Radiation effects are greater for smokers than for nonsmokers at age less than 35 years (P < 0.01), although cigarette smoking was associated with increased hemoglobin levels. Sex and birth cohort differences in radiation effects were not found after adjusting for smoking. The radiation-induced reduction in hemoglobin levels could not be explained by the presence of certain anemia-associated diseases.

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.

Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes.

To investigate the anti-atherogenic effect of metformin, we prospectively evaluated the effect of metformin treatment on common carotid intima-media thickness (CCA-IMT) in patients with type 2 diabetes. A 2-year open prospective study was performed. Thirty-six patients were treated with metformin (500-750 mg per day). CCA-IMT was measured after 1- and 2-year treatment. Changes in CCA-IMT were compared with control patients. After 2-year metformin therapy, the progression of CCA-IMT was significantly less than 56 control patients (0.02+/-0.08 mm versus 0.07+/-0.08 mm, P<0.01). Metformin therapy did not alter body weight, blood pressure, HbA1c, and serum lipids relative to the control. Thus, metformin attenuates the progression of CCA-IMT. This anti-atherogenic effect is not mediated through changes in classical cardiovascular risk factors.

Inflammation and insulin resistance are independently related to all-cause of death and cardiovascular events in Japanese patients with type 2 diabetes mellitus.

Insulin resistance (IR)/hyperinsulinemia and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP]) can predict cardiovascular disease. However, because IR and inflammation (IF) have not been evaluated simultaneously, it is not known whether IR and IF are independently related to cardiovascular disease. Furthermore, the combined effect of IR and IF on the prediction of cardiovascular disease is presently unknown. Thus, we measured insulin sensitivity (K index of the insulin tolerance test; KITT) and hs-CRP in 350 Japanese patients with type 2 diabetes, and followed them for 1-7 years (mean, 4.5 years). During the follow-up, 33 patients died and 53 patients developed non-fatal coronary artery disease or stroke (endpoint). Age, systolic blood pressure, current smoking, past history of cardiovascular disease, KITT, and hs-CRP independently and significantly correlated with endpoint. One-S.D. difference was associated with a significant increase of relative risk in KITT (1.45; 95% CI 1.09-1.91) and hs-CRP (1.30; 1.04-1.67). When patients were subdivided to tertile, the relative risk in the highest tertile of KITT was 1.76 (95% CI 1.01-3.11) and hs-CRP was 2.00 (1.03-3.85) compared with the patients with lowest tertile. The relative risk in the highest tertile of both KITT and hs-CRP was 5.32 (1.18-24.0) compared with the lowest tertile of both values. In conclusion, low-grade IF and IR are independently related to all-cause of death and cardiovascular disease in Japanese patients with type 2 diabetes. Coexistence of low-grade IF and IR amplify this effect.

Combination therapy of alpha-glucosidase inhibitor and a sulfonylurea compound prolongs the duration of good glycemic control.

The aim of this study was to investigate whether combination therapy of alpha-glucosidase inhibitor and a sulfonylurea (SU) drug can prolong the duration of good glycemic control compared with SU alone in patients with type 2 diabetes. The open prospective study included 124 Japanese patients with type 2 diabetes and inadequate glycemic control (hemoglobin A(1c) [HbA(1c)] gt; 7.0%). Patients were given either voglibose plus a SU compound (glibenclamide or gliclazide, n = 61) or SU drug alone (n = 63). The first 6-month run-in period (targeted to HbA(1c) /= 8.0%). Fifty patients on combination therapy and 48 patients on SU alone completed the trial. During the follow-up, 21 patients on combination therapy and 30 patients on SU alone showed deterioration of glycemic control and reached the endpoint (P =.04). The combination therapy significantly prolonged the duration of good glycemic control (HbA(1c) < 8.0%) compared with SU alone by Kaplan-Meier estimated survival analysis using a log-rank test (P =.02). Thus, combination therapy with voglibose and a SU agent prolongs the duration of good glycemic control compared with SU alone in patients with type 2 diabetes.

High serum concentrations of soluble E-selectin correlate with obesity but not fat distribution in patients with type 2 diabetes mellitus.

Serum concentrations of soluble adhesion molecules, eg, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are elevated in patients with type 2 diabetes. However, little is known about the role of obesity or abnormal fat distribution in inducing upregulation of adhesion molecules. To investigate this issue, soluble ICAM-1, VCAM-1, and E-selectin levels were evaluated in 40 obese and 30 nonobese patients with type 2 diabetes. Both groups were matched for age, sex, and glycosylated hemoglobin (HbA(1c)) levels. Computed tomography (CT) was used to measure the abdominal subcutaneous and visceral fat areas. Soluble ICAM-1 and VCAM-1 levels did not differ significantly between obese and nonobese patients. However, serum concentrations of soluble E-selectin were significantly higher in obese than in nonobese patients (90 +/- 7 v 56 +/- 4 ng/mL, P <.01). Soluble E-selectin levels significantly correlated with body mass index, subcutaneous fat area, and visceral fat area (Rho = 0.48, 0.37, and 0.30, respectively). Stepwise multiple regression analysis showed that body mass index (F = 16.7), but not subcutaneous and visceral fat areas (F = 0.29 and 0.01, respectively), significantly and independently correlated with soluble E-selectin levels. Our results suggest that obesity may induce endothelial activation or increased shedding of cell surface E-selectin that leads to subsequent increase in soluble E-selectin levels. The high serum concentrations of E-selectin closely correlated with increased total fat volume, but not with regional fat distribution.

Effect of filtration leukocytapheresis therapy: modulation of white blood cell enzyme activities in patients with rheumatoid arthritis.

We treated 12 patients with rheumatoid arthritis by filtration leukocytapheresis (FLCP) and evaluated its effect on leukocyte enzyme activities. We calculated the number of leukocytes removed and assessed the clinical response. We also evaluated the cellular enzyme activities of elastase and dipeptidylpeptidase IV (DPP IV). Out of 12 patients, 7 patients achieved 20% improvement for 4 weeks following FLCP. The FLCP treatment resulted in removal of 96% of granulocytes, 98% of monocytes, and 61% of lymphocytes. Granulocytes and monocytes with high elastase activity were effectively removed by FLCP. The elastase activity of granulocytes was increased 4 weeks after the last FLCP only in responders. On the other hand, the DPP IV activity of lymphocytes was low at 4 weeks after the last FLCP in responders. Modulation of leukocyte enzyme activities is one of the main effects of FLCP therapy and alteration of granulocytes, monocytes, and lymphocytes.