Hypothyroidism and autoimmune thyroid disorders in rheumatoid arthritis: relationship with disease activity.

Background and aims: Thyroid function abnormalities and thyroid autoantibodies have previously been described in rheumatoid arthirits (RA) with limited data. In some studies, a relationship was found between thyroid autoantibodies and RA disease activity. However, there are not strong studies in the literature indicating the relationship between thyroid diseases and RA. The aim of this study was to determine the frequency of hypothyroidism and to investigate the relationship between thyroid hormone levels, autoantibodies and disease activity in patients with rheumatoid arthritis (RA). Methods : 1017 patients with the diagnosis of RA were recruited. This observational study was conducted between January 2014 and July 2015. Demographic variables were recorded. Anti-nuclear antibodies (ANA), anti-cyclic citrulli-nated peptide antibody (anti-CCP), Rheumatoid Factor (RF), C reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), anti-microsomal antibody (anti-TPO )and anti-thyroglobulin antibody (anti-TG) were determined. Visual analog score and Disease Activiy Score 28 (DAS-28) ESR and DAS-28 CRP were recorded. The relationship between thyroid hormone levels and thyroid antibodies and disease activity parameters were determined. Results: 98 (%9,7) patients had hypothyroidism and 61 (%6) patients had hyperthyroidism. 210 (20,7%) patients with RA was positive for TPOAb and 165(16,3%) for anti-TG. Positive correlation was detected between anti-TPO positivity and anti-CCP levels (p:0.005, r:0,274). In anti-TG antibody positive patients, there was a significant positive correlation of thyroid hormone levels with CRP and DAS 28-CRP (p:0.01, r:0,120; p:0.01, r:0,169). Conclusion: Thyroid autoantibodies were found to be positive in 16-21% of patients with RA. Though hypothyroidism is not very frequent in RA patients, autoimmune thyroid disease is quite common, which may be related to disease activity.

Age-specific association between thyroid autoimmunity and hypothyroidism in Chinese adults aged over 65 years: a cross-sectional study.

Background: The correlation between thyroid autoimmune (TAI) disease and hypothyroidism in the elderly of different ages remains unclear. This study aimed to investigate the epidemiological characteristics of hypothyroidism, including subclinical hypothyroidism (Shypo) and overt hypothyroidism (Ohypo) in those aged ≥65 years from iodine-adequate areas and reveal the correlation between TAI and hypothyroidism in the elderly of different ages. Methods: It was a cross-sectional study involving 2,443 subjects aged ≥65 years from two iodine-adequate areas in China by cluster sampling. They were assigned to the 65-69-, 70-79-, and ≥80-year-old age group. All subjects were surveyed by questionnaires and received physical examinations, laboratory testing, and thyroid ultrasound. Epidemiological characteristics of thyroid diseases in the elderly were compared among the three groups. Risk factors for hypothyroidism were predicted by binary logistic regression analysis. Results: The median urinary iodine level was 238.70 (197.00, 273.70) µg/L. Thyroid peroxidase antibody or thyroglobulin antibody positivity (11.87%) and Shypo (9.13%) were common in the elderly. The prevalence of hypothyroidism in the elderly increases with age. TAI was a risk factor for Shypo (OR, 1.94; 95% CI, 1.35, 2.80; p < 0.01) and Ohypo (OR, 7.64; 95% CI, 3.40, 17.19; p < 0.01) in elderly Chinese. There was an age-specific correlation between TAI and hypothyroidism in the elderly. However, a significant correlation was not identified between TAI and hypothyroidism in ≥80-year-old age group (p > 0.05). Conclusion: Hypothyroidism, particularly Shypo, is common in the elderly from iodine-adequate areas in China. TAI serves as a risk factor for hypothyroidism in the elderly, with an age-specific correlation with hypothyroidism.

Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

PURPOSE: Thyroid alterations including de novo appearance of thyroid autoimmunity are adverse effects of tyrosine kinase inhibitors, used in solid and hematologic cancer therapy, but the relationship between thyroid alterations during this treatment and the outcome of chronic myeloid leukemia remains unclear. Aim of this study was to investigate whether the presence of thyroid alterations may affect the clinical outcome of chronic myeloid leukemia on tyrosine kinase inhibitors. METHODS: We evaluated thyroid function and autoimmunity in 69 chronic myeloid leukemia patients on long-term therapy looking at the association between thyroid abnormalities and disease molecular response. RESULTS: Overall, 24 of 69 (34.8%) had one or more thyroid abnormalities during therapy. A high percentage of patients (21/69, 30.4%) showed thyroid autoimmunity (positive thyroid autoantibodies with ultrasound hypoechogenicity), while clinical and subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, found in 4 of 69 (5.8%) and 3 of 69 (4.3%) of cases. Second-generation tyrosine kinase inhibitors resulted significantly associated (14/32, 43.7%) with Hashimoto's thyroiditis, compared to first generation (7/37, 18.9%; p = 0.03). Interestingly, we also found a significant association between euthyroid (14/26, 53.8%) and hypothyroid Hashimoto's thyroiditis (4/26, 15.4%) in patients with deep molecular response, as compared to euthyroid (3/43, 7%; p = 0.0001) and hypothyroid (0/43, 0%; p = 0.02) Hashimoto's thyroiditis patients with major molecular response. CONCLUSIONS: Our study confirms and extends our knowledge on the tyrosine kinase inhibitors effects on thyroid, showing that thyroid autoimmunity is frequently observed in chronic myeloid leukemia patients on long-term therapy and is associated with a better oncological response.

Association between vitamin D deficiency and hypothyroidism: results from the National Health and Nutrition Examination Survey (NHANES) 2007-2012.

PURPOSE: Many smaller studies have previously shown a significant association between thyroid autoantibody induced hypothyroidism and lower serum vitamin D levels. However, these finding have not been confirmed by large-scale studies. In this study, we evaluated the relationship between hypothyroidism and vitamin D levels using a large population-based data. METHODS: For this study, we used National Health and Nutrition Examination Survey (NHANES) during the years 2007-2012. We categorized participants into three clinically relevant categories based on vitamin D levels: optimal, intermediate and deficient. Participants were also split into hypothyroid and hyperthyroid. Weighted multivariable logistic regression analyses were used to calculate the odds of being hypothyroid based on vitamin D status. RESULTS: A total of 7943 participants were included in this study, of which 614 (7.7%) were having hypothyroidism. Nearly 25.6% of hypothyroid patients had vitamin D deficiency, compared to 20.6% among normal controls. Adjusted logistic regression analyses showed that the odds of developing hypothyroidism were significantly higher among patients with intermediate (adjusted odds ratio [aOR], 1.7, 95% CI: 1.5-1.8) and deficient levels of vitamin D (aOR, 1.6, 95% CI: 1.4-1.9). CONCLUSION: Low vitamin D levels are associated with autoimmune hypothyroidism. Healthcare initiatives such as mass vitamin D deficiency screening among at-risk population could significantly decrease the risk for hypothyroidism in the long-term.

Genetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade.

Activation of systemic immune responses using PD-1 checkpoint inhibitors is an essential approach to cancer therapy. Yet, the extent of benefit relative to risk of immune related adverse events (irAE) varies widely among patients. Here, we study endocrine irAE from 7 clinical trials across 6 cancers where atezolizumab (anti-PD-L1) was combined with chemotherapies and compared to standard of care. We show that atezolizumab-induced thyroid dysfunction is associated with longer survival. We construct a polygenic risk score (PRS) for lifetime risk of hypothyroidism using a GWAS from the UK Biobank and apply this PRS to genetic data collected from 2,616 patients of European ancestry from these trials. Patients with high PRS are at increased risk of atezolizumab-induced thyroid dysfunction and lower risk of death in triple negative breast cancer. Our results indicate that genetic variation associated with thyroid autoimmunity interacts with biological pathways driving the systemic immune response to PD-1 blockade.

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. METHODS: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. RESULTS: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. CONCLUSION: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.

Association of thyroid antibodies status on the outcomes of pregnant women with hypothyroidism (maternal hypothyroidism on pregnancy outcomes, MHPO-4).

BACKGROUND: Autoimmunity increases with age and is often commonly evaluated in women of the reproductive age group. Prevalence of thyroid antibodies is common even in euthyroid pregnant women. We aim to compare the association of thyroid antibody status on the maternal and neonatal outcomes in pregnant women with hypothyroidism. METHODS: We conducted a cross-sectional retrospective study on 718 cases in the Aga Khan University Hospital. Information was collected on pregnant women who have been diagnosed with hypothyroidism before conception or during their antenatal period. Laboratory data were recorded for thyroid peroxidase antibodies, anti-thyroglobulin antibodies, and thyroid-stimulating hormone levels. Maternal and neonatal outcomes were also noted from medical file records. Data analysis was performed on Statistical Package for the Social Sciences version 20.0. RESULTS: Overall, 146 out 718 cases were included for final analysis. Thyroid peroxidase antibodies were positive in 66.4% and anti-thyroglobulin was positive in 52.1% cases, whereas 43.8% of cases had both antibodies positive. Pre-gestational diabetes was significantly associated with thyroid autoimmunity. There was a 73% less chance of gestational hypertension for thyroid autoimmune groups. Gestational diabetes and maternal (chronic) hypertension were found to have an independent effect on postpartum hemorrhage. Hypertensive disorders in pregnancy were found to have an independent risk for premature birth. CONCLUSION: Our study reports a 74.7% prevalence of positive thyroid antibodies in hypothyroid pregnant women, with higher association with pre-gestational diabetes. Gestational hypertension was least likely to occur in thyroid autoimmune groups. None of the outcomes were independently associated with worse outcomes.

Primary hypothyroidism and autoimmune thyroiditis alter the transcriptional activity of genes regulating neurogenesis in the blood of patients.

Objective. Thyroid hormones play an important role in the development and maturation of the central nervous symptom and their failure in the prenatal period leading to an irreversible brain damage. Their effect on the brain of adult, however, has not been fully studied. With the discovery of neurogenesis in the adult brain, many recent studies have been focused on the understanding the basic mechanisms controlling this process. Many neurogenesis regulatory genes are not only transcribed but also translated into the blood cells. The goal of our study was to analyze the transcriptional activity of neurogenesis regulatory genes in peripheral blood cells in patients with thyroid pathology.Methods. The pathway-specific PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) was used to identify and validate the neurogenesis regulatory genes expression in patients with thyroid pathology and control group.Results. The results showed that GFRA3, NGFR, NRG1, NTF3, NTRK1, and NTRK2 significantly decreased their expression in patients with autoimmune thyroiditis with rising serum of autoantibodies. The patients with primary hypothyroidism, as a result of autoimmune thyroiditis and postoperative hypothyroidism, had significantly lower expression of FGF2, NGFR, NRG1, and NTF3. The mRNA level of CNTFR was markedly decreased in the group of patients with postoperative hypothyroidism. No change in the ARTN, PSPN, TFG, MT3, and NELL1 expression was observed in any group of patients.Conclusion. The finding indicates that a decrease in thyroid hormones and a high level of autoantibodies, such as anti-thyroglobulin antibody and anti-thyroid peroxidase antibody, affect the expression of mRNA neurogenesis-regulated genes in patients with thyroid pathology.

Subclinical Hypothyroidism as the Most Common Thyroid Dysfunction Status in Children With Down's Syndrome.

Introduction: Thyroid dysfunctions are one of the most common abnormalities coexisting in children with Down's syndrome (DS) and have been reported in up to 54% of cases. Aim of the Study: The purposes of this retrospective study were to investigate the course of subclinical hypothyroidism in children with DS, to evaluate the thyroid function of these subjects in relation to the risk of developing overt thyroid disease and autoimmunity, and to identify clinical and biochemical characteristics of patients prescribed L-T4 therapy in children and adolescents with DS and SH. Material and Methods: The records of DS patients referred to the Endocrinology Outpatient Clinic between 2010 and 2015 for screening of thyroid function were observed till the end of 2019 June and analyzed retrospectively. The children diagnosed with congenital hypothyroidism, acute lymphoblastic leukemia, and seizures and treated with drugs that may have interfered with thyroid function like lithium, antiepileptic, or iodinated drugs and glucocorticoids were excluded from the study. Results: The data of 77 DS patients were collected, evaluated, and analyzed. The study group consisted of 73 patients (32 girls and 41 boys with the mean age at baseline of 3.0 ± 4.5 years). A total of 63/73 (87%) children were diagnosed with SH. The 16/63 (25.4%) patients were followed-up without the treatment (group SH-T0), and therapy with levothyroxine (L-T4) was introduced in 47/63 (74.6%) SH children with a mean dosage of 1.8 ± 1.0 µg/kg/day (group SH-T1). Thyroxine supplementation did not improve growth expressed as ΔhSDS (0.1 ± 1.3, ranged -2.1 to 3.8 in SH-T0 vs. 0.0 ± 0.7, ranged -1.7 to 1.4 in SH-T1, p = 0.96) and ΔBMI Z-score (0.3 ± 0.9, ranged -0.9 to 2.6 in SH-T0 vs. 0.3 ± 1.1, ranged -2.1 to 2.9 in SH-T1, p = 0.65). Positive anti-TPO and anti-TG antibodies were detected in 7/63 (11.1%) DS cases. Conclusions: SH is the most frequent presentation of thyroid gland dysfunction in DS children. A small percentage of patients develop an overt hypothyroidism, particularly in females with mostly positive titer of antithyroid autoantibodies.

Evaluation of Serum Ferritin and Anti-Thyroid Peroxidase Antibody Status in Newly Diagnosed Subclinical Cases of Hypothyroidism.

BACKGROUND: Serum ferritin concentrations are altered in hypothyroidism, but there is no available literature regarding the status of serum ferritin in anti-thyroid peroxidase (anti-TPO) positive hypothyroidism. The objectives of our study were to evaluate the titer of anti-TPO and serum ferritin in newly diagnosed hypothyroid patients and to find out any difference in serum ferritin concentration between antibody-positive and antibody-negative patients. METHODS: A total of 143 subjects above the age of 18 years were recruited, and serum Thyroid Stimulating Hormone (TSH), free T3, free T4, anti-TPO, and ferritin were assayed by chemiluminescence method. According to their serum analysis findings, three groups were made as Group 1 of 49 subjects with hypothyroidism and anti-TPO positive, Group 2 of 47 subjects with hypothyroidism and anti-TPO negative, and Group 3 of 47 euthyroid and anti-TPO negative controls. RESULTS: Kruskal Wallis H test was applied, and the difference in concentration of TSH, FT3, FT4, Ferritin, anti-TPO amongst the three groups was found to be significant. The relationship between anti-TPO levels and serum ferritin concentration was further studied by multinomial logistic regression. We have found that there is a significant difference between the concentrations of ferritin; hence, it is highly likely that those with a high level of anti-TPO antibody shall have a higher concentration of serum ferritin. CONCLUSION: Ferritin concentrations were decreased in anti-TPO negative hypothyroidism, but in the case of anti-TPO positive hypothyroidism the ferritin concentrations are raised. Hence, hypothyroidism should not always be considered as an iron deficiency state.

Thyroid function abnormality induced by PD-1 inhibitors have a positive impact on survival in patients with non-small cell lung cancer.

BACKGROUND: Thyroid function abnormality (TFA) is a common immune-related adverse event (irAEs), but the association between it and the efficacy of programmed cell death protein 1 (PD-1) inhibitor in advanced non-small cell lung cancer (NSCLC) is finitely understood. MATERIALS AND METHODS: We conducted a single center, retrospective study of advanced NSCLC patients who were treated with PD-1 inhibitors between 10 October 2016 and 1 April 2020. TFA was characterized as new onset subclinical hypothyroidism, overt hypothyroidism, subclinical hyperthyroidism and overt hyperthyroidism. Frequency of development of TFA-irAEs, and its relationship with overall survival (OS) and progression free survival (PFS) were evaluated. RESULTS: In our study, 191 patients were treated with PD-1 inhibitors. Among them, forty patients (20.9%) developed TFA, of whom 10 (5.2%) presented with subclinical hypothyroidism, 15 (7.9%) with overt hypothyroidism, 6 (3.1%) with subclinical hyperthyroidism and 9 (4.7%) with overt hyperthyroidism. Survival analysis showed that the OS (16.8 months vs. 11.1 months, p < 0.001) and PFS (10.4 months vs. 5.5 months, p < 0.001) were significantly longer in patients with TFA-irAEs than in those without TFA-irAEs. In subgroup analysis of hypothyroidism and hyperthyroidism groups, similar trends were also obtained for both OS and PFS. After adjusting for potential confounding variables, patients with TFA-irAEs had a lower mortality risk (HR 0.334, 95%CI 0.196-0.571) than those without TFA-irAEs. CONCLUSIONS: TFA-irAEs is associated with enhanced PD-1 inhibitor efficacy in advanced NSCLC patients and it may be a biomarker for antitumor immune response.

Thyroid Hormone Receptor α1 Mutants Impair B Lymphocyte Development in a Mouse Model.

Background: Mutations of the thyroid hormone receptor α (THRA) gene cause resistance to thyroid hormone (RTHα). RTHα patients exhibit very mild abnormal thyroid function test results (serum triiodothyronine can be high-normal to high; thyroxine normal to low; thyrotropin is normal or mildly raised) but manifest hypothyroid symptoms with growth retardation, delayed bone development, and anemia. Much has been learned about the in vivo molecular actions in TRα1 mutants affecting abnormal growth, bone development, and anemia by using a mouse model of RTHα (Thra1PV/+ mice). However, it is not clear whether TRα1 mutants affect lymphopoiesis in RTHα patients. The present study addressed the question of whether TRα1 mutants could cause defective lymphopoiesis. Methods: We assessed lymphocyte abundance in the peripheral circulation and in the lymphoid organs of Thra1PV/+ mice. We evaluated the effect of thyroid hormone on B cell development in the bone and spleen of these mice. We identified key transcription factors that are directly regulated by TRα1 in the regulation of B cell development. Results: Compared with wild-type mice, a significant reduction in B cells, but not in T cells, was detected in the peripheral circulation, bone marrow, and spleen of Thra1PV/+ mice. The expression of key transcription regulators of B cell development, such as Ebf1, Tcf3, and Pax5, was significantly decreased in the bone marrow and spleen of Thra1PV/+ mice. We further elucidated that the Ebf1 gene, essential for lineage specification in the early B cell development, was directly regulated by TRα1. Thus, mutations of TRα1 could impair B cell development in the bone marrow via suppression of key regulators of B lymphopoiesis. Conclusions: Analysis of lymphopoiesis in a mouse model of RTHα showed that B cell lymphopoiesis was suppressed by TRα1 mutations. The suppressed development of B cells was, at least in part, via inhibition of the expression of key regulators, Ebf1, Tcf3, and Pax5, by TRα1 mutations. These findings suggest that the mutations of the THRA gene in patients could lead to B cell deficiency.

Anti-thyroid peroxidase antibody and subclinical hypothyroidism in relation to hypertension and thyroid cysts.

Hypertension frequently occurs in subclinical hypothyroidism (SCH). By bolstering thyroid inflammation, anti-peroxidase antibody (TPO-Ab) causes autoimmune thyroiditis, which is one of the most common causes of SCH. Since the absence of thyroid cysts is associated with TPO-Ab (+) based on the indication of latent thyroid damage, we explored the potential mechanism underlying the association among TPO-Ab, SCH, hypertension, and thyroid cysts. A cross-sectional study of 1,483 Japanese aged 40-74 years was conducted. Thyroid cysts were defined as those having a maximum diameter of ≥ 2.0 mm, containing no solid component. TPO-Ab (+) was positively associated with SCH with hypertension (adjusted odds ratio [OR] and 95% confidence interval [CI], 2.62 [1.40, 4.89]) but not with SCH without hypertension (0.84 [0.37, 1.89]), respectively. Moreover, among participants without thyroid cysts, SCH was positively associated with hypertension (2.15 [1.23, 3.76]) but not among participants with thyroid cysts (0.58 [0.16, 2.16]), respectively. TPO-Ab was positively associated with SCH with hypertension, but not with SCH without hypertension. In addition, status of thyroid cysts might act as a determinant factor on the association between SCH and hypertension. These findings are efficient tools to clarify the background mechanism that underlies SCH.

TPO antibody positivity and adverse pregnancy outcomes.

Thyroid autoimmunity (TAI) is prevalent amongst women of reproductive age. TAI describes the presence of circulating anti-thyroid autoantibodies that are targeted against the thyroid, with or without thyroid dysfunction. Thyroid peroxidase antibodies (TPOAb) are the most common anti-thyroid autoantibodies. Around 10% of biochemically euthyroid individuals also have an elevated TPOAb titre. Many studies have linked the presence of TPOAb to adverse maternal and fetal outcomes in pregnancy, in particular miscarriage and pre-term birth, even in the absence of thyroid dysfunction. The causal pathway is poorly understood and few trials have looked to find treatments to reduce adverse outcomes. This review discusses in detail the associated adverse outcomes of TPOAb in pregnancy and the results of trials exploring methods to reduce such outcomes. Recommendations for counselling and monitoring of women with TPOAb and suggested areas for future work are also outlined.

Metformin reduces autoimmune antibody levels in patients with Hashimoto's thyroiditis: A systematic review and meta-analysis.

BACKGROUND: In the past few years, an increasing number of studies have proposed the idea of extending the therapeutic range of metformin from traditional hypoglycaemic to autoimmune diseases, and confirmed in a variety of autoimmune diseases. However, whether metformin can be used to treat Hashimoto's thyroiditis (HT), which is characterised by thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), is unknown. Therefore, we conducted a systematic review and meta-analysis to evaluate whether metformin can reduce the levels of TPOAb and TgAb in patients with HT or subclinical hypothyroidism (SH), so as to provide a theoretical basis for metformin treatment of these diseases. METHODS: PubMed, Web Of Science and Embase were searched for observational studies investigating the changes of TPOAb and TgAb in patients with HT after metformin treatment. Two authors extracted data from eligible studies and classified them as HT and subclinical hypothyroidism subgroups. The calculation was then performed by weighted mean difference (WMD) combined with a fixed-effects model analysis or standard mean difference (SMD) with a random-effects model analysis, based on the measurement of the outcome. RESULTS: Metformin significantly reduced TPOAb levels and TgAb levels in patients with HT and SH, especially TPOAb (HT: pTPOAb = .009, pTgAb = .046; SH: pTPOAb = .034, pTgAb = .066). In addition, metformin also reduced the levels of thyroid stimulating hormone (TSH), homeostasis model assessment of insulin resistance (HOMA-IR) in patients with HT and SH (HT: pTSH = .000 and pHOMA-IR = .000; SH: pTSH = .000 and pHOMA-IR = .000, respectively). CONCLUSION: Metformin significantly reduces TPOAb level and TgAb level in patients with HT and SH, especially TPOAb. This study is the first to provide a preliminary theoretical basis for the clinical application of metformin in the treatment of HT.

Thyrotoxicosis in patients with COVID-19: the THYRCOV study.

OBJECTIVE: This study assessed thyroid function in patients affected by the coronavirus disease-19 (COVID-19), based on the hypothesis that the cytokine storm associated with COVID-19 may influence thyroid function and/or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly act on thyroid cells, such as previously demonstrated for SARS-CoV-1 infection. DESIGN AND METHODS: This single-center study was retrospective and consisted in evaluating thyroid function tests and serum interleukin-6 (IL-6) values in 287 consecutive patients (193 males, median age: 66 years, range: 27-92) hospitalized for COVID-19 in non-intensive care units. RESULTS: Fifty-eight patients (20.2%) were found with thyrotoxicosis (overt in 31 cases), 15 (5.2%) with hypothyroidism (overt in only 2 cases), and 214 (74.6%) with normal thyroid function. Serum thyrotropin (TSH) values were inversely correlated with age of patients (rho -0.27; P < 0.001) and IL-6 (rho -0.41; P < 0.001). In the multivariate analysis, thyrotoxicosis resulted to be significantly associated with higher IL-6 (odds ratio: 3.25, 95% confidence interval: 1.97-5.36; P < 0.001), whereas the association with age of patients was lost (P = 0.09). CONCLUSIONS: This study provides first evidence that COVID-19 may be associated with high risk of thyrotoxicosis in relationship with systemic immune activation induced by the SARS-CoV-2 infection.

Nerve impulse transmission pathway-focused genes expression analysis in patients with primary hypothyroidism and autoimmune thyroiditis.

OBJECTIVE: Thyroid hormones have important actions in the adult brain. They regulate genes expression in myelination, differentiation of neuronal and glial cells, and neuronal viability and function. METHODS: We used the pathway-specific real-time PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) to identify and verify nerve impulse transmission pathway-focused genes expression in peripheral white blood cells of patients with postoperative hypothyroidism, hypothyroidism as a result of autoimmune thyroiditis (AIT) and AIT with elevated serum an anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies. RESULTS: It was shown that patients with postoperative hypothyroidism and hypothyroidism resulting from AIT had significantly lower expression of BDNF and CBLN1. In patients with AIT with elevated serum anti-Tg and anti-TPO antibodies, the expression of GDNF was significantly down-regulated and the expression of PNOC was up-regulated. The expression levels of MEF2C and NTSR1 were decreased in the group of patients with postoperative hypothyroidism and AIT, correspondingly. CONCLUSIONS: The results of this study demonstrate that AIT and hypothyroidism can affect the expression of mRNA nerve impulse transmission genes in gene specific manner and that these changes in gene expressions can be playing a role in the development of neurological complications associated with thyroid pathology. Detection of the transcriptional activity of nerve impulse transmission genes in peripheral white blood cells can be used as an important minimally invasive prognostic marker of the risk for developing neurological complications comorbid with thyroid pathology.

Targeted Antenatal Screening for Predicting Postpartum Thyroiditis and Its Evolution Into Permanent Hypothyroidism.

Postpartum thyroiditis (PPT) has a prevalence of 1-22%, with an ~50% rate of evolution into permanent hypothyroidism (PH). PPT risk is assessed by measuring serum thyroid antibodies during gestation, as 1/3-1/2 of Ab+ve pregnant women will develop PPT. Family and personal history positive for autoimmune non-thyroid diseases (AINTDT), and consumption of swordfish increases while consumption of small oily fish decreases the risk of PPT. Monitoring thyroid function in a very high-risk subgroup avoids the costs of the Ab-based universal screening. We aimed at identifying such subgroup in 412 women followed from week 7-11 of gestation to month 12 postpartum. At study entry, we measured serum TPOAb, TgAb, TSH, FT4, FT3, and evaluated seafood consumption, familial history for thyroid diseases and AINTD, and personal history for AINTD. We measured TSH, FT4, FT3 at 1.5, 3, 6, and 12 months postpartum. PPT occurred in 63 women (15.3%), and PH in 34/63 (54%). Based on positivity/negativity for the three histories, women were classified into 8 categories, with PPT rates of 3.8-100%. Seafood consumption allowed further separation of subgroups having different PPT risks. We considered 11 possible strategies, termed [a] through [k]. Strategy [a] consisted in omitting gestational screening, while performing universal postpartum monitoring with TSH and one thyroid hormone; strategy [k] consisted in selective gestational screening with TPOAb and TgAb, based on history and fish consumption, and selective postpartum monitoring in TPOAb and/or TgAb+ve women. The 100% sensitivity, specificity and diagnostic accuracy of strategy [a] were counterbalanced by the highest costs (Euro 32,960 or 523 per each PPT caught). The corresponding numbers for strategy [k] were 78, 95, 93%, and Euro 8,920 or 182/PPT caught. These savings stem from gestational screening being done in 186 women, and postpartum monitoring done in 65/186 women. One gestational screning-free strategy was the cheapest (Euro 2,080 or 83/PPT caught), because based on postpartum monitoring of only 26 women, but had the lowest sensitivity (40%). Identification of pregnant women having different risks for PPT is feasible, with the costless evaluation of history and seafood consumption driving gestational screening of thyroid antibody status and postpartum monitoring of thyroid function.

Prevalence of thyroid autoimmunity and effect of levothyroxine treatment in a cohort of 1064 patients with recurrent pregnancy loss.

RESEARCH QUESTION: Does initiating levothyroxine treatment based on thyroid-stimulating hormone (TSH) >2.5 mIU/l or thyroid autoimmunity improve pregnancy continuation rates in recurrent pregnancy loss (RPL) patients? DESIGN: A retrospective cohort study of 1064 RPL patients, in which subjects were classified as either euthyroid (TSH 0.1 to ≤2.5 mIU/l), borderline-subclinical hypothyroid (borderline-SCH, TSH 2.5 to ≤4 mIU/l) or subclinical hypothyroid (SCH, TSH 4 to ≤10 mIU/l). For subjects with ≥2 pregnancy losses and a subsequent pregnancy with known outcome, a comparison was done of the pregnancy continuation rate past 10 weeks of treated and untreated borderline-SCH (n = 98) and untreated euthyroid (n = 279) subjects, and between subjects with positive (n = 18) and negative (n = 206) thyroid peroxidase (TPOAb tests) within the borderline-SCH and euthyroid groups. RESULTS: 72.7% were euthyroid (721/992), 19.4% (192/992) were borderline-SCH, and 5.4% (54/992) were subclinically hypothyroid (SCH). Of 401 women with a subsequent pregnancy of known outcome at 10 gestational weeks, 21% received treatment with levothyroxine. 57.7% of subjects had a TPOAb test, which was positive in 9.25% (37/400) in euthyroid, 16.5% (22/133) in borderline-SCH subjects and 35.3% (12/34) in SCH subjects. Treatment did not improve pregnancy continuation rates in borderline-SCH subjects (P = 0.392). There was no difference in pregnancy outcomes based on TPOAb status and treatment for borderline-SCH subjects (P = 0.4214), or based on TPOAb status for euthyroid subjects (P = 0.2668). CONCLUSIONS: Treatment of hypothyroidism in pregnancy should be initiated based on a TSH >4 mIU/l. Treatment initiation based on thyroid autoimmunity or a TSH >2.5 mIU/l may result in overtreatment.