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Objective: To explore the association between maternal thyroid peroxidase antibody (TPOAb) exposure and 5- to 6-year-old children's cardiometabolic risk (CMR)., Methods: A total of 2129 mother-child pairs were recruited from the Ma'anshan Birth Cohort (MABC) study. Serum TPOAb was retrospectively measured in pregnant women using an electrochemiluminescence immunoassay. CMR score was evaluated by the serum glycolipids, blood pressure, and waist circumference for children aged 5-6 years. Growth mixture modelling was used to fit trajectories of TPOAb levels throughout pregnancy. Multiple linear regression models and logistic regression models were used for statistical analyses., Results: Two thousand one hundred twenty-nine mother-child pairs (mean [SD] age, 26.6 [3.6] years) were enrolled for the final study. Maternal TPOAb exposure in the first trimester increased children's overall CMR, glucose level, HOMA-IR, triglyceride level, boys' overall CMR, boys' glucose level, and girls' glucose level. TPOAb exposure in the first trimester was also associated with lower boys' high-density lipoprotein cholesterol (HDL-C) level. In the second trimester, maternal TPOAb exposure was positively associated with children's triglyceride level. Compared with low TPOAb trajectory, children with high maternal TPOAb trajectory had an increased risk of developing high CMR (OR = 3.40; 95% CI, 1.30-8.90), hyperglycemia (OR = 5.20; 95% CI, 2.20-12.28), insulin-resistance (adjusted OR = 2.12; 95% CI, 1.10-4.07), and hypertriglyceridemia (OR = 2.55; 95% CI, 1.06-6.14)., Conclusions: The first trimester of pregnancy is a critical period for maternal TPOAb exposure to affect CMR in children, with some sex specificity, mainly to the detriment of boys., Competing Interests: Conflict of interest: Authors, consisting of Yuzhu Teng, Jixing Zhou, Manyu Zhang, Penggui Wu, Lu Chen, Wenjin Cai, Juan Tong, Yan Han, Shuangqin Yan, Fangbiao Tao, and Kun Huang disclaimed that the study was performed without any business or financial affiliation that would be interpreted as a potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Postpartum depression (PPD) has a major impact on maternal and offspring well-being, with multiple possible risk factors: Studies on the association of thyroid peroxidase antibody (TPOAb) positivity and thyroid function with PPD provide heterogeneous results., Objective: To study the association of thyroid function and TPOAb positivity with PPD., Design: We assessed the association of TPOAb and thyroid function with PPD in a population-based prospective cohort study and performed a systematic literature review and meta-analysis., Methods: We measured thyroid stimulating hormone (TSH), free thyroxine (FT4), and TPOAb between 9- and 17-week gestation. Postpartum depression was assessed with Edinburgh Postpartum Depression Scale at 2-month postpartum and Brief Symptom Inventory at 2-, 6-, and 36-month postpartum. Additionally, we performed a systematic literature review and meta-analysis assessing this association., Results: In the present study, there was no association of thyroid function with PPD (TSH: odds ratio [OR] 0.83, 95% CI 0.58-1.19, P = .32; FT4: OR 0.99, 95% CI 0.95-1.05, P = .86) or TPOAb positivity with PPD (OR 0.79, 95% CI 0.47-1.33, P = .37). An impaired thyroidal response to human chorionic gonadotropin (hCG), a surrogate marker for TPOAb positivity, was associated with a lower risk of PPD (P for interaction TSH = 0.04; FT4 = 0.06). Our systematic review and meta-analysis included 3 articles that were combined with the present study. There was no statistically significant association of TPOAb positivity with PPD (OR 1.93, 95% CI 0.91-4.10, P = .08), but the results were heterogeneous (I2 = 79%)., Conclusions and Relevance: There was no significant association of TPOAb positivity, TSH, or FT4 with PPD. Our systematic review and meta-analysis revealed high heterogeneity of the current literature. Although TPOAb-positive women should be monitored for postpartum thyroiditis, our findings do not support routinely screening for PPD., Competing Interests: Conflict of interest: All authors declare no conflict of interest that could affect the impartiality of the research reported. Coauthor W.E.V. is on the editorial board of EJE. He was not involved in the review or editorial process for this paper, on which he is listed as author., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Objective: Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance., Methods: Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9-16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery., Results: Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7-74.9%) for TSH, 67.5% (59.8-75.3%) for fT4, 59.7% (54.4-65.0%) for fT3 and 48.8% (40.6-56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4., Conclusion: Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

Objective: 3,5,3'-Triiodothyronine (T(3))-predominant Graves' disease is characterized by the increasing volume of thyroid goiter resulting in poor prognosis. Although type 1 and type 2 iodothyronine deiodinases (DIO1 and DIO2 respectively) are known to be overexpressed in the thyroid tissues of T(3)-predominant Graves' disease, the pathogenesis of this disease is still unclear. The aim of our study is to identify genes that characterize T(3)-predominant Graves' disease tissue in order to clarify the molecular mechanism of this disease., Design and Methods: mRNAs from two thyroid tissues of both typical T(3)-predominant and common-type Graves' disease were analyzed with DNA microarrays with probes for 28 869 genes. Genes identified to be differentially expressed between the two groups were further analyzed in the second and third screenings using 70 Graves' thyroid tissues by real-time quantitative RT-PCR., Results: Twenty-three candidate genes were selected as being differentially expressed in the first screening with microarrays. Among these, seven genes, leucine-rich repeat neuronal 1 (LRRN1), bone morphogenetic protein 8a (BMP8A), N-cadherin (CDH2), phosphodiesterase 1A (PDE1A), creatine kinase mitochondrial 2 (CKMT2), integrin beta-3 (ITGB3), and protein tyrosine phosphatase non-receptor type 4 (PTPN4), were confirmed to be differentially expressed in DIO1 or DIO2 over- and underexpressing Graves' tissues., Conclusions: These genes are related to the characteristics of T(3)-predominant Graves' disease, such as high titer level of serum anti-TSH receptor antibody, high free T(3) to free thyroxine ratio, and a large goiter size. They might play a role in the pathogenesis of T(3)-predominant Graves' disease.

Objective: Type 2 deiodinase gene (DIO2) polymorphisms have been associated with changes in pituitary-thyroid axis homeostasis. The -258A/G (SNP rs12885300) polymorphism has been associated with increased enzymatic activity, but data are conflicting. To characterize the effects of -258A/G polymorphism on intrathyroidal thyroxine (T(4)) to triiodothyronine (T(3)) conversion and thyroid hormone (TH) secretion pattern, we studied the effects of acute, TRH-mediated, TSH stimulation of the thyroid gland., Design: Retrospective analysis., Methods: The TH secretion in response to 500  μg i.v. TRH injection was studied in 45 healthy volunteers., Results: Twenty-six subjects (16 females and ten males, 32.8 ± 10.4 years) were homozygous for the ancestral (-258A/A) allele and 19 (11 females and eight males, 31.1 ± 10.9 years) were carriers of the (-258G/x) variant. While no differences in the peak TSH and T(3) levels were observed, carriers of the -258G/x allele showed a blunted rise in free T(4) (FT(4); P<0.01). The -258G/x92Thr/Thr haplotype, compared with the other groups, had lower TSH values at 60  min (P<0.03). No differences were observed between genotypes in baseline TH levels., Conclusions: The -258G/x DIO2 polymorphism variant is associated with a decreased rate of acute TSH-stimulated FT(4) secretion with a normal T(3) release from the thyroid gland consistent with a shift in the reaction equilibrium toward the product. These data indicate that the -258G DIO2 polymorphism causes changes in the pattern of hormone secretion. These findings are a proof of concept that common polymorphisms in DIO2 can subtly affect the circulating levels of TH and might modulate the TH homeostasis.

Objective: 3,5,3'-triiodothyronine-predominant Graves' disease (T(3)-P-GD) is characterized by a persistently high serum T(3) level and normal or even lower serum thyroxine (T(4)) level during antithyroid drug therapy. The source of this high serum T(3) level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T(3) level in T(3)-P-GD., Methods: We measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T(3)-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy., Results: Thyroidal D1 activity in patients with T(3)-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P<0.05) than that in patients with CT-GD (320.7±151.9 pmol/mg prot per h). On the other hand, thyroidal D2 activity in patients with T(3)-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P<0.005) than that in patients with CT-GD (194.8±131.6 fmol/mg prot per h). There was a significant correlation between the thyroidal D1 activity in patients with T(3)-P-GD and CT-GD and the serum FT(3)-to-FT(4) ratio (r=0.370, P<0.05). Moreover, there was a strong correlation between the thyroidal D2 activity in those patients and the serum FT(3)-to-FT(4) ratio (r=0.676, P<0.001)., Conclusions: Our results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT(3)-to-FT(4) ratio in T(3)-P-GD.

Objective: Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism., Subjects and Methods: TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane., Conclusions: Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism.

Objectives: Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3)., Methods: Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4., Results: Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal., Conclusions: We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

Objective: The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T3), normal to elevated thyroxine (T4), elevated reverse T3 (rT3) and normal TSH levels. The aim of this work was to clarify if impaired T4 and rT3 5'-deiodination is an underlying mechanism., Design and Methods: We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human type I 5'-iodothyronine deiodinase (5'DI) enzyme activity in the human hepatocarcinoma cell line HepG2, i.e. in a homologous human system. Furthermore, we analysed transcriptional effects of the cytokines by transient transfection assays using the luciferase or chloramphenicol acetyltransferase (CAT) reporter genes under the control of 1480 nucleotides of the human 5'DI promoter., Results: IL-6 at 500 pg/ml and TNF-alpha at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-gamma or 10 ng/ml IL-1beta reduced 5'DI enzyme activity to 77.9 and 59.5% of control values. IFN-gamma did not alter, IL-6 and TNF-alpha moderately decreased (in the case of IL-6 only in the CAT system), and IL-1beta (0.01-10 ng/ml) dose-dependently inhibited 5'DI promoter activity to a minimum of 38.1%., Conclusion: IL-1beta inhibited both 5'DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5'DI gene transcription.

Objective: It is suggested that iodide organification defects account for 10% of all cases with congenital hypothyroidism (CH). One candidate gene for these defects is the thyroid peroxidase (TPO) gene., Design: Exons 2, 8-10 and 14 of the TPO gene were examined in 30 patients with permanent CH without a family history of CH. This group was characterized by the presence of an orthotopic thyroid gland and elevated TSH levels., Methods: The mutational screening was performed by single-strand conformational polymorphism followed by sequence analysis of fragments with abnormal migration patterns and by restriction enzyme analysis., Results: In four patients we were able to identify mutations on both alleles which have not been described so far. One patient was a carrier of a new homozygous point mutation in exon 9 resulting in an exchange from Leu to Pro at codon 458. Another patient was found to be compound heterozygous for two mutations, a 20 bp duplication in exon 2 and a new mutation in exon 9 (Arg491His). Two brothers of consanguineous parents showed a homozygous T deletion in exon 14 at position 2512., Conclusions: Our findings confirm the genetic heterogeneity of TPO defects and support the suggested prevalence of organification defects.

Objective: Thyroid hormone is essential for maintaining normal neurological functions both during development and in adult life. Type III-iodothyronine deiodinase (D3) degrades thyroid hormones by converting thyroxine and 3,5,3'-triiodothyroinine (T3) to inactive metabolites. A regional expression of D3 activity has been observed in the human central nervous system (CNS), and a critical role for D3 has been suggested in the regulation of local T3 content in concert with other enzymes., Design: This study was undertaken to further characterize D3 activity in human CNS and to understand its role in the local regulation of T3 content., Methods: Autoptic specimens from various areas of human CNS were obtained 6--27 h postmortem from 14 donors who died from cardiovascular accident, neoplastic disease or infectious disease. D3 was determined by measuring the conversion of T3 to 3,3'-diiodothyronine. The T3 content was measured by radioimmunoassay in ethanol extracts, using a specific antiserum., Results: High levels of D3 activity were observed in hippocampus and temporal cortex, lower levels being found in the thalamus, hypothalamus, midbrain cerebellum, parietal and frontal cortex, and brain stem. An inverse relationship between D3 activity and T3 content in these areas was demonstrated., Conclusions: We have concluded that D3 contributes to the local regulation of T3 content in the human CNS.

Objective: In the recently revised guidelines on the management of thyroid dysfunction during pregnancy, treatment with thyroid hormone (LT4) is not recommended in women without thyroid autoimmunity (TAI) and TSH levels in the range 2.5-4.0 mIU/L, and in a recent study in that particular group of pregnant women, more complications were observed when a treatment with LT4 was given. The objective of the study was therefore to investigate whether variation in thyroid function within the normal (non-pregnant) range in women free of thyroid disease was associated with altered pregnancy outcomes?. Design: Cross-sectional data analysis of 1321 pregnant women nested within an ongoing prospective collection of pregnant women's data in a single centre in Brussels, Belgium. Methods: Thyroid peroxidase antibodies (TPO-abs), thyroid-stimulating hormone (TSH), free T4 (FT4) and ferritin levels were measured and baseline characteristics were recorded. Women taking LT4, with TAI and thyroid function outside the normal non-pregnant range were excluded. Pregnancy outcomes and baseline characteristics were correlated with all TSH and FT4 levels within the normal range and compared between two groups (TSH cut-off < and ≥2.5 mIU/L). Results: Tobacco use was associated with higher serum TSH levels (OR: 1.38; CI 95%: 1.08-1.74); P = 0.009. FT4 levels were inversely correlated with age and BMI (rho = -0.096 and -0.089; P < 0.001 and 0.001 respectively) and positively correlated with ferritin levels (rho = 0.097; P < 0.001). Postpartum haemorrhage (>500 mL) was inversely associated with serum FT4 levels (OR: 0.35; CI 95%: 0.13-0.96); P = 0.040. Also 10% of women free of thyroid disease had serum TSH levels ≥2.5 mIU/L. Conclusions: Variation in thyroid function during the first trimester within the normal (non-pregnant) range in women free of thyroid disease was not associated with altered pregnancy outcomes. These results add evidence to the recommendation against LT4 treatment in pregnant women with high normal TSH levels and without TPO antibodies. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the relation between the serum levels of thyroid hormones and their biological effects. For this purpose, hypothyroid rats were studied after stopping treatment with a long-acting thyroid hormone, thyroxine (T4) and a short-acting one, triiodothyroacetic acid (Triac). Based on preliminary experiments with different doses of T4 and Triac, hypothyroid rats (N = 84) received over 6 days' injections of 10 nmol Triac or 2 nmol T4/100 g body wt per day. Biological effects of Triac and T4 were measured in the pituitary, liver and kidney up to 8 days after stopping treatment. With Triac, serum thyrotropin (TSH) levels were inhibited completely 6 h after injection, yet after 24 h they were 4.9 +/- 1.8 micrograms/l (hypothyroid 14.5 +/- 0.8 micrograms/l). The rapid changes in serum TSH levels were followed by a more gradual increase in serum TSH levels were followed by a more gradual increase in serum TSH, which was similar to that after T4 injection. Even 8 days after Triac treatment, serum TSH levels did not reach the hypothyroid control levels. Changes in beta-TSH mRNA levels also showed a prolonged inhibition after both treatments and a slow return to hypothyroid values, which was not complete 8 days after stopping treatment. A second parameter was hepatic 5'-deiodinase type I (5'D-I). The 6-day treatment with Triac had a markedly stronger effect on 5'D-I enzyme activity and mRNA levels than treatment with T4.(ABSTRACT TRUNCATED AT 250 WORDS)

The identification of autoantibody epitopes is important to the understanding of autoimmune thyroid diseases. In the case of thyroid peroxidase antibodies (TPO-ab), recent reports have disagreed about the number and type of autoantibody epitopes found in human TPO. In order to clarify the nature of these epitopes, we used an approach that provides recombinant human TPO produced by bacterial cells. The cDNA of four slightly overlapping fragments of human TPO-TPO 1(Glu 17-Ser 227), TPO 2(Tyr 226-Thr 476), TPO 3(Glu 471-Ser 720) and TPO 4(Phe 709-Leu 993)--were amplified by polymerase chain reaction and subcloned into the expression vector pMAL. In addition, a TPO 3 species for an alternatively spliced form of TPO of 876 amino acids was constructed (TPO 3M). Each of these constructs encodes a fusion protein, in which the amino terminal portion is maltose-binding protein, followed by the sequence of the fragment of human TPO. The plasmid constructs were transformed in Escherichia coli and, after growth, bacterial cells were harvested, lysed and the lysate was passed over an amylose affinity column and eluted with maltose. Western blots were performed using 33 sera from patients with autoimmune thyroid disease (group 1) and 17 sera from patients with nodular goiter and focal thyroiditis (group 2), all positive for TPO-ab measured by radio-immunoassay; sera from 10 healthy people with no clinical evidence of thyroiditis and positive for TPO-ab measured by radioimmunoassay (group 3) and sera from 30 patients with antigastric parietal cell antibodies without signs or symptoms of thyroiditis, 16 negative for TPO-ab (group 4a) and 14 positive for TPO-ab (group 4b), were included in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To investigate the concordance of serologic and sonographic evidence of Hashimoto's thyroiditis with its gold standard histopathologic identification., Design: We performed a retrospective analysis on a cohort of 825 consecutive patients in whom TPOAb and thyroid ultrasound were performed, and in whom thyroid nodule evaluation led to surgical and histopathologic analysis. The presence or absence of Hashimoto's thyroiditis on histopathology was correlated with serologic and sonographic markers. We further assessed the impact of low versus high titers of TPOAb upon this concordance., Results: Of 825 patients, 277 (33.5%) had histologic confirmation of Hashimoto's thyroiditis, 235 patients (28.4%) had elevated serum levels of TPOAb, and 197 (23.8%) had sonographic evidence of diffuse heterogeneity. Of those with histopathologic evidence, only 64% had elevated TPOAb (sensitivity: 63.9%; specificity: 89.4%), while only 49% were sonographically diffusely heterogeneous (sensitivity: 49.1%; specificity: 88.9%). A subset of only 102 of 277 (37%) with histologically proven Hashimoto's thyroiditis was positive for both TPOAb and diffusely heterogeneous. Concordance analysis demonstrated that TPOAb and histopathology had higher agreement (κ = 0.55) than did ultrasound and histopathology (κ = 0.40) for the diagnosis of Hashimoto's thyroiditis. Higher titers of TPOAb correlated with a higher likelihood of Hashimoto's thyroiditis, with a best cutoff of 2.11-fold the upper normal level of TPOAb., Conclusion: Only moderate concordance exists between serological evidence of Hashimoto's thyroiditis and histopathologic findings, though it increases with higher TPOAb concentration. Diffuse heterogeneity on ultrasound is a less-sensitive diagnostic tool than elevated TPOAb.

Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence of thyroid dysfunction (TD) and IgG subclasses of thyroid autoantibodies (TAs) and to determine the predictive factors of TD in chronic hepatitis C (CHC) patients. Design: Three hundred and twelve untreated hepatitis C virus-infected patients without a history of TD or treatment with thyroid hormones were enrolled in a cross-sectional study. Clinical and biological factors were statistically analyzed to determine the correlation between TD and this patient population. Results: The incidence of TD was 12.5% in CHC patients. Clinical hypothyroidism (5.8%) and subclinical hypothyroidism (3.8%) were more frequent than clinical hyperthyroidism (1.6%) and subclinical hyperthyroidism (1.3%). The percentage of TA-positive patients was significantly higher in people >60 years than in those ⩽60 years (31.9 vs 18.6%; P=0.042). Positive thyroid peroxidase antibody (TPOAb) was more frequent, and alanine aminotransferase (ALT) levels were lower in patients who displayed TD (TPOAb: 62.1 vs 10.8%, P=0.000; ALT: 43.5 vs 51 IU/l, PZ0.046). The positive percentage of TPOAb IgG2 subclass in the TD group was significantly higher than that of patients without TD (66.7 vs 16.7%, P=0.005). Multiple logistic regression analysis indicated that only TPOAb IgG2 subclass positivity was an independent risk factor for TD in CHC patients (odds ratioZ8; 95% CI: 1.225-52.246; P=0.030). Conclusions: TPOAb IgG2 subclass positivity is a risk factor for TD in CHC patients before antiviral treatment. IgG2 subclass of TPOAb might play an important role in the presence of TD in CHC patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: 3,5,3'-triiodothyronine-predominant Graves' disease (T3-P-GD) is characterized by a persistently high serum T3level and normal or even lower serum thyroxine (T4) level during antithyroid drug therapy. The source of this high serum T3level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T3level in T3-P-GD. METHODS: We measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T3-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy. RESULTS: Thyroidal D1 activity in patients with T3-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P<0.05) than that in patients with CT-GD (320.7±151.9 pmol/mg prot per h). On the other hand, thyroidal D2 activity in patients with T3-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P<0.005) than that in patients with CT-GD (194.8±131.6 fmol/mg prot per h). There was a significant correlation between the thyroidal D1 activity in patients with T3-P-GD and CT-GD and the serum FT3-to-FT4ratio (r=0.370, P<0.05). Moreover, there was a strong correlation between the thyroidal D2 activity in those patients and the serum FT3-to-FT4ratio (r=0.676, P<0.001). CONCLUSIONS: Our results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT3-to-FT4ratio in T3-P-GD. [ABSTRACT FROM AUTHOR]

Objective: Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited., Design and Methods: One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees., Results: Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes ( DUOX2 , DUOXA2 , DUOXA1 , TG , TPO and TSHR ) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2 , DUOXA2 , TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes ( FOXE1 , NKX2-1 , PAX8 and HHEX ) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands., Conclusions: Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries., (© 2018 The authors.)

Objective: The presence of thyroid antibodies in pregnancy has been associated with preterm birth. In the non-pregnant population, the implementation of the Danish iodine fortification program has increased the prevalence of thyroid antibodies. This study investigated the prevalence of thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) in pregnant Danish women before, during and after implementation of the iodine fortification program and association with preterm birth., Design: Comparative cohort study of 1368 pregnancies from three cohorts gathered before (1996-1998), during (2000-2003) and after (2008-2009) the iodine fortification program., Methods: In cohort 1 ( n  = 297), TPOAbs were measured (DYNOtest (BRAHMS)). In cohorts 2 ( n  = 148) and 3 ( n  = 923), both TPOAbs and TgAbs were measured (Kryptor immunofluorescent assay (BRAHMS)). The prevalence and effect of antibody positivity were explored using three cut-offs: TPOAbs and/or TgAbs >100 kU/L, TPOAbs and/or TgAbs >60 kU/L and TPOAbs >30 and/or TgAbs >20 kU/L. National preterm birth data were extracted from the National Birth Registry., Results: In the three cohorts, TPOAb levels >60 kU/L were found in 5.4, 8.1 and 12.0% ( χ 2 (2, n  = 1367) = 11.7, P  = 0.003) respectively, and TPOAbs and/or TgAbs >60 kU/L in 8.1 and 16.2% in cohorts 2 and 3 respectively ( χ 2 (2, n  = 1070) = 6.5, P  = 0.01). TgAb levels (>20 kU/L) had increased plenty-fold from cohort 2 to 3 ( χ 2 (1, n  = 1071) = 136.5, P  < 0.001). Preterm birth occurred in 4.1% of all pregnancies with no effect from antibody positivity (TPOAbs and/or TgAbs >60 kU/L, χ 2 (1, n  = 1039) = 0.0, P  = 0.98, aOR = 1.1, 95% CI (0.4-2.7)). The national preterm birth-rate showed no increase over the same period., Conclusions: Thyroid antibody positivity in Danish pregnant women has more than doubled upon the implementation of the iodine fortification program without an increase in preterm birth-rate., (© 2017 European Society of Endocrinology.)

Background: Despite some studies indicating that thyroid antibody positivity during pregnancy has been associated with adverse pregnancy outcomes, evidence regarding the effects of levothyroxine (LT4) treatment of euthyroid/subclinical hypothyroid pregnant women with autoimmune thyroid disease on pregnancy outcome is limited. We aimed to assess whether pregnant women with autoimmune thyroid disease, but without overt thyroid dysfunction are affected by higher rates of adverse pregnancy outcomes. In addition, we aimed to explore whether LT4 treatment improves the pregnancy outcome of affected women., Methods: A prospective study was carried out on pregnant women from the first trimester to delivery. The study was conducted among pregnant women receiving prenatal care in centers under coverage of Shahid Beheshti University of Medical Sciences. Of a total of 1746 pregnant women, screened for thyroid dysfunction, 1028 euthyroid TPOAb-negative (TPOAb - ) and 131 thyroid peroxidase antibody-positive (TPOAb + ) women without overt thyroid dysfunction entered the second phase of the study. TPOAb + women were randomly divided into two groups: group A (n = 65), treated with LT4 and group B (n = 66), received no treatment. The 1028 TPOAb - women (group C) served as a normal population control group. Primary outcomes were preterm delivery and miscarriage and secondary outcomes included placenta abruption, still birth, neonatal admission and neonatal TSH levels., Results: Groups A and C displayed a lower rate of preterm deliveries compared with group B (RR = 0.30, 95% CI: 0.1-0.85, P = 0.0229) and (RR = 0.23, 95% CI: 0.14-0.40, P < 0.001) respectively. There was no statistically significant difference in the rates of preterm labor between groups A and C (RR = 0.79, 95% CI: 0.30-2.09, P = 0.64). The number needed to treat (NNT) for preterm birth was 5.9 (95% CI: 3.33–25.16)., Conclusions: Treatment with LT4 decreases the risk of preterm delivery in women who are positive for TPOAb., (© 2017 European Society of Endocrinology.)

Objective: We have aimed to study the relation between Hashimoto's thyroiditis (HT) and thyroid autoantibodies and oxidative stress parameters in euthyroid, subclinical and overt hypothyroid stages., Design and Methods: A total of 124 patients were included in the study; 93 of whom were newly diagnosed with HT (31 patients in each of the euthyroid, subclinical hypothyroid and overt hypothyroid subgroups), aged over 18 and had not received any prior treatment and 31 of whom were healthy volunteers., Results: Total oxidant status (TOS) and oxidative stress index (OSI) levels were higher, and total antioxidant status (TAS) and total thiol and arylesterase levels were lower in the overt hypothyroid group compared to other groups. TOS and OSI levels increased, and TAS levels decreased significantly in each phase from euthyroid, subclinical hypothyroid, to overt hypothyroid subgroups among HT patients. There was a negative correlation between TAS, log (paraoxonase1) and paraoxonase1/HDL and anti-thyroid peroxidase and a negative correlation between anti-thyroglobulin and total thiol. It was also determined that overt hypothroidism was an individual predictor that effects all of the oxidative stress parameters, but not total thiol, levels., Conclusion: Our results suggest that oxidative stress increases continuously during the development of subclinical hypothyroidism and overt hypothyroidism in patients with HT. To determine whether this is a cause or result, randomized, controlled trials that study the effect of antioxidant treatment on the development of overt hypothyroidism and its consequences, e.g., increase in total cholesterol levels, may be performed in euthyroid and/or subclinical hypothyroid patients with HT., (© 2015 European Society of Endocrinology.)

Aim: To follow-up for 5 years thyroid status evolution in 127 girls with mild (TSH 5-10 mU/l) subclinical hypothyroidism (SH) of different etiologies., Patients: The population was divided into two age-matched groups of 42 and 85 girls with either idiopathic (group A) or Hashimoto's thyroiditis (HT)-related SH (group B). Group B was in turn divided into three subgroups, according to whether SH was either isolated or associated with Turner syndrome (TS) or Down syndrome (DS)., Results: At the end of follow-up the rate of girls who became euthyroid was higher in group A (61.9% vs 10.6%), whereas the rates of patients who remained SH (55.3% vs 26.2%), became overtly hypothyroid (30.6% vs 11.9%) or required levothyroxine (l-T4) therapy (63.5% vs 23.8%) were higher in group B. Among the girls of group B, the risk of remaining SH or developing overt hypothyroidism was higher in the subgroups with TS or DS than in those with isolated HT., Conclusions: Long-term prognosis of mild and idiopathic SH is frequently benign, even though a l-T4 treatment may be needed throughout follow-up in almost a quarter of cases; long-term prognosis is different in the girls with either idiopathic or HT-related SH; and the association with either TS or DS impairs the outcome of HT-related SH., (© 2015 European Society of Endocrinology.)

Objective: Aberrations in maternal thyroid function and autoimmunity during pregnancy have been associated with negative obstetric outcome. In Denmark, a national iodine fortification program was implemented in the year 2000 with the aim to alleviate the mild-moderate iodine deficiency. Following the iodine implementation, there has been an increase in thyroid autoimmunity in the background population. This study investigates the thyroid status of pregnant Danish women following the iodine fortification program, and a possible association with preterm delivery., Design: Historical cohort study of 1278 randomly selected pregnant Danish women attending the national Down's syndrome screening program., Methods: The main outcome measures were thyroid status according to laboratory- and gestational-age-specific reference intervals, and association with risk of abnormal obstetric outcome. Antibody-positivity was defined as an antibody-level (thyroid peroxidase and/or thyroglobulin antibodies) above 60 U/ml., Results: Establishing laboratory-specific gestational-age-dependent reference intervals, we found a prevalence of maternal thyroid dysfunction of 10%-15.8% by use of the cut-off suggested by the American Thyroid Association. Thyroid dysfunction was significantly associated with antibody-positivity (P<0.05). No associations were found between preterm delivery and thyroid dysfunction (adjusted OR 0.6, 95% CI: 0.1-2.3) or autoimmunity (adjusted OR 1.1, 95% CI: 0.4-2.7)., Conclusions: After the implementation of the Danish iodine fortification program, the prevalence of thyroid dysfunction and autoimmunity in Danish pregnant women is high - even higher by use of pre-established reference intervals from international consensus guidelines. However, no associations were found with abnormal obstetric outcome. Large randomized controlled trials are needed to clarify the benefit of treating slight aberrations in pregnant women's thyroid function., (© 2015 European Society of Endocrinology.)

Objective: Many patients treated for primary hypothyroidism have an unexplained reduced quality of life (QOL). We studied the relation between QOL and various parameters in treated hypothyroid patients., Design and Methods: QOL analysis was done in 90 consecutive patients (77.8% females) treated for primary hypothyroidism. QOL was measured by the questionnaires Short-Form 36, Hospital Anxiety and Depression Scale and MFI20. Post hoc analysis was performed on the relation of QOL at baseline and BMI, thyroid hormones and other serum values. QOL in patients was also compared to the general population., Results: QOL was decreased compared to the general population. We found an inverse relationship between QOL and BMI. A relationship between QOL and serum thyroid parameters or auto-antibodies could not be found. Higher sex hormone binding globulin (SHBG) levels corresponded with a better QOL, which is explained by the negative association of SHBG with body weight and BMI., Conclusions: A decreased QOL in hypothyroid patients on thyroxine treatment is related to a higher body weight (BMI). Weight gain needs more attention in the treatment of hypothyroidism., (© 2015 European Society of Endocrinology.)

Background: Thyroid cancer incidence has dramatically increased worldwide over the last two decades. The rise is mostly due to an increased detection of small papillary thyroid carcinomas (PTCs) (≤20  mm), predominantly microPTC (≤10  mm). Although small tumors generally have an excellent outcome, a considerable percentage may have a more aggressive disease and worse prognosis. The clinical challenge is to preoperatively identify those tumors that are more likely to recur., Aim: To improve risk stratification and patient management, we sought to determine the prognostic value of BRAF V600E, NRAS or RET/PTC mutations in patients with PTC measuring <20  mm, mainly microPTC., Methods: The prevalence of RET/PTC fusion genes was examined by quantitative RT-PCR. BRAF V600E and NRAS Q61 mutations were determined by PCR sequencing. To further elucidate why some small PTC are less responsive to radioactive iodine treatment therapy, we explored if these genetic alterations may modulate the expression of iodine metabolism genes (NIS, TPO, TG, TSHR and PDS) and correlated with clinico-pathological findings that are predictors of recurrence., Results: This study shows that tumors measuring ≤20  mm exhibited higher prevalence of BRAF V600E mutation, which correlated with aggressive histopathological parameters, higher risk of recurrence, and lower expression of NIS and TPO. Although this correlation was not found when microPTC were evaluated, we show that tumors measuring 7-10  mm, which were positive for BRAF mutation, presented more aggressive features and lower expression of NIS and TPO., Conclusion: We believe that our findings will help to decide the realistic usefulness of BRAF V600E mutation as a preoperative marker of poor prognosis in small PTC, primarily in microPTC., (© 2015 European Society of Endocrinology.)

Aim: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism. Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified. Objective: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations. Patients: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6 mU/l. Twenty-two of the patients had low serum free thyroxine (fT4) levels (0.17-1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine. Methods: We analyzed the DUOX2, thyroid peroxidase, Na+/I- symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing. Results: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal. Conclusion: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old). [ABSTRACT FROM AUTHOR]

Objective: To assess thyroid function, the presence of thyroid antibodies, as well as the presence of goiter and/or nodules in subjects without a prior diagnosis of thyroid disorders, in a region with mild to moderate iodine deficiency., Design and Methods: This cross-sectional study is based on data obtained from first and third visits of participants in the Sardinian survey. We performed two different analyses. In one, we assessed the prevalence of unknown thyroid dysfunctions among 6252 subjects who had a medical examination and blood collection for assays of thyrotropin, free thyroxine, and antibodies against thyroperoxidase (AbTPO) and against thyroglobulin (AbTG). In a second analysis, we evaluated the frequency of undiagnosed goiter and nodules among 3377 subjects who had a thyroid ultrasound scan. Subjects were excluded if they had a previous history of thyroid disorders or presence of goiter and/or nodules, or thyroid surgery, or if they were taking drugs that could impair thyroid function., Results: We found a low prevalence of overt thyroid dysfunction (hyperthyroidism 0.4% and hypothyroidism 0.7%). The rates of subclinical hypothyroidism and hyperthyroidism were 4.7 and 2.4% respectively. Almost 16% of participants were positive for at least one antibody and 5.2% for both AbTG and AbTPO. Nodules were detected in 17.4% of subjects and the prevalence of goiter was 22.1%., Conclusions: Undiagnosed biochemical thyroid dysfunctions, unknown nodules, and goiter were common in subjects living in a mild to moderate iodine-deficient area. In this community, thyroid disorders often go undetected and screening could be reasonable in subjects at a higher risk., (© 2014 European Society of Endocrinology.)

Objective: The diagnosis of autoimmune diabetes in non-obese adults is based on the detection of glutamic acid decarboxylase autoantibodies (GADA), islet cell antibodies (ICA) and antibodies to tyrosine phosphatase (IA-2A). Zinc transporter 8 (ZnT8) has been identified as a new autoantigen in patients with type 1 diabetes mellitus. The coincidence of autoimmune thyroiditis (AITD) with diabetes is common; therefore, screening of TSH and thyroid peroxidase antibodies (ATPO) is recommended during the diagnosis of diabetes. In this study, we determined whether the occurrence of islet autoantibodies is associated with a positive titre of ATPO in newly diagnosed adult-onset autoimmune diabetic patients., Design and Methods: THE STUDY INVOLVED 80 NON-OBESE ADULTS AGED 44 (INTERQUARTILE RANGE (IQR): 37-51) years with a BMI of 24.0 (IQR: 22.2-26.0) kg/m(2) and new-onset diabetes. The markers of autoimmune diabetes (GADA, ICA, IA-2A and ZnT8A), TSH and thyroid peroxidase antibodies (ATPO) were evaluated., Results: IN THE STUDY POPULATION, 70% (N=56) OF THE SUBJECTS WERE POSITIVE FOR AT LEAST ONE OF THE FOUR ASSESSED MARKERS OF AUTOIMMUNE DIABETES (83.9% GADA, 62.5% ICA, 42.8% IA-2A AND 33% ZNT8A) AND 37.5% OF THE SUBJECTS WERE POSITIVE FOR ATPO. THE ZNT8A-POSITIVE SUBJECTS HAD HIGHER ATPO TITRES THAN THE ZNT8A-NEGATIVE SUBJECTS (172.7 (IQR: 0.36-410.4) vs 92.4 (IQR: 0-23.7) IU/ml, P=0.001). Based on the assessed islet autoantibodies, the occurrence of positive ZnT8A and GADA was found to be related to a positive titre of ATPO using logistic regression (OR=5.48, 95% CI: 1.65-18.14, P=0.006 and OR=3.42, 95% CI: 1.09-10.71, P=0.03 respectively)., Conclusions: In non-obese adults with new-onset diabetes, the presence of GADA and especially ZnT8 autoantibodies increases the risk of AITD.

Objective: A new autosomal dominant disorder due to mutation of THRA, which encodes thyroid hormone receptor α, is characterised by severely delayed skeletal development but only slightly abnormal thyroid status. Adult mice with disrupted thyroid hormone action in bone due to a mutation of Thra or deletion of Dio2, encoding the type 2 deiodinase, have high bone mass and mineralisation despite essentially euthyroid status. No individuals with DIO2 mutations have been described and the adult phenotype of patients with THRA mutations is largely unknown. We hypothesised that screening euthyroid adults with high bone mineral density (BMD) could be used to identify individuals with mutations of THRA or DIO2., Design: The Osteoporosis and Ultrasound Study (OPUS) is a 6-year prospective study of fracture-related factors from five European centres., Methods: A cohort of 100 healthy euthyroid post-menopausal women with the highest BMD was selected from the OPUS population. We sequenced the intron-exon boundaries and critical exons of THRA and DIO2 in these subjects. TSH, free 3,5,3'-l-triiodothyronine, free thyroxine, vitamin D, parathyroid hormone and bone turnover marker concentrations, and BMD measurements were available in all OPUS participants., Results: No coding sequence or splice site mutations affecting THRA or DIO2 were identified., Conclusions: Mutations affecting THRA or DIO2 are not a common cause of high BMD in healthy euthyroid post-menopausal women.

Objective: Autoimmune thyroid disease (AITD) has been associated with adverse pregnancy outcomes in subfertile women with spontaneous and assisted reproductive technology-induced pregnancies. The underlying pathophysiology is still elusive and an association with thyroid dysfunction or other infertility causes is discussed. However, whether thyroid autoimmunity (TAI) per se has a negative impact on female fertility has not yet been clarified. In this study, we investigated whether TAI in healthy women undergoing intracytoplasmic sperm injection (ICSI) for male infertility may affect pregnancy outcome., Design: A retrospective, single-centre study., Methods: THE ICSI OUTCOME DATA OBTAINED FROM 835 EUTHYROID WOMEN (AGE: 31.4±4.3 years, BMI: 23.7±4.2 kg/m(2)) were correlated with pre-ICSI TAI status. The known causes of female subfertility were excluded. Outcome parameters included rates of pregnancy, birth, miscarriage and preterm delivery. Blood analysis was carried out retrospectively using blood samples drawn before ICSI. TAI was defined by elevation of anti-thyroperoxidase- or anti-thyroglobulin-antibodies >100 U/l., Results: TAI-POSITIVE AND -NEGATIVE GROUPS DID NOT DIFFER IN AGE, BMI OR TSH LEVELS. TAI STATUS DID NOT INFLUENCE ANY ICSI OUTCOME PARAMETERS. IN CONTRAST, INCREASING MATERNAL AGE WAS SIGNIFICANTLY CORRELATED WITH LOWER PREGNANCY RATE (ODDS RATIO (OR): 0.94 (95% CI: 0.91-0.97); P=0.0003) and birth rate (OR: 0.93 (95% CI: 0.09-0.97); P<0.0001)., Conclusions: Our study suggests that TAI per se does not influence ICSI outcome. A strict definition of AITD and TAI and consideration of TAI-associated and -independent confounders are important to further elucidate the interplay between TAI and reproduction.

Objective: To determine whether thyroid hormone (free thyroxine (fT₄)) rather than TSH is directly related to bone mineral density (BMD)., Design: Cross-sectional population cohort study of peri-menopausal women., Methods: Of a sample of 6846 peri-menopausal Dutch women who participated in an osteoporosis-screening programme, a cohort of 2584 was randomly selected for the assessment of thyroid function (TSH, fT₄ and thyroid peroxidase antibodies (TPO-Abs)). TPO-Ab-positive women, with a previous history of thyroid dysfunction, overt thyroid disease, subclinical hypothyroidism, osteoporosis or bilateral oophorectomy and those receiving thyroid hormone or hormone replacement therapy were excluded. Of 1477 eligible women, 1426 had TSH and fT₄ within the reference range and 51 had low or undetectable serum TSH. BMD was measured at the lumbar spine and low BMD was defined as <0.937 g/cm(2)., Results: The mean BMD in the 51 women with low or undetectable serum TSH was 0.984 g/cm(2) compared with 1.001 g/cm(2) in the remaining 1426 (t=0.94, P=0.35); 33% of women with low or undetectable serum TSH had low BMD compared with 34% in 1426 euthyroid women. High fT₄ but not low TSH in euthyroid women was related to low BMD by multiple logistic regression corrected for age, BMI and smoking (OR, 1.30; 95% CI, 1.02-1.69)., Conclusions: Higher fT₄ levels within the normal reference range but not low or undetectable serum TSH were independently related to decreased BMD at lumbar spine in peri-menopausal women.

Objective: We have previously reported that the absence of thyroid peroxidase antibodies (TPOAb) in Graves' disease (GD) was associated with an increased risk of Graves' ophthalmopathy (GO). This observation raised the possibility that TPOAb could act as a protective factor. However, the presence of thyroid peroxidase (TPO) in the orbit has not been previously reported. The aim of this study was to confirm or exclude the presence of orbital TPO., Methods and Design: Relative TPO mRNA expression from GO (n=6) and normal (n=5) orbital fat tissue was determined using real-time PCR technique. Orbital fat in the normal group from blepharoplasty represents extraconal (anterior) fat. mRNA expression in fibroblasts grown from these tissues before and after adipocyte differentiation was also documented. Finally, Western blotting was carried out to verify translation of TPO mRNA transcripts., Results and Discussion: TPO transcripts were detected in the orbital fat tissue obtained from normal and GO subjects using the real-time PCR technique. TPO expression was increased in GO compared to normal (N) tissues. However, TPO expression in cultured fibroblasts was similar in both groups and adipogenesis did not appear to alter TPO expression. Protein was detected by Western blot analysis using the TPO MAB 47 (mAb 47). The predicted 110-kDa band was detected in orbital fat as well as in orbital fibroblasts. Our results suggest the presence of TPO in GO and N orbital tissues. We hypothesise that immune responses directed against orbital TPO might play a role in modulating the clinical expression of GO.

Objective: We earlier reported marked qualitative differences between the effect of 3,5,3'-tri-iodothyroacetic acid (Triac) and tri-iodothyronine (T3) on cardiac hypertrophy at equivalent thyroid-stimulating hormone (TSH)-suppressive doses. We have now extended these studies to specific cardiac parameters. Due to its rapid metabolic clearance rate, Triac is not suitable for TSH suppression and therefore the slowly metabolized 3,5,3',5'-tetraiodothyroacetic acid (Tetrac), the precursor of Triac, was studied., Methods: Hypothyroid rats were infused over 13 days with 1.5-40.5 nmol Tetrac/day per 100 g body weight (BW) or with 0.5-13.5 nmol thyroxine ((4)T4)/day per 100 g BW., Results: The responses of serum TSH and of hepatic monodeiodinase type 1 were parallel for both hormones, their potency ratios could therefore be compared. Tetrac was revealed as being only half as active on hepatic monoiodinase type 1 despite a similar serum TSH levels. Tetrac can therefore be considered to have a preferential action on serum TSH suppression. The cardiac effects on Ca2+-ATPase (SERCA 2a) and monodeiodinase type 1 activity were qualitatively different and therefore one cannot give an overall quantitative estimate of these differences. The results showed clearly, however, that Tetrac is less efficient for all parameters studied, namely induction of cardiac hypertrophy, alpha-myosin heavy chain mRNA, monodeiodinase type 1 activity and mRNA levels of the sarcoplasmic SERCA 2a., Conclusion: We postulate therefore that, in the rat and possibly in man, Tetrac could represent a favorable alternative for suppression of serum TSH levels.

Objective: Variation in thyroid hormone (TH) concentrations between subjects is greater than in a single subject over a prolonged period of time, suggesting an individual set point for thyroid function. We have previously shown that TH levels within normal range are associated with clinical indices such as bone mass, BMI, and heart rate. The aim of this study on young men was therefore to gain insight into the determinants of variation in TH levels among healthy subjects., Methods: Healthy male siblings (n=941, 25-45 years) were recruited in a cross-sectional, population-based study; a history or treatment of thyroid disease and thyroid auto-immunity were exclusion criteria. A complete assessment of TH status was performed (TSH, free thyroxine (FT4), free triiodothyronine (FT3), thyroperoxidase, and thyroglobulin antibodies, reverse T3 (rT3), thyroid-binding globulin (TBG), and urinary iodine levels). Genotyping was performed by TaqMan and KASP (KBiosciences) genotyping assays., Results: (F)T4, rT3, and TBG had heritability estimates between 80 and 90%. Estimates were lower for (F)T3 (60%) and lowest for TSH (49%). Significant associations were observed between different single-nucleotide polymorphisms (SNPs) in the thyroid pathway and TSH, FT4, ratio FT3:FT4, and rT3. Nevertheless, these SNPs only explain a limited part of the heredity. As to age and lifestyle-related factors, (F)T3 was negatively related to age and education level, positively to smoking and BMI (all P<0.0001) but not substantially to urinary iodine concentrations. Smoking was also negatively related to TSH and positively to FT4., Conclusion: Both genetic and lifestyle-related factors play a role in determining between-subject variation in TH levels in euthyroid young men, although genetic factors seem most important.

Objective: Autoimmune diseases such as rheumatoid arthritis (RA) and hypothyroidism tend to cluster, and this coexistence amplifies the elevated cardiovascular risk in RA. Whether thyroid peroxidase antibodies (TPOabs) are associated with increased cardiovascular disease (CVD) risk has not been studied extensively. Therefore, this study determined firstly the prevalence of TPOabs in RA and secondly whether TPOabs were associated with CVD. Moreover, this study explored whether TPOabs were related to RA characteristics., Design and Methods: Data from the CARRÉ Study, an ongoing study investigating CVDs and its risk factors in RA (n=322), was used to ascertain the prevalence of TPOabs in RA patients. In addition, cardiovascular and RA disease characteristics were compared between TPOabs-positive and -negative patients at baseline and at a second visit after 3 years., Results: TPOabs were present in 47/322 (15%) RA patients and TSH levels were higher in TPOabs-positive patients (1.40 mU/l) compared with TPOabs-negative patients (1.26 mU/l, P=0.048). At baseline and after 3 years no association was observed between TPOabs and (risk factors for) CVD. Regression analyses revealed a significantly larger progression of carotid intima media thickness (cIMT; β=0.13 mm) in TPOabs-positive compared with TPOabs-negative patients independent of risk factors for cIMT progression. RA disease activity scores (DAS28) were higher in TPOabs-positive compared with TPOabs-negative patients (4.4 vs 3.8 P=0.018)., Conclusions: TPOabs were associated with increased cIMT progression. Moreover, an association between TPOabs and DAS28 was observed. Hence, TPOabs seems to have a role in the amplified cardiovascular risk in RA patients.

Objective: To investigate the prevalence of thyroid dysfunction (TD) and IgG subclasses of thyroid autoantibodies (TAs) and to determine the predictive factors of TD in chronic hepatitis C (CHC) patients., Design: Three hundred and twelve untreated hepatitis C virus-infected patients without a history of TD or treatment with thyroid hormones were enrolled in a cross-sectional study. Clinical and biological factors were statistically analyzed to determine the correlation between TD and this patient population., Results: The incidence of TD WAS 12.5% in CHC patients. Clinical hypothyroidism (5.8%) and subclinical hypothyroidism (3.8%) were more frequent than clinical hyperthyroidism (1.6%) and subclinical hyperthyroidism (1.3%). The percentage of TA-positive patients was significantly higher in people 60 years than in those 60 years (31.9 VS 18.6%; P=0.042). Positive thyroid peroxidase antibody (TPOAb) was more frequent, and alanine aminotransferase (ALT) levels were lower in patients who displayed TD (TPOAb: 62.1 vs 10.8%, P=0.000; ALT: 43.5 vs 51 IU/l, P=0.046). The positive percentage of TPOAb IgG2 subclass in the TD group was significantly higher than that of patients without TD (66.7 vs 16.7%, P=0.005). Multiple logistic regression analysis indicated that only TPOAb IgG2 subclass positivity was an independent risk factor for TD in CHC patients (odds ratio=8; 95% CI: 1.225-52.246; P=0.030)., Conclusions: TPOAb IgG2 subclass positivity is a risk factor for TD in CHC patients before antiviral treatment. IgG2 subclass of TPOAb might play an important role in the presence of TD in CHC patients.

Objective: To investigate regional variations in the frequency of undiagnosed thyroid disorders among 25- to 88-year-old men and women in two communities in the northeast and the south of Germany. In addition, autoantibodies to thyroperoxidase (TPO-Abs) and urinary iodine excretion were determined., Methods: Two population-based surveys of men and women using a common standardized protocol, the Study of Health in Pomerania (SHIP) in the northeast of Germany (2505 participants) and the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) in the south of Germany (2316 participants), were compared with regard to the frequency of undiagnosed thyroid disorders., Results: Compared with the northeast of Germany, urinary iodine excretion and serum thyroid-stimulating hormone (TSH) levels were significantly higher in the south. The median urinary iodine concentration was 110 μg/l (64; 169 μg/l) in SHIP and 151 μg/l (97; 214 μg/l) in KORA, and the median TSH value was 0.81 mIU/l (0.56; 1.15 mIU/l) in SHIP and 1.22 mIU/l (0.84; 1.80 mIU/l) in KORA. The frequency of elevated TSH (TSH ≥ 2.12 mIU/l) was 4.3% in SHIP and 14.1% in KORA (P<0.001); the corresponding values for suppressed TSH (<0.25 mIU/l) were 3.5 and 1.7% (P<0.001). The proportion of ultrasonographic findings was 55.5% in SHIP and 68.0% in KORA. The frequency of serum TPO-Abs did not differ significantly between northeast and south Germany., Conclusions: There were considerable regional disparities in the frequency of thyroid disorders within Germany. These differences can be explained not only by different regional histories of natural iodine deficiency but also by current differences in the iodine supply under an identical nationwide iodine fortification program.

Objective: Thyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus., Design: Fifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied., Methods: Sections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3., Results: We found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age., Conclusions: This study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells.

Context: Vitamin D deficiency has been identified as a risk factor for a number of autoimmune diseases including type 1 diabetes and multiple sclerosis., Objective: We hypothesized that low levels of vitamin D are related to the early stages of autoimmune thyroid disease (AITD)., Design: Two case-control studies were performed. In the cross-sectional study A, euthyroid subjects with genetic susceptibility for AITD but without thyroid antibodies were compared with controls. Cases were subjects from the Amsterdam AITD cohort (euthyroid women who had first- or second-degree relatives with overt AITD) who at baseline had normal TSH and no thyroid antibodies; controls were healthy women examined at the same period. In the longitudinal study B, subjects who developed de novo thyroid peroxidase antibody (TPO-Ab) were compared with those who did not. Cases and controls were subjects from the Amsterdam AITD cohort who at baseline had normal TSH and no thyroid antibodies and during follow-up developed TPO-Ab (cases) or remained without thyroid antibodies (controls). Controls in both studies were matched for age, BMI, smoking status, estrogen use, month of blood sampling, and in study B for the duration of follow-up., Results: Serum 25(OH)D levels were as follows: study A: 21.0 ± 7.9 vs 18.0 ± 6.4 ng/ml (78 cases vs 78 controls, P=0.01); study B: baseline, 22.6 ± 10.3 vs 23.4 ± 9.1; follow-up 21.6 ± 9.2 vs 21.2 ± 9.3 ng/ml (67 cases vs 67 controls, NS)., Conclusions: Early stages of thyroid autoimmunity (in study A genetic susceptibility and in study B development of TPO-Ab) are not associated with low vitamin D levels.

Context: Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T(3)) and low/normal thyroxine (T(4)). MCT8 contributes to hormone release from the thyroid gland., Objective: To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice., Design: Thyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8(-/y) model., Results: We show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6- to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (l-T(4)), the preoperative, inadequately low T(4) and free T(4) remained, while increasing the l-T(4) dosage led to T(3) serum concentrations above the normal range., Conclusions: Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities.

Objective: With the introduction of iodized salt worldwide, more and more people are exposed to more than adequate iodine intake levels with median urinary iodine excretion (MUI 200-300 μg/l) or excessive iodine intake levels (MUI >300 μg/l). The objective of this study was to explore the associations between more than adequate iodine intake levels and the development of thyroid diseases (e.g. thyroid dysfunction, thyroid autoimmunity, and thyroid structure) in two Chinese populations., Design: A population-based cross-sectional study was conducted in two areas in which people are exposed to different levels of iodine intake (Rongxing, MUI 261 μg/l; Chengshan, MUI 145 μg/l). A total of 3813 individuals were recruited by random sampling. Thyroid hormones, thyroid autoantibodies in serum, and iodine levels in urine were measured. B-mode ultrasonography of the thyroid was also performed for each participant., Results: The prevalence of subclinical hypothyroidism was significantly higher for subjects who live in Rongxing than those who live in Chengshan (5.03 vs 1.99%, P<0.001). The prevalence of positive anti-thyroid peroxidase antibody (TPOAb) and positive anti-thyroglobulin antibody (TgAb) was significantly higher for subjects in Rongxing than those in Chengshan (TPOAb: 10.64 vs 8.4%, P=0.02; TgAb: 10.27 vs 7.93%, P=0.01). The increase in thyroid antibodies was most pronounced in the high concentrations of TPOAb (TPOAb: ≥500 IU/ml) and low concentrations of TgAb (TgAb: 40-99 IU/ml) in Rongxing., Conclusions: More than adequate iodine intake could be a public health concern in terms of thyroid function and thyroid autoimmunity in the Chinese populations.

Objective: The type 2 deiodinase (D2) is a key enzyme for intracellular triiodothyronine (T(3)) generation. A single-nucleotide polymorphism in D2 (Thr92Ala) has been associated with increased insulin resistance in nondiabetic and type 2 diabetes (DM2) subjects. Our aim was to evaluate whether the D2 Thr92Ala polymorphism is associated with increased risk for DM2., Design and Methods: A case-control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms 'rs225014' odds ratio (OR) 'thr92ala' OR 'T92A' OR 'dio2 a/g'., Results: In the case-control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (n=173) versus 12.0% (n=62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03-1.94, P=0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78-2.51)), Grarup (OR 1.09 (95% CI 0.92-1.29)), and Maia (OR 1.22 (95% CI 0.78-1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03-1.36, P=0.02)., Conclusions: Our results indicate that in a case-control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a meta-analysis including 11 033 individuals, and support a role for intracellular T(3) concentration in skeletal muscle on DM2 pathogenesis.

Objectives: Thyroid autoimmunity decreases in the very old. We investigated whether glucocorticoid (GC) activity, which increases in old age, is involved in this process., Subjects and Methods: A total of 321 ambulatory subjects (age 51-95 years, median 71, 207 female) were studied. Thyroid function tests, cortisol, glucose, insulin and biochemical parameters were measured. A modified overnight dexamethasone suppression test (0.25 mg) was performed as an index of GC sensitivity., Results: Forty subjects had positive anti-thyroid peroxidase antibodies and 36 had positive anti-thyroglobulin antibodies, while 57 had either one or the other or both thyroid autoantibodies (ThAbs) positive. Mean basal cortisol levels were significantly lower in the ThAbs (+) groups (320+/-125 vs 378+/-128 nmol/l, P=0.002). Triiodothyronine, free thyroxine, post-dexamethasone cortisol levels, C-reactive protein, homeostasis model assessment-insulin-resistance-index and body mass index did not differ between these two groups. Mean age of ThAbs (+) subjects was lower compared to the ThAbs (-) group (67.38+/-7.38 vs 71.64+/-8.57 years, P=0.001)., Conclusions: Reduced GC activity is associated with an increased prevalence of ThAbs positivity in older ambulatory subjects. Subjects without ThAbs in this population sample are relatively older. It is not known whether this is related to increasing GC activity with age.

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T(4)) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T(4)/tri-iodothyronine (T(3)) combination therapy over T(4) monotherapy. However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T(4) (FT(4)) to free T(3) (FT(3)) concentrations. Development of a sustained-release T(3) preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT(4)-FT(3) ratio's throughout 24 h. Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T(4)/T(3) combination therapy than on T(4) monotherapy.

Background: Insufficient function of the thyroid gland can cause low concentrations of thyroid gland hormones which are necessary for the proper development of the foetus brain, especially during the beginning of pregnancy. We determined the reference interval for TSH in the first trimester of pregnancy and the decision point for anti-TPO antibodies' positivity., Methods: We tested 5520 women from the central part of the Czech Republic during the first trimester of pregnancy for serum TSH, anti-TPO and FT4 by chemiluminometric immunoanalysis on an ADVIA Centaur system (Siemens). The reference interval for TSH during the first trimester of pregnancy was determined using the log transformation, and then summarized as the geometrical mean (95% CI); following which, a suitable decision point for anti-TPO positivity was set., Results: The reference interval for TSH was determined to be 0.06-3.67 mU/l. The suppression of TSH was found in 2.93% of the women; a raised concentration of TSH had been found in 4.48% of the women. For anti-TPO, the cut-off was established at 143 kU/l; 11.2% of the pregnant women were found to be anti-TPO positive., Conclusion: Determination of the reference interval for TSH during early pregnancy is one of the basic requirements when implementing a general examination of the thyroid gland at the beginning of pregnancy. The decision level for positivity of anti-TPO is more than double the manufacturer's reference interval.