The pathogenesis and manifestation of autoimmune thyroid diseases (AITDs), Graves\' disease (GD), and Hashimoto\'s disease (HD) are associated with T cell activation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) plays a crucial role in the regulation of T cell activation. DNA methylation levels of eight CpG sites in the CTLA4 gene and expression levels of soluble CTLA-4 were examined. Methylation levels of +22 CpG and CT60 CpG-SNPs in patients with GD and HD with the CT60 GG genotype were lower than those in control subjects. Methylation levels of the-15 CpG sites were lower in patients with intractable GD than those in GD patients in remission. These results suggest that demethylation of +22 CpG and CT60 CpG-SNPs may be associated with susceptibility to GD and HD in subjects with the CTLA4 CT60 GG genotype, and that demethylation of -15 CpG may be associated with the intractability of GD.

There is growing evidence suggesting an association between severe acute respiratory coronavirus syndrome coronavirus 2 (SARS-CoV-2) infection and various extrapulmonary diseases since the advent of coronavirus disease 2019 (COVID-19) pandemic. However, case reports of fulminant type 1 diabetes mellitus (FT1D) following SARS-CoV-2 infection are limited. We encountered a 44-year-old Japanese woman who developed FT1D accompanied by subclinical thyrotoxicosis caused by autoimmune thyroid disease (AITD) approximately one week after SARS-CoV-2 infection. The patient developed fever and flu-like symptom 4 days before transportation and tested positive then for the SARS-CoV-2 antigen self-test. She subsequently developed sudden thirst, polyuria, and fatigue of 1 day duration and was urgently brought to our emergency room. Laboratory findings indicated diabetic ketoacidosis (DKA) without marked elevation of serum glycated hemoglobin (HbA1c) levels (glucose, 930 mg/dL; HbA1c, 7.4%). Her insulin secretory capacity was almost completely depleted, and islet-specific autoantibodies were negative. Endocrine examinations revealed subclinical thyrotoxicosis, which was positive for thyroid stimulation hormone receptor antibodies. Based on these results, the patient was diagnosed with FT1D accompanied by AITD and immediately started on intensive insulin therapy with a basal-bolus subcutaneous insulin regimen. Human leukocyte antigen analysis revealed haplotypes, indicating susceptibility to both FT1D and AITD. Further studies are required to elucidate the causal relationship between SARS-CoV-2 infection, FT1D, and AITD. However, clinicians must be vigilant about possible development of FT1D and AITD to enable accurate diagnosis and treatment of patients with DKA during the COVID-19 pandemic.

BACKGROUND: Patients afflicted by type 1 diabetes (T1D) exhibit polyautoimmunity (PolyA). However, the frequency and distribution of PolyA in T1D is still unknown.
OBJECTIVE: We conducted a systematic review and meta-analysis to define the prevalence of latent and overt PolyA in individuals with T1D.
METHODS: Following PRISMA guidelines, a comprehensive search across medical databases identified studies on latent and overt PolyA in T1D. Two researchers independently screened, extracted data, and assessed study quality. A random effects model was utilized to calculate the pooled prevalence, along with its corresponding 95 % confidence interval (CI), for latent PolyA and overt PolyA. Meta-regression analysis was conducted to study the effect of study designs, age, sex, and duration of disease on pooled prevalence.
RESULTS: A total of 158 articles, encompassing a diverse composition of study designs were scrutinized. The analysis included 270,890 individuals with a confirmed diagnosis of T1D. The gender was evenly distributed (50.30 % male). Notably, our analysis unveiled an overt PolyA prevalence rate of 8.50 % (95 % CI, 6.77 to 10.62), with North America having the highest rates (14.50 %, 95 % CI, 7.58 to 24.89). This PolyA profile was further characterized by a substantial incidence of concurrent autoimmune thyroid disease (7.44 %, 95 % CI, 5.65 to 9.74). Moreover, we identified a notable prevalence of latent PolyA in the T1D population, quantified at 14.45 % (95 % CI, 11.17 to 18.49) being most frequent in Asia (23.29 %, 95 % CI, 16.29 to 32.15) and Oceania (21.53 %, 95 % CI, 16.48 to 27.62). Remarkably, this latent PolyA phenomenon primarily featured an array of autoantibodies, including rheumatoid factor, followed by Ro52, thyroid peroxidase antibodies, and thyroglobulin antibodies. Duration of the disease was associated with a highest frequency of latent (β: 0.0456, P-value: 0.0140) and overt PolyA (β: 0.0373, P-value: 0.0152). No difference in the pooled prevalence by study design was observed.
CONCLUSIONS: This meta-analysis constitutes a substantial advancement in the realm of early detection of PolyA in the context of T1D. Individuals with T1D should regularly undergo assessments to identify potential concurrent autoimmune diseases, especially as they age.

BACKGROUND: One of the sensitive markers for autoimmune thyroid disease (AITD) clinical identification is TRAb. To quickly distinguish TRAb with distinct antigenic epitopes, a straightforward and uncomplicated technique has not yet been created.
OBJECTIVE: To search for molecular diagnostic targets for different types of AITD (Graves\' disease (GD), Graves\' orbitopathy (GO), GD with III degree goiter (GD(3)), Hypothyroidism combined with positive TRAb (HT(TRAb+))) as molecular diagnostic targets.
METHODS: Following action on thyroid cells, differential genes (DEGs) generated by TRAb with distinct antigenic epitopes were detected and identified by RNA-seq, bioinformatics analysis, and RT-qPCR in the serum of AITD patients. Using the EdU assay, the effect of co-culturing thyroid cells with different antigenic TRAb epitopes on the cells\' capacity to proliferate was investigated.
RESULTS: Bioinformatics analysis and RT-qPCR validation identified one GD key gene (AHSG), two GO key genes (ADRA1D and H2BC18), two GD(3) key genes (SOCS1 and CYBB), and one HT (TRAb+) key gene (MASP2). Correlation analysis and ROC curves showed that the above genes could be used as molecular diagnostic targets for different types of AITD. Finally, EdU results showed that TRAb inhibited thyroid cell proliferation in the HT (TRAb+) group compared with the normal control group, while the remaining three groups promoted thyroid cell proliferation, with a statistically significant difference (P < 0.05).
CONCLUSIONS: We identified six key genes for different types of AITD, which have diagnostic value for different types of AITD. Meanwhile, we found that TRAb of different antigenic epitopes in AITD have different biological functions.

BACKGROUND: Bioassays provide information on the functionality of thyrotropin receptor antibodies (TSH-R-Ab) and thus may offer more clinical utility than binding assays.
OBJECTIVE: In this prospective, blinded, US-based study, the clinical performance of several TSH-R-Ab assays was compared.
METHODS: US endocrinology clinic.
METHODS: One hundred sixty-two unselected, consecutive, well-documented patients with various thyroid diseases and healthy controls.
METHODS: Blinded TSH-R-Ab measurements.
METHODS: Sensitivity and specificity of 4 TSH-R-Ab assays.
RESULTS: The 4 TSH-R-Ab assays were negative in all 42 patients without autoimmune thyroid disease (AITD). In 104 patients with Graves\' disease (GD), irrespective of the disease duration, TSH-R-Ab positivity was present in 65 (63%), 67 (65%), and 87 (84%) for the Cobas and Immulite binding assays and stimulatory TSH-R-Ab [thyroid-stimulating immunoglobin (TSI)] bioassay, respectively (TSI vs Immulite P < .0025, TSI vs Cobas P < .0009). Fifteen newly diagnosed GD patients were all positive in the TSI bioassay, but only 11 (73%) were positive in the Cobas and Immulite binding assays. Nine GD patients with biochemical subclinical hyperthyroidism were TSI-positive but Immulite- and Cobas-negative. Two GD patients were blocking TSH-R-Ab [thyroid-blocking immunoglobin (TBI)]-positive and TSI-negative, and the Immulite and Cobas were positive in both. Additional serum samples from AITD patients that consisted of 30 TBI-positive and 10 TSI-positive samples were blindly tested in the binding assays. Only 6 of the 10 TSI-positive samples were positive in both binding assays, and 30 and 28 of the TBI-positive samples were positive in the Cobas and Immulite assays, respectively.
CONCLUSIONS: Binding TSH-R-Ab assays are less sensitive than TSI bioassays and are not specific for stimulating antibodies. Measuring the function of TSH-R-Ab in a bioassay can provide useful information to clinicians.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is frequently associated with other autoimmune disorders that are characterized by the presence of organ-specific autoantibodies. Autoimmune thyroid disease (AIT) is the most frequent autoimmune disorder associated with T1DM. Thyroid peroxidase antibodies (TPOAb) serve as a marker for diagnosing AIT. Prior research indicates that thyroid dysfunction can negatively impact linear growth and glycemic control in subjects with T1DM. The present study was done to determine the impact of thyroid autoimmunity on the clinical and biochemical characteristics of patients with newly diagnosed T1DM.
METHODS: In this single-center, hospital-based, observational cross-sectional study, we enrolled 70 patients with newly diagnosed T1DM ≤18 years of age. Type 1 diabetes mellitus was diagnosed based on the acute onset of osmotic symptoms with or without diabetic ketoacidosis (DKA), severe hyperglycemia (blood glucose >13.9 mmol/l (>250 mg/dl)), and insulin requirement from the onset of diabetes. Secondary diabetes, pancreatic diabetes (Type 3c), and maturity-onset diabetes of the young (MODY) were excluded. Participants were screened for AIT disease using TPOAb testing. Based on the presence or absence of TPOAb, the participants were categorized into two groups: Group A comprised individuals with T1DM who tested positive for TPOAb, while Group B consisted of those who tested negative for TPOAb.
RESULTS: Out of 70 patients, 41.4% were girls and 58.6% were boys, with a mean age of 9.8±4.4 years. The prevalence of TPOAb among the cohort was 18.6%. A significant majority of patients (71.4%), presented with DKA. Group A showed significantly lower mean height standard deviation scores (SDS) compared to Group B (-0.3±0.6 vs. -0.8±0.5, p = 0.004), but no differences in weight SDS or BMI SDS. Hemoglobin A1C (HbA1c) levels, C-peptide levels, and frequency of DKA did not differ between groups. Group A had higher mean thyroid-stimulating hormone (TSH) levels (4.8±3.7 µU/ml vs. 2.6±1.5 µU/ml, p = 0.001) and a greater proportion of patients with TSH levels above the upper limit of normal compared to Group B (38.4% vs. 7.1%, p = 0.008). Additionally, Group A exhibited a higher frequency of glutamic acid decarboxylase antibody (GADA) positivity compared to Group B (46.1% vs. 17.5%, p = 0.04).
CONCLUSIONS: Patients positive for TPOAb exhibited significantly lower height SDS compared to TPOAb-negative patients. Additionally, T1DM patients with TPOAb positivity showed an increased frequency of GADA compared to those without TPOAb. However, no significant differences were found in HbA1c levels, C-peptide levels, or hematological parameters between TPOAb-positive and TPOAb-negative patients. These findings emphasize the impact of TPOAb on growth parameters in T1DM and advocate for routine screening of TPOAb in all T1DM patients, starting at the time of diabetes diagnosis.

OBJECTIVE: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define pre-clinical autoimmune thyroid disease (AITD) which can progress to either clinical hypo- or hyperthyroidism. We determined the age at seroconversion in children genetically at risk for type 1 diabetes.
METHODS: TPOAb and TgAb seropositivity were determined in 5066 healthy children with HLA DR3 or DR4 containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Children seropositive on the cross-sectional initial screen at 8-13 years of age had longitudinally collected samples (from 3.5 months of age) screened retrospectively and prospectively for thyroid autoantibodies to identify the age at seroconversion. First-appearing autoantibody was related to sex, HLA genotype, family history of AITD, and subsequent thyroid dysfunction and disease.
RESULTS: The youngest appearance of TPOAb and TgAb was 10 and 15 months of age, respectively. Girls had higher incidence rates of both autoantibodies. Family history of AITD was associated with a higher risk of TPOAb hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.17, 3.08; and TgAb HR 2.55, 95% CI 1.91, 3.41. The risk of progressing to hypo- or hyperthyroidism was not different between TgAb and TPOAb, but children with both autoantibodies appearing at the same visit had a higher risk compared to TPOAb appearing first (HR 6.34, 95% CI 2.72, 14.76).
CONCLUSIONS: Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypo- or hyperthyroidism.

Background/Objectives: The interplay between thyroid function and kidney graft function following kidney transplantation remains incompletely understood. Thyroid disorders are more prevalent in kidney transplant recipients than in the general population and are associated with poorer outcomes. Methods: This prospective, single-center study was designed to estimate thyroid function (thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), free thyroxine (FT4), as well as anti-thyroid peroxidase antibody (anti-TPO), anti-thyroglobulin antibody (anti-Tg), and thyroid-stimulating immunoglobulin (TSI)) and its influence on kidney graft function among a cohort of 23 kidney transplant recipients during a follow-up period of 12 months. Results: Significantly increased levels of T4 and T3 were observed 12 months post-transplantation, with FT3 levels increasing significantly after 6 months. The prevalence of immeasurably low anti-Tg antibodies rose during follow-up. Initially, 8% of patients showed positive TSI, which turned negative for all after 6 months. A statistically significant correlation was found between the initial TSH and the estimated glomerular filtration rate (eGFR) value 6 months after transplantation (p = 0.023). The graft function was stable. Proteinuria was statistically significantly lower 12 months after transplantation. Conclusions: Identifying additional risk factors, understanding their impact on kidney graft function, and recognizing cardiovascular comorbidities could enhance patient care. Notably, this study marks the first prospective investigation into thyroid function after kidney transplantation in Croatia, contributing valuable insights to the global understanding of this complex interplay.

OBJECTIVE: To investigate the expression of microRNA-142 (miR-142) in children with autoimmune thyroid disease (AITD) and its relationship with the imbalance of helper T cell 17 (Th17) and regulatory T cell (Treg).
METHODS: A total of 89 children hospitalized for AITD from January 2019 to December 2022 were prospectively selected as the study subjects, including 48 children with Graves\' disease (GD group) and 41 children with Hashimoto\'s thyroiditis (HT group). Additionally, 55 healthy children undergoing physical examinations during the same period were selected as the control group. The differences in serum miR-142, antithyroglobulin antibody (TGAb), antithyroperoxidase antibody (TPOAb), Th17/Treg, and interleukin-17 (IL-17) expression were compared among the groups.
RESULTS: The expression of miR-142, TPOAb, TGAb, Th17, Th17/Treg, and IL-17 in the GD group and HT group was higher than that in the control group, while Treg was lower than that in the control group (P<0.05). Pearson correlation analysis revealed that in the GD group, miR-142 was positively correlated with TPOAb, TGAb, Th17, Th17/Treg, and IL-17 (r=0.711, 0.728, 0.785, 0.716, 0.709, respectively; P<0.001) and negatively correlated with Treg (r=-0.725, P<0.001); in the HT group, miR-142 was positively correlated with TPOAb and TGAb (r=0.752, 0.717, respectively; P<0.001).
CONCLUSIONS: miR-142 is highly expressed in children with AITD, and its expression may be related to the Th17/Treg imbalance in children with GD.
目的: 探究微小RNA-142（microRNA-142, miR-142）在儿童自身免疫性甲状腺疾病（autoimmune thyroid disease, AITD）中表达及其与辅助性T细胞17（helper T cell 17, Th17）/调节性T细胞（regulatory T cell, Treg）失衡的关系。方法: 前瞻性选取2019年1月—2022年12月住院治疗的89例AITD患儿为研究对象，包括48例Graves病患儿（Graves disease, GD；设为GD组）和41例桥本甲状腺炎患儿（Hashimoto thyroiditis, HT；设为HT组），另选取55例同期体检的健康儿童为对照组，比较各组血清miR-142、甲状腺球蛋白抗体（antithyroglobulin antibody, TGAb）、抗甲状腺过氧化物酶抗体（antithyroperoxidase antibody, TPOAb）、Th17/Treg及白细胞介素-17（interleukin-17, IL-17）表达差异。结果: GD组和HT组miR-142、TPOAb、TGAb、Th17、Th17/Treg、IL-17表达高于对照组，Treg水平低于对照组（P<0.05）。Pearson相关分析显示，GD组miR-142与TPOAb、TGAb、Th17、Th17/Treg、IL-17呈正相关（分别r=0.711、0.728、0.785、0.716、0.709，P<0.001），与Treg呈负相关（r=-0.725，P<0.001）；HT组miR-142与TPOAb、TGAb呈正相关（分别r=0.752、0.717，P<0.001）。结论: miR-142在儿童AITD中高表达，且其表达可能与GD患儿Th17/Treg失衡有关。.

Autoimmune thyroid diseases (AITD) are among the most frequent autoimmune disorders, with a multifactorial etiology in which both genetic and environmental determinants are probably involved. Celiac disease (CeD) also represents a public concern, given its increasing prevalence due to the recent improvement of screening programs, leading to the detection of silent subtypes. The two conditions may be closely associated due to common risk factors, including genetic setting, changes in the composition and diversity of the gut microbiota, and deficiency of nutrients like vitamin D. This comprehensive review discussed the current evidence on the pivotal role of vitamin D in modulating both gut microbiota dysbiosis and immune system dysfunction, shedding light on the possible relevance of an adequate intake of this nutrient in the primary prevention of AITD and CeD. While future technology-based strategies for proper vitamin D supplementation could be attractive in the context of personalized medicine, several issues remain to be defined, including standardized assays for vitamin D determination, timely recommendations on vitamin D intake for immune system functioning, and longitudinal studies and randomized controlled trials to definitely establish a causal relationship between serum vitamin D levels and the onset of AITD and CeD.