Risk Of Autoimmune Thyroid Disease Research Articles

The causal relationship between vitiligo and autoimmune thyroid diseases: A bidirectional two-sample Mendelian randomization analysis.

Vitiligo is an acquired autoimmune depigmented disorder characterized by the presence of white and well-defined patches on the skin, mucous membrane, or both. It is associated with a significant disease burden and has a profoundly impacts patients' quality of life. Autoimmune thyroid diseases (AITDs) result from an autoimmune system dysregulation, leading to an erroneous immune attack on the thyroid gland. Previous observational and epidemiological studies have suggested the association between vitiligo and AITDs. However, the bidirectional cause-effect relationship between vitiligo and AITDs has not been formally assessed. Two-sample bidirectional Mendelian randomization (MR) analysis was conducted to explore potential causal relationships between genetically increased risk of vitiligo and AITDs, using summary statistics from genome-wide association studies in European populations. Causal effects were primarily estimated using the inverse variance weighted method, and additional quality control was performed using the MR-Egger, weighted median, simple mode, and weight mode methods. Sensitivity analysis was conducted to assess the robustness of the results. The forward MR analysis showed a positive causal relationship between vitiligo and autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD). The odds ratio (OR) were 1.17 (95% CI, 1.01-1.35; p=0.04), 1.12 (95% CI, 1.03-1.22; p=0.01), and 1.13 (95% CI, 1.06-1.20; p<0.01), respectively. In the reverse MR analysis, a positive causal relationship was found between AIT and vitiligo, with an OR of 1.10 (95% CI, 1.01-1.35; p=0.04). However, no causal relationship was observed between AIH (p=0.10) or GD (p=0.61) and vitiligo. Sensitivity analysis revealed no evidence of horizontal pleiotropy or heterogeneity. The genetic-level investigation provides evidence of a genetic causal association between susceptibility to vitiligo and an increased risk of AITDs. Additionally, the results demonstrate a genetic causal association between susceptibility to AIT and an increased risk of vitiligo, while not indicating a similar association with susceptibility to AIH or GD.

Height, Autoimmune Thyroid Disease, and Thyroid Cancer: A Mendelian Randomization Study.

Background: Increased height has been associated with increased risk of hypothyroidism or thyroid cancer in epidemiological studies. However, the potential causal association between height and hypothyroidism or thyroid cancer has not been thoroughly explored. Autoimmune thyroid disease (AITD) mainly presents as hypothyroidism, thus we aim to evaluate the causal relationship between height as exposure and its association with AITD or thyroid cancer. Methods: Mendelian randomization (MR) analyses were performed by using genetic instruments associated with height, which were selected from the largest genome-wide association meta-analysis for height in up to 5.4 million individuals. Summary-level data for AITD and thyroid cancer (including 30,234 and 3001 cases, respectively) were collected from the large number of available genome-wide association studies. Bidirectional MR was performed to test for reverse causal association between AITD and adult height. Results: MR analyses showed that increased genetically predicted height was associated with a 4% increased risk of AITD ([CI 1.02 to 1.07], p-value = 1.99E-03) per 1-standard deviation (SD) increase in genetically predicted height. The bidirectional MR did not show any causal association between AITD and adult height. Additionally, increased genetically predicted height was associated with 15% increased risk of thyroid cancer ([CI 1.07 to 1.23], p-value = 2.32E-04) per 1-SD increase in height. Sensitivity analysis confirmed the main results. Conclusions: This MR study showed that 1-SD increase in genetically predicted height was associated with increased risk of AITD and thyroid cancer. In contrast, there was no evidence of a causal association of genetically predicted AITD with height. These results could further aid in investigation of height-related pathways as a means of gaining new mechanistic insights into AITD and thyroid cancer.

Exposure of Akwesasne Mohawk women to polychlorinated biphenyls and hexachlorobenzene is associated with increased serum levels of thyroid peroxidase autoantibodies

ABSTRACT Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and dichlorodiphenyltrichloroethane (p,p’-DDT) were reported to influence immunological activity. As endocrine-disrupting chemicals (EDC), these pollutants may disrupt normal thyroid function and act as catalysts for development of autoimmune thyroid disease by directly and indirectly affecting levels of thyroid peroxidase antibodies (TPOAbs). Native American communities are disproportionately exposed to harmful toxicants and are at an increased risk of developing an autoimmune disease. The aim of this study was to determine the association between POPs and TPOAbs in serum obtained from Native American women. This assessment was used to measure whether increased risk of autoimmune thyroid disease occurred as a result of exposure to POPs. Data were collected from 183 Akwesasne Mohawk women, 21–38 years of age, between 2009 and 2013. Multivariate analyses were conducted to determine the association between toxicant exposure and levels of TPOAbs. In multiple logistic regression analyses, exposure to PCB congener 33 was related to elevated risk of individuals possessing above normal levels of TPOAbs. Further, HCB was associated with more than 2-fold higher risk of possessing above normal levels of TPOAbs compared to women with normal levels of TPOAbs. p,p’-DDE was not associated with TPOAb levels within this study. Exposure to PCB congener 33 and HCB was correlated with above normal levels of TPOAbs, a marker of autoimmune thyroid disease. Additional investigations are needed to establish the causes and factors surrounding autoimmune thyroid disease which are multiple and complex.

Predicting the risk of autoimmune thyroid disease in patients with vitiligo: Development and assessment of a new predictive nomogram.

This study aimed to develop an autoimmune thyroid disease (AITD) risk prediction model for patients with vitiligo based on readily available characteristics. A retrospective analysis was conducted on the clinical characteristics, demographics, skin lesions, and laboratory test results of patients with vitiligo. To develop a model to predict the risk of AITD, the Least Absolute Shrinkage and Selection Operator (LASSO) method was used to optimize feature selection, and logistic regression analysis was used to select further features. The C-index, Hosmer-Lemeshow test, and decision curve analysis were used to evaluate the calibration, discrimination ability and clinical utility of the model. Internally, the model was verified using bootstrapping; externally, two independent cohorts were used to confirm model accuracy. Sex, vitiligo type, family history of AITD, family history of other autoimmune disease, thyroid nodules or tumors, negative emotions, skin involvement exceeding 5% of body surface area, and positive immune serology (IgA, IgG, IgM, C3, and C4) were predictors of AITD in the prediction nomogram. The model showed good calibration and discrimination (C-index: 0.746; 95% confidence interval: 0.701-0.792). The accuracy of this predictive model was 74.6%.In both internal validation (a C-index of 1000 times) and external validation, the C-index outperformed (0.732, 0.869, and 0.777). The decision curve showed that the AITD nomogram had a good guiding role in clinical practice. The novel AITD nomogram effectively evaluated the risk of AITD in patients with vitiligo.

Interferon-based therapy increases risk of autoimmune thyroid diseases

Interferon-based therapy increases risk of autoimmune thyroid diseases

Association of interferon-based therapy with risk of autoimmune diseases in patients with chronic hepatitis C virus infection: A population-based Taiwanese cohort study.

BackgroundInterferon in combination with ribavirin has been the standard of care for chronic hepatitis C virus infection (HCV) for the past few decades. However, its effect on the risk of autoimmune diseases (ADs) among patients with HCV infection remains unclear. We assessed the potential association between interferon-based therapy (IBT) and AD risk in patients with HCV infection.MethodsThis retrospective cohort study identified patients diagnosed with HCV infection between January 1, 2006, and December 31, 2015, from Taiwan’s National Health Insurance Research Database. In total, 16,029 patients with HCV infection who received IBT and 141,214 patients with HCV infection who did not receive IBT were included. Both cohorts were followed up to assess the development of ADs. Hazard ratios (HRs) were calculated using the Cox proportional hazards regression model, which was adjusted for potential confounders.ResultsThe median follow-up period for IBT and non-IBT users was 4.53 and 3.34 years, respectively. No significant difference in the risk of overall ADs (adjusted HR [aHR]: 0.96, 95% confidence interval [CI]: 0.81–1.14) or systemic ADs (aHR: 0.88, 95% CI: 0.71–1.10) was noted during the study period. However, a slight increase in the risk of organ-specific ADs was noted among IBT users (incidence rate ratio: 1.33, 95% CI: 1.02–1.72). Furthermore, analysis of AD subgroups revealed a significant increase in the risks of Graves’ disease (aHR: 6.06, 95% CI: 1.27–28.8) and Hashimoto’s thyroiditis (aHR 1.49, 95% CI 1.01–2.21) among IBT users.ConclusionsIBT use increases the risk of autoimmune thyroid diseases (Hashimoto’s thyroiditis and Graves’ disease) in patients with HCV infection to a greater extent than non-IBT use.

Prevalence of autoimmune thyroid disease in patients with psoriasis: a meta-analysis

ObjectivePsoriasis is a chronic inflammatory disease with autoimmune aetiology. A possible link between psoriasis and autoimmune thyroid disease (AITD) has been suggested in some studies with inconsistent findings. This meta-analysis...

The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study.

Background: Primary biliary cholangitis (PBC) is an autoimmune disease and is often accompanied by thyroid dysfunction. Understanding the potential causal relationship between PBC and thyroid dysfunction is helpful to explore the pathogenesis of PBC and to develop strategies for the prevention and treatment of PBC and its complications. Methods: We used a two-sample Mendelian randomization (MR) method to estimate the potential causal effect of PBC on the risk of autoimmune thyroid disease (AITD), thyroid-stimulating hormone (TSH) and free thyroxine (FT4), hyperthyroidism, hypothyroidism, and thyroid cancer (TC) in the European population. We collected seven datasets of PBC and related traits to perform a series MR analysis and performed extensive sensitivity analyses to ensure the reliability of our results. Results: Using a sensitivity analysis, we found that PBC was a risk factor for AITD, TSH, hypothyroidism, and TC with odds ratio (OR) of 1.002 (95% CI: 1.000–1.005, p = 0.042), 1.016 (95% CI: 1.006–1.027, p = 0.002), 1.068 (95% CI: 1.022–1.115, p = 0.003), and 1.106 (95% CI: 1.019–1.120, p = 0.042), respectively. Interestingly, using reverse-direction MR analysis, we also found that AITD had a significant potential causal association with PBC with an OR of 0.021 (p = 5.10E−4) and that the other two had no significant causal relation on PBC. Conclusion: PBC causes thyroid dysfunction, specifically as AITD, mild hypothyroidism, and TC. The potential causal relationship between PBC and thyroid dysfunction provides a new direction for the etiology of PBC.

Association of IL-1β, NLRP3, and COX-2 Gene Polymorphisms with Autoimmune Thyroid Disease Risk and Clinical Features in the Iranian Population.

Background Grave's disease (GD) and Hashimoto's thyroiditis (HT) are autoimmune diseases of the thyroid gland in which genetic predisposition plays a major role in their development. Currently, the role of NLRP3 inflammasome and COX-2 has been documented in many autoimmune diseases. The purpose of the study is to delineate the impact of IL-1β (rs1143634), NLRP3 (rs3806265), and COX-2 (rs2745557) gene polymorphisms in the development of GD and HT. Methods A total of 256 newly diagnosed patients with autoimmune thyroid disease (135 patients with HT and 121 GD patients) as case groups and 145 controls were included in the study. Results Recessive and overdominant models showed a significant association between IL-1β rs1143634 SNP and HT development risk. The frequency of TT genotype and T allele of IL-1β rs1143634 SNP in the control group was significantly higher than the GD group. There was no significant association between NLRP3 rs3806265 polymorphism and HT and GD development. The frequency of GA genotype of COX-2 (rs2745557) in the control group was significantly higher than that in the HT group. There was no significant association between COX-2 rs2745557 genotypic and allelic distribution and GD development risk. The results revealed a significant relationship between some clinical features of HT and GD groups and SNPs studied. Conclusion The results manifest the significant impact of IL-1β rs1143634 and COX-2 (rs2745557) SNPs and HT development and IL-1β rs1143634 SNP on GD occurrence risk. Furthermore, a significant relationship was observed between some clinical features of HT and GD groups and studied SNPs.

Associations of GWAS-Supported Non-MHC Genes with Autoimmune Thyroiditis in Patients with Type 1 Diabetes.

PurposeA genome-wide association study (GWAS) in Caucasian population identified five non-MHC genes (PHTF1, PTPN22, MAGI3, BCL2L15, and QRFPR) associated with risk of the co-occurrence of autoimmune thyroid diseases (AITD) and type 1 diabetes (T1D). The aim of this study is to replicate these associations with AITD in patients with T1D in Chinese Han population.Patients and MethodsA case–control study was designed. Five single-nucleotide polymorphisms (SNPs) PHTF1 rs1111695, PTPN22 rs1217407, MAGI3 rs2153977, BCL2L15 rs2358994, and QRFPR rs7679475 were genotyped in 489 patients with T1D. Associations between genotypes and AITD risk were analyzed with logistic regression model.ResultsAITD occurred in 159 (32.5%) patients. When adjusting multiple factors by logistic regression, QRFPR rs7679475 was significantly associated with an increased risk of AITD in T1D patients in codominant model (G/G vs A/A, OR 2.93; 95% CI 1.44–5.96; P = 0.003), dominant model (G/A-G/G vs A/A, OR 1.81; 95% CI 1.17–2.79; P = 0.007) and recessive model (G/G vs A/A-G/A, OR 2.28; 95% CI 1.17–4.43; P = 0.015). Furthermore, we found a significant interaction between rs7679475 and female (P interaction = 0.005). In silico analysis indicated that rs7679475 is located in histone modification marked region and can change the binding of regulatory motifs.ConclusionOur results suggested that QRFPR rs7679475 may influence the risk of AITD in patients with T1D in Chinese Han population, and this effect may be modulated by sex.

Association Study of the Thyroid Peroxidase Gene in Autoimmune Thyroid Diseases

Introduction: The etiology of autoimmune thyroid diseases (AITDs), such as Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), is largely unknown. However, genetic susceptibility is believed to play a major role. Recently, a case-control association study performed in Croatia showed a significant association of the single nucleotide polymorphism (SNP) rs11675434 near thyroid peroxidase (TPO) with HT, and also with thyroid autoantibodies against TPO (TPOAb) levels. High TPOAb levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. Therefore, we conducted a case-control study to determine the genetic association of the rs11675434 near TPO with AITD in a cohort of the Japanese population. Methods: We genotyped the rs11675434 near TPO in 457 Japanese patients with AITD (286 with GD, 171 with HT) and 242 matched Japanese control subjects. The SNP was analyzed using TaqMan probe method, and association study was performed using the χ 2 and Fisher’s exact tests with Yates correction. Results: Both GD and HT showed no significant associations. Moreover, when patients with GD were stratified according to Graves’ ophthalmopathy (GO) (n=96), there were no allelic associations with GO, although there were weak associations between GO and controls (P=0.0494, Odds ratios (ORs)=0.3102). Conclusions: Our finding suggest that the rs11675434 near TPO may not contribute to the risk of AITD in the Japanese population, although the study was in insufficient and underpowered sample size.

The Relationship between PTPN22 R620W Polymorphisms and the Susceptibility to Autoimmune Thyroid Diseases: An Updated Meta-analysis

ABSTRACT The protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W polymorphism has been related to susceptibility to autoimmune thyroid disease (AITD) with inconsistent results. Therefore, this meta-analysis was designed to assess a more accurate association between the PTPN22 R620W polymorphism and AITD susceptibility. A systematic search of the EMBASE, PubMed, Web of Science, CBM, CNKI, and WanFang databases was performed to determine relevant publications. Statistical analyses of the odds ratios (ORs), 95% confidence intervals (CIs), and p values were performed using STATA software. Our meta-analysis included 18 separate studies comprised of 4,726 cases and 4,220 controls. In the allele and all genetic models, PTPN22 R620W polymorphism and Graves’ disease (GD) (allele model TvsC: OR = 1.573; 95% CI = 1.378–1.795; P < .001) and Hashimoto’s thyroiditis (HT) (allele model TvsC: OR = 1.737; 95% CI = 1.230–2.454; P = .002) susceptibility was positively associated. A racial subgroup analysis showed that the T allele significantly increased AITD susceptibility in all genetic models involving Caucasians, but not in Asians. This meta-analysis showed that the PTPN22 R620W polymorphism is associated with the risk of GD and HT in the overall study population. In addition, the PTPN22 R620W polymorphism is associated with elevated AITD risk in Caucasians, but not in Asians.

Analysis of Polymorphisms rs7093069-IL-2RA, rs7138803-FAIM2, and rs1748033-PADI4 in the Group of Adolescents With Autoimmune Thyroid Diseases.

IntroductionThe pathogenesis of autoimmune thyroid diseases is complicated and not completely known. Among the causes of thyroid autoimmunity, we distinguish genetic predisposition and environmental factors. Graves’ disease and Hashimoto’s thyroiditis are associated with a disturbance of immune tolerance of thyroid antigen molecules. The IL2RA gene is located on chromosome 10 and encodes the interleukin 2 receptor (IL2RA), which is expressed by the regulatory T-cells (Tregs) responsible for suppression. It has been shown that this gene and its polymorphism occur in people with various autoimmune diseases (e.g. type 1 diabetes mellitus, rheumatoid arthritis, Graves’ disease, or multiple sclerosis). The FAIM2 gene is located on chromosome 12 and encodes the molecule involved in the apoptosis inhibition process. The PADI4 gene is located on chromosome 1, and its expression is associated with activation of T-cells, differentiation of macrophages, which leads to increased inflammation.AimThe aim of the study was to analyze the polymorphisms of the IL-2RA (rs7093069), FAIM2 (rs7138803) and PADI4 (rs1748033) genes and their correlation to thyroid hormones and anti-thyroid antibodies in pediatric patients with Graves’ disease and Hashimoto’s thyroiditis compared to the control group.Material and MethodsThe study was performed in 180 patients with GD (mean age 16.5 ± 2), 80 with HT (mean age, 15.2 ± 2.2), and 114 children without any autoimmune diseases (mean age 16.3 ± 3) recruited from the endocrinology outpatient clinic. Three single nucleotide polymorphisms (SNPs): rs7138803-FAIM2, rs7093069-IL-2RA, and rs1748033 PADI4 were determined by TaqMan SNP QuanStudio 12K Flex-OpenArray genotyping with PCR and correlated to thyroid hormones and anti-thyroid antibodies.ResultsRs7090369-IL-2RA allele T was more frequent in patients with AITDs (33.7% in GD vs 28.7% in HT, p = 0.077, OR = 1.52) compared with healthy children (25%). Allele T of that gene predisposes to the occurrence of autoimmune thyroid diseases, especially GD and TT genotype gives a statistically significant 5.2 times higher risk of GD (p = 0.03, OR = 5.26) and increased risk of HT (p = 0.109, OR = 4.46). Allele A rs7138803-FAIM2 is more frequent in patients with GD (p = 0.071, OR = 1.45) and HT (p = 0.028, OR = 1.8). In our data the presence of GG genotype of that gene significantly reduces the risk of autoimmune thyroid diseases (p = 0.05, OR = 0.42). Allele C rs1748033PADI4 and its CC genotype were more frequent in patients with autoimmune thyroid diseases, but it was not statistically significant. The occurrence of CT genotype significantly reduces the risk of HT (p = 0.03, OR = 0.4).Conclusions1). Polymorphisms rs7138803-FAIM2 and rs1748033-PADI4 are more frequent in patients with autoimmune thyroid diseases, more frequent in patients with Hashimoto’ thyroiditis, but the occurrence of GG rs7138803-FAIM2 genotype could reduce the risk of thyrocyte apoptosis inhibition. 2). The TT rs7093069-IL2RA genotype may increase the risk of autoimmune thyroid diseases. 3). Analysis of polymorphisms of given genes in clinical practice will allow to determine predisposition to autoimmune thyroid disease development, to find symptoms of thyroid gland dysfunction earlier and to use appropriate treatment.

Infliximab Therapy Could Decrease the Risk of the Development of Thyroid Disorders in Pediatric Patients With Crohn's Disease.

Autoimmune diseases, including autoimmune thyroid diseases (AITDs), may be associated with Crohn's disease (CD). Taking into consideration the role of tumor necrosis factor alpha (TNF-alpha) in the immune-mediated inflammation that underlies both diseases, we evaluated an ultrasound of thyroid gland in pediatric CD patients, naïve, and treated with infliximab (IFX), an anti-TNF-alpha antibody, to assess the risk for AITD and evaluated the usefulness of ultrasonography to diagnose AITD in patients with CD. Sixty-one patients with CD were enrolled in the study, including 36 patients (mean age 14.5 ± 3.5 years) treated with IFX (IFX group) for a mean of 13.9 ± 16.6 months and 25 patients (mean age 14.7 ± 2.3 years) who never received anti-TNF-alpha therapy (control group). An ultrasound examination of the thyroid gland was performed; thyroid function tests and thyroid antibodies were assessed. We found 10-times higher prevalence of decreased thyroid echogenicity in CD and IFX-naive patients compared to IFX-treated group [a significant reduction in thyroid echogenicity in 1/36 (2.8%) patients receiving IFX compared to 7/25 (28%) patients naive to biologic therapy]. The latter showed significantly lower thyroid-stimulating hormone (TSH) levels (p = 0.034) and higher levels of thyroid antibodies (p = 0.042) in comparison to control. Our data suggest the protective role of IFX therapy in the development of thyroid disorders and indicate the usefulness of thyroid ultrasound to identify the risk of probable AITD in pediatric patients with CD.

FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234cases and 725,172controls from Iceland and the UK Biobank, we find 99sequence variants at 93loci, of which 84 variants are previously unreported2-7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR)=1.46, P=2.37×10-24). rs76428106-C is also associated with systemic lupus erythematosus (OR=1.90, P=6.46×10-4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR=1.41, P=4.31×10-4) and coeliac disease (OR=1.62, P=1.20×10-4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcriptsthat are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR=1.90, P=5.40×10-3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

1318-P: Characteristics of Autoimmune Thyroid Disease in African American and Caucasian Children with Type 1 Diabetes Mellitus

Background: Patients with type 1 diabetes mellitus (T1DM) are at increased risk of autoimmune thyroid disease (AIT). In the pediatric age group, the prevalence of AIT varies across a wide range (3-50%), depending on the population studied. There is very limited data describing the association of T1DM and AIT disease in African-American (AA) children. Objective: Characterize the association between T1DM and AIT in AA and Caucasian children presenting to the same medical center. Methods: After IRB approval, the medical records of 130 AA and 130 Caucasian children with T1DM presenting to the Children’s Hospital of Michigan were reviewed. Data collected included age, gender, ethnicity, presence of AIT evidenced by positive anti-TPO or anti-TG antibodies, TSH, free T4, anti-islet, anti-insulin and anti-GAD antibodies. Comparison was drawn between the two ethnicities in regards to the prevalence of AIT as well as predisposing factors for the onset of AIT. Results: 12.3% of AA with T1DM developed AIT versus 23.8% of Caucasian. This difference was statistically significant with a p-value of 0.023. In the Caucasian group, female was a risk factor for developing AIT (37.9% in females vs. 12.5% in males, p-value 0.001) while gender was not a significant risk factor for AA patients (p-value 0.790). The presence of anti-insulin antibodies was a risk factor for Caucasians (p-value 0.024) but not for AAs (p-value 0.185). The survival analysis showed mean time for onset of AIT in AA with T1DM is 15.1 years vs. 11.7 years in Caucasians (Log Rank p-value 0.025). Discussion: Our study shows a significantly lower prevalence AIT in AA compared to Caucasian children with T1DM. Female gender and anti-insulin antibody are risk factors for Caucasians but not in AAs. Differences could be secondary to different genes implication given the different genetic background. Further investigation can lead to a better understanding of T1DM and thyroid autoimmunity in the AA population. Disclosure M. El Bejjani: None. M. Zidan: None. H. Zidan: Speaker’s Bureau; Self; Novo Nordisk Inc.

MON-472 A Case of Resistance to Thyroid Hormone with Concurrent Hashimoto’s Thyroiditis and Post-Surgical Hypothyroidism

Introduction: Resistance to thyroid hormone (RTH) is a rare defect that results in impaired sensitivity to thyroid hormone. While most commonly caused by mutations in the thyroid hormone receptor beta (THRβ) gene, in 15% of patients with the RTH phenotype, no mutation is identified.1 This entity is known as non-thyroid hormone receptor RTH (nonTR-RTH). Patients with RTH have an increased risk of autoimmune thyroid disease with a reported odds ratio of 2.36.2 Hashimoto’s thyroiditis or other etiologies of hypothyroidism add a layer of complexity to RTH as such individuals may require high doses of levothyroxine to overcome hormone resistance.Clinical Case: A 36-year-old male was referred for abnormal thyroid function tests. He denied symptoms of thyroid dysfunction. Physical examination was notable for a goiter. Weight was 83 kg. Initial labs revealed TSH 6.8 mcIU/mL (0.3-4.7 mcIU/mL), free T4 2.0 ng/dL (0.8-1.7 ng/dL), free T3 491 pg/dL (222-383 pg/dL), and thyroid peroxidase antibody >600 IU/mL (≤20 IU/mL). Additional work-up demonstrated elevated free T4 by equilibrium dialysis 2.5ng/dL (0.9-2.2 ng/dL) and elevated TSH with HAMA treatment 5.96 mIU/L (0.40-4.50 mIU/L), thereby ruling out familial dysalbuminemic hyperthyroxinemia and HAMA interference. Alpha-subunit of 0.30 ng/mL (<0.55 ng/mL) and normal pituitary MRI did not support a TSH-secreting adenoma. Quest Diagnostics RTH Gene Sequencing was negative for a mutation in the THRβ gene. The patient was subsequently diagnosed with nonTR-RTH. Thyroid ultrasound showed multiple thyroid nodules, including a 1.8 cm hypoechoic, complex nodule in the left inferior gland and a 1.7 cm isoechoic nodule in the right inferior gland. Fine needle aspiration of the left nodule was suspicious for papillary thyroid carcinoma and the right nodule showed lymphocytic thyroiditis. The patient underwent total thyroidectomy and pathology demonstrated a benign left nodule and an incidental 0.3 cm right papillary thyroid carcinoma. The patient started levothyroxine 150 mcg daily (1.8 mcg/kg) post-operatively with subsequent TSH of 18.1 mcIU/mL. His dose was increased to 200 mcg daily (2.4 mcg/kg) and TSH was still elevated at 11.7 mcIU/mL. His levothyroxine dose was subsequently increased to 250 mcg daily (3 mcg/kg) and TSH is outstanding.Conclusions: This case highlights the diagnostic challenge in nonTR-RTH. It also demonstrates the complex management of patients with RTH and concurrent hypothyroidism. Such patients need close monitoring and aggressive titration of levothyroxine to achieve desired hormone levels.1. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830:3987-4003.2. Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010;95:3189-93.

SAT-411 Vitamin D Levels and Risk of Thyroid Immune Related Adverse Events in Patients on Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICI), such as monoclonal antibodies to cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and PD ligand 1 (PD-L1) are recognized as effective cancer-directed therapies. Yet, ICI-induced activation of the immune system results in immune-related adverse events (irAEs) affecting many organs, including the thyroid. Separately, Vitamin D (Vit D) deficiency has been associated with increased risk of autoimmune thyroid disease. We hypothesized that patients who were Vit D deficient at the time of initiating ICI therapy would be more likely to develop thyroid irAEs. We retrospectively collected data for 411 patients who received ICIs at our institution between January 2011 and April 2017. We then identified 91 of these patients who had 25-OH Vit D levels obtained; 2 were excluded from analysis due to previous thyroidectomy. We recorded demographics, cancer type, Vit D level closest to the start date of ICI therapy, and thyroid irAEs. Patients were categorized as Vit D deficient (<20ng/mL), insufficient (20-29.9ng/mL) or sufficient (≥30ng/mL). We compared patient demographic and clinical characteristics between the VitD categories. Proportions were compared using Fisher’s Exact Test. Of the 89 patients, 48.3% were female and 51.7% were male. Mean age was 67.2 (SD±10.6) years with 57% white, 8% black, 10% hispanic, 7% Asian, and 18% other / unknown. 20% of patients had non-small cell lung cancer, 15% melanoma, 13% hepatocellular carcinoma, 12% multiple myeloma (MM), 8% renal cell carcinoma (RCC), 7% head and neck squamous cell carcinoma, 7% urothelial carcinoma and 18% other cancer types. 21.3% were Vit D deficient, 40.4% were insufficient, and 38.2% were sufficient. Patients with Vit D deficiency and insufficiency were younger (age 64.1± 11.7, 65.9±9.5 years, respectively) than the Vit D sufficiency group (70.1±10.5years, p=0.046). No significant differences between males and females were observed between Vit D categories. Across cancer types, the highest prevalence of Vit D deficiency was in RCC (42.9%) and MM (36.4%). Hispanic and Asian patients had the highest prevalence of Vit D deficiency (44.4% and 33.3%, respectively). 11 patients (12.4%) developed a thyroid irAE. Thyroid irAEs occurred in 5.3% with Vit D deficiency, 8.1% with Vit D insufficiency, and 20% with Vit D sufficiency, but the association was not statistically significant (p=0.2). In contrast to our hypothesis, Vit D deficiency was not associated with a higher rate of thyroid irAEs. In fact our data suggest that patients who are vitamin D sufficient at the time of starting ICI therapy may be at greater risk of developing thyroid irAEs. Our study is limited by small numbers and the retrospective nature of the study. Prospective studies should be performed to determine the significance of Vit D levels on ICI related thyroid disease.

Микроэлементы и региональная частота аутоиммунного заболевания щитовидной железы среди детей России

В работе представлены данные о связи между региональной заболеваемостью российских детей аутоиммунной патологией щитовидной железы и содержанием в их волосах некоторых микроэлементов, обладающих адъювантным действием на иммунную систему. Изучены показатели по всем федеральным округам за 2008-2017 гг. Найдены положительные корреляции между региональной заболеваемостью тиротоксикозом и содержанием йода и ртути, но не алюминия в волосах детей. Предложена регрессионная модель таких взаимосвязей. Неблагоприятно сказываться на аутоиммунитете может увеличение экспозиции не только токсичным, но и эссенциальным микроэлементам сверх потребности. Полученные данные обсуждены в сопоставлении с мировой литературой по данной теме и в контексте предсказания и профилактики риска аутоиммунных тиропатий в педиатрии, в частности относительно оптимального выбора вакцин. Затронуты вопросы пермиссивного действия различных факторов мозаичности аутоиммунитета на результирующие изменения реактивности. Отмечено, что в законопроекте о сплошном обязательном йодировании поваренной соли в Российской Федерации не учтены региональные различия в обеспеченности микроэлементами.

Association of cytokine Th2 gene polymorphisms with autoimmune thyroid diseases in Tunisian population.

Autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are complex genetic diseases. Th2 cytokines act on the development of AITD. This study was conducted on Tunisian patients with AITD to investigate the association of Th2 cytokine gene polymorphisms and haplotype combination with GD or HT risk. A total of 156 controls, 160 patients with HT and 88 patients with GD were genotyped for IL-4 rs2243250, IL-5 rs2069812, IL-6 rs1800796 and IL-13 rs1800925 polymorphisms by PCR-RFLP. The AITD risk was assessed by a logistic regression analysis using the SNP stats statistical program. False-positive report probability (FPRP) was estimated to evaluate significant findings. IL-13 rs1800925 was associated with GD, after adjustment for age and gender, in codominant, dominant and allele genetic models (p=.0072; p=.0018; p=.012, respectively). Significant association of the IL-6 rs1800796C/G genotype with GD was also detected (p=.025). Furthermore, increased risk of HT was still found for IL-13 rs1800925T allele (p=.039, OR=1.39) and for IL-4 rs2243250T/T genotype both in codominant (p=.033, OR=2.59) and recessive (p=.011, OR=2.73) models after adjustment for age and gender. Interestingly, haplotype analysis performed on the IL-4, IL-5 and IL-13 genes revealed a high risk of HT with CTT haplotype (p=.008, OR=2.12). However, the CCT haplotype is a protective factor (OR=0.36). Patients carrying the CT haplotype with only one minor allele had a moderate risk of HT (OR=1.56). The FPRP analysis showed that the association of IL-13 rs1800925 polymorphism with GD and HT and the association of CTT haplotype with HT were noteworthy. In conclusion, the IL-4, IL-5, IL-6 and IL-13 polymorphism may play a role in susceptibility to GD and HT in the Tunisian population. Furthermore, gene-gene interaction between the IL-4, IL-5 and IL-13 significantly increases the risk of AITD. Further studies with larger numbers of individuals are needed to confirm the results.