Prevalence and factors associated with thyroid autoimmunity among children newly diagnosed with type 1 diabetes before and during the COVID-19 pandemic: Evidence from Kuwait.

AIMS: This study reports the prevalence and characteristics related to the development of thyroid autoimmunity among children newly diagnosed with type I diabetes (T1D) during the COVID-19 pandemic in Kuwait. MATERIALS AND METHODS: This is a prospective observational study of all children under age 14 years newly diagnosed with T1D in Kuwait. We define the duration of the COVID-19 pandemic from the official declaration of the first identified positive COVID-19 case on 24 February 2020 until 31 December 2022. For comparison, we use the time period directly before the COVID-19 pandemic, 1 January 2017 to 23 February 2020. RESULTS: One thousand twenty-four (1024) children newly diagnosed with T1D in Kuwait during the study period were included. Among newly diagnosed children, 20.3% tested positive for thyroid antibodies during the COVID-19 pandemic, compared with 14.5% during the pre-pandemic period (p = 0.015). Children with positive COVID-19 status were more likely to present with thyroid antibodies (p = 0.035). After adjusting for other characteristics, patients diagnosed with T1D during the COVID-19 pandemic had double the odds of testing positive for thyroid antibodies (Adjusted odds ratio = 2.173, 95%CI: 1.108, 4.261, p = 0.024). CONCLUSIONS: Incident cases of T1D during the COVID-19 pandemic may be different in aetiology or contextual factors leading to a higher risk of thyroid autoimmunity. Longitudinal studies are needed to understand the role of COVID-19 in the onset and progression of T1D and on thyroid autoimmunity and disease.

The relationship between thyroid and human-associated microbiota: A systematic review of reviews.

In recent years, a growing number of studies have examined the relationship between thyroid pathophysiology and intestinal microbiota composition. The reciprocal influence between these two entities has been proven so extensive that some authors coined the term "gut-thyroid axis". However, since some papers reported conflicting results, several aspects of this correlation need to be clarified. This systematic review was conceived to achieve more robust information about: 1)the characteristics of gut microbiota composition in patients with the more common morphological, functional and autoimmune disorders of the thyroid; 2)the influence of gut microbial composition on micronutrients that are essential for the maintenance of thyroid homeostasis; 3)the effect of probiotics, prebiotics and synbiotics, some of the most popular over-the-counter products, on thyroid balance; 4)the opportunity to use specific dietary advice. The literature evaluation was made by three authors independently. A five steps strategy was a priori adopted. After duplicates removal, 1106 records were initially found and 38 reviews were finally included in the analysis. The systematic reviews of reviews found that: 1) some significant variations characterize the gut microbiota composition in patients with thyroid disorders. However, geographical clustering of most of the studies prevents drawing definitive conclusions on this topic; 2) the available knowledge about the effect of probiotics and synbiotics are not strong enough to suggest the routine use of these compounds in patients with thyroid disorders; 3) specific elimination nutrition should not be routine suggested to patients, which, instead have to be checked for possible micronutrients and vitamins deficiency, often owed to gastrointestinal autoimmune comorbidities.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

Impact of thyroid autoimmunity on the cumulative live birth rates after IVF/ICSI treatment cycles.

BACKGROUND: Cumulative live birth rate (CLBR) is considered as the most important endpoint for assessing the probability of having a baby in a complete in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycle. Many previous studies have focused on the association between thyroid autoimmunity (TAI) and live birth rate after first embryo transfer cycle, however, evidence on whether the presence of TAI affects the CLBR is lacking. The purpose of this study is to investigate the impact of TAI on the CLBR in a complete IVF/ICSI cycle. METHODS: This retrospective study included 12,796 women who underwent their first IVF/ICSI treatment between January 2019 and February 2021. Based on the levels of thyroid antibodies, 2,603 women were assigned to the TAI group, and 10,193 women were assigned to the control group. Subgroup analysis was performed according to the different causes of infertility (including male factor only, ovulation disorder, tubal factor, endometriosis and unexplained infertility) and different types and titres of thyroid antibodies. The primary outcome in this study was CLBR, which included live births from the fresh embryo transfer cycle and all subsequent frozen-thawed embryo transfer cycles performed before December 2021. RESULTS: There was no significant difference in the CLBR between the TAI and control groups, even after adjusting for relevant confounders including age, body mass index, cause of infertility, thyroid function, protocols of controlled ovarian stimulation, type of transfer (fresh vs. frozen), type of transferred embryo (cleavage-stage embryo vs. blastocyst), and fertilization method (IVF vs. ICSI) (cumulative live birth: 50.6% vs. 52.1%, OR 0.94, 95% CI 0.86-1.02, adjusted OR 0.97, 95%CI 0.89-1.06). Subgroup analysis showed that no significant difference was observed in CLBR between the TAI and control groups for all causes of infertility, except for infertility attributed to endometriosis. Among women with endometriosis, the CLBR was significantly lower in the TAI group than that in the control group; however, this difference was not significant after adjusting for potential confounders including age, body mass index, thyroid function, protocols of controlled ovarian stimulation, type of transfer (fresh vs. frozen), type of transferred embryo (cleavage-stage embryo vs. blastocyst), and fertilization method (IVF vs. ICSI) (cumulative live births: 43.1% vs. 51.0%, OR 0.73, 95% CI 0.53-0.99, adjusted OR 0.74, 95% CI 0.53-1.02). Another subgroup analysis demonstrated that the type and titre of thyroid antibody did not affect CLBR in women with TAI. CONCLUSIONS: In our study, there was no significant difference in the CLBR between women with TAI and those without TAI, which suggests that TAI did not affect the chances of having a baby in a complete IVF/ICSI treatment cycle.

Long-term outcome of Graves' orbitopathy following treatment with sirolimus.

OBJECTIVES: Sirolimus was found to be associated with a better outcome of Graves' orbitopathy (GO) at 24 weeks compared to methylprednisolone. We conducted a retrospective study to investigate its efficacy and safety over a longer period. METHODS: Data from 40 consecutive patients with moderate-to-severe, active GO, 20 treated with sirolimus and 20 with methylprednisolone, were collected. PRIMARY OUTCOME: overall outcome (composite evaluation) of GO at 48 weeks. SECONDARY OUTCOMES: (1) GO outcome at 24 weeks, and, at 24 and 48 weeks: (2) outcome of single eye features; (3) quality of life (GO-QoL); (4) TSH-receptor antibodies; (5) GO relapse at 48 weeks; (6) adverse events. RESULTS: The overall GO outcome at 48 weeks did not differ between the two groups (responders: 55% vs 55%). At 24 weeks, prevalence of responders was greater in sirolimus group (65% vs 25%; P = 0.01). A reduction ≥ 1 point in clinical activity score (CAS) was more frequent in sirolimus patients at 24 (85% vs 40%; P = 0.005) and 48 weeks (75% vs 60%; P = 0.03). The proportion of GO-QoL responders (appearance subscale) at 24 weeks was greater in sirolimus group (62.5% vs 26.3%; P = 0.03). No difference was observed for the remaining outcome measures. CONCLUSIONS: Treatment with sirolimus is followed by a greater overall response of GO compared with methylprednisolone at 24 weeks, but not at 48 weeks, when only CAS is affected. A more prolonged period of treatment may be required for a better outcome to be observed over a longer period.

Thyroid autoimmunity in different phenotypes of polycystic ovary syndrome: a single-center experience.

PURPOSE: Polycystic ovary syndrome (PCOS) has been associated with Hashimoto's thyroiditis (HT) and 4 phenotypes have been described in this syndrome. The aim of this work was to investigate the frequency of anti-thyroid antibodies (TAb) and thyroid function in the 4 phenotypes of PCOS. PATIENTS: This study included 448 patients with PCOS: 260 (58.0%) with phenotype A, 119 (26.6%) with phenotype B, 38 (8.5%) with phenotype C and 31 (6.9%) with phenotype D. RESULTS: TAb positivity was detected in 90/448 patients (20.1%) and was statistically significant higher (p = 0.03) in the grouped phenotypes A-B (83/379, 21.9%) than in phenotypes C-D (7/69, 10.1%). Positive anti-thyroglobulin antibodies (TgAb) were detected in 74/448 (16.5%) patients and positive anti-thyroperoxidase antibodies (TPOAb) in 66/448 (14.7%) patients. Both TgAb and TPOAb positivity was higher but not statistically significant in phenotype A-B than phenotype C-D. High titer TgAb (> 100 UI/ml) frequency was significantly higher (p = 0.005) in grouped phenotypes A-B (39/379, 10.3%) than in phenotypes C-D (0/69, 0.0%), while no significant difference was observed for low titer TgAb (≤ 100 UI/ml). According to a binary logistic regression analysis hypothyroidism was significantly associated with TAb positivity (OR 4.19; CI 2.25-7.79; p < 0.01) but not with PCOS phenotype. Androgen profile was not associated with TAb positivity. CONCLUSION: A higher frequency of positive TAb and of high titer TgAb and TPOAb have been detected in PCOS women with phenotypes A and B, probably in relation to the greater imbalances between estrogen and progesterone levels present in these phenotypes.

Thyroid ultrasonic changes relate to implantation failure in euthyroid women with thyroid autoimmunity undergoing in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To determine whether ultrasonic manifestations of Hashimoto's thyroiditis (HT) related to embryo qualities or pregnancy outcomes in women with thyroid autoimmunity (TAI) undergoing in vitro fertilization/intracytoplasmic sperm injection. METHODS: Our study was a retrospective cohort study. A total of 589 euthyroid women enrolled from January 2017 to December 2019. 214 TAI women and 375 control women were allocated in each group according to serum levels of thyroid peroxidase antibodies (TPOAb) and/or anti-thyroglobulin antibodies (TgAb). Basal serum hormone levels and thyroid ultrasound were assessed, embryo qualities, pregnancy outcomes were collected from medical records. Diagnosis of thyroid ultrasound was used for subanalysis. Logistic regression was used to evaluate outcomes of embryo development and pregnancy. RESULTS: Implantation rate was significantly lower in euthyroid women with TAI compared with control group (TAI group: 65.5% vs. Control group: 73.0%, adjusted OR (95% CI): 0.65 (0.44, 0.97), p = 0.04). We further stratified TAI group into two groups: one group with HT features under ultrasound and another group with normal thyroid ultrasound. After regression analysis, TAI women with HT morphological changes had a lower chance of implantation compared with control group (TAI group with HT: 64.1% vs. Control group: 73.0%, adjusted OR (95% CI): 0.63 (0.41, 0.99), p = 0.04), while there was no significant difference on implantation rate between TAI women with normal thyroid ultrasound and control group. Other outcomes, such as embryo qualities and pregnancy rate, were comparable between TAI and control groups. CONCLUSIONS: A higher risk of implantation failure was seen among euthyroid women with TAI, especially women with HT morphological changes under ultrasound. The underlying mechanisms of implantation failure among euthyroid HT patients need further research.

Impact of age, sex, and thyroid autoimmunity on the association between selenium intake and type 2 diabetes mellitus.

BACKGROUND: The association between dietary selenium(Se) intake and type 2 diabetes mellitus (T2DM) remains controversial. The present study aimed to investigate this association using data from the National Health and Nutrition Examination Survey (NHANES) database for the years 2007-2012. METHODS: Three thousand seventy three individuals aged 20 years and above were eligible for inclusion in this cross-sectional study. The average age of the participants was 50.74 years and the proportions of males and females were nearly equal (49.12% vs. 50.88%). The odds ratios (OR) of the association between dietary Se intake (log2-transformed) and T2DM were examined through the multivariate logistic regression model. Subgroup analyses were conducted based on age, sex, and thyroid autoimmunity to assess the potential impact of these variables on the relationship. Fitted smoothing curves and threshold effect analysis were conducted to describe the nonlinear relationship. RESULTS: In the fully adjusted model, a significant positive association between Se intake and T2DM was observed (OR = 1.49, 95% CI: 1.16, 1.90, p = 0.0017). After stratifying the data by age, sex, and thyroid autoimmunity, a significant positive association between Se intake and T2DM was observed in individuals under 65 years of age, males, and those with negative thyroid autoimmunity. A two-segment linear regression model was analyzed for sex stratification, revealing a threshold effect in males with an inflection point of 90.51 µg, and an inverted U-shaped relationship in females with an inflection point of 109.90 µg, respectively. CONCLUSIONS: The present study found a positive relationship between Se intake and the prevalence of T2DM. This association is particularly significant in younger individuals, males, and those with negative thyroid autoimmunity. Our results should be validated in future large prospective studies in different populations.

Hashimoto's Thyroiditis Negatively Influences Intracytoplasmic Sperm Injection Outcome in Euthyroid Women on T4 Substitution Therapy: A Retrospective Study.

OBJECTIVE: The objective of this study was to analyze the impact of thyroid autoimmunity (TAI) on reproductive outcome parameters of intracytoplasmic sperm injection (ICSI) cycles as compared to TAI-negative ICSI cycles. DESIGN: In this single in vitro fertilization (IVF) center retrospective study, 86 infertile women with elevated thyroid peroxidase or TGAb levels, but euthyroid after thyroxine replacement (study group), were compared to 69 female patients with no thyroid abnormalities (controls). Following ICSI treatment fertilization rate (FR), clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR) were analyzed. MATERIALS, SETTING, METHODS: All subjects with various infertility factors were treated with ICSI in university-based IVF center. Patients in the study group received thyroxine replacement and were euthyroid at IVF treatment. Before the IVF cycles, endocrinological parameters were uniformly assessed: thyroid function and antibodies, reproductive hormones (anti-Müllerian hormone [AMH], follicular stimulating hormone [FSH], luteinizing hormone, E2, PRL, testosterone, DHEAS, 17-OHP, AD) and OGTT (0-60-120 min glucose and insulin). Following descriptive comparison of laboratory parameters, age-adjusted analyses of FR, CPR, MR, and LBR were performed. RESULTS: TAI-positive women were older (mean age 35.31 ± 4.95 vs. 32.15 ± 4.87 years; p = 0.002), had higher FSH (8.4 ± 3.4 vs. 7.4 ± 2.32 U/L; p = 0.024), higher E2 (53.94 ± 47.61 vs. 42.93 ± 18.92 pg/mL; p = 0.025) levels, while AMH (2.88 ± 2.62 vs. 3.61 ± 1.69 ng/mL; p = 0.0002) was lower. There were no differences in TSH levels (1.64 ± 0.96 vs. 1.66 ± 0.65 µIU/mL; p = 0.652) between the two groups. FT3 (2.63 ± 0.58 vs. 2.98 ± 0.55 pg/mL; p = 0.002) was lower and FT4 (1.3 ± 0.29 vs. 1.13 ± 0.21 ng/dL; p = 0.0002) was higher in the TAI-positive group, reflecting clinically irrelevant differences. Egg cell counts (6 ± 3.8 vs. 7.5 ± 3.95; p = 0.015) were lower in TAI and remained so following age adjustment. Although the overall ICSI FR did not differ (62.9% vs. 69.1%, p = 0.12), it was lower for patients under 35 with TAI showing decreasing differences in line with age. The CPR (36.04% vs. 69.56%; p < 0.001) and LBR (23.25% vs. 60.86%; p < 0.001) were lower, the MR (35.48% vs. 12.5%; p = 0.024) was higher in the TAI group, and these differences remained after age adjustment. LIMITATIONS: Since the higher age of the study group may interfere with the effect of TAI, age adjustment calculations were necessary to perform to eliminate this confounding factor. CONCLUSION: Despite optimal thyroid supplementation in clinical or subclinical hypothyroidism, the presence of TAI negatively influences CPR and is connected to a higher MR, thus resulting in a lower LBR after ICSI. Decreased FR with ICSI in TAI patients may also contribute to poorer outcomes, especially in younger women.

Levothyroxine for subclinical hypothyroidism during pregnancy: an updated systematic review and meta-analysis of randomized controlled trials.

PURPOSE: We aimed to perform a systematic review and meta-analysis addressing the efficacy of levothyroxine therapy in pregnant women with subclinical hypothyroidism considering most recent evidence and subgroups of interest for clinical practice. METHODS: PubMed, Embase, and Cochrane Central were searched from inception for randomized controlled trials (RCTs) comparing levothyroxine with placebo or no intervention in pregnant women with subclinical hypothyroidism. We used a random-effects model and conducted subgroup analyses based on thyroid peroxidase antibody status, thyroid stimulating hormone levels, fertility treatment, and recurrent miscarriage. RESULTS: We included 11 RCTs comprising 2,749 pregnant women with subclinical hypothyroidism. Patients treated with levothyroxine (1,439; 52.3%) had significantly lower risk of pregnancy loss (risk ratio 0.69; 95% confidence interval 0.52-0.91; p < 0.01; 6 studies). However, there was no significant association between levothyroxine and live birth (risk ratio 1.01; 95% confidence interval 0.99-1.03; p = 0.29; 8 studies). No statistically significant interaction was observed across subgroups (p > 0.05). CONCLUSION: Levothyroxine replacement therapy for subclinical hypothyroidism during pregnancy may decrease pregnancy loss when early prescribed. Nevertheless, further investigation is needed in patients with thyroid stimulating hormone above four milliunits per liter, especially when associated with recurrent miscarriage or infertility.

Zinc and Ferritin Levels and Their Associations with Functional Disorders and/or Thyroid Autoimmunity: A Population-Based Case-Control Study.

Population zinc and iron status appear to be associated with an increased risk of thyroid function abnormalities and thyroid autoimmunity (AITD). In the present study, we aimed to determine whether zinc and/or iron levels (assessed by ferritin levels) were associated with the presence of AITD and with alterations in thyroid function. A population-based case-control study (n = 1048) was conducted (cases: n = 524; controls: n = 524). Participants were measured for blood concentrations of zinc and ferritin, TSH, FT4, FT3, and thyroid autoantibodies. No significant differences were found in relation to ferritin levels between cases and controls. Among cases, the prevalence of low zinc levels in those with hypothyroidism (both subclinical and overt) was 49.1% [odds ratio (OR) of low zinc levels: 5.926; 95% CI: 3.756-9.351]. The prevalence of low zinc levels in participants with hyperthyroidism (both subclinical and overt) was 37.5% [OR of low zinc levels: 3.683; 95% CI: 1.628-8.33]. The zinc value that best discriminated the highest frequency of AITD was 70.4 µg/dL [sensitivity: 0.947, 1-specificity: 0.655, specificity: 0.345]. The highest frequency of AITD was calculated based on a zinc value <70 µg/dL (relative to a normal value), with this frequency being significantly higher in cases than in controls [OR: 9.3; 95% CI: 6.1-14.3 (p = 0.001)]. In conclusion, the results of our study suggest that zinc deficiency is associated with an increased frequency of functional thyroid disorders and thyroid autoimmunity.

Expression of thyroid antigens in the female reproductive system.

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.

L'auto-immunité thyroïdienne (AIT) est associée à des troubles de la fertilité et à des complications de grossesse, même chez les femmes euthyroïdiennes. Cependant, le mécanisme physiopathologique sous-jacent à cette association n'est pas entièrement élucidé. Cette étude vise à examiner l'expression des antigènes thyroïdiens dans le système reproducteur féminin humain, afin d'identifier des cibles potentielles pour les anticorps antithyroïdiens. Des biopsies d'endomètre et de cellules de granulosa ont été analysées pour l'expression de la thyroperoxydase (TPO) et de la thyroglobuline (TG) par immunohistochimie. Les résultats montrent, pour la première fois, l'expression de la TG et confirment la présence de la TPO dans l'endomètre et les cellules de granulosa humaines. Ces résultats suggèrent que les anticorps anti-TPO et anti-TG pourraient interagir avec la TPO et TG exprimés au niveau du système reproducteur des patientes présentant des anticorps thyroïdiens positifs, perturbant ainsi leur fonction et entraînant une réponse inflammatoire pouvant conduire à des troubles de la fertilité et des complications de grossesse.

Raised First Trimester Thyroid Peroxidase Antibodies May Predict First Trimester Miscarriage: A Case Control Study.

Miscarriages constitute a significant aspect of failed pregnancies and a source of worry for the patient and caregiver. Some of the causes of miscarriages remain unknown. Immunological conditions such as thyroid autoimmunity could play significant roles. Our objective was to determine the relationship between raised thyroid peroxidase antibodies and first trimester miscarriages in a low resource setting. This was a case control study at the Gynaecological Clinic of the University of Calabar Teaching Hospital, Nigeria; from 14th February 2020 to 13th January 2021, involving 145 cases who had first trimester miscarriages, and their matched controls who had apparently normal pregnancies, at same gestational ages. Sera of venous blood from both participants and controls were analysed for thyroid peroxidase antibodies using enzyme-linked immunosorbent assay, and analysed using SPSS version 20, and GraphPad Prism 8.4.3 statistical software. Being a civil servant and low social status had significant odds for first trimester miscarriage. Raised thyroid peroxidase antibodies in the first trimester had 10-fold odds for miscarriage. Odds ratio 10.34, 95% CI: 3.22 to 32.98, P-value = 0.0001. The test had a sensitivity of 89.66% and specificity of 54.41%. The positive predictive value was 17.93%, while the negative predictive value was 97.93% and a likelihood ratio of 1.966. Rising thyroid peroxidase antibodies in early pregnancy could be a predictor for miscarriage. This is so because patients with raised thyroid peroxidase antibodies in the first trimester had a 10-fold risk of having a first trimester miscarriage.

Single cell transcriptomic analysis of Graves' disease thyroid glands reveals the broad immunoregulatory potential of thyroid follicular and stromal cells and implies a major re-interpretation of the role of aberrant HLA class II expression in autoimmunity.

The study of the immune response in thyroid autoimmunity has been mostly focused on the autoantibodies and lymphocytes, but there are indications that intrinsic features of thyroid tissue cells may play a role in disrupting tolerance that needs further investigation. The overexpression of HLA and adhesion molecules by thyroid follicular cells (TFC) and our recent demonstration that PD-L1 is also moderately expressed by TFCs in autoimmune thyroid indicates that TFCs they may activate but also inhibit the autoimmune response. Intriguingly, we have recently found that in vitro cultured TFCs are able to suppress the proliferation of autologous lymphocyte T in a contact-dependent manner which is independent of the PD-1/PD-L1 signaling pathway. To get a more comprehensive picture of TFC activating and inhibitory molecules/pathways driving the autoimmune response in the thyroid glands, preparations of TFCs and stromal cells from five Graves' disease (GD) and four control thyroid glands were compared by scRNA-seq. The results confirmed the previously described interferon type I and type II signatures in GD TFCs and showed unequivocally that they express the full array of genes that intervene in the processing and presentation of endogenous and exogeneous antigens. GD TFCs lack however expression of costimulatory molecules CD80 and CD86 required for priming T cells. A moderate overexpression of CD40 by TFCs was confirmed. GD Fibroblasts showed widespread upregulation of cytokine genes. The results from this first single transcriptomic profiling of TFC and thyroid stromal cells provides a more granular view of the events occurring in GD. The new data point at an important contribution of stromal cells and prompt a major re-interpretation of the role of MHC over-expression by TFC, from deleterious to protective. Most importantly this re-interpretation could also apply to other tissues, like pancreatic beta cells, where MHC over-expression has been detected in diabetic pancreas.

Thyroid cells from normal and autoimmune thyroid glands suppress T lymphocytes proliferation upon contact revealing a new regulatory inhibitory type of interaction independent of PD1/PDL1.

Immune Checkpoint Receptors include a number of inhibitory receptors that limit tissue damage during immune responses; blocking PD-1/PD-L1 checkpoint receptor axis led to a paradigm shift in cancer immunotherapy but also to autoimmune adverse effects, prominently thyroid autoimmunity. Although PD-L1 is known to be expressed on thyroid follicular cells (TFCs) of autoimmune glands the role on PD-1/PD-L1 in the interaction between T cells and thyroid cells in the tissue has not been investigated. Here we report that autologous primary TFCs, but not transformed TFCs, inhibit CD4 and CD8 T cell proliferation but no cytokine production. This effect is not, however, mediated by PD-1/PD-L1 nor locally produced cytokines. Beta galactosidase analysis excluded culture-induced senescence as an explanation. High resolution flow cytometry demonstrated that autologous TFC/T cells co-culture induced the expansion of several clusters of double negative (DN) T cells characterized by high expression of activation markers and negative immune checkpoints. Single cell transcriptomic profiling demonstrated that dissociated TFC express numerous candidate molecules for mediating this suppressive activity, including CD40, E-Cadherin and TIGIT ligands. These ligands directly or through the generation of a suppressor population of DN T cells, and not the PD-1/PD-L1 axis, are most likely the responsible of TFC immunosuppressive activity. These results contribute to reveal the complex network of inhibitory mechanism that operate at the tissue level to restrain autoimmunity but also point to pathways, other that PD-1/PD-L1, that can contribute to tumor evasion.

Impact of thyroid autoimmunity on pregnancy outcomes in euthyroid women following fresh/frozen-thawed embryo transfer.

OBJECTIVE: To investigate whether thyroid autoimmunity (TAI) is associated with assisted reproductive technology (ART) outcomes in euthyroid women undergoing fresh embryo transfer (ET) and frozen-thawed embryo transfer (FET). DESIGN: A retrospective cohort study. Pregnancy and neonatal outcome after fresh ET or FET were compared between the positive and negative thyroid autoimmune antibody groups. PATIENTS: A total of 5439 euthyroid women who started their ART cycle at our centre between 2015 and 2019 were included. RESULTS: The thyroid antibody positive group had a greater mean age than the thyroid antibody negative group (32(29,35) vs. 31(28,34), p < .001). Women with positive thyroid antibody presented with a higher prevalence of diminished ovarian reserve (DOR) (9.1% vs. 7.1%, p = .026) and lower number of oocyte retrieved (9(5,15) vs. 10(6,15), p = .020), but difference was not significant after adjusting for age. The pregnancy rate, live birth rate, pregnancy loss rate, preterm delivery rate and low birthweight rate between the thyroid antibody positive and thyroid antibody negative groups were comparable both in fresh ET cycles and FET cycles. Subanalysis of the treatment outcomes when using a stricter threshold of TSH of 2.5 mIU/L showed no difference to that achieved when using an upper limit of 4.78 mIU/L. CONCLUSIONS: The present study reveals that patients with anti-thyroid peroxidase antibodies (TPOAbs) and/or antithyroglobulin antibodies (TgAbs) showed no significant differences in pregnancy outcomes following fresh ET and FET when compared with patients with negative thyroid antibodies.

High level of thyroid peroxidase antibodies as a detrimental risk of pregnancy outcomes in euthyroid women undergoing ART: A meta-analysis.

Thyroid autoimmunity (TAI) triggered by genetic and epigenetic variation occurs mostly in women of reproductive age. TAI is described mainly by positivity of anti-thyroid peroxidase antibody (TPO-Ab) and/or thyroglobulin antibody (TG-Ab). TPO-Ab, but not TG-Ab, was suggested to be associated with pregnancy outcome in euthyroid women undergoing assisted reproductive technology (ART), but their results are conflicting. This meta-analysis was performed to decide whether the presence of TPO-Ab-in a concentration dependent manner-correlates with the success of ART. A systematic literature search was performed in the PubMed, Web of Science, and EMBASE databases for relevant articles published from January 1999 to April 2022, and these studies focused on the effect of TAI on pregnancy outcomes of women who underwent in vitro fertilization, intracytoplasmic sperm injection and intrauterine insemination and met the inclusion criteria: (i) the studies were prospective or retrospective study; (ii) all patients undergoing ART were tested for thyroid-related antibodies; (iii) the assessed ART outcomes included miscarriage rate (MR) or delivery rate (DR). The exclusion criteria were: (i) female congenital uterine malformation, chromosomal diseases and other infectious diseases; (ii) overt hypothyroidism or pre-existing thyroid disease; (iii) thrombus tendency. We divided the included patients into three groups according to the TPO-Ab threshold they defined: (i) TPO-Ab (-), threshold <34 IU/mL; (ii) TPO-Ab-34, threshold >34 IU/mL; (iii) TPO-Ab-100, threshold >100 IU/mL. We then extracted necessary relevant data, including MR and DR. Egger's test was used to evaluate the risk of publication bias. This meta-analysis included a total of 7 literatures involving 7466 patients with TAI (-) and 965 patients with TAI (+) and revealed that there was no significant difference between group TPO-Ab-34 and group TPO-Ab (-) in MR [risk ratio (RR): 0.61 (0.35, 1.08), p = 0.09] and DR [RR: 0.97 (0.83, 1.13), p = 0.69]. By contrast, compared to TPO-Ab (-) group, TPO-Ab-100 patients showed markedly higher MR [RR: 2.12 (1.52, 2.96), p = 0.0046], and lower DR [RR: 0.66 (0.49, 0.88), p < 0.0001] with high degree of statistical significance. This meta-analysis suggests that, for euthyroid patients, high level of TPO-Ab (>100 IU/mL) could adversely influence the pregnancy outcome of ART.

Impact of thyroid autoimmunity on pregnancy outcomes in euthyroid patients with recurrent implantation failure.

RESEARCH QUESTION: Does thyroid autoimmunity (TAI) adversely affect pregnancy outcomes after IVF/intracytoplasmic sperm injection (ICSI) in euthyroid patients with recurrent implantation failure (RIF)? DESIGN: This retrospective cohort study was conducted at the Reproductive Hospital Affiliated with Shandong University from November 2016 to September 2021. A total of 1031 euthyroid patients diagnosed with RIF were enrolled. Based on serum thyroid autoantibody concentrations, the participants were divided into two groups: the TAI-positive group (219 women with RIF) and the TAI-negative group (812 women with RIF). The parameters were compared between the two groups. Additionally, logistic regression was used to adjust related confounders for primary outcomes, and subgroup and stratified analyses were performed according to different thyroid autoantibody types and TSH concentrations. RESULTS: There was no significant difference in ovarian reserve, ovarian response, embryo quality, pregnancy outcome or neonatal outcome between the two groups (P > 0.05). After adjustments for age, body mass index, thyroid-stimulating hormone and free thyroxine, the biochemical pregnancy rate in the TAI-positive group was significantly lower than that in the TAI-negative group (odds ratio 1.394, 95% CI 1.023-1.901, adjusted P = 0.036). Regarding the implantation rate, clinical pregnancy rate, pregnancy loss rate, stillbirth rate and live birth rate, no significant differences were observed even with subgroup and stratified analyses (P > 0.05). CONCLUSIONS: TAI had no impact on pregnancy outcomes in euthyroid RIF patients who underwent IVF/ICSI. In clinical practice, interventions targeting thyroid autoantibodies in these patients should be implemented with caution and additional evidence is needed.

Direct-acting antivirals used in HCV-related liver disease do not affect thyroid function and autoimmunity.

PURPOSE: It is well known that interferon-α (IFN-α), used for long time as the main therapy for HCV-related disease, induces thyroid alterations, but the impact of the new direct-acting antivirals (DAAs) on thyroid is not established. Aim of this prospective study was to evaluate if DAAs therapy may induce thyroid alterations. METHODS: A total of 113 HCV patients, subdivided at the time of the enrollment in naïve group (n = 64) and in IFN-α group (n = 49) previously treated with pegylated interferon-α and ribavirin, were evaluated for thyroid function and autoimmunity before and after 20-32 weeks of DAAs. RESULTS: Before starting DAAs, a total of 8/113 (7.1%) patients showed Hashimoto's thyroiditis (HT) all belonging to IFN-α group (8/49, 16.3%), while no HT cases were found in the naïve group. Overall, 7/113 (6.2%) patients were hypothyroid: 3/64 (4.7%) belonging to naïve group and 4/49 (8.2%) to IFN-α group. Furthermore, a total of 8/113 patients (7.1%) showed subclinical hyperthyroidism: 2/64 (3.1%) were from naïve group and 6/49 (12.2%) from IFN-α group. Interestingly, after DAAs therapy, no new cases of HT, hypothyroidism and hyperthyroidism was found in all series, while 6/11 (54.5%) patients with non-autoimmune subclinical thyroid dysfunction became euthyroid. Finally, the only association between viral genotypes and thyroid alterations was genotype 1 and hypothyroidism. CONCLUSIONS: This study supports evidence that DAAs have a limited or missing influence on thyroid in patients with HCV-related diseases. Moreover, it provides preliminary evidence that subclinical non-autoimmune thyroid dysfunction may improve after HCV infection resolution obtained by DAAs.

TPOAb positivity can impact ovarian reserve, embryo quality, and IVF/ICSI outcomes in euthyroid infertile women.

The aim of this study was to investigate the effects of positive anti-thyroid peroxidase (TPO) antibodies on fertility, embryo quality, and pregnancy outcomes in women with normal thyroid function. A cross-sectional study of 1223 infertile women who received assisted reproductive technology (ART) treatment for the first time was conducted at our hospital from January 2019 to March 2022. Overall, 263 infertile women were included, comprising 263 cycles and 1813 embryos, and were divided into a positive group and a control group based on TPO antibody levels. The positive group was further divided into two subgroups according to the median antibody titer, and the therapeutic indices and pregnancy outcomes for each group were compared. The results showed that the AMH level in the positive group was significantly lower than that in the control group (2.37 (1.26-3.63) ng/ml vs. 3.54 (1.74-5.41) ng/ml, p < 0.001). The high-quality embryo rate (40.04% vs. 45.49%, p = 0.034) and live birth rate (23.26% vs. 36.16, p = 0.035) of the positive group were lower than those of the control group; the miscarriage rate was higher than that of the control group (37.50% vs. 17.95%, p = 0.035). The live birth rate in the low-titer group was significantly higher than that in the high-titer group (32.56% vs. 13.95%, p = 0.041). Studies have shown that positive anti-thyroid peroxidase antibodies are associated with a decreased ovarian reserve and decreased embryo quality. High titers of anti-thyroid peroxidase antibodies can reduce the live birth rate.