Search

Background: The prognosis of Graves' disease (GD) is reportedly related to sex, age, and genetic factors, although there is no consensus. The objective of this study was to investigate the relation...

Background: This study aimed to compare the effectiveness and safety of radioiodine (RAI) and long-term methimazole (MMI) in the treatment of subclinical hyperthyroidism (SH) in the elderly. Method...

BACKGROUND: Hyperthyroidism is associated with bone mass reduction and increased fracture risk, but the effects on other important bone parameters have been sparsely examined. Therefore, we investigated bone microarchitecture and estimated bone strength, by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hyperthyroid patients at diagnosis and after being euthyroid for at least one year.METHODS: Two approaches were used: A) a case-control study comparing 61 hyperthyroid women with 61 euthyroid women matched for age- and menopause status; B) a follow-up study, in which 46 of the 61 women were re-examined after having been euthyroid for one year. HR-pQCT of the distal radius and tibia, and dual energy X-ray absorptiometry (DXA) of the lumbar spine and the hip were performed.RESULTS: In analysis A: In the radius, compared to healthy controls, hyperthyroid patients had higher total area (16.9 ±29.5%; pCONCLUSIONS: Compared to a healthy control group, hyperthyroid women had lower vBMD, lower estimated bone strength, and compromised cortical microarchitecture in the radius. After restoration of euthyroidism, significant improvements in vBMD and cortical microarchitecture were observed, highlighting the importance of achieving and maintaining euthyroidism.

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.

Background: The most commonly reported symptom of hyperthyroidism is weight loss; successful treatment increases weight. Weight gain faced by patients with hyperthyroidism is widely considered a si...

Background: The prevalence of antithyroid drug (ATD)-related drug-induced liver injury (DILI) has been reported to vary among patients in several countries. The purpose of this study was to summari...

Agranulocytosis occurs in 0.2-0.5% of patients treated with the antithyroid drugs (ATDs) methimazole and propylthiouracil. The objectives of this study were to evaluate the risk of ATD-related agranulocytosis in patients with amiodarone-induced thyrotoxicosis (AIT), and to compare it with the agranulocytosis risk in patients with thyrotoxicosis due to other etiologies treated with ATDs.This was a retrospective cohort study. Participants were 14,781 adult patients with thyrotoxicosis, newly treated with an ATD between January 1, 2002, and December 31, 2015. Among them were 593 patients treated by ATDs due to AIT. The main outcome measures were incidence rates and crude and adjusted hazard ratios using univariate and multivariable Cox regression models for ATD-related agranulocytosis within one year of treatment initiation, in association with AIT.Agranulocytosis occurred in 28 (0.19%) of patients newly treated with methimazole or propylthiouracil during the first year of follow-up. Of these 28 patients, 8/593 (1.35%) were AIT patients and 20/14,188 (0.14%) were thyrotoxic patients that was not AIT related (p 0.001). Incidence rates were 22 (9.47-43.36) cases/1000 person-years of follow-up in AIT, and 1.79 (1.09-2.76)/1000 person-years of follow-up in non-AIT thyrotoxicosis (p 0.0001). In univariate Cox regression analysis, risk for ATD agranulocytosis associated with AIT was 9.71 (4.28-22.05) compared to the risk in non-AIT thyrotoxicosis. In a multivariable model, adjusting for age, sex, body mass index, smoking history, year of cohort entry, diabetes mellitus, hypertension, renal failure, beta blockers, calcium channel blockers, anti-aggregants, and dose of ATDs, the risk associated with AIT was 5.70 (2.14-15.21). In a model adjusted for a propensity score to receive amiodarone, risk for ATD agranulocytosis associated with AIT was 6.32 (1.22-32.70).ATD use is associated with a higher risk for agranulocytosis in patients with AIT.

This study sought to investigate the clinical characteristics and outcomes of propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in patients with Graves' disease.Sixteen patients diagnosed with PTU-induced ANCA-associated vasculitis at the authors' hospital from January 2010 to June 2017 were analyzed retrospectively.All 16 patients with PTU-induced ANCA-associated vasculitis were female. The mean age ± standard deviation of the patients was 39.4 ± 15.3 years (range 19-69 years), and the median time of onset was 36 months (range 1-193 months) post-PTU initiation. The median dose at the onset of PTU-induced ANCA-associated vasculitis was 150 mg/day (range 50-300 mg/day). All patients had a positive serum perinuclear staining pattern (p-ANCA) and antibodies directed against myeloperoxidase (anti-MPO). Six patients tested positive for both anti-MPO antibodies and antibodies directed against proteinase-3. Seven (43.8%) patients presented with involvement of a single organ. The kidney was the organ most commonly affected, as 12 (75%) patients were found to have disease involving this organ. PTU was stopped in all patients, corticosteroids were administered to two patients, and immunosuppressive agents and corticosteroids were administered to five patients. Three patients were lost to follow-up. However, the remaining patients achieved remission after a median follow-up period of 38 months (range 6-76 months). Patients who were positive for pANCA and displayed cytoplasmic staining showed negative findings at rates of approximately 53.8% (7/13) and 100% (6/6), respectively, following treatment.PTU-induced ANCA-positive vasculitis occurs at varying times and after exposure to various doses of PTU. The condition has a milder course and has a better prognosis after PTU cessation.

Antithyroid drug (ATD) is a widely used treatment for Graves' disease (GD). However, its long-term efficiency remains unclear. This study investigated the long-term disease prognosis and predictive factors for relapse in ATD-treated GD patients.Newly diagnosed, ATD-treated GD patients with at least four years of follow-up were recruited (n = 187). Remission was defined as maintaining a euthyroid status for more than one year after ATD withdrawal.During 11.1 years (range 4.0-23.7 years) of median follow-up, overall, 51.9% of the newly diagnosed ATD-treated GD patients achieved remission, 32.1% continued ATD treatment, and 13.4% underwent other ablation treatments. The 10-year remission rates were higher in the first (34.2%) and second (25.5%) ATD courses than in any of the other subsequent ATD courses, and decreased as ATD treatments were repeated. The 10-year relapse rate was the highest after the third ATD treatment (71.4%) compared with that after the first (60.5%) and second (58.3%) courses. Longer duration of ATD treatment (odds ratio [OR] = 1.4 [confidence interval (CI) 1.2-1.7], p 0.001), higher number of relapses (OR = 4.7 [CI 2.3-9.8], p 0.001), and moderate to severe Graves' ophthalmopathy (OR = 4.1 [CI 1.1-15.2], p = 0.032) were associated with persistent disease status.A second course of ATD can be considered for GD patients after the first relapse because the chance of remission and the relapse rate are similar to the one after the first ATD treatment course. For GD patients with more than two relapses, or with an ATD treatment duration of more than four to five years, low-dose maintenance of ATD or ablative treatment needs to be considered.

The optimum therapy for Graves' disease (GD) is chosen following discussion between physician and patient regarding benefits, drawbacks, potential side effects, and logistics of the various treatment options, and it takes into account patient values and preferences. This cohort study aimed to provide useful information for this discussion regarding the usage, efficacy, and adverse-effect profile of radioactive iodine (RAI), antithyroid drugs (ATDs), and thyroidectomy in a tertiary healthcare facility.The cohort included consecutive adults diagnosed with GD from January 2002 to December 2008, who had complete follow-up after treatment at the Mayo Clinic, Rochester, Minnesota. Data on treatment modalities, disease relapses, and adverse effects were extracted manually and electronically from the electronic medical records. Kaplan-Meier analyses were performed to evaluate the association of treatments with relapse-free survival.The cohort included 720 patients with a mean age of 49.3 years followed for a mean of 3.3 years. Of these, 76.7% were women and 17.1% were smokers. The initial therapy was RAI in 75.4%, ATDs in 16.4%, and thyroidectomy in 2.6%, while 5.6% opted for observation. For the duration of follow-up, ATDs had an overall failure rate of 48.3% compared with 8% for RAI (hazard ratio = 7.6; p 0.0001). Surgery had a 100% success rate; 80% of observed patients ultimately required therapy. Adverse effects developed in 43 (17.3%) patients treated with ATDs, most commonly dysgeusia (4.4%), rash (2.8%), nausea/gastric distress (2.4%), pruritus (1.6%), and urticaria (1.2%). Eight patients treated with RAI experienced radiation thyroiditis (1.2%). Thyroidectomy resulted in one (2.9%) hematoma and one (2.85%) superior laryngeal nerve damage, with no permanent hypocalcemia.RAI was the most commonly used modality within the cohort and demonstrated the best efficacy and safety profile. Surgery was also very effective and relatively safe in the hands of experienced surgeons. While ATDs allow preservation of thyroid function, a high relapse rate combined with a significant adverse-effect profile was documented. These data can inform discussion between physician and patient regarding choice of therapy for GD.

Understanding the roles of circulating microRNAs (miRNAs) can provide important and novel information regarding disease pathogenesis and a patient's clinical condition. Circulating miRNAs, such as exosomal miRNA, may regulate various bioactivities related to intercellular communication. However, the circulation of miRNAs in Graves' disease (GD) in relation to disease activity has never been elucidated. This study aimed to identify circulating miRNAs in GD in relation to disease activity and whether their exosomes play a role in the pathogenesis of GD.Circulating miRNAs were measured in serum obtained from seven intractable GD patients, seven GD patients in remission, and seven healthy controls using the miScript miRNA PCR Array. Altered miRNAs selected from array data were validated in 65 subjects. To investigate exosome biology, peripheral blood mononuclear cells (PBMCs) were incubated with exosomes isolated from the subjects' sera. mRNAs were quantified for cytokines using quantitative real-time polymerase chain reaction.Circulating miR-23b-5p and miR-92a-39 were increased in GD patients in remission compared with intractable GD patients (p 0.05). On the other hand, let-7g-3p and miR-339-5p were decreased in GD patients in remission compared with intractable GD patients (p 0.05). Exosomes from intractable GD patients stimulated mRNA expression for IL-1β and TNF-α compared with GD patients in remission or healthy controls.This study demonstrates that different levels of circulating miRNAs are associated with intractable GD. Moreover, serum exosomes of patients with intractable GD may activate immune cells, which may play an important role in GD pathogenesis.

Thionamides are associated with a high risk of recurrence following cessation. Thyrotropin receptor-stimulating antibody (TRAb) levels at diagnosis and/or after thionamides may be biomarkers of this risk. This study assesses the natural history of Graves' thyrotoxicosis following thionamide withdrawal and factors that predict recurrence, particularly TRAb levels at diagnosis and cessation.An observational study was conducted of patients with a first presentation of Graves' disease, who were prescribed (and completed) a course of primary thionamide treatment (n = 266) in a university teaching hospital endocrine clinic. Recurrence rates over four years and factors predictive of recurrent thyrotoxicosis were assessed.The relapse rate was 31% at one year and 70% at four years. Younger age (39 years [range 30-49 years] vs. 47 years [range 37-53 years]; p = 0.011), higher TRAb levels at diagnosis (8.8 IU/L [range 5.3-17.0 IU/L] vs. 5.7 IU/L [range 4.1-9.1 IU/L]; p = 0.003), and higher TRAb levels at cessation of therapy (1.2 IU/L [range 0-2.3 IU/L] vs.0.9 IU/L [range 0-1.3 IU/L]; p = 0.003) were associated with a higher risk of relapse. By four years, cessation TRAb0.9 IU/L was associated with a 58% risk of recurrence compared with 82% with TRAb1.5 IU/L (p = 0.001). TRAb at diagnosis12 IU/L was associated with an 84% risk of recurrence over four years compared with 57% with TRAbs5 IU/L (p = 0.002).High TRAb at diagnosis and/or positive TRAb at cessation of therapy suggest a high likelihood of relapse, mostly within the first two years. They stratify patients likely to need definitive therapy (radioiodine or surgery).

Antithyroid drug (ATD)-induced agranulocytosis is a rare but life-threatening disease. Clinical features of ATD-induced agranulocytosis and outcomes remain incompletely understood.Patients with clinically diagnosed ATD-induced agranulocytosis were retrospectively studied, involving 9690 patients who were referred for radioiodine treatment during a 15-year period (2000-2015) in China. There were 114 cases of agranulocytosis attributable to ATD included, and their clinical characteristics and therapy outcomes were analyzed.The female-to-male ratio of ATD-induced agranulocytosis was 10.4:1. The mean age (±standard deviation) of the patients with ATD-induced agranulocytosis was 41.7 ± 12.3 years. The methimazole and propylthiouracil doses given at the onset were 22.9 ± 8.0 mg/day and 253.6 ± 177.5 mg/day, respectively. ATD-induced agranulocytosis occurred in 45.1%, 74.3%, and 88.5% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. Fever (78.9%) and sore throat (72.8%) were the most common symptoms when agranulocytosis was diagnosed. The mean recovery time of agranulocytosis was 13.41 ± 7.14 days. Recovery time in the granulocyte colony-stimulating factor (G-CSF)-treated group (12.7 ± 6.0 days) did not differ from that in the group not treated with G-CSF (16.4 ± 10.6 days; p = 0.144). Treatment with (131)I was successful in 87/98 patients (88.8%). The success rate of (131)I was equivalent (p = 1.000) between the groups receiving methimazole (88.2%, 75/85) and propylthiouracil (92.3%, 12/13).This largest single-institution study in China shows that ATD-induced agranulocytosis tends to occur within the first 12 weeks after the onset of ATD therapy. For patients with ATD-induced agranulocytosis, G-CSF does not improve the recovery time of agranulocytosis, and (131)I is an optimal treatment approach.

Whether the addition of immunosuppressive drugs to standard antithyroid drugs reduces the relapse risk in Graves' disease remains uncertain.The aim of this study was to investigate the effects of immunosuppressive drugs on the relapse rate after a first episode of hyperthyroidism due to Graves' disease.Based on a pre-specified protocol, PubMed (1946-July 2015), EMBASE (1947-July 2015), and Cochrane (1992-July 2015) databases were searched. The search was for (randomized) controlled trials comparing immunosuppressive drugs with a control group. PRISMA and SIGN statements were used for assessing data quality. Two reviewers extracted data, with any disagreement being resolved by consensus. Data were pooled using a random-effects model.The primary endpoint was relapse of disease until follow-up. Secondary endpoints included reduction of thyroid volume and decrease in thyrotropin-receptor antibody (TRAb) levels. Seven trials with 862 participants were included. Most trials were small with a moderate to high risk of bias. There were 113 relapses in 481 (23.5%) patients receiving immunosuppressive drugs compared with 225 relapses in 381 (59.1%) control patients (risk ratio for recurrence 0.55; [confidence interval (CI) 0.41-0.75]). Subgroup analyses showed similar effects for randomized trials and controlled trials (I(2) 0%), and for trials using corticosteroid and non-corticosteroid immunosuppressive drugs (I(2) 0%). Use of immunosuppressive drugs also resulted in significant reductions in thyroid volume (-10.72 mL [CI -15.59 to -5.85]) and TRAb levels (-17.01 IU/L [CI -33.31 to -0.72]). Immunosuppressive drug-related adverse effects were not systematically reported, and thus were not included in the quantitative analysis.Current evidence suggests a possible relevant reduction in relapse risk when immunosuppressive drugs are added to standard treatment of Graves' disease. The small number of trials with high heterogeneity in regard to treatment modalities and the lack of systematic reporting of adverse effects calls for larger, conclusive trials.

Methimazole (MMI) is usually used at an initial dose of 30 mg/day for severe Graves' disease (GD) hyperthyroidism, but adverse effects are more frequent at this dose than at MMI 15 mg/day.We designed a regimen to address the lack of a primary therapeutic effect of the MMI 15 mg/day by combining it with inorganic iodine at 38.2 mg/day. Our aim was to compare the two regimens (MMI 15 mg+inorganic iodine at 38.2 mg/day (M15+I) vs. MMI 30 mg/day (M30)) in terms of therapeutic effect, adverse effects, and remission rate.In a prospective study, 310 patients with untreated GD (serum free thyroxine (fT4) ≥5 ng/dL) were assigned to one of the two regimens. Potassium iodide was discontinued in the M15+I group as soon as the serum fT4 level was within the reference range (0.8-1.6 ng/dL).Percentages of patients achieving an fT4 level within reference range in ≤30, ≤60, or 90 days on the study treatment regimens were 45.3%, 73.9%, and 82.0% respectively for the M15+I group, and 24.8%, 63.1%, and 75.2% respectively for the M30 group. Hence, the proportions of patients achieving this goal in ≤30 or ≤60 days were significantly larger in the M15+I group. Adverse effects that required discontinuation of MMI were more frequent in the M30-treated than in the M15+I-treated group (14.8% vs. 7.5%; p=0.0387). The remission rates in the M15+I and M30 groups were 19.9% and 14.8%-higher in the former, but the difference did not reach statistical significance.The results of this study raise the possibility that M15+I is superior to M30 as a primary treatment for moderate to severe hyperthyroidism caused by GD.

Background: Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated. Methods: Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730). Results: Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04–11.86) and in the urinary system 2.73 (1.22–6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs). Conclusions: We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.

Agranulocytosis is a serious adverse effect of antithyroid drugs (ATDs) and mainly develops within three months after the start of uninterrupted ATD treatment. Agranulocytosis can also develop for the first time after interruption and subsequent resumption of the same ATD treatment. However, little is known with regard to agranulocytosis that develops after resumption of the same ATD treatment.We investigated the characteristics of patients who developed agranulocytosis during their second or later course of ATD treatment.A total of 81 patients at our hospital were diagnosed with ATD-induced agranulocytosis. In 14 of the cases (methimazole (MMI), n=10; propylthiouracil (PTU), n=4), the agranulocytosis developed for the first time in the context of the second or later course of treatment with the same ATD; those patients were designated the "resumed group." The 35 patients (MMI, n=28; PTU, n=7) who developed agranulocytosis during their first uninterrupted course of ATD therapy were designated the "first group."The median total duration of ATD treatment before the diagnosis of agranulocytosis was 559 days (range 86-1775 days), and the median interval between the final day of the previous course and the first day of the course in which agranulocytosis was diagnosed was 916.5 days (range 153-8110 days). There were no cases in which agranulocytosis developed when treatment with the same ATD was resumed after discontinuation for less than five months. The difference between the start of ATD treatment in the course in which agranulocytosis was diagnosed and the time interval at which agranulocytosis was diagnosed was similar when comparing the first group and the resumed group (39 (20-98) days in the first group vs. 32.5 (21-95) days in the resumed group; n.s.). There were no significant differences between the groups in terms of granulocyte count at the time agranulocytosis was diagnosed, mortality rate, or the interval between the diagnosis of agranulocytosis and recovery.When ATD treatment is resumed, patient follow-up is essential in order to monitor for the development of agranulocytosis.

Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity that affects various organs with increased IgG4 positive plasmacytes and progressive fibrosis. While IgG4-RDs in association with Hashimoto's thyroiditis or Riedel's thyroiditis have been reported, the relationship between IgG4-RD and Graves' disease (GD) is yet unknown. To elucidate the relation of GD to IgG4-RD, serum IgG4 levels and their clinical implications in patients with GD were investigated.In this prospective study, serum IgG4 levels were measured in 109 patients with GD and classified into two groups according to the comprehensive diagnostic criteria of IgG4-RD previously established: (i) GD with elevated-IgG4 levels (≥ 135 mg/dL), and (ii) GD with nonelevated IgG4 (135 mg/dL).Seven out of 109 patients with GD (6.4%) had elevated serum IgG4 levels [mean ± standard deviation (range): 175.0 ± 44.5 (136-266) mg/dL] and elevated ratios of IgG4/IgG [12.7 ± 4.5% (7.6%-21.2%)]. The remaining patients with GD had serum IgG4 levels and IgG4/IgG ratios of 39.6 ± 27.6 (3-132) mg/dL and 3.2 ± 2.2% (0.3%-11.5%), respectively. Ages in the elevated IgG4 group were significantly higher than those of the nonelevated IgG4 group: 54.7 ± 6.2 versus 43.4 ± 15.4 years, respectively. Ultrasound examinations revealed that the elevated IgG4 group had significantly increased hypoechogenic areas in the thyroid in comparison to the nonelevated IgG4 group (low echo scoring: 1.66 ± 0.81 vs. 0.61 ± 0.89, respectively). In the correlation analysis, TSAb (rs=0.385, n=42) titers were significantly correlated with se rum IgG4 levels, while they were not significantly different between the two groups. In the elevated IgG4 group, symptoms were controllable with a small dose of antithyroidal drug (ATD; n=4), a combination treatment with ATD and L-T4 (n=1), or L-T4 administration only one year after the first visit (n=2).A small portion of GD patients harbored elevated serum IgG4 levels. They were older, had increased hypoechoic areas in the thyroid, and appeared to be responsive or prone to be hypothyroid after ATD treatment. Thus, the present study suggests the presence of a novel subtype of GD. Measuring serum IgG4 levels may help to distinguish this new entity and provide potential therapeutic options for GD.

Graves' disease is commonly treated with curative intent using radioactive iodine (RAI). While higher doses have been shown to increase success rates, more evidence is needed. Further, very few studies assess the time to treatment success without the need for antithyroid drugs after a single dose of RAI within the first year post-dose, despite earlier success being an important treatment objective. We aimed to evaluate the outcome of different RAI doses in terms of success rates and time to achieve this success (eu- or hypothyroidism). We hypothesized that higher doses would not only increase success rates, but bring about successful treatment earlier.We retrospectively analyzed the medical records of all patients diagnosed with Graves' disease between 1994 and 2009. Details of RAI treatment and outcomes thereof were documented. In our analysis, we divided the patients who received RAI treatment into three groups according to the dose received: I (≤15 mCi); II (16-20 mCi); III (≥21 mCi).There were 498 patients diagnosed with Graves' disease. However, 105 were either lost to follow-up or still undergoing treatment. Of the remaining 393, there were 258 who received RAI treatment. The average initial dose was 21.42±6.5 mCi and overall success rate was 86%. Success rates were 74%, 85%, and 89% (p0.05), while average time to successful treatment was 8.1, 4.6, and 2.9 months, respectively (p0.001), for groups I, II, and III. When 20 mCi was given empirically, 85% obtained successful treatment; most of these within 3 months (mean 3.9; mode and median 3 months).This study provides additional evidence that success post-treatment correlates with administered dose and shows clearly, for the first time, that successful treatment is achieved earlier with higher doses. This knowledge is relevant to all clinicians managing Graves' disease as it can be taken into consideration when discussing treatment plans with patients.

Propylthiouracil (PTU) therapy is associated with a variety of adverse reactions, among the most rare being interstitial pneumonia. To date, this has been reported in four Asian patients with autoimmune hyperthyroidism. Here we describe a Caucasian woman who developed a bronchiolitis obliterans organizing pneumonia (BOOP)-like interstitial pneumonia after PTU administration for amiodarone-induced thyrotoxicosis.The patient was a 68-year-old woman who had been treated with amiodarone for chronic atrial fibrillation starting in May 2004. She had been a heavy smoker with a history of hypertension but no dust exposures. In October 2006, amiodarone was stopped after she developed thyrotoxicosis. In January 2007 serum thyroid-stimulating hormone (TSH) was 0.01 mIU/L (0.35-4.94) and free T4 was 17.5 pg/mL (7 to 15). She was initially started on methimazole and then changed to PTU after she developed pruritus. She developed severe dyspnea 9 months after starting PTU. At the time she was also taking warfarin, enalapril, and sotalol. Chest X-ray showed diffuse interstitial peripheral opacities and transbronchial lung biopsy revealed subacute lung injury with organizing pneumonia with hyperplasia of the alveolar type 2 pneumocytes, and characteristics of BOOP-like interstitial pneumonia. Signs and symptoms progressively improved after PTU discontinuation as confirmed at X-ray and computed tomography (CT) scan of the chest and by respiratory function tests. She has been recurrence free for 4 years after stopping PTU.This woman of Caucasian ancestral origin developed BOOP-like interstitial pneumonia after PTU treatment for apparent amiodarone-induced thyrotoxicosis, with resolution of her lung disease after stopping PTU. Tests for TSH receptor antibodies, thyroid peroxidase antibodies, and antinuclear cytoplasmic autoantibody were negative. Thyroid ultrasound was consistent with thyroiditis without nodules.PTU-associated interstitial pneumonia is not limited to patients of Asian origin or those with autoimmune thyroid disease. PTU must be withdrawn in the presence of respiratory symptoms and documented interstitial pneumonia. X-ray films, CT-scan, respiratory function tests, and lung biopsy are needed to diagnose PTU-induced interstitial pneumonia with certainty and to monitor the evolution of the disease after PTU discontinuation.

It is still debated which treatment modality for Graves' hyperthyroidism (GH) is most appropriate when Graves' orbitopathy (GO) is present. The preference in our center has been always to continue antithyroid drugs for GH (as the block-and-replace [B-R] regimen) until all medical and/or surgical treatments for GO are concluded and the eye disease does not require any further therapy (except prescription of lubricants). This usually takes more than 2 years. The aim of this study was to evaluate the outcome of long-term B-R regimen for GH in GO patients by assessment (after discontinuation of B-R) of (a) the recurrence rate of GH and (b) the relapse rate of GO and its association with recurrent GH and/or (131)I therapy. A retrospective follow-up study was done among all patients referred to the Academic Medical Center in Amsterdam between 1995 and 2005 for GO. The inclusion criteria for the study were a history of GH and GO and a history of treatment for GH with a B-R regimen for more than 2 years. The exclusion criteria were a history of (131)I therapy or thyroidectomy before the end of GO treatment. A questionnaire was sent to 255 patients and returned by 114. Of these patients, 73 qualified for the study. Recurrences of GH and/or GO as indicated by returned questionnaires were checked with treating physicians. Patients were treated with B-R for a median of 41 months (range: 24-132). The median follow-up after discontinuation of the B-R regimen was 57 months (range: 12-170). Recurrent GH occurred in 27 of the 73 study patients (37%) at a median of 3 months (range: 1-65) after withdrawal of antithyroid drug therapy. Nineteen of the 27 patients with recurrent hyperthyroidism were treated with (131)I therapy. A relapse of GO was not encountered in any of the 73 patients. The study suggests that long-term B-R treatment of GH in GO patients is associated with a recurrence rate of hyperthyroidism of about 37%. With the regimen employed, recurrence of hyperthyroidism and recurrence of hyperthyroidism followed by treatment with (131)I appears not to be a likely cause of relapse of GO. The data suggest that B-R treatment of GH until GO has become inactive and does not require any further treatment is a feasible option and does not jeopardize the improvement that occurred in GO

A major problem with antithyroid drug (ATD) therapy in Graves' disease is the high relapse rate. Therefore, clinicians have sought prognostic indicators of permanent remission. Suppression of serum thyrotropin (TSH) when ATD therapy is stopped carries a poor prognosis, but little is known regarding the significance of elevated serum TSH concentrations in the course of ATD therapy. The objective of this study was to determine if elevated serum TSH concentrations during methimazole (MMI) therapy is associated with a favorable long-term prognosis.We retrospectively studied patients with Graves' disease who were initially on MMI, in whom this drug was stopped because they had undetectable thyroid-stimulating antibodies (TSAbs) or were euthyroid after at least 24 months on MMI treatment. A strategy of high MMI doses plus T4 was not used in these patients. We identified 40 patients with elevated serum TSH concentration (10 microIU/mL) during MMI therapy (H-TSH group). Eighty-five percent of the H-TSH group had negative tests for TSAb. The H-TSH group was sex- and age-matched with 37 patients who had similar selection criteria, but did not have elevated serum TSH concentration during MMI therapy (N-TSH group). The H-TSH and N-TSH groups were similar in gross thyroid size, percentage of patients with exophthalmos, serum free thyroxine, duration of MMI treatment, TSAb status, duration that their TSAb tests remained negative, and thyroid peroxidase antibody titers. The patients were followed for 24 months after stopping MMI.In the H-TSH group, MMI-associated hypothyroidism typically occurred after 7-8 months of treatment with daily doses of 10-15 mg MMI. No patient had severe symptoms of hypothyroidism. The percentage of patients in remission at 6, 12, and 24 months after discontinuation of MMI was 90.0, 87.5, and 85.0, respectively, in the H-TSH group and 70.3, 67.6, and 54.1, respectively, in the N-TSH group (p 0.05 for the comparison of groups at 6 and 12 months and p 0.001 for comparison of the groups at 24 months).In patients with Graves' disease who are treated with MMI for at least 2 years and become euthyroid, the occurrence of elevated serum TSH concentrations during MMI treatment is a favorable indicator for long-term remission and is independent of multiple other factors including TSAb status, duration of MMI treatment, and gross parameters of goiter size.

Thymic hyperplasia is associated with Graves' disease, particularly in young patients. The degree of thymic transformation is minimal in most but not all patients. In the latter group radiological measurements of thyroid size and their change with treatment have rarely been reported. We present two patients with Graves' disease and relatively rapid resolution of thymic enlargement after successful treatment of their hyperthyroidism.Three patients with thyrotoxicosis secondary to Graves' disease and marked thymic enlargement were seen at our institution during a 2-year period. On computed tomography (CT) studies their volumes were 67, 81, and 54 cm(3). Thymic hyperplasia in the setting of Graves' disease was the diagnosis of exclusion. Two of the patients returned for follow-up after successful treatment of thyrotoxicosis as requested. On repeat CT their thymic volumes had decreased by 72% and 78%, respectively. Two types of histological modifications of the thymus have been described in association with Graves' disease, namely, thymic parenchyma hyperplasia and medullary lymphoid hyperplasia. The mechanisms underlying thymic transformation in patients with Graves' hyperthyroidism are not completely elucidated, but autoimmune processes underlying Graves' disease are presumed to play a role. The clinical course of our patients is consistent with earlier literature, indicating that thymic enlargement may occur in conjunction with Graves' hyperthyroidism, and that it usually resolves as hyperthyroidism is treated, but there is little quantitative pre- and posttreatment of hyperthyroidism data.Although every patient must be individually considered, it appears that thymic hyperplasia can be diagnosed in most Graves' hyperthyroid patients by considering the clinical context and appropriate radiologic studies such as CT. Raising awareness of the association of thymic hyperplasia in patients with Graves' hyperthyroidism and its resolution with the reversibility of the hyperthyroid state should prevent unnecessary thymic evaluation and surgery with its attendant risks.

Autoimmunity against the thyrotropin receptor (TSH-R) is a key pathogenic element in Graves' disease (GD) and the autoimmune aberration may be modified by antithyroid treatment. An association between radioactive iodine (RAI) therapy for GD and the development or worsening of Graves' orbitopathy (GO) is widely quoted. RAI-associated leakage of thyroid antigen(s) leads to an increased production of TSH-R antibodies that may initiate the eye injury.RAI therapy leads to prolonged worsening of autoimmunity against the TSH-R, and the number of patients entering remission of TSH-R autoimmunity is considerably lower than with other antithyroid therapies. Scientific evidence has indicated that RAI treatment for GD is associated with increased risk of occurrence or progression of GO compared with antithyroid drugs (ATD) and thyroid surgery. The risks of developing new GO or worsening of preexisting GO is around 20% after RAI and around 5% after ATD. The risk of developing severe GO after RAI is around 7%. Smoking, high levels of pretreatment serum triiodothyronine, and post-RAI hypothyroidism are associated with increased risk of GO, whereas a high TSH-R autoantibody titer is an independent risk factor for the progression of GO. In patients with mild preexisting GO, steroid prophylaxis is effective in preventing deterioration of GO. Also, routine use of prophylactic oral steroids with RAI therapy should be considered in GD patients without overt GO, but even more so in those at higher risks of eye complications such as smokers, old men, and those with severe hyperthyroidism or high TSH-R antibody titers.In contrast to ATD, remission of TSH-R autoimmunity after RAI therapy is less common, and RAI for GD is associated with definite increased risk of GO. Oral steroids are beneficial for patients with preexisting GO, particularly smokers.

Background: Thyroid storm is a rare and potentially fatal condition. Various unusual presentations in patients with thyroid storm have been described but multiorgan dysfunction is uncommonly seen. Summary: We describe a 35-year-old patient with a history of Graves' disease who was diagnosed with thyroid storm at 2 weeks postpartum. This was complicated by acute liver failure, acute kidney injury, severe lactic acidosis, disseminated intravascular coagulation, and heart failure with acute pulmonary edema. The multiorgan dysfunction was reversed by prompt institution of antithyroid drugs and supportive management in the intensive care unit. Conclusion: Thyroid storm is a medical emergency. One of the challenges lies in recognizing its varied presentations. Early diagnosis and appropriate treatment is important to prevent the catastrophic outcomes associated with this condition.

Knowledge on the action of thyroid hormone (TH) is augmented by the study of tissue responses to TH in vitro. In order to support the growth of cells in vitro, calf serum (CS) is usually added to the medium to provide necessary nutrients and growth factors. However, the content of endogenous TH in the CS may obfuscate changes with small doses of TH. We therefore compared the use of TH-depleted medium, either by resin treatment (stripped-CS) or by the use of CS from a thyroidectomized calf (TxCS) for gene expression studies.We describe the method for preparing a thyroidectomized calf, harvesting the blood and preparing the serum. We utilized methimazole in conjunction with the thyroidectomy to prevent TH synthesis in the event of regrowth of the thyroid remnant.Total triiodothyronine (T(3)) and thyroxine concentrations in TxCS were low at30 ng/dL and1 microg/dL, respectively. We compared the effect of T(3) on basic transcription element-binding protein (BTEB)1 and stanniocalcin (STC)-1 mRNA expression in human fibroblasts from a normal individual and a subject with resistance to TH (RTH) cultured in stripped-CS to TxCS and demonstrated that with stripped-CS and TxCS differences in the BTEB1 and STC-1 expression of normal and RTH fibroblasts could be detected.Both stripped-CS and TxCS are suitable to detect subtle differences in TH responsiveness between normal and RTH human skin fibroblasts, yet TxCS is not as costly as stripped-CS and relatively easy to prepare.

Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs.Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA.All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed.RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs, controlling compressive symptoms, and treating thyroid hyperfunction. When performed in experienced medical centers, RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs. It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective.

Antithyroid drugs have been used for more than 50 years for the management of hyperthyroidism. Most patients tolerate treatment well but some may develop life threatening side effects such as agranulocytosis and aplastic anemia (AA). We review all cases of antithyroid drug induced AA and describe, as illustrative cases, two women with Graves' disease who developed AA after 8 and 24 weeks of carbimazole (CBM) and methimazole (MMI) treatment respectively.To date, at least 34 cases of aplastic anemia (AA) due to antithyroid drugs [(1 with CMZ, 31 with MMI, and 2 with propylthiouracil (PTU)] have been published, not including the two patients described here. In addition, at least another 14 patients in whom AA developed after treatment with antithyroid drugs (11 with CMZ, and 3 with MMI) have been reported in Yellow Card Scheme data analysis. Patients with AA usually exhibit sudden onset of symptoms after a relative short time of exposure to the drugs, and all have concomitant agranulocytosis. Most have a rapid recovery following discontinuation of the drug and supportive treatment. Although only two antithyroid drug induced AA deaths have been published, the mortality rate was higher in the Yellow Card Scheme data analysis.Aplastic anemia associated with antithyroid drug treatment is rarer than antithyroid drug associated agranulocytosis. The prognosis of patients with antithyroid drug induced AA is good overall, but may not be as favorable as that of antithyroid drug induced isolated agranulocytosis.

There are potentially complex interrelationships between thyroid function, leptin, ghrelin, body mass index (BMI), and percentage of body fat (%BF). The goal of this study was to determine if normalization of thyroid status in premenopausal women with hyperthyroidism and hypothyroidism would be associated with changes in serum leptin and ghrelin in the absence of thyroid dysfunction treatment-associated changes in BMI and %BF.The study was carried out in 47 selected premenopausal women: 17 with hyperthyroidism, 11 with hypothyroidism, and 19 healthy individuals who constituted the control group. Patients with thyroid dysfunction were selected for study if their BMI and %BF did not change after treatment of thyroid dysfunction. Subjects in the control group were selected on the basis of the age, BMI, and the %BF characteristics of the patients with thyroid dysfunction. Concentrations of free thyroxine (fT4), free triiodothyronine (fT3), thyrotropin, leptin, and ghrelin in serum were determined before and after treatment of thyroid dysfunction and in the control group.Serum leptin concentrations were similar in patients with hyperthyroidism and hypothyroidism before treatment and in normal subjects and did not change significantly after treatment of hyperthyroidism or hypothyroidism. Serum ghrelin concentrations were lower in patients with hyperthyroidism, and higher in patients with hypothyroidism than in the control group (hypothyroidism = 2345 (1157-7015) [median (range)], hyperthyroidism = 1205 (438-2914), control = 2398 (1542-4920), p0.05).In premenopausal women with hyperthyroidism or hypothyroidism, treatment of thyroid dysfunction that is not associated with changes in BMI or %BF does not influence serum leptin but does affect serum ghrelin. Thyroid status itself, in the absence of alterations in the BMI and %BF, has an important influence on circulating ghrelin but not leptin.

Although transient thyrotoxicosis occurring after antithyroid drug (ATD) withdrawal in patients with Graves' hyperthyroidism has been reported, the prevalence of transient thyrotoxicosis after ATD therapy is as yet unknown. When patients with transient hyperthyroidism are mistakenly regarded as recurrences, they receive unnecessary therapy. The aim of this study was to investigate the prevalence of transient thyrotoxicosis after ATD withdrawal.We selected 110 consecutive patients with Graves' disease whose ATD therapy was stopped from December 2002 to September 2004 prospectively. Patients were observed for more than 1 year after ATD withdrawal, and 12 patients dropped out. Serum levels of free thyroxine (FT(4)), thyrotropin, and thyrotropin-binding inhibitor immunoglobulin were measured at ATD withdrawal, and 3, 6, and 12 months after withdrawal. When the patients showed mild thyrotoxicosis (serum FT(4) level of less than 3.00 ng/dL), we followed them up for 1 month without medication.The remission rate of the study group was 61.8% (68/110). Twenty-eight patients became euthyroid after transient thyrotoxicosis, equivalent to 41.2% of the remission patients. Eight of 28 patients showed overt thyrotoxicosis, and the rest subclinical thyrotoxicosis. Transient thyrotoxicosis occurred mostly 3-6 months after ATD withdrawal.Transient thyrotoxicosis after ATD withdrawal in patients with Graves' disease is not a rare phenomenon. Clinicians should be aware that the recurrence of Graves' disease after the withdrawal of ATD may be transient.

In this study, we investigated whether the CD40 or cytotoxic T lymphocyte-associated molecules-4 (CTLA-4) polymorphisms, which are associated with the susceptibility of Graves' disease (GD), can predict the clinical outcome after antithyroid drug (ATD) withdrawal. All patients with GD were treated with ATD. GD patients were divided into two groups: remission or failure. The remission group was defined as patients who maintained a euthyroid state for 1 year after ATD withdrawal. The failure group was defined as patients who relapsed within 1 year after the discontinuation of ATD or who could not discontinue their ATD treatment within 24 months. The rate of treatment failure after ATD withdrawal was 72.2%. For the susceptible genes, the CC genotype in the CD40, the GG genotype in the CTLA-4 exon 1, and the CC genotype in the CTLA-4 promoter region have shown no significant association with a clinical outcome after ATD withdrawal. However, clinical parameters, such as male gender, severe thyrotoxicosis, high thyroid-stimulating hormone-binding inhibitory immunoglobulin value, and a large goiter, were related to treatment failure. These findings suggest that the genetic markers associated with the development of GD cannot be used to predict the relapse of GD patients in place of clinical parameters.

To determine the course of thyrotropin (thyroid-stimulating hormone [TSH]) receptor antibodies (TRAbs) in children and adolescents with Graves' disease treated using antithyroid drugs (ATDs).Retrospective, cross-sectional study of 86 children and adolescents with Graves' disease treated medically for3 years. Patients with Hashimoto's thyroiditis and idiopathic short stature (n = 30) served as controls. A second-generation enzyme-linked immunosorbent assay (ELISA) for TRAbs was used.Twenty-two out of 23 (95.7%) patients with newly diagnosed Graves' disease, but 0/30 controls, had detectable TRAbs (22.0 +/- 13.5 U/L [mean +/- SD] vs. 0.9 +/- 0.9 U/L, p0.0001). Mean TRAb levels decreased with duration of therapy, but even after 13-24 months, TRAbs had normalized in only 3/16 (18.8%) patients. The initial TRAb titer correlated significantly with severity of the initial hyperthyroidism, but did not predict the response to therapy as indicated by the dosage of ATD required to control the hyperthyroidism at 6 and 12 months.Unlike adults, most children and adolescents with Graves' disease require2 years of ATD treatment before TRAbs are normalized. Although initial TRAb activity reflects disease severity, it does not predict the response to medical therapy. Recommendations as to treatment duration developed for adult patients should not be applied to the young.

To determine the present condition of treatment of childhood-onset Graves' disease in Japan, a nationwide questionnaire survey was conducted among councilors of the Japanese Society for Pediatric Endocrinology and the Japan Thyroid Association.Responses were received from 125 individuals, and the rate of collection of questionnaires was 47%. Methimazole was selected for first-line initial antithyroid drug therapy by 92% of respondents. Antithyroid drugs tended to be given at larger initial doses and over longer periods of time to childhood-onset patients than to adult patients, and these tendencies were more pronounced for pediatric endocrinologists. Combination therapy with an antithyroid drug and thyroxine was used more frequently by pediatric endocrinologists. Thyroidologists had more experience with radioiodine therapy than pediatric endocrinologists. Opinions regarding preparation of guidelines for the initial dose of methimazole in childhood-onset Graves' disease were almost equally divided among the following: the dose of methimazole should be adjusted according to the severity of disease as in adult cases, methimazole should be started at a dose of 1mg/kg per day in all patients, and the dose should be determined based on results of a randomized study.The present condition of treatment of childhood-onset Graves' disease in Japan was clarified.

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.

The cause of continued suppression of serum thyroid-stimulating hormone (TSH) levels during antithyroid drug therapy in some Graves' patients is unclear. Recently, there has been a notable explanation involving the direct inhibition of TSH receptor antibody (TRAb) on TSH secretion in the pituitary gland. The purpose of this study is to verify the relation between TRAb or other clinical parameters and the continued suppression of serum TSH level during antithyroid drug therapy in patients with Graves' disease. We reviewed the medical records of patients with Graves' disease between 1995 and 2002 at Samsung Medical Center. We selected 167 Graves' patients who had been euthyroid for at least 12 months after recovery of serum T3 and T4 levels during the antithyroid drug therapy. We analyzed the correlation of the interval until recovery of serum TSH with the pretreatment clinical parameters. We compared the recovery rates of suppressed TSH levels between pretreatment thyrotrophin-binding inhibitory immunoglobulin (TBII)-positive (>15%) and TBII-negative patients. We also compared the clinical parameters between two groups at the time of diagnosis and after recovery of thyroid hormone. Pretreatment serum T3 level, (131)I uptake, TBII activity, and the time to recovery of T3 or T4/free T4 level showed significant positive correlations with the interval until recovery of serum TSH level ( p < 0.05). Recovery rates of serum TSH levels at 3 months after recovery of thyroid hormone were significantly lower in pretreatment TBII-positive patients than those in TBII-negative patients ( p < 0.01). Serum TSH levels were significantly lower in TBII-positive patients at 3 months after recovery of thyroid hormone ( p < 0.05). TBII activities inversely correlated only with serum TSH levels at 3months after recovery of thyroid hormone ( p < 0.001). In conclusion, continued suppression of serum TSH level may be attributed to TRAb activity as well as the pretreatment severity of thyrotoxicosis and the time to recovery of thyroid hormone in patients with Graves' disease during antithyroid drug therapy.

In this study, we compared the evolution of thyroid peroxidase antibody (TPOAb) and thyroid-stimulating antibody (TSAb) activities before, during, and after treatment of Graves' disease (GD) with carbimazole. TPOAb and TSAb were measured in sera from 75 patients with GD, during an 18-month block-replace regimen and after drug withdrawal (12, 24, and 36 months). At diagnosis, TPOAb were present in 85% of the patients versus 99% for TSAb. During the treatment, TPOAb values and prevalence significantly decreased, as observed with TSAb. After drug withdrawal, TPOAb levels increased once again to reach the pretreatment values, whereas TSAb remained unchanged. TPOAb values and prevalence at drug withdrawal were not significantly different between patients who remained euthyroid and those who had a relapse of hyperthyroidism. In contrast, TSAb values and prevalence were higher at drug withdrawal in relapse patients. In conclusion, TPOAb and TSAb changes are similar during GD treatment by carbimazole but diverge after drug withdrawal. TPOAb might reflect autoimmune perturbations independently of the clinical status and of the thyroid-stimulating activity.

Management of a hyperthyroid patient unable to take oral or rectal medication is a difficult clinical problem. The need for an alternative parenteral route of antithyroid medication administration in thyrotoxic patients occurs in certain rare cases, such as emergent gastrointestinal surgery, bowel ileus or obstruction, or severe vomiting and diarrhea. We report a simple and successful protocol for the preparation and use of intravenous methimazole (MMI) for treatment of hyperthyroidism in patients intolerant of orally and rectally administered thionamides.Five hundred milligrams of methimazole USP powder was reconstituted with pH-neutral 0.9% sodium chloride solution to a final volume of 50 mL using aseptic technique, then filtered through a 0.22-microm filter. MMI injection was administered as a slow intravenous push over 2 minutes and followed by a saline flush.A 76-year-old man, intolerant of oral and rectal medications because of an ileus and intractable diarrhea, who developed worsening thyrotoxicosis after an emergent spinal cord decompression, and a 42-year-old man with chronic liver disease and hyperthyroidism, requiring emergent exploratory laparotomy and maintenance of complete bowel rest because of persistent gastrointestinal bleeding were rendered euthyroid using intravenous MMI.Two cases of hyperthyroidism successfully treated with a preparation of intravenous MMI are described.

This study determined the cost effectiveness of treating thyrotoxicosis using thionamide therapy, radioiodine or surgery in the United Kingdom.One hundred thirty-five patients diagnosed with thyrotoxicosis (62% Graves' disease, 7% nodular disease, 5% thyroiditis, and 27% unknown aetiology) referred in 12 months were offered a fully informed choice of treatment modality. Thirteen patients with transient thyrotoxicosis were subsequently excluded from the analysis. Seventy-four patients (61%) received an 18-month course of thionamide therapy, 43 received radioiodine therapy (35%), and 5 had a thyroidectomy (4%) within the first year of diagnosis as their primary treatment. A successful outcome ("cure") was defined as euthyroidism 12 months after thionamide therapy or euthyroidism or hypothyroidism on thyroxine replacement at 24 months following radioiodine or thyroidectomy. Costs were calculated for outpatient attendances, laboratory tests, and initial and subsequent treatments.In the thionamide group 73% were "cured" at 30 months after initiating treatment compared to 95% in the radioiodine group and 100% treated by thyroidectomy at 24 months. Cost per "cure" was calculated to be 3,763 pounds (5,644 dollars) per patient who received thionamides, 1,375 pounds (2,063 dollars) per patient given radioiodine and 6,551 pounds (9,826 dollars) per patient who underwent thyroidectomy.The most cost-effective primary treatment modality for thyrotoxicosis is radioiodine.

The effects of treatment modality for Graves' disease (GD) were studied with respect to long-term quality of life and present health status. A total of 179 patients with GD were randomized during the period 1983-1990 for treatment with antithyroid drugs, radioiodine, or surgery. A 36-item Short Form Health Status Survey questionnaire and specific questions for GD were sent to patients 14-21 years after randomization. Present medical records, and clinical and laboratory status were recorded. No major significant differences in quality of life among the three treatments were observed. Compared to a large Swedish reference group, all treatment groups had significantly lower scores for vitality (p < 0.05). The Mental Component Summary was lower for both the young medical, young surgical, and the older medical group (p < 0.05). Radioiodine-treated patients had a lower General Health score. Young medical patients (

Selective thyromimetics have been designed and shown to exhibit some of the beneficial effects of thyroid hormones, such as lowering of cholesterol and weight reduction, without the adverse thyroid hormone action on muscle, bone, and heart rate. Progress has also been made in attempting to treat hyperthyroidism by synthesizing antagonists that block thyroid hormone action, at the level of the thyroid hormone receptor or of the thyrotropin receptor. Clinical trials are still awaited, however, to verify whether these potentially promising agents will indeed prove to be of clinical therapeutic value.

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.

This retrospective study was aimed at revealing the incidence of normal white blood cell (WBC) count agranulocytosis in patients treated with antithyroid drugs (ATDs). From January 1975 to December 2001, 109 patients (0.35%) presented with ATD-induced agranulocytosis at our clinic. In 18 patients (16.5%), the WBC count exceeded 3.0 x 10(9)/L at the onset of agranulocytosis. Ten showed a downward trend in WBC count (3.0-3.9 x 10(9)/L) after the initiation of ATDs. Four had symptoms of infection. In the remaining 4 patients, routine WBC and granulocyte count monitoring detected an agranulocytosis. During the first 3 months of ATD treatment, 3347 patients (10.9%) had WBC count 3.0-3.9 x 10(9)/L even once with no symptom and normal granulocyte count and 26672 patients had WBC count >or= 4.0 x 10(9)/L with no symptom and normal granulocyte count. When agranulocytosis was found, twelve patients with normal WBC count agranulocytosis (0.36%) had WBC count 3.0-3.9 x 10(9)/L with no symptom, whereas only 2 patients with agranulocytosis (0.008%) had WBC count >or= 4.0 x 10(9)/L with no symptom. In conclusion, clinicians should take normal WBC count agranulocytosis into consideration at least during the first 3 months of antithyroid drug therapy, especially when WBC count is 3.0-3.9 x 10(9)/L.

A 35-year-old Asian male, treated for hyperthyroidism, systemic lupus erythematosis, and uremia presented with low serum total thyroxine (T4) and normal serum thyrotropin (TSH) levels. He had been receiving prednisone and methimazole for 15 weeks. Free T4 measured by direct equilibrium dialysis was in the hypothyroid range (0.3 ng/dL; normal, 0.8-2.7). Two possibilities were considered: (1) a weakly bound dialyzable inhibitor in uremic serum that interfered with this serum free T4 determination or (2) hypothyroidism with persistent TSH suppression because of prior hyperthyroidism. To determine whether a weakly bound inhibitor was involved, the patient's serum was serially diluted using two diluents: (1) an ultrafiltrate of the patient's serum, which would contain any unbound inhibitor, as well as free T4 and (2) an inert diluent. Free T4 measurements were similar with both, providing evidence against the presence of a dialyzable and ultrafilterable inhibitor. In conclusion, this patient was hypothyroid because of antithyroid drug administration, associated with prolonged central TSH suppression from preexisting hyperthyroidism. Discontinuation of methimazole resulted in normalization of serum total T4 and TSH values. Thus, paired, serial serum dilutions, using two different diluents, provided evidence for differentiation of appropriately low free T4 measurements (because of hypothyroidism), from spuriously low free T4 measurements (because of an interfering inhibitor).

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication.

The intractability of Graves' disease (GD) and the severity of Hashimoto's disease (HD) vary among patients. We previously reported that peripheral immunoglobulin (Ig) G3-secreting cells were increased in patients with intractable GD (i.e., requiring continuous antithyroid drug therapy). Isotype switching to IgG3 is induced by interleukin (IL)-4 and IL-10. To clarify which of these cytokines is related to the intractability or severity of autoimmune thyroid disease (AITD), we examined the serum concentrations of IL-10 and IL-4 by enzyme immunoassay in 166 patients with AITD and in 53 healthy controls. The serum IL-10 concentration was significantly higher in patients with GD and continuously positive for thyrotropin (TSH) receptor antibody (TRAb) despite more than 5 years of antithyroid drugs treatment than in patients with GD in remission. The serum IL-4 concentration did not differ between these two groups of patients. However, the serum IL-10 concentration was not related to the severity of HD. These results indicate that IL-10, but not IL-4, is related to the intractability of GD, but not to the severity of HD.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. Interferon-gamma (IFN-gamma) is an important mediator of inflammatory and immune responses. The aim of the present study was to investigate whether the polymorphism of IFN-gamma gene is associated with the development of GD or with clinical course during the antithyroid drug therapy. We have studied the CA repeat polymorphisms in the first intron of IFN gamma gene in Japanese patients with GD (n = 162) and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 133). There was no difference in allele frequency of IFN-gamma gene polymorphism between patients with GD and control subjects. However, the allele 4 (15 CA repeats) frequency was significantly greater in patients whose antithyrotropin receptor antibody (TRAb) became negative within 3 years by antithyroid drug treatment than those with consistently positive TRAb for more than 3 years (34.1% vs. 15.7%, chi2 = 8.545, p = 0.0035, pc = 0.049). The in vitro production of IFN-gamma by concanavalin A-stimulated peripheral blood mononuclear cells was significantly smaller in control subjects with the allele 4 compared to those with the other alleles. In conclusions, the CA repeat polymorphism of the IFN-gamma gene might be associated with the outcome of anti-thyroid drug treatment.

Subclinical hyperthyroidism is a relatively common condition for which prospectively derived evidenced-based management guidelines do not exist. We have conducted a case-based mail survey to solicit opinions from members of the American Thyroid Association (ATA) about various issues that arise in the management of patients with this disorder. The survey was completed and returned by 185 of 300 (62%) of the original survey recipients. Four hypothetical cases varying in age, thyrotropin (TSH) level and underlying etiology were presented. The majority of respondents recommended further evaluation of all cases, most commonly choosing a radioactive iodine uptake (42%-71%), thyroid scan (39%-68%) and antithyroid (TPO/Tg) antibodies (49%-55%) as the additional tests to be ordered. The large majority (84%) recommended observation rather than active treatment for a young patient with a low but detectable serum TSH level. A small majority also recommended observation alone for a young woman with an undetectable serum TSH level (58%) and for an older woman with a low but detectable serum TSH value (63%). However, the majority (66%) favored treating an older woman with an undetectable serum TSH. When treatment was advised in the patients with subclinical hyperthyroidism, the respondents strongly favored anti-thyroid drugs when the etiology was Graves' disease and radioactive iodine when the etiology was toxic nodular thyroid disease. In the absence of adequate evidence-based guidelines, it is hoped that this survey of expert opinions may provide useful guidance for physicians providing care for patients with subclinical hyperthyroidism.