Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves' disease.

BACKGROUND: Euthyroid Graves' disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb). PATIENTS AND METHODS: Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects. RESULTS: Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms. CONCLUSION: TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future.

The characteristics of osteoporotic patients in Graves' disease patients newly diagnosed after menopause: a prospective observational study.

Overt hyperthyroidism is associated with reduced bone density. The extent of restoration of reduced bone density caused by hyperthyroidism in postmenopausal Graves' disease (GD) patients has not fully been investigated. We examined 85 newly diagnosed postmenopausal GD patients, and we measured their serum thyroid hormone levels as well as their bone turnover marker levels and the bone mineral density (BMD) of their lumbar spine (LS), both femoral necks (FN), and left distal radius (DR). We prospectively observed the patients for changes in BMD and bone turnover marker levels during a 24-month period after euthyroidism had been established by ATD treatment. The median age of the subjects was 57 years old (range: 50 to 79). 46 (54.1%) patients had osteoporosis. 42 of the 46 osteoporosis patients had low BMD in the DR. The patients with osteoporosis were significantly older, had a significantly lower BMI, and had significantly higher bone turnover marker levels compared to the normal BMD patients. The best predictor of the BMD in the DR was BMD in the FN (ß = 0.40, p < 0.0001). A total of 42 patients were followed up for 24 months after attainment of euthyroidism, and 19 of them were osteoporosis at the first visit. The BMD of the 19 osteoporotic patients had increased by 4.9% in the LS, 11.9% in the FN, and 9.3% in the DR at 24 months. After maintaining a euthyroid state for 24 months by means of ATD treatment, 26% of the osteoporotic patients had recovered from osteoporosis.

TSH receptor antibody titers measured with a third-generation assay did not reflect the activity of Graves' ophthalmopathy in untreated Japanese Graves' disease patients.

TSH receptor antibody (TRAb) titer has been reported to be correlated with Graves' ophthalmopathy (GO). However, the correlation between GO activity and TRAb titer assessed with a third-generation assay has not been reported. We enrolled 238 untreated Graves' disease patients who came to the outpatient clinic of Ito Hospital and 28 patients who were euthyroid. All of the patients were assessed for GO by an ophthalmologist within 3 months of their initial visit to Ito Hospital. Clinical activity score (CAS), short inversion time inversion recovery (STIR), and sum of the maximum external orbital muscle areas (SEOMA) on a frontal sectional magnetic resonance imaging (MRI). The TRAb titer was significantly higher in patients with inactive ophthalmopathy (the inactive-GO group) than in patients with active ophthalmopathy (the active-GO group) (17.7 ± 13.5 IU/L vs. 13.0 ± 13.1 IU/L, p=0.0082). The SEOMA values were not correlated with TRAb titer. The prevalence of active-GO was higher in euthyroid patients than in hyperthyroid patients although the difference was not significant. In conclusion, TRAb titer measured with a third-generation assay dose not correlate with GO activity based on MRI findings in untreated Graves' disease patients, and the prevalence of active-GO is higher in euthyroid patients with lower TRAb titers than in hyperthyroid patients.

Inhibitory effect of low-dose inorganic iodine on thyroidal radioactive iodine uptake in healthy Japanese adults.

In the event of a nuclear power plant accident, prophylactic administration of potassium iodide (KI) is recommended to prevent thyroid damage due to uptake of radioiodine. To assess the inhibitory effect of low-dose inorganic iodine on thyroidal radioactive iodine uptake (RAIU) in healthy adults without dietary iodine restriction, single or repeated doses of 10 mg inorganic iodine solution were given to 22 Japanese volunteers, 18 men and 4 women with the mean age of 35.7 years, between 2011 and 2013. Changes in urinary iodine excretion, thyroid function and 24-hour RAIU were also evaluated. The median 24-hour RAIU without iodine restriction was 13% (range, 5-26%). A single-dose of 10 mg inorganic iodine suppressed the median 24-hour RAIU measured one hour after iodine administration to 3% (range, 1-7 %) and, in 90.9% of 22 participants their 24-hour RAIU was < 5%. For seven participants given 10 mg of inorganic iodine daily for 14 days, the median 24-hour RAIU measured at 24 hours after the last administration of iodine was 6% (range, 2-12%), although the inhibitory effect was diminished in two participants. Serum thyroid stimulating hormone concentration was slightly elevated in three participants without decreased serum FT3 and FT4 levels. We conclude that a single-dose of 10 mg inorganic iodine is sufficient to inhibit RAIU in adults, although the inhibitory effect of repeated-dose on RAIU is diminished when KI is given once daily. The dose, duration or interval of iodine administration should be evaluated in iodine-sufficient regions in a future.

Substituting Potassium Iodide for Methimazole as the Treatment for Graves' Disease During the First Trimester May Reduce the Incidence of Congenital Anomalies: A Retrospective Study at a Single Medical Institution in Japan.

BACKGROUND: To control hyperthyroidism due to Graves' disease, antithyroid drugs should be administered. Several studies have shown that exposure to methimazole (MMI) during the first trimester of pregnancy increases the incidence of specific congenital anomalies that are collectively referred to as MMI embryopathy. Congenital anomalies associated with exposure to propylthiouracil (PTU) have also recently been reported. METHODS: This study investigated whether substituting potassium iodide (KI) for MMI in the first trimester would result in a lower incidence of major congenital anomalies than continuing treatment with MMI alone. The cases of 283 women with Graves' disease (GD) were reviewed whose treatment was switched from MMI to KI in the first trimester (iodine group), as well as the cases of 1333 patients treated with MMI alone (MMI group) for comparison. Another major outcome of interest was the incidence of neonatal thyroid dysfunction. The subjects of the analysis of major congenital anomalies and neonatal thyroid dysfunction were live-born infants. RESULTS: The incidence of major anomalies was 4/260 (1.53%) in the iodine group, which was significantly lower than the incidence of 47/1134 (4.14%) in the MMI group. Two neonates in the iodine group had anomalies consistent with MMI embryopathy (0.8%), as opposed to 18 neonates in the MMI group (1.6%). None of the neonates exposed to KI had thyroid dysfunction or goiter. CONCLUSIONS: Substituting KI for MMI as a means of controlling hyperthyroidism in GD patients during the first trimester may reduce the incidence of congenital anomalies, at least in iodine-sufficient regions.

Radioiodine-Associated Exacerbation of Graves' Orbitopathy in the Japanese Population: Randomized Prospective Study.

CONTEXT: Exacerbation of Graves' orbitopathy (GO) after radioiodine (RAI) therapy has been examined in some populations but has not been fully described in Japanese populations. OBJECTIVE: The purpose of this study was to clarify the characteristics of GO exacerbation after RAI therapy and the effectiveness of low-dose prophylactic corticosteroid (PCS). DESIGN AND SETTING: This was a prospective randomized study in Tokyo, Japan. PATIENTS: Between June 2011 and June 2012, 295 patients with Graves' disease with either inactive GO or no GO received RAI therapy. Of these, 147 received no PCS (PCS-Off group), whereas 148 received low-dose PCS (starting dose, 15 mg/day of prednisolone) for 6 weeks (PCS-On group). We used magnetic resonance imaging to thoroughly evaluate GO before and 1 year after RAI therapy. MAIN OUTCOME MEASURES: Outcomes of GO 1 year after RAI therapy were determined. RESULTS: GO exacerbation occurred in 29 patients (9.8%), and only 7 patients (2.4%) required ophthalmic treatment. No significant difference in the frequency of GO exacerbation was seen between the groups (PCS-On group: n = 18 [12.1%]; PCS-Off group: n = 11 [7.5%]; P = .17). Significant prognostic factors were identified as thyroid-stimulating antibody (by 100% linear increase: risk ratio, 1.15; 95% confidence interval, 1.07-1.24; P = .0003) and clinical activity score (≥1 vs 0: risk ratio, 6.40; 95% confidence interval, 2.17-19.7; P = .0009). CONCLUSION: Exacerbation of GO after RAI therapy in the Japanese population appears less common than in other populations. Low-dose PCS did not produce a significant preventive effect and appeared insufficient. Patients presenting with risk factors would thus be recommended to receive higher-dose PCS.

Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: Is the serum hCG level useful for differentiating between active Graves' disease and GTT?

Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT, and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves' disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was significantly higher than in GTT group, and was a better parameter for differentiation.

Comparison of efficacy and adverse effects between methimazole 15 mg+inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves' disease patients with moderate to severe hyperthyroidism.

BACKGROUND: 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. OBJECTIVES: 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. DESIGN AND PATIENTS: 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). RESULTS: 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. CONCLUSION: 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.

Changes in pediatric thyroid sonograms in or nearby the Kanto region before and after the accident at the Fukushima Daiichi nuclear power plant.

Following the accident at the Fukushima Daiichi Nuclear Power Station which occurred on March 11, 2011 due to the Eastern Japan Great Earthquake (the Accident), there have been concerns over elevation of the risk of thyroid cancer among children due to internal exposure to radioactive iodine. In Fukushima Prefecture, screening of children with thyroid ultrasonography has been carried out, yielding numerous findings, suggesting a possible influence from the Accident. We report thyroid ultrasonographic findings, used by similar device at Fukushima Prefecture's study, at Ito-hospital. Of the 2721 children aged 15 or less who visited our hospital between January 2005 and March 2013, 1214 children (330 boys and 884 girls; median age, 12; range of age, 4-15) were covered by evaluation of thyroid ultrasonographic findings, excluding children known in advance to have thyroid disease on the basis of disease history, palpation and blood tests. Among these 1214 children, 709 children (58.4%) were found cysts (≤ 5 mm in 665 cases) by ultrasonography, 43 children (3.5%) were found nodules (≤ 5 mm in 18 cases) and 9 children (5.2%) were found an intrathyroid ectopic thymus. Analysis of the data before and after the Accident using the same device, involving age adjustment on the basis of the standard population in 2010, showed no difference in the incidence rate of cysts or nodules. In children examined, the incidence rate of cyst formation (particularly ≤ 5 mm) was higher, and there was no difference in the incidence rate of cysts or nodules between the pre- and post-accident period.

Lower incidence of postpartum thyrotoxicosis in women with Graves disease treated by radioiodine therapy than by subtotal thyroidectomy or with antithyroid drugs.

PURPOSE OF THE REPORT: The incidence of postpartum thyrotoxicosis (PT) in Graves disease (GD) patients treated with antithyroid drugs (ATDs) is higher than in the general population, but the incidence of PT among GD patients who had been treated with radioiodine (RI) or by subtotal thyroidectomy before their pregnancy is not well known. SUBJECTS AND METHODS: We reviewed the cases of women with GD who had become pregnant, and we selected the 188 women who had undergone RI therapy before the pregnancy and the 148 women who had undergone subtotal thyroidectomy for GD before the pregnancy as the subjects of this study. The ATD subjects were 107 women with GD who had become pregnant after being treated with ATDs alone before their pregnancy and were in remission before and throughout the pregnancy. RESULTS: The overall incidence of PT was 2.1% (4/188) in the RI group, 23.6% (35/148) in the subtotal thyroidectomy group, and 55.1% (59/107) in the ATD group. There were no cases of permanent thyrotoxicosis in the RI group. CONCLUSIONS: The incidence of PT among women with GD who have undergone RI therapy before their pregnancy was significantly low compared to thyroidectomy group and ATD group. This finding is interesting because the incidence of PT in the RI group was lower than subtotal thyroidectomy group even though thyroid volume had been greatly reduced by thyroidectomy. RI treatment is recommended in the choice of treatment for childbearing-age women as regards the risk of postpartum recurrence.

Rituximab-including combined modality treatment for primary thyroid lymphoma: an effective regimen for elderly patients.

BACKGROUND: Primary thyroid lymphoma (PTL) develops mostly in middle-aged and older females. However, the optimal treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL), which accounts for most PTL cases, is unclear. Rituximab is a promising drug that, in combination with traditional combination therapy, has demonstrated an increased antitumor effect without a substantial increase in toxicity. In this study, treatment outcomes of elderly patients with thyroid DLBCL who underwent rituximab-including combination therapy were analyzed. METHOD: Between January 2005 and December 2011, 43 patients 60 years of age or older (median 71 years, range 60-80 years) were diagnosed as having stage IE (n=12) or stage IIE (n=31) DLBCL, and three courses of R-CHOP therapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, adriamycin 40 mg/m2, vincristine 1.4 mg/m2, and prednisolone 100 mg/body) and involved field irradiation were planned. Treatment outcomes of these patients were retrospectively reviewed. RESULTS: Two patients terminated the treatment because of interstitial pneumonia during R-CHOP therapy. Only one patient showed treatment resistance and the regimen was changed; 42 patients (98%) responded to the treatment. Five-year overall survival and event-free survival were 87% (95% confidence interval [95% CI], 64-96%) and 74% (95% CI, 50-89%), respectively. CONCLUSION: The results of the present study indicate that rituximab-including combination therapy was effective for elderly patients with thyroid DLBCL. A multicenter, long-term observational study is needed to confirm this, and additional refinement of the treatment protocol is required to optimize the antitumor effect.

Frequency of Adverse Events of Antithyroid Drugs Administered during Pregnancy.

The frequency and types of adverse events after initial antithyroid drug (ATD) therapy during pregnancy have never been reported, nor has whether the frequency of adverse events is the same as among nonpregnant subjects ever been investigated. We investigated retrospectively the frequency of adverse events after initial ATD administration to previously untreated Graves' disease (GD) patients during pregnancy. We reviewed the charts of cases of 91 untreated pregnant women who came to our hospital for the first time and were newly diagnosed with GD during the period between January 1, 1999, and December 31, 2011. Thiamazole (MMI) was used to treat 40 patients and 51 patients were treated with propylthiouracil (PTU). Adverse events occurred in 5 patients (5/40; 12.5%) treated with MMI, and they consisted of cutaneous reactions in 5 patients. Adverse events occurred in five patients (5/51; 9.8%) treated with PTU, and they consisted of hepatotoxicity in two patients and cutaneous reactions in three patients. No patients experienced agranulocytosis or ANCA-related vasculitis. Comparison with the expected rate of adverse events in nonpregnant individuals showed that the frequency of adverse events in pregnant individuals was low.

Characteristics of agranulocytosis as an adverse effect of antithyroid drugs in the second or later course of treatment.

BACKGROUND: 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. OBJECTIVES: We investigated the characteristics of patients who developed agranulocytosis during their second or later course of ATD treatment. METHODS: 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." RESULTS: 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. CONCLUSIONS: When ATD treatment is resumed, patient follow-up is essential in order to monitor for the development of agranulocytosis.

Antithyroid drug treatment for graves' disease in children: a long-term retrospective study at a single institution.

BACKGROUND: The management of Graves' disease (GD) in children is associated with a dilemma. Although the established initial treatment for GD in children is antithyroid drug (ATD) treatment, the remission rate in children is said to be lower than in adults, and severe propylthiouracil-induced adverse events (AEs) are an issue. Definitive treatments are effective, but they often result in permanent hypothyroidism and the need for lifelong T4 supplementation. OBJECTIVE: The objective of this study was to investigate the outcome of ATD treatment, identify significant predictors of a remission, and evaluate the AEs of ATDs in a large pediatric population of GD patients. METHODS: We retrospectively assessed the reports of 1138 children up to 18 years of age who had been newly diagnosed with GD at our institution between 1982 and 2006. Their median age at diagnosis was 16 years (range: 3-18 years), and there were 995 females and 143 males. All patients were initially treated with an ATD. Remission was defined as maintenance of euthyroidism for more than 12 months after discontinuing ATD treatment and the absence of any relapses during the follow-up period. RESULTS: Of the 1138 patients, 723 continued on ATD treatment, 271 underwent surgery or radioactive iodine therapy, and 144 dropped out. Of the 723 patients who continued on ATD treatment, ATD treatment was subsequently ongoing in 84 and was discontinued in 639 (median duration of treatment: 3.8 years; range: 0.3-24.8 years). Of the 639 patients who discontinued ATD treatment, 334 (46.2%) achieved a remission, 247 (34.2%) experienced a relapse, and 58 (8.0%) dropped out. The cumulative remission rate increased with the duration of ATD treatment up until five years. No significant predictors of a remission were identified. The overall incidences of AEs associated with methimazole and propylthiouracil were 21.4% and 18.8% respectively. There were no fatal AEs in our population. While most AEs (91.6%) occurred within the first three months of ATD treatment, 2.7% developed more than two years after the start of ATD treatment. Seven of the eight late-onset AEs were induced by propylthiouracil. CONCLUSION: Long-term ATD treatment is a useful treatment option for GD in children.

Determination of pediatric reference levels of FT3, FT4 and TSH measured with ECLusys kits.

Reference ranges for serum thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in children were set using the assay kits currently used in clinical settings. A total of 342 children (111 males and 231 females) who were negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonographic examination of the thyroid gland were divided into 6 age groups: 4-6 years (45 children), 7-8 years (40), 9-10 years (53), 11-12 years (65), 13-14 years (83), and 15 years (56) for the study. FT3, FT4 and TSH levels were determined by electrochemiluminescence immunoassay (ECLIA) (ECLusys FT3, FT4 and TSH).The reference range for FT3 (pg/mL) was 2.91-4.70 for the age group of 4-6 years, 3.10-5.10 for the age group of 7-8 years, 3.10-4.87 for the age group of 9-10 years, 2.78-4.90 for the age group of 11-12 years, 2.77-4.59 for the age group of 13-14 years, and 2.50-4.64 for the age group of 15 years . The reference range for FT4 (ng/dL) was 1.12-1.67, 1.07-1.61, 0.96-1.60, 1.02-1.52, 0.96-1.52, 0.95-1.53. The reference range for TSH (µU/mL) was 0.62-4.90, 0.53-5.16, 0.67-4.52, 0.62-3.36, 0.54-2.78, 0.32-3.00. Serum FT3, FT4 and TSH levels in children differ from those in adults. It is, therefore, of importance to perform evaluation of thyroid function in children using reference values appropriate for the chronological ages, because misdiagnosis of hypothyroidism or inappropriate secretion of TSH (SITSH) and oversight of mild subclinical hypothyroidism could occur if the diagnosis is made using reference values for adults.

Pharmacological conversion of atrial fibrillation in the patients of Graves' disease.

BACKGROUND: Hyperthyroidism is one of the common causes of atrial fibrillation (AF), and AF is associated with increased morbidity and mortality due to thromboembolism. The sinus rhythm maintenance rate of hyperthyroidism-induced AF patients after conversion to sinus rhythm is excellent. The present study was undertaken to assess the efficacy and safety of bepridil, a multichannel blocker, in patients with hyperthyroidism-induced persistent AF. METHODS AND RESULTS: Sixty-two patients with hyperthyroidism-induced persistent AF were treated with bepridil. Oral bepridil therapy resulted in conversion to sinus rhythm in 32 (51.6%) of the 62 patients. There were no significant differences in clinical characteristics between the responders and non-responders. At the observation period of an average of 23.9 months, the sinus rhythm maintenance rate was found to be 81.3%. Adverse effects consisted of abnormal QTc prolongation in 3 patients and sinus bradycardia in 10 patients. There was one death in which a causal association with bepridil could not be ruled out. CONCLUSIONS: Bepridil is as beneficial treatment to convert AF for the patients with hyperthyroidism-induced persistent AF as it is for the patients with AF due to other causes. However, bepridil should be used with caution to avoid serious side effects.

Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation.

BACKGROUND: Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy. OBJECTIVES: We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women. METHODS: We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations. RESULTS: The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation. CONCLUSIONS: In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.

Hepatotoxicity and cutaneous reactions after antithyroid drug administration.

OBJECTIVE: Use of the antithyroid drugs (ATDs) thiamazole (MMI) and propylthiouracil (PTU) is associated with a high frequency of side effects. When patients experience side effects with one (the 1st) ATD, it is usually discontinued and another is administered (the 2nd ATD). We investigated side effects associated with the 1st and 2nd ATDs. DESIGN AND PATIENTS: Four hundred forty-nine patients with untreated Graves' disease (GD) were randomly assigned to three groups according to ATD type and/or dosage: 15 mg/day MMI, 30 mg/day MMI and 300 mg/day PTU. The type, frequency and onset of side effects were assessed. We also studied the side effects associated with the 2nd ATD after cessation of the 1st ATD. MEASUREMENTS: Cutaneous reactions, liver dysfunction and other side effects were examined every 2 weeks after starting ATD administration. RESULTS: The overall frequency of side effects in patients taking 15 mg/day MMI was low. The frequencies of cutaneous reactions in patients taking 30 mg/day MMI and hepatotoxicity in those taking 300 mg/day PTU were high. Hepatotoxicity developed later than cutaneous reactions with PTU. Hepatotoxicity developed earlier in the 30 mg/day MMI group than in the other two groups. The frequency of side effects did not differ between the 2nd and 1st ATDs. Hepatotoxicity occurred at a higher frequency in patients who were switched from MMI to PTU because of hepatotoxicity of the former. CONCLUSION: Attention to the onset times of side effects and cross-reactivity of ATDs can lead to safer treatment of GD.

Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease.

CONTEXT: Although antithyroid drug (ATD)-induced hematopoietic damage is a significant concern, it has not been comprehensively investigated. OBJECTIVE: Our objective was to describe the clinical features of ATD-induced hematopoietic damage. DESIGN AND SETTING: This was a retrospective cohort study in Tokyo, Japan. PATIENTS: Between January 1983 and December 2002, 50,385 patients at Ito Hospital were diagnosed with Graves' disease. We retrospectively reviewed their medical, pathological, and laboratory records between January 1983 and December 2010. MAIN OUTCOME: Incidence and clinical features of ATD-induced agranulocytosis and pancytopenia were evaluated. RESULTS: Of 55 patients with documented hematopoietic damage, 50 had agranulocytosis and 5 had pancytopenia. All of them received ATD, either methimazole (n = 51) or propylthiouracil (n = 4). Median intervals between initiation of ATD therapy and the onset of agranulocytosis and pancytopenia were 69 d (range, 11-233 d) and 41 d (range, 32-97 d), respectively. Either anemia or thrombocytopenia was also documented in seven of the 50 patients with agranulocytosis. Agranulocytosis was the first manifestation of hematopoietic damage in four of the five patents with pancytopenia. Hematopoietic damage recovered with supportive measures including granulocyte colony-stimulating factor (n = 37), steroids (n = 10), and other supportive measures (n = 8) in 54 patients, whereas the remaining patient died of complications from infection. This study failed to identify the risk factors for ATD-induced hematopoietic damage. CONCLUSIONS: This study showed that ATD cause hematopoietic changes, which are occasionally severe and potentially fatal. The pathogenesis of agranulocytosis and pancytopenia might overlap, and additional studies are warranted to clarify this and to establish an optimal treatment strategy.

Reference limits for serum thyrotropin in a Japanese population.

The aim of the present study was to establish new reference intervals for serum thyrotropin (TSH) levels in Japanese subjects without antithyroid antibodies. We reviewed the serum TSH level of all patients 20 years of age and over who attended the outpatient clinic of our hospital between January 1, 2003, and September 20, 2010. The thyroid gland of every patient was examined by ultrasonography, and subjects found to have a normal thyroid were chosen. The following subjects were excluded: subjects with past history of thyroid diseases; subjects whose serum was positive for antithyroid antibodies; pregnant women; patients taking medication that might affect their free thyroxine (fT(4)) level or TSH levels. Ultimately, 1388 subjects were included in the reference population. The serum TSH levels shifted to higher ranges as the age of the groups increased. The calculated reference range was 0.39-4.29 mIU/L in the 20-29-year-old group, 0.34-3.90 mIU/L in the 30-39-year-old group, 0.56-5.02 mIU/L in the 40-49-year-old group, 0.51-5.30 mIU/L in the 50-59-year-old group, 0.60-4.85 mIU/L in the 60-69-year-old group, 0.62-6.15 mIU/L in the over 70-year-old group. The results of this study showed that the upper limit of the normal range of serum TSH levels increased with age in a Japanese population. Since the number of elderly reference subjects was relatively small, further study is needed. Setting the age- and race-specific reference limits for serum TSH levels is important in order to prevent significant misclassifications of patients with abnormal TSH levels.