ResearchPad - benign-thyroid-disease-and-health-disparities-in-thyroid-i Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-410 Long Term Evaluation of TSH Receptor Antibodies and Thyroid Stimulating Immunoglobulin After Radioiodine Therapy for Thyrotoxicosis]]> Background Radioioactive iodine therapy (RAI) is an excellent choice to treat thyrotoxicosis, particularly Graves′ disease (GD) patients. After RAI therapy, it is well known that TSH receptor antibodies (TRAb) rise in GD patients and autoimmunity can eventually surge in patients with toxic multinodular or uninodular goiter (TNG). Recently, biological assay distinguishes stimulating TRAb, called thyroid stimulating immunoglobulin (TSI) bringing a new perspective on follow-up, as TSI is involved in Graves′ pathogenesis of persistent thyrotoxicosis and ophthalmopathy after RAI therapy. Objective Analyze TRAb and TSI levels after 6 and 12 months of RAI therapy for thyrotoxicosis. Patients and Methods Patients were evaluated prospectively immediately before and 6 to 12 months after RAI therapy for thyrotoxicosis. Thyroid hormones were all measured using immunoassays (Roche Diagnostics Ltd). TRAb was analyzed by Elecsys Anti-TSHR assay (Roche Diagnostics, Germany) and was considered negative if < 1.75 IU/L (analytical range: 0.3 to 40 IU/L). TSI was measured by Immulite TSI assay (Siemens Healthcare, UK) and was considered negative if < 0.55 IU/L (analytical range: 0.1 to 40 IU/L). Clinical data and comparison of assays were analyzed by SPSS and MedCalc softwares. Results From 2017 to 2019, 54 patients (44 females) were prospectively evaluated after 6 months of RAI therapy, mostly because of GD (40 patients). A high degree correlation was observed between TRAb and TSI (Spearman correlation coefficient =0.875; p < 0.0001, 95% CI 0.784 to 0.929). After 6 months, among patients with GD, 5/40 patients had negative TRAb levels and 2/40 had negative TSI levels, whereas all TNG patients had both negative TRAb and TSI levels. In GD group, 4 patients showed subclinical hyperthyroidism and relapse occurred in 1 case. All patients with TNG showed euthyroidism status with or without thyroid medications. One year after RAI therapy, we evaluated 32 patients (23 GD) and 4/23 of GD had negative TRAb levels and only 1/23 had negative TSI level. All patients with TNG had negative TRAb and TSI levels after one year fo treatment. Subclinical hyperthyroidism was diagnosed in 5 patients with GD but none with TNG. Along follow-up, 4 patients with clinical diagnosis of GD with TRAb negative before RAI therapy became positive after RAI therapy and 3 patients became TSI positive. Conclusions Long term after RAI therapy for thyrotoxicosis treatment, TRAb and TSI are still positive in most GD patients and few cases can even turned to positive levels. Nevertheless, in TNG patients, RAI therapy is safe as TRAb and TSI maintained at negative concentrations and thyrotoxicosis is properly resolved.

<![CDATA[SAT-420 Interaction Between Gene Polymorphisms and Urine Iodine Levels on Susceptibility to TPOAb Positivity in the Chinese Population]]> Objective: Hashimoto thyroiditis, characterized by positive thyroid peroxidase antibodies (TPOAbs), is caused by the interaction of genetic and environment factors. The aim of this study was to clarify the interaction of gene polymorphisms and iodine intake in the incidence of TPOAb positivity. Methods: 1733 subjects were included in this study. Genomic DNA was extracted from peripheral blood white cells. Seven SNPs (rs10944479, rs11675434, rs1230666, rs3094228, rs653178, rs9277555 and rs301799) were selected for genotyping. Thyroid hormones and autoimmune antibodies (TPOAb and TGAb) were determined using the electrochemiluminescence immunoassay method. Results: The mean TSH level in TPOAb-positive subjects was higher than in TPOAb-negative subjects (P<0.001). There were no significant differences in urine iodine and blood iodine between these two groups. Genotype GG of rs9277555 and genotype TT of rs11675434 were associated with an increased risk of TPOAb positivity. Logistic regression analysis showed rs9277555 was associated with TPOAb positivity in all models. Furthermore, rs9277555 was also associated with TPOAb levels in linear regression analysis. The cross-validation consistency and the testing accuracy indicated that there were no significant differences between SNPs and urine iodine interaction. Conclusion: rs9277555 was associated with an increased risk of TPOAb positivity in a Chinese Han population. Furthermore, there was no gene polymorphisms-iodine intake interactions in our cohort.

<![CDATA[SAT-418 Finding the Needles in the Haystack: Harnessing the Electronic Health Record to Find Thyroid Immune Related Adverse Events]]> Background: Immune checkpoint inhibitors (CPIs) are being used to effectively treat a growing number of cancers but can cause immune related adverse events (irAE). Thyroid dysfunction is the most common endocrine irAE. A meta-analysis of clinical trials estimated that following CPI exposure, 6.6% will become hypothyroid and 2.9% will have hyperthyroidism1. It is unclear if this reflects the real-world incidence of these irAEs. We used electronic health record (EHR) data to identify patients who developed thyroid dysfunction after CPI to estimate the real-world incidence of these irAEs.

Methods: Data were derived from the EHR of a large U.S. academic center. We identified subjects treated with CPIs between 2012 and 2018 and excluded those with thyroid cancer or pre-existing thyroid disease. Thyroid dysfunction was identified as either a TSH > 10, an abnormal free T4 or a prescription for thyroid hormone replacement or anti-thyroid medication. Those with thyroid dysfunction were then categorized as having pre-existing disease or a new-onset thyroid irAE based on the timing of CPI initiation. Logistic regression was used to evaluate the association of thyroid irAE with age, gender, CPI and type of cancer.

Results: In total, 1146 individuals without pre-existing thyroid disease that received CPIs were assessed. Pembrolizumab was the most common treatment (45%), followed by nivolumab (20%). Less than 10% of subjects received atezolizumab, durvalumab, ipilimumab monotherapy, combined ipilimumab/nivolumab, or other combinations of CPIs. Melanoma was the most common cancer treated (32%), followed by non-small cell lung cancer (13%). The prevalence of any other cancer was < 10% each. Overall, 19% developed thyroid irAEs. After adjustment for gender and age, the type of cancer was significantly associated with new onset thyroid dysfunction (p=0.01). The rates of thyroid irAEs ranged from 10% in glioblastoma to 40% in renal cell cancer. Although there was no significant association between irAEs and specific CPIs in the overall analysis, thyroid irAEs were more common in subjects who received combined ipilimumab/ nivolumab (31%) compared to pembrolizumab (18%, p=0.03), nivolumab (18%, p<0.01) and ipilimumab (15%, p=0.02).

Conclusion: Thyroid irAEs are much more common in real world practice than in clinical trials and there is emerging evidence that certain cancer types incur a higher risk of thyroid irAEs even after adjustment for CPI exposure. Clinicians and patients should be educated about these risks. Future work should focus on exploring the reasons underlying the differing rates of thyroid irAEs among different cancers including effect on cancer outcomes.

1Barroso-Sousa et al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens. JAMA Oncol. 2017; 02215: 1–10.

<![CDATA[SAT-412 Genetic Susceptibility to Graves’ Disease Conferred by HLA-DQβ1 Position 57]]> Introduction: Human leukocyte antigen (HLA) locus is the major genetic risk factor for autoimmune endocrine diseases. The amino acid variability at the HLA-DQβ1 position 57 encoded by both DQB1 alleles was identified as critical risk residue for type 1 diabetes. We therefore investigated this amino acid residue at HLA-DQβ1 position 57 in Graves’ disease (GD). Subjects and methods: DNA samples were obtained from 572 healthy controls (HC, 262 females/310 males) and 299 patients with GD (255 females/44 males) and genotyped for HLA-DQB1 using a sequence specific primer (SSP, 13 primer pairs) approach. The PCR amplified products were analyzed by gel electrophoresis. The HLA-DQB1 alleles were defined with their corresponding amino acid residues at the DQß chain positon 57 as follows: Ala57 (DQB1*0201,*0302), Asp57 (DQB1*0301,*0303,*0401,*0402,*0503,*0601,*0602*,0603) Val57 (DQB1*0501,*0604) and Ser57 (DQB1*0502). Finally, the frequencies for amino acid variabilities and their combinations (Ala/Ala, Ala/non-Ala and non-Ala/non-Ala) were calculated and compared by Pearson-Mantel-Haenszel Chi-squared test. Results: The presence of Ala57 was significantly more frequent in patients with GD compared to HC (25% vs. 39%, OR: 1.77; p=7x10-4), whereas Val57 was less frequent (19% vs. 12%, OR: 0.59; p=0.04). In contrast, no difference in the distribution between GD and HC concerning the amino acids Asp57 and Ser57 was observable. Similar results were found in female (Ala57 23% vs. 38%, OR:2.01; p=1.2x10-3 and Val57 19% vs. 13%, OR:0.35; p=1.2x10-4) but not in males (p >0.5). Furthermore, homozygous HLA-DQB1 Ala (8% vs. 15%, OR:1.98; p=5x10-3) as well as heterozygous HLA-DQB1 Ala/non-Ala (34% vs. 45%, OR:1.58; pc=5x10-3) were significantly more prevalent, while non-Ala/non-Ala (58% vs. 40%, OR:0.49 pc=3x5x10-6) was found to be less frequent in patients than in HC. By gender stratification there was a significant difference between female patients with GD and female HC in the distribution of the mentioned amino acid combinations (Ala p=4.5x10-3, Ala/non-Ala pc=0.02, non-Ala/non-Ala p=1x10-5). Conclusion: We identify a strongly predisposing role for HLA-DQβ1 Ala5 7to GD, particularly in women, highlighting the gender specific disease risk. Immunogenetic testing may pave the way towards personalized treatment.

<![CDATA[SAT-417 Personalized Treatment Planning for Radioiodine Therapy of Graves’ Disease;The Collar Therapy Indicator(CoTI)]]> Introduction Since its introduction 80 years ago, the therapeutic I-131 dosage has usually been tailored to individual patient requirements based on the uptake of a tracer radio-iodine(RAI) dose. Estimated exposure has typically been extrapolated from the results of activity measurements at one or two time points, e.g., at 4 and 24 hours. We now know that treatment of hyperthyroid Graves disease with these methods lead to a 13–25% rate of failure to cure hyperthyroidism and a 46–80% rate of long-term hypothyroidism in cured patients. There is a need for a much more personalized approach to RAI dosing based on individual RAI tissue uptake, kinetics. This can be achieved only after including multiple data points during the evaluation of tissue uptake. The Collar Therapy Indicator (CoTI), a device placed in cloth collar around the neck resembling a turtle neck sweater collar with a connecting wire and recording box, has been shown in small feasibility studies to provide data regarding radioiodine exposure that correlates with conventional methods of measuring I-123 and I-131 uptakes after diagnostic dose administration and/or therapy for thyroid disorders Methods; We hypothesized that the device’s continuous measurement capability will permit more accurate estimates of radiation exposure to thyroid tissue than conventionally employed methods assessing fractional uptake at one or a few time points. It may also provide information about the extent of variability in the absorbed radiation dose among patients with hyperthyroidism. We performed a feasibility study in a patient with graves’ disease to see the difference between tradition methods of I-123 uptake and the CoTI; (1) We compared the conventional quantitative uptake-derived thyroid time activity curve (TAC) as well as the Area Under the Curve (AUC)(based on percent uptake at 6 hour and 24 hour time points) to that obtained using the CoTI.(2) We evaluated the uptake and clearance kinetics of diagnostic I-123 administered.(3) We also evaluated patient experience in using the CoTI device with a survey instrument. Results; The CoTI plotted TAC and AUC offered a different approach from the conventional methods of calculation (6 hr and 24 hr % uptake) of I-123 TAC and AUC. The patient reported no difficulty in using the device and the device itself was not inconvenient. Conclusions; The calculation of % uptake as well as rate of uptake within the thyroid by CoTI might help us, in achieving a more personalized approach to I-131 RAI dose calculation for treatment of Graves’ disease. The preliminary research findings that we have generated will help us investigate different aspects of RAI uptake within the thyroid and will hopefully lead to solutions, for some of the common issues and problems arising out of random dosing of RAI.

<![CDATA[SAT-424 Assessing Content Validity of the Graves’ Ophthalmopathy Quality of Life Questionnaire (GO-QOL) in the United States]]> Introduction: Thyroid eye disease (TED) is an autoimmune condition that negatively impacts patient’s quality of life (QOL). The GO-QOL questionnaire was originally developed in the Netherlands to quantify how TED and treatments affect patient QOL. This questionnaire includes eight questions each on visual functioning and appearance related QOL; the items are answered on a 3-point Likert scale and transformed to a 0 (worst) to 100 (best) scale. Though widely used and validated outside the US, the questionnaire has not been validated in the United States (US). Here we examine the content validity.

Methods: Patients with moderate or severe TED were identified using an existing market research patient database, clinician referrals, patient groups, and social media. Interested participants were screened for eligibility prior to completing the GO-QOL. Subjects were also questioned about TED-related signs, symptoms, and treatments and underwent a cognitive interview following GO-QOL completion.

Results: Thirteen TED patients completed the assessments (mean age = 44.8 ± 11.5 years, range: 26-67); all were female. Mean TED duration was 4.6 ± 5.5 years (range: 0.4-20.7). Twelve patients (92.3%) had Graves’ disease and one had Hashimoto’s thyroiditis. Descriptions of how TED signs and symptoms impacted quality of life were consistent with GO-QOL items, and qualitative interviews indicated that patients found the GO-QOL content relevant and complete. Responses indicated that minor wording changes may be needed to account for US cultural and language conventions and prevent confusion (specifically related to a bicycling question [12/13 reported not regularly riding a bike before TED symptom onset]). Visual functioning impacts most commonly-reported during the interview were difficulty driving a motor vehicle (92% of participants), difficulty with electronic screens (e.g., televisions, smart phones, and computers; 77%), difficulty moving around outdoors (including issues with light sensitivity, uneven surfaces, and depth perception; 69%), and difficulty doing hobbies or pastimes (69%). Emotional/psychological impacts frequently reported by participants were change in appearance (92%), depression and anxiety (including fear and worry; 77%), and frustration and anger (including moodiness; 69%). Negative reactions from others (staring, asking questions), social impacts and isolation, and lack of self-confidence and embarrassment were also reported (each 62%).

Conclusion: This analysis of US patient interviews offered strong support for GO-QOL content validity. Therefore, the GO-QOL is appropriate to quantify TED-related QOL impact in a US population. However, a few slight wording modifications may be needed for future optimal use in the US.Reference: Terwee CB. Br J Ophthalmol 1998;82:773-779

<![CDATA[SAT-421 Novel Role of Chloroquine and Hydroxychloroquine in Graves’ Orbitopathy Therapy by Targeting Orbital Fibroblasts]]> Abstract: Context: Graves’ orbitopathy (GO) presents with infiltrative exophthalmos due to excessive proliferation, adipogenesis and glycosaminoglycans production of orbital fibroblasts (OFs). There are few therapies potent for proptosis. Intervention in autophagy of OFs could be a potential therapy. Objectives: Here, our purpose was to evaluate the effects of chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), as autophagy inhibitors commonly used in clinical practice, on GO-OFs from human orbit in vitro. Design/Setting/Participants: OFs isolated from patients with GO (n = 10) or control persons (non-GO) (n = 8) were allowed to proliferate in the proliferation medium (PM) or differentiate into adipocytes in the differentiation medium (DM), co-treated with CQ of different concentrations, and subsequently examined in vitro. Main Outcome Measures: CCK-8, EdU incorporation and flow cytometry were used to assess cellular viability. Adipogenesis was assessed by Western blot, real time-PCR, and Oil Red O staining. Hyaluronan was determined by real time-PCR and ELISA. Autophagy flux was detected using RFP-GFP-LC3 fluorescent staining and Western blot. Results: CQ (10μM) or HCQ (10μM) treatment for 48h was sufficient to block autophagy flux without exhibiting cell toxicity in OFs from either GO or non-GO participants. Cellular proliferation of GO-OFs was halted by both CQ and HCQ. Also CQ and HCQ exerted an inhibitory action on lipid accumulation of GO-OFs during differentiation as well as expression of adipogenetic markers such as PPARγ and c/EBP-α/β. Moreover, hyaluronan secretion, concurrent with expression of hyaluronan synthase 2 (HAS2), was obviously decreased by CQ and HCQ. Conclusions: We reported the efficacies of CQ and HCQ on proliferation, adipogenesis and hyaluronan generation of GO-OFs via inhibiting autophagy, providing proof of concept that quinoline-based antimalarial (QBA) drugs like CQ and HCQ have potential to be a new treatment for GO as autophagy inhibitors.

<![CDATA[SAT-432 Pharmacokinetics (PK) and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor (IGF-1R) Blocking Antibody, in Active Thyroid Eye Disease (TED)]]> Introduction: Teprotumumab treatment resulted in statistically and clinically meaningful improvements across multiple facets of active TED and was generally well-tolerated in Phase 2 and 3 trials.1,2 An initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks was selected based on in vitro activity and clinical PK profile, to maintain pharmacologically active exposures and >90% saturation of IGF-1R over dosing intervals and to achieve efficacy at a well-tolerated dose for this vision-threatening disease.

Methods: Population PK analysis were performed on data from a Phase 1 oncology study (n=60)3 and Phase 2 and 3 trials in active TED (N=83)2,3 and covariate effect on PK was assessed. Exposure-response relationship was evaluated in TED studies for key efficacy endpoints (proptosis response rate, % patients with a clinical activity score value of 0 or 1, and diplopia responder rate) and selected safety variables (hyperglycemia and muscle spasms).

Results: Teprotumumab PK was linear in TED patients and consistent with other immunoglobulin G1 monoclonal antibodies (IgG1 mAbs), with low systemic clearance (0.334 L/day), low volume of distribution (3.9 L for central compartment and 4.2 L for peripheral compartment), and long elimination half-life (19.9 days). 4,5 Model-predicted mean (± standard deviation) steady-state area under the concentration curve (AUCss), peak (Cmax,ss), and trough (Cmin,ss) concentrations in TED patients were 131 (± 30.9) mg∙hr/mL, 643 (± 130) µg/mL and 157 (± 50.6) µg/mL, respectively, suggesting low inter-subject variability.

Population PK analysis indicated no significant impact of baseline age, gender, race, weight, smoking status, renal impairment (mild/moderate), and hepatic function (total bilirubin, aspartate and alanine aminotransferases) on teprotumumab PK. Female patients had 15% higher Cmax,ss but similar AUC compared to male patients, which is not considered clinically relevant.

Exposure-response analysis from the TED dose regimen indicated no meaningful correlations between exposures (AUCss, Cmax,ss and Cmin,ss) and key efficacy endpoints or selected safety variables, supporting the demonstrated, favorable benefit-risk profile of the TED dose regimen.2

Conclusion: Teprotumumab PK was characterized in TED patients by long elimination half-life, low systemic clearance and low volume of distribution, consistent with other IgG1 mAbs. There was no meaningful exposure-response relationship at the selected TED dose regimen for both efficacy and safety endpoints, supporting the teprotumumab dose regimen used in TED patients.

Reference: (1) Smith TJ, et al. N Engl J Med 2017;376:1748-1761. (2) Douglas RS, et al. AACE 2019 late-breaking abstract. (3) NCT00400361. (4) Dirks NL et al. Clin Pharmacokinet. 2010;49(10):633-59. (5) Ryman JT et al. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-88.

<![CDATA[SAT-427 Quality of Life Following Treatment for Graves’ Disease: A Comparison of Radioactive Iodine Ablation and Surgery]]> Introduction: Quality of Life (QoL) is reduced in patients with Graves’ disease, however the impact of treatment modality is unclear, with conflicting evidence from recent studies (1–3). We hypothesized that surgery would have a greater impact than radioiodine on QoL in Graves’ disease, especially with regard to the physical-symptom subdomain.

Methods: Patients treated with thyroid surgery for benign disease (n=425) or radioactive iodine for hyperthyroidism (n=1637) at a single tertiary institution between 2000 and 2017 were invited to complete a validated thyroid-specific QoL instrument (City of Hope), reporting scores 0–10, where higher scores are associated with greater QoL. Responses were received from 307 patients, of whom 114 (37%) had Graves’ disease, treated with total thyroidectomy (n=23) or doses of 15mCi (550MBq) radioiodine (n=91, including 19 patients receiving 2 or more doses). The results of patients with Graves’ disease are reported here. Medians [interquartile ranges] are compared with the Mann-Whitney test (alpha 0.05).

Results: 85% of respondents were female, with no difference in gender between groups (p=0.11). Thyroidectomy patients were more likely to be younger (36 [31–49] vs 50 [39–59] years, p=0.004); and have a shorter duration between treatment and survey (5.9 [2.4–9.6] vs 7.6 [4.9–11.6] years, p=0.04). No overall QoL deficit was seen in patients treated with surgery compared to radioiodine (6.8 [5.2–7.3] vs 7.0 [5.8–8.1], p=0.08). However, patients treated with surgery reported reduce QoL in psychological (6.6 [4.7–7.5] vs 7.0 [5.9–8.2] p=0.05) and social (7.9 [6.4 – 8.9] vs 8.9 [7.4–9.8] p=0.01) subdomains compared to radioiodine-only treated patients. Within the social subdomain, the QoL detriment was driven by lower scores relating to questions regarding impact on personal and family relationships, support, and isolation (p<0.001), and not by impact on activities of daily living or employment concerns. Interestingly, there was no between group difference in the physical symptom subdomain (p=0.16). QoL differences between treatment modalities were preserved when patients receiving multiple doses of radioiodine were excluded.

Discussion In this non-randomised cross-sectional study from a tertiary-hospital population in Australia, a QoL deficit was demonstrable in subdomain scores for patients with Graves’ disease treated with surgery compared to radioiodine, although the overall result was not significantly different. Better understanding of patient experiences is required to guide treatment strategies and appropriately counsel patients.

References (1) Torring et al. Thyroid. 2019;29(3):322–31. (2) Abraham-Nordling et al. Thyroid. 2005;15(11):1279–86. (3) Ljunggren et al. Thyroid. 1998;8(8):653–9.

<![CDATA[SAT-431 Insulin Resistance, Lipid Profile and High-Sensitivity C-Reactive Protein in Patients with Autoimmune Thyroiditis]]> Introduction: Thyroid function and autoimmunity has been associated with cardiovascular events in patients with autoimmune thyroiditis. Objectives: To evaluate the association between thyroid function, antithyroid antibodies levels, insulin resistance and markers of cardiovascular risk in patients with autoimmune thyroiditis. Methods: We evaluated 228 patients with autoimmune thyroiditis, 93.9 % female, with a mean age of 47.06 ± 15.35 years. We analyzed thyroid function, anti-thyroglobulin antibodies (anti-Tg), anti-thyroid peroxidase antibodies (anti-TPO), HOMA-IR, HOMA-B, QUICKI, HISI (Hepatic Insulin Sensitivity Index), WBISI (Whole-Body Insulin Sensitivity Index), the levels of lipid profile, high-sensitivity C-reactive protein (hs-CRP), homocysteine, folic acid, and vitamin B12. We defined 3 groups based on TSH levels: TSH between 0.35-2.49 µUI/ml, (n = 166), TSH between 2.50-4.94 µUI/ml, (n = 43) and TSH over 4.95 µUI/ml, (n = 19), and normal levels of free T4 and free T3. A 75-g OGTT was performed in the morning and blood samples were obtained every 30 min for 120 min for measurements of plasma glucose, insulin, and C-peptide. For the statistical analysis we used the Mann-Whitney test and Spearman correlations. Results are expressed as means ± SD or percentages. A two-tailed p<0.05 was considered statistically significant. Results: There were no significant differences regarding median age or median BMI between groups. We did not find any significant differences comparing group with TSH 0.35-2.49 and group with TSH 2.50-4.94, in all parameters evaluated. Group with TSH 2.50-4.94 had higher indexes of QUICKI (0.69 ± 0.39 vs 0.48 ± 0.13; p = 0.02) and HISI (79.83 ± 63.72 vs 41.73 ± 29.02; p = 0.01) than group with TSH over 4.95. The group with TSH over 4.95 demonstrated a higher index of HOMA-IR than group with TSH 2.50-4.94 (3.77 ± 2.93 vs 1.95 ± 1.24; p = 0.01). In the TSH 0.35-2.49 group we found significant correlations between TSH and HOMA-IR (r= 0.18; p = 0.01), total cholesterol and anti-TPO (r =0.23; p = 0.002), anti-Tg and HDL-cholesterol (r= -0.17; p=0.002), anti-Tg and triglycerides (r=0.34; p < 0.001), and anti-Tg and LDL-cholesterol (r=0.16; p=0.03). In the TSH 2.50-4.94 group we observed positive correlation between Apo A1 and HOMA-B (r=0.58; p<0.001), HOMA-IR and LDL-cholesterol (r=0.34; p=0.02) and WBISI and HDL-cholesterol (r=0.34; p=0.02). In the TSH over 4.95 group we observed a correlation between TSH and triglycerides (r=0.70; p<0.001) and between anti-Tg and hs-CRP (r=0.64; p=0.004). Conclusions: The association among TSH, lipid profile, insulin resistance, hs-CRP and antithyroid antibodies in patients with autoimmune thyroiditis may contribute to an increased cardiovascular risk, not only in patients with subclinical hypothyroidism but also in those classified as euthyroid.

<![CDATA[SAT-428 Sex-Specific Risk Gene of Graves’ Disease]]> Graves’ disease is one of the most common forms of autoimmune thyroid disease, with several susceptibility single nucleotide polymorphisms identified by the case-control association studies. In this study, we aim to determine whether any observed differences in genetic associations are influenced by sex in Chinese Han populations. A total of 8,835 patients with Graves’ disease and 9,936 sex-matched healthy controls were enrolled in the study. We conducted sex specific analysis among 20 Graves’ disease susceptibility loci confirmed by two-stage association analysis. A significant sex-gene interaction was detected primarily at rs5912838 on Xq21.1 between the GPR174 and ITM2A gene, whereby men patients with Graves’ disease possessed a significantly higher frequency of risk alleles than women. Interestingly, men patients with Graves’ disease had a higher cumulative genetic risk than women. Our findings suggest one potential sex-specific link of Graves’ disease on Xq21.1, which could increase our understanding of the pivotal mechanisms behind Graves’ disease and ultimately the provision of possible therapeutic targets.

<![CDATA[SAT-433 The Influence of Thyroid Autoimmunity on Pregnancy Outcome in Infertile Women]]> Background: Women with subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) reportedly have high risks of miscarriage and preterm birth. Infertile women undergoing assisted reproductive technology (ART) are recommended for levothyroxine (L-T4) supplementation to maintain TSH levels below 2.5 mIU/mL according to ATA guideline; however, insufficient evidence exists to determine whether L-T4 treatment for infertile women with TSH levels between 2.5 and 5.0 mIU/mL. Objective: To clarify the influence of TAI on pregnancy in infertile women under L-T4 treatment to maintain TSH levels below 2.5 mIU/mL, and to compare its influence depending on fertility treatments. Methods: A total of 595 infertile women who visited a fertility clinic between January 2013 and December 2015 were prospectively recruited to this study. Five patients with Graves’ disease were excluded and remained 590 women were included in the analysis. Infertile women with TSH levels above 2.5 mIU/mL were treated with L-T4 followed by evaluation of fertility status and pregnancy outcomes. Factors affecting pregnancy were analyzed statistically depending on fertility treatments. Written informed consent was obtained from all patients, and the study protocol was approved by the Ethics Committee. Results: The proportion of SCH and thyroid peroxidase antibodies (TPOAb).positivity was 19.6% and 10.4%, respectively. Women who did not become pregnant were older than those who became pregnant (p=0.003), but no influence of thyroid-associated factors on pregnancy was confirmed. Pregnancy outcome contrarily showed that women who had a miscarriage were older (p<0.001) and higher TPOAb titers (p=0.038) than those who had a live birth. In addition, higher age (OR 26.4, p<0.001) and high TPOAb titer (OR 11.8, p=0.043) were decided as risk factors for miscarriage through multiple logistic regression analysis. Among women who treated with intrauterine insemination, TPOAb titers were higher in women who had a miscarriage than in those who had a live birth (p=0.040). We further focused on the difference between ART methods including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Women undergoing IVF had higher TPOAb titers in women who had miscarriage than those who had a live birth (p=0.023), but in women undergoing ICSI there was no association between TPOAb titers and pregnancy outcome. Conclusion: Infertile women with high TPOAb titers are susceptible to miscarriage despite appropriate L-T4 treatment. The influence of TPOAb titers as well as TPOAb positivity on pregnancy should be considered, when undergoing fertility treatments.

<![CDATA[SAT-429 Systemic Safety Analysis of Mycophenolate in Graves’ Orbitopathy]]> Context

The dual antiproliferative mechanism of mycophenolate appears to be beneficial in Graves’ orbitopathy (GO).


The safety data, which is of utmost importance in immunomodulation, from the two major randomized mycophenolate trials [“Chinese trial” (1) and “European Group on Graves’ Orbitopathy (EUGOGO) trial” (2)] and the original database of the EUGOGO trial were systematically analyzed. Treatment efficacy stratified by individual visual parameters of clinical disease activity and severity were also compared.


A total of 129 adverse events (AE) involving 50 patients (29.4%) were noted among all mycophenolate-treated patients. Mycophenolate sodium plus intravenous glucocorticoid (MPS+GC) group of the EUGOGO trial recorded significantly more AE (55.4% versus 4.6% of patients affected) and serious adverse events (SAE) (12.5% versus 0%) than mycophenolate mofetil (MMF) group of the Chinese trial. The excess of AE may partly be contributed by GC use. None of those SAE was side effect (SE). Most SE in MPS+GC group (79%) were mild. Gastrointestinal disorders, infection and liver dysfunction affected 8.8%, 7.1% and 1.2% of all mycophenolate-treated patients (versus 5.4%, 5.4% and 1.2% of all patients on GC monotherapy, respectively). When compared to GC monotherapy, MPS+GC did not significantly increase the overall SE rate (25.3% versus 19.7%) nor did risks of infection or liver dysfunction, but it result in more mild gastrointestinal disorders (SE rate in EUGOGO trial 10.8% versus 4.9%). No cytopenia, serious infection, severe hepatotoxicity or treatment related mortality was reported among mycophenolate-treated patients. The much higher AE rates of mycophenolate trials in other autoimmune diseases or transplantations suggested that major mycophenolate toxicities were mostly dose- and duration-dependent. Regarding efficacy, mycophenolate achieved better overall response than GC monotherapy. Approximately 70% (versus 90% in MMF group) and 30% (versus 60–70% in MMF group) of patients in MPS+GC group achieved endpoints in most individual visual parameters of activity and severity, respectively. MPS+GC group of the EUGOGO trial performed better than MMF group in terms of improvement of pain and eye movement.


The risk-benefit ratio of 6-month courses of low dose mycophenolate treatment in active moderate-to-severe GO, either as monotherapy or as combination with GC, is highly favorable given its reassuring safety profile with low rate of mild to moderate SE and promising efficacy.


(1) Ye et al., Clin Endocrinol (Oxf). 2017;86(2):247–55

(2) Kahaly et al. Lancet D&E. 2018;6(4):287–98

<![CDATA[SAT-426 Macro-Thyroid Stimulating Hormone (TSH) in Children]]> AbstractMacro-TSH is mainly a complex of TSH with anti-TSH autoantibodies. Due to its large molecular size (>150 kDa), it accumulates in the circulation resulting in elevated serum TSH concentrations. Because the bioactivity of macro-TSH is low, treatment with thyroxine is not necessary. The prevalence of macro-TSH is no more than 1% in adult patients with subclinical hypothyroidism. However, the prevalence of macro-TSH in children is not known. We report here two cases of macro-TSH in pediatric setting.[Case reports] Case 1. Six-year and eight-month-Japanese boy visited a pediatric hospital because of hyperactivity disorder. Physical examination revealed that he had a slight mental retardation (IQ 63 by Tanaka-Binet test). Thyroid tests showed that fT4 1.21 ng/dL, TSH 120.4 µU/mL, Tg antibody 1.9 IU/mL, TPO antibody <0.1 IU/mL. His serum was sent to our laboratory to examine the causes of inappropriate high serum TSH concentration. Case 2. Eight-year and three-month-Turkish girl was brought to a pediatric hospital by her parents because of her yellowish palms, which was not identified at the hospital. She did not have any complaints and physical signs attributable to thyroid dysfunction. Laboratory data disclosed that fT4 1.5 ng/dL, TSH 19.6 µU/mL, Tg Ab negative, TPO Ab negative. Levothyroxine treatment started but serum TSH concentration was still high (39.0 µU/mL) after two months. Her serum sample was sent to our laboratory to examine the causes of inappropriate high serum TSH concentrations.[Lab. Tests for macro-TSH]When serum was mixed with the same amount of 25% polyethylene glycol (PEG) and γ-globulin fraction was precipitated, TSH concentration in the supernatant decreased significantly from 109.3 µU/mL to 2.3 µU/mL (PEG precipitation ratio 97.9%) in case 1, and from 17.3 µU/mL to 0.15 µU/mL (PEG precipitation ratio 99.1%) in case 2. HAMA blockers did not significantly change TSH concentration in both cases. High proportion of serum TSH bound to a protein G column, which binds IgG, in case 1 (91.3%) and in case 2 (57.7%), indicating that TSH was associated with IgG. Gel filtration chromatography (GFC) revealed that TSH was mostly eluted at the fraction > 150 kDa rather than 28 kDa of authentic TSH in both cases. Serum was incubated with 37.7 µU of TSH for one hour and subjected to GFC. TSH concentration in the fraction of 150 kDa (macro-TSH) increased from 2.8 µU/mL to 5.6 µU/mL in case 1 and from 0.4 µU/mL to 2.0 µU/mL in case 2, suggesting that macro-TSH was produced by the binding of exogenous TSH to anti-TSH autoantibodies.[Conclusion]Macro-TSH exists in children and careful evaluation is required in patients with inappropriate high serum TSH concentrations to avoid unnecessary treatment. ]]> <![CDATA[SAT-LB76 Impact of Glucocorticoid Cosecretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease]]> <![CDATA[SAT-430 Quality of Life After Thyroidectomy for Patients with Hashimoto’s Disease and Persistent Symptoms]]> <![CDATA[SAT-LB75 Thyroid Peroxidase Antibody Positivity Predicts Relapse Free Survival Following Anti-Thyroid Drug Treatment for Graves Disease]]> <![CDATA[SAT-416 Novel Autoantibodies for Thyroid-Specific Transcriptional Factors in Patients with Immune-Related Adverse Events Involving the Thyroid Gland]]> <![CDATA[SAT-411 Vitamin D Levels and Risk of Thyroid Immune Related Adverse Events in Patients on Immune Checkpoint Inhibitors]]> <![CDATA[SAT-414 A Single Center Retrospective Analysis and Review of Endocrinopathies from Immune Checkpoint Inhibitors Between 2007 and 2017]]>