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The effectiveness of potassium iodide (KI) (100 mg/day) was evaluated in 504 untreated patients with Graves' hyperthyroidism (GD). Initial response to KI within 180 days, the effect of additional methylmercaptoimidazole (MMI) or radioactive iodine (RI) in resistant or escaped patients, and long-term prognosis were evaluated. Serum fT

To clarify the actual administration of thiamazole (MMI), the first choice of antithyroid drugs, the actual therapy provided by the Japan Thyroid Association (JTA) members for the following conditions was surveyed. The subjects included adult patients, pregnant women, and pediatric patients with Graves' disease who visited each medical institution from September 2019 to February 2020. Initial doses, frequency of administration, maintenance doses, maximum doses, consultation intervals for pregnant women, and dosages administrated to breastfeeding mothers were surveyed. The total number of cases collected was 11,663. Administration of 15 mg once a day was the most common initial therapy, constituted 74.4% (2,526/3,397 cases) of adults, 33.8% (44/130) of pregnant women, and 50.8% (61/120) of children. The maintenance dose before discontinuation was equivalent to 2.5 mg/day in 52.3% (3,147/6,015). The most common maximum dose for adults and children was 30 mg/day, administrated to 57.5% of adults (223/388) and 59.6% (28/47) of children; for pregnant women, it was 15 mg/day, administrated to 71.1% (27/38). The most common consultation interval for pregnant women was every four weeks (32.1%, 341/1,063). In lactating mothers, the dose was 10 mg/day or less in 366 of 465 cases (78.7%). Breastfeeding was also allowed 4-6 hours after the administration of 15-20 mg/day in 69 patients (14.8%). Breastfeeding was prohibited in 26 patients (5.6%). In conclusion, initial MMI therapy was started with 15 mg once a day in most patients, and MMI was also administrated to lactating mothers following the Graves' disease treatment guidelines by the JTA.

The treatment of Graves' hyperthyroidism (GD) complicated with malignancy is challenging, as anti-thyroid thionamide drugs (ATDs) and anti-cancer chemotherapy are both associated with a risk of neutropenia. Treatment with conventional ATDs, radioactive iodine (RAI) or potassium iodide (KI) was attempted in 8 patients with malignancy (34-80 years of age; 2 males and 6 females) in whom GD had been fortuitously diagnosed during a detailed systematic examination. Three patients requiring surgery were initially treated conventionally with methylmercaptoimidazole (MMI), MMI and KI or RAI (group A; one patient each). The patients became euthyroid on days 17-31 and underwent surgery on days 25-47. RAI therapy was administered to one patient after surgery. The patients were then treated with KI during chemotherapy. Five other patients who did not require surgery were initially treated with 100 mg KI monotherapy (group B). The serum free T4 level declined immediately in all of these patients, and they became euthyroid on days 7-18, remaining almost entirely euthyroid for more than 120 days. Anti-cancer chemotherapy was successfully completed for three of the patients while taking KI, despite the patients experiencing repeated episodes of anti-cancer chemotherapy-induced neutropenia. Our present findings suggest that, in patients with GD and malignancy, MMI + KI or RAI may be required if immediate surgery is scheduled, but KI monotherapy may be worth trying, if anti-cancer chemotherapy is scheduled, thus avoiding the possibility of thionamide-induced neutropenia.

Since there have been few reports on the long-term prognosis of Graves' hyperthyroidism, the prognosis of 549 Graves' hyperthyroidism patients initially treated with thionamide and followed for >8 (range: 8.6-36.4) years was studied, evaluating the change in the TSH binding inhibitor immunoglobulin activity (TBII). The distribution of the time required for the first disappearance of TBII was normal after logarithmic conversion, and the mean ± 2 SD was 1.5 (0.3-8.1) years. TBII became negative once within 5 years in 78.9% of patients. However, TBII re-elevation was observed in 47.8% of this group (fluctuating type). Remission was observed in 88.9% of the non-fluctuating type (smooth remission) and 37.2% of the fluctuating type patients. TBII remained positive for >5 years in 21.1% (smoldering type) of patients, with remission observed in only 19.8% of patients. Final remission was observed in 301 (54.8%) patients; the median time to remission was 6.8 (interquartile range: 4.0-10.9) years. A longer time until normalization of TBII and higher final thyroid weight were associated with a poor prognosis. Spontaneous hypothyroidism was observed in 6.0% of patients, independent of the TBII change. Our findings suggest that remission of Graves' hyperthyroidism mostly occurred after 4-11 years treatment. While predicting the prognosis before therapy was difficult, the clinical course may suggest a better prognosis if TBII disappears within five years without TBII fluctuation or enlargement of the goiter. Patients may safely wait more than five years to undergo ablative therapy if they hope to avoid permanent hypothyroidism.

Propylthiouracil (PTU)-induced otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is an extremely rare adverse event associated with anti-thyroid drugs and is not well recognized. A 42-year-old woman with Graves' disease undergoing PTU therapy for 8 years visited our hospital because of earache and congested feeling in her left ear. Blood tests, a computed tomography scan and pure tone audiometry revealed otitis media and moderate mixed hearing impairment. Antibiotics, ear drops with antibiotics and painkillers were administered. However, her earache and hearing loss gradually got worse and symptoms of facial nerve palsy appeared. At several weeks after initiation of the treatment, a high serum level of myeloperoxidase (MPO)-ANCA, 75.6 U/mL, was revealed. After excluding other causes, she was diagnosed with OMAAV. PTU was suspected as the cause of her OMAAV and was immediately discontinued, and prednisolone was started. Hearing impairment in her left ear gradually got better and showed substantial improvement. Facial nerve palsy disappeared. Although PTU-induced OMAAV is an extremely rare disease, it is important to recognize the disease, as delayed treatment can lead to irreversible hearing loss, hypertrophic pachymeningitis, and subarachnoid hemorrhage. When patients taking anti-thyroid drugs, especially PTU, are diagnosed with refractory otitis media or hearing loss, it is possible that OMAAV might be the cause and thus serum ANCA levels should be evaluated.

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.

Methimazole (MMI) and propylthiouracil (PTU) are commonly used for the treatment of Graves' disease. They share similar inhibitory effects on thyroid hormone biosynthesis by interfering with thyroid peroxidase (TPO)-mediated oxidation and organification of iodine. However, their potential effects on other thyroid functional molecules have not been explored in depth. To identify novel effects of MMI and PTU, DNA microarray analysis, real-time PCR, Western blotting, immunofluorescence staining and confocal laser scanning microscopy were performed using FRTL-5 rat thyroid cells. DNA microarray analysis indicated that both MMI and PTU suppress iodotyrosine deiodinase 1 (Iyd, Dehal1) mRNA levels. Further studies revealed that Dehal1 mRNA levels was stimulated by TSH, insulin and serum, while it was suppressed by iodine and a follicular concentration of thyroglobulin. MMI and PTU significantly suppressed Dehal1 expression induced by TSH, insulin and serum. On the other hand, although MMI suppressed Dehal1 expression in the absence of TSH, PTU only weakly suppressed Dehal1 without TSH. These results suggest that PTU and MMI may use different mechanisms to regulate Dehal1 expression, and TSH may play essential and differential roles in mediating PTU and MMI signals in thyrocytes. The drugs also inhibited re-distribution of Dehal1 protein into newly formed lysosomes following thyroglobulin endocytosis. These findings imply complex and multifaceted regulation of Dehal1 in the thyroid and suggest that MMI and PTU modulate Dehal1 expression and distribution of the protein in thyrocytes to exert their effect.

This study is aimed to explore the relationship between bone marrow characteristics and clinical prognosis of antithyroid drug (ATD) induced agranulocytosis. A retrospective study was conducted in the first affiliated hospital of the University of South China. A total of 33 hospitalized patients diagnosed with ATD-induced agranulocytosis were analyzed. The bone marrow characteristics were classified into two types. Type I was characterized by reduction or absence of granulocytic precursors and type II was recognized as hypercellular bone marrow with dysmaturity of granulocytic cells. Bone marrow of 20 cases (61%) were characterized with type I whereas 13 cases (39%) with type II. The median duration of neutrophil recovery and high-grade fever were 4.7 ± 1.0 days and 3.6 ± 2.5 days respectively for type II, compared to 8.0 ± 2.8 days and 8.6 ± 3.1 days for type I (p < 0.01 in both compared groups). However, there was no significant difference between the two types in terms of age, median duration of drug administration before the diagnosis of agranulocytosis, the amount of neutrophil count on admission and the total administration dose of granulocyte-colony stimulating factor (G-CSF) before bone marrow examination. Two cases of type I died of complications from infection. This study showed that the bone marrow characteristics of ATD-induced agranulocytosis could be classifed into two types. Also, the clinical prognosis was closely related to the bone marrow features. Type I is the dominant type which is usually associated with worse clinical prognosis compared to type II.

We previously reported that serum interleukin-18 (IL-18) levels were significantly increased in hyperthyroid Graves' disease patients. The development of insulin resistance in hyperthyroidism has been documented. We investigated the relationship between IL-18 and insulin resistance in patients with hyperthyroid Graves' disease and in experimental hyperthyroid mice. Then, we examined whether IL-18 induces insulin resistance in mice injected with IL-18 for a week. A significant positive correlation was observed between serum IL-18 levels and parameters such as thyroid functions and homeostasis model assessment for insulin resistance in hyperthyroid Graves' disease. In experimental hyperthyroid mice, IL-18 was significantly elevated. Insulin resistance increased in experimental hyperthyroid mice and IL-18-injected mice. These findings suggest IL-18 to be an important factor inducing insulin resistance in hyperthyroidism.

This study is to explore the role of IL-23/IL-17 axis in subjects with Graves' disease, while IL-23/IL-17 axis plays an important role in a number of autoimmune diseases, but it's not clear in Graves' disease. Thirty-three patients with Graves' disease as a GD group, 15 patients with euthyroid GD as eGD group and 22 healthy volunteers as a control group whose age- and sex-matched. Peripheral blood was collected and peripheral blood mononuclear cells (PBMCs) were isolated in the both groups, then PBMCs were cultured in the presence or absence of IL-23 in vitro. The expression of retinoid-related orphan receptor gamma t (RORγt) and IL-17 mRNA were examined by Semi-quantitative RT-PCR, and the levels of IL-17 protein were measured by enzyme-linked immunosorbent assay. The expression of RORγt, IL-17 mRNA and IL-17 protein levels were markedly higher in GD and euthyroid GD group as compared with the control group. IL-17 levels were still higher in euthyroid GD patients. When PBMCs derived from the three groups were cultured in vitro with or without IL-23, the expression of RORγt in GD group with IL-23 dramatically increased as compared with that in GD group without IL-23 and in control group with IL-23. RORγt expression of PBMCs from eGD group cultured with IL-23 was increased compared with that cultured without IL-23. The levels of IL-17 mRNA and the protein were also significantly higher than that of GD and eGD cultured without IL-23 and control group. There was no difference of the expression of RORγt mRNA and IL-17 protein levels between GD and eGD group cultured with or without IL-23. Our studies demonstrated that IL-23/IL-17 axis is associated with the pathogenesis of Graves' disease in it activated term. This effect is not dependent on thyroid function, but may be associated to the immunity.

Propylthiouracil (PTU) is recommended as a first-line antithyroid drug (ATD) during first trimester organogenesis in pregnancy because recent evidence suggests that methimazole (MMI) may be associated with congenital anomalies. However, PTU more commonly causes myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which usually occurs during prolonged treatment, compared with MMI. We report a case of MPO-ANCA-associated vasculitis in a 35-year-old woman with Graves'disease. Although her thyroid function could be maintained euthyroid by MMI, her ATD was switched to PTU because she wished to become pregnant. The patient presented with flu-like symptoms 8 days after starting PTU and developed hemoptysis and dyspnea at 22 days. Her MPO-ANCA titer was 21 ELISA units (EUs) before PTU treatment but increased to 259 EUs at 22 days after PTU treatment. Her clinical condition improved with the discontinuation of PTU and with immunosuppressive therapy. This case indicated that MPO-ANCA vasculitis occurred within several weeks after the initiation of PTU and that this side effect could be caused by the change from MMI to PTU. Thus, our clinical observation suggests that patients treated with PTU should be carefully monitored for MPO-ANCA titers and variable manifestations of MPO-ANCA-associated vasculitis regardless of the period of administration.

Thyroid storm is an endocrine emergency which is characterized by multiple organ failure due to severe thyrotoxicosis, often associated with triggering illnesses. Early suspicion, prompt diagnosis and intensive treatment will improve survival in thyroid storm patients. Because of its rarity and high mortality, prospective intervention studies for the treatment of thyroid storm are difficult to carry out. We, the Japan Thyroid Association and Japan Endocrine Society taskforce committee, previously developed new diagnostic criteria and conducted nationwide surveys for thyroid storm in Japan. Detailed analyses of clinical data from 356 patients revealed that the mortality in Japan was still high (∼11%) and that multiple organ failure and acute heart failure were common causes of death. In addition, multimodal treatment with antithyroid drugs, inorganic iodide, corticosteroids and beta-adrenergic antagonists has been suggested to improve mortality of these patients. Based on the evidence obtained by nationwide surveys and additional literature searches, we herein established clinical guidelines for the management of thyroid storm. The present guideline includes 15 recommendations for the treatment of thyrotoxicosis and organ failure in the central nervous system, cardiovascular system, and hepato-gastrointestinal tract, admission criteria for the intensive care unit, and prognostic evaluation. We also proposed preventive approaches to thyroid storm, roles of definitive therapy, and future prospective trial plans for the treatment of thyroid storm. We hope that this guideline will be useful for many physicians all over the world as well as in Japan in the management of thyroid storm and the improvement of its outcome.

A questionnaire administered in 2009 found that members of the Korean Association of Thyroid-Endocrine Surgeons (KATES) favored more aggressive treatment of well-differentiated thyroid carcinoma (WDTC) than physicians from other countries. This study assessed the changes in practical management of WDTC in Korea from the previous survey. Questionnaires were sent by e-mail to KATES members. A total of 101 members completed the questionnaire. Their responses were compared with response for the 2009 survey. Of the respondents, 53.5% and 80.2% indicated that they would perform fine-needle aspiration cytology on nodules that were

According to the guideline issued by the Japan Thyroid Association in 2006 for treatment of Graves' disease, discontinuing antithyroid drug (ATD) therapy is recommended when serum free thyroxine (FT4) and thyroid stimulating hormone (TSH) concentrations have been maintained within the reference range for a certain period after treatment with one ATD tablet every other day (minimum maintenance dose therapy, MMDT). In this retrospective study, the relationship between MMDT duration and remission rate was investigated. The participants were 107 consecutive patients with Graves' disease whose ATD therapy was stopped according to the guideline. Serum FT4, TSH, and TSH receptor antibody (TRAb) levels were measured when ATD was discontinued and every 3 months thereafter. The percentage of patients in remission was 86.9% at 6 months, 73.8% at 1 year, and 68.2% at 2 years after ATD discontinuation. The remission rate increased with MMDT duration, being significantly higher in patients with MMDT durations of 19 months or more than those with MMDT durations of 6 months or less. In patients with MMDT durations of 6 months or less, the remission rate was significantly lower in TRAb-positive patients than in TRAb-negative patients at the time of withdrawal of ATD; however, this was not observed in patients with MMDT durations of 7 months or more. These findings suggest that in patients who discontinue ATD after a certain MMDT duration, the remission rate increases as the MMDT duration increases, and ATD should not be discontinued in TRAb-positive patients with MMDT durations of 6 months or less.

A 19-year-old girl presented at our emergency room with hypokalemic periodic paralysis. She had a thyrotoxic goiter and had experienced three paralytic attacks during the previous 2 years on occasions when she stopped taking antithyroid drugs. In addition to thyrotoxic periodic paralysis (TPP), she had metabolic acidosis, urinary potassium loss, polyuria and polydipsia. Her reduced ability to acidify urine during spontaneous metabolic acidosis was confirmed by detection of coexisting distal renal tubular acidosis (RTA). The polyuria and polydipsia were caused by nephrogenic diabetes insipidus, which was diagnosed using the water deprivation test and vasopressin administration. Her recurrent and frequent paralytic attacks may have been the combined effects of thyrotoxicosis and RTA. Although the paralytic attack did not recur after improving the thyroid function, mild acidosis and nephrogenic DI have been remained subsequently. Patients with TPP, especially females with atypical metabolic features, should be investigated for possible precipitating factors.

A 34-year-old Japanese woman was referred to the hospital because of general fatigue and palpitations. She was diagnosed as having resistance to thyroid hormone (RTH) and Hashimoto's thyroiditis at the age of 28. She felt general fatigue, palpitations, heat intolerance, and sweating for 6 months. Thyroid function tests demonstrated elevated levels of free triidothyronine (T3) and free thyroxine (T4) that were above detectable ranges and a completely suppressed level of TSH that was below the detectable range. Titers of anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) were positive. A 20-minute Technetium-m99 pertechnetate thyroid uptake imaging study showed an elevated value of 39.53% and a normal-shaped thyroid gland. These results indicated that Graves' disease (GD) caused primary hyperthyroidism. Pituitary and peripheral tissues responded to the presence of excess thyroid hormone in the patient. Oral administration of methimazole was started and continued for 1 year 10 months, after which it was ceased. Two years after the cessation of methimazole treatment, level of free T4 was elevated compared to reference range, but levels of TSH and free T3 were within normal reference ranges. Titers of TRAb and TSAb remained negative for 2 years. These findings indicated that the patient's GD was in remission. In conclusion, it is difficult to make a differential diagnosis between GD with RTH and GD alone if RTH is not diagnosed before the onset of GD. An antithyroid drug is able to cause the remission of GD with RTH.

The effect of ingesting seaweed "Kombu" (Laminaria japonica) on thyroid function was studied in normal Japanese adults. Ingesting 15 and 30 g of Kombu (iodine contents: 35 and 70 mg) daily for a short term (7-10 days) significantly increased serum thyrotropin (TSH) concentrations, exceeding the normal limits in some subjects. The serum free thyroxine (FT(4)) and/or free 3,5,3'-triiodothyronine (FT(3)) concentrations were slightly decreased within the normal limits. During long term daily ingestion of 15 g of Kombu (55-87 days), the TSH levels were elevated and sustained while the FT(4) and FT(3) levels were almost unchanged. Urinary excretion of iodine significantly increased during ingestion of Kombu. These abnormal values returned to the initial levels 7 to 40 days after discontinuing the ingestion of Kombu. Based on these findings that thyroid function was suppressed during ingestion of Kombu, though the effect was reversible, we recommend Japanese people avoid ingesting excessive amounts of seaweed.

We experienced a case of fetal goitrous hypothyroidism in an infant delivered by a 33-year-old woman receiving 300 mg/day of propylthiouracil (PTU) for hyperthyroidism due to Graves' disease. A large fetal goiter (maximum diameter, 60 mm) was detected by magnetic resonance imaging (MRI) at 36 weeks of gestation. Initial fetal blood sampling revealed hypothyroidism with a serum thyroid-stimulating hormone (TSH) of 99 microIU/mL, free triiodothyronine (T(3)) of 1.97 pg/mL, and free thyroxine (T(4)) of 0.29 ng/dL. Consequently, a diagnosis of fetal goitrous hypothyroidism due to transplacental passage of maternal PTU was made. To reduce the risk of perinatal complications, 300 microg of levothyroxine sodium (L-T(4)) was administered into the maternal amniotic fluid twice between 37 and 38 weeks of gestation. Subsequent fetal MRI showed that the size of goiter had decreased. At 38 weeks and 5 days of gestation, a 3042-g male infant was born by cesarean section. There were no severe complications at delivery, although mild tachypnea was observed and the infant's thyroid gland was slightly enlarged. He was treated with L-T(4) for two weeks. At present, his growth and neurological development are normal. This case indicates that intrauterine therapy by the intraamniotic administration of L-T(4) can be effective in treating fetal goitrous hypothyroidism even during late gestation.

Studies on thyrotropin receptor autoantibodies (TRAb) by measurement of both thyroid-stimulating antibodies (TSAb) and thyrotropin-binding inhibitory immunoglobulins (TBII) in serum from children with Graves' disease are limited in number of studies. The aim of this study was to investigate the levels of serum TSAb and TBII in children with Graves' disease, and to evaluate the clinical significance of these antibodies. We measured the serum TSAb and TBII at diagnosis and during management in 65 children with Graves' disease. Patients were divided into four groups according to their metabolic state: those with untreated active Graves' disease, those receiving treatment with antithyroid drugs, those in remission, and those in relapse. At diagnosis, both TSAb and TBII assays had high sensitivities and high specificities. In follow-up, the levels of both TSAb and TBII paralleled the course of the disease. There was a strong positive correlation between TSAb and TBII. TBII levels were significantly higher in the patients with ophthalmopathy than those without ophthalmopathy in untreated Graves' children. It was concluded that TSAb and TBII measurements are valuable in the diagnosis and management of children with Graves' disease.

Hyperhomocysteinemia is a risk factor for premature atherosclerotic vascular diseases. It is known that plasma homocysteine levels are higher in hypothyroid patients compared to healthy subjects. The aim of our study was to assess plasma total homocysteine concentrations in hyperthyroid patients before and after treatment when euthyroid status was reached and compare them with control group. Thirteen hyperthyroid patients (age, 42.9 +/- 15.6 year) and eleven healthy subjects (age, 39.9 +/- 12.5 year) were involved in the study. Plasma levels of homocysteine and serum cholesterol, triglyceride, HDL cholesterol, urea, creatinine, vitamin B12, folate were measured before and after treatment. LDL cholesterol and creatinine clearances were calculated. Pretreatment homocycteine levels of the hyperthyroid patients were significantly lower than healthy controls (11.5 +/- 3.6 micromol/L vs. 15.1 +/- 4.5 micromol/L, respectively, p

Although many researchers have reported clinical and laboratory parameters for prediction of remission in Graves' disease during or after anti-thyroid drug therapy, there is no reliable one to assure the complete remission. We prospectively examined a practical therapy with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease. Fifty-seven patients with Graves' disease were treated with anti-thyroid drugs at the initial dose of 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU). Then, doses were gradually decreased, and finally discontinued when the patients were able to maintain euthyroid (normal FT4 and TSH) for at least 6 months with the minimum maintenance dose (MMI 5 mg every other day or PTU 50 mg every other day). After discontinuation of drugs, FT4, FT3, TSH and TSH-binding inhibitory immunoglobulin (TBII) were measured every one to two months for the first 6 months and every 3-4 months for the next 18 months to confirm continuous remission. After 2 years of drug cessation, 46 (81%) of 57 patients were in remission and the other 11 patients had relapsed into thyrotoxicosis. At the time of drug discontinuation, the serum concentration of FT4, FT3 and TSH, titers of anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies, goiter size were not different between the remission and relapse groups. At the time of drug cessation, the activities of TBII and thyroid-stimulating antibodies (TSAb) overlapped between the two groups, although they were significantly lower in the remission group than in the relapse group (p

We describe a patient with right adrenal tumor detected incidentally. The tumor was diagnosed as pheochromocytoma by endocrinological and radiological studies, and was removed surgically. Graves' disease, which had been in remission for more than two decades after discontinuation of antithyroid drug treatment, relapsed during preoperative evaluation of pheochromocytoma when the patient was treated with alpha- and beta1-adrenergic antagonists. Administration of methimazole resulted in a rapid improvement of thyroid function and the patient remained euthyroid on small doses of methimazole. This case may suggest possible involvement of excessive catecholamine secretion and beta2-adrenergic receptor activation by pheochromocytoma in the relapse of Graves' disease.

Objective: Controversy abounds on the issue of seasonal variation in new onset of Graves' disease, partly due to the difficulty of precisely dating the exact start of symptoms. To address the possible relationship between climatic changes and disease activity from a different perspective, we reviewed time of relapse during regular follow-up after successful drug treatment with thionamides. Design: Retrospective analysis of a case series in a university clinic. Patients and measurements: We consecutively registered patients who experienced re-emergence of hyperthyroidism between 1992 and 2001 after successful antithyroid drug therapy. Excluded were subjects with superimposing painless thyroiditis, in postpartum, on immunomodulatory drugs, or off thionamides prematurely on their own volition. Results: Fifty-two patients recurred 2 to 36 months after drug cessation. The frequency was higher in spring and summer (March to August) than in autumn and winter (September to February). With a new coated-tube radioreceptor assay, TSH binding inhibitor immunoglobulin activity was detected in sera from 87.5% of the reworsened patients. Conclusions: Graves' disease tends to relapse more frequently in spring and summer. Further clinical studies are warranted to clarify underlying mechanism (s) for this seasonal variation.

In this study, we retrospectively analyzed 18 patients in whom antithyroid drug (ATD)-induced agranulocytosis developed during treatment of Graves' disease. All patients were more than 20 years of age, and we saw no correlation between age and the development of agranulocytosis. In 17 of 18 patients, ATD-induced agranulocytosis developed within 2 to 12 weeks of starting ATD treatment. Development of agranulocytosis was related to the dose of ATD. In some patients, agranulocytosis developed abruptly, and even weekly routine WBC and granulocyte counts failed to predict all case occurrences. Fever and sore throat were the earliest symptoms of agranulocytosis; patients who developed either of these symptoms were closely monitored immediately with WBC and granulocyte count examinations. In this series of patients, treatment with granulocyte-macrophage colony stimulating factor (GM-CSF) increased the granulocyte counts, whereas the effectiveness of glucocorticoid treatment was not confirmed.

A 48-year-old woman was diagnosed and treated for Graves' disease (GD) in 1999 but she discontinued treatment at her own discretion. In 2011, she was admitted to a local hospital for management of thyrotoxic crisis. Treatment with propylthiouracil, iodide potassium (KI), and prednisolone (PSL) was started, which resulted in improvement of the general condition. PSL and KI were discontinued before she was transferred to our hospital. At the local hospital, fasting plasma glucose (FPG) was 212 mg/dL and hemoglobin A1c concentration was 11.2%; intensive insulin therapy had been instituted. Upon admission to our hospital, FPG level was 122 mg/dL, but insulin secretion was compromised, suggesting aggravation of thyroid function and deterioration of glycemic control. The FPG level increased to 173 mg/dL; continuous glucose monitoring (CGM) identified dawn phenomenon at approximately 0400 h. Resumption of KI resulted in improvement of FPG and disappearance of the dawn phenomenon, as assessed by CGM. These results indicate that in patients with compromised insulin secretion, hyperthyroidism can induce elevation of not only postprandial blood glucose, but also FPG level due to the dawn phenomenon and that the dawn phenomenon can be alleviated with improvement in thyroid function. To our knowledge, no studies have assessed glucose variability by CGM before and after treatment of Graves' disease. The observations made in this case shed light on the understanding of abnormal glucose metabolism associated with Graves' disease.

We report a 49-year-old man with primary hyperthyroidism who presented with pancytopenia. The patient presented with leg edema, sinus tachycardia, cardiomegaly, and pleural effusions, all from congestive heart failure. Laboratory data showed pancytopenia and primary hyperthyroidism; echocardiogram showed diffuse hyperkinesis of the left ventricular wall and right ventricular overloading. The bone marrow was moderately hypercellular and compatible with arrested hematopoiesis. Pancytopenia and heart failure improved after administration of methimazole and diuretics. However, high levels of thyroid hormone recurred with pancytopenia 4 months after admission. Therefore, subtotal thyroidectomy was performed, and the levels of thyroid hormones and peripheral blood cell counts have remained normal. Pancytopenia may be caused by hyperthyroidism.

A 65-year-old woman with Graves' disease presented marked diurnal changes in white blood cell (WBC) and granulocyte counts. Granulocyte count was low and sometimes decreased to 0.2-0.3 x 10(9)/l in the early morning and increased in the afternoon irrespective of her thyroid status. She did not develop sore throat or fever during the investigation period. The present study indicates that these unusual diurnal changes in WBC and granulocyte counts should be considered in the differential diagnosis of agranulocytosis in Graves' disease patients treated with an antithyroid drug.

Here we report three cases of hyperthyroid Graves' disease that occurred after partial thyroidectomy for papillary carcinoma. In Case 1, the patient first developed hyperthyroidism 2 years after resection of left thyroid lobe, was treated for 2 years with antithyroid drug which was then discontinued, and relapsed with periodic paralysis after 8 years of remission. In Case 2, a hyperfunctioning remnant thyroid was noted 22 years after right hemithyroidectomy. In Case 3, where thyrotoxic symptoms became evident 7 weeks after right hemithyroidectomy, autoantibodies to thyroglobulin and thyroid microsome were positive in preoperative serum, in line with a report by others detecting these antibodies in 2 out of 3 such cases examined. Later bioassay revealed activity of thyroid stimulating antibodies in that serum, with further increase in titer in the sample taken at the clinical manifestation. Hence in Case 3, surgical stress may have altered immunological homeostasis, promoting a preclinical Graves' disease to full-blown hyperthyroidism.

Although many cases of simultaneous presentation of thyrotoxicosis (thyroid storm) and diabetic ketoacidosis have been reported, it is a clinically unusual situation and remains a diagnostic and management challenge in clinical practice. The diagnosis of diabetic ketoacidosis or thyrotoxicosis may be masked leading to serious complications. We report two patients with simultaneous thyrotoxicosis and diabetic ketoacidosis resulted in sudden cardiac arrest, emphasizing early recognition and prompt treatment when these two disease are presented concomitantly.

High titer of maternal thyroid-stimulating hormone receptor antibody (TRAb) in patients with Graves' disease could cause fetal hyperthyroidism during pregnancy. Clinical features of fetal hyperthyroidism include tachycardia, goiter, growth restriction, advanced bone maturation, cardiomegaly, and fetal death. The recognition and treatment of fetal hyperthyroidism are believed to be important to optimize growth and intellectual development in affected fetuses. We herein report a case of fetal treatment in two successive siblings showing in utero hyperthyroid status in a woman with a history of ablative treatment for Graves' disease. The fetuses were considered in hyperthyroid status based on high levels of maternal TRAb, a goiter, and persistent tachycardia. In particular, cardiac failure was observed in the second fetus. With intrauterine treatment using potassium iodine and propylthiouracil, fetal cardiac function improved. A high level of TRAb was detected in the both neonates. To the best of our knowledge, this is the first report on the changes of fetal cardiac function in response to fetal treatment in two siblings showing in utero hyperthyroid status. This case report illustrates the impact of prenatal medication via the maternal circulation for fetal hyperthyroidism and cardiac failure.

Body composition was assessed by bioelectrical impedance analysis (BIA) in 11 female patients with Graves' disease and in 49 age-matched healthy Japanese women. Patients with Graves' disease were examined in the hyperthyroid state before treatment and in the stable euthyroid state after treatment with antihyroid drugs for 6 to 18 months. Body weight (BW), percent body fat (BF/BW), percent lean body mass (LBM/BW) and percent total body water (TBW/BW) were not statistically different between hyperthyroid Graves' patients and healthy subjects. Percent body cell mass (BCM/BW) was much lower in hyperthyroid Graves' patients than in healthy subjects (mean +/- SEM; 33.9 +/- 2.4% vs. 41.5 +/- 0.5%, P0.001). Percent ratio of extracellular water to total body water (ECW/TBW) was much greater in hyperthyroid Graves' patients than in healthy subjects (53.9 +/- 3.0% vs. 41.8 +/- 0.5%, P0.001). These abnormal ratios, BCM/BW and ECW/TBW, were normalized after treatment. Serum free T4 levels showed a positive correlation with ECW/TBW (r = 0.779) and a reverse correlation with BCM/BW (r = -0.760) in all of the patients with Graves' disease examined. These findings indicate that body composition is affected by thyroid hormones and that body composition in hyperthyroid Graves' disease is characterized by decreased BCM associated with increased ECW.

We observed a patient manifesting spontaneous hypothyroidism with thyroid stimulation blocking antibody (TSBAb) long after treatment with antithyroid drugs (ATDs) for hyperthyroid Graves' disease. A 19-year-old female with Graves' disease was treated with ATDs for approximately 2 years; after cessation of ATDs, hyperthyroidism did not recur. Nine years later, she was again seen in our hospital because of symptoms indicative of hypothyroidism. Thyroid hormone replacement was commenced after laboratory confirmation of hypothyroidism. TSH-binding inhibitor immunoglobulin and TSBAb were both positive, while thyroid stimulating antibody (TSAb) was negative, at the time of diagnosis of hypothyroidism. These results indicated that the alterations in thyroid function in this patient appeared to relate to the presumed decline in the activity of TSAb and the appearance of TSBAb years after ATDs administration had been discontinued.

We evaluated the developmental prognosis of 31 infants born to mothers with autoimmune thyroiditis. Four of the babies developed transient neonatal hypothyroidism. Their mothers all had low thyroid hormone concentrations during pregnancy. Neonatal thyroid function tended to correlate with maternal thyroid function at delivery in babies born to mothers with Graves';disease who were taking antithyroid drugs. Since severe fetal hypothyroidism sometimes results in neurological damage, it is important to maintain normal maternal thyroid function during pregnancy.

Propylthiouracil (PTU) is known to induce myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) in patients with Graves disease (GD). Previously, we showed that serum MPO-ANCA were frequently seen in patients with GD treated with PTU. In this study, we analyzed 13 patients with positive MPO-ANCA examining a long-term clinical consequence of these patients as well as antibody titers during 5.6 +/- 3.0 years. PTU therapy was continued in 8 patients and discontinued in 5 patients. Antibody titers decreased in 7 of 8 patients who discontinued PTU therapy but remained positive in 5 patients 5 years after PTU withdrawal. The initial MPO-ANCA levels were significantly higher in those antibody titers remained positive for longer than 5 years (n=5) than in those titers turned to be negative within 5 years after PTU withdrawal (n=3) (203 +/- 256 EU and 22 +/- 2 EU, respectively, P=0.04), but there were no significant differences in age, gender, duration of PTU therapy or dosage of PTU. Among 5 patients who continued PTU therapy, 2 patients with initially low MPO-ANCA titers turned to having negative antibody. No patients had new symptoms or signs of vasculitis throughout the follow-up periods. The long-term follow-up study suggests that higher MPO-ANCA levels remain positive for years after PTU withdrawal but are rarely associated with vasculitis.

The prevalence and titer of glutamic acid decarboxylase antibody (GADAb) in type 1 diabetes mellitus (T1DM) has been reported to be higher in patients with autoimmune thyroid diseases (AITD) than those without them. However, we have no data about the influence of GADAb on AITD. We therefore studied the clinical characteristics of Graves' disease (GD) with GADAb in order to clarify the influence of GADAb on GD. Twelve GD patients with GADAb were enrolled and were compared to 40 GD patients without DM. The male to female ratio and age of onset of GD showed no statistical difference. The titer of TSH receptor antibody (TRAb) at the onset of GD was similar in both groups. Initial treatment with methimazole (MMI) was started in all patients with GADAb but radioactive iodine (RI) therapy was carried out in five patients because of adverse effects of MMI or poor control of hyperthyroidism. The initial titer of TRAb was significantly lower in patients treated with MMI alone compared to that in RI treated patients but none of the patients treated with MMI alone went into remission after more than 3-years of follow up. We also compared these GADAb-positive patients with 14 patients with diabetes mellitus who had matched clinical features. The number of diabetic patients who remained in possible remission was significantly higher than that of GADAb-positive patients (5 in 14 vs 0 in 12). Moreover, the rate of remission in the diabetic patients was no different from that of 21 control patients without diabetes followed for more than 7 years (5 in 14 vs 7 in 21). These data suggested that GADAb-positive patients are unlikely to go into remission with antithyroid agents. Therefore, definitive therapies might be preferable for the initial treatment of GADAb-positive patients.

Objective: Thyroid hormone affects adipocyte function, which in turn influences lipid and carbohydrate metabolism. Adiponectin is one of the adipocytokines that regulates lipid and carbohydrate metabolism. The aim of our study was to evaluate circulating levels of adiponectin in patients with thyroid dysfunction before and after normalization of thyroid function with appropriate medication. Design & Methods: One hundred and twenty patients with hyperthyroidism were recruited at the time of diagnosis. Measurements of free T4 (FT4), thyroid-stimulating hormone (TSH), thyrotropin binding inhibitor immunoglobulin (TBII), adiponectin, fasting blood glucose, fasting serum insulin, lipid profile, and body mass index (BMI) were taken before and after 6 months of medical treatment, at which point all patients were in a euthyroid state. Results: Any change in BMI was strongly correlated with changes in serum-adiponectin levels (r = -0.789, p

In most trials, at least 30-60% of patients with Graves' disease treated with antithyroid drugs relapse within 2 years after therapy withdrawal. At present, there are no prognostic parameters available early in treatment to indicate patients likely to achieve long-term remission. Because thyrotropin receptor autoantibodies (TRAb) are specific for Graves' disease, we evaluated the ability of their levels and of their rate of change to predict long-term prognosis. In our study 216 consecutive patients with newly diagnosed Graves' disease started a therapy with methimazole. Patients were treated until they achieved euthyroidism and TRAb were measured at 6-month intervals throughout a follow up of 120 months. Our study demonstrated that at the onset of hyperthyroidism patients' age, sex, fT4 levels and goiter size had no prognostic value in predicting long-term prognosis (respectively p = 0.79; p = 0.98; p = 0.83; p = 0.89). On the contrary, at the time of diagnosis TRAb titer was a good predictor of the final outcome (p

The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

In this study we confirmed our previous findings on the importance of IgE in Graves' disease and further investigated the relationships existing among Graves' disease, IgE, and interleukin-4. Two hundred and thirty-two newly diagnosed Graves' disease patients were treated with methimazole for 2 years, and were classified into 3 groups according to their response to the therapy. Incidence of IgE elevation (IgEor =170 IU/ml) before treatment was lowest, 23.8%, in the group who achieved remission without recurrence, while it was 41.7% in the group who achieved remission but recurrence occurred within 4 years. Incidence of IgE elevation before treatment was highest, 60.7%, in the group who failed to achieve remission, significantly higher than that of the group without recurrence. Incidence of IgE elevation before treatment in all these patients of Graves' disease were 35.3%, significantly higher than those of Hashimoto's thyroiditis (17.5%) and of simple goiter (7.0%). Serum IL-4 levels before treatment were significantly higher in the patients of Graves' disease with IgE elevation than in those without IgE elevation. Serum T4 concentration and TSAb titration before treatment were also significantly higher in elevated IgE group than in normal IgE group. These results support our previous findings and suggest that IL-4 may play important roles in the elevation of IgE, TBII, and TSAb in patients of Graves' disease, and that IL-4 and IgE may be involved in the development, progression, and maintenance of Graves' disease.

The appropriate period of antithyroid drug (ATD) discontinuation before radioiodine therapy is the most critical problem in Graves' disease patients under going treatment with ATD. To determine the optimal period that does not alter the outcome of radioiodine therapy or exacerbate hyperthyroidism, we compared serum FT4 levels at radioiodine uptake (RAIU) and therapy outcomes between a 2-day withdrawal group and 7-day withdrawal group. We prospectively recruited 43 patients for the 2-day withdrawal protocol and retrospectively reviewed 49 patients treated with radioiodine following the protocol of 7-day withdrawal. There was no significant difference in RAIU between the 2 groups. The mean serum FT4 level measured on the first day of 24-h RAIU of the 7-day group was significantly higher than that in the 2-day group. There were no significant differences in the outcomes at each point (6 months, 1 year, and 2 years after therapy) between the 2 groups. Our results indicated that withdrawal of ATD for 2 days is superior to 7 days in that 2 days discontinuation did not exacerbate hyperthyroidism. In order to prevent serum thyroid hormone increase after ATD withdrawal and radioiodine therapy, a 2-day ATD withdrawal period before radioiodine therapy may be useful for high-risk patients such as the elderly and patients with cardiac complications. We believe that the 2-day ATD withdrawal method may be useful for patients undergoing treatment with ATD who are to undergo radioiodine therapy.

Prediction of remission is one of the main problems of antithyroid drug (ATD) therapy for Graves' disease especially in patients who are treated with a minimum maintenance dose of ATD. We evaluated the ability of new sensitive TSH receptor antibody (TRAb) assays to predict remission in Graves' patients using two commercially available kits (TRAb-CT from Cosmic Corporation and TRAb-Dyno from Yamasa Corporation), compared to the original PEG assay. When a euthyroid state was achieved for more than 6 months with methimazole 5 mg/day or propylthiouracil 50 mg/day and thereafter for three months with 5 mg every other day or 50 mg every other day, respectively, we discontinued ATD medication. One year of observation after discontinuation of ATD was completed in 71 patients (60 females, median age 43 years, range 18-71), and TRAb values from these patients were analyzed in relation to prognosis. Twenty-six (37%) of the 71 patients had relapse of thyrotoxicosis and 45 remained euthyroid. The median TRAb levels in the relapse group were significantly higher than those in the remission group (P < 0.05). Relapse occurred in 15/51 patients negative by TRAb-CT, in 11/20 patients positive by TRAb-CT (chi2 = 4.1; P < 0.05), in 11/42 patients negative by TRAb-Dyno and in 15/29 patients positive by TRAb-Dyno (chi2 = 4.8; P < 0.05). By contrast, relapse occurred in 23/64 patients with negative TRAb by PEG assay and in 3/7 patients with PEG assay positive values (n.s.). All patients with TRAb-CT values of 30% inhibition or greater, or TRAb-Dyno values of 3.0 U/L or greater relapsed during the observation period. Thus, measurement of TRAb by the new sensitive assays is useful for prediction of remission in our patients.

Granulocyte colony-stimulating factor (G-CSF) levels in serum were determined by a highly-sensitive chemiluminescent enzyme immunoassay (limit of detection, 0.5 pg/ml) in 54 patients with Graves' disease including 6 patients complicated with methimazole-induced agranulocytosis. Serum G-CSF levels in patients with Graves' disease were not different from normal subjects and did not correlate with serum FT4 level or circulating neutrophil counts. Before the onset of agranulocytosis, there was no difference in serum G-CSF level between the patients complicated with agranulocytosis and the uncomplicated patients. When circulating neutrophil counts decreased to less than 0.5 x 10(9)/L, serum G-CSF level elevated with the mean of 106.8 +/- 82.2 (SD) pg/ml, but the level did not correlate with the duration of agranulocytosis. Interestingly, maximum serum G-CSF level during the treatment with recombinant human G-CSF (100 microg/day) was related to bone marrow finding at the onset of agranulocytosis and correlated with the duration of agranulocytosis (r = 0.824, p0.05). In conclusion, measuring serum G-CSF levels with a highly-sensitive chemiluminescent enzyme immunoassay revealed that 1) thyrotoxicosis does not affect serum G-CSF level, 2) serum G-CSF level during antithyroid drug treatment does not play an important role in development of agranulocytosis, 3) the maximum serum G-CSF level in the course of agranulocytosis is related to the responsiveness of bone marrow to G-CSF and the recovery time from agranulocytosis.

The development of silent thyroiditis in patients with a history of Graves' disease is common, especially in the postpartum period. We describe herein patients with Graves' disease who developed transient hyperthyroidism but not silent thyroiditis after withdrawal of antithyroid drug (ATD). If such patients are diagnosed as recurrence of Graves' disease, they may receive ATD or radioiodine therapy unnecessarily. We investigated the characteristics of these patients to prevent unnecessary therapy. We retrospectively studied 22 patients with Graves' disease who showed transient thyrotoxicosis after withdrawal of ATD. Two of 22 patients were male and the mean ages (+/- SD) were 33.7 +/- 12.6 yr. We observed these patients for 28.5 +/- 12.8 (mean +/- SD; range 12-53) months after transient thyrotoxicosis, and measured TSH, FT4, and TSH binding inhibitor immunoglobulin in sera. Radioiodine uptake was measured in 6 of them. The radioiodine uptake in the 4 patients was not suppressed (27.5%, 28.0%, 32.7%, 38.1%). These uptake levels indicate that their thyrotoxicosis was not caused by silent thyroiditis. Most of the 22 patients became euthyroid within 6 months. This study suggests a new therapeutic option as follows: in the case of young patients with mild thyrotoxicosis after withdrawal of ATD, physicians should follow them up for one month without medication unless they have unbearable symptoms or complications.

In a 76-year-old woman with hyperthyroidism, hyperprolactinemia and thickening of the pituitary stalk on magnetic resonance imaging (MRI) was presented. Thyroid stimulating antibody (TSAb) was positive and anti-pituitary antibodies against 49 and 68 kD human anterior pituitary membrane antigens were detected immunologically. Secretion of pituitary hormones was almost normal except for suppressed TSH and hyperprolactinemia. As autoimmune etiologies were likely involved in the disorders, autoimmune hypophysitis associated with Graves' disease was arrived at as the plausible diagnosis.

A 33-year old female was diagnosed as Graves' disease and started on carbimazole. One month later when she was already euthyroid only on carbimazole therapy, she developed acute pancreatitis associated with mild cholestatic hepatitis and erythema nodosum. Carbimazole therapy was interrupted, pancreatic and liver function gradually improved and became normalized two weeks later. Other potential etiological causes of acute pancreatitis, hepatitis and erythema nodosum were excluded. Rechallenge with a single dose of carbimazole led to a new episode of acute pancreatitis and cholestatic hepatitis one day later. The appearance of different hypersensitivity reactions including pancreatitis, hepatitis and erythema nodosum, together with the observation that the interval between drug intake and onset of symptoms became shorter with repeated exposure to carbimazole, point to an immune-mediated mechanism. Carbimazole has to be added to the list of drugs capable of inducing acute pancreatitis, and should be emphasized the need to discontinue this medication as soon as there is evidence of pancreatic dysfunction.

Patients with Graves' disease (n = 61) treated with propylthiouracil (PTU) or thiamazole (MMI) were studied retrospectively to investigate differences in the prevalence of anti-myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA) in relation to treatment with anti-thyroid drugs. The patients were divided into two groups: PTU-treated group (n = 32) and MMI-treated group (n = 29). There were no significant differences between the two groups in terms of age, gender distribution, or duration of treatment. In the PTU group, 8/32 (25%) patients were positive for MPO-ANCA, whereas in the MMI group, 1/29 (3.4%) patients were positive. There were no significant differences in age, duration, or dosage between the MPO-ANCA positive and negative patients. Most of the MPO-ANCA positive patients were asymptomatic, except for two patients in whom rheumatic arthritis or membranous glomerulonephritis developed. None of the MPO-ANCA positive patients were diagnosed as having classical ANCA-associated vasculitis. Thus, there is a high frequency of MPO-ANCA in patients with Graves' disease treated with PTU, compared with patients treated with MMI, although classical ANCA-associated vasculitis develops in only a few MPO-ANCA positive patients.

The presence of TSH receptor antibody (TRAb) is rarely responsible for hyperthyroidism due to metastatic lesions of thyroid carcinoma. A 70-year-old woman was incidentally found to be thyrotoxic around the time that external irradiation was performed for multiple bone metastases 9 years after subtotal thyroidectomy for follicular carcinoma. Hyperthyroidism persisted after oral administration of thiamazole. Relevant laboratory data were as follows: FT4 9.6 ng/L, FT3 7.3 ng/L, TSH

We report the case of a 31-year-old man with Graves' disease who manifested malignant hyperthermia during subtotal thyroidectomy. His past medical history and family history were unremarkable. Before surgery, his condition was well controlled with propylthiouracil, beta-adrenergic blocker and iodine. During the operation, anesthesia was induced by intravenous injection of vecuronium and thiopental, followed by suxamethonium for endotracheal intubation. Anesthesia was maintained with nitrous oxide and sevoflurane. One hour after induction of anesthesia, his end tidal carbon dioxide concentration (ET(CO2)) increased from 40 to 50 mmHg, heart rate increased from 90 to 100 beats per min and body temperature began to rise at a rate of 0.3 degrees C per 15 min. Suspecting thyroid storm, propranolol 0.4 mg and methylprednisolone 1,500 mg were administered, which, however, had little effect. Despite the lack of muscular rigidity, the diagnosis of malignant hyperthermia was made based on respiratory acidosis. Sevoflurane was discontinued and dantrolene was given by intravenous bolus. Soon after the treatment, ET(CO2), heart rate and body temperature started to fall to normal levels. His laboratory findings showed abnormally elevated serum creatine phosphokinase and myoglobin but normal thyroid hormone levels. Since dantrolene is efficacious in thyrotoxic crisis and malignant hyperthermia, an immediate intravenous administration of dantrolene should be considered when a hypermetabolic state occurs during anesthesia in surgical treatment for a patient with Graves' disease.

We report a rare case of Graves' disease associated with struma ovarii. A 26-year-old Japanese woman had preexisting Graves' disease and was positive for TSH receptor antibody. She had been on antithyroid medication at presentation. She noted a mass in the lower left abdomen, which was diagnosed as a left struma ovarii by radiological work-up including computed tomography, magnetic resonance imaging and scintigraphy. The surgically excised teratomatous tumor, containing cystic spaces with thyroid tissue, was histologically proved to be struma ovarii. Since thyroid function tests and TSH receptor antibody did not change after surgery, her hyperthyroidism was considered to be due to Graves' disease. Our case was diagnosed as struma ovarii before surgery using various imaging studies.