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Introduction: The most common cause of hyperthyroidism, Graves' disease is a common organ-specific autoimmune disease. Selenium is an essential trace element of the human body that is mainly concentrated in the thyroid gland and is involved in the synthesis and metabolism of thyroid hormones. Most studies have shown that the level of selenium is closely related to the occurrence and development of thyroid diseases, and selenium supplementation can help improve thyroid function. This study aims to evaluate the efficacy of selenium supplementation for patients with Graves' hyperthyroidism during methimazole treatment., Methods and Analysis: We will search the electronic databases including PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Data and Chinese Biomedical Literature, and the time was deadline to December 2023. To evaluate the efficacy of methimazole combined with selenium supplementation in the treatment of Graves' hyperthyroidism, randomised controlled trials will be included. The Cochrane Collaboration's risk of bias tool will be used to assess the quality of all included studies, and the baseline data of all the studies are extracted by the authors. A random-effects model or a fixed-effects model is used to analyse the outcomes. The primary outcomes are the levels of selenium, triiodothyronine, free thyroxine and thyroid-stimulating hormone (TSH), whereas the secondary outcomes include TSH receptor antibody, thyroid peroxidase antibody and thyroglobulin antibody., Ethics and Dissemination: Ethics approval is not required since no original data will be collected. The results of this study will be published in a peer-reviewed journal., Prospero Registration Number: CRD42023410999., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves’ disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts (CBC) monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of CBC may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia., Competing Interests: Conflict of interest: None declared., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

We describe the clinical presentation and evaluation of a 10-year-old boy who presented to our medical center with years of progressive proximal muscle weakness, muscle atrophy, and weight loss. In addition to a myopathic phenotype, he was found to have tachycardia, tremor, and learning difficulties. Electromyography revealed chronic myopathic changes and laboratory screening was notable for undetectable thyroid stimulating hormone. Follow-up testing revealed elevated thyroid peroxidase antibodies and thyroid stimulating immunoglobulins. Ultrasound examination revealed an enlarged heterogeneous thyroid gland. Four weeks after treatment with atenolol and methimazole, his strength and cognition began to improve. This case highlights the importance of evaluating for potentially reversible toxic-metabolic etiologies in children presenting with any progressive neurologic symptoms., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Pseudo-orthostatic tremor is a hyperkinetic movement disorder usually associated with other neurological comorbidities, mainly Parkinson's disease., Case Report: A 65-year-old male presented with unsteadiness and leg tremor while standing. Electrophysiological evaluation confirmed the presence of pseudo-orthostatic tremor. Blood test showed an undiagnosed Graves' disease. A complete remission of tremor was achieved with methimazole. Dopamine transporter scintigraphy showed a mild reduction of the striatal binding, bilaterally., Discussion: Graves' disease can be associated with pseudo-orthostatic tremor. Thyroid function should be assessed in patients complaining of unsteadiness. The causative role of hyperthyroidism in determining dopaminergic degeneration and uncovering subclinical parkinsonism warrants further investigations., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Graves' disease (GD), an autoimmune thyroid disease, is one of the main autoimmune diseases in the general population. It is known that the pathophysiology of this disease may be related to immunological mechanisms dysregulation. These mechanisms can be influenced by GD therapies, such as iodide or antithyroid drugs (ATD)., Objective: Verify relation between clinical, biochemical and treatment modalities used prior to surgery and histopathological characteristics observed in total thyroidectomy products from patients previously diagnosed with Graves' disease. Furthermore, these data were related to composition of lymphocytic infiltrate in terms of proportions of lymphocytes CD4 + , CD8 + , CD25 + and CD20 + . We aim to contribute to the understanding of the evolution pattern of GD, whose pathophysiology is not yet completely understood., Methods: Cross-sectional study assessing thyroidectomy products for the presence of lymphocytic infiltrate, as well as the proportion and intensity of CD4 + , CD8 + , CD25 + and CD20 + markers. We selected 50 patients who underwent total or partial thyroidectomy in a tertiary service between 1996 and 2013 due to GD with histopathological confirmation. The control group (non-autoimmune disease group) consisted of 12 patients with histopathological data compatible with normal perilesional thyroid parenchyma. The intensity of lymphocytic infiltrate and immunohistochemical expression of the markers CD4 + (helper T lymphocytes), CD8 + (cytotoxic T lymphocytes), CD25 + (regulatory T lymphocytes) and CD20 + (B lymphocytes) were retrospectively evaluated and relationship with ultrasound, laboratory and clinical data was assessed., Results: No differences were found in intensity, presence of lymphoid follicles, and expression of CD4+/CD8+/CD25+ in patients with GD who did or did not use ATD or iodide. In the group that did not use ATD, a higher proportion of CD20 + expression was found. The GD group was associated with hyperplastic epithelium and the control group was associated with simple epithelium. There was no difference in ultrasound thyroid volume between the groups. In GD patients with mild lymphocytic infiltrate, higher free thyroxin (FT4) levels were observed than those in patients with no infiltrate or moderate infiltrate., Conclusion: We found a lower proportion of intrathyroidal CD20 + B lymphocytes in patients under use of methimazole. However, no difference was observed in intrathyroidal lymphocyte subpopulations related to the short-term use of iodide. The understanding of thyroid autoimmunity, as well as identifying points of pharmacological modulation, are very important for advancement and improvement in treatments for these diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Denise Engelbrecht Zantut Wittmann reports equipment, drugs, or supplies and statistical analysis were provided by State University of Campinas. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A 49-year-old Japanese woman was admitted to our hospital with weight loss of 15 kg, nephrotic-range proteinuria (4.5 g/g.Cre), and hematuria over a 6-month period. She had received two doses of the coronavirus disease 2019 (COVID-19) vaccine one year before the onset of the disease, after which the estimated glomerular filtration rate increased. Laboratory tests and other tests led to a diagnosis of hyperthyroidism, and a kidney biopsy showed thrombotic microangiopathy-like glomerular microangiopathy comprising mainly glomerular endothelial cell damage. Thiamazole (30 mg) was started for the hyperthyroidism. Three months later, the thyroid function normalized, and two months later, the proteinuria and hematuria disappeared, suggesting that COVID-19 vaccination and these events were related.

Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10-1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger ( p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD.

Only one report on the successful use of filgrastim (granulocyte colony-stimulating factor) in cats for severe neutropenia following azathioprine toxicity exists. Here, we report on a case in which a cat was prescribed methimazole but the medication was filled incorrectly with azathioprine tablets and the prescription label indicated a methimazole dosing regimen that was administered for three days before recognition of the error. On presentation, the cat's physical examinations were consistent with previous examinations before ingestion of azathioprine. A complete blood cell count revealed neutropenia and leukopenia. The cat later developed hyporexia, dehydration, and vomiting. Treatment included antinausea and appetite stimulant medications, filgrastim, and antibiotics. Filgrastim given as subcutaneous injections over the course of treatment increased neutrophil cell counts after suppression. The cat made a full recovery after responding to the treatment protocol. Based on the perceived response to filgrastim in this single feline case report, its use can be considered for the treatment of azathioprine-induced neutropenia in cats., (© 2024 by American Animal Hospital Association.)

Purpose: In Graves' disease, administration of low-dose methimazole for more than 60 months induces higher remission rates compared with the conventional duration of 12-18 months. However, the risk of recurrence and its predictors beyond 48 months of drug withdrawal are not known. The aims of this study were to determine the risk of recurrence during 84 months after withdrawal of short- or long-term methimazole therapy and a risk stratification for recurrence of hyperthyroidism., Methods: A total of 258 patients were treated with methimazole for a median of 18 months and randomized to discontinuation of the drug(conventional short-term group; n = 128) or continuation of the treatment up to 60-120 months(long-term group; n = 130). Patients were followed for 84 months after methimazole withdrawal. Cox proportional hazards modeling was performed to identify factors associated with relapse and develop a risk-scoring model at the time of discontinuing the treatment., Results: Hyperthyroidism recurred in 67 of 120(56%) of conventionally-treated patients versus 20 of 118(17%) of those who received long-term methimazole treatment, p < 0.001. Age, sex, goiter grade, triiodothyronine, thyrotropin, and thyrotropin receptor antibodies were significant predictors of recurrence in both "conventional" and "long-term" groups but free thyroxine just in the "long-term" group. The risk-scoring model had a good discrimination power (optimism corrected c-index = 0.78,95%CI = 0.73-0.82) with a range of 0-14 and sensitivity of 86% and specificity of 62% at the risk-score of eight., Conclusion: A relapse-free state was achieved in 83% of patients with Graves' hyperthyroidism 84 months after cessation of long-term methimazole treatment which could be predicted by some significant predictors in a simple risk-scoring system., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To assess response predictors to radioactive iodine (RAI) therapy without using thyroid uptake for dose estimate in patients pretreated with methimazole., Methods: Retrospective analysis was performed of patients with Graves' disease treated with RAI doses determined without using uptake studies., Results: In 242 patients (median age, 41.9 years; 66.1% female), initial mean free thyroxine (FT4) level was 4.7 ng/dL with an estimated thyroid size of 49.15 g. Prior to RAI therapy, average methimazole dose was 22.7 mg/day. Mean RAI dose was 737.0 ±199.4 MBq (19.9 ± 5.4 mCi). Two hundred eight patients (85.9%) responded to RAI therapy; 185 (88.9%) became hypothyroid and 23 (11.1%) became euthyroid. The majority (90.4%) responded within 6 months of therapy with a quicker response (13.9 ± 8.3 vs 17.5 ± 13.5 weeks) for those treated with doses per gram of ≥14.8 MBq (0.4 mCi). Thirty-four nonresponders had a higher initial FT4 level and larger thyroid size with a lower RAI dose per gram of thyroid tissue. In multivariate analysis, the independent response predictor to therapy was dose per gram of thyroid tissue of ≥14.8 MBq (0.4 mCi) (hazard ratio, 3.18; 95% CI, 1.1-9.7). Doses per gram of 14.8 to 18.1 MBq (0.4-0.5 mCi) achieved maximal response rate without added advantage of higher doses. Thyroid size prior to RAI therapy, FT4 levels at diagnosis, and age were inversely related to response., Conclusion: RAI therapy for Graves' disease without uptake studies for dose estimates is an effective treatment method. In patients pretreated with methimazole, an RAI dose per gram of thyroid tissue of ≥14.8 MBq (0.4 mCi) showed high response rate. Prospective studies are needed to confirm the viability of this simplified and cost-effective approach., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Rationale: A rare and intractable case of apathetic Graves' disease (GD) with severe liver and kidney damage induced by coronavirus disease 2019 (COVID-19) carries a certain risk of missing diagnosis and delayed treatment during the COVID-19 pandemic., Patient Concern: A 60-year-old female patient developed anorexia, exhaustion, jaundice, nausea, and vomiting 10 days after COVID-19 infection. She was admitted to the Infectious Diseases Department because of recurring symptoms for more than a month., Diagnosis: Based on the patient's epidemiological history, clinical symptoms, and prior history, she was preliminarily diagnosed with GD induced by COVID-19 with severe hyperthyroid-related liver injury and chronic kidney disease stage 4. Drug-induced and radiation-induced liver injuries occurred sequentially throughout the therapy., Intervention: Methimazole (MMI) (10 mg/d) was administered for 1 week, and the patient's symptoms, thyroid function, and liver and kidney function improved. Nevertheless, the aforementioned symptoms and liver and kidney function deteriorated 20 days after increasing the MMI dose (20 mg/d). Therefore, in the presence of an artificial liver, hemodialysis, and other medical conditions, the treatment schedule was adjusted to individualized 131I anti-hyperthyroidism therapy., Outcome: After 131I treatment, the patient's liver function returned to almost normal levels after a month, but worsened when the hepatoprotective drugs were stopped. Renal function did not deteriorate significantly and returned to baseline after 3 months. Thyroid function was restored to normal approximately 4 months later., Conclusion: COVID-19 may induce GD. Multidisciplinary collaboration can be initiated as early as possible. Individualized 131I therapy or long-term low-dose MMI (10 mg/d) can be considered to manage hyperthyroidism in GD patients with liver and kidney dysfunction and to prolong liver protection therapy appropriately., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: YKL-40, which is also known as Chitiniase 3-like 1, has been found to be up-regulated in many autoimmune diseases including asthma, systemic sclerosis and systemic lupus, etc. However, the relationship between serum levels of YKL-40 and one another common autoinmmue thyroid disease - Graves' disease (GD) has not yet been investigated. Objective: The current study was performed to investigate the correlation of serum YKL-40 levels with disease severity of initially diagnosed GD. Methods: A total of 142 newly diagnosed active GD and 137 healthy individuals were enrolled in the study. Methimazole was given to 55 GD patients and then 2-month study of follow-up was performed. A commercial ELISA kit was applied for the detection of YKL-40 in serum. Degree of goiter was assessed according to Pérez's Grade. Receiver operating characteristic (ROC) curve analysis was carried out to detect the diagnostic value of serum YKL-40 with regard to goiter degree. The velocity of the peak systolic blood-flow and the thyroid tissue blood flow (TBF) were examined using Color Flow Doppler ultrasonography (CFDU). Results: The patients with GD exhibited dramatically higher YKL-40 in serum compared to those of healthy controls (606.1 ± 149.8 pg/mL vs. 397.4 ± 95.1 pg/mL, P  < 0.001). Positive associations of YKL-40 with free T3 (FT3) and T4 (FT4), as well as the negative correlation of YKL-40 with TSH in serum, were observed. Additionally, the YKL-40 in serum was dramatically reduced after methimazole intervention, and the correlation of the decline with the reduced FT3 and FT4 was also found (all P  < 0.001). Serum YKL-40 levels were positively correlated with goiter degree. ROC curve analysis demonstrated that serum YKL-40 concentration may act as a decent marker for goiter degree. The positive correlations of YKL-40 in serum with the average superior thyroid artery velocity (STV) and thyroid tissue blood flow (TBF) were also observed. Conclusion: Our findings implicated that YKL-40 may be closely connected to the pathogenesis of GD. Increased YKL-40 levels are linked with disease severity of initially diagnosed GD.

Background: When the antithyroid drugs were discovered in the early 1940s, they were immediately recognized as a revolutionary new treatment for hyperthyroidism. Although much has been learned about their mechanism of action and clinical utility, they continue to be used today in much the same way as they have been since their introduction. Summary: In 1995, Dr. Clark Sawin gave an address on the history of antithyroid drug development at the 11th International Thyroid Congress in Toronto, Ontario, Canada. In his review, Dr. Sawin recounted the original observations by Drs. Julia and Cosmo Mackenzie and Curt Richter at the Johns Hopkins University School of Medicine, and how their work ultimately led to Dr. Edwin (Ted) B. Astwood's seminal 1943 report on the use of thiourea and thiouracil in the Journal of the American Medical Association. He also described the development of propylthiouracil and methimazole as less toxic alternatives. He concluded his remarks by noting the often-serendipitous pathway of drug development and the role of pharmaceutical companies in the process. Conclusions: Antithyroid drugs remain a cornerstone of thyroid therapeutics. It is informative to review the process by which they came into use, as this is a seminal part of the history of thyroid disease in the 20th century. This knowledge may also spark additional research leading to new pharmacotherapies for patients with hyperthyroidism.

Rationale: We present a case of a 43-year-old female patient diagnosed with hyperthyroidism. This study aims to demonstrate the rare association between hyperthyroidism and severe cholestatic jaundice, and the effectiveness of methimazole treatment., Patient Concerns: The patient developed severe jaundice, a typically mild symptom in most hyperthyroidism cases., Diagnosis: The severe jaundice was suspected to be a result of cholestasis induced by hyperthyroidism, with other potential causes such as drug-induced or autoimmune liver dysfunction being ruled out., Outcomes: The patient was effectively treated with methimazole. Outcomes: Treatment with methimazole alleviated the severe cholestatic jaundice and restored normal thyroid function., Lessons: The specific mechanism of cholestasis as a secondary complication of hyperthyroidism remains unclear, and there are no specific biochemical markers for cholestasis caused by this hormonal disease. This case underscores the possibility of severe jaundice as a clinical manifestation of hyperthyroidism, and highlights antithyroid drug treatment as an effective strategy for managing severe cholestatic jaundice., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Thyrotoxic periodic paralysis (TPP) is an acute complication of hyperthyroidism. Thyrotoxic periodic paralysis is treatable, and the management consists of potassium correction, beta-blockers, and antithyroid drug (ATD) therapy. While TPP is well described in the literature, we describe a case of TPP with urticarial dermographia (UD) that resolved with a short course of antihistamines while continuing ATD therapy. To the best of our knowledge, this is the first reported case of UD after methimazole (MMI) therapy in a TPP patient. A 25-year-old Cambodian active duty male with no significant past medical history presented to the emergency department with acute loss of lower extremity muscle tone with hypokalemia in the setting of previously undiagnosed Graves' disease (GD). He was started on MMI but within 2 weeks developed a rash consistent with UD. This was successfully treated with a second-generation antihistamine while continuing his MMI. Thyrotoxic periodic paralysis is primarily treated by controlling the underlying thyroid disease causing paralysis. Methimazole is commonly chosen as a treatment due to its rapid efficacy and long duration of action. However, adverse effects like UD can occur. Current recommendations are that minor cutaneous reactions can be treated with antihistamines for the management of Graves' disease. However, this case and others show that even moderate reactions can be managed in this manner. In a patient with TPP with UD after treatment with MMI, it is reasonable to attempt a trial of antihistamine before changing to another ATD., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 (FT 3 ) ( r = -0.023, p  = .899), free thyroxine (FT 4 ) ( r  = 0.111, p  = .540), T 3 ( r = -0.144, p  = .425), and T 4 ( r  = 0.037, p  = .837). On the 14th day after admission, FT 3 , FT 4 , T 3 , T 4 , 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 FT 3 , FT 4 , T 3 , T 4 , 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.

Background: Antithyroid drugs (ATDs) are frequently used to achieve euthyroidism in patients with hyperthyroidism. ATDs cause characteristic common and rare adverse events; however, comprehensive comparisons between methimazole (MMI) and propylthiouracil (PTU) in terms of adverse events are limited. Methods: In this study, we thoroughly explored adverse events in association with MMI and PTU use with a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database and evaluated the prevalence of MMI and PTU prescriptions using the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan. We analyzed 3271 cases of MMI use and 1029 cases of PTU use with respect to 9789 preferred terms (PTs) for adverse events registered in the JADER database by calculating and comparing reporting odds ratios (RORs). Results: We found that 8 PTs, including agranulocytosis ( p  < 0.0001, 4.01-fold), aplasia cutis congenita ( p  < 0.0001, 123.22-fold), and exomphalos ( p  = 0.0002, 22.17-fold), demonstrated significantly higher RORs (more than 4-fold) for MMI use than for PTU use. Nineteen PTs, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis ( p  < 0.0001, 29.84), rapidly progressive glomerulonephritis ( p  < 0.0001, 6.44), and pulmonary alveolar hemorrhage ( p  < 0.0001, 7.77), had RORs for PTU use more than four times those for MMI use. NDB Open Data Japan showed more frequent PTU prescriptions than MMI prescriptions for women of reproductive age. Conclusions: This large-scale study confirmed that a variety of congenital malformations were identified as having significantly high RORs for MMI use, while diseases related to ANCA-associated vasculitis were specific to PTU.

Objective: Outcomes of childhood-onset Graves' disease (GD) and suggested duration of anti-thyroid drug (ATD) therapy have been controversial. This study aimed to determine long-term outcomes following ATD therapy, including remission and relapse rates., Design, Patients and Measurements: A retrospective study of 265 paediatric patients with GD who were initially treated with ATD was conducted. Long-term outcomes were analysed., Results: Median (IQR) age at diagnosis was 11.5 (9.4, 13.7) years. Duration of ATD treatment was 4.3 (2.3, 6.7) years and time since diagnosis to the enrolment was 7.1 (3.8, 10.9) years. There were 77, 93 and 95 patients who underwent definitive treatment, had ATD discontinuation, and were still being treated with ATD, respectively. The remission rate was 21% (56 out of 265 patients) and relapse rate was 40% (37 out of 93 patients). Cumulative incidence of first remission increased with the duration of ATD treatment with maximum remission rate at 5.3 years following ATD therapy. Among patients who experienced relapse, approximately 50% had disease relapse which occurred within 1 year after ATD discontinuation. Patients with goitre size of less than 3.5 cm, thyroid-stimulating hormone receptor antibody of less than 10 IU/L, no ophthalmopathy at diagnosis and methimazole dose requirement of less than 0.25 mg/kg/day at 1 year after treatment were more likely to achieve remission., Conclusions: Remission rate of childhood-onset GD was relatively low following ATD treatment. Longer-term ATD therapy was associated with increased remission rate. Approximately 50% of patients with relapse had disease relapse within 1 year following ATD discontinuation., (© 2022 John Wiley & Sons Ltd.)

The effect of potassium iodide (KI) on radioiodine uptake (RAIU) before radioisotope therapy in Graves' disease (GD) patients was investigated. A total of 82 patients who had been treated with KI monotherapy before 24-hour RAIU (24 h RAIU) were evaluated and 354 of those who had been treated with thiamazole (MMI) monotherapy were extracted from the 1,130 GD patients who were identified as having had appropriate iodine restriction based on urinary iodine excretion. Urinary iodine excretion (UIE) <200 μg/day was confirmed in all subjects. Propensity score-matching was performed to identify the difference in 24 h RAIU between the KI group and the MMI group. In addition, multiple regression analysis was performed to evaluate related to 24 h RAIU. Propensity score-matching resulted in 57 matched patients in each group. After matching, 24 h RAIU was still significantly lower in the KI group than in the MMI group (median 53% (interquartile range 47-61%) vs. 63% (56-66%); p = 0.001). In addition, KI monotherapy was weakly negatively correlated with 24 h RAIU, whereas the female sex and FT3 were very weakly positively correlated on multiple regression analysis. The results suggest that KI monotherapy likely suppressed 24 h RAIU more than MMI monotherapy in GD patients with appropriate iodine restriction, given the difference in the mechanism of hormone suppression.

Objective: A common problem with antithyroid drugs (ATD) treatment in patients with Graves' disease (GD) is the high recurrence rate after drug withdrawal. Identifying risk factors for recurrence is crucial in clinical practice. We hereby prospectively analyze risk factors for the recurrence of GD in patients treated with ATD in southern China., Subjects and Methods: Patients who were newly diagnosed with GD and aged > 18 years were treated with ATD for 18 months and followed up for 1 year after ATD withdrawal. Recurrence of GD during follow-up was assessed. All data were analyzed by Cox regression with P values < 0.05 considered statistically significant., Results: A total of 127 Graves' hyperthyroidism patients were included. During an average follow-up of 25.7 (standard deviation = 8.7) months, 55 (43%) had a recurrence within 1 year after withdraw of anti-thyroid drugs. After adjustment for potential confounding factors, the significant association remained for the presence of insomnia (hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.47-5.88), greater goiter size (HR 3.34, 95% CI 1.11-10.07), higher thyrotrophin receptor antibody (TRAb) titer (HR 2.66, 95% CI 1.12-6.31) and a higher maintenance dose of methimazole (MMI) (HR 2.14, 95% CI 1.14-4.00)., Conclusion: Besides conventional risk factors (i.e., goiter size, TRAb and maintenance MMI dose) for recurrent GD after ATD withdraw, insomnia was associated with a 3-fold risk of recurrence. Further clinical trials investigating the beneficial effect of improving sleep quality on prognosis of GD are warranted.

Introduction: Methimazole (MMI) represents the conventional therapeutic agent for Graves' disease (GD) hyperthyroidism, but MMI efficacy is limited since it marginally affects the underlying autoimmune process. In a previous study, we randomly assigned 42 newly diagnosed GD patients with insufficient vitamin D (VitD) and selenium (Se) levels to treatment with MMI alone (standard) or combined with selenomethionine and cholecalciferol (intervention) and observed a prompter resolution of hyperthyroidism in the intervention group., Methods: In the present study, we aimed to explore changes in peripheral T regulatory (Treg) and circulating natural killer (NK) cell frequency, circulating NK cell subset distribution and function, during treatment., Results: At baseline, circulating total CD3 - CD56 + NK cells and CD56 bright NK cells were significantly higher in GD patients than in healthy controls (HC) (15.7 ± 9.6% vs 9.9 ± 5.6%, p=0.001; 12.2 ± 10.3% vs 7.3 ± 4.1%, p=0.02, respectively); no differences emerged in Treg cell frequency. Frequencies of total NK cells and CD56 bright NK cells expressing the activation marker CD69 were significantly higher in GD patients than in HC, while total NK cells and CD56 dim NK cells expressing CD161 (inhibitory receptor) were significantly lower. When co-cultured with the K562 target cell, NK cells from GD patients had a significantly lower degranulation ability compared to HC (p<0.001). Following 6 months of treatment, NK cells decreased in both the intervention and MMI-alone groups, but significantly more in the intervention group (total NK: -10.3%, CI 95% -15.8; -4.8% vs -3.6%, CI 95% -9; 1.8%, p=0.09 and CD56 bright NK cells: -6.5%, CI 95% -10.1; -3 vs -0.9%, CI 95% -4.4; 2%, p=0.03). Compared to baseline, CD69 + NK cells significantly decreased, while degranulation ability slightly improved, although no differences emerged between the two treatment groups. Compared to baseline, Treg cell frequency increased exclusively in the intervention group (+1.1%, CI 95% 0.4; 1.7%)., Discussion: This pilot study suggested that VitD and Se supplementation, in GD patients receiving MMI treatment, modulates Treg and NK cell frequency, favoring a more pronounced reduction of NK cells and the increase of Treg cells, compared to MMI alone. Even if further studies are needed, it is possible to speculate that this immunomodulatory action might have facilitated the prompter and better control of hyperthyroidism in the supplemented group observed in the previous study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gallo, Bruno, Gallazzi, Cattaneo, Veronesi, Genoni, Tanda, Bartalena, Passi, Piantanida and Mortara.)

Background: Immune thrombocytopenic purpura is a condition associated with an unusual, unexplained, and sometimes very severe reduction in the level of platelets in the blood. Though documented, its association with Graves' disease is not very common and can easily be missed or misdiagnosed, leading to excessive bleeding and mortality. Treatment with steroids and antithyroid medications has been shown to be beneficial in correcting thrombocytopenia in these patients, although the response is varied. We report on a patient with Graves' disease who presents with immune thrombocytopenic purpura., Case Presentation: A 37-year-old Ghanaian female presented to our hospital's emergency department with a complaint of palpitations, difficulty breathing, easy fatigue, and headaches. She had been referred from a peripheral hospital as a case of thrombocytopenia, severe anemia, and anterior neck swelling. She was diagnosed with Graves' disease 2 years ago, became euthyroid during treatment, but defaulted. On further examination and investigation, she was diagnosed with immune thrombocytopenic purpura and was also found to have elevated free T3 and T4, and suppressed thyroid stimulating hormone. She also had high thyroid autoantibodies. She was initially started on oral prednisolone but there was no stabilization of platelets until methimazole was introduced, which improved and normalized her platelet count., Conclusion: The association of Graves' disease with immune thrombocytopenic purpura, though documented, is uncommon, and very few cases have been reported thus far. There have not been any reported cases in Ghana or Sub-Saharan Africa and hence, clinicians should be aware of this association when investigating immune thrombocytopenic purpura and should consider Graves' disease as a possible cause. From this study, we observed that there was no improvement in platelet count following the use of corticosteroid therapy until methimazole was started., (© 2023. The Author(s).)

Importance: Thyroid storm is the most severe form of thyrotoxicosis, with high mortality, and is treated with propylthiouracil and methimazole. Some guidelines recommend propylthiouracil over methimazole, although the difference in outcomes associated with each treatment is unclear., Objective: To compare outcomes associated with use of propylthiouracil vs methimazole for the treatment of thyroid storm., Design, Setting, and Participants: This comparative effectiveness study comprised a large, multicenter, US-based cohort from the Premier Healthcare Database between January 1, 2016, and December 31, 2020. It included 1383 adult patients admitted to intensive or intermediate care units with a diagnosis of thyroid storm per International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and treated with either propylthiouracil or methimazole. Analyses were conducted from July 2022 to February 2023., Exposure: Patients received either propylthiouracil or methimazole for treatment of thyroid storm. Exposure was assigned based on the initial thionamide administered., Main Outcomes and Measures: The primary outcome was the adjusted risk difference of in-hospital death or discharge to hospice between patients treated with propylthiouracil and those treated with methimazole, assessed by targeted maximum likelihood estimation., Results: A total of 1383 patients (656 [47.4%] treated with propylthiouracil; mean [SD] age, 45 [16] years; 473 women [72.1%]; and 727 [52.6%] treated with methimazole; mean [SD] age, 45 [16] years; 520 women [71.5%]) were included in the study. The standardized mean difference for age was 0.056, and the standardized mean difference for sex was 0.013. The primary composite outcome occurred in 7.4% of of patients (102 of 1383; 95% CI, 6.0%-8.8%). A total of 8.5% (56 of 656; 95% CI, 6.4%-10.7%) of patients who initiated propylthiouracil and 6.3% (46 of 727; 95% CI, 4.6%-8.1%) who initiated methimazole died in the hospital (adjusted risk difference, 0.6% [95% CI, -1.8% to 3.0%]; P = .64). There were no significant differences in duration of organ support, total hospitalization costs, or rates of adverse events between the 2 treatment groups., Conclusion and Relevance: In this comparative effectiveness study of a multicenter cohort of adult patients with thyroid storm, no significant differences were found in mortality or adverse events in patients who were treated with propylthiouracil or methimazole. Thus, current guidelines recommending propylthiouracil over methimazole for treatment of thyroid storm may merit reevaluation.

Background: Adults with hyperthyroidism have been found to have decreased bone mineral density (BMD) and higher fracture risk. The most typical cause of hyperthyroidism is Graves' disease. However, there are limited studies on how hyperthyroidism affects bone metabolism and fractures in children. We describe a unique instance of a patient who initially displayed a fragility fracture and was ultimately identified with Graves' disease after biochemical evaluations., Case Summary: A 2-year-8-month-old female presented with fragility fractures three times in only 7 months. A series of examinations were performed to evaluate any possible malformations or abnormalities of bone metabolism. Graves' disease was found, and drug therapies were employed (methimazole, propranolol, calcium carbonate, vitamin D). Since children with Graves' disease and fragility fractures have been uncommonly described in the past, a stringent and thorough long-term follow-up was initiated., Conclusions: Children with undiagnosed Graves' disease had a higher risk of fractures and osteoporosis. This case suggests that BMD measurement may be necessary for the initial evaluation of Graves' disease in children.

Methimazole is the most commonly used medication for hyperthyroidism with good effects and little adverse reactions. However, improper selection of initial dose will affect the efficacy, such as excessive dose is proven to various adverse reactions; insufficient dose can hardly achieve desired efficacy. Based on the literature and personal clinical experience, the author discusses the following clinical issues related to methimazole in the treatment of hyperthyroidism, including the selection of initial dose, dose adjustment and withdrawal of methimazole, drug therapy for patients with liver function injury, and management strategies for methimazole-related adverse reactions.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as Drug-induced hypersensitivity syndrome (DiHS), is a severe adverse drug reaction. Propylthiouracil, a member of thiouracils group, is widely used in medical treatment of hyperthyroidism. Propylthiouracil is associated with multiple adverse effects such as rash, agranulocytosis hepatitis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but rarely triggers DRESS/DiHS syndrome. Here, we describe a severe case of propylthiouracil-induced DRESS/DiHS syndrome., Case Presentation: A 38-year-old female was treated with methimazole for hyperthyroidism at first. 4 weeks later, the patient developed elevated liver transaminase so methimazole was stopped. After liver function improved in 2 weeks, medication was switched to propylthiouracil therapy. The patient subsequently developed nausea and rash followed by a high fever, acute toxic hepatitis and multiple organ dysfunction (liver, lung and heart), which lasted for 1 month after propylthiouracil was started. According to the diagnostic criteria, the patient was diagnosed of DRESS/DiHS syndrome which was induced by propylthiouracil. As a result, propylthiouracil was immediately withdrawn. And patient was then treated with adalimumab, systematic corticosteroids and plasmapheresis in sequence. Symptoms were finally resolved 4 weeks later., Conclusions: Propylthiouracil is a rare cause of the DRESS/DiHS syndrome, which typically consists of severe dermatitis and various degrees of internal organ involvement. We want to emphasize through this severe case that DRESS/DiHS syndrome should be promptly recognized to hasten recovery., (© 2023. The Author(s).)

Introduction: The thionamide anti-thyroid drugs namely carbimazole, methimazole, and propylthiouracil, have been the predominant therapy modality for Graves' hyperthyroidism for over 60 years. Although these agents have proven efficacy and favorable side-effect profiles, non-thionamide alternatives are occasionally indicated in patients who are intolerant or unresponsive to thionamides alone. This review examines the available non-thionamide drug options for the control of Graves' hyperthyroidism and summarizes their clinical utility, efficacy, and limitations., Areas Covered: We reviewed existing literature on mechanisms, therapeutic utility, and side-effect profiles of non-thionamide anti-thyroid drugs. Established non-thionamide agents act on various phases of the synthesis, release, and metabolism of thyroid hormones and comprise historical agents such as iodine compounds and potassium perchlorate as well as drug repurposing candidates like lithium, glucocorticoids, beta-blockers, and cholestyramine. Novel experimental agents in development target key players in Graves' disease pathogenesis including B-cell depletors (Rituximab), CD40 blockers (Iscalimab), TSH-receptor antagonists, blocking antibodies, and immune-modifying peptides., Expert Opinion: Non-thionamide anti-thyroid drugs are useful alternatives in Graves' hyperthyroidism and more clinical trials are needed to establish their safety and long-term efficacy in hyperthyroidism control. Ultimately, the promise for a cure will lie in novel approaches that target the well-established immunopathogenesis of Graves' disease.

Objective: We investigated longitudinal changes in circulating CD4 + and CD8 + T cells positive for programed cell death protein-1 (PD-1) and in other subsets of CD4 + T cells in untreated hyperthyroid patients with Graves' disease after treatment with methimazole (MMI)., Design and Patients: The study included 18 untreated hyperthyroid patients with Graves' disease and 18 age-matched controls. Before and after 12-week treatment with MMI, we used flow cytometry to measure circulating PD-1 +  D4 + and PD-1 + CD8+ T cells and subsets of CD4 + T cells in peripheral blood, as well as serum levels of chemokines related to T-helper type 1 (Th-1) and Th-2 cells., Results: At baseline, the percentage of CD4 + and CD8 + T cells expressing PD-1 was significantly higher in patients than in age-matched controls. Serum levels of chemokines related to Th-1 and Th-2 also were higher in patients. Twelve weeks after initiation of MMI, the percentage of CD4 + T cells expressing PD-1 was significantly lower than at baseline, but no such change was seen in CD8 + T cells. Furthermore, the percentage of Th-1 cells among CD4 + T cells and the serum levels of soluble CD26/dipeptidyl peptidase-4, a surface marker of Th-1 cells, also were significantly lower than at baseline., Conclusions: The expression of PD-1 on circulating CD4 + and CD8 + T cells is increased in hyperthyroid patients with active Graves' disease. MMI significantly decreases levels of circulating PD-1 +  CD4 + T cells, suggesting that PD-1 + T lymphocytes may be associated with the pathogenesis of Graves' disease., (© 2022 John Wiley & Sons Ltd.)

Backgruound: An excess of thyroid hormones in Graves' disease (GD) has profound effects on systemic energy metabolism that are currently partially understood. In this study, we aimed to provide a comprehensive understanding of the metabolite changes that occur when patients with GD transition from hyperthyroidism to euthyroidism with methimazole treatment., Methods: Eighteen patients (mean age, 38.6±14.7 years; 66.7% female) with newly diagnosed or relapsed GD attending the endocrinology outpatient clinics in a single institution were recruited between January 2019 and July 2020. All subjects were treated with methimazole to achieve euthyroidism. We explored metabolomics by performing liquid chromatography-mass spectrometry analysis of plasma samples of these patients and then performed multivariate statistical analysis of the metabolomics data., Results: Two hundred metabolites were measured before and after 12 weeks of methimazole treatment in patients with GD. The levels of 61 metabolites, including palmitic acid (C16:0) and oleic acid (C18:1), were elevated in methimazole-naïve patients with GD, and these levels were decreased by methimazole treatment. The levels of another 15 metabolites, including glycine and creatinine, were increased after recovery of euthyroidism upon methimazole treatment in patients with GD. Pathway analysis of metabolomics data showed that hyperthyroidism was closely related to aminoacyl-transfer ribonucleic acid biosynthesis and branched-chain amino acid biosynthesis pathways., Conclusion: In this study, significant variations of plasma metabolomic patterns that occur during the transition from hyperthyroidism to euthyroidism were detected in patients with GD via untargeted metabolomics analysis.

Background: This study aimed to compare the time to achieve euthyroidism and sustained control of hyperthyroidism after treatment with radioactive iodine (RAI) or long-term methimazole (LT-MMI) in patients with post-RAI relapsed hyperthyroidism., Methods: Sixty four patients with recurrence of hyperthyroidism after RAI treatment were randomly assigned to either RAI or LT-MMI treatment. Both groups were followed every 1-3 months in the first year and then every 6 months for a total of 60 months., Results: In RAI and LT-MMI groups, mean age was 49.0 ± 12.1 and 50.1 ± 14.6 years and time of relapse of hyperthyroidism after previous RAI treatment was 23.2 ± 18.8 and 20.8 ± 17.1 months, respectively. At the end of study, in the LT-MMI group, 31 (97%) and 1 (3%) were euthyroid and hypothyroid, respectively; in the RAI group, 8 (25%) patients were euthyroid, whereas 18 (56%), 3 (9.5%) and 3 (9.5%) had overt hypothyroidism, subclinical hypothyroidism and hyperthyroidism, respectively. Mean time to euthyroidism was 9.4 ± 5.0 months in the RAI group and 3.5 ± 2.8 months in the LT-MMI group (p < 0.001). Patients in the RAI group spent 77.7 ± 14.0 percent and those in the LT-MMI group spent 95.2 ± 5.9 percent of 60 months in the euthyroid state (p < 0.001)., Conclusion: In patients with post-RAI relapse of hyperthyroidism, LT-MMI treatment was superior to radioiodine because of faster achievement of euthyroidism and more sustained control of hyperthyroidism during 60 months of follow-up., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R 2 =0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.

Objectives: Methimazole is an antithyroid drug and is used clinically in hyperthyroidism. Liver dysfunction is one of the side effects of methimazole. Catechins are natural flavonoids and have antioxidant, antithyroid, and liver protection effects. Despite the wide range of biological properties of catechins, their effective use is limited due to poor water solubility, low stability, and low bioavailability. Catechin niosomal nanoencapsulation improves the properties of catechin and increases its antioxidant activities., Methods: Niosomal vesicles were synthesized by the Thin Film Hydration method and their physicochemical characteristics, morphology, and percentage of trapped catechin in them were determined by dynamic light scattering (DLS), transmission electron microscopy (TEM), and spectrophotometry, respectively. In this study, 32 adult male rats were divided into 4 groups: control, 50 mg/kg methimazole, 100 mg/kg catechin, and 100 mg/kg nanocapsule niosomal form of catechin. The drugs were administered orally and the duration of treatment was 8 weeks. Then, the serum concentration of thyroid hormones and thyroid stimulating hormone (TSH) by enzyme-linked immunosorbent assay (ELISA) method, and serum liver function tests were performed using an autoanalyzer. The activities of hepatic oxidative enzymes were measured spectrophotometrically., Results: Our study showed that the percentage of catechin encapsulation in the niosome was calculated to be 51%. A significant difference was observed in the catechin and encapsulated catechin treatment groups compared to the methimazole group (p <0.0001). In all three treatment groups of methimazole, catechin, and niosomal nanocapsule catechin, serum levels of TT3, TT4, FT3, FT4, body weight and daily consumption of water and food were significantly reduced compared to the control group (p <0.0001)., Conclusions: The antithyroid effects of catechin and its encapsulated form were comparable to methimazole. Also, the encapsulation improved the hepatoprotective effects of catechin., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background Graves' disease occurrence during pregnancy is not a frequent event, showing an incidence of 0.2-0.4% in unselected pregnant women. Depending on their functional properties, TSH-receptor antibodies can induce hypothyroidism or hyperthyroidism. Recognizing the signs of altered thyroid function is essential to prevent possible complications on the fetus. Materials and methods The case of a pregnant woman without previous history of thyroid disease presenting with severe overt hypothyroidism during the first trimester is reported. Levothyroxine therapy was started and 6 weeks later overt hyperthyroidism was observed. TRAb were detected at high titers. Levothyroxine was withdrawn and low dose methimazole was started. Serial obstetric ultrasound scans were negative for indirect signs of fetal thyroid dysfunctions and no fetal goiter was visualized throughout pregnancy. Spontaneous delivery occurred without complications at 39 weeks of gestation. In the post-partum, severe overt hypothyroidism recurred, thus methimazole was discontinued and levothyroxine was restarted. TRAb persisted at high levels. The infant experienced a transient thyrotoxicosis, which fully resolved in three months with normalization of thyroid function and negativization of TRAb levels. Results The present case report allows us to overview the challenges related to the management of hypo and hyperthyroidism in patients with high TRAb levels, requiring strict monitoring aimed at early detection of both maternal and fetal consequences. Conclusions This case underlines the importance of close follow-up and the need of collaboration in a multidisciplinary team when Graves's disease is diagnosed in a pregnant woman to prevent adverse neonatal outcomes.

Typical symptoms which should lead to suspicion of hyperthyroidism are unintentional weight loss, tachycardia, and palpitations, heat intolerance, and hyperactivity. It is diagnosed by suppressed thyroid-stimulating hormone (TSH) with elevated thyroid hormone (TH) levels. Graves' disease (GD) due to antibodies stimulating the TSH receptor is the leading cause, and first-line treatment is with methimazole (MMI). Emerging data suggest MMI treatment, up to 8 years is effective and safe in improving the rate of remission. Radioactive iodine (RAI) and thyroidectomy offer definitive treatment and induce permanent hypothyroidism. Thyroid storm is a life-threatening condition with systemic decompensation and hyperpyrexia. Neonates of mothers with current or past GD are at risk for neonatal hyperthyroidism (NH). Appropriate identification and follow-up of at-risk neonates will reduce complications., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prompt and stable control of hyperthyroidism is fundamental to avoid the detrimental effects of thyroid hormone excess, and antithyroid drugs, mainly methimazole (MMI), represent the first-line treatment for Graves' disease (GD) hyperthyroidism. Decreased serum concentrations of selenium (Se) and calcifediol (25(OH)D, VitD) have been reported in newly diagnosed GD patients in observational studies. Low Se levels might exacerbate oxidative stress by compromising the antioxidant machinery's response to reactive oxygen species, and low VitD levels might hamper the anti-inflammatory immune response. We performed a randomized controlled clinical trial (EudraCT 2017-00505011) to investigate whether Se and cholecalciferol (VitD) addition to MMI is associated with a prompter control of hyperthyroidism. Forty-two consecutive patients with newly-onset GD and marginal/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. Se treatment was withdrawn after 180 days, while the other treatments were continued. Combination therapy resulted in a significantly greater reduction in serum FT4 concentration at 45 days (-37.9 pg/ml, CI 95%, -43.7 to -32.2 pg/ml) and 180 days (-36.5 pg/ml, CI 95%, -42 to -30.9 pg/ml) compared to MMI monotherapy (respectively: -25.7 pg/ml, CI 95%, -31.6 to -19.7 pg/ml and -22.9 pg/ml, CI 95%, -28 to -17.3 pg/ml, p 0.002). Data at 270 days confirmed this trend (-37.8 pg/ml, CI 95%, -43.6 to -32.1 pg/ml vs -24.4 pg/ml, CI 95%, -30.3 to -18.4 pg/ml). The quality of life (QoL) score was investigated by the validated "Thyroid-related Patient-Reported Outcome" questionnaire (ThyPRO). ThyPRO composite score showed a greater improvement in the intervention group at 45 days (-14.6, CI 95%, -18.8 to -10.4), 180 (-9, CI 95%, -13.9 to -4.2) and 270 days (-14.3, CI 95%, -19.5 to -9.1) compared to MMI group (respectively, -5.2, CI 95%, -9.5 to -1; -5.4, CI 95%, -10.6 to -0.2 and -3.5, CI 95%, -9 to -2.1, p 0-6 months and 6-9 months <0.05). Our results suggest that reaching optimal Se and VitD levels increases the early efficacy of MMI treatment when Se and VitD levels are suboptimal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gallo, Mortara, Veronesi, Cattaneo, Genoni, Gallazzi, Peruzzo, Lasalvia, Moretto, Bruno, Passi, Pini, Nauti, Lavizzari, Marinò, Lanzolla, Tanda, Bartalena and Piantanida.)

We present the case of a 65 years old patient with Graves disease associated with hyperthyroidism and a medical history of bipolar disorder treated with lithium. Hyperthyroidism was initially treated with high-dose methimazole monotherapy and later the patient developed overt hypothyroidism (clinical and biochemical), but without remission of the underlying autoimmune disease. A "block and replace" therapeutic regimen was then started with reduced methimazole doses in combination with levothyroxine, which resulted in a short time in normalization of the hormonal profile and significant improvement of the clinical picture. Therefore, the "block and replace" regimen represents a valid therapeutic alternative to anti-thyroid drugs monotherapy in the treatment of hyperthyroidism due to Graves disease in selected cases.

Background: Graves' disease is an autoimmune disorder characterised by excessive production of thyroid hormones, which induces increased cellular metabolism in most tissues and increased production of reactive oxygen species (ROS). The aim of this work was to analyse the effect of ROS on cell viability and the expression of catalase (CAT), glutathione peroxidase-1 (GPx-1), superoxide dismutase (SOD-1) and DNA methyltransferase-1 (DNMT-1) in peripheral blood mononuclear cells (PBMC) from patients with newly diagnosed Graves' disease or treated with methimazole., Patients and Methods: For this study, women patients with newly diagnosed Graves' disease (n=18), treated with methimazole (n=6) and healthy subjects (n=15) were recruited. ROS were evaluated by flow cytometry, and the viability/apoptosis of PBMC was analysed by flow cytometry and fluorescence microscopy. Genomic expression of CAT, GPx-1, SOD-1 and DNMT-1 was quantified by real-time PCR., Results: We found high levels of ROS and increased expression of CAT, GPx-1, SOD-1 and DNMT-1 in PBMC from patients with newly diagnosed Graves' disease. Methimazole treatment reversed these parameters. Cell viability was similar in all study groups., Conclusions: ROS induces the expression of CAT, GPx-1, and SOD-1. The activity of these enzymes may contribute to the protection of PBMC from the harmful effect of free radicals on cell viability. Increased expression of DNMT-1 may be associated with aberrant methylation patterns in immunoregulatory genes contributing to autoimmunity in Graves' disease., (Copyright © 2021 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: The objective of this study was to evaluate the presence of traces of thiamazole in the urine of owners of hyperthyroid cats treated with antithyroid drugs., Methods: Urine was collected from 24 owners of hyperthyroid cats, five human patients treated with thiamazole and five healthy humans without any contact with antithyroid drugs. All owners of hyperthyroid cats were asked to fill out a questionnaire. Urine of hyperthyroid cats was collected by spontaneous micturition. All urine samples were stored at -20°C until analysis by ultra-high-performance liquid chromatography coupled to high-resolution quadrupole Orbitrap mass spectrometry., Results: These owners were assessed to have a lot of contact with their cat. Adherence to antithyroid medication handling guidelines was rather poor. High concentrations of thiamazole were detected in all feline samples (median concentration 2818 ng/ml; range 104-15,127) and in the urine of all human patients treated with thiamazole (median concentration 4153 ng/ml; range 1826-5009). No thiamazole was detected in the urine of owners of hyperthyroid cats (limit of detection 3.88 ng/ml; limit of quantification 11.75 ng/ml)., Conclusions and Relevance: The results regarding the potential exposure of owners of hyperthyroid cats to antithyroid drugs are reassuring. Nevertheless, prudence is still warranted when administering antithyroid drugs. Whether these results can be extrapolated to the use of transdermal application requires further investigation.

Background: Following the conventional 12-18 month antithyroid drug (ATD) treatment in Graves' disease (GD), 50% of patients experience relapse of hyperthyroidism., Objective: The aim of this systematic scoping review was critical appraisal of duration of ATD therapy in the last 80 years., Methods: Articles were identified through the search of PubMed from January 1, 1941 to April 30, 2021. All study types were included. Articles were eligible if they reported data on the length of ATD treatment, particularly thyroid hormones and TSH receptor antibodies (TRAb) concentrations and specifically those with data on the remission and/or relapse rates., Results: We described major progress regarding the duration of ATD therapy and related outcomes at every 20 years. Articles of 1941-1960 were mainly concerned with determination of favorable treatment, minimal effective dose, side effects and rate of remission after < 12-month ATD therapy. Studies with larger number of patients and longer follow-ups appeared in 1961-1980; higher remission rate after 18-24 months versus 6 months of ATD therapy was reported. Articles of 1981-2000 focused on identification of factors associated with high relapse rates after discontinuation of ATD. In 2001-2021, ATD became the first choice of treatment in many countries. However, 12-18 months of ATD therapy was arbitrarily chosen as the appropriate option. According to recent studies, persistent normalization of TRAb occurs after 5 years of methimazole therapy and ATD treatment of > 60 months could offer a 4-year remission rate of 85%., Conclusion: Long-term ATD treatment for more than 60 months is safe and effective, has the highest remission rate and cures most patients with GD; hence, it should be considered as the most appropriate duration for ATD therapy in these patients., (© 2021. Italian Society of Endocrinology (SIE).)

Background: Methimazole (MMI) is the first-line treatment for patients with Graves' disease (GD). While there are empirical recommendations for initial MMI doses, there is no clear guidance for subsequent MMI dose titrations. We aimed to (a) develop a mathematical model capturing the dynamics of free thyroxine (FT4) during MMI treatment (b), validate this model by use of numerical simulation in comparison with real-life patient data (c), develop the software application Digital Thyroid (DigiThy) serving either as a practice tool for treating virtual patients or as a decision support system with dosing recommendations for MMI, and (d) validate this software framework by comparing the efficacy of its MMI dosing recommendations with that from clinical endocrinologists., Methods: Based on concepts of automatic control and by use of optimization techniques, we developed two first order ordinary differential equations for modeling FT4 dynamics during MMI treatment. Clinical data from patients with GD derived from the outpatient clinic of Endocrinology at the Medical University of Graz, Austria, were used to develop and validate this model. It was subsequently used to create the web-based software application DigiThy as a simulation environment for treating virtual patients and an autonomous computer-aided thyroid treatment (CATT) method providing MMI dosing recommendations., Results: Based on MMI doses, concentrations of FT4, thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb), a mathematical model with 8 patient-specific constants was developed. Predicted FT4 concentrations were not significantly different compared to the available consecutively measured FT4 concentrations in 9 patients with GD (52 data pairs, p=0.607). Treatment success of MMI dosing recommendations in 41 virtually generated patients defined by achieved target FT4 concentrations preferably with low required MMI doses was similar between CATT and usual care. Statistically, CATT was significantly superior (p<0.001)., Conclusions: Our mathematical model produced valid FT4 predictions during MMI treatment in GD and provided the basis for the DigiThy application already serving as a training tool for treating virtual patients. Clinical trial data are required to evaluate whether DigiThy can be approved as a decision support system with automatically generated MMI dosing recommendations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Theiler-Schwetz, Benninger, Trummer, Pilz and Reichhartinger.)

Background: Extragonadal choriocarcinoma is rare and can be associated with hyperthyroidism when producing very high levels of human chorionic gonadotropin., Case Presentation: A 62-year-old Hispanic female presented with a 3-week history of shortness of breath, palpitations, extreme weakness, new-onset hot flashes, and right flank pain. Her physical examination was remarkable for tachycardia, hepatomegaly, hyperreflexia, and tremor; goiter was absent. Laboratory studies revealed increased lactate dehydrogenase, alkaline phosphatase, suppressed thyroid stimulating hormone, very elevated T4, and absent thyroid stimulating immunoglobulin. 18 F-fluorodeoxyglucose positron emission tomography-computed tomography exhibited hepatomegaly with multiple large fluorodeoxyglucose-avid liver masses and a focus of fluorodeoxyglucose avidity in the stomach with no structural correlate. A thyroid scan ( 99m TcO 4 - ) showed diffusely increased tracer uptake. She was started on propranolol and methimazole. Upon stabilization of severe thyrotoxicosis, upper endoscopy was performed, showing a ~ 5 cm bleeding lesion in the greater stomach curvature body; biopsy was consistent with choriocarcinoma; beta-human chorionic gonadotropin hormone was 2,408,171 mIU/mL. The patient received methotrexate followed by etoposide and cisplatin. Methimazole was titrated down, and upon liver failure the medication was stopped. The thyrotoxicosis was effectively controlled with antithyroid drug and concurrent chemotherapy. At ~ 1.5 months after initial diagnosis, the patient died due to bleeding/acute liver failure with coagulation defects followed by multiple organ failure., Conclusions: Severe thyrotoxicosis can represent an unusual initial presentation of metastatic choriocarcinoma in the setting of extreme elevation of beta-human chorionic gonadotropin. Primary gastric choriocarcinoma is an aggressive malignancy with very poor outcomes. The co-occurrence of severe thyrotoxicosis with advanced primary gastric choriocarcinoma and imminent liver failure complicates management options., (© 2022. The Author(s).)

Immune dysfunction caused by environmental factors plays an important role in the development of Graves' disease (GD), and environmental factors are closely related to the intestinal flora. Our previous study showed significant changes in the intestinal flora in GD patients compared with healthy volunteers. This study analyzed the relationships between changes in the intestinal flora, thyroid function and relevant thyroid antibodies in GD patients before and after methimazole treatment. The subjects were divided into the UGD group (18 newly diagnosed GD patients), the TGD group (10 GD patients with normal or approximately normal thyroid function after methimazole treatment) and the NC group (11 healthy volunteers). Their fresh stool samples were sent for 16S rRNA gene amplification and Illumina platform sequencing. The correlations of the relative abundance of Bifidobacterium with the levels of TRAb, TgAb and TPOAb in the NC group and the UGD group were analyzed. A total of 1,562,445 high-quality sequences were obtained. In the UGD group, the abundances of Bifidobacterium and Collinsella were higher than that in the NC group; Bacteroides abundance in the TGD group was higher than that in the NC group, while Prevotella and Dialister abundances were lower than that in the NC group; Prevotella and Collinsella abundances in the UGD group were higher than that in the TGD group. The predominant abundance distribution of Bifidobacteriaceae in the UGD group at the family level was superior to that in the NC group. The abundance of Bifidobacterium was positively correlated with the levels of TRAb, TgAb, and TPOAb. The biological diversity of the intestinal flora was reduced in GD patients. After methimazole treatment, the composition of the intestinal flora was significantly altered. The change in Bifidobacterium abundance was positively correlated with TRAb, TgAb and TPOAb, suggesting that it might be related to the immune mechanism of GD. The results of this study may deepen our understanding of the pathogenesis of GD and provide a new idea for the treatment of GD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Zheng, Wu, Zhang, Yang, Yu, Liu, Zha, Gong, Yang, Sun and Zeng.)

Background: Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have confirmed a relationship between thyrotoxicosis and muscle dysfunction, few have measured changes in plasma metabolites and immune cells during the development and recovery from thyrotoxic myopathy. The aim of this study was to identify specific plasma metabolites and T-cell subsets that predict thyrotoxic myopathy recovery in patients with Graves' disease., Methods: One hundred patients (mean age, 40.0 ± 14.2 years; 67.0% female), with newly diagnosed or relapsed Graves' disease were enrolled at the start of methimazole treatment. Handgrip strength and Five Times Sit to Stand Test performance time were measured at Weeks 0, 12, and 24. In an additional 35 patients (mean age, 38.9 ± 13.5 years; 65.7% female), plasma metabolites and immunophenotypes of peripheral blood were evaluated at Weeks 0 and 12, and the results of a short physical performance battery assessment were recorded at the same time., Results: In both patient groups, methimazole-induced euthyroidism was associated with improved handgrip strength and lower limb muscle function at 12 weeks. Elevated plasma metabolites including acylcarnitines were restored to normal levels at Week 12 regardless of gender, body mass index, or age (P trend <0.01). Senescent CD8 + CD28 - CD57 + T-cell levels in peripheral blood were positively correlated with acylcarnitine levels (P < 0.05) and decreased during thyrotoxicosis recovery (P < 0.05). High levels of senescent CD8 + T cells at Week 0 were significantly associated with small increases in handgrip strength after 12 weeks of methimazole treatment (P < 0.05), but not statistically associated with Five Times Sit to Stand Test performance., Conclusions: Restoring euthyroidism in Graves' disease patients was associated with improved skeletal muscle function and performance, while thyroid hormone-associated changes in plasma acylcarnitines levels correlated with muscle dysfunction recovery. T-cell senescence-related systemic inflammation correlated with plasma acylcarnitine levels and was also associated with small increases in handgrip strength., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Rationale: Hyperthyroidism, such as Basedow disease, causes fluid retention, although the common cause is volume overload due to congestive heart failure. In addition, hyperthyroidism and Basedow disease are known to cause pulmonary hypertension. Edematous thickening of the gallbladder wall is caused by venous blood congestion. The feature of edematous wall thickening of the gallbladder on abdominal computed tomography (CT) is subserosal edema and is often accompanied by a periportal collar sign., Patient Concerns: A 30-year-old woman was referred to our hospital because of liver dysfunction, edematous gallbladder wall thickening, and fluid retention. In addition, the patient developed hyperthyroidism and heart failure. Enhanced abdominal CT revealed edematous wall thickening of the gallbladder and a periportal collar sign., Diagnosis: We suspected that fluid retention and congestion were caused by hyperthyroidism and Basedow disease., Interventions: On admission, we started thiamazole therapy for Basedow disease, and her thyroid hormone levels normalized., Outcomes: Abdominal CT revealed disappearance of edematous wall thickening of the gallbladder, which was likely associated with an improvement in thyroid function. The patient was discharged 10 days after admission., Lessons: We encountered a case of hyperthyroidism and Basedow disease accompanied by edematous wall thickening of the gallbladder and various fluid retentions as the first symptoms. Such edematous wall thickening of the gallbladder and various fluid retentions were reduced, together with the improvement of hyperthyroidism., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Graves' disease, a typical metabolism disorder, causes diffuse goiter accompanied by ocular abnormalities and ocular dysfunction. Although methimazole (MI) is a commonly used drug for the treatment of GD, the efficacy of methimazole is only limited to the control of clinical indicators, and the side effects of MI should be seriously considered. Here, we designed a 6-month clinical trial that divided the patients into two groups: a methimazole group ( n =8) and a methimazole combined with potential prebiotic berberine group ( n =10). The effects of both treatments on thyroid function and treatment outcomes in patients with GD were assessed by thyroid index measurements and gut microbiota metagenomic sequencing. The results showed that the addition of berberine restored the patients' TSH and FT3 indices to normal levels, whereas MI alone restored only FT3. In addition, TRAb was closer to the healthy threshold at the end of treatment with the drug combination. MI alone failed to modulate the gut microbiota of the patients. However, the combination of berberine with methimazole significantly altered the microbiota structure of the patients, increasing the abundance of the beneficial bacteria Lactococcus lactis while decreasing the abundance of the pathogenic bacteria Enterobacter hormaechei and Chryseobacterium indologenes . Furthermore, further mechanistic exploration showed that the addition of berberine resulted in a significant upregulation of the synthesis of enterobactin, which may have increased iron functioning and thus restored thyroid function. In conclusion, methimazole combined with berberine has better efficacy in patients with GD, suggesting the potential benefit of berberine combined with methimazole in modulating the composition of intestinal microbes in the treatment of GD, providing new strong evidence for the effectiveness of combining Chinese and Western drugs from the perspective of modulating the intestinal microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Han, Cen, Ou, Pan, Zhang, Huo and Chen.)

To investigate the effects of levothyroxine combined with methimazole on the clinical efficacy of hyperthyroidism treatment. A total of 102 patients with hyperthyroidism admitted to our hospital from January 2018 to June 2020 were selected and randomly assigned into the combination group (levothyroxine combined with methimazole) and the control group (methimazole treatment alone). 3 months after treatment, the two groups were compared with regard to clinical efficacy, changes in ultrasound findings, the thyroid hormones, and serum indexes and the adverse reactions rate. The combination group (98.04%) outperformed the control group (86.27%) in total effective rate, and the overall efficacy garnered the similar result. After treatment, the combination group showed advantages in thyroid hormone level, serum index level, thyroid volume, superior thyroid artery diameter, and maximum blood flow rate when compared with those of the control group (P<0.05). As for the adverse reactions rate, the combination group was superior to the control group (3.92%vs15.69%) (P<0.05). Levothyroxine combined with methimazole promotes the clinical efficacy of hyperthyroidism treating, reduces thyroid volume and the diameter of superior thyroid artery, enhances the patient's thyroid function and serum index, with higher safety profile.

Background: Hyperthyroidism is related to vascular atherosclerosis. Propylthiouracil (PTU) and methimazole, other than their antithyroid effects, may have different mechanisms in preventing atherogenesis in Graves' disease., Objective: This study aimed to investigate the effect of antithyroid drugs on markers of vascular atherosclerosis in Graves' hyperthyroidism., Methods: This study was a single-blind, randomized clinical trial conducted on 36 patients with Graves' disease in Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from June 2019 until July 2020. Graves' disease was diagnosed from clinical manifestation of hyperthyroidism with diffuse goiter and then confirmed by thyroid stimulation hormone (TSH), free T4 (fT4), and TSH-receptor antibody (TRAb) measurements. Participants were randomly assigned to either a PTU or a methimazole treatment group and followed up for 3 months. Markers of vascular atherosclerosis were represented by adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin], carotid artery stiffness [pulse wave velocity (PWV)], and thickness [carotid intima media thickness (cIMT)]., Results: By the end of the study, 24 participants reached euthyroid condition (13 from the PTU group and 11 from the methimazole group). After 3 months of follow-up, in the PTU group, we noticed an improvement of ICAM-1 [pretreatment: 204.1 (61.3) vs. posttreatment: 141.6 (58.4) ng/ml; p = 0.001], VCAM-1 [837 (707-977) vs. 510 (402-630) ng/ml; p < 0.001] and E-selectin [32.1 (24.1-42.7) vs. 28.2 (21.6-36.8) ng/ml; p = 0.045] in the PTU group. In the methimazole group, only VCAM-1 improvement [725 (565-904) vs. 472 (367-590); p = 0.001] was observed. Meanwhile, we found no significant changes in PWV or cIMT in either group., Conclusion: Antithyroid treatment in Graves' disease leads to improvement in adhesion molecules, with a lesser effect on methimazole, whereas there were no significant changes in PWV or cIMT. PTU may have a better mechanism compared with methimazole in terms of improving adhesion molecules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wisnu, Alwi, Nafrialdi, Harimurti, Pemayun, Jusman, Santoso, Harahap, Suwarto and Subekti.)