Dynamic Risk Model for the Medical Treatment of Graves' Hyperthyroidism according to Treatment Duration.

Background: Changes in thyrotropin receptor antibody (TRAb) levels are associated with the clinical outcomes of Graves' hyperthyroidism. However, the effects of the patterns of TRAb changes on patient prognosis according to the treatment duration of antithyroid drugs (ATDs) are not well established. Methods: In this retrospective cohort study, 1,235 patients with Graves' hyperthyroidism who were treated with ATDs for more than 12 months were included. Patients were divided into two groups according to treatment duration: group 1 (12-24 months) and group 2 (>24 months). Risk prediction models comprising age, sex, and either TRAb levels at ATD withdrawal (model A) or patterns of TRAb changes (model B) were compared. Results: The median treatment duration in groups 1 (n=667, 54%) and 2 (n=568, 46%) was 17.3 and 37.1 months, respectively. The recurrence rate was significantly higher in group 2 (47.9%) than in group 1 (41.4%, P=0.025). Group 2 had significantly more goiter, thyroid eye disease, and fluctuating and smoldering type of TRAb pattern compared with group 1 (all P<0.001). The patterns of TRAb changes were an independent risk factor for recurrence after adjusting for other confounding factors in all patients, except in group 1. Integrated discrimination improvement and net reclassification improvement analyses showed that model B performed better than model A in all patients, except in group 1. Conclusion: The dynamic risk model, including the patterns of TRAb changes, was more suitable for predicting prognosis in patients with Graves' hyperthyroidism who underwent longer ATD treatment duration.

Neutropenia Occurs More Often Under Carbimazole than Under Methimazole Treatment in Pediatric Graves' Disease Patients.

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.

Hypothyroidism After Use of Immune Checkpoint Inhibitor Therapy in Patient With Graves' Disease: Cure?

Immune checkpoint inhibitors (ICIs) are frequently used as treatment for many malignancies. Immune-related adverse events (irAEs) due to use of ICIs are common. Thyroid involvement is the most common endocrine irAE. Here, we present an unusual case of Graves' disease potentially cured due to destructive thyroiditis caused by inflammation due to ICIs. Thyroid irAEs are more common with programmed cell death protein-1 (PD-1) inhibitor or programmed cell death-ligand 1 (PD-L1) inhibitors than cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Baseline and serial monitoring of thyroid function tests is recommended.

Effect of iodine nutritional status on the recurrence of hyperthyroidism and antithyroid drug efficacy in adult patients with Graves' disease: a systemic review.

Aim: To probe the appropriate iodine nutritional status for patients with Graves'disease (GD) hyperthyroidism and on antithyroid drugs (ATD) or after drugwithdrawal. Method: Studies were retrieved from three databases (Embase, Medline, and Cochrane Library) and were screened and evaluated using predefined criteria. The risk of bias of each trial was assessed using a tool from Cochrane. The iodine nutritional status of the subjects was redefined according to the World Health Organization (WHO) criteria and classified as insufficient/adequate/above requirements/excessive iodine intake. Result: Two randomized controlled trials (RCTs) and 3 observational studies were selected from the 376 retrieved papers, which had different degrees of risk of bias in study design. The heterogeneity among them prevented us from further synthesizing effect indicators and subsequent statistical analyses. Two RCTs with high quality showed that insufficient or above requirements iodine intake was detrimental for ATD-treated GD patients; adequate iodine intake was associated with a lower risk of recurrence and better efficacy in controlling thyrotoxicosis. It could be speculated from three low-quality observational studies that excessive iodine intake may be associated with higher (or similar) recurrence rates and lower remission rates compared to above requirements iodine intake in these patients, but none of them could answer the question of the effect of insufficient or adequate iodine intake on this issue. Conclusion: Although the available evidence is suboptimal, this systematic review tentatively suggests that in adult patients with GD hyperthyroidism receiving ATDs and according to WHO criteria for iodine nutritional status, adequate iodine intake is associated with a lower recurrence rate, a higher remission rate and a better efficacy to control thyrotoxicosis than insufficient, above requirement, or excessive iodine intake. Future RCTs with large samples are expected to elucidate the actual impact of different iodine nutritional statuses on the recurrence rate of hyperthyroidism and the efficacy of ATD to control thyrotoxicosis in these patients. Systematic review registration: identifier CRD42022359451.

Therapeutic Management and Long-Term Outcome of Hyperthyroidism in Patients with Antithyroid-Induced Agranulocytosis: A Retrospective, Multicenter Study.

BACKGROUND: Antithyroid drug-induced agranulocytosis (AIA) (neutrophils <500/µL) is a rare but serious complication in the treatment of hyperthyroidism. METHODOLOGY: Adult patients with AIA who were followed up at 12 hospitals in Spain were retrospectively studied. A total of 29 patients were studied. The etiology of hyperthyroidism was distributed as follows: Graves' disease (n = 21), amiodarone-induced thyrotoxicosis (n = 7), and hyperfunctioning multinodular goiter (n = 1). Twenty-one patients were treated with methimazole, as well as six patients with carbimazole and two patients with propylthiouracil. RESULTS: The median (IQR) time to development of agranulocytosis was 6.0 (4.0-11.5) weeks. The most common presenting sign was fever accompanied by odynophagia. All of the patients required admission, reverse isolation, and broad-spectrum antibiotics; moreover, G-CSF was administered to 26 patients (89.7%). Twenty-one patients received definitive treatment, thirteen patients received surgery, nine patients received radioiodine, and one of the patients required both treatments. Spontaneous normalization of thyroid hormone values occurred in six patients (four patients with amiodarone-induced thyrotoxicosis and two patients with Graves' disease), and two patients died of septic shock secondary to AIA. CONCLUSIONS: AIA is a potentially lethal complication that usually appears around 6 weeks after the initiation of antithyroid therapy. Multiple drugs are required to control hyperthyroidism before definitive treatment; additionally, in a significant percentage of patients (mainly in those treated with amiodarone), hyperthyroidism resolved spontaneously.

The Clinical Implications of Anti-thyroid Peroxidase Antibodies in Graves' Disease in Basrah.

Background Graves' disease (GD) is an autoimmune disease, with thyrotropin receptor antibodies (TRAbs) being the most important cause in the pathogenesis. The aim of this study is to assess the clinical significance of anti-TPO Abs in GD. Methods A retrospective study was conducted at the Faiha specialized Diabetes, Endocrine, and Metabolism Center (FDEMC) in Basrah during the period between December 2021 and December 2022. A total of 141 patients with GD were involved in this study, and of them, 97 (68.8%) were women. They were divided into two groups: patients with positive and negative anti-TPO Abs groups. Results Positive anti-TPO Abs were seen in 83 patients (58.9%) with GD. Pretreatment-free thyroxine level (ng/dL) was higher in the anti-TPO Abs positive GD patients than in those with negative antibodies (3.7±0.2 versus 3.0±0.2 with a p=0.021). Similarly, higher TRAb titers (IU/ml) at baseline were also seen in patients with positive anti-TPO Abs (9.8±0.7 versus 6.8±0.8) with a p=0.008. Giraffe appearance on thyroid ultrasound was more common in the group with positive anti-TPO Abs as compared to patients with negative anti-TPO Abs: 20 (87.0%) versus 3 (13.0%) with a p=0.005. A higher anti-TPO Abs titer (IU/mL) was associated with a baseline TRAb level of more than 6.4 IU/mL, and giraffe appearance on thyroid ultrasound (206.5±20.0 p-value<0.0001 and 228.0±35.3 p value=0.007, respectively). Conclusion A positive anti-TPO Abs in GD is associated with a high TRAb titer and free T4 level at baseline, as well as a giraffe appearance on thyroid ultrasound.

Sepsis-induced Pancytopenia in an Adolescent Girl with Thyroid Storm: A Case Report.

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 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 complete blood count 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.

Clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years.

Objective: The authors aimed to investigate the clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years. Methods: The data of patients with antithyroid drug-induced aplastic anemia were retrieved from PubMed and Wanfang Medical Network databases from 1992 to August 2022. The clinical characteristics, such as age distribution, gender tendency, common symptoms, blood cell count, bone marrow features, treatment strategy, and prognosis, were analyzed. Results: A total of 17 cases (male:female = 1:16) had been retrieved. Patients' age ranged from 16 to 74 years (median 50 years). Among them, 82.3% (14/17) of the patients were administered methimazole (MMI), and 78.6% of them had MMI ≥30 mg/day. In addition, 88.2% (15/17) of the patients had sore throat and fever, and 47.1% (8/17) of the patients had hemorrhagic symptoms. Aplastic anemia occurred within 6 months after initiation of the antithyroid therapy in 94.1% of the patients. Agranulocytosis (94.1%) was the most common and earliest blood cell change, and 47.1% of the patients experienced progressive platelet decline during the treatment process. The treatments include timely withdrawal of antithyroid drugs, broad-spectrum antibiotics, granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF), glucocorticoids and other immunosuppressive agents, and supportive treatments such as erythrocyte transfusion and platelet transfusion. Moreover, 70.6% of the patients had complete or near-complete remission within 8 days to 6 weeks. Conclusion: Aplastic anemia is a rare and serious adverse reaction of antithyroid drugs, which is more common in women. It usually occurs during early treatment with high-dose antithyroid drugs. Most patients have a good prognosis after timely drug ceasing and appropriate treatment.

Long-term follow-up result of antithyroid drug treatment of Graves' hyperthyroidism in a large cohort.

Objective: This study evaluated the efficacy of antithyroid drugs (ATDs) and risk factors associated with the recurrence of Graves' hyperthyroidism using a comprehensive retrospective cohort. Methods: We included 1829 patients newly diagnosed with Graves' hyperthyroidism, with sufficient follow-up data. Clinical outcomes of the patients and risk factors associated with recurrence-free survival, including the changes in thyrotropin receptor antibody, were evaluated. Results: The median age of the patients was 44.5 years, and 69% were female. Among the patients, 1235 had a chance to withdraw ATD after a median of 23 (interquartile range (IQR) 17.0-35.5) months of treatment. The first remission rate was 55.6% during a median of 72.7 months of follow-up. After the first recurrence, 95% of patients underwent the second course of ATD treatment for a median of 21.1 (IQR 14.8-31.7) months, and the remission rate was 54.1%. During a median of 67 months of follow-up, 7.7% of patients underwent surgery, and 10.5% underwent radioactive iodine therapy. Approximately 30% were still on ATD therapy for recurrent disease or prolonged low-dose maintenance. Younger age (<45 years), male sex, and fluctuating or smoldering of TRAb levels were independent risk factors of the first recurrence after ATD treatment. Conclusions: ATD treatment is an acceptable option for the initial treatment of Graves' hyperthyroidism as well as for recurrent disease. The optimal treatment period for ATD treatment needs to be determined using the individual risk factors of recurrence.

Approach to the Patient With a Suppressed TSH.

Subclinical hyperthyroidism (SCH) is a laboratory diagnosis defined by a serum thyrotropin (TSH) concentration below the reference range (< 0.4 mU/L in most assays), and a free thyroxine (FT4) and 3,5,3'-triiodothyronine levels (FT3) in the reference range. Many patients diagnosed with SCH will be clinically euthyroid while others may present with manifestations characteristic of thyroid hormone excess, such as tachycardia, tremor, intolerance to heat, bone density loss, or weight loss. In addition to the laboratory abnormalities, patient factors such as age, symptoms, and underlying heart and bone disease are used to stratify patients for the risk of adverse outcomes and determine the appropriate treatment. Evaluation should include repeat thyroid function tests to document persistent TSH suppression, investigation of the underlying cause, as well as evaluation of the patient's risk of adverse outcomes in the setting of a subnormal TSH. Persistent SCH has been associated with an increased risk of a range of adverse events, including cardiovascular events such as atrial fibrillation and heart failure, bone loss and fracture, and in some studies, cognitive decline. Despite the consistent association of these adverse events with SCH, prospective studies showing improved outcomes with treatment remain limited. Management options include observation without active therapy, radioactive iodine ablation of the thyroid, antithyroid medication, thyroid surgery, or radiofrequency ablation, as appropriate for the patient and clinical setting. The choice of therapy should be guided by the underlying etiology of disease, patient factors, and the risks and benefits of each treatment option.

Painless thyroiditis mimicking relapse of hyperthyroidism during or after potassium iodide or thionamide therapy for Graves' disease resulting in remission.

The diagnosis of painless thyroiditis (PT) during antithyroid drug (ATD) treatment of Graves' disease (GD) is difficult. We evaluated the thyroidal radioactive iodine uptake (RAIU) in 100 patients with relapsed thyrotoxicosis during or after careful ATD treatment. The RAIU was <5%/5 h in 35 patients (35%) (Group A - PT), 5%-15%/5 h in 6 patients (6%) (Group B - indefinite) and >15%/5 h in 59 patients (59%) (Group C - relapsed GD [rGD]). TSH receptor antibody (TBII) was positive in 4 (11.4%), 3 (50.0%) and 39 (only 66.1%) patients in Groups A, B and C, respectively. In Group A, the serum fT4 level spontaneously normalized after 35 (26-56) days, sometimes followed by transient hypothyroidism, confirming the diagnosis of PT. Nineteen (54.3%) had been treated with potassium iodide, and PT frequently occurred ironically when the ATD dosage was reduced. PT repeatedly occurred in nine patients. All went into remission smoothly or developed hypothyroidism, except one patient with strongly positive TBII who developed rGD after the resolution of PT (PT on GD). In 10 (50%) of 20 patients with negative TBII despite rGD in Group C, TBII became positive afterwards. In conclusion, it is important to recognize that PT can occur in the clinical course of GD, resulting in frequent remission despite relapse of PT. The thyroid function reflects the balance between the stimulating TBII activity and the responsiveness of the thyroid tissue (sometimes unresponsive and other times autostimulated). The RAIU is still a valuable tool in cases of ambiguous thyrotoxicosis.

The relationship between atherosclerotic disease and relapse during ATD treatment.

Background: Clinical relapse is a potential risk for traditional antithyroid drug (ATD) treatment in hyperthyroid patients. Evidence suggests that atherosclerotic disease is closely associated with hyperthyroidism, while the relationship between atherosclerosis and relapse remains unclear. Methods: Two hundred and twenty-five patients with GD who underwent ATD as their first treatment were studied; 88 and 137 patients were categorized as drug reduction relapse and drug reduction remission, respectively. Logistic regression was used to analyze risk factors of drug reduction relapse in patients with GD. Results: During a median of 48 months followed up 88 patients who relapsed. According to multivariate analyses, atherosclerosis related diseases, FT4, goiter, and anxiety rating scores are independent risk factors for drug reduction. According to K-M survival analysis, patients with atherosclerosis related diseases, FT4 > 18.82 pmol/L, anxiety rating scores > 23, and gradation of goiter ≥ Grade II had a higher risk of relapse than those with lower levels. ROC analysis shown atherosclerosis related diseases significantly improved the predictive accuracy of relapse. Conclusions: Atherosclerotic disease is closely related to the relapse of hyperthyroidism, ATD treatment in hyperthyroid patients with atherosclerosis should be given more attention.

Outcomes of Early-Pregnancy Antithyroid Drug Withdrawal in Graves' Disease: A Preliminary Prospective Follow-Up Study.

Objective: The use of antithyroid drugs (ATDs) carries potential risk for teratogenic effects. For women with well-controlled hyperthyroidism on a low dose of ATDs, drug withdrawal upon pregnancy is recommended by international medical guidelines. Therefore, it is necessary to determine the characteristics of patients suitable for ATD withdrawal, subsequent changes in thyroid function after ATD discontinuation, and its impact on pregnancy and offspring outcomes. Methods: This prospective study recruited 63 pregnant women with well-controlled Graves' hyperthyroidism who had stopped ATDs during early pregnancy. Patients were followed up until the end of pregnancy and data on pregnancy outcomes were collected. Results: Overall, 20 patients (31.7%) had rebound of hyperthyroidism. Patients with either subnormal thyrotropin (TSH) levels (TSH <0.35 mIU/L, odds ratio [OR] = 5.12, confidence interval [CI = 1.29-20.34], p = 0.03) or positive thyrotropin receptor antibody (TRAb) (TRAb >1.75 IU/L, OR = 3.79, [CI = 1.17-12.30], p = 0.02) at the time of ATDs withdrawal presented a higher risk of rebound than those with either normal TSH levels or negative TRAb. Patients with both subnormal TSH and positive TRAb at the time of ATD withdrawal were more likely to experience rebound (83.3%, 5/6) than those with both normal TSH and negative TRAb (13%, 3/23, OR = 33.33, [CI = 2.83-392.60], p = 0.003). The prevalence of adverse pregnancy outcomes was significantly higher in patients who experienced rebound compared with those who did not (55.0% vs. 9.3%, OR = 11.92, [CI = 3.08-46.18], p = 0.0002). Conclusions: Subnormal TSH levels and TRAb positivity at the time of ATD withdrawal in early pregnancy may be associated with rebound of Graves' hyperthyroidism. Rebound of hyperthyroidism during pregnancy may increase the risk of adverse pregnancy outcomes. Larger prospective studies are needed to confirm these findings.

A hypothyroid mother after subtotal thyroidectomy delivered a newborn with hyperthyroidism from fetal stage: a case report.

BACKGROUND: Neonatal hyperthyroidism is an extension of fetal disease. Most cases of neonatal hyperthyroidism are transient but may excessively harm multiple organ functions through the actions of maternal thyroid-stimulating hormone receptor antibodies on the neonatal thyroid gland. CASE PRESENTATION: The hyperthyroid mother underwent subtotal thyroidectomy before pregnancy and regularly took levothyroxine to avoid hypothyroidism, but still had a high-level thyroid-stimulating hormone receptor antibody (TRAb). The neonate suffered from hyperthyroidism due to the transplacental TRAb. After a regular medication schedule of an antithyroid drug, combined with a ß-blocker to control the ventricular rate, the infant gradually recovered, allowing normal motor and intellectual development. CONCLUSIONS: Maternal subtotal thyroidectomy cannot prevent the secretion of thyroid receptor antibodies, which may cause either hypothyroidism or hyperthyroidism. The balance between antithyroid drugs and levothyroxine is critical in clinical practice.

Iodide-sensitive Graves' hyperthyroidism and the strategy for resistant or escaped patients during potassium iodide treatment.

The effectiveness of potassium iodide (KI) (100 mg/day) was evaluated in 504 untreated patients with Graves' hyperthyroidism (GD). Initial response to KI within 180 days, the effect of additional methylmercaptoimidazole (MMI) or radioactive iodine (RI) in resistant or escaped patients, and long-term prognosis were evaluated. Serum fT4 levels became low or normal in 422 patients (83.7%, KI-sensitive group) without serious side effects. Among these patients, serum TSH levels became high (n = 92, hypothyroid) or normal (n = 78) in 170 patients (33.7%) (KI-sensitive with a recovered TSH response, Group A), but remained suppressed in 252 patients (50.0%) (KI-sensitive with TSH suppression, Group B). Serum fT4 levels decreased but remained high in 82 patients (16.3%) (KI-resistant, Group C). Older patients, or those with small goiter and mild GD were more KI-sensitive with a recovered TSH response than others. Escape from KI effect occurred in 0%, 36% and 82% in Group A, B and C, respectively. Patients in Group B and C were successfully treated with additional low-dosage MMI or RI. After 2-23 years' treatment (n = 429), remission (including possible remission) and spontaneous hypothyroidism were significantly more frequent in Group A (74.3% and 11.1%, respectively,) than in Groups B (46.3% and 2.8%, respectively) or C (53.6% and 1.5%, respectively) (p < 0.0001). In conclusion, a high KI sensitivity with a recovered TSH response was observed in about a third of the patients in GD associated with a better prognosis. Additional MMI or RI therapy was effective in escaped or KI-resistant patients with suppressed TSH level.

Appropriate duration of antithyroid drug treatment as a predictor for relapse of Graves' disease: a systematic scoping review.

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.

Predictive effect of antithyroid antibody for relapse of Graves' disease.

BACKGROUND: The remission rate in children with Graves' disease (GD) after 2-6 years of antithyroid drug (ATD) treatment is 40-50%. It has been reported that it is difficult to predict the GD prognosis based on the thryroid stimulating hormone (TSH) receptor antibody (TRAb) level at the cessation of ATD treatment. We studied whether the persistence of negative TRAb at ATD treatment cessation increased the remission rate in pediatric patients with GD. METHODS: We included 22 patients diagnosed with GD who discontinued ATD treatment after confirmation of negative TRAb on two or more consecutive tests. Remission was defined as the maintenance of normal thyroid function, including serum TSH level, with negative TRAb more than 2 years after ATD discontinuation. RESULTS: Of the 22 patients, 12 achieved remission (remission rate 54.5%), with no significant between-group difference in the median duration of ATD treatment in the remission and relapse groups (4.4 vs 3.9 years). Of the 10 patients who relapsed, four (40.0%) relapsed within 2 years after ATD discontinuation, and 4 (40.0%) relapsed more than 5 years after ATD discontinuation. CONCLUSIONS: The persistence of negative TRAb at ATD treatment cessation might indicate prolonged duration of remission but does not increase the final remission rate in patients with childhood-onset GD.

Hyperthyroidism in adolescents.

The term 'hyperthyroidism' refers to a form of thyrotoxicosis due to inappropriate high synthesis and secretion of thyroid hormone(s) by the thyroid. The leading cause of hyperthyroidism in adolescents is Graves' disease (GD); however, one should also consider other potential causes, such as toxic nodular goitre (single or multinodular), and other rare disorders leading to excessive production and release of thyroid hormones. The term 'thyrotoxicosis' refers to a clinical state resulting from inappropriate high thyroid hormone action in tissues, generally due to inappropriate high tissue thyroid hormone levels. Thyrotoxicosis is a condition with multiple aetiologies, manifestations, and potential modes of therapy. By definition, the extrathyroidal sources of excessive amounts of thyroid hormones, such as iatrogenic thyrotoxicosis, factitious ingestion of thyroid hormone, or struma ovarii, do not include hyperthyroidism. The aetiology of hyperthyroidism/and thyrotoxicosis should be determined. Although the diagnosis is apparent based on the clinical presentation and initial biochemical evaluation, additional diagnostic testing is indicated. This testing should include: (1) measurement of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAb); (2) analysis of thyroidal echogenicity and blood flow on ultrasonography; or (3) determination of radioactive iodine uptake (RAIU). A 123I or 99mTc pertechnetate scan is recommended when the clinical presentation suggests toxic nodular goitre. A question arises regarding whether diagnostic workup and treatment (antithyroid drugs, radioiodine, surgery, and others) should be the same in children and adolescents as in adults, as well as whether there are the same goals of treatment in adolescents as in adults, in female patients vs in male patients, and in reproductive or in postreproductive age. In this aspect, different treatment modalities might be preferred to achieve euthyroidism and to avoid potential risks from the treatment. The vast majority of patients with thyroid disorders require life-long treatment; therefore, the collaboration of different specialists is warranted to achieve these goals and improve patients' quality of life.

Hyperthyroidism in Pregnancy: The Delicate Balance between Too Much or Too Little Antithyroid Drug.

Overt hyperthyroidism (HT) during pregnancy is associated with a risk of maternal-fetal complications. Antithyroid drugs (ATD) have a potential risk for teratogenic effects and fetal-neonatal hypothyroidism. This study evaluated ATD treatment and thyroid function control during pregnancy, and pregnancy outcome in women with HT. PATIENTS AND METHODS: A retrospective analysis of 36 single fetus pregnancies in 29 consecutive women (median age 30.3 ± 4.7 years) with HT diagnosed before or during pregnancy; a control group of 39 healthy euthyroid pregnant women was used. RESULTS: Twenty-six women had Graves' disease (GD, 33 pregnancies), 1 had a hyperfunctioning autonomous nodule, and 2 had gestational transient thyrotoxicosis (GTT). Methimazole (MMI) was administered in 22 pregnancies (78.5%), Propylthiouracil (PTU) in 2 (7.1%), switch from MMI to PTU in 4 (14.2%), no treatment in 8 pregnancies (3 with subclinical HT, 5 euthyroid with previous GD remission before conception). In the 8 pregnancies of GD patients diagnosed during gestation or shortly before (<6 weeks), i.e., with fetal exposure to uncontrolled HT, there was 1 spontaneous abortion at 5 weeks (3.4% of all ATD-treated pregnancies), and 1 premature delivery at 32 weeks with neonatal death in 24 h (3.4%); 1 child had neonatal hyperthyroidism (3.3% of live children in GD women) and a small atrial sept defect (4% of live children in ATD treated women). In women treated more than 6 months until conception (20 pregnancies): (a) median ATD doses were lower than those in women diagnosed shortly before or during pregnancy; (b) ATD was withdrawn in 40% of pregnancies in trimester (T)1, all on MMI < 10 mg/day (relapse in 14.2%), and in up to 55% in T3; (c) TSH level was below normal in 37%, 35% and 22% of pregnancies in T1, T2 and T3 respectively; FT4 was increased in 5.8% (T1) and subnormal in 11.75% in T2 and T3; (d) no fetal birth defects were recorded; one fetal death due to a true umbilical cord knot was registered. Mean birth weight was similar in both ATD-treated and control groups. Hyperthyroidism relapsed postpartum in 83% of GD patients (at median 3 ± 2.6 months). CONCLUSION: In hyperthyroid women with long-term ATD treatment before conception, drugs could be withdrawn in T1 in 40% of them, the thyroid function control was better, and pregnancy and fetal complications were rarer, compared to women diagnosed during pregnancy. Frequent serum TSH and FT4 monitoring is needed to maintain optimal thyroid function during pregnancy.

Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism.

OBJECTIVE: Agranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with hyperthyroidism. METHODS: This retrospective study included 3558 inpatients with Graves disease treated in a Class A Grade 3 hospital between 2015 and 2019. The clinical presentation and laboratory workup of patients with antithyroid drug (ATD)-induced agranulocytosis was analyzed. RESULTS: Agranulocytosis was thought to be caused by ATDs in 36 patients. The hospital length of stay was 12 (10-16) days, and hospitalization costs were approximately $2810.89 ($2156.50-$4164.67). The median duration of ATD therapy prior to agranulocytosis development was 30 (20-40) days. Fever (83.33%) and sore throat (75%) were the most common symptoms as early signs of agranulocytosis. The lowest neutrophil counts were 0.01 (0.00-0.03) × 109/L and 0.14 (0.02-0.29) × 109/L in the methimazole and propylthiouracil groups, respectively (P = .037). The recovery times of agranulocytosis were 9.32 ± 2.89 days and 5.60 ± 4.10 days in the methimazole and propylthiouracil groups, respectively (P = .016). Patients with severe agranulocytosis required a longer time to recover (P < .001) and had closer to normal serum thyroxine and triiodothyronine levels. The interval between the first symptom of agranulocytosis and ATD withdrawal was 1 (0-3) day. CONCLUSIONS: Patients with agranulocytosis needed a long hospital length of stay and incurred high costs. Methimazole was prone to causing a more serious agranulocytosis than propylthiouracil. High thyroid hormone was unlikely to play a role in adverse drug reactions. Patient education is important.