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Background: We aimed to assess the long-term effects of the transition in iodine status on the incidence of thyroid disorders over 20 years of follow-up. Methods: The original prospective cohort study, started in 1999 (n = 3761), classified three regions in north China based on iodine status (insufficient iodine, more than adequate iodine, and excessive iodine, respectively) for 5 years. Subsequently, participants were followed for up to another 15 years to assess the long-term effects of shifts to adequate iodine on the incidence of thyroid disorders. Panshan transitioned from insufficient to adequate iodine, and Huanghua transitioned from excessive to more than adequate iodine. Both regions were compared with Zhangwu, in which iodine status changed from more than adequate to adequate iodine (from 214 to 167.2 μg/L). A cluster sampling method was used to select participants in the three regions. Participants completed questionnaires and underwent thyroid ultrasonography. Urinary iodine concentrations (UICs), serum thyroid hormone concentration, and thyroid antibodies were measured. Results: When the iodine status changed from insufficient to adequate (with the median UIC increasing from 88 to 141.9 μg/L), the incidence density of subclinical hyperthyroidism, positive thyroperoxidase antibody, positive thyroglobulin antibody (TgAb), and goiter decreased significantly (p < 0.05 for all). Additionally, the cumulative incidence of subclinical hypothyroidism was significantly lower compared with the region where the iodine status changed from being more than adequate to adequate (1.9% vs. 6.0%, p < 0.001). When the iodine status changed from excessive to more than adequate (median UIC from 634 to 266.7 μg/L), a significant decrease in the incidence density of subclinical hyperthyroidism, positive thyroid antibodies, positive TgAb, and goiter (p < 0.05 for all) were also found. However, an increase in thyroid nodule incidence density (17.26 vs. 28.25 per 1000 person-years, p < 0.001) was seen. Conclusions: The incidence of thyroid disorders (except for thyroid nodules) stabilized or decreased among adults in the three communities from year 5 to year 15 of follow-up. Appropriate iodine fortification is safe and effective over the long term. Restoring urinary iodine to appropriate levels reduces population risk for thyroid disorders. [ABSTRACT FROM AUTHOR]

Background: Thyroid peroxidase antibody (TPOAb) positivity can attenuate gestational thyroid responses to human chorionic gonadotropin (hCG) during pregnancy, whereas the effects of thyroglobulin antibodies (TgAb) remain unknown. The aim of our study was to explore the thyroid response to hCG in women with thyrotropin (TSH) levels within the method-specific reference range under different conditions of thyroid autoimmunity. Methods: The study screened 822 women at 7–20 weeks of gestation using the pregnancy-specific reference range for TSH. Serum TSH, free thyroxine (fT4), TPOAb, TgAb, and β-hCG levels were measured using electrochemiluminescence immunoassays. Results: The enrolled pregnant women were subdivided into four subgroups based on TPOAb/TgAb positivity: co-positive for TPOAb and TgAb (group 1), isolated TPOAb positive (group 2), isolated TgAb positive (group 3), and co-negative for TPOAb and TgAb (group 4). TSH was negatively associated with hCG in all four groups (p < 0.05). fT4 was positively associated with hCG in groups 3 and 4 (p < 0.01) but not in groups 1 (p = 0.096) and 2 (p = 0.758). Group 2 was further stratified into tertiles according to TPOAb concentrations. No negative TSH/hCG association was observed in the middle- and upper-tertile groups when TPOAb were ≥53 IU/mL (p > 0.05). There was no positive fT4/hCG association in any of the three subgroups (p > 0.05). Similarly, group 3 was further stratified into tertiles according to TgAb levels. TSH was negatively associated with hCG in the lower and middle tertiles (p < 0.01), but the association was not found in the upper tertile when TgAb was ≥356 IU/mL (p = 0.191). fT4 was positively associated with hCG in the lower tertile (p = 0.027) but not in subgroups when TgAb was ≥219 IU/mL (p > 0.05). Conclusions: When TSH was within the pregnancy-specific reference range, high concentrations of TPOAb and TgAb attenuated the fT4 stimulation and suppression of TSH by hCG. The results imply that TgAb, in addition to TPOAb, could also interfere with thyroidal responses to hCG during the first half of pregnancy. [ABSTRACT FROM AUTHOR]

Background: The fact that serum thyrotropin (TSH) levels increase with age may influence the diagnosis of thyroid diseases in older adults. This study aimed to establish an age-specific serum TSH reference range, examine the prevalence of thyroid diseases in older adults ≥65 years, and analyze the risk factors. Methods: A cross-sectional study of adult populations in 10 cities in China was conducted from 2010 to 2011. A total of 15,008 subjects were randomly selected and completed the present study. Urinary iodine concentration, serum TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) titers were measured. Thyroid ultrasonography and questionnaires were completed by all the subjects. When the TSH level was abnormal, free thyroxine and/or free triiodothyronine levels were measured. Results: When the reference range of the general population was used, the prevalence rates of overt hypothyroidism (Ohypo) and subclinical hypothyroidism (Shypo) in older adults ≥65 years were significantly higher than those in younger adults <65 years (2.09% vs. 0.80% and 19.87% vs. 16.23%, respectively; p < 0.001). Positive TPOAb and positive TgAb were associated with the prevalence of Shypo in older adults. An age-specific serum TSH reference range was formulated according to guidelines set forth by the National Academy of Clinical Biochemistry. Both the median and upper limit values of serum TSH in older adults were higher than those in younger adults (2.58 [0.75–8.86] mIU/L vs. 2.38 [0.76–6.57] mIU/L; p < 0.001). Using the age-specific serum TSH reference range, the prevalence of Shypo in older adults was 3.3%, which was significantly lower than the prevalence based on the reference range of the general population (3.3% vs. 19.87%). The prevalence rates of Ohypo, overt hyperthyroidism (Ohyper), and subclinical hyperthyroidism (Shyper) did not change much (Ohypo: 1.6% vs. 2.09%; Ohyper: 0.7% vs. 0.52%; and Shyper: 3.8% vs. 0.73%). Positive TPOAb, but not positive TgAb, was also associated with the prevalence of Shypo as diagnosed with the age-specific serum TSH reference range. Conclusion: The serum TSH level increases with age, which may represent a normal compensatory phenomenon in older adults ≥65 years. To prevent misdiagnosis and mistreatment, the use of an age-specific serum TSH reference range is recommended in older adults for the diagnosis of thyroid diseases. [ABSTRACT FROM AUTHOR]

Background: Recent intervention studies have suggested that selenium (Se) is an effective treatment for autoimmune thyroiditis (AIT). However, the exact effect of Se on AIT is unclear as well as the mechanism of action. The aim of the present study was to explore the effect of Se on thyroid peroxidase antibody (TPOAb) titers in patients with AIT and to analyze the potential impact of the genetic background on the effect of Se supplementation. Methods: This was a randomized, placebo-controlled, double-blind trial. Three hundred and sixty-four patients with elevated TPOAb (>300 IU/mL) were recruited and randomized to receive Se yeast 200 μg/day supplementation or placebo. Urinary iodine concentration, serum thyrotropin, free thyroxine, TPOAb, Se, malondialdehyde, and serum glutathione peroxidase activity were measured at baseline and follow-up. Ninety-six patients were genotyped for single nucleotide polymorphism r25191G/A in the selenoprotein P (SEPP1/SELENOP) gene. Results: The median urinary iodine concentration was 182 μg/L. Serum Se increased significantly (p < 0.001) after Se treatment. TPOAb titer decreased by 10.0% at 3 months and by 10.7% at 6 months after Se supplementation, while there was a moderate increase in TPOAb titers over the follow-up period in patients receiving placebo. Glutathione peroxidase activity significantly increased (p < 0.001), and malondialdehyde significantly decreased (p < 0.001) after 6 months of Se supplementation. TPOAb titers decreased to variable extents in patients with different genotypes of single nucleotide polymorphism r25191G/A after Se supplementation. Serum TPOAb titers in patients with the AA genotype showed a more significant decrease (by 46.2%) than those with the GA and GG genotypes (by 14.5 and 9.8% respectively) at 3 months of Se supplementation (p = 0.070). Conclusions: Se supplementation significantly reduced TPOAb titers in patients with AIT, and there may be an important genetic component influencing interindividual differences in the decrease in TPOAb titers. [ABSTRACT FROM AUTHOR]

Background: Pregnant women are highly vulnerable to iron deficiency (ID) due to the increased iron needs during pregnancy. ID decreases circulating thyroid hormone concentrations likely through impairment of iron-dependent thyroid peroxidase. The present study aimed to explore the association between ID and hypothyroxinemia in a retrospective cohort of pregnant women in China. Methods: To investigate the relationship between ID and hypothyroxinemia, 723 pregnant women were retrospectively analyzed, including 675 and 309 women in the second and third trimesters, respectively. Trimester-specific hypothyroxinemia was defined as free thyroxine (fT4) levels below the 2.5th percentile of the reference range with normal serum thyrotropin (TSH) or TSH higher than the 97.5th percentile of the reference range in each trimester of pregnancy. Serum TSH, fT4, thyroid peroxidase antibodies, thyroglobulin antibodies, serum ferritin, soluble transferrin receptor, and urinary iodine concentrations were measured. Serum ferritin, soluble transferrin receptor, and total body iron were used to indicate the nutritional iron status. Results: Cross-sectional multiple linear regression analysis showed that iron status was positively associated with serum fT4 levels in the first and second trimesters of pregnancy, but not in the third trimester. Logistic regression analysis showed that ID was an independent risk factor for hypothyroxinemia (odds ratio = 14.86 [confidence interval 2.31–95.81], p = 0.005 in the first trimester and odds ratio = 3.36 [confidence interval 1.01–11.21], p = 0.048 in the second trimester). The prospective analysis showed that pregnant women with ID during the first trimester of pregnancy had lower serum fT4 levels and a higher rate of hypothyroxinemia in the second or third trimester than those without ID. Conclusions: ID appears to be a risk factor to predict hypothyroxinemia in the first and second trimesters of pregnancy, but not in the third trimester. Pregnant women with ID in the first and second trimesters should be regarded as a high-risk group for maternal hypothyroxinemia. [ABSTRACT FROM AUTHOR]

Background: The intercellular adhesion molecule 1 ( ICAM1) gene is not expressed in normal thyroid tissue but was shown to be expressed in the thyroid tissue of autoimmune thyroiditis (AIT) patients. Methods: This study aimed to explore whether the DNA methylation and hydroxymethylation status of the ICAM1 promoter are aberrantly altered in the thyroid cells of AIT patients and whether this change is associated with dysfunctional expression of ICAM1. A total of 35 AIT patients and 35 sex- and age-matched controls were studied. After the isolation of thyrocytes via density-gradient centrifugation, ICAM1 mRNA expression was measured using real-time PCR. The DNA methylation and hydroxymethylation status were assessed using quantitative PCR following T4 β-glucosyltransferase treatment and MspI/ HpaII cleavage at −937 bp, −701 bp, −226 bp, and −65 bp upstream of the transcription start site (TSS). The DNA methylation level was verified via pyrosequencing. Results: The AIT group showed increased DNA hydroxymethylation at −937 bp and −226 bp and decreased methylation at −937 bp, −701 bp, and −226 bp upstream of the TSS. Pyrosequencing also revealed DNA hypomethylation at −708 bp, −692 bp, −690 bp, and −688 bp upstream of the TSS. The DNA methylation status at −708 bp, −692 bp, and −226 bp upstream of the TSS was negatively associated with ICAM1 mRNA expression. Conclusion: In summary, we identified aberrant DNA methylation and hydroxymethylation of the ICAM1 gene promoter in the thyrocytes of AIT patients. This aberrant epigenetic modification is associated with increased expression of the ICAM1 gene. [ABSTRACT FROM AUTHOR]

Background: High mobility group box-1 (HMGB1), a non-histone protein, plays an important role in autoimmune diseases. However, the significance of HMGB1 in the pathogenesis of autoimmune thyroiditis has not been reported. The purpose of this study was to explore whether HMGB1 participates in the pathogenesis of autoimmune thyroiditis, and whether glycyrrhizin (GL), a direct inhibitor of HMGB1, attenuates the severity of thyroid inflammatory infiltration in a murine model of autoimmune thyroiditis. Methods: A total of 80 male NOD.H-2h4 mice were randomly divided into a control or iodine supplement (NaI) group at four weeks of age, and the control group was fed with regular water, whereas the NaI group was supplied with 0.005% sodium iodine water. Another 24 male NOD.H-2h4 mice were also randomized into three groups (eight mice per group) as follows: control, NaI, and GL treatment after iodine supplementation (NaI + GL). The NOD.H-2h4 mice were fed with 0.005% sodium iodide water for eight weeks to enhance autoimmune thyroiditis. After iodine treatment, the mice received intraperitoneal injections of GL for four weeks. The severity of lymphocytic infiltration in the thyroid gland was measured by histopathological studies. The serum levels of HMGB1, tumor necrosis factor alpha, interleukin (IL)-6, IL-1β, and thyroglobulin antibody titers were measured using an enzyme-linked immunosorbent assay. HMGB1 expression was measured by immunohistochemical staining and real-time polymerase chain reaction. TLR2, HMGB1, MyD88, and nuclear transcription factor κB were measured by Western blot. Results: The mRNA expression of HMGB1 was significantly higher at 8 and 16 weeks in the NaI group than it was in the control group. Serum levels of thyroglobulin antibodies, HMGB1, tumor necrosis factor alpha, IL-6, and IL-1β were significantly increased in the NaI group, but they were dramatically attenuated with GL injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly decreased in the NaI + GL group. GL administration also significantly reduced the protein expression of TLR2, MyD88, HMGB1 and nuclear transcription factor κB in the thyroid gland and attenuated the severity of thyroiditis. Conclusion: HMGB1 may play a crucial role in autoimmune thyroiditis by causing inflammatory infiltration, thus increasing the severity of autoimmune thyroiditis. GL effectively attenuated thyroiditis in the iodine-induced NOD.H-2h4 mice via a molecular mechanism related to the inhibition of TLR2-HMGB1 signaling. [ABSTRACT FROM AUTHOR]

Background: A self-sequential longitudinal reference interval may be expected to minimize the inter-individual variation of thyroid function. Comparison between the self-sequential longitudinal reference interval (SLRI) and cross-sectional reference interval (CSRI) in pregnancy has not been well investigated. The objectives of this study were to establish a stringent SLRI of thyroid function in pregnant women and to compare it with the conventional CSRI. Methods: Three cohorts were enrolled: group 1, pregnant women for an SLRI ( n = 99); group 2, pregnant women for a CSRI ( n = 1318); group 3, non-pregnant control women (NC) as a control group ( n = 301) according to the criteria of the National Academy of Clinical Biochemistry. Thyrotropin (TSH), total thyroxine (TT4), free thyroxine (fT4), total triiodothyronine (TT3), free triiodothyronine (fT3), serum ferritin (SF), and urine iodine concentration (UIC) were measured in the three groups. Results: Compared with CSRI, the reference interval of the SLRI group had narrower reference intervals of fT4 in the first and second trimesters ( p < 0.05). The median of TSH was at a low level during the first trimester, and then gradually elevated in the second and third trimesters. The median of fT4 persistently decreased from 12 weeks, and did not return to the level of the NC group until 12 months postpartum. The TT4 increased to 131.4 nmol/L at gestational week 8, and reached a peak (170.0 nmol/L) at gestational week 12. In the first trimester, the prevalence of hypothyroxinemia was 9.1%, 4.0%, and 2.0% with a fT4 value below the 10th, 5th, and 2.5th percentile, respectively. In contrast, 29.3% of TT4 values were below the lower non-pregnancy reference limit multiplied by 1.5. Conclusions: No significant difference was found between a SLRI and a CSRI, even in a stringent self-sequential longitudinal reference interval of thyroid function in pregnant women. In addition, the limit of TT4 below the non-pregnant level multiplied by a factor 1.5 is not appropriate for diagnosing hypothyroxinemia in the first trimester. [ABSTRACT FROM AUTHOR]

Background: The goal of eliminating iodine deficiency worldwide was successfully achieved in China after the implementation of a mandatory universal salt iodization program for the last 16 years. Thus, China has been assessed as a country with more than adequate iodine levels. This survey aimed to investigate the current iodine status in China and the effects of an increased iodine intake on the spectrum and prevalence of thyroid disorders. Methods: A total of 15,008 adult subjects from 10 cities in eastern and central China were investigated. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and urine iodine concentration (UIC) were measured, and an ultrasonography of the thyroid was performed in all subjects. Free thyroxine (fT4) and free triiodothyronine (fT3) levels were only measured if the serum TSH was outside the normal range. Results: The median UIC values were 197 μg/L in school-age children (SAC) and 205 μg/L in a cohort population. Six cities were classified as regions with adequate iodine intake (AII), and four cities as regions with more than adequate iodine intake (MTAII), according to median SAC UIC. The prevalence of clinical hypothyroidism, subclinical hypothyroidism, and positive thyroid antibodies was significantly higher in MTAII cities than it was in AII cities. Moreover, the prevalence of clinical hyperthyroidism (1.1% vs. 0.8%, p = 0.033) and Graves' disease (0.8% vs. 0.5%, p = 0.019) also significantly increased in MTAII cities. Compared with a five-year prospective study conducted in 1999, the prevalence of goiter significantly decreased (2.9% vs. 5.02%, p = 0.001), but there was a significant increase in thyroid nodules (12.8% vs. 2.78%, p = 0.001). The prevalence of subclinical hypothyroidism (16.7% vs. 3.22%), positive TPOAb (11.5% vs. 9.81%), and positive TgAb (12.6% vs. 9.09%) significantly increased, while no changes were seen in clinical hyperthyroidism, subclinical hyperthyroidism, or Graves' disease. Conclusion: The goal of eliminating iodine deficiency has been successfully achieved in China. However, the prevalence and spectrum of thyroid disorders has increased, reflecting possible adverse effects of increased iodine intake. [ABSTRACT FROM AUTHOR]

Background: Recent clinical studies have demonstrated the suppressive effect of selenium (Se) treatment on serum thyroid-specific antibody titers in patients with autoimmune thyroiditis (AIT), but the mechanism underlying this process is not clear. The aim of the present study was to investigate the effects of selenium on the incidence and severity of AIT, titers of thyroid autoantibodies, and selenoprotein expression in thyroid in a spontaneous autoimmune thyroiditis (SAT) model. Methods: NOD.H-2h4 mice at four weeks of age were randomly divided into control, iodine supplement (SAT), and selenium supplement groups (SAT+Se). Mice were given 0.005% sodium iodide water for eight weeks to induce SAT and then 0.3 mg/L sodium selenite in drinking water for 8 weeks and 16 weeks. The severity of lymphocytic infiltration in the thyroid, serum thyroglobulin antibody (TgAb) titers, serum selenium concentration, expression of glutathione peroxidase-1 (GPx1), thioredoxin reductase-1 (Txnrd1), and peroxiredoxin 5 were measured. Results: Serum selenium concentration significantly increased after selenium supplementation. Serum TgAb levels were significantly lower in the selenium group compared with the SAT group ( p<0.05). The prevalence of thyroiditis and the degree of infiltration of lymphocytes decreased gradually over time in the group provided with selenium supplementation. The expression of GPx1 and Txnrd1 by Western blotting were found to be significantly higher in the SAT+Se group than in other groups ( p<0.05). Conclusions: These results indicate that selenium treatment can increase the function of antioxidation by upregulating the expression of selenoproteins in the thyroid and have an inhibitory effect on TgAb titers, which may have an impact on AIT. [ABSTRACT FROM AUTHOR]

Background: Increasing data suggest that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes, but there are limited data on the association of these conditions in early pregnancy with subsequent miscarriage. Methods: In this prospective cohort study, we screened 3315 women at low risk for thyroid dysfunction at four to eight weeks' gestation from iodine-sufficient areas of China between January 2012 and September 2012. Thyrotropin (TSH), free thyroxine (fT4), and the autoantibodies thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were measured. Based on these results, women were divided into four groups for comparison: euthyroidism (ET), isolated SCH, isolated TAI (positive TPOAb or/and TgAb), and SCH with TAI (SCH+TAI). The SCH group was stratified into two subgroups (SCH 1 and SCH 2) on the basis of the level of TSH (2.5≤TSH<5.22 or 5.22≤TSH<10 respectively). Accordingly, the SCH+TAI group was also stratified into two subgroups (SCH+TAI 1 and SCH+TAI 2). The outcome of interest was miscarriage, defined as spontaneous pregnancy loss prior to 20 weeks. Results: Compared to women with ET, the risk of miscarriage was significantly higher among women with SCH 2 (7.1% vs. 2.2%, aOR 3.40 [CI 1.62-7.15]; p=0.002), isolated TAI (5.7% vs. 2.2%, aOR 2.71 [CI 1.43-5.12]; p=0.003), SCH+TAI 1 (10.0% vs. 2.2%, aOR 4.96 [CI 2.76-8.90]; p=0.000), and SCH+TAI 2 (15.2% vs. 2.2%, aOR 9.56 [CI 3.76-24.28]; p=0.000). The gestational ages of 110 women at miscarriage were lower among women with subclinical thyroid abnormalities compared to ET (11.13±3.21 weeks with subclinical thyroid abnormalities vs. 9.33±1.71 weeks with ET; p=0.024). In parallel with the higher TSH levels, there were earlier gestation ages at miscarriage between subgroups of SCH and SCH+TAI (SCH 1 vs. SCH 2: 10.79±1.77 vs. 9.70±1.47 weeks, p=0.039; SCH+TAI 1 vs. SCH+TAI 2: 9.59±1.97 vs. 8.88±1.24 weeks, p=0.031). Conclusions: Women with SCH and TAI are at an increased risk of miscarriage between four and eight gestational weeks. Women with a combination of SCH and TAI were found to have the highest risk and earlier gestational ages of miscarriage. [ABSTRACT FROM AUTHOR]

Background: This 8-year follow-up study is aimed at determining the relapse and development of Graves' disease (GD) and the potential risk factors that could be associated with the development of thyroid dysfunction and autoantibodies in Chinese pedigrees. Methods: Fifty-four Chinese Han GD pedigrees (322 members) were recruited in 2000. Forty-five pedigrees (263 members) were followed up. Their clinical and laboratory characteristics and fasting urinary iodine were measured with the same method at the two time points. Results: We found that the mean age for onset of GD in offspring was much younger than that of their parents ( p=0.013). At baseline, the prevalence of hyperthyroidism, hypothyroidism, and subclinical hypothyroidism in first-degree relatives were 5.5%, 1.6%, and 1.1%, respectively. Individuals with thyroid dysfunction were positive for thyroid autoantibodies. The prevalence of positive thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), or TSH receptor antibody (TRAb) in the first-degree relatives with euthyroidism in these pedigrees was 18.6%, 17.4%, or 56.9%, respectively. At follow-up, individuals with positive TPOAb were at risk of developing thyroid dysfunction, whereas patients with positive TRAb had increased risk for relapse even after drug treatment. The percentage of nonsmokers with positive TPOAb and TgAb was significantly higher than that of smokers ( p<0.05), but the levels of serum TRAb were significantly higher in smokers at follow-up than baseline ( p<0.01). Conclusions: Genetic factors are crucial for the development of autoimmune thyroid disease (AITD), thyroid dysfunction, and the outcomes of Graves' patients following treatment with medicines. Although smoking was negatively associated with the presence of thyroid antibodies (TPOAb/TgAb), smoking may induce or aggravate GD. [ABSTRACT FROM AUTHOR]