Hyperthyroid Graves Research Articles

Graves disease: latest understanding of pathogenesis and treatment options.

Graves disease is the most common cause of hyperthyroidism in iodine-sufficient areas. The main responsible mechanism is related to autoantibodies that bind and activate the thyrotropin receptor (TSHR). Although Graves hyperthyroidism is relatively common, no causal treatment options are available. Established treatment modalities are antithyroid drugs, which reduce thyroid hormone synthesis, radioactive iodine and surgery. However, emerging drugs that target the main autoantigen (monoclonal antibodies, small molecules, peptides) or block the immune pathway have been recently tested in clinical trials. Graves disease can involve the thyroid exclusively or it can be associated with extrathyroidal manifestations, among which Graves orbitopathy is the most common. The presence of Graves orbitopathy can change the management of the disease. An established treatment for moderate-to-severe Graves orbitopathy is intravenous glucocorticoids. However, recent advances in understanding the pathogenesis of Graves orbitopathy have allowed the development of new target-based therapies by blocking pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R), with several clinical trials providing promising results. This article reviews the new discoveries in the pathogenesis of Graves hyperthyroidism and Graves orbitopathy that offer several important tools in disease management.

A sight into the pathogenesis and treatment of thyroid-associated ophthalmopathy

Introduction and aim. Thyroid-associated ophthalmopathy (TAO), often referred to as thyroid eye disease or Graves’ ophthalmopathy, is a syndrome characterized by autoimmune inflammation affecting the eye muscles, connective tissue, and orbital fat. The aim of this literature review is to present TAO and integrate the available data in the literature regarding the pathogenesis and treatment methods. Based on these, the authors aim to examine whether, despite the extensive knowledge already available on TAO, there are still issues to be investigated. Material and methods. In this literature review, books and scientific publications in both Polish and English languages have been assessed. The search criteria included keywords such as TAO, Graves’ disease, thyroid-associated ophthalmopathy. The evaluation covered the following databases: PubMed, Scopus, Google Scholar. Analysis of the literature. Typically, the eyeball is not involved, but in exceptional cases, corneal ulceration may occur, or inflammation of the optic nerve may ensue. TAO most commonly occurs in the course of hyperthyroidism in Graves’ disease, involving up to 25–50% of cases. The coexistence of autoantigens shared between the thyroid and orbital tissues is considered the primary cause of TAO when it occurs concurrently with hyperthyroidism, later in its course, or even preceding the manifestation of hyperthyroidism, with or without concurrent thyroid dysfunction. TAO is generally bilateral, although dominance on one side is often observed. Common symptoms include eye pain, photophobia, diplopia, varying degrees of proptosis, and impaired vision. The cornerstone of treatment lies in managing hyperthyroidism, as TAO cannot be cured without it. Conclusion. First-line treatment involves glucocorticoids, with radiation therapy as a supplementary option, and in cases unresponsive to pharmacological treatment, surgical intervention may be necessary.

Hyperthyroidism in Graves' disease: practical advice on the choice of treatment and indications for radioiodine use.

Hyperthyroidism in Graves' disease: practical advice on the choice of treatment and indications for radioiodine use.

T3, T4, TSH, Anti-TPO, and Anti-TG Autoantibodies Distribution in Autoimmune Thyroid Patients with Chlamydia Trachomatis Infection

Autoimmune thyroid disorders (AITDs) include a variety of inflammatory conditions affecting the thyroid gland, with Graves' disease (GD) and Hashimoto's thyroiditis (HT) being the most commonly seen types. Autoimmune thyroid illnesses often include the existence of antibodies against thyroid peroxidase (TPO), thyroglobulin (Tg), and thyroid stimulating hormone receptor (TSHR). We specifically targeted recently diagnosed adult patients with Graves' disease (GD), Hashimoto's thyroiditis (HT), and those with normal thyroid function as controls. The study looked at and compared different groups' levels of anti-TG antibodies, anti-TPO antibodies, and anti-chlamydia antibodies in the blood, as well as several clinical and biochemical markers, such as thyroid function tests. We analyzed data from a cohort of 60 patients diagnosed with Hashimoto's thyroiditis (HT), 60 patients diagnosed with Graves' disease (GD), and 60 healthy individuals serving as controls. The study found a strong link between having anti-TPO Abs and having Hashimoto's hypothyroidism (63.3%) and Graves' hyperthyroidism (86.7%). In the groups without anti-TPO Abs, Hashimoto's hypothyroidism was found in 36.7% of people and Graves' hyperthyroidism was found in 13.3% (P<0.03). Anti-thyroid peroxidase antibodies (anti-TPO Abs) are found in 86.7% of people with Graves' disease, which is more than the 63.3% of people with Hashimoto's disease who have these antibodies. There is no significant link between the percentage of people who have anti-TG antibodies and either Hashimoto's hypothyroidism (96.7%) or Graves hyperthyroidism (90%), according to the study. The significance level was set at P = 0.143. This is in comparison to the percentage of negativity in Hashimoto's hypothyroidism (3.3%) and Graves's hyperthyroidism (10.0%). The study showed how the groups were spread out based on the presence of Chlamydia trachomatis IgG antibodies. Chlamydia trachomatis IgG antibodies were much more common in people with Hashimoto's hypothyroidism (42) and Graves hyperthyroidism (26) than in the control group (0) (P<0.01).

Characterizing TSH-receptor antibody (TRAb) seropositive and TRAb seronegative patients with Graves hyperthyroidism - a cross-sectional study

Characterizing TSH-receptor antibody (TRAb) seropositive and TRAb seronegative patients with Graves hyperthyroidism - a cross-sectional study

The determination of the optimal threshold on measurement of thyroid volume using quantitative SPECT/CT for Graves' hyperthyroidism

PurposeTo investigate the optimal threshold for measuring thyroid volume in patients with Grave's hyperthyroidism (GH) by SPECT/CT.Materials and methodsA 53 mL butterfly-shaped hollow container made of two 45-degree transparent elbows was put into a NEMA IEC phantom tank. The butterfly-shaped container and the tank were then filled with Na99mTcO4 of different radioactive concentrations, respectively, which could simulate thyroid gland with GH by different target-to-background ratios (T/B) (200:1, 600:1, 1000:1). The different T/B of planar imaging and SPECT/CT were acquired by a Discovery NM/CT 670 Pro SPECT/CT. With Thyroid software (Version 4.0) of GE-Xeleris workstation, the region of the thyroid gland in planar imaging was delineated. The thyroid area and average long diameter of both lobes were substituted into the Allen formula to calculate the thyroid volume. The calculation error was compared with the actual volume. Q-Metrix software was used to perform CT-based attenuation correction, scatter correction, resolution recovery. Ordered-subsets expectation maximization was used to reconstruct SPECT data. 20%, 25%, 30%, 40%, 50%, 60% thresholds were selected to automatically delineate the volume of interest and compared with the real volume, which determinated the optimal threshold. We measured the thyroid volume of 40 GH patients using the threshold and compared the volumes obtained by planar imaging and ultrasound three-dimensional. The differences of the volumes with different T/B and thresholds were compared by the ANOVA and least significant difference t test. The volumes delineated by SPECT/CT were evaluated using ANOVA, least significant difference t test, correlation analysis and, linear regression and Bland–Altman concordance test plot. The differences and consistency of thyroid volume were compared among the above three methods.ResultsThere was no significant difference in the results between different T/B models (P > 0.05). The thyroid volume calculated by the planar imaging formula method was higher than the real volume, with an average overestimation of 22.81%. The volumes delineated by SPECT/CT threshold automatically decreased while the threshold increased. There were significant differences between groups with different thresholds (P < 0.001). With an average error of 3.73%, the thyroid volume analyzed by the threshold of 25% was close to the results of ultrasound measurement (P > 0.05). Thyroid volume measured by planar imaging method was significantly higher than ultrasound and SPECT/CT threshold automatic delineation method (P < 0.05). The agreement between the SPECT/CT 25% threshold and ultrasound (r = 0.956, b = 0.961) was better than that between the planar imaging and ultrasound (r = 0.590, b = 0.574). The Bland–Altman plot also showed that the thyroid volume measured by the 25% threshold automatic delineation method was in good agreement with the ultrasound measurement.ConclusionsThe T/B has no effect on the measurement of thyroid volume in GH patients; planar imaging method can significantly overestimate thyroid volume in GH patients, and 25% threshold automatic delineation method can obtain more accurate thyroid volume in GH patients.

Effect of previous administration of potassium iodine and different durations of low iodine diets for radioiodine therapy on the treatment of Graves' disease in iodine-rich areas.

To examine whether adherence to a low-iodine diet (LID) enhances the therapeutic efficacy of radioiodine therapy (RAI) in Graves' hyperthyroidism (GH) in iodine-rich areas. We retrospectively evaluated 185 patients with GH from Aichi (n = 114) and Hokkaido (n = 71) Prefectures. Patients aged ≥ 18years with GH who underwent RAI between December 2012 and March 2022 were divided into subgroups based on pretreatment with anti-thyroid drug (ATD) or potassium iodide (KI). Patients were followed up with LID from 18days (group A) or 7days (group H) before RAI to 3days after RAI. The dose of radioactive iodine 131 (131I) was adjusted to deliver > 100Gy to the thyroid. The associations between urinary iodine concentration on UIC2 vs. 24hRU and UIC2 vs. the 1-year RAI success rate (SR) were investigated. Compared with UIC1, UIC2 was significantly decreased in all subgroups (P < 0.01). An inverse correlation between UIC2 and 24hRU was observed in the four groups; however, the difference was insignificant. The SR in groups A and H was 85% and 89%, respectively. Univariate analysis revealed no association between UIC2 and SR in each group. Additionally, stratification of the 185 patients into quartiles using UIC2 yielded no significant differences in SR (p = 0.79). LID sufficiently reduced UIC in patients undergoing RAI. Although a lower UIC2 may increase 24hRU, it did not increase the success of RAI. The benefit of LID in enhancing the efficacy of RAI in GH treatment remains uncertain.

Prevalence, predictors and rhythm outcome of Atrial fibrillation (AF) in patients with Graves hyperthyroidism

Prevalence, predictors and rhythm outcome of Atrial fibrillation (AF) in patients with Graves hyperthyroidism

THU669 Time To Achieve Euthyroidism In Graves Disease Using Methimazole In An Urban Population

Abstract Disclosure: S.S. Habbsa: None. E. Yunasan: None. A. Krishnan: None. K.M. Munir: None. Context: Previous studies of treatment response in Graves disease have shown that that the mean time to reach euthyroidism with methimazole (MMI) was several weeks to months. In 1987 Okamura et al. concluded that the average period was 6-7 weeks with MMI 30mg daily. Nakamura et al. showed similar data in 2007 (5.8 +/- 4 weeks). These studies were performed in Japanese hospitals over 15 years ago. Limited data exists regarding treatment response times with different doses in a diverse urban population, which may vary with regards to typical dietary patterns, thyroid hormone metabolism and thionamide pharmacokinetics. Objective: The objective of this retrospective chart review was to determine the mean time to achieve euthyroidism with MMI in patients with newly diagnosed Graves disease in Baltimore City. Methods: Patients with Graves hyperthyroidism newly diagnosed in the last 5 years were identified from outpatient endocrine and primary care clinics within the University of Maryland Medical Center healthcare system. Time to achieve euthyroidism (from the start of thionamide therapy to date of euthyroid labs, defined as normal free T4 level) was assessed. Results: 128 patients with recently diagnosed Graves hyperthyroidism were identified (126 patients treated with MMI only and 2 with PTU only). 78% of subjects were female and the mean age at diagnosis was 47 years. The average daily dose of MMI ranged from 2.5mg to 60mg. On average, Free T4 decreased by 0.47 ng/dL per week. The mean time to achieve euthyroidism was 10.1 weeks (8.6, 11.6) overall, similar in males and females. On sub analysis, time to achieve euthyroidism was lower in younger males (age &amp;lt; 40 years) [6.6 weeks (3.9, 9.3)] and older females (age &amp;gt; 40 years) [8.3 (6.9, 9.7)]. Conclusion: The above data may inform expectations for treatment response for newly diagnosed Graves disease, specifically in an urban population on a Westernized diet. Patient forums have shown increasing interest in therapeutic alternatives to thionamides, including specialized diets. This data may help to determine whether other proposed therapies for initial treatment of Graves hyperthyroidism are more or less efficacious. Presentation: Thursday, June 15, 2023

OR26-01 A Novel Small Molecule Thyrotropin Receptor Antagonist

Abstract Disclosure: G.J. Kahaly: None. A. George: None. L. Steiner: None. T. Weirauch: None. J. Henseling: None. L. Frommer: None. J. Wolf: None. Background &amp; aims: Treatment of both Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) is still far from adequate, hence new therapeutic modalities, which specifically target the autoantigens in GH/GO, are warranted. This study determined the preclinical in vitro efficacy of SYD5115, a novel thyrotropin receptor (TSH-R) antagonist. Methods: SYD5115 is a nanomolar potent low molecular weight TSH-R antagonist with in vivo activity in rats after oral dosing. The compound consists of an N-acetylated dihydropyrrole pyrimidine core containing several substituents such as a difluorinated-spirocyclohexyl ring and a chiral carbamate group on the pyrimidine ring. The TSH-R inhibiting capability of SYD5115 was tested through stimulation of wild type and chimeric TSH-R expressed in Chinese hamster ovary (CHO) cells using-two functional (stimulatory and blocking) cell-based TSH-R-Ab bioassays. TSH-R expressing human orbital fibroblasts, collected from GH+GO patients (GOF), were stimulated with the monoclonal antibody M22 or with stimulatory TSH-R-Ab (TSAb)-positive sera with cyclic adenosine monophosphate (cAMP) or hyaluronic acid (HA) release as read-outs. The effect of SYD5115 on the viability of GOF was tested in both 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide and the “scratch” cell growth assays. Results: The new small molecule SYD5115 significantly and dose-dependently inhibited the TSH-R activation through M22 or TSAb-positive sera in all performed bioassays. Inhibition showed similar levels in the TSAb reporter bioassay and in the cAMP assay with GOF. The % inhibition and compound concentration showed a sigmoidal relationship, with all seven TSAb positive sera markedly inhibited by SYD5115. A SYD5115 dose-dependent inhibition of M22 (10ng/ml, 6 hours)-stimulated HA and/or cAMP-release from GOF was observed. Strong SYD5115-induced inhibitions of M22-stimulated cAMP production in GOF were registered with SYD5115 concentrations of one (p=0.0029), 10 (p&amp;lt;0.0001), 100 (p&amp;lt;0.0001), 1,000 (p&amp;lt;0.0001), and 10,000 (p&amp;lt;0.0001) nM/L, respectively. SYD5115-induced inhibition of M22-stimulated HA production was noted with SYD5115 concentrations of 100 (p=0.0392), 1,000 (p=0.0431), and 10,000 (p=0.0245) nM/L, respectively. The inhibitory activity of SYD5115 was confirmed in a human osteosarcoma U2OS cell line stably expressing human TSH-R with cAMP as read-out. SYD5115 induced 100% inhibition of the M22-induced cAMP levels with a potency of 193 nM. Compared to control, SYD5115 affected neither the growth nor the migration of cultivated GOF. In addition, SYD5115 did not alter the viability of GOF. Conclusions: SYD5115 blocked M22- and TSAb-induced TSH-R activity with a nanomolar potency in TSH-R overexpressed CHO cells as well as primary GOF, which demonstrates the ability of this novel small molecule to inhibit TSH-R overactivity. Presentation: Saturday, June 17, 2023

FRI569 A Therapeutic Dilemma: Spontaneous Oscillating Graves' Disease And Hypothyroidism

Abstract Disclosure: D. Suravajjala: None. J. Case: None. S. Kolli: None. V. Eranki: None. Spontaneous recurrent conversions between hyperthyroidism and hypothyroidism in Graves’ disease (GD) is very rare. We present a case of GD with spontaneous oscillation since diagnosis. From our review, less than 10 cases have been reported in the literature with alternating hyper and hypothyroidism. The patient is a 68-year-old female diagnosed with GD 4 years back with TSH &amp;lt;0.01 (0.4 - 4.5 uIU/mL) and TSI 25.70 (0.00-0.5 IU/L). She denied viral illness, radiation exposure, Lithium or Amiodarone use. Ultrasound thyroid was consistent with GD. Thyroid uptake scan was also consistent with GD. Eventually, Methimazole (MMI) 10 mg daily was initiated. About five months after MMI treatment, she was found to be hypothyroid with TSH 9.030 (0.4-4.5 uIU/mL) and FT4 0.99 (0.9-2.2 ng/dl) which led to discontinuation of MMI. 2 months later, she was clinically hyperthyroid with TSH 0.026, FT4 2.93 (0.9-2.2 ng/dl), TSI 9.59 (0-0.55 IU/L). MMI 5 mg daily was resumed, and as she preferred medical management, other treatment options for GD were not considered. Six months after low dose MMI, patient again reverted to hypothyroidism with TSH 21.420, FT4 0.82. MMI 5 mg was changed to every other day. After 8 months, she was found to be clinically and biochemically hypothyroid with TSH 147, FT4 0.41 (0.9-2.2 ng/dl), TSI 7.98 (0-0.55 IU/L). With the suspicion that she had burnt out GD, she was started on Levothyroxine (LT4) 100 mcg daily. Two months after LT4 initiation, she became clinically hyperthyroid with TSH 0.010 (0.4-4.5 uIU/mL) and FT4 1.91 (0.9-2.2 ng/dl). When trial of LT4 dose reduction failed to alleviate patient hyperthyroid symptoms, it was discontinued and MMI was resumed at 2.5 mg qd. Within 3 months she reverted to hypothyroidism. HAMA interference was as well ruled out. Although the patient's thyroid function ranged spontaneously from hyperthyroidism to hypothyroidism, she was still reluctant for definitive treatment options for GD, including RAI ablation and total thyroidectomy. As GD patients may have definitive treatment early, spontaneous conversion between hyperthyroidism and hypothyroidism is usually not seen in GD and most episodes usually occur several years after discontinuation of antithyroid drugs. It is known that both TSH receptor stimulating antibodies (TSAb) and TSH receptor blocking antibodies (TBAb) can be produced at the same time. The presence of hyper or hypothyroidism may depend on the equilibrium between stimulating and blocking antibodies. Switching of TSH receptor antibodies between stimulation and blockage is uncommon. Diagnosis demands careful clinical and biochemical assessments. Alternatively, the case may be easily mistaken for excessive thyroid suppression or replacement. This condition is difficult to manage, and definitive treatment options could be considered with I-131 ablation, thyroidectomy, or pharmacological treatment (block and replace). Presentation: Friday, June 16, 2023

THU657 Racing Hearts: A Closer Look At The Connection Between Hyperthyroidism And Coronary Vasospasm

Abstract Disclosure: A. Elahi: None. R.I. Mateo: None. The cardiovascular system is a major target of thyroid hormone action in which subtle changes in thyroid function can lead to cardiac complications such as coronary vasospasm. There are many proposed mechanisms in how this occurs, but further studies are needed to understand the specific pathophysiology. This case illustrates the clinical relevance of encountering a hyperthyroid patient complaining of chest pain and how to address it in real work practice. A 62 year old African American male with history of Graves hyperthyroidism, type 2 diabetes, hypertension, peripheral artery disease, and stroke with residual aphasia presented with acute onset chest pain, shortness of breath, and palpitations. He was noncompliant with his methimazole (MMI) and subsequent labs were significant for free T4 of 2.5 ng/dL, undetectable TSH, and free T3 of 11.53 pg/mL. His high sensitivity troponins were elevated at 29,569 ng/dL. EKG showed sinus tachycardia with T-wave inversions in leads II, III, and AVF with a bedside echo showing inferior lateral wall motion abnormality. He was started on MMI 20mg daily and admitted to the intensive care unit for non-ST elevation myocardial infarction management. Left heart catheterization (LHC) was done after 1 dose of MMI with findings suggestive of vasospasm; specifically, decreased blood flow of the right coronary artery which improved when the catheter was withdrawn and significant dampening of the arterial wave form of the left main coronary artery. Given the unclear differentiation between true coronary artery disease and vasospasm he needed a repeat LHC once his hyperthyroidism was more controlled. His free T3 levels were monitored every 1-2 days with administration of escalating doses of MMI up to 40mg daily. By day 7 of admission, his free T3 level was 4.54 pg/mL, free T4 was 2 ng/dL and repeat LHC was performed showing open vessel lumens with multiple occlusions requiring 2 stents in the right coronary artery and 1 stent in the left circumflex artery. Given that thyroid hormone receptors are present in the myocardium and vascular tissue, alterations in thyroid hormone concentration can affect cardiovascular function. The documentation of coronary spasm, however, is rare and to date, there are only a few limited cases describing the underlying pathophysiology. This case illustrates via cardiac catheterization images and corresponding labs, the positive correlation of coronary vasospasm with thyroid hormone levels in hyperthyroidism. Presentation: Thursday, June 15, 2023

Levels of Antithyroid Antiperoxidase and Antithyroglobulin Antibodies in Patients with Graves Hyperthyroidism – Predictors of Initial and Sustained Remission and Consecutive Hypothyroidism

BACKGROUND: Initial and sustained remission is the principal objective in patients with Graves hyperthyroidism (GH) treated with antithyroid drugs (ATD). AIMS: Our study aimed to investigate the predictive value of antithyroid antiperoxidase (aTPO) and antithyroglobulin (aTg) levels on initial and sustained remission or consecutive hypothyroidism in subjects with GH treated with ATD. METHODS: Randomized, prospective, and longitudinal study during period 2013–2018 was performed. Eighty GH patients (thyrotropin [TSH] &lt;0.01 mIU/L, free thyroxine [FT4] &gt;30 pmol/L, triiodothyronine [FT3] &gt;8 pmol/L), 59 females (73.75%), and 21 males (26.25%), aged 51 ± 12 years were included in the study. Subjects were divided into four subgroups (each with 20 patients) according to aTPO and aTg levels: Group I – no antibodies; Group II – (&lt;500 IU/mL), Group III – (500–1000 IU/mL), and Group IV – (&gt;1000 IU/mL). All subjects underwent 24 months of propylthiouracil treatment with follow-up of 24 months after remission (TSH &gt;0.4 mIU/L, FT4 11–25 pmol/L, FT3 2.8–6.5 pmol/L). Blood samples were analyzed every 4 months. RESULTS: In Group I, 11 (55%) of the patients attained remission; during follow-up, 5 (45%) of them had disease relapse. In Group II, 12 (60%) attained remission and 5 (42%) had relapse. In Group III, 15 (75%) attained remission, 2 (13%) had disease relapse, and 4 (26%) developed hypothyroidism. In Group IV, 18 (90%) attained remission, 1 (5%) had disease relapse, and 9 (50%) developed hypothyroidism. Patients with values below 500 IU/mL attained remission in 60%, similar as the group without antibodies in 55% (p &lt; 0.3). Patients in Group III and IV had significantly higher remission rates compared to Group I and II (p &lt; 0.001). Baseline values of aTPO and aTg &gt;1000 IU/mL were significant predictors of consecutive hypothyroidism (p &lt; 0.05). CONCLUSION: Baseline aTPO and aTg values above 500 IU/mL were significantly prognostic for attaining and sustaining remission in GH and values above 1000 IU/mL were significant predictors of consecutive hypothyroidism.

Clinical manifestations and early effectiveness of methimazole in patients with graves’ hyperthyroidism-related severe hepatic dysfunction

Background Graves’ hyperthyroidism (GH) is often accompanied by mild to moderate liver injury, but severe hepatic dysfunction (SHD) is relatively rare. Whether patients with GH-related SHD can be treated with methimazole (MMI) remains controversial. This study aimed to determine the clinical characteristics and to evaluate the role of low-dose MMI for such patients. Methods 33 patients with GH-related SHD were selected for this retrospective study in the Fifth Medical Center of Chinese PLA General Hospital from January 2017 to July 2022. The clinical manifestations, therapeutic responses, and effectiveness of MMI were evaluated. Results Systemic jaundice (100.0%), yellow urine (100.0%), fatigue (87.9%), and goiter (66.7%) were the main symptoms. Total bilirubin (TBIL) had no linear correlation with free triiodothyronine (FT3) (r = −0.023, p = .899), free thyroxine (FT4) (r = 0.111, p = .540), T3 (r = −0.144, p = .425), and T4 (r = 0.037, p = .837). On the 14th day after admission, FT3, FT4, T3, T4, TBIL, direct bilirubin (DBIL), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), and international normalized ratio (INR) decreased compared with the baseline (p < .05). The decrease rates of FT3, FT4, T3, T4, TBIL, and DBIL in the MMI group were higher than those in the non-MMI group (p < .05). The improvement rate of the MMI group (77.8%) was higher than that of the non-MMI group (9.5%, p = .001). MMI treatment is an independent predictor affecting the early improvement of patients (OR = 0.022, p = .010). Conclusions The main clinical manifestations of patients with GH-related SHD were symptoms related to liver disease. Low-dose MMI was safe and effective for them.

The Incidence of Graves’ Hyperthyroidism Before and After COVID-19 Messenger RNA Vaccination

ObjectiveCase reports of postvaccine early-onset Graves’ hyperthyroidism (PVGD) after the administration of COVID-19 vaccination have emerged. Our aim was to investigate whether the incidence of Graves’ hyperthyroidism (GD) has increased after the introduction of COVID-19 vaccination. MethodsWe compared the incidence of new-onset GD at a single academic center during 2 periods: December 2017 to October 2019 and December 2020 to October 2022, ie, before and after the implementation of COVID-19 vaccinations. We defined PVGD as laboratory-confirmed hyperthyroidism and GD within 4 weeks after the vaccination or clear onset of symptoms of thyrotoxicosis within 4 weeks of vaccination with evidence of hyperthyroidism and GD within 3 months. ResultsDuring the prevaccination period, 803 patients carried diagnoses of GD, and of these, 131 were new. During the postvaccination period, 901 patients carried diagnoses of GD, and of these, 138 were new. There was no statistically significant difference in the incidence of GD (P = .52), age at onset, gender, or race between the 2 groups. Twenty-four of 138 newly diagnosed patients in the post–COVID-19 group met the criteria for PVGD. The median free T4 was higher, but this was not statistically significant (3.9 vs 2.5 ng/dL, P = .05). There were no differences in age, gender, race, antibody titers, or type of vaccination between PVGD and controls. ConclusionThere was no increase in new-onset GD after COVID-19 vaccination. Median free T4 was higher in patients with PVGD, but this was not statistically significant.

Thyrotropin Receptor Antagonism by a Novel Small Molecule: Preclinical In Vitro Observations.

Background: Treatment of Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) is far from adequate, and hence, new substances that specifically target the autoantigens in GH/GO are warranted. This study determined the preclinical in vitro efficacy of SYD5115, a novel low-molecular-weight compound that inhibits the thyrotropin receptor (TSH-R). Methods: The TSH-R inhibiting capability of SYD5115 was tested through stimulation of wild-type and chimeric TSH-R expressed in Chinese hamster ovary (CHO) cells using two functional (stimulatory and blocking) cell-based TSH-R-Ab bioassays. TSH-R expressing human orbital fibroblasts, collected from GH+GO patients (GOF), were stimulated with the monoclonal antibody M22 or with stimulatory TSH-R-Ab (TSAb)-positive sera with cyclic adenosine monophosphate (cAMP) or hyaluronic acid (HA) release as readouts. The effect of SYD5115 on the viability of GOF was tested in 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide and scratch cell growth assays. Results: SYD5115 significantly and dose dependently inhibited the TSH-R activation through M22 or TSAb-positive sera in all performed bioassays. Inhibition showed similar levels in the TSAb reporter bioassay and in the cAMP assay with GOF. The % inhibition and compound concentration showed a sigmoidal relationship, with all seven TSAb-positive sera markedly inhibited by SYD5115. An SYD5115 dose-dependent inhibition of M22 (10 ng/mL, 6 hours)-stimulated HA and/or cAMP-release from GOF was observed. Strong SYD5115-induced inhibitions of M22-stimulated cAMP production in GOF were registered with SYD5115 concentrations of 1 (p = 0.0029), 10 (p < 0.0001), 100 (p < 0.0001), 1,000 (p < 0.0001), and 10,000 (p < 0.0001) nM, respectively. SYD5115-induced inhibition of M22-stimulated HA production was noted with SYD5115 concentrations of 100 (p = 0.0392), 1000 (p = 0.0431), and 10,000 (p = 0.0245) nM, respectively. The inhibitory activity of SYD5115 was confirmed in a human osteosarcoma U2OS cell line stably expressing human TSH-R with cAMP as readout. SYD5115 induced 100% inhibition of the M22-induced cAMP levels with a potency of 193 nM. Compared with control, SYD5115 did neither impact the growth nor the migration of cultivated GOF. In addition, SYD5115 did not alter the viability of GOF. Conclusions: SYD5115 blocked M22- and TSAb-induced TSH-R activity with a nanomolar potency in TSH-R-overexpressed CHO cells as well as primary GOF, which demonstrates the ability of this small molecule to block TSH-R overactivity.

Abstract #1402994: Unilateral Exophthalmos in A Patient with Hashitoxicosis: Case Report and Review of the Literature

Hashitoxicosis is a transient period of hyperthyroid state in a patient with Hashimoto thyroiditis. Ii is not common condition. Exophthalmos is usually bilateral disease commonly associated with Graves's hyperthyroidism. It rarely occurs in Hashimoto thyroiditis or hashitoxicosis. Unilateral exophthalmos is a less common presentation of Graves's ophthalmopathy. So, we present this case of a male with Hashimoto thyroiditis, who presented with unilateral exophthalmos and Hashitoxicosis. A 41-year-old male presented with protrusion of his right eye. He was diagnosed 9 months ago with Hashimoto thyroiditis based on clinical ground, laboratory tests and thyroid scan. His TSH was 18.5 (N 0.4- 4) and FT4 was 0.023 (N12-22). TPO was positive (Thyroid Peroxidase anti-bodies). Thyroid scan showed diffused homogeneous reduced uptake. He was started on Thyroxine 100ug/day. Six months later his thyroid function test on follows up showed features of subclinical hyperthyroidism. His Thyroxine was reduced gradually till it was stopped. Three months later, he developed palpitations, weight loss and noticed changes in his right eye. On examination he was toxic his pulse 100 bpm, right eye there is exophthalmos, lid retraction and lid lag. He has small goiter and no bruit. No pretibial myxedema or proximal myopathy. Laboratory tests showed suppressed THS 0,013 and high FT4 26.8. We diagnosed him as having Hashitoxicosis and started on Propranolol 20 mg three times daily. He did not improve and repeated TSH was 0.006 and FT4 was 46.3(12-22). Neomercazole was started at a dose of 30 mg/day, Over the next 6 months Neomercazole was tapered until the patient become hypothyroid and thyroxine was restarted. Currently he is on thyroxine 100ug and is doing well. However, the exophthalmos did not resolve completely. Hashimoto thyroiditis is the most common cause of hypothyroidism in Iodine sufficient areas. It is characterized by elevated levels of thyroid anti-bodies (Anti TPO antibodies are present in 90% of cases). Hashitoxicosis is the hyperthyroid phase in chronic autoimmune thyroiditis. it occurs due to the release of preformed thyroid hormones from the inflamed thyroid gland. The exact duration of the disease is not well described, in average it last less than 8 months. The term Hshitoxicosis sometimes used to describe an autoimmune thyroid disease overlap syndrome of Graves's disease and Hashimoto disease. The presentation of our patient was consistent with Hashitoxicosis. But due to his severe symptoms and development of exophthalmos we suspect overlap syndrome, so we started antithyroid medication. Wasniewska et al. investigated the outcome of Hashitoxicosis in 14 children. Due to more severe presentation, four patients required antithyroid medications as in our patient. A definitive resolution of hyperthyroidism was recorded 8.3- 6.3 months after the diagnosis, as in our patient who recovered over a period of 6 months. Graves's orbitopathy (GO) usually associated with Graves's hyperthyroidism, rarely occurs in hypo- or euthyroid state, unlike our patient who developed unilateral exophthalmos in hypothyroidism.

Comparison Between Thyroid Stimulating Immunoglobulin and TSH-Receptor Antibodies in the Management of Graves' Orbitopathy.

TSH-receptor antibodies (TRAb) targeting the TSH receptor (TSH-R) induce hyperthyroidism in Graves´ disease (GD). Graves´ orbitopathy (GO) is influenced by stimulation of the TSH-R in the orbita. GO has been, among other factors, linked to high TRAb levels. Thyroid stimulating immunoglobulins (TSI) is a relatively new method for assessing TSH-receptor antibodies. The aim of this study was to investigate the role of TSI in the management of GO. Patients with newly diagnosed GD (n=30, median age 55 years (range 35-72), 29 women) received pharmacological therapy (methimazole+++thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. Eleven patients had GO at diagnosis, and another six developed GO during treatment. Blood samples for TSI and other thyroidal biomarkers were obtained at baseline and on five occasions during the 24-month follow-up. Twenty-two subjects completed the drug regimen without surgery or radioiodine treatment. At baseline, TSI was highly correlated with TRAb (r s =0.64, p<0.001), and both assays similarly correlated to fT3 values. TSI and TRAb did not differ significantly between GO and non-GO patients for visit v1 (n=30, 17 GO during the whole study) or at follow-up (n=22, 12 GO during the whole study). During follow-up, levels of TSI and TRAb decreased and normalized in both groups. The present study does not support any added benefit of TSI compared to TRAb for the prediction and management of GO.

Long-Term, Low-Dose Methimazole Therapy Is Effective in Protecting against Relapses in Graves’ Disease

Clinical ThyroidologyVol. 35, No. 02 HyperthyroidismFree AccessLong-Term, Low-Dose Methimazole Therapy Is Effective in Protecting against Relapses in Graves’ DiseaseGiuseppe BarbesinoGiuseppe BarbesinoThyroid Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.Search for more papers by this authorPublished Online:8 Feb 2023https://doi.org/10.1089/ct.2023;35.54-56AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of: Lertwattanarak R, Kunavisarut T, Sriussadaporn S 2022 Benefits of Long-term continuation of low-dose methimazole therapy in the prevention of recurrent hyperthyroidism in Graves' hyperthyroid patients: A randomized prospective controlled study. Int J Endocrinol 2022:1705740. PMID: 36267362.SUMMARYBackgroundThe management of Graves’ disease (GD) hyperthyroidism has been evolving over the past two decades. The traditional standard of care suggested treatment with methimazole for 12 to18 months followed by radioactive iodine (RAI) treatment or surgery (1) in patients not achieving remission, where remission is defined as the ability to maintain euthyroidism after discontinuation of methimazole. This recommendation is supported by the recognition that longer courses of antithyroid drugs do not increase the rate of lasting remissions after discontinuation (2). This strategy has become less attractive owing to increasing evidence that RAI can cause or worsen thyroid eye disease (3) on the one hand and on the other to concerns about quality of life with hypothyroidism, even when thyroid hormone is optimally replaced (4). This study (5) was conducted to understand whether long-term therapy with low-dose methimazole could protect GD patients from relapses of hyperthyroidism.MethodsThis was a randomized controlled study in adult GD patients who had been euthyroid while taking methimazole for at least 6 months prior to randomization. The patients were randomly assigned to either continue methimazole at low doses (2.5–5 mg daily) or discontinue methimazole. The subjects’ thyroid function was then monitored every 6 months for 36 months. Standard diagnostic criteria for GD were adopted for inclusion. Patients who had already experienced a relapse were excluded. The primary outcome measured was the cumulative incidence of relapsing hyperthyroidism in the two groups.ResultsNinety-two patients were randomly assigned to the discontinuation group and 92 to the low-dose treatment group. Except for minor differences, the two groups were very similar for most epidemiologic parameters (86% female vs. 84% and mean [±SD] age, 39.9±10.9 vs. 42.2±14.9 years), indicating a reliable randomization process. The average duration of methimazole therapy prior to randomization was 37 months in the discontinuation group and 32 months in the low-dose group (not statistically different). In the discontinuation group, the number of relapses increased progressively and uniformly during the study time, reaching 41.2% at 36 months. In the low-dose group, the rate of relapse was 11%, and it was reached 18 months after randomization, with no additional relapses after that time. There were no recorded side effects during the study period.ConclusionsIn patients with GD, long-term treatment with 2.5 to 5 mg of methimazole daily is safe and effective in preventing the relapse of hyperthyroidism. This strategy is a valid alternative to RAI therapy and thyroidectomy in patients who want neither and yet worry about relapses of hyperthyroidism.COMMENTARYGraves’ disease, like many other autoimmune diseases, is often characterized by flares and remissions (6). Patients taking methimazole are typically treated for 12 to 18 months, after which a discontinuation trial is performed, in the hope of a lasting remission. Measuring serum TSH receptor antibodies (TRAbs) before antithyroid drug discontinuation helps to identify patients who are at high risk for early relapses in the 3 to 6 months after discontinuation (7). However, 20 to 30% of patients negative for TRAbs will still relapse months to years after the discontinuation (8,9). This observation, and mounting diffidence towards RAI therapy and surgery, has led to increased interest for long-term methimazole treatment. The data so far available have been mostly retrospective, or have addressed only select patient groups (for example, patients who already have experienced a relapse) (10). Like other endocrinologists, I have been advising some of my patients with GD who appear to be “currently” in remission, to continue methimazole indefinitely at very low doses, typically 2.5 mg daily. This article provides good-quality evidence to support such a practice, which I will continue to apply, especially to older patients and patients who had experienced particularly intense symptoms from the hyperthyroidism at the time of its first presentation.Disclosures: The author has no relevant conflicts of interest to declare.

Lithium as an alternative option in thionamide-resistant Graves’ disease

Conventional treatments for Graves’ disease include thionamides, radioactive iodine therapy (RAI), and thyroidectomy. Occasionally, patients may develop resistance to thionamides and may require additional treatment. We present the case of an adolescent girl with thionamide-resistant Graves’ disease who was successfully treated with lithium and subsequent RAI after stabilizing her thyroid hormone levels. Following RAI, the patient developed hypothyroidism, and thyroxine replacement therapy was initiated. This case highlights the potential of lithium as a safe and effective alternative for controlling hyperthyroidism in Graves’ disease and its role in preparing patients for more definitive treatment.