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Thyroid as a target of adjuvant autoimmunity/inflammatory syndrome due to mRNA-based SARS-CoV2 vaccination: from Graves' disease to silent thyroiditis.
Pujol, A, Gómez, LA, Gallegos, C, Nicolau, J, Sanchís, P, González-Freire, M, López-González, ÁA, Dotres, K, Masmiquel, L
Journal of endocrinological investigation. 2022;(4):875-882
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Abstract
BACKGROUND As COVID-19 became a pandemic, the urgent need to find an effective treatment vaccine has been a major objective. Vaccines contain adjuvants which are not exempt from adverse effects and can trigger the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). There is very little information about autoimmune endocrine disease and the ASIA after the use of mRNA-based SARS-CoV2 vaccination. CASE SERIES We report three cases and also review the literature showing that the thyroid gland can be involved in the ASIA induced by the mRNA-based SARS-CoV2 vaccination. We present the first case to date of silent thyroiditis described in the context of SARS-CoV2 vaccination with Pfizer/BioNTech. Also, we discuss the first subacute thyroiditis in the context of SARS-CoV2 vaccination with the Moderna's vaccine. Finally, we provide another case to be added to existing evidence on Graves' disease occurring post-vaccination with the Pfizer/BioNTech vaccine. DISCUSSION Adjuvants play an important role in vaccines. Their ability to increase the immunogenicity of the active ingredient is necessary to achieve the desired immune response. Both the Moderna and the Pfizer/BioNTech vaccines use mRNA coding for the SARS-CoV2 S protein enhanced by adjuvants. In addition, the cross-reactivity between SARS-CoV2 and thyroid antigens has been reported. This would explain, at least, some of the autoimmune/inflammatory reactions produced during and after SARS-CoV2 infection and vaccination. CONCLUSION The autoimmune/inflammatory syndrome induced by adjuvants involving the thyroid could be an adverse effect of SARS-CoV2 vaccination and could be underdiagnosed.
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An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders.
Tagami, T
Endocrine journal. 2021;(5):509-517
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Abstract
Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of β type of resistance to thyroid hormone (RTHβ). The differential diagnoses of RTHβ include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHβ, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHβ and TSHoma. The FT3/FT4 values in RTHβ were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.
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Cryo-EM: A new dawn in thyroid biology.
Coscia, F, Taler-Verčič, A
Molecular and cellular endocrinology. 2021;:111309
Abstract
The thyroid gland accumulates the rare dietary element iodine and incorporates it into iodinated thyroid hormones, utilising several tightly regulated reactions and molecular mechanisms. Thyroid hormones are essential in vertebrates and play a central role in many biological processes, such as development, thermogenesis and growth. The control of these functions is exerted through the binding of hormones to nuclear thyroid hormone receptors that rule the transcription of numerous metabolic genes. Over the last 50 years, thyroid biology has been studied extensively at the cellular and organismal levels, revealing its multiple clinical implications, yet, a complete molecular understanding is still lacking. This includes the atomic structures of crucial pathway components that would be needed to elucidate molecular mechanisms. Here we review the currently known protein structures involved in thyroid hormone synthesis, regulation, transport, and actions. We also highlight targets for future investigations that will significantly benefit from recent advances in macromolecular structure determination by electron cryo-microscopy (cryo-EM). As an example, we demonstrate how cryo-EM was crucial to obtain the structure of the large thyroid hormone precursor protein, thyroglobulin. We discuss modern cryo-EM compared to other structure determination methods and how an integrated structural and cell biological approach will help filling the molecular knowledge gap in our understanding of thyroid hormone metabolism. Together with clinical, cellular and high-throughput 'omics' studies, atomic structures of thyroid components will provide an important framework to map disease mutations and to interpret and predict thyroid phenotypes.
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Dietary Intake of Endocrine Disrupting Substances Presents in Environment and Their Impact on Thyroid Function.
Sokal, A, Jarmakiewicz-Czaja, S, Tabarkiewicz, J, Filip, R
Nutrients. 2021;(3)
Abstract
According to the available data, environmental pollution is a serious problem all over the world. Between 2015 and 2016, pollution was responsible for approximately nine million deaths worldwide. They also include endocrine disrupting chemicals (EDCs) that can interfere with the functioning of the thyroid gland. They are characterized by high persistence in the environment. These substances can enter the body through the gastrointestinal tract, respiratory system, as well as contact with the skin and overcome the placental barrier. EDC can be found in food, water, and personal care products. They can get into food from the environment and as a result of their migration to food products and cosmetics from packaging. EDCs can disrupt the functioning of the thyroid gland through a number of mechanisms, including disrupting the activation of thyroid receptors and the expression of genes that are related to the metabolism, synthesis, and transport of thyroid hormones (HT). There is a need to strengthen the food safety policy that aimed at the use of appropriate materials in direct contact with food. At the same time, an important action is to reduce the production of all waste and, when possible, use biodegradable packaging, which may contribute to the improvement of the quality of the entire ecosystem and the health of food, thus reducing the risk of developing thyroid diseases.
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Celiac Disease and the Thyroid: Highlighting the Roles of Vitamin D and Iron.
Starchl, C, Scherkl, M, Amrein, K
Nutrients. 2021;(6)
Abstract
Celiac disease (CD) and autoimmune thyroid diseases (AITD) like Hashimoto's thyroiditis (HT) and Graves' disease (GD) frequently coexist, entailing numerous potential impacts on diagnostic and therapeutic approaches. Possible correlations might exist through gut microbiota, regulating the immune system and inflammatory responses, promoting autoimmune diseases, as well as shared cytokines in pathogenesis pathways, cross-reacting antibodies or malabsorption of micronutrients that are essential for the thyroid like iron or vitamin D. Vitamin D deficiency is a common finding in patients with AITD, but might protect from autoimmunity by wielding immunoregulatory and tolerogenic impacts. Additionally, vitamin D is assumed to be involved in the onset and progression of CD, presumably plays a substantial protective role for intestinal mucosa and affects the thyroid via its immunomodulatory effects. Iron is an essential micronutrient for the thyroid gland needed for effective iodine utilization by the iron-dependent enzyme thyroid iodine peroxidase (TPO). Despite being crucial for thyroid hormone synthesis, iron deficiency (ID) is a common finding in patients with hypothyroidism like HT and is frequently found in patients with CD. A literature research was conducted to examine the interplay between CD, AITD, vitamin D and iron deficiency. This narrative review highlights the relevant correlation of the two disease entities CD and AITD, their reciprocal impact and possible therapeutic options that should be further explored by future studies.
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Synchronous intrathyroidal parathyroid carcinoma and thyroid carcinoma: case report and review of the literature.
De Falco, N, Santangelo, G, Chirico, F, Cangiano, A, Sommella, MG, Cosenza, A, Ronchi, A, Accardo, M, Pellino, G, Parmeggiani, D, et al
BMC endocrine disorders. 2021;(1):60
Abstract
BACKGROUND Parathyroid carcinoma is a rare endocrine malignancy, rarer when synchronous with a non medullary well differentiated thyroid carcinoma. Parathyroid carcinoma accounts of 0.005% of all malignant tumors and it is responsible for less than 1% of primary hyperparathyroidism. The intrathyroidal localization of a parathyroid gland is not frequent with a reported prevalence of 0.2%. Carcinoma of parathyroids with intrathyroidal localization represents an even rarer finding, reported in only 16 cases described in literature. The rare constellation of synchronous parathyroid and thyroid carcinomas has prompted us to report our experience and perform literature review. CASE PRESENTATION We herein report a case of a 63-years-old man with multinodular goiter and biochemical diagnosis of hyperparathyroidism. Total thyroidectomy with radio-guide technique using gamma probe after intraoperative sesta-MIBI administration and intraoperative PTH level was performed. The high radiation levels in the posterior thyroid lobe discovered an intrathyroidal parathyroid. Microscopic examination revealed a parathyroid main cell carcinoma at the posterior thyroidal left basal lobe, a classic papillary carcinoma at the same lobe and follicular variant of papillary carcinoma at the thyroidal right lobe. To the best of our knowledge, this is the first case documenting a synchronous multicentric non medullary thyroid carcinomas and intrathyroidal parathyroid carcinoma. CONCLUSIONS Our experience was reported and literature review underlining challenging difficulties in diagnostic workup and surgical management was carried out.
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Prevalence of thyroid dysfunction in postpartum women with suboptimal iodine and selenium and adequate iron status.
Jin, Y, Coad, J, Zhou, SJ, Skeaff, S, Ramilan, T, Brough, L
Clinical endocrinology. 2021;(6):873-881
Abstract
OBJECTIVE Postpartum women experience thyroid dysfunction at twice the prevalence of the general population. Adequate biosynthesis of thyroid hormones depends on three trace elements: iodine, selenium and iron. This study aimed to investigate thyroid dysfunction within a cohort of women at six months postpartum in relation to iodine, selenium and iron status. DESIGN This cross-sectional study was part of an observational longitudinal cohort Mother and Infant Nutrition Investigation; data obtained at six months postpartum are reported. SUBJECTS Mother-infant pairs (n = 87) were recruited at three months postpartum and followed up at six months postpartum (n = 78). MEASUREMENTS Thyroid hormones (free triiodothyronine, free thyroxine, thyroid-stimulating hormone) and thyroid peroxidase antibodies were measured. Urinary iodine concentration, breast milk iodine concentration, serum thyroglobulin, plasma selenium, serum ferritin and serum soluble transferrin receptors were determined. Nonparametric data were expressed as median (25th, 75th percentile). RESULTS Thyroid dysfunction was found in 18% of women, and 4% of women had iron deficiency. Median urinary iodine concentration was 85 (43, 134) µg/L, median breast milk iodine concentration was 59 (39, 109) µg/L, and median serum thyroglobulin at 11.4 (8.6, 18.6) µg/L, indicating iodine deficiency. Median plasma selenium concentration was 105.8 (95.6, 115.3) µg/L. Women with marginally lower plasma selenium concentration were 1.12% times more likely to have abnormal TSH concentrations (p = .001). CONCLUSIONS There was a high prevalence of thyroid dysfunction. Plasma selenium concentration was the only significant predictor of the likelihood that women had thyroid dysfunction within this cohort, who were iodine deficient and mostly had adequate iron status. Strategies are required to improve both iodine and selenium status to better support maternal thyroid function.
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miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves' Patients.
Craps, J, Joris, V, Baldeschi, L, Daumerie, C, Camboni, A, Buemi, A, Lengelé, B, Behets, C, Boschi, A, Mourad, M, et al
International journal of molecular sciences. 2021;(1)
Abstract
Graves' disease (GD) is an autoimmune thyroiditis often associated with Graves' orbitopathy (GO). GD thyroid and GO orbital fat share high oxidative stress (OS) and hypervascularization. We investigated the metabolic pathways leading to OS and angiogenesis, aiming to further decipher the link between local and systemic GD manifestations. Plasma and thyroid samples were obtained from patients operated on for multinodular goiters (controls) or GD. Orbital fats were from GO or control patients. The NADPH-oxidase-4 (NOX4)/HIF-1α/VEGF-A signaling pathway was investigated by Western blotting and immunostaining. miR-199a family expression was evaluated following quantitative real-time PCR and/or in situ hybridization. In GD thyroids and GO orbital fats, NOX4 was upregulated and correlated with HIF-1α stabilization and VEGF-A overexpression. The biotin assay identified NOX4, HIF-1α and VEGF-A as direct targets of miR-199a-5p in cultured thyrocytes. Interestingly, GD thyroids, GD plasmas and GO orbital fats showed a downregulation of miR-199a-3p/-5p. Our results also highlighted an activation of STAT-3 signaling in GD thyroids and GO orbital fats, a transcription factor known to negatively regulate miR-199a expression. We identified NOX4/HIF-1α/VEGF-A as critical actors in GD and GO. STAT-3-dependent regulation of miR-199a is proposed as a common driver leading to these events in GD thyroids and GO orbital fats.
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Effects of an Iodine-Containing Prenatal Multiple Micronutrient on Maternal and Infant Iodine Status and Thyroid Function: A Randomized Trial in The Gambia.
Eriksen, KG, Andersson, M, Hunziker, S, Zimmermann, MB, Moore, SE
Thyroid : official journal of the American Thyroid Association. 2020;(9):1355-1365
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Abstract
Background: Iodine supplementation is recommended to pregnant women in iodine-deficient populations, but the impact in moderate iodine deficiency is uncertain. We assessed the effect of an iodine-containing prenatal multiple micronutrient (MMN) supplement in a rural Gambian population at risk of moderate iodine deficiency. Materials and Methods: This study uses data and samples collected as a part of the randomized controlled trial Early Nutrition and Immune Development (ENID; ISRCTN49285450) conducted in Keneba, The Gambia. Pregnant women (<20 weeks gestation) were randomized to either a daily supplement of MMNs containing 300 μg of iodine or an iron and folic acid (FeFol) supplement. Randomization was double blinded (participants and investigators). The coprimary outcomes were maternal urinary iodine concentration (UIC) and serum thyroglobulin (Tg), assessed at baseline and at 30 weeks' gestation. Secondary outcomes were maternal serum thyrotropin (TSH), total triiodothyronine (TT3), total thyroxine (TT4) (assessed at baseline and at 30 weeks' gestation), breast milk iodine concentration (BMIC) (assessed at 8, 12, and 24 weeks postpartum), infant serum Tg (assessed at birth [cord], 12, and 24 weeks postpartum), and serum TSH (assessed at birth [cord]). The effect of supplementation was evaluated using mixed effects models. Results: A total of 875 pregnant women were enrolled between April 2010 and February 2015. In this secondary analysis, we included women from the MMN (n = 219) and FeFol (n = 219) arm of the ENID trial. At baseline, median (interquartile range or IQR) maternal UIC and Tg was 51 μg/L (33-82) and 22 μg/L (12-39), respectively, indicating moderate iodine deficiency. Maternal MMN supplement increased maternal UIC (p < 0.001), decreased maternal Tg (p < 0.001), and cord blood Tg (p < 0.001) compared with FeFol. Maternal thyroid function tests (TSH, TT3, TT4, and TT3/TT4 ratio) and BMIC did not differ according to maternal supplement group over the course of the study. Median (IQR) BMIC, maternal UIC, and infant Tg in the MMN group were 51 μg/L (35-72), 39 μg/L (25-64), and 87 μg/L (59-127), respectively, at 12 weeks postpartum, and did not differ between supplement groups. Conclusions: Supplementing moderately iodine-deficient women during pregnancy improved maternal iodine status and reduced Tg concentration. However, the effects were not attained postpartum and maternal and infant iodine nutrition remained inadequate during the first six months after birth. Consideration should be given to ensuring adequate maternal status through pregnancy and lactation in populations with moderate deficiency.
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Iodine Supplementation in Mildly Iodine-Deficient Pregnant Women Does Not Improve Maternal Thyroid Function or Child Development: A Secondary Analysis of a Randomized Controlled Trial.
Verhagen, NJE, Gowachirapant, S, Winichagoon, P, Andersson, M, Melse-Boonstra, A, Zimmermann, MB
Frontiers in endocrinology. 2020;:572984
Abstract
Background: Iodine deficiency during pregnancy may be associated with lower offspring IQ, but there are few data on the safety and efficacy of maternal iodine supplementation on child development. In a previously reported multi-center randomized trial conducted in Thailand and India, we assessed the effect of iodine supplementation in mildly iodine-deficient pregnant women on offspring development. In this secondary analysis of that trial, we report data only from the Thai pregnant women in the study, who were more iodine deficient at entry. Methods: Pregnant women in Bangkok, Thailand, were randomized to receive daily 200 μg oral iodine or placebo until delivery. We assessed thyroid size and thyroid function during pregnancy and cognitive and motor development at ages 1, 2, and 5.7 years. The trial was registered at www.clinicaltrials.gov/NCT00791466. Findings: Women (n = 514) entered the trial between November 2008 and March 2011 at a mean ± SD gestational age of 11 ± 2.8 weeks; their median (IQR) UIC was 112 (75, 170) μg/L. Mean compliance with supplementation was 88%. We assessed 397 mothers in the 3rd trimester, 231 infants at age 2 y, and 157 children at mean age 5.7 y. During pregnancy, there was a slightly greater decrease in free and total thyroxine concentrations in the iodine group (p < 0.05). At age 2 years, the iodine group had borderline lower scores for combined fine and gross motor function (p = 0.05), but there were no other significant differences in development. At 5.7 years, there were no significant group differences in child development. Conclusion: Daily iodine supplementation in mildly iodine deficient pregnant women was associated with small negative effects on maternal thyroxine concentrations, but did not affect child development. The safety and efficacy of iodine supplementation in mildly-iodine deficient pregnant women needs to be evaluated further in large randomized controlled trials.