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Thyroid autoimmunity (TAI) has been linked to fertility disorders and pregnancy complications, even in euthyroid women. However, the exact pathophysiological mechanism underlying this association is not fully understood. This study seeks to investigate the expression of thyroid antigens within the human female reproductive system, potentially identifying targets for thyroid antibodies. Human biopsies of endometrium and follicular granulosa cells were collected and thyroperoxidase (TPO) and thyroglobulin (TG) expression was evaluated in these tissues by immunohistochemistry. Results showed, for the first time, the expression of TG protein and confirmed the presence of thyroid TPO in human endometrium and granulosa cells. Results suggest that TPO antibodies (TPOAbs) and TG antibodies (TGAbs) could interact with TPO and TG expressed in the reproductive system in patients with positive thyroid antibodies, thereby disrupting the function of TPO and TG and generating an inflammatory response, leading to fertility disorders and pregnancy complications., Competing Interests: The Authors declared no conflict of interest, (African Journal of Reproductive Health © 2024.)

Antibodies to thyroid peroxidase (AB-TPO), antibodies to thyroglobulin (AB-TG), and the content of α2-macroglobulin (α2-MG) have been studied in serum samples of patients with autoimmune thyroiditis (AIT). All the patients were divided into 3 groups depending on age: 25-35, 36-50, 51-65 years. We found a significant change in the thyroid panel parameters in AIT, but without significant changes in the average concentration of α2-MG in the age groups of patients. This may be due to the accumulation and retention of complexes of defective forms of α2-MG in the circulation associated with their decreased ability to bind to receptors.

Objective: Identify molecular mimicry between TPO, eosinophil peroxidase (EPX), thyroglobulin and IL24 and microorganism antigens., Methods: Through in silico analysis, we performed local alignments between human and microorganism antigens with PSI-BLAST. Proteins that did not present a 3D structure were modeled by homology through the Swiss Modeller server and epitope prediction was performed through Ellipro. Epitopes were located in the 3D models using PYMOL software., Results: A total of 38 microorganism antigens (parasites, bacteria) had identities between 30% and 45%, being the highest with Anisakis simplex. The alignment between 2 candidate proteins from A. simplex and EPX presented significant values, with identities of 43 and 44%. In bacteria, Campylobacter jejuni presented the highest identity with thyroglobulin (35%). 220 linear and conformational epitopes of microorganism antigens were predicted. Peroxidasin-like proteins from Toxocara canis and Trichinella pseudospiralis presented 10 epitopes similar to TPO and EPX, as possible molecules triggering cross-reactivity. No virus presented identity with the human proteins studied., Conclusion: TPO and EPX antigens shared potential cross-reactive epitopes with bacterial and nematode proteins, suggesting that molecular mimicry could be a mechanism that explains the relationship between infections and urticaria/hypothyroidism. In vitro work is needed to demonstrate the results obtained in the in silico analysis.

Miscarriage frequently occurs in euthyroid women with thyroid autoimmunity (TAI), but its mechanisms remain unclear. Our previous study has found that the serum level of anti-protein disulfide isomerase A3 autoantibody (PDIA3Ab) was significantly increased in mice with TAI. This study was aimed to explore whether there could be an association between the expression of PDIA3Ab and the occurrence of miscarriage in euthyroid TAI women. It was found that the serum level of PDIA3Ab was significantly increased in euthyroid TAI women as compared with that of non-TAI controls. Especially, serum PDIA3Ab level was markedly higher in euthyroid TAI women with miscarriage than the ones without miscarriage. Furthermore, binary logistic regression analysis showed that the serum PDIA3Ab level was an independent risk factor for spontaneous abortion in euthyroid TAI women with an odds ratio of 13.457 (95% CI, 2.965-61.078). The receiver operating characteristic (ROC) analysis of serum PDIA3Ab expression for predicting the miscarriage in euthyroid TAI women showed that the area under the curve was 0.707 ± 0.05 (P < 0.001). The optimal cut-off OD450 value of serum PDIA3Ab was 0.7129 with a sensitivity of 52.5% and specificity of 86.3% in euthyroid TAI women. Trend test showed that the prevalence of spontaneous abortion was markedly increased with the rise of serum PDIA3Ab level among TAI women in a titer-dependent manner. In conclusion, serum PDIA3Ab expression may imply an increased risk of spontaneous abortion in euthyroid TAI women, and it can be used as a new predictive bio-marker., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro . We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo . These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket., Competing Interests: YT declares that he was previously (1/2015 – 6/2017) the principal investigator on a basic research project jointly funded by the Juvenile Diabetes Research Foundation and Pfizer. The current manuscript is not related to that research project. YT and CL declare that they submitted a patent application for Cepharanthine as a treatment for APS3v and T1D. YT, RO, and LF have additional patent applications that are not related to the content of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Osman, Menconi, Faustino, Kim, Clarke, Hou and Tomer.)

Objective: Resolvins are produced by the catabolism of polyunsaturated fatty acids (PUFAs) and play vital roles in inflammation resolution. Resolvins have been associated with autoimmune disorders. This study aimed to measure the level of Resolvin D1 (RVD1) in the serum of Hashimoto's thyroiditis (HT) patients and healthy controls (HCs) and to further analyse its correlation with thyroid autoantibodies and inflammatory factors., Methods: Sixty-three participants were recruited, namely, 30 untreated HT patients and 33 sex- and age-matched HCs. Serum RVD1 and inflammatory chemokine (MCP-1 and IP-10) levels were measured by ELISA according to the manufacturer's protocol. Serum total T3 (TT3), TT4, free T3 (FT3), FT4, thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb) and thyroid-stimulating hormone (TSH) levels were measured using an electrochemiluminescence immunoassay. Thyroid homeostasis parameters, including the thyroid secretory capacity (SPINA-GT), the total deiodinase activity (SPINA-GD), Jostel's TSH index (TSHI) and the thyrotroph thyroid hormone sensitivity index (TTSI), were calculated., Results: Serum RVD1 levels in HT patients (134.76, 85.35-201.36 pg/mL) were significantly lower than those in HCs (187.64, 131.01-326.85 pg/mL) (P=0.004). As the TPOAb level increased, the RVD1 level showed a decreasing trend (P for trend=0.002). Both multinomial and ordinal logistics analyses revealed that serum RVD1 levels were negatively correlated with TPOAb levels in the adjusted models. Moreover, RVD1 showed a negative correlation with the inflammatory chemokine IP-1 0 (r=-0.276, P=0.034), TSHI (r=-0.269, P=0.036) and TTSI (r=-0.277, P=0.031)., Conclusions: Thyroid autoimmunity may be associated with low levels of RVD1. Decreased RVD1 levels indicate impaired resolution of inflammation in HT patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objective: Obesity is known to affect thyroid function. Recently, waist-height ratio (WHtR) has been considered as a useful marker of subclinical hypothyroidism in obese cases, but its relation with thyroid autoimmunity still remains unclear. We evaluated the effect of body fat mass, WHtR, and metabolic parameters on thyroid autoantibody levels in children with obesity., Methods: This was a cross-sectional study carried out with an obese [n=56, male/female (M/F): 29/26] and a healthy group (n=38, M/F: 19/19). All subjects underwent anthropometric measurements, laboratory investigations for thyroid function tests, thyroid peroxidase (TPO-ab) and thyroglobulin-antibodies (Tg-ab), transaminases, blood glucose, insulin levels, and lipids after overnight fasting; homeostatic model assessment for insulin resistance (HOMA-IR) was calculated for assessment of insulin resistance. Fat mass was estimated by multiple frequency bioimpedance analysis in the obese group, which was further divided into two subgroups according to the median of WHtR. All parameters were compared between the groups/subgroups., Results: In the obese group, weight, height, body mass index (BMI), free triiodothyronine, thyrotropin, TPO-ab, insulin, low density lipoprotein-cholesterol, total cholesterol, alanine aminotransferase levels, and HOMA-IR were significantly higher than the controls group (p<0.05 for all). Median of WHtR was 0.6 in the obese group. In the “WHtR >0.6” subgroup (n=28), weight, BMI, fat mass, TPO-ab, Tg-ab, insulin and triglyceride levels were higher than WHtR ≤0.6 subgroup (p<0.05). A positive correlation was obtained between Tg-ab and WHtR (rho=0.28, p=0.041)., Conclusion: Euthyroid children with obesity and a WHtR >0.6 are likely to have higher thyroid antibody levels, and Tg-ab levels have a positive correlation with WHtR, which reveals an association of central adiposity with thyroid autoantibody levels in these cases.

Background: Thyroid autoimmunity(TAI) is the most prevalent autoimmune condition in women of fertile age. There are increasing data regarding the association of thyroid dysfunction and thyroid autoimmunity with adverse pregnancy outcomes but there is no consensus regarding infertility and TPOAb positivity; thus we aimed to evaluate the association between thyroid TPOAb positivity and infertility in females and males in a population-based study (TTS)., Methods: Cross-sectional study of 3197 female and male participants in Tehran Thyroid Study (TTS) at the framework of the Tehran Lipid and Glucose Study (TLGS). Data included biochemical measurements and a self-administered questionnaire., Results: A total of 12,823 cases in phase 4, 3719 cases (2108 female and 1611 male) were analyzed. The mean TSH of the infertile female and male was 2.52 ± 2.68 μIU/ml and 3.24 ± 10.26 μIU/ml respectively. The TPO median(IQR) of women with and without a history of infertility were 6.05 (3.30-13.96)and 6.04 (3.17-11.15);(P = 0.613), they were 5.08 (3.20-125.68) and 5.31 (3.93-125.68);(P = 0.490) in male participants, respectively. Results of crude and adjusted logistic regression analysis of the development of infertility by thyroid function and TPOAb, except for fT4 in male subjects, depicted no association between infertility and other variables in both crude and adjusted models., Conclusion: Based on the result, thyroid autoimmunity was not associated with infertility in both females and males.

Background: Pemphigus is a rare but life-threatening autoimmune skin disease characterized by blistering on skin and/or mucous membranes. The physiological process of blister formation involves IgG antibodies against the desmogleins (Dsgs) and desmocollins (Dscs). Additional autoAbs have also been suggested to mediate the disease heterogeneity, such as anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies, the essential culprits of the immune system in autoimmune thyroid diseases., Purpose: To investigate the levels and antibody positivity of anti-TPO and anti-Tg antibodies in pemphigus patients., Methods: Antibody positivity and levels of anti-TPO and anti-Tg antibodies in pemphigus patients as compared to healthy controls were examined. A meta-analysis was conducted by reviewing six similar studies., Results: 98 Chinese pemphigus patients and 65 healthy controls were enrolled in the study. Our meta-analysis revealed a significant correlation between increased presence of positive anti-TPO and anti-Tg antibodies and pemphigus, particularly for pemphigus vulgaris (PV). Such correlation was also observed in our own hospitalized PV patients, but not in pemphigus foliaceus (PF) patients. In addition, the status of anti-TPO and anti-Tg antibodies were also compared between females and males within PV patients, PF patients or controls, as well as compared for females or males between pemphigus patients and controls. In the analysis of T cell counts, we found abnormal low CD3 + T cell counts (< 690 n/µl) were only detected in patients whose thyroid antibody levels were less than 20 IU/ml., Conclusion: Pemphigus patients showed higher levels and antibody positivity of anti-TPO and anti-Tg antibodies than healthy controls. Further investigations are needed to identify the pathogenic functions of these antibodies in pemphigus, as well as to identify the potential shared susceptibility genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Yang, Hu, Zhang, Cai, Guo, Xiao, Chen, Gao and Qiao.)

Hashimoto's disease is listed among the most common endocrine causes of obesity. As treatment of obesity in women with Hashimoto's disease is frequently unsuccessful, the aim of this study was to evaluate the effectiveness of two different reducing diets and their influence on changes in thyroid parameters in female patients. A six-month observational/interventional study was performed on 100 women aged 18-65 years, previously diagnosed with Hashimoto's disease and obesity and receiving L-thyroxine. The women were randomly assigned to the test group (group A, n = 50) following elimination/reducing diets, and the control group (group B, n = 50) following reducing diets with the same caloric content (without elimination). Anthropometric and thyroid parameters were evaluated at the beginning, after 3 months and after 6 months of treatment. In both groups a significant decrease in BMI and body fat percentage was achieved, but in test group A the decrease in BMI and body fat percentage was significantly greater than in control group B ( p < 0.002 and p = 0.026, respectively). Serum TSH (thyroid stimulating hormon) levels decreased significantly more in group A than in group B ( p < 0.001). Group A exhibited significantly greater increases in fT4 and fT3 levels than the control group ( p < 0.001) as well as significantly greater decreases in the levels anti-TPO (thyroid peroxidase) ( p < 0.001) and anti-TG (thyreoglobulin) antibodies ( p = 0.048). The application of reducing diets with product elimination was found to be a more beneficial tool for changing anthropometric and thyroid parameters in women suffering from obesity and Hashimoto's disease than classic reducing diets with the same energy values and macronutrient content.

Autoimmune thyroid disease is the most common endocrine disorder during pregnancy. Thyroid autoantibodies (TAs) have been suggested to serve a role in implantation failure and spontaneous abortion. Until now, there are no data on the potential interaction of TAs with human reproductive organs. Here, we set out for the first time to test this hypothesis by studying the expression of thyroid peroxidase (TPO) at gene and protein level in human reproductive organs. Endometrial samples were taken from normal women, and placenta tissues were collected after full-term caesarian section. Expression of TPO messenger RNA (mRNA) was investigated by qRT-PCR. In addition, polyclonal anti-TPO antibodies were produced and the expression of TPO protein in mentioned tissues was evaluated by immunohistochemistry and Western blot analysis. The reactivity of anti-TPO antibody in human embryos was evaluated by immunofluorescent staining. For the first time, our study showed that TPO is expressed at gene and protein levels in endometrium and placenta. TPO expression was mainly localized to glandular and luminal epithelial cells in the endometrium. In placenta, the syncytiotrophoblasts and invasive trophoblast cells were the main cell types that expressed TPO protein. Specific band of approximately 110 kDa was observed in all endometrial and placental tissues by Western blot analysis. However, no expression of TPO protein was observed in human embryo. TPO expression in endometrium and placenta may explain higher frequency of abortion and infertility in patients with thyroid autoimmunity.

Problem: Antibody-mediated autoimmune diseases, such as autoimmune thyroid diseases (ATD), systemic lupus erythematosus (SLE), and antiphospholipid syndrome (APS), often are associated with recurrent fetal loss. One of the ATD is Hashimoto's thyroiditis which recently showed association with complications of pregnancy with increased levels of circulating autoantibodies reactive with epitopes on thyroid tissue such as thyroid peroxidase (anti-TPO). In retrospective study of sera analyses in patients with Hashimoto's thyroiditis, all patients had mainly elevated circulating anti-TPO autoantibodies., Aim: We assessed the potential of human anti-TPO highly positive IgG, derived from patients with Hashimoto's thyroiditis sera associated with complications of pregnancy, to cause directly complications of pregnancy in murine model., Method of Study: Naïve ICR female mice, infused intravenously with 100 μg of anti-TPO-positive IgG, showed increased fetal loss and embryo small for date (P < .001) in comparison with mice passively transferred with commercial IgG or PBS. Moreover, we observed embryos small for date in the mice passively transferred with anti-TPO-positive IgG, exemplified by reduced weight of embryos and placentae (P = .001). Histopathological examination revealed delay in fetal development in 50% cases of anti-TPO-positive IgG-treated mice. Importantly, pathological changes in the transition zone, state of glycogen cells, and significant structural changes in the labyrinth part of placenta were observed in all anti-TPO-positive IgG samples., Conclusion: The current study shows in the first time, a direct proof of concept, on the association of human TPO-positive IgG from Hashimoto's thyroiditis patients on fetal loss induction in murine model., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate whether levothyroxine is associated with improved live birth and other benefits in women with thyroid autoimmunity., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): Women positive for thyroid peroxidase antibody., Intervention(s): MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched without any language restrictions. Pooled effect sizes were calculated using random-effects models., Main Outcome Measure(s): The primary outcome was the incidence of live birth, miscarriage, preterm birth, clinical pregnancy, ectopic pregnancy, neonatal admission, and birth weight. The summary measures were reported as relative risk (RR) with 95% confidence interval., Result(s): Levothyroxine supplementation was not associated with an increased rate of live birth or a decreased risk of miscarriage. Results were similar in subgroup analyses of live birth by age, baseline thyrotropin, baseline thyroid peroxidase antibody, body mass index, and use of assisted conception. For live birth, the effect estimate lay within the futility boundary for RR of 20% and 15%, but at a 10% RR, the effect estimate lay between the futility boundary and the inferior boundary., Conclusion(s): High- to moderate-quality evidence demonstrated that the use of levothyroxine was not associated with improvements in clinical pregnancy outcomes among women positive for thyroid peroxidase antibody., Registration Number: PROSPERO CRD42019132976., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Problem: Our study aims to investigate whether the anti-thyroperoxidase antibody (TPO-Ab) and TSH level in euthyroid women have any association with reproductive outcomes after the ART cycle., Methods of Study: A total of 1107 patients who were enrolled in the study were divided into four groups based on serum TSH level and TPO-Ab status: group A, 0.3 ≤ TSH < 2.5 mIU/L and TPO-Ab - ; group B, 0.3 ≤ TSH < 2.5 mIU/L and TPO-Ab + ; group C, 2.5 ≤ TSH < 4.2 mIU/L, and TPO-Ab - ; and group D, 2.5 ≤ TSH < 4.2 mIU/L, TPO-Ab + . The differences in ART cycles and pregnancy outcomes were analyzed between study groups., Results: The fertilization rate in group D (73%) was significantly lower than that in groups A (83% P < .001), B (84% P = .001), and C (82% P = .002). The biochemical pregnancy rates of groups B (7%) and D (12%) were significantly higher than those of group A (2%) (P = .028 and P = .017, respectively). TPO-Ab was related to a higher biochemical pregnancy rate (P = .002, OR = 5.311, 95% CI 1.859-15.169) and TSH over 2.5 mIU/L was related to higher ICSI rate (P = .001, OR = 1.759, 95% CI 1.250-2.476) by logistic regression analysis. The receiver operating characteristic (ROC) also verified the results., Conclusion: The impacts of TSH ≥ 2.5 mIU/L on the intracytoplasmic sperm injection (ICSI) rate, TSH ≥ 2.5 mIU/L and TPO-Ab + on the fertilization rate, and TPO-Ab + on the biochemical pregnancy rate, rather than the effect on abortion, clinical pregnancy, and live birth, were emphasized., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Antithyroid antibodies, which include thyroid-stimulating hormone receptor antibodies (TRAbs), thyroid peroxidase antibodies (TPOAbs), and thyroid globulin antibodies (TgAbs), are widely known for their tight association with thyroid autoimmune diseases. The variation in all three kinds of antibodies also showed different trends during and after pregnancy (Weetman, 2010). This article reviewed the the physiological changes, while focusing on the variation of thyroid antibodies concentration in women during and after pregnancy, and adverse consequences related to their elevation. Since abnormal elevations of these antithyroid antibodies may lead to adverse outcomes in both mothers and fetuses, special attention must be paid to the titer of the antibodies during pregnancy. The molecular mechanisms of the variations in those antibodies have yet to be explained. The frequency and timing of thyroid antibody measurement, as well as different reference levels, also remain to be elucidated., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Chuyu Li et al.)

Purpose: Thyroid autoimmunity might be in relation to other autoimmune endocrine disease or non-endocrine disorders and there are innate and adaptive immune cells in breast cancer. Because autoimmune factors are common characteristics of both thyroid autoimmunity and breast cancer, these two types of diseases may occur concurrently in certain patients. The chief goal of this meta-analysis is to perform a combined analysis of the raw data from all included studies, and thereby obtain a reliable conclusion concerning whether TgAb or TPOAb positivity and breast cancer are indeed correlated., Methods: To determine whether a correlation exists between TgAb or TPOAb positivity and breast cancer, this study performed a review of the literature that began by searching for articles in Chinese or English from the Medline, Embase, Web of Science core, Wanfang, Weipu and SinoMed databases, published during the time span extending from January 1980 to December 2017. On the basis of these raw data, we calculated odds ratio (OR) values, 95% confidence interval (CI) values, and P values., Results: A total of 11 studies were included in this study. By combining the raw data from the retrieved studies, we were able to perform a meta-analysis. The results of this meta-analysis support the hypothesis that patients with breast cancer have a higher TgAb or TPOAb positive rate than the non-breast disease control group (TgAb: OR = 2.71, 95% CI = 1.81-4.05, P < 0.001; TPOAb: OR = 2.86, 95% CI = 2.17-3.77, P < 0.001, respectively). Testing for publication bias indicated that no significant publication bias was present in this meta-analysis, and sensitivity analysis indicated that the results of analysis were stable and reliable., Conclusions: The results of this meta-analysis suggest strongly that, the TgAb or TPOAb positive rate among patients with breast cancer should be higher than among the non-breast disease control group.

Aim: In the current cross-sectional study, we aimed to explore whether thyroid function or thyroid autoimmunity are associated with psychopathological symptoms and social functioning in patients with early psychosis. We hypothesized that psychopathological severity is greater in those patients with positive thyroid autoimmunity., Methods: We studied 70 outpatients with early psychosis (<3 years of illness) and 37 healthy subjects. Psychopathological symptoms (positive, negative, disorganized, excited and depressive) and social functioning were assessed. Thyroid autoimmunity (antibodies against thyroid peroxidase [TPO-Abs] and thyroglobulin [TG-Abs]) and thyroid function (thyroid-stimulating hormone [TSH] and free thyroxin [FT4]) were determined. Associations of thyroid variables and psychometric measures were assessed with Spearman's correlations. Logistic regression was performed to explore the association between psychopathological symptoms and positive anti-thyroidal antibodies while adjusting for covariates., Results: When compared to patients without thyroid antibodies, those with positive thyroid antibodies had more negative symptoms and poorer function (P < .05). Titres of TPO-Abs were significantly correlated with negative and depressive PANSS domains and poorer functioning. TG-Abs were also associated with poorer functioning but not with psychopathological symptoms. TSH and FT4 concentrations were not associated with clinical symptoms. In the logistic regression analysis adjusted for age, gender, antipsychotic treatment, lithium, TSH and FT4 concentrations, negative symptoms were associated with thyroid autoimmunity (OR = 1.2, P = .019)., Conclusions: Our study suggests that anti-thyroid antibodies are associated with a more severe phenotype with increased negative symptoms and poorer functioning in early psychotic patients. Since causality cannot be inferred with cross-sectional data, future longitudinal studies are needed to overcome this limitation., (© 2019 John Wiley & Sons Australia, Ltd.)

Purpose: The association between obesity and autoimmune diseases has been suggested by several previous studies. The objective of our study was to assess the association of abdominal obesity phenotypes with thyroid autoimmunity., Materials and Methods: This study was conducted within the framework of a population-based cohort study, Tehran Thyroid Study (TTS) on 4708 subjects without thyroid autoimmunity at baseline. Participants were categorized into four abdominal obesity phenotypes according to waist circumference (WC) and other metabolic syndrome components. Serum concentrations of thyroid peroxidase antibody (TPOAb), free T4 (FT4), thyrotropin (TSH), glucose, and lipid profiles were measured after 3, 6 and 9 years of follow-up. Cox proportional hazard models were used to evaluate associations of different phenotypes with the incidence of thyroid autoimmunity, adjusted for age, sex, FT4, and TSH., Results: Highest and lowest incidence rates of TPOAb positivity were observed among metabolically unhealthy, non-abdominally obese (MUNAO) [8.78 (7.31-10.55) per 1000 person-years of follow-up] and metabolically unhealthy abdominally obese (MUAO) [4.98 (3.88-6.41) per 1000 person-years of follow-up] phenotypes. Considering the metabolically healthy non-abdominal obese (MHNAO) individuals as reference, none of metabolically healthy abdominally obese (MHAO), MUNAO, and MUAO phenotypes were associated with increased risk of developing TPOAb positivity. Compared to individuals with high WC, the incidence rate (95%CI) of TPOAb positivity was higher among those with normal WC: 8.44 (7.13-10.0) vs 5.11 (4.01-6.51) per 1000 person-years, respectively. Higher WC was not associated with incident TPOAb positivity., Conclusion: There was no significant association between baseline abdominal obesity phenotype status and development of TPOAb positivity over 9 years of follow-up.

Background: The prevalence of allergic and autoimmune conditions has been steadily increasing in wealthy nations over the past century. One hypothesis put forward to explain this is the Old Friends Hypothesis, which posits that increased hygiene, urbanization, and lifestyle changes have reduced our exposure to parasites and microbes that we co-evolved with, resulting in immune dysregulation. However, research in traditionally living populations, who are exposed to greater parasite and pathogen loads such as those encountered during our evolution, is limited, in part due to a lack of minimally invasive, field-friendly biomarkers of autoimmune disorders. We therefore developed an ELISA to assess positivity for thyroid peroxidase autoantibody (TPO-Ab), an indicator of autoimmune thyroid disease, based on dried blood spot (DBS) samples., Results: We used the Accubind anti-thyroid peroxidase test system to screen our validation samples comprising matched fingerprick DBS, venous DBS, and plasma samples from 182 adults. After confirming that we had TPO-Ab-positive individuals in our validation sample (n = 12), we developed an indirect ELISA to measure TPO-Ab levels from one 3-mm DBS punch. The sensitivity and specificity of our assay for DBS samples ranged from 91.7-100% and 98.2-98.8%, respectively, using a cut-off value of ≥ 26 IU/mL. Intra-assay reliability for duplicate quality control DBS punches was 5.2%, while inter-assay reliability ranged from 11.5-24.4% for high, medium, and low DBS controls. Dilutional linearity ranged from 80 to 120%, and spike and recovery experiments indicated that the DBS matrix does not interfere with the detection of TPO-Ab. TPO-Ab levels remained stable in DBS samples stored at - 28 °C or - 80 °C, but decreased over time in DBS samples kept at 22 °C or at 37 °C., Conclusions: We developed an in-house, kit-independent indirect ELISA assay to determine individuals' TPO-Ab positivity based on dried blood spots, representing a cost-effective method with potential applications in a range of research settings.

Aim: To analyze the association of thyroid function and hormone levels with metabolic syndrome (MetS) and its components., Methods: This cross-sectional population-based study involved 2183 Croatian individuals with no history of thyroid disease, hypertension, diabetes, and hyperlipidemia. MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III criteria., Results: We found no association between thyroid function groups and the prevalence of MetS and its components. Clinically hypothyroid participants showed significantly higher triceps skinfold measurements than subclinically hypothyroid and euthyroid participants. Furthermore, clinically hypothyroid participants had higher abdominal skinfold thickness than subclinically hypothyroid participants. Otherwise, suprailiac and abdominal skinfold measurements were higher in the subclinically and clinically hyperthyroid group of participants compared with euthyroid and subclinically hypothyroid participants. A strong positive association of thyroid-stimulating hormone (TSH) and strong negative association of free triiodothyronine (fT3) and free thyroxine (fT4) levels with HOMA-IR and cholesterol levels were found. Furthermore, the fT4 level also showed a strong negative association with HDL and triceps skinfold thickness., Conclusions: This study supports the standing that TSH, fT3, and fT4 levels are important variables to determine the association of thyroid function with MetS.

Introduction: Autoantibodies (autoAbs) against desmoglein-1 (DSG1) and desmoglein-3 (DSG3) have conventionally been studied and well accepted in the pathogenesis of pemphigus vulgaris (PV) and foliaceus (PF). Recent studies have suggested that non-DSG autoAbs may contribute to the pathogenesis of pemphigus, including autoAbs directed at acetylcholine receptors (AChR) and thyroid peroxidase (TPO). The purpose of this study is to retrospectively analyze PV and PF patient sera to better understand the relationship between anti-AChR and -TPO Abs to disease activity and DSG reactivity between patients treated with prednisone and steroid sparing agents (SSA; n = 22) or prednisone and rituximab (n = 21)., Methods: Patients were evaluated at 2 time points, T1 and T2, for disease activity using the Pemphigus Disease Area Index (PDAI), and sera were tested for the presence of TPO, DSG1, DSG3, muscarinic (M3) and nicotinic (n) AChR IgG autoAbs, as well as antibodies against Varicella Zoster Virus (VZV) by ELISA., Results: Disease activity significantly decreased in patients from T1 to T2 (p < .0001). A significant difference was seen in IgG anti-DSG1 (p < .0001) and anti-DSG3 (p = .0049) levels when T1 was compared to T2 in both treatment groups. A significant increase was found between pemphigus patients and normal subjects with nAChR (p < .0001) at T1 but not with m3AChR, TPO or VZV Abs. No significant difference was seen between T1 and T2 values in patients with pemphigus for the non-desmoglein Abs TPO (p = .7559), M3AChR (p = .9003), nAChR (p = .5143) or VZV (p = .2454). These findings demonstrate that although an increase in IgG anti-nAChR autoAbs was found in PV and PF subjects, these Abs did not decrease with treatment. No other non-DSG Abs were increased or significantly changed over time in patients with pemphigus. This suggests that anti -AChR and -TPO Abs may not play a direct role in the pathogenesis of most patients with pemphigus, but does not rule out a role for non-DSG auto antibodies in distinct subsets of pemphigus patient., Competing Interests: The authors have declared that no competing interests exist.

Background: Human proteins such as interleukin-24 (IL24), thyroperoxidase (TPO) and thyroglobulin (Tg) are targets of IgE or IgG autoantibodies. Why these proteins are recognized by autoantibodies in some patients with chronic spontaneous urticaria (CSU) or hypothyroidism is unknown., Objective: Through in silico analysis, identify antigen patches of TPO, Tg and IL24 and compare the sequences of these human proteins with some prevalent allergens., Methods: The amino acids sequences of IL24, thyroperoxidase and thyroglobulin were compared between them and with 22 environmental allergens. Phylogenetic studies and multiple pairing were carried out to explore the degree of protein identity and cover. The proteins without 3D structure reported in the database, were modeled by homology with "Swiss Modeller" and compared through PYMOL. Residues conserved and accessible to the solvent (rASA> 0.25) were located in the 3D model to identify possible areas of cross-reactivity and antigen binding., Results: We build a 3D model of the TPO and thyroglobulin protein base on proteins closely related. Five epitopes for TPO, six for IL24 and six for thyroglobulin were predicted. The amino acid sequences of allergens from different sources (Dermatophagoides pteronyssinus, Blomia tropicalis, Betula verrucosa, Cynodon dactylon, Aspergillus fumigatus, Canis domesticus, Felis domesticus) were compared with human TPO, Tg and IL24. The cover and alignments between allergens and human proteins were low., Conclusion: We identify possible linear and conformational epitopes of TPO, Tg and IL24 that could be the target of IgE or IgG binding in patients with urticaria or hypothyroidism; These epitopes do not appear to be present among common environmental allergens, suggesting that autoreactivity to these human proteins are not by cross-reactivity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Purpose: The expressions of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) are very common in the sera of patients with autoimmune thyroid diseases (AITD). The relationship between thyroid autoantibodies and the occurrence of glucose and lipid metabolic disorders remains unclear. This study was performed to investigate the correlation between the presence of serum TPOAb/TgAb and those metabolic disorders in euthyroid general population. Methods: The data of this study were derived from the Thyroid Disease, Iodine status, and Diabetes National epidemiological (TIDE) survey from all 31 provinces of mainland China. A total of 17,964 euthyroid subjects including 5,802 males (4,000 with TPOAb - TgAb - and 1,802 with TPOAb + /TgAb + ) and 12,162 females (8,000 with TPOAb - TgAb - and 4,162 with TPOAb + /TgAb + ) were enrolled in this study. The blood glucose and lipid levels were compared between individuals with TPOAb - TgAb - and those with TPOAb + TgAb - , TPOAb - TgAb + , TPOAb + TgAb + . Results: Both fasting blood glucose (FBG) concentration and the proportion of individuals with impaired FBG (IFG) showed the decreased trends in TPOAb - TgAb + males as compared with TPOAb - TgAb - men. There were significantly lower FBG and higher HDL-C levels as well as tendencies toward decreased incidences of IGT and hypertriglyceridemia in TPOAb - TgAb + females when compared with TPOAb - TgAb - women. Binary logistic regression analysis further showed that serum TgAb single positivity in males was an independent protective factor for IFG with an OR of 0.691 (95% CI, 0.503-0.949). For females, serum TgAb single positivity was an independent protective factor for hypertriglyceridemia with an OR of 0.859 (95% CI, 0.748-0.987). Trend test showed that with the increase of serum TgAb level, there were significant decreases in the prevalence of IFG among the men with TSH ≤ 2.5 mIU/L and that of hypertriglyceridemia in the women, especially among non-obese females. Conclusion: Serum TgAb single positivity may imply a reduced risk of IFG in euthyroid men and that of hypertriglyceridemia in euthyroid women. The mechanisms for the independent protective roles of TgAb await further investigation., (Copyright © 2020 Zhang, Gao, Li, Teng, Xue, Yan, Yang, Yang, Yao, Ba, Chen, Du, He, Lai, Teng, Shi, Li, Chi, Liao, Liu, Liu, Qin, Qin, Quan, Shi, Sun, Tang, Tong, Wang, Zhang, Wang, Ye, Zhang, Zhang, Zhu, Zhu, Teng, Shan and Li.)

Importance: Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormone synthesis, the prevalence of thyroid dysfunction in alkaptonuria is unknown., Objective: To assess thyroid structure and function in patients with alkaptonuria., Design, Setting, and Participants: A single-center cohort study was conducted in a tertiary referral center including patients with alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation., Main Outcomes and Measures: Prevalence of thyroid dysfunction in adults with alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels., Results: Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 [57.6%]). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, -0.001 to 0.04; P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24; P < .001). Women were more likely to have primary hypothyroidism than men (odds ratio, 10.99; 95% CI, 3.13-38.66; P < .001). Patients with TPO antibodies had a higher likelihood of primary hypothyroidism than those without TPO antibodies (odds ratio, 7.36; 95% CI, 1.89-28.62; P = .004). There was no significant difference in the prevalence of thyroid nodules between patients in this study (29 of 49 [59.2%]) vs the general population (68%) (difference, 0.088; 95% CI, -0.44 to 0.73; P = .20) or of cancer (7% vs 5%; difference, 0.01; 95% CI, -0.01 to 0.17; P = .86)., Conclusions and Relevance: The high prevalence of primary hypothyroidism noted in patients with alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.

Context: The impact of mild TSH elevation (2.5-4.08 mIU/L) on pregnancy outcomes is unclear. The treatment strategy for mild TSH elevation is dependent on thyroid peroxidase antibody (TPOAb) status according to the guidelines., Objective: To assess the effects of mild thyroid dysfunction combined with TPOAb status in the first trimester on pregnancy outcomes and the impact of levothyroxine (L-T4) treatment on pregnancy outcomes., Design: The study retrospectively evaluated 3562 pregnant women. A total of 3296 untreated women were divided into 4 subgroups: group A: 4.08 < TSH <10 mIU/L, TPOAb+/-; group B: 2.5 < TSH ≤ 4.08 mIU/L, TPOAb+; group C: 2.5 < TSH ≤ 4.08 mIU/L, TPOAb-; and group D: 0.23 ≤ TSH ≤ 2.5 mIU/L, TPOAb+/-. The other 266 women with L-T4 treatment were divided into TSH 4.08 to 10 mIU/L and 2.5 to 4.08 mIU/L subgroups., Setting: The study was conducted at Peking University First Hospital in China., Patients: A total of 3562 pregnant women were evaluated., Main Outcome Measures: The incidence of pregnancy outcomes in the untreated subgroups (groups A-D) and treated subgroups were measured., Results: Miscarriage and maternal composite outcome risks were 3.53 (1.85-6.75) and 2.19 (1.26-3.81) times greater in group A; 1.58 (1.17-2.13) and 1.27 (1.04-1.54) times greater in group C than in group D. L-T4 improved the miscarriage risk in the TSH 4.08 to 10 and 2.5 to 4.08 mIU/L groups but doubled the risk of gestational diabetes mellitus in the TSH 2.5 to 4.08 mIU/L treated group compared with the untreated group., Conclusions: TSH 2.5 to 4.08 mIU/L combined with TPOAb- during early pregnancy was associated with miscarriages and maternal composite outcomes. The advantages and disadvantages of L-T4 administration in TSH 2.5 to 4.08 mIU/L pregnant women remain uncertain., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Thyroid autoimmunity has been associated with bipolar disorder (BD). However, results from previous studies on the seroprevalence of anti-thyroid peroxidase antibodies (TPO-abs) in BD are inconsistent., Objectives: The aim of the present study is to investigate whether the seroprevalence and titer levels of TPO-abs are related to BD., Method: TPO-abs were measured in plasma samples of 760 patients with bipolar disorder, 261 first-degree relatives and 363 controls by enzyme-linked immunosorbent assay (ELISA). To address methodological limitations of previous studies, we assessed clinical characteristics with several (self-reported) questionnaires to investigate whether TPO-abs positivity is related to particular clinical subgroups of BD patients. We performed an additional meta-analysis of seroprevalences of TPO-abs in BD patients including data from present and previous studies., Results: Seroprevalence or titer levels of TPO-abs did not significantly differ between patients with BD, their first-degree relatives, and controls. In BD patients, the prevalence of TPO-abs was unrelated to specific clinical factors, including lithium use. Our meta-analysis of twelve studies showed an overall odds ratio of 1.3 (CI 95 %: 0.7-2.3; p = 0.30), reaffirming the absence of an association of BD with TPO-abs., Conclusions: In the largest study of TPO-abs in BD to date, our findings indicate that TPO-abs are not associated with (the risk for) bipolar disorder., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Indeterminate fine-needle aspiration cytology (FNAC) imposes challenges in the management of thyroid nodules. This study aimed to examine whether preoperative anti-thyroid antibodies (Abs) and TSH are indicators of thyroid malignancy and aggressive behavior in patients with indeterminate FNAC., Methods: This was a retrospective study of thyroidectomy patients from 2008 to 2016. We analyzed Abs and TSH levels, FNAC, and histopathology. Serum antibody levels were categorized as 'Undetectable', 'In-range' if detectable but within normal range, and 'Elevated' if above upper limit of normal. 'Detectable' levels referred to 'In-range' and 'Elevated' combined., Results: There were 531 patients included. Of 402 patients with preoperative FNAC, 104 (25.9%) had indeterminate cytology (Bethesda III-V). Of these, 39 (37.5%) were malignant and 65 (62.5%) benign on histopathology. In the setting of indeterminate FNAC, an increased risk of malignancy was associated with 'Elevated' thyroglobulin antibodies (TgAb) (OR 7.25, 95% CI 1.13-77.15, P = 0.01) and 'Elevated' thyroid peroxidase antibodies (TPOAb) (OR 6.79, 95% CI 1.23-45.88, P = 0.008). Similarly, while still 'In-range', TSH ≥ 1 mIU/L was associated with an increased risk of malignancy (OR 3.23, 95% CI 1.14-9.33, P = 0.01). In all patients with malignancy, the mean tumor size was 8 mm larger in those with TSH ≥ 1 mIU/L (P = 0.03); furthermore, in PTC patients, 'Detectable' TgAb conferred a 4 × risk of lymph node metastasis (95% CI 1.03-13.77, P = 0.02)., Conclusion: In this cohort, in indeterminate FNAC patients, Abs and TSH were associated with an increased risk of malignancy. Additionally, TgAb and TSH were potential markers of aggressive biology. As such, they may be diagnostic and prognostic adjuncts.

Thyroid autoimmunity, being recognized by the presence of auto-antibodies against thyroid peroxidase (TPO) and thyroglobulin, has known to be associated with increased risk of recurrent spontaneous abortion (RSA), even in euthyroid subjects. There was no robust evidence regarding T cell deviations in anti-TPO positive RSA patients. The aim of this study was to investigate if the numbers of different CD4+T  subsets were different in women who experienced RSA and have an anti-TPO antibody from those without autoantibody and normal fertile women or not. In this study, peripheral blood samples were obtained from three groups of women (age: 20-35 years) including RSA anti-TPO positive (n=17), RSA anti-TPO negative (n=27), and fertile (n=29) groups. The frequency of T helper (Th) 1, Th2, Th17, and regulatory T cells (Tregs) and also, the proportions of Th1/Th2 and Th17/Treg were measured by flow cytometry and compared between groups in different menstrual phases. The findings indicated elevated levels of Th1 in anti-TPO+ RSA in comparison with those without anti-TPO (p-value: 0.004), exclusively in the luteal phase. Other T cell subsets were different only between RSA and control groups. Also, the Th1/Th2 and Th17/Treg ratios were increased in both RSA groups compared to fertile women. The only subset of CD4+ T cell different between RSA groups (i.e. with and without anti-TPO) was Th1 cells. Other CD4+ T cells' deviations including Th2, Th17, and Treg cells could be related to the presence of abortion, regardless of the underlying thyroid autoimmunity state.

Aims: Investigation thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes mellitus., Background: This article was written to evaluate the thyroid function and anti-thyroid peroxidase (anti- TPO) antibodies in pregnant women with gestational diabetes mellitus (GDM)., Methods: A total of 252 women with GDM and 252 healthy pregnant women were enrolled. Thyroid tests, including TSH, FreeT3, Free T4, and anti-TPO were performed for all women at 24-28 weeks of gestation. Data analysis was then carried out using SPSS ver. 22., Results: There was a significant difference between the experimental group (38.4%) and the control group (14.06%) in terms of the prevalence of subclinical hypothyroidism (p= 0.016). The frequency of anti-TPO was higher in the experimental group than the control group and positive anti-TPO was observed in 18.6% of women with GDM and 10.3% of healthy pregnant women (P= 0.008)., Conclusion: Thyroid disorders are observed in pregnant women with GDM more frequently than healthy individuals and it may be thus reasonable to perform thyroid tests routinely., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Dysfunction of the thyroid gland has profound effects on the cardiovascular system., Objective: We aimed to explore the relation of serum thyroid peroxidase antibody (TPO-Ab), as a marker of thyroid autoimmunity with incident hypertension among a euthyroid population., Methods: A total of 3681 participants (1647 men) entered the study. Multivariate Cox proportional hazard models were conducted to estimate the association between TPO-Ab and incident hypertension., Results: The mean age (standard deviation) of the participants was 37.5 (12.8) years. During a median follow-up of 12.2 years, 511 men and 519 women developed hypertension. The multivariable hazard ratios (HRs) and related 95% confidence intervals (CIs) of 1-unit increase in natural logarithm (ln) of TPO-Ab for incident hypertension were 1.09 (1.00-1.19), 1.03 (0.97-1.10), and 1.05 (1.00-1.11) for men, women, and total population, respectively. Moreover, considering the TPO-Ab status as a categorical variable (i.e. TPO-Ab positive or TPO-Ab negative), the multivariate-adjusted HRs (95% CIs) of TPO-Ab positivity for incident hypertension, were 1.33 (0.95-1.85), 1.12 (0.86-1.45) and 1.19 (0.97- 1.46) for men, women, and total population, respectively., Conclusion: Elevated serum TPO-Ab level can contribute to the development of hypertension among euthyroid men during a long follow-up; suggesting a role for thyroid autoimmunity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hashimoto's encephalopathy (HE) is a syndrome occurring in some patients with Hashimoto's thyroiditis or, less frequently, Graves' disease. Three known autoantigens are involved in HE: alpha-enolase, dimethylargininase-I (DDAHI) and aldehyde reductase-I (AKRIAI). We searched for amino acid sequence homologies between these proteins and the three classical thyroid autoantigens (thyroperoxidase (TPO), thyroglobulin (Tg), TSH-receptor (TSH-R)), which are also expressed in the central nervous system (CNS). TSH-R shows homologies with alpha-enolase (n=4), DDAHI (n=2) and AKRIAI (n=5); of these segments, two, two and four, respectively, overlap totally or partially with epitope-containing TSH-R segments. Tg has 10 homologies with alpha-enolase, five with DDAHI, and eight with AKRIAI; epitope-containing segments of Tg overlap four, three and four segments, respectively. TPO has six segments homologous to alpha-enolase, three to DDAHI and seven to AKRIAI; of these segments, five, one and four, respectively, are located in epitope-containing parts. These data suggest that cross-reactivity between CNS autoantigens and thyroid autoantigens might contribute to the HE pathogenesis, together with other proposed mechanisms, including autoimmunity involving autoantigens common to CNS and thyroid.

Objective: The purpose of this prospective study was to assess the effects of selenium supplementation on TSH and interferon-γ inducible chemokines (CXCL9, CXCL10 and CXCL11) levels in patients with subclinical hypothyroidism due to Hashimoto's thyroiditis., Patients and Methods: Patients with subclinical hypothyroidism due to Hashimoto thyroiditis were prospectively enrolled in the SETI study. They received 83mcg of selenomethionine/day orally in a soft gel capsule for 4 months with water after a meal. No further treatment was given. All patients were measured thyroid hormone, TPOAb, CXCL9, CXCL10, CXCL11, iodine, and selenium levels at baseline and at study end., Results: 50 patients (43/7 female/male, median age 43.9±11.8 years) were enrolled, of which five withdrew from the study. At the end of the study, euthyroidism was restored in 22/45 (48.9%) participants (responders), while 23 patients remained hypothyroid (non-responders). There were no significant changes in TPOAb, CXCL9, CXCL10, CXCL11, and iodine levels from baseline to the end of the study in both responders and non-responders. TSH levels were re-tested six months after selenomethionine withdrawal: 83.3% of responding patients remained euthyroid, while only 14.2% of non-responders became euthyroid., Conclusions: The SETI study shows that short-course supplementation with selenomethionine is associated to a normalization of serum TSH levels which is maintained 6 months after selenium withdrawal in 50% of patients with subclinical hypothyroidism due to chronic autoimmune thyroiditis. This TSH-lowering effect of selenium supplementation is unlikely to be related to changes in humoral markers of autoimmunity and/or circulating CXCL9., (Copyright © 2019 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) is a heterogeneous disease with some frequent comorbidities like autoimmune diseases, drug reactions, and inducible urticaria. IgE antibodies against thyroid peroxidase (anti-TPO IgE) could be associated with some of these clinical characteristics., Objective: To explore the clinical characteristics of CSU patients, according to the presence of anti-TPO IgE in serum., Methods: Anti-TPO IgE levels were measured during the clinical control period (Urticaria Activity Score, 0 point) and exacerbation period (≥3 points) in 100 CSU patients. Patients with self-reported exacerbation of skin involvement by foods, nonsteroidal anti-inflammatory drugs (NSAIDs), and physical triggers underwent controlled challenge tests., Results: We identified 2 groups of patients: (1) patients with anti-TPO IgE during the clinical control period or during an exacerbation, who had a higher frequency of atopy, asthma, and positive challenge test results with NSAIDs and (2) patients without anti-TPO IgE during any period, who had a higher frequency of positive challenge test results for inducible urticaria. Among the first group (anti-TPO IgE at any point), we identified 3 subgroups: patients with anti-TPO IgE during the clinical control period ( n = 12); patients with anti-TPO IgE during the clinical control period and significantly increased levels during an urticaria exacerbation ( n = 18); and patients with anti-TPO IgE only during an exacerbation ( n = 13). None of the patients with self-reported food reactions had a positive challenge test result., Conclusion: Anti-TPO IgE is a useful biomarker for differentiating between clinical phenotypes of patients with CSU. Elevation of anti-TPO IgE during exacerbation periods supports an association between this autoantibody and the pathogenesis of urticaria., Competing Interests: We declare no conflicts of interest., (Copyright © 2019 Jorge Sánchez et al.)

Background: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU., Methods: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA)., Results: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively., Conclusions: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Thyroid dysfunction (TD) is caused by thyroid peroxidase (TPO) antibody, as seen in Hashimoto's disease. TD is a common problem of reproductive age and may impair fetal development. Here, we determined the effect of TPO antibody on perinatal outcomes in Japanese women with TD before conception. A retrospective study involving cases of maternal TD with term singleton birth was conducted. The subjects with TD were divided into two groups according to the presence (n = 22) or absence (n = 20) of TPO antibody. The control groups matched for age, parity, and gestational weeks were selected for TPO antibody-positive (n = 44) and -negative TD subjects (n = 40), respectively. Using the standard curve of Japanese placental weight, the frequency of placental weight less than the 50th percentile (small placenta) was examined. Placental weight was lower among TPO antibody-positive TD subjects, compared with TPO antibody-negative TD subjects (p < 0.01). However, other outcomes were similar between the groups. Importantly, compared with control mothers, placental weight was significantly lower (p < 0.01), birth weight tended to be lower (p = 0.07), and the incidence of gestational diabetes mellitus was higher (p = 0.02) among TPO antibody-positive subjects. There was no significant difference in placental weight between TPO antibody-negative subjects and controls. The frequency of small placenta was significantly higher in TPO antibody-positive subjects (odds ratio: 16.7) even when considering diabetes and pregnancy induced hypertension. Thus, the presence of TPO antibody is associated with lower placental weight among Japanese women having TD.

Introduction: Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease., Methods: We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected., Results: The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Frataxin is the protein that is down-regulated in Friedreich ataxia (FRDA), an autosomal recessive genetic disease caused by an intronic GAA repeat expansion in intron-1 of the FXN gene. The GAA repeats result in epigenetic silencing of the FXN gene and reduced expression of the cytosolic full-length frataxin (1-210) protein. Full length frataxin translocates to the mitochondria, leading to formation of mature frataxin (81-210) formed by cleavage of the mitochondrial targeting sequence at K-80 of the full-length protein. There are currently no approved treatments for FRDA, although experimental approaches involving up-regulation or replacement of mature frataxin protein through numerous approaches are being tested. Many of the pre-clinical studies of these experimental approaches are conducted in mouse and monkey models as well as in human cell lines. Consequently, well-validated antibodies are required for use in western blot analysis to determine whether levels of various forms of frataxin have been increased. Here we examined the specificity of five commercially available anti-frataxin antibodies and determined whether they detect mature frataxin in mouse heart tissue. Four protein standards of monkey, human, and mouse frataxin as well as mouse heart tissue were examined using polyacrylamide gel electrophoresis (PAGE) in combination with western blot analysis. One antibody failed to detect any of the frataxin standards or endogenous frataxin in mouse heart tissue. Three of the antibodies detected a protein in mouse heart tissue that ran slightly faster on PAGE (at 23.4 kDa) to that predicted for full-length frataxin (23.9 kDa). One antibody detected all four frataxin standards as well as endogenous mouse mature frataxin in mouse tissue. Significantly, this antibody, which will be useful for monitoring mature frataxin levels in monkey, human, and mouse tissues, did not detect a protein in mouse heart tissue at 23.4 kDa. Therefore, antibodies detecting the immunoreactive protein at 23.4 kDa could be misleading when testing for the up-regulation of frataxin in animal models., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To investigate the association of systemic lupus erythematosus (SLE) with thyroid diseases in a medical center in central Taiwan., Methods: This is a retrospective cohort of 2796 SLE patients in a tertiary referral medical center from 2000 to 2013. We screened SLE by catastrophic illness registration from national insurance bureau; and thyroid diseases by ICD 9 codes, then confirmed by thyroid function test, auto-antibody, medical and/or surgical intervention. We compared the rate of hyperthyroidism, hypothyroidism and autoimmune thyroid disease (AITD) in SLE patients and the 11,184 match controls. We calculated the rate of these thyroid diseases and positive antibodies to thyroglobulin (ATGAb), thyroid peroxidase (TPOAb) in SLE patients grouped by the presence of overlap syndrome and anti-dsDNA antibody. We also compared the association of thyroid diseases to severe SLE conditions, including renal, central nervous system (CNS) involvement, and thrombocytopenia., Results: Compared to the matched controls, the cumulative incidence of thyroid disease, including hyperthyroidism, hypothyroidism and AITD, were all higher in SLE patients (p < 0.0001). The average age of SLE patients with thyroid diseases patients were older than those without thyroid diseases (p = 0.002). Those had euthyroid AITD were younger than other patients with thyroid diseases (p = 0.02). Up to 30.3% SLE patients had overlap syndrome and had higher relative risk of thyroid diseases than those without overlap syndrome, in terms of hypothyroidism and AITD, but not hyperthyroidism. SLE patients with thyroid diseases also carry higher risk for severe complications such as renal involvement (p = 0.024) central nervous system involvement (p < 0.0001)., Conclusion: SLE patients had significantly higher rate of hyperthyroidism, hypothyroidism, and AITD than the matched control. Among lupus patients, the risks of thyroid diseases are even higher in the presence of overlap syndrome. SLE patients with thyroid diseases had higher risk of renal and CNS involvement., (Copyright © 2017. Published by Elsevier B.V.)

Objective: To determine the risk of hypothyroidism in pregnant women with autoimmune thyroid disease and thyrotropin (TSH) < 2,5 mIU/l at the beginning of pregnancy., Methods: Prospective longitudinal study of pregnant women with no personal history of thyroid disease, and with TSH < 2.5 mIU/l in the first trimester. TSH, free thyroxine (FT4), anti peroxidase (TPO) and anti thyroglobulin antibodies were measured in the 3 trimesters of pregnancy. We compared thyroid function throughout pregnancy, and the development of gestational hypothyroidism (TSH >4 mIU/l) among pregnant women with positive thyroid autoimmunity and those with negative autoimmunity., Results: We included 300 pregnant women with mean baseline TSH 1.3 ± 0.6 mIU/l (9 th gestational week). Positive thyroid autoinmunity was detected in 17.7% of women (n = 53) at the first trimester. Between the first and the third trimesters, TPO and anti thyroglobulin antibodies titers decreased 76.8% and 80.7% respectively. Thyroid function during pregnancy was similar among the group with positive autoimmunity and the group with negative autoimmunity, and the development of hypothyroidism was 1.9% (1/53) and 2% (5/247) respectively. Pregnant women in whom TSH increased above 4 mIU/l (n = 6), had higher baseline TSH levels compared to those who maintained TSH ≤4 mIU/l during pregnancy (1.8 vs. 1.3 mIU/l; p=.047)., Conclusion: In our population, women with TSH levels <2.5 mIU/l at the beginning of pregnancy have a minimal risk of developing gestational hypothyroidism regardless of thyroid autoimmunity., (Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Aims: To investigate the prevalence of adult-onset autoimmune diabetes (ADM) and predisposition to autoimmune diseases by quantifying serum organ-specific autoantibodies in people with phenotype of type 2 diabetes (T2D)., Materials and Methods: We included a nationally representative sample of 46 239 adults aged ≥20 years from 14 provinces, of whom 4671 had diabetes, plus 1000 control subjects with normal glucose tolerance (NGT). Participants were screened centrally for autoantibodies to glutamic acid decarboxylase (GAD), islet antigen 2 (IA2) and zinc transporter isoform-8 (Znt8) and were defined as having ADM where positive for these antibodies. We then assayed thyroid peroxidase (TPO), tissue transglutaminase (tTG) and 21-hydroxylase (21-OH) autoantibodies in randomly selected participants with ADM and in age-matched, sex-matched and non-ADM controls with T2D plus controls with NGT., Results: Post-normalization, the standardized prevalence rate of ADM was 6.0% (95% confidence interval [CI] 5.3-6.8) in initially non-insulin-requiring participants with ADM, corresponding to six million adults in China, in whom adjusted antibody positivity was: TPO autoantibodies 16.3% (95% CI 10.8-21.8), tTG autoantibodies 2.1% (95% CI 0.0-4.2), and 21-OH autoantibodies 1.8% (95% CI -0.2 to 3.8). Those participants with ADM who were GAD autoantibody-positive had high risk of TPO autoantibody positivity (odds ratio [OR] 2.39, P = 0.0031) and tTG autoantibody positivity (OR 6.98, P = 0.027), while those positive for IA2 autoantibodies had a high risk of tTG autoantibody positivity (OR 19.05, P = 0.001)., Conclusions: A proportion of people with phenotype of T2D in China have ADM, with diabetes-associated autoantibodies, and may be at risk of developing other organ-specific autoimmune diseases; therefore, it may be clinically relevant to consider screening such Chinese populations., (© 2018 John Wiley & Sons Ltd.)

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.

Background: Early pregnancy fetal growth is a relevant determinant of pregnancy outcome and child health during later life. During the first trimester, fetal growth depends on the transfer of maternal thyroid hormone, and optimal thyroid hormone availability is ensured via stimulation of the maternal thyroid by human chorionic gonadotropin (hCG). The potent stimulatory effects of hCG on gestational thyroid function and its clinical relevance with early fetal growth remain unknown and need to be examined., Methods: This study comprised 46,186 mothers for whom early pregnancy thyrotropin (TSH), free thyroxine (fT4), triiodothyronine, thyroperoxidase antibodies, hCG, as well as ultrasound crown-rump length (CRL) measurements were available. Data were also available on potential confounders, including maternal age, parity, anthropometrics, and fetal sex., Results: There was a negative association of TSH with CRL and a positive association of fT4 with CRL, with effect estimates of roughly 0.1 standard deviation (SD) across the full ranges. However, when taking into account thyroid stimulation by hCG, an impaired thyroidal response to hCG stimulation was associated with up to a 0.2 SD lower CRL (high hCG with high TSH) and up to a 0.6 SD lower CRL (high hCG with low fT4). Even within the normal range of TSH and fT4, an impaired thyroidal response to hCG stimulation was associated with a lower CRL., Conclusions: Low maternal thyroid function during the first trimester is associated with a modestly lower CRL. However, an impaired thyroidal response to hCG stimulation is associated with a considerably lower CRL for which effect estimates are in the range of or even supersede those of well-known risk factors. These data can help to improve the identification of pregnancies at high risk of fetal growth restriction and adverse pregnancy or child outcomes.

The link between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is widely recognized. Considering the strong association between raised antithyroidperoxidase antibody (TPOAb) and CLT, we postulated that the preoperative TPOAb can predict the prognosis of PTC, particularly for recurrence. A total of 2,070 patients who underwent total thyroidectomy for classical type PTC with tumor size ≥1 cm and with available data on preoperative TPOAb and TgAb were enrolled to compare disease-free survival (DFS) according to the presence of preoperative TPOAb, TgAb, and coexistent CLT. Patients with positive preoperative TPOAb had a significantly better DFS compared to patients without positive preoperative TPOAb (hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.30-0.94, p = 0.028) while no difference in DFS was found according to preoperative TgAb status. Positive preoperative TPOAb was an independent prognostic factor for structural persistent/recurrent disease after adjustment for major preoperative risk factors such as age, sex, and tumor size (HR 0.52, 95% CI 0.28-0.99, p = 0.048). Although the coexistence of CLT lowered the risk for structural persistence/recurrence in univariate analysis (HR 0.52, 95% CI 0.31-0.86, p = 0.012), it was not an independent favorable prognostic factor by multivariate analysis (HR 0.65, 95% CI 0.38-1.10, p = 0.106). However, when coexistent CLT was combined with positive preoperative TPOAb, it indicated an independent protective role in structural persistent/recurrent disease (HR 0.39, 95% CI 0.16-0.98, p = 0.045). Our study clearly showed that presence of preoperative TPOAb can be a novel prognostic factor in predicting structural persistence/recurrence of PTC., (© 2018 UICC.)

Background and Objective: The modulatory role of prolactin in autoimmune regulation is well established. Hyperprolactinemia is often associated with autoimmune disease like systemic lupus erythematosus and autoimmune thyroid diseases. The objective was to compare levels of direct and indirect autoimmune factors in different categories of hyperprolactinemia cases and predict the direction of association between hyperprolactinemia and autoimmune factors, if any., Methods: A total of 102 hyperprolactinemia cases (>100 ng/mL serum prolactin level) were included along with 24 controls. Among 102 hyperprolactinemia cases, there were 36 idiopathic cases, 19 pituitary adenoma cases, 36 drug-induced cases, and 11 cases associated with other secondary/systemic diseases (chronic renal failure, chronic hepatic failure, etc)., Measurements: Direct autoimmune markers, IL-2, IFN-γ, IL-4, and IL-5, were measured in serum by ELISA. Indirect autoimmune markers, anti-TPO, anti-tg, anti-CCP, VDRL, platelet count, and aPTT, were measured as per laboratory-defined protocol., Results: Serum levels of IL-4 and anti-TPO were significantly high in idiopathic hyperprolactinemia cases. Serum IL-4 levels were also significantly high in pituitary adenoma cases, drug-induced cases, and in cases with other secondary causes of hyperprolactinemia. Serum anti-TPO levels were also significantly high in drug-induced hyperprolactinemia cases., Conclusion: No significant difference in autoimmune factors is observed between macroprolactinemia and true hyperprolactinemia. Serum IL-4 and anti-TPO were high in all categories of hyperprolactinemia. This suggests a possible association of hyperprolactinemia with autoimmune conditions (high IL-4 and anti-TPO), mostly subclinical. Thus, hyperprolactinemia case with serum prolactin level >100 ng/mL may require long-term follow-up for the development of autoimmune disease in future., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.

Mycobacterium tuberculosis , one of the world's leading causes of death, must acquire nutrients, such as iron, from the host to multiply and cause disease. Iron is an essential metal and M. tuberculosis possesses two different systems to acquire iron from its environment: siderophore-mediated iron acquisition (SMIA) and heme-iron acquisition (HIA), involving uptake and degradation of heme to release ferrous iron. We have discovered that Mycobacterium bovis BCG, the tuberculosis vaccine strain, is severely deficient in HIA, and we exploited this phenotypic difference between BCG and M. tuberculosis to identify genes involved in HIA by complementing BCG's defect with a fosmid library. We identified ppe37 , an iron-regulated PPE family gene, as being essential for HIA. BCG complemented with M. tuberculosis ppe37 exhibits HIA as efficient as that of M. tuberculosis , achieving robust growth with <0.2 µM hemin. Conversely, deletion of ppe37 from M. tuberculosis results in a strain severely attenuated in HIA, with a phenotype nearly identical to that of BCG, requiring a 200-fold higher concentration of hemin to achieve growth equivalent to that of its parental strain. A nine-amino-acid deletion near the N terminus of BCG PPE37 (amino acids 31 to 39 of the M. tuberculosis PPE37 protein) underlies BCG's profound defect in HIA. Significant genetic variability exists in ppe37 genes across different M. tuberculosis strains, with more than 60% of sequences from completely sequenced M. tuberculosis genomes having mutations that result in altered PPE37 proteins; furthermore, these altered PPE37 proteins are nonfunctional in HIA. Our findings should allow delineation of the relative roles of HIA and SMIA in M. tuberculosis pathogenesis., (Copyright © 2019 American Society for Microbiology.)

Background Pregnancy is an important event in reproductive years of women life. It has a reversible effect on the thyroid gland and its functions. The role of thyroid gland function and conception has been known for a long time. The most common thyroid gland dysfunction in pregnancy is hypothyroidism. It is estimated that the prevalence is 1.5-4.4% of pregnant women. It is known to cause complications during pregnancy leading to adverse pregnancy outcomes. Objective To observe the pregnancy outcomes in patients with hypothyroidism. Method This is a retrospective study conducted from January 2015 to December 2018. Two hundred and thirty nine patients with hypothyroidism were included. They were investigated for thyroid stimulating hormone (TSH), free tri iodothyronin (FT ), free thyroxine (FT ) levels and for auto-antibodies against thyroperoxidase (anti TPO). All these patients after the detection of hypothyroidism were under thyroxine hormone replacement. Result Amongst 239 ladies with hypothyroidism 97.5% came from hilly region. Seventy seven (32%)of them had history of abortions. Twenty three (9.8%) of them had antepartum hemorrhage. Eleven (4.6%) had preeclampsia during this pregnancy. Seven (2.9%) had fetuses with intrauterine growth restriction (IUGR). Seven (2.9%) had fetuses with preterm delivery. Twenty seven (11.3%) of fetuses had APGAR Score of < 6. Conclusion Of 239 women with hypothyroidism, many had history of recurrent abortions and also complications during antenatal period like preeclampsia, abruption placenta, IUGR and preterm delivery. After thyroxine replacement, risk is much lowered and it has a positive outcome.