Antithyroid Drug Treatment Research Articles

Maternal Graves Disease and Abnormal CYP2D6 Genotype with Fetal Hyperthyroidism

Fetal hyperthyroidism is a rare yet potentially fatal complication of past or present maternal Graves disease (GD). Our objective was to present a unique case of fetal hyperthyroidism in a mother with a prior history of GD and a cytochrome P450 2D6 (CYP2D6) polymorphism. The clinical course in addition to serial laboratory and imaging results are presented. These include thyroid-stimulating hormone, free thyroxine, and thyrotropin receptor antibody levels, as well as fetal ultrasound, doppler fetal heart rate, and cordocentesis testing. A 27-year-old with a history of GD previously treated with radioiodine and a known cytochrome P450 polymorphism was referred to an endocrinology clinic at 17 weeks gestation for evaluation and management of fetal thyrotoxicosis. Despite close follow-up with a multidisciplinary care team and an aggressive "block and replace" treatment approach, progressive disease resulted in intrauterine fetal demise at 28 weeks gestation. To our knowledge, this is the first published case report of fetal hyperthyroidism accompanied by a maternal CYP2D6 polymorphism. We hypothesize that the maternal CYP2D6 poor metabolizer phenotype prevents formation of antithyroid drug (ATD) metabolites and thus decreases the efficacy of ATD treatment. We suggest this as an area of future research.

Long-Term Antithyroid Treatment in Pediatric and Juvenile Graves’ Disease

Context: Thyroid hormones can affect the development and function of the central nervous system and various other organs. As such, the pathologic excess of these hormones, known as thyrotoxicosis, can be the source of significant damage during childhood and adolescence. The objective of this study was to review the management of Graves’ disease (GD) in the pediatric age group, especially concerning long-term antithyroid drug (ATD) treatment. Evidence Acquisition: A thorough search of literature published from 1980 to 2019 was performed in PubMed only for English language literature. The following key terms were used: “Graves’ disease, hyperthyroidism, thyrotoxicosis in children, thyrotoxicosis remission, thyrotoxicosis relapse, definite therapy, radioactive iodine, thyroidectomy, anti-thyroid drugs, propylthiouracil, methimazole, and carbimazole”. We also did a thorough search in review articles, observational studies, open-label/controlled randomized/non-randomized trials, and meta-analyses, as well as the articles cited by textbooks, chapters, and review articles, which led us to locate older sources of information on the topic. Results: More than 90% of thyrotoxicosis in the pediatric age group is attributable to GD. A host of strategies, including ATDs, radioiodine therapy, and surgery, are employed to treat this entity. However, there is still significant controversy regarding the most optimal strategy. Current evidence suggests that ATDs are the best initial treatment in pediatric patients with GD. Although ATDs are widely used, the duration of their administration is controversial and varies significantly between protocols. A major problem is the high relapse rate (up to 70%), but extending the duration of such treatment could potentially bring the remission rate up to 88%. Indications for using radioactive iodine treatment include the lack of remission following years of receiving ATDs, poor compliance, and the emergence of a major side effect. In pediatric patients aged five-years-old or younger who suffer from very large goiter, severe ophthalmopathy, and persistent hyperthyroidism, as well as those with the lack of response to or showing adverse effects of ATDs, it is advisable to consider total or near-total thyroidectomy. Conclusions: Antithyroid drugs are the mainstay of treatment of juvenile GD, and long-term methimazole therapy increases the remission rate in pediatric GD.

Long-Term Antithyroid Drug Treatment: Trends in Serum TSH and TSH Receptor Antibody Changes in Patients with Graves’ Disease

Objectives: Trends in serum thyroid-stimulating hormone (TSH) and TSH receptor antibody (TRAb) changes during antithyroid drug treatment, and long-term prognosis were evaluated in Graves’ hyperthyroidism (GD). Methods: In 609 GD patients initially treated with 15 mg of methyl-mercapto imidazole (MMI), the changes in serum TRAb and long-term prognosis were compared in the TSH-normalized group (A) and the TSH-suppressed group (B and C) during the initial 180 days of treatment. Results: Early responses to MMI during 180 days of treatment were as follows: 48 cases (7.9%) became hypothyroid with elevated TSH (A1), and 188 cases (30.9%) became euthyroid with normal TSH (A2). Among patients with continuously suppressed TSH, the free T4 (fT4) level was low in 31 cases (5.1%) (B1-inappropriately suppressed TSH), fT4 and fT3 were normal in 185 cases (30.4%) (B2), fT4 was normal, but fT3 remained high in 84 cases (13.8%) (B3), and fT4 remained high in 73 cases (12.0%) (C-refractory). Serum TRAb became negative after < 5 years then remained negative in 25% - 51% of the cases (smooth type), became negative after < 5 years then became positive again in 30% - 43% of the cases (fluctuating type), and remained positive after > 5 years in 10% - 42% of the cases (smoldering type). In total, remission occurred after 6.2 (3.0 - 10.4) years of treatment in 42%, possible remission on a small maintenance dosage of antithyroid drug occurred in 13%, and spontaneous hypothyroidism occurred in 4.4% of the cases. The smoldering type was more frequent in the B1 and C groups than in others, and remission was less frequent. The difference in the long-term prognosis depending on the early response to MMI disappeared after excluding the ablated patients. Without ablation, remission or spontaneous hypothyroidism could be expected in 60% - 75% of patients after tenacious treatment for > 10 years. Conclusions: Prolonged suppression of serum TSH may suggest active TRAb activity during treatment, and continuous TRAb positivity for more than 5 years suggests persistent GD activity.

Remission Rate of Graves' Disease and the Trend of Changes in Serum TSH Receptor Antibodies in Prolonged Antithyroid Drug Treatment

Context: Graves’ disease is an autoimmune disease caused by thyrotropin receptor antibodies (TRAb). These antibodies can be measured and used for the diagnosis, prediction of remission, and risk of Graves’ orbitopathy development. There are three treatments for Graves’ disease that have remained unchanged for the last 75 years: Antithyroid drugs, radioiodine, and surgery. Antithyroid drugs are the first treatment option worldwide and are usually used for 12 - 18 months. Recent reports suggest the use of antithyroid drugs for more than 18 months with better outcomes. This review focuses on two aspects of treatment with antithyroid drugs: The impact of using antithyroid drugs for more than 12 - 18 months on remission rates and the trend of TRAb during prolonged antithyroid drug treatment. Evidence Acquisition: A review was performed in Medline on the published work regarding the duration of ATD treatment and remission of Graves' disease and also ATD treatment and TRAb status during the 1990 - 2019 period. Results: Remission rates are variable (30% - 80%), and many clinical and genetic factors serve as predictors. The long-term use of antithyroid drugs appears to increase remission rates. TRAb values usually decline during ATD treatment, but the trend could occur in two ways: Becoming negative or showing a fluctuating pattern. However, approximately 10% of the patients will remain TRAb-positive after five years of treatment with antithyroid drugs. Conclusions: Antithyroid drugs can be used for long periods with an increase in remission rates, and a gradual decrease in TRAb levels, with the disappearance of TRAb in 90% of the patients after 60 months.

Long-Term Treatment with Antithyroid Drugs: Efficacy and Safety

Context: Medical therapy of hyperthyroidism has been the Astwood’s gift to medicine. However, controversy remains about its mechanisms of action, the ideal treatment duration, and its proper use in pregnancy. The concept that hyperthyroidism could be controlled ‘indefinitely’ with antithyroid drugs (ATDs) is also a topic of current debate. The purpose of this review was to highlight the pros and cons of long-term ATD therapy. Evidence Acquisition: PubMed, Scopus, Web of Science, and Google Scholar databases were searched for retrieving studies conducted on long-term treatment with ATDs up to Jan 2020. The final selection of the papers was made based on their relevancy with the safety and efficacy of long-term treatment with ATDs. Results: The main drawback of the ATD treatment is the high relapse rate after drug discontinuation. On the other hand, ATDs may have a favorable immunosuppressive effect, either primarily, in the diminution of thyroid-specific autoimmunity, or secondarily, as a result of controlling the hyperthyroid state, hence keeping patients in a euthyroid state for a prolonged period to diminish autoimmunity and hyperthyroid relapse. This often calls for long-term use of methimazole, but with the lowest possible dose to minimize the risk of side effects. Emerging evidence demonstrates that the long-term treatment with ATDs has relatively few adverse events, most of which arise within the starting months of treatment and in subjects on larger doses. Hence, once we have reached the end of a conventional course of ATD treatment (12 - 18 months), the hazard is eliminated, and adverse events are very rare to occur. Therefore, by continuing low-dose ATD, we could safely maintain the patient’s euthyroid status. Conclusions: Long-term ATD treatment is safe, especially at a low dose. It can be considered as the preferred treatment for selected hyperthyroid patients.

Pharmacodynamic Response to Anti-thyroid Drugs in Graves' Hyperthyroidism.

Objective: Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole.Design: Retrospective cohort study.Methods: Participants were patients (n = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD.Results: Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4*0.97–11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity.Conclusion: We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.

Long-Term Treatment of Hyperthyroidism with Antithyroid Drugs: 35 Years of Personal Clinical Experience.

Background: None of the current therapeutic approaches for management of Graves' disease has been able to re-establish normal thyroid function in all patients. Objective: To describe the author's 35 years of personal experience in the management of Graves' hyperthyroidism and, in doing so, review current articles published on the long-term medical treatment of hyperthyroidism. Methods: All published articles related to ≥4 years of continuous antithyroid drug (ATD) treatment were searched. Findings were added and compared with studies published by the authors on the same topic. Results: Long-term ATD treatment is effective and safe, both in children and adults, for treatment of hyperthyroidism. Treatment of Graves' patients with ATDs >60 months causes euthyroidism up to 4 years after discontinuation of ATDs in the majority of patients. Long-term ATD therapy is not inferior to radioiodine therapy and may sometimes even be superior in some aspects, when considering serum lipid profile, cardiac function, mood, and cognition. Conclusions: Long-term ATD therapy for Graves' hyperthyroidism is efficient and safe and induces control of hyperthyroidism, without rendering the patient hypothyroid in the majority of patients.

SAT-LB75 Thyroid Peroxidase Antibody Positivity Predicts Relapse Free Survival Following Anti-Thyroid Drug Treatment for Graves Disease

Objective: Graves disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRABs) are clearly pathogenic, but the role of thyroid-peroxidase antibodies (TPOAb) in Graves disease is unknown. Design: We retrospectively studied whether TPOAb positivity reduced risk of relapse following anti-thyroid drug treatment in newly diagnosed Graves disease. Results: During follow-up of 204 patients with TRAB positive Graves disease, 107 (52%) relapsed following withdrawal of anti-thyroid medication. Mean age was 40.0 years and 82% were female. The average duration of anti-thyroid drug (ATD) treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAb significantly increased risk of Graves relapse (OR 2.21) and displayed a trend towards shorter time to relapse. Male sex and younger age were additional factors significantly associated with increased risk of relapse. Conclusion: TPO-antibody positivity significantly improves odds of remission following ATD treatment in newly diagnosed Graves disease.

SAT-434 Phenotype and Genotype Analysis of Patients with Resistance to Thyroid Hormone β: A Single-Center Experience

Introduction Resistance to thyroid hormone β (RTHβ) is caused by mutations in THRB, the gene that encodes thyroid hormone receptor β. The clinical phenotype is variable and may include goiter, tachycardia, and learning disability with or without hyperactive behavior. The biochemical hallmark of RTHβ is elevated T4 and T3 with non-suppressed TSH concentrations. We here describe the phenotype and genotype of three Thai patients diagnosed with RTHβ in a pediatric referral center. Patients had previously been misdiagnosed and inappropriately treated with antithyroid drugs (ATDs). Methods Clinical features and thyroid function tests (TFTs) of three unrelated RTHβ patients were retrospectively reviewed. Genomic DNA of the RTHβ patients and affected family members was amplified for exon 7-10 of the THRB gene and sequenced to identify mutation by Sanger sequencing. The impact of the p.L341V novel mutation on the affinity for T3 and T3-induced transcriptional activity was previously determined in vitro. Results Three female patients were diagnosed with RTHβ. All of them had been misdiagnosed with hyperthyroidism and treated with ATDs prior to referral. The mean age at diagnosis was 8 years. The main presenting symptoms were diffuse goiter and tachycardia. The mean duration of ATD treatment was 3 years. During the treatment, patients had fluctuating thyroid hormone and increased TSH levels. An older sister and mother of one patient also had similar TFTs abnormalities, for which the mother had undergone a subtotal thyroidectomy. RTHβ was diagnosed based on the high FT3 and FT4 with normal (non-suppressed) TSH concentrations and confirmed by mutation analysis. Anti-thyroid peroxidase, anti-thyroglobulin, and TSH receptor antibody (TRAb) were negative, excluding autoimmune thyroid disease. Heterozygous missense mutations of the THRB gene were identified in all patients and affected family members. Two mutations had been previously reported (p.R243W and p.L456F), and one mutation was novel (p.L341V). In vitro studies confirmed an important role of Leu341 in T3 binding of the TRβ and functional impairment of the p.L341V novel mutation and were reported separately. According to available literature, only nine Thai RTHβ patients (in three families) carrying three different mutations (p.G251V, p.M313T, and p.A317T) had been previously reported. Goiter was the most common clinical finding, and almost all patients had a history of receiving unnecessary treatment with ATDs. Conclusion We report a series of RTHβ patients carrying THRB gene mutations, including one novel mutation (p.L341V). Clinicians should be alert that RTHβ can be found in patients with goiter and tachycardia. Elevated T4 and T3 with non-suppressed TSH concentration is the main diagnostic clue for this disease. Mutation analysis allows definitive diagnosis of RTHβ and may help to avoid potential misdiagnosis and improper treatment.

Patterns of Use, Efficacy, and Safety of Treatment Options for Patients with Graves' Disease: A Nationwide Population-Based Study.

Background: Considerable uncertainty remains about the pattern of use of treatment options for Graves' disease (GD) and their comparative effectiveness and safety. Methods: Between 2005 and 2013, we identified patients with GD who received antithyroid drugs (ATDs), radioactive iodine (RAI) or surgery, and were represented in a large administrative data set in the United States (OptumLabs® Data Warehouse). Results: We identified 4661 patients with GD: mean age 48 (SD ±14) years, white (63%), and female (80%). Patients received ATD, n = 2817 (60%), RAI, n = 1549 (33%), or surgery, n = 295 (6%). Success rates were 50% for ATD, 93% for RAI, and 99% for surgery. Median time to treatment failure was 6.8 months for ATD and 3 months for RAI and surgery. When patients were required to be on ATD for at least one year before assessing failure, the failure rate decreased to 25%. Adverse effects occurred in 12% of patients receiving ATD, 6% with RAI, and 24% with surgery. Factors associated with treatment success were age >55 years (for ATD) and female sex (for RAI). About 12% of patients receiving ATD continued this treatment for >24 months as initial therapy. When patients failed ATD therapy, the most common second-line therapy was reinitiation of ATD (65%), RAI (26%), and surgery (9%). Overall, 26% of patients remain on ATD therapy (combined first or second line). Conclusions: ATD therapy was the most common GD therapy and demonstrated the lowest efficacy and infrequent significant adverse effect profile. With one fourth of patients remaining on ATD treatment (initial or second modality treatment), it becomes imperative to determine the long-term efficacy, safety, costs, and burdens of this modality of treatment.

Long-term outcomes of graves disease in children treated with anti-thyroid drugs

Graves disease (GD) is the most common cause of thyrotoxicosis in children and adolescents, accounting for 15% of all thyroid diseases during childhood. Anti-thyroid drugs (ATD) are recommended as the first-line treatment in children and adolescents. However, the remission rate is lower in children than in adults, and the optimal treatment duration and favorable factors associated with remission remain unknown. We aimed to investigate long-term outcomes of pediatric GD patients receiving ATD. We retrospectively reviewed medical charts of 396 GD subjects from 1985 to 2017at MacKay Children's Hospital. Ninety-six patients were excluded from the analyses, including 71 patients followed for less than one year, 6 patients who received radioactive therapy and 19 patients who received surgery. The remaining 300 patients initially treated with ATD and followed up for more than 1 year constituted our study population. The 300 patients comprised 257 (85.7%) females and 43 (14.3%) males. Their median age at diagnosis was 11.6 (range 2.7-17.8) years with 11 patients (3.7%) younger than 5 years. Their median follow-up period was 4.7 (range 1.1-23.9) years. Overall, 122 patients achieved the criteria for discontinuing ATD treatment, and seventy-nine (39.9%) patients achieved remission, with a median follow-up period of 5.3 (range 1.5-20.1) years. Patients in the remission group were more likely to be aged <5 years (remission vs. relapse vs. ongoing ATD; 11.4 vs. 0 vs. 2.6%, P=0.02), less likely to have a family history of thyroid disease (24.1 vs. 42.1 vs. 52.6%, P=0.001), and had lower TSH receptor antibody (TRAb) levels (42.8 vs. 53.6 vs. 65.1%, P=0.02) at the time of diagnosis. Long-term ATD remains an effective treatment option for GD in children. Pediatric GD patients aged <5 years, having no family history of thyroid disease and having initial lower TRAb levels were more likely to achieve remission.

Inhibition of thyroid hormone signaling protects retinal pigment epithelium and photoreceptors from cell death in a mouse model of age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Dry AMD is characterized by a progressive macular degeneration of the retinal pigment epithelium (RPE) and photoreceptors, and the RPE oxidative damage/dystrophy is at the core of the disease. Recent population/patients-based studies have shown an association of high free serum thyroid hormone (TH) levels with increased risk of AMD. This work investigated the effects of TH signaling inhibition on RPE and photoreceptor damage/cell death in an oxidative stress-induced mouse model of AMD. TH signaling inhibition was achieved by anti-thyroid drug treatment and oxidative stress was induced by sodium iodate (NaIO3) administration. Mice treated with NaIO3 showed severe RPE and photoreceptor cell death/necroptosis, destruction, oxidative damage, retinal stress, and reduced retinal function. Treatment with anti-thyroid drug protected RPE and photoreceptors from damage/cell death induced by NaIO3, reduced oxidative damage of RPE and photoreceptors, and preserved retinal function. Gene expression analysis showed that the NaIO3-induced RPE/photoreceptor damage/cell death involves multiple mechanisms, including cellular oxidative stress responses, activation of necroptosis/apoptosis signaling, and inflammatory responses. Treatment with anti-thyroid drug abolished these cellular stress/death responses. The findings of this study demonstrate a role of TH signaling in RPE and photoreceptor cell death after oxidative stress challenge, and support a role of TH signaling in the pathogenesis of AMD.

Treatment of juvenile thyrotoxicosis: A review with emphasis on radioiodine treatment

Objective: The aim of the present study was to evaluate the utility of radioiodine treatment for thyrotoxicosis in childhood and adolescence and to evaluate its outcomes. Methods: This was a retrospective monocentric study of 15 patients (ages 7- 18 years) with a diagnosis of thyrotoxicosis who received iodine-131 (I-131) treatment from January 2015 to July 2019 in the Nuclear Medicine department of King Fahd Medical city. Age, gender, duration of antithyroid drug (ATD) treatment, thyroid uptake, total dose and number of treatments with I-131, and thyroid status at 6 months after treatment were recorded. Results: The outcomes of 15 patients (100% female) treated with radioactive iodine were analyzed to assess the effectiveness of therapy by iodine 131. All children and adolescents underwent 99m technetium thyroid scan with uptake before the procedure. There was no pre-existing ophthalmopathy. Thyroid uptake value was calculated using Sodium Pertechnetate. The average of the treatment activity of iodine 131was 340.4 MBq (247.9-555). There was no vomiting in all cases. Six 6 months after treatment, 7/15 were euthyroid, and 8/15 were hypothyroid. There was no hyperthyroid. All the patients received single radioiodine treatment. Conclusions: Radioiodine treatment is safe and effective for thyrotoxicosis in childhood and adolescence. The results of this present study support the use of radio dine 131 in treating hyperthyroidism in this particular population. It is suitable as a good Second-line therapy for patients who fail to respond to ATD treatment. Although special treatment precautions may be required in this age group, the ease of administration, effectiveness and safety of radio dine 131 continue to make it more and more attractive for initial treatmentof hyperthyroidism, especially when the appropriate treatment activity is prescribed.

Evolution of Graves’s Disease: Impact of Socio-Demographic and Clinical Factors in Senegalese Subject

Background: In Graves’s disease, there is a lack of description specific to the gender and age among sub-Saharan African subject. The objective was to evaluate the impact of gender and age on the profile of Graves’ disease in Senegalese subject in order to understand the evolution and improve the therapeutic choices. Methods: This is a retrospective study conducted from January 1, 2010 to December 31, 2017 (07 years) at Abass Ndao University Hospital (Senegal), focused on patients with Graves’ disease followed up under antithyroid drugs treatment for at least 18 months. Results: There were 244 men, 404 subjects between [0 - 25 years], and 101 subjects more than 50 years old. Factors associated with goitre size were male gender (p < 0.001), young age (p < 0.001). Graves orbitopathy was correlated with male gender (p = 0.015), and young age (p < 0.001). Among 580 patients who had stopped medical treatment after more than 18 months of follow-up, relapse involved in 30.3%. Durable remission was achieved in 38.8% of all included patients and 69.7% of subjects who had a cessation of medical treatment. The factors associated with sustained remission were female gender (p = 0.049), absence of orbitopathy (p = 0.011), small goiter (p < 0.001), advanced age (p = 0.006) and early start of the maintenance treatment (p = 0.006). Conclusion: In our Senegalese study, men and young patients are particularized by a trend of voluminous goitre and low rate of remission. These data remain a basis for predicting the outcome of medical treatment and make timely use of radical treatments such as surgery or irratherapy in the presence of risk factors for recurrence.

Advances in research on anti-thyroid drugs for recurrence risk factors and predictive models of Graves′ disease

Graves′ disease, also known as diffuse toxic goiter, is an autoimmune disease with increased secretion of thyroid hormone. There are three effective treatments for Graves′ disease, which including anti-thyroid drugs (ATD), radioactive iodine and thyroidectomy. In general, ATD is the first choice of Graves′ disease treatment for domestic physicians, but the high recurrence rate has always been the deficiency of ATD treatment. Recurrence is mainly related to gender, age, smoking, course of disease, goiter and other factors. Among them, the reliability and applicability of single risk factor in evaluating the recurrence rate of Graves′ disease after ATD treatment are poor. The prediction model of multi-factor comprehensive score is helpful for the naive patients to choose the best treatment plan, to achieve the goal of precise treatment and to improve the remission rate of Graves′ disease drug treatment. In this paper, the reliability of risk factors for Graves′ disease recurrence after ATD treatment is evaluated, and the development and application of prediction models such as Graves′ recurrent events after therapy (GREAT) score, GREAT + score, and clinical severity score (CSS) are reviewed. Key words: Anti-thyroid drugs; Recurrence of Graves′ disease; Risk factor; Predictive model

Increased Remission Rates After Long-Term Methimazole Therapy in Patients with Graves' Disease: Results of a Randomized Clinical Trial.

Background: Studies differ regarding whether, compared with courses of conventional duration, longer-term antithyroid drug treatment increases frequency of remission in patients with Graves' hyperthyroidism. We prospectively conducted a randomized, parallel-group study comparing relapse rates in patients receiving longer-term versus conventional-length methimazole therapy. We also sought variables associated with relapse following the latter. Methods: We enrolled 302 consecutive patients with untreated first episodes of Graves' hyperthyroidism. After 18-24 months of methimazole, 258 patients (85.4%) were randomized to an additional 36-102-month courses ("long-term group": n = 130; scheduled total time on methimazole: 60-120 months) or discontinuation of methimazole ("conventional group": n = 128). Patients were followed 48 months postmethimazole cessation. We performed Cox proportional hazards modeling to identify factors associated with relapse after conventional courses. Results: Methimazole was given for 95 ± 22 months in long-term patients and 19 ± 3 months in the conventional group. Fourteen patients experienced cutaneous reactions and 2 liver enzyme elevations during the first 18 months of treatment; no further methimazole-related reactions were observed despite therapy for up to another 118 months. Hyperthyroidism recurred within 48 months postmethimazole withdrawal in 15% (18/119) of long-term patients versus 53% (65/123) of conventional group patients. In the conventional group, older age, higher triiodothyronine or thyrotropin receptor antibody concentrations, lower thyrotropin concentration, or possession of the rs1879877 CD28 polymorphism or the DQB1-05 HLA polymorphism were independently associated with relapse. Conclusion: Administration of low-dose methimazole for a total of 60-120 months safely and effectively treats Graves' hyperthyroidism, with much higher remission rates than those attained by using conventional 18-24-month courses.

Graves’ disease

Graves' disease develops when pathogenic thyroid receptor antibodies stimulate the thyroid gland resulting in excessive thyroid hormone production. Children and adolescents with Graves' disease can present in a variety of ways to many different clinical teams with a diverse range of underlying symptoms and signs. Graves' disease is usually managed initially with the anti-thyroid drug (ATD) carbimazole. However, only 20–25 % of young patients remit (remaining euthyroid when the ATD is stopped in the longer term) after a 2 year course of ATD treatment. Some families or patients who relapse then opt for surgery (total thyroidectomy) or radioiodine (RI) rather than returning to ATD. Unfortunately the young person then requires life-long thyroid hormone replacement. This is not an ideal outcome and new therapeutic approaches are needed if patients with Graves’ are to spend their adult lives free of daily medication with ATD or thyroxine replacement. This article discusses the known science and offers advice for diagnosis and treatment options.

Changes of sex hormones and sex hormone-binding globulin levels in male adults with hyperthyroidism before and after antithyroid drug treatment

Objective: To observe the changes of sex hormone and sex hormone-binding globulin (SHBG) levels in young male patients with hyperthyroidism before and after antithyroid drug (ATD) treatment. Methods: Between January 2015 and July 2016, forty male patients with hyperthyroidism aged 19-52 years (with an median age of 33.1 years) were enrolled in the Department of Endocrinology of Peking Union Medical College Hospital. Blood samples were taken before treatment and at 1 month, 2 months, 3 months and 5 months after treatment to evaluate thyroid function, follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone(T), free testosterone(FT), estradiol(E2), prolactin and SHBG. Results: A total of 40 patients were enrolled but only 35 patients completed the follow-up. The patients had high levels of thyroid function, SHBG and sex hormones before treatment. Before treatment, free thyroxine (FT(4)), free triiodothyronine (FT(3)), SHBG, LH, estradiol, testosterone and free testosterone was (0.30±0.12) pmol/L, (9.68±4.73) pmol/L, (146±111) nmol/L, (8.41±3.61) U/L, (19.9±7.7) pmol/L, (29.9±9.5) nmol/L and (0.24±0.08) nmol/L, respectively. After treatment, the level of triiodothyronine, thyroxine, FT(3) and FT(4) gradually decreased to normal (all P<0.001). Thyroid stimulating hormone (TSH) gradually increased to normal (P<0.001). LH and estradiol levels gradually decreased (all P<0.001). FSH decreased but the difference was not statistically significant. Prolactin did not change significantly. Testosterone and SHBG levels decreased significantly while the levels of free testosterone, free testosterone percentage (FT%), bio-available testosterone (BAT), bio-available testosterone percentage (BAT%), free androgen index (FAI) gradually increased and stabilized (all P<0.001). The difference was not statistically significant between T/LH and E2/LH before and after treatment (all P>0.05). However FT/LH gradually increased and its difference was statistically significant (P<0.001). Conclusion: The levels of LH, estradiol, testosterone and SHBG in male patients with hyperthyroidism significantly increased, while the free testosterone level decreased, but they all gradually returned to normal with the lowering of thyroid hormone levels during ATD treatment.

Hyperthyroidism in the personalized medicine era: the rise of mathematical optimization.

Thyroid over-activity or hyperthyroidism constitutes a significant morbidity afflicting the world. The current medical practice of dose titration of anti-thyroid drug (ATD) treatment for hyperthyroidism is relatively archaic, being based on arbitrary and time-consuming trending of thyroid function that requires multiple clinic monitoring visits before an optimal dose is found. This prompts a re-examination into more deterministic and efficient treatment approaches in the present personalized medicine era. Our research project seeks to develop a personalized medicine model that facilitates optimal drug dosing via the titration regimen. We analysed 49 patients' data consisting of drug dosage, time period and serum free thyroxine (FT4). Ordinary differential equation modelling was applied to describe the dynamic behaviour of FT4 concentration. With each patient's data, an optimization model was developed to determine parameters of synthesis rate, decay rate and IC50. We derived the closed-form time- and dose-dependent solution which allowed explicit estimates of personalized predicted FT4. Our equation system involving time, drug dosage and FT4 can be solved for any variable provided the values of the other two are known. Compared against actual FT4 data within a tolerance, we demonstrated the feasibility of predicting the FT4 subsequent to any prescribed dose of ATD with favourable accuracy using the initial three to five patient-visits' data respectively. This proposed mathematical model may assist clinicians in rapid determination of optimal ATD doses within allowable prescription limits to achieve any desired FT4 within a specified treatment period to accelerate the attainment of euthyroid targets.

Long-Term Antithyroid Drug Treatment of Patients With Graves’ Disease

Long-Term Antithyroid Drug Treatment of Patients With Graves’ Disease