Evaluation of the therapeutic efficacy of different doses of LT4 in pregnant women with high-normal TSH levels and TPOAb positivity in the first half of pregnancy.

BACKGROUND: The objective was to investigate the efficacy of different doses of levothyroxine therapy among pregnant women exhibiting high-normal thyroid stimulating hormone levels and positive thyroid peroxidase antibodies throughout the first half of pregnancy. METHODS: Pregnant women exhibiting high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positivity throughout the initial half of pregnancy were selected from January 2021 to September 2023. Based on the different doses of levothyroxine, the pregnant women were categorized into the nonintervention group (G0, 122 women), 25 µg levothyroxine intervention group (G25, 69 women), and 50 µg levothyroxine intervention group (G50, 58 women). Serum parameters, gastrointestinal symptoms, small intestinal bacterial overgrowth (SIBO), maternal and neonatal outcomes were compared after the intervention among the three groups. RESULTS: After the intervention, in the G25 and G50 groups, the thyroid stimulating hormone, triglyceride and low-density lipoprotein levels were notably less in contrast to those in the G0 group (P < 0.05). The rates of abdominal distension and SIBO in the G25 and G50 groups were notably lower in contrast to the G0 group (P = 0.043 and 0.040, respectively). The G50 group had a lower rate of spontaneous abortion and premature membrane rupture than the G0 group (P = 0.01 and 0.015, respectively). Before 11+ 2 weeks of gestation and at thyroid peroxidase antibodies levels ≥ 117 IU/mL, in contrast to the G0 group, the G50 group experienced a decreased rate of spontaneous abortion (P = 0.008). The G50 group had significantly higher newborn weight than the G0 group (P = 0.014), as well as a notably longer newborn length than the G0 and G25 groups (P = 0.005). CONCLUSIONS: For pregnant women with high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positive during the first half of pregnancy, supplementation with 50 µg levothyroxine was more effective in improving their blood lipid status and gastrointestinal symptoms, reducing the incidence of SIBO and premature rupture of membranes, and before 11+2 weeks, TPOAb ≥ 117 IU/mL proved more beneficial in mitigating the risk of spontaneous abortion.

Evaluating the link between DIO3-FA27 promoter methylation, biochemical indices, and heart failure progression.

BACKGROUND: Heart failure (HF) is a disease that poses a serious threat to individual health, and DNA methylation is an important mechanism in epigenetics, and its role in the occurrence and development of the disease has attracted more and more attention. The aim of this study was to evaluate the link between iodothyronine deiodinase 3 promoter region fragment FA27 (DIO3-FA27) methylation levels, biochemical indices, and HF. RESULTS: The methylation levels of DIO3-FA27_CpG_11.12 and DIO3-FA27_CpG_23.24 significantly differed in HF patients with different degrees. Multivariate logistic regression analysis indicated that the relative HF risk in the third and fourth quartiles of activated partial thromboplastin time and fibrin degradation products. The results of the restricted cubic spline model showed that the methylation levels of DIO3-FA 27_CpG_11.12 and DIO3-FA 27_CpG_23.24 were associated with coagulation indicators, liver function, renal function, and blood routine. CONCLUSIONS: Based on the differential analysis of CpG methylation levels based on DIO3-FA27, it was found that biochemical indicators combined with DIO3-FA27 promoter DNA methylation levels could increase the risk of worsening the severity classification of HF patients, which provided a solid foundation and new insights for the study of epigenetic regulation mechanisms in patients with HF.

The impact of gut microbiota on autoimmune thyroiditis and relationship with pregnancy outcomes: a review.

Autoimmune thyroiditis (AITD) is a T-cell-mediated, organ- specific autoimmune disease caused by interactions between genetic and environmental factors. Patients with AITD show thyroid lymphocyte infiltration and an increase in the titer of thyroid autoimmune antibodies, thereby altering the integrity of thyroid follicle epithelial cells and dysregulating their metabolism and immune function, leading to a decrease in multi-tissue metabolic activity. Research has shown that patients with AITD have a significantly higher risk of adverse pregnancy outcomes, such as infertility and miscarriage. Levothyroxine(LT4) treatment can improve the pregnancy outcomes of normal pregnant women with thyroid peroxidase antibodies(TPOAb) positivity, but it is not effective for invitro fertilization embryo transfer (IVF-ET) in women with normal thyroid function and positive TPOAb. Other factors may also influence pregnancy outcomes of patients with AITD. Recent studies have revealed that the gut microbiota participates in the occurrence and development of AITD by influencing the gut-thyroid axis. The bacterial abundance and diversity of patients with Hashimoto thyroiditis (HT) were significantly reduced, and the relative abundances of Bacteroides, fecal Bacillus, Prevotella, and Lactobacillus also decreased. The confirmation of whether adjusting the composition of the gut microbiota can improve pregnancy outcomes in patients with AITD is still pending. This article reviews the characteristics of the gut microbiota in patients with AITD and the current research on its impact in pregnancy.

Is There a Link between Thyroid Peroxidase Gene Promoter Polymorphisms and Autoimmune Thyroiditis in the Polish Population?

(1) Autoimmune thyroiditis (AIT) is the most common cause of primary hypothyroidism and one of the most frequent organ-specific autoimmune diseases. Its pathogenesis is polygenic and still requires further research. The aim of the study was to assess, for the first time in the Caucasian population, the role of selected TPO gene promoter polymorphisms (rs2071399 G/A, rs2071400C/T, rs2071402 A/G, and rs2071403 A/G) in the development of AIT. A total of 237 patients diagnosed with AIT and 130 healthy controls were genotyped for four TPO gene polymorphisms, and the results were statistically analyzed to check for the role of these polymorphisms. There were no significant differences in the genotype and allele frequencies of the studied TPO gene promoter polymorphisms between patients and controls (p > 0.05). The haplotype distribution (rs2071400-rs2071402-rs2071403) between the two studied groups was similar for the most common variants (CGA, CAG, TGG). Only a rare haplotype (CGG) occurred more frequently among patients compared to controls (p = 0.04). The studied TPO gene promoter polymorphisms did not show an association with susceptibility to AIT in the Caucasian Polish population, contrary to the results in Japanese patients.

Mice lacking DIO3 exhibit sex-specific alterations in circadian patterns of corticosterone and gene expression in metabolic tissues.

Disruption of circadian rhythms is associated with neurological, endocrine and metabolic pathologies. We have recently shown that mice lacking functional type 3 deiodinase (DIO3), the enzyme that clears thyroid hormones, exhibit a phase shift in locomotor activity, suggesting altered circadian rhythm. To better understand the physiological and molecular basis of this phenotype, we used Dio3+/+ and Dio3-/- mice of both sexes at different zeitgeber times (ZTs) and analyzed corticosterone and thyroxine (T4) levels, hypothalamic, hepatic, and adipose tissue expression of clock genes, as well as genes involved in the thyroid hormone action or physiology of liver and adipose tissues. Wild type mice exhibited sexually dimorphic circadian patterns of genes controlling thyroid hormone action, including Dio3. Dio3-/- mice exhibited altered hypothalamic expression of several clock genes at ZT12, but did not disrupt the overall circadian profile. Expression of clock genes in peripheral tissues was not disrupted by Dio3 deficiency. However, Dio3 loss in liver and adipose tissues disrupted circadian profiles of genes that determine tissue thyroid hormone action and physiology. We also observed circadian-specific changes in serum T4 and corticosterone as a result of DIO3 deficiency. The circadian alterations manifested sexual dimorphism. Most notable, the time curve of serum corticosterone was flattened in Dio3-/- females. We conclude that Dio3 exhibits circadian variations, influencing the circadian rhythmicity of thyroid hormone action and physiology in liver and adipose tissues in a sex-specific manner. Circadian disruptions in tissue physiology may then contribute to the metabolic phenotypes of DIO3-deficient mice.

Association of thyroid autoantibodies and diabetic kidney disease in hospitalised patients with type 2 diabetes mellitus: a cross-sectional study from a Chinese university hospital.

OBJECTIVES: To analyse and explore the association between thyroid autoantibodies and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). DESIGN: A cross-sectional study. SETTING: Patients were from the inpatient unit at The Second Endocrinology Department of Shengjing Hospital Affiliated to China Medical University (Shenyang, China) between January 2015 and September 2019. PARTICIPANTS: A total of 150 Chinese adults with T2DM were included in the study, including 83 men and 67 women. Their age ranged between 25 and 92 years. METHODOLOGY: They grouped by the presence of DKD, urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate, and levels of thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb). Data on the patients' general characteristics and laboratory measurements (levels of fasting plasma glucose, glycated haemoglobin, and albumin; renal function; and thyroid function) were collected. Binary logistic regression was performed to identify risk factors for DKD. RESULTS: The level of TPOAb, the positivity rates of TPOAb (p<0.01) and TgAb (p<0.05) were higher in patients with DKD than in those without DKD. The TPOAb level in patients with a UACR<30 mg/g creatinine was lower than that in patients with a UACR between 30 and 300 mg/g creatinine (p<0.05). The prevalence of DKD was higher in patients with a TPOAb-positive or TgAb-positive status. The result of binary logistic regression analysis showed that a TPOAb-positive status was significantly associated with DKD in patients with T2DM (OR=7.683, 95% CI 1.583 to 37.286, p<0.05). CONCLUSIONS: TPOAb-positive status is in association with DKD in patients with T2DM. Large scale, prospective cohort studies are warranted to confirm our findings.

Dissociating Mechanisms That Underlie Seasonal and Developmental Programs for the Neuroendocrine Control of Physiology in Birds.

Long-term programmed rheostatic changes in physiology are essential for animal fitness. Hypothalamic nuclei and the pituitary gland govern key developmental and seasonal transitions in reproduction. The aim of this study was to identify the molecular substrates that are common and unique to developmental and seasonal timing. Adult and juvenile quail were collected from reproductively mature and immature states, and key molecular targets were examined in the mediobasal hypothalamus (MBH) and pituitary gland. qRT-PCR assays established deiodinase type 2 (DIO2) and type 3 (DIO3) expression in adults changed with photoperiod manipulations. However, DIO2 and DIO3 remain constitutively expressed in juveniles. Pituitary gland transcriptome analyses established that 340 transcripts were differentially expressed across seasonal photoperiod programs and 1,189 transcripts displayed age-dependent variation in expression. Prolactin (PRL) and follicle-stimulating hormone subunit beta (FSHß) are molecular markers of seasonal programs and are significantly upregulated in long photoperiod conditions. Growth hormone expression was significantly upregulated in juvenile quail, regardless of photoperiodic condition. These findings indicate that a level of cell autonomy in the pituitary gland governs seasonal and developmental programs in physiology. Overall, this paper yields novel insights into the molecular mechanisms that govern developmental programs and adult brain plasticity.

[The association between baseline TPOAb and/or TgAb positivity and thyroid immune-related adverse events in patients with malignancies following treatment with immune checkpoint inhibitors].

Objective: To investigate the association between positive anti-thyroid peroxidase antibody (TPOAb) and/or anti-thyroglobulin antibody (TgAb) and the occurrence of thyroid immune-related adverse events (irAEs) in patients with malignant tumors who treated with immune checkpoint inhibitors (ICIs). Methods: A case-control study. A total of 116 patients with malignant tumor who received ICIs treatment and underwent thyroid function evaluation at Peking Union Medical College Hospital from January 2017 to April 2023 were enrolled retrospectively, including 77 males and 39 females, with a median age of (M(Q1, Q3)) 63.0 (55.0, 70.0) years. The patients were divided into the euthyroid group (n=58) and the thyroid irAEs group (n=58) according to whether thyroid irAEs occurred after ICIs treatment. The clinical characteristics and baseline anti-thyroid antibodies associated with the occurrence of thyroid irAEs after ICIs treatment in patients with malignant tumors were evaluated. Variables with statistical significance in univariate analysis were included in multivariate logistic regression model to analyze the risk factors for thyroid irAEs in patients with malignant tumors who received ICIs treatment. Results: In irAEs group, therewore 4 (3.4%) cases of clinical thyrotoxicosis, 23(19.8%) cases of subclinical thyrotoxicosis, 23 (19.8%) cases of clinical hypothyroidism, and 8(6.9%) cases of subclinical hypothyroidism. The positive rate of anti-thyroid antibodies at baseline in the thyrioid irAEs group was higher than that in the euthyroid group［16/58（27.6%）vs 3/58（5.2%），P=0.001］. After at least one course of ICIs treatment, the incidence of thyroid irAEs in patients with positive anti-thyroid antibodies at baseline was 84.2% (16/19), whereas it was 43.3% (42/97) in patients with negative anti-thyroid antibodies(P=0.001). Univariate logistic regression analysis showed that gender (OR=2.812, 95%CI:1.257-6.293), baseline thyroid autoantibodies were positive (OR=6.984, 95%CI: 1.909-25.547), baseline TgAb positivity (OR=8.909, 95%CI: 1.923-41.280), and baseline TPOAb positivity (OR=7.304, 95%CI: 1.555-34.308) were associated with thyroid irAEs (all P<0.05). Multivariate logistic regression analysis indicated that baseline TgAb positivity (OR=7.637, 95%CI: 1.617-36.072) was a risk factor for thyroid irAEs (P=0.01). Conclusions: The incidence of thyroid irAEs is higher in patients who are positive for baseline TPOAb and/or TgAb compared to those who are negative for TPOAb and TgAb. Patients with positive TgAb at baseline are at high risk of developing thyroid irAEs.

Platelet-rich plasma efficacy in alopecia areata patients with normal and elevated levels of antibodies against thyroglobulin and thyroid peroxidase.

AIM: To evaluate and compare the efficacy of platelet-rich plasma (PRP) therapy in alopecia areata (AA) patients with normal and with elevated levels of anti-thyroglobulin antibodies and/or anti-thyroid peroxidase antibodies.

The relationship between thyroid peroxidase antibody and differentiated thyroid cancer: a systematic review and meta-analysis.

Background: Thyroglobulin antibody (TgAb) has been found to be associated with the occurrence and development of differentiated thyroid cancer (DTC) for several years, but there is still controversy over whether thyroid peroxidase antibody (TPOAb) is related to differentiated thyroid cancer. Methods: We scrutinized relevant studies published up to July 2023 across four major databases including PubMed, Embase, Cochrane Library, and Web of Science, to examine the association between TPOAb and DTC. Clinical outcome measures include the incidence of DTC, tumor size, extrathyroidal invasion, lymph node metastasis, multifocality, recurrence and bilaterality. Results: 12 original studies were included, involving a total of 20,330 subjects. Our analysis of the included studies revealed that TPOAb+ individuals exhibited a higher risk of developing DTC (OR=1.57 [95% CI: 1.00-2.45], p=0.049) than TPOAb- individuals. Furthermore, TPOAb+ DTC patients were more prone to present with bilateral (OR=1.40 [95% CI: 1.21-1.62], p<0.00001) and multifocal (OR=1.40 [95% CI: 1.23-1.60], p<0.00001) tumors than TPOAb- patients. Sensitivity analysis indicated a high sensitivity for these three findings. No significant differences in the risk of extrathyroidal extension and lymph node metastasis, recurrence rate, tumor size, were observed between TPOAb+ and TPOAb- DTC patients. Conclusion: The presence of TPOAb is correlated with an increase prevalence of DTC. However, its effectiveness as a prognostic marker for DTC patients warrants further investigation. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023448824.

A combination of silymarin and garlic extract enhances thyroid hormone activation and body metabolism in orally intoxicated male rats with atrazine: Impact on hepatic iodothyronine deiodinase type 1.

Atrazine is a widely applied herbicide to improve crop yield and maintain general health. It has been reported to impair thyroid function and architecture in experimental animals. Alterations in thyroid hormones disrupt normal body function and metabolism. Silymarin, a hepatoprotective flavonolignan, was found to improve thyroid function and body metabolism. Additionally, garlic displays several protective effects on body organs. Therefore, this study explored the prophylactic impact of natural compounds comprising silymarin and garlic extract on disrupted thyroid function, hepatic iodothyronine deiodinase type 1, and metabolic parameters in atrazine-intoxicated male rats. We found that daily pre- and co-treatment of atrazine-intoxicated male rats with silymarin (100 mg/kg, p.o) and/or garlic extract (10 mg/kg, p.o) significantly improved thyroid activation and hepatic functionality as evidenced by the re-establishment of T3, T3/T4, and TSH values as well as ALT and AST activities. Interestingly, individual or concurrent supplementation of the atrazine group with silymarin and garlic extract prevented the down-regulation in hepatic iodothyronine deiodinase type 1. These effects were coupled with the repletion of serum and hepatic antioxidants and the amelioration of lipid peroxidation. In addition, current natural products markedly alleviated weight gain, dyslipidemia, hyperglycemia, glucose intolerance, and insulin resistance. Notably, a cocktail of silymarin and garlic extract exerted superior protection against atrazine-triggered deterioration of thyroid, hepatic, and metabolic functioning to individual treatments. Present findings pinpoint the prophylactic and synergistic influence of silymarin and garlic extract combinatorial regimen on thyroid activation and body metabolism via enhancing antioxidant potential, maintaining hepatic function, and iodothyronine deiodinase type 1.

Effect of DIO2 Gene Polymorphism on Thyroid Hormone Levels and Its Correlation with the Severity of Schizophrenia in a Pakistani Population.

Low levels of triiodothyronine (T3) in the brain lead to increased dopamine receptor sensitivity, potentially resulting in schizophrenia. Iodothyronine deiodinase 2 (DIO2) is the only enzyme which converts tetraiodothyronine (T4) to T3 in the brain. DIO2 polymorphism of rs225014 results in the expression of non-functioning DIO2. Therefore, this study aimed to investigate the association of rs255014 with schizophrenia and its impact on thyroid hormone levels. This study included 150 schizophrenia cases and 150 controls. DNA was extracted from blood and subjected to PCR and amplicon sequencing. Serum thyroid profiles were determined using chemiluminescent magnetic microparticle immunoassay. Statistical analyses involved independent sample t-tests, Chi-square, and Pearson's correlation tests. The results revealed a higher frequency of the reference genotype (TT) in controls compared to cases (p < 0.05). However, rs225014 did not influence serum thyroid levels or the severity of schizophrenia (p > 0.05). Interestingly, control subjects exhibited significantly higher T3 levels (p < 0.001) than cases. Regardless of the genotype (TT or CC), the control group had higher mean T3 levels than the corresponding case group (p < 0.05). In conclusion, rs225014 is associated with schizophrenia and has no effect on serum thyroid hormone levels.

A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells.

BACKGROUND: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers. METHODS: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants. RESULTS: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides. CONCLUSIONS: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.

Association of thyroid autoimmunity with extra-thyroid diseases and the risk of mortality among adults: evidence from the NHANES.

Background: Thyroid autoimmunity is one of the most prevalent autoimmune diseases. However, its association with extra-thyroid diseases and mortality risk in the general population remains uncertain. Our study aims to evaluate the association of thyroid autoimmunity with extra-thyroid disease and the risk of mortality. Methods: A prospective cohort study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) with participants from 2007-2008, 2009-2010, and 2011-2012, tracking their mortality until 2019. Associations between thyroid autoimmunity, which was defined as having positive thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TgAb), and extra-thyroid disease including diabetes, hypertension, cardiovascular disease, chronic lung disease, arthritis, cancer and chronic renal disease and the risk of mortality were investigated. Results: A total of 7431 participants were included in this study. Positive The prevalence of positive TgAb was 7.54%, and positive TPOAb prevalence was 11.48%. TgAb was significantly associated with diabetes (Model 1: OR=1.64, 95% CI:1.08-2.50; Model 2: OR=1.93, 95% CI: 1.21-3.08) and hypertension (Model 1: OR=0.67, 95% CI: 0.49-0.91; Model 2: OR=0.62, 95% CI: 0.44-0.88). TPOAb was associated with a lower prevalence of chronic lung disease (model 1: OR=0.71, 95% CI: 0.54-0.95; model 2: OR=0.71, 95% CI: 0.53-0.95). No associations were observed between TgAb, TPOAb and other extra-thyroid diseases. Neither TgAb nor TPOAb were associated with all-cause mortality or heart disease mortality. Conclusion: TgAb was linked to a higher prevalence of diabetes and a lower prevalence of hypertension, while TPOAb was associated with a decreased prevalence of chronic lung disease. However, neither TgAb nor TPOAb posed a risk for all-cause mortality or heart disease mortality.

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.

Contactin 6, A Novel Causative Gene for Congenital Hypothyroidism, Mediates Thyroid Hormone Biosynthesis Through Notch Signaling.

Background: Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. In patients with CH in China, thyroid dyshormonogenesis is more common than thyroid dysgenesis; however, the genetic causes of CH due to thyroid dyshormonogenesis remain largely unknown. Therefore, we aimed at identifying novel candidate causative genes for CH. Methods: To identify novel CH candidate genes, a total of 599 patients with CH were enrolled and next-generation sequencing was performed. The functions of the identified variants were confirmed using HEK293T and FTC-133 cell lines in vitro and in a mouse model organism in vivo. Results: Three pathogenic contactin 6 (CNTN6) variants were identified in two patients with CH. Pedigree analysis showed that CH caused by CNTN6 variants was inherited in an autosomal recessive pattern. The CNTN6 gene was highly expressed in the thyroid in humans and mice. Cntn6 knockout mice presented with thyroid dyshormonogenesis and CH due to the decreased expression of crucial genes for thyroid hormone biosynthesis (Slc5a5, Tpo, and Duox2). All three CNTN6 variants resulted in the blocking of the release of the Notch intracellular domain, which could not translocate into the nucleus, impaired NOTCH1 transcriptional activity, and decreased expression of SLC5A5, TPO, and DUOX2. Further, we found that DTX1 was required for CNTN6 to promote thyroid hormone biosynthesis through Notch signaling. Conclusions: This study demonstrated that CNTN6 is a novel causative gene for CH through the mediation of thyroid hormone biosynthesis via Notch signaling, which provides new insights into the genetic background and mechanisms involved in CH and thyroid dyshormonogenesis.

Effects of altitude on thyroid disorders according to Chinese three-rung, ladder-like topography: national cross-sectional study.

BACKGROUND: Chinese topography appears a three-rung ladder-like distribution of decreasing elevation from northwest to southeast, which is divided by two sloping edges. Previous studies have reported that prevalence of thyroid diseases differed by altitude, and geographical factors were associated with thyroid disorders. To explore the association between three-rung ladder-like regions and thyroid disorders according to unique Chinese topographic features, we conducted an epidemiological cross-sectional study from 2015-2017 that covered all 31 mainland Chinese provinces. METHODS: A total of 78,470 participants aged ≥ 18 years from a nationally representative cross-sectional study were included. Serum thyroid peroxidase antibody, thyroglobulin antibody, and thyroid-stimulating hormone levels; urine iodine concentration; and thyroid volume were measured. The three-rung ladder-like distribution of decreasing elevation from northwest to southeast in China was categorized into three topographic groups according to elevation: first ladder, > 3000 m above sea level; second ladder, descending from 3000-500 m; and third ladder, descending from 500 m to sea level. The third ladder was further divided into groups A (500-100 m) and B (< 100 m). Associations between geographic factors and thyroid disorders were assessed using linear and binary logistic regression analyses. RESULTS: Participants in the first ladder group were associated with lower thyroid peroxidase (ß = -4.69; P = 0.00), thyroglobulin antibody levels (ß = -11.08; P = 0.01), and the largest thyroid volume (ß = 1.74; P = 0.00), compared with the other groups. The second ladder group was associated with autoimmune thyroiditis (odds ratio = 1.30, 95% confidence interval [1.18-1.43]) and subclinical hypothyroidism (odds ratio = 0.61, 95%confidence interval [0.57-0.66]) (P < 0.05) compared with the first ladder group. Group A (third ladder) (500-100 m) was associated with thyroid nodules and subclinical hypothyroidism (P < 0.05). Furthermore, group B (< 100 m) was positively associated with autoimmune thyroiditis, thyroid peroxidase and thyroglobulin antibody positivity, and negatively associated with overt hypothyroidism, subclinical hypothyroidism, and goiter compared with the first ladder group(P < 0.05). CONCLUSION: We are the first to investigate the association between different ladder regions and thyroid disorders according to unique Chinese topographic features. The prevalence of thyroid disorders varied among the three-rung ladder-like topography groups in China, with the exception of overt hyperthyroidism.

A Computational Approach: The Functional Effects of Thyroid Peroxidase Variants in Thyroid Cancer and Genetic Disorders.

PURPOSE: Thyroid peroxidase (TPO) is essential for the synthesis of thyroid hormones. However, specific mutations render TPO antigenic and prone to autoimmune attacks leading to thyroid cancer, TPO deficiency, and congenital hypothyroidism (CH). Despite technological advancement, most experimental procedures cannot quickly identify the genetic causes of CH nor detect thyroid cancer in the early stages. METHODS: We performed saturated computational mutagenesis to calculate the folding energy changes (∆∆G) caused by missense mutations and analyzed the mutations involved in post-translational modifications (PTMs). RESULTS: Our results showed that the functional important missense mutations occurred in the heme peroxidase domain. Through computational saturation mutagenesis, we identified the TPO mutations in G393 and G348 affecting protein stability and PTMs. Our folding energy calculations revealed that seven of nine somatic thyroid cancer mutations destabilized TPO. CONCLUSION: These findings highlight the impact of these specific mutations on TPO stability, linking them to thyroid cancer and other genetic thyroid-related disorders. Our results show that computational mutagenesis of proteins provides a quick insight into rare mutations causing Mendelian disorders and cancers in humans.

The Ratio of Peripheral Blood Natural Killer Cells is not a Solid Surrogate Immune Index in Unexplained Recurrent Miscarriage.

Background: Immunotherapies targeting peripheral natural killer (pbNK) cells in unexplained recurrent miscarriage (uRM) remain controversial. We hypothesized that the change in pbNK cell count might be a result of innate immune responses rather than a cause. Objective: To explore whether the pbNK count is significantly different in women testing positive than those testing negative for commonly studied autoimmune markers. Methods: Peripheral blood samples were collected from 302 eligible patients with uRM for the antinuclear antibody (ANA) testing determined by the enzyme-linked immunosorbent assay (ELISA), anti-thyroid peroxidase antibody (TPO-Ab) testing and anti-thyroglobulin antibody (Tg-Ab) testing determined by the chemiluminescent immunoassay, and pbNK cell testing determined by flow cytometry. The patients were divided into two groups according to the pbNK normal range, and the comparative analysis entailed an examination of the prevalence rates of autoantibodies within the high pbNK group and the normal pbNK group, followed by a comprehensive investigation into the potential correlations between autoantibodies and pbNK cells. Results: There was a positive association between TPO-Ab positivity and high pbNK cells (p=0.016, OR=5.097, 95% CI 1.356-19.159), while there was a negative association between ANA positivity and high pbNK cells (p=0.013, OR=0.293, 95% CI 0.111-0.773). TPO-Ab-positive patients had a higher pbNK cell count compared with TPO-Ab-negative patients, while ANA-positive patients had a lower pbNK cell count compared with ANA-negative patients. Conclusion: The change in pbNK cell count may be a consequence of immune responses, and there should be careful consideration in applying it as an immunotherapeutic index.

Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.

BACKGROUND: Developing neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic. OBJECTIVES: This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons. METHODS: Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV. RESULTS: At 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14-21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency. CONCLUSIONS: These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.