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We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R

We report two cases of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma with associated amyloid protein deposition. While other primary thyroid neoplasms sush as medullary carcinoma and plasmacytoma with associated amyloid protein are known to occur and have been previously described by fine-needle aspiration cytology (FNAC), to our knowledge, the current cases are the first of thyroid MALT lymphoma with amyloid deposition to be detailed in the cytopathology literature. Case 1 was a 73-year-old female with chronic thyroiditis. FNAC suspected MALT lymphoma. The amyloid material was not noticed, nevertheless it existed. Case 2 was a 71-year-old female with a nodule of the thyroid. Malignant lymphoma and medullary carcinoma were suspected by FNAC. The possibility of medullary carcinoma was excluded by a measurement of serum calcitonin and carcinoembryonic antigen. After follow-up for two years, the nodule was diagnosed as MALT lymphoma associated with plasma cell differentiation and amyloidosis by the fourth FNAC. When we encounter small round cell tumors associated with amyloid in thyroid FNAC, we should consider not only medullary carcinoma but also MALT lymphoma.

Oral glucocorticoids are administered in moderate and severe cases of subacute thyroiditis (SAT), providing dramatic relief from pain and fever. However, there have been no reports regarding the optimal dose of prednisolone (PSL) for treatment of SAT. In this study, we used 15 mg/day of PSL as the initial dosage and tapered it by 5 mg every 2 weeks. We assessed the effectiveness of this treatment protocol.We examined 384 consecutive and untreated patients with SAT who visited our thyroid clinic between February 2005 and December 2008. We excluded patients who did not fit our protocol, and the final number of subjects was 219. When patients complained of pain in their neck or C-reactive protein (CRP) was still high, physicians were able to extend the tapering of the dose of PSL or increase it at 2-week intervals. The endpoint of the study was the duration of the PSL medication. We also compared the severity of thyrotoxicosis and rate of hypothyroidism after SAT between the short medication group (patients who recovered within 6 weeks) and long medication group (patients who recovered in 12 weeks or more).The number of patients whose thyroiditis improved within 6 weeks and did not recur was 113 (51.6%), and 61 (27.9%) improved within 7 to 8 weeks and did not have a recurrence. The longest duration was 40 weeks. Seven patients (3.2%) needed increases in the dosage of PSL. Thyroid hormone (free thyroxine and free triiodothyronine) levels measured at the initial visit in the short medication group were significantly higher than those in the long medication group (p0.05). Serum CRP, male-to-female ratio, body weight, and age showed no differences between the two groups. There were no differences in the rate of hypothyroidism after SAT between the two groups (p=0.0632).The treatment protocol that we employed had 15 mg/day of PSL as the initial dosage for the treatment of SAT, with tapering by 5 mg every 2 weeks, and was effective and safe for Japanese patients. However, 20% of patients with SAT needed longer than 8 weeks to recover from the inflammation.

Objective When patients with Graves' disease show severe allergic cutaneous reactions, physicians often suggest that they undergo radioiodine therapy instead of receiving propylthiouracil (PTU), another antithyroid drug, because anti-neutrophil cytoplasmic antibody (ANCA) -related vasculitis can occur with PTU, especially with long-term use. However, some patients refuse radioiodine therapy and chose PTU. Sometimes PTU treatment may be prolonged. Since the frequency of adverse effects of methimazole (MMI) is dose-related, there is a possibility that we can re-administer a low dose without adverse effects to patients well-controlled with PTU who once experienced an allergic reaction to MMI. Methods I prospectively re-administered a low dose of MMI to patients who previously experienced an allergic reaction to MMI at initial treatment. The dose of re-administered MMI ranged from 5 mg twice a week to 5 mg daily. Patients Nine patients with Graves' disease who developed urticaria at initial treatment with MMI and had been treated with PTU for 6 to 21 years were recruited. Results Eight of the 9 patients were successfully controlled with MMI without allergic cutaneous reactions. Only one patient felt itchiness 2 days after switching to MMI. However, skin change was not observed. Conclusion If the patients show allergic cutaneous reactions as a side effect of MMI at the initial treatment for Graves' disease, then there is a strong possibility that such patients can tolerate a low dose of MMI without adverse effects after the disease activity has subsided.

To identify genetic variants that confer the risk of Graves' disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1(*)0501 and HLA-A(*)0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1(*)0501 and HLA-A(*)0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.

Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene.The proband was a 64-year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism.A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway.Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial.

Multiple cysts of the thyroid gland have not been recognized as one of the causes of hypothyroidism. Here we present six patients from a region with relatively high iodine intake in whom multiple cysts of the thyroid were associated with hypothyroidism or the development of hypothyroidism.All patients were women and ranged in age from 49 to 71. Their thyroids were mildly enlarged, tests for thyroid autoantibodies were negative, and multiple cysts were detected in the thyroid by ultrasonography. By dietary questionnaire their iodine intake was estimated to range from 2 to 10 mg of iodine daily. Otherwise, there was no evidence for disorders or factors associated with hypothyroidism. All four patients who agreed to dietary iodine restriction became euthyroid at approximately 1 month after a low-iodine diet (less than 0.5 mg iodine per day) was started.Although these patients were from a region with high-iodine intake and had a relatively high intake compared with most regions of the world, this amount of iodine intake is not associated with hypothyroidism in otherwise healthy persons. Therefore, we propose that multiple thyroid cysts, which we have termed polycystic goiter, is probably a cause of hypothyroidism in patients with a relatively high iodine intake.

Summary Objective Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves’ disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. Design and patients A total of 134 untreated patients with Graves’ disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation. Measurements Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography. Results After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P

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

Summary Objective Differentiation between destruction-induced thyrotoxicosis and Graves’ thyrotoxicosis is important for selection of proper therapy. It is, however, often difficult to make this distinction without measurement of radioactive iodine uptake. We investigated the possibility that assessment of thyroid blood flow would allow differentiation between the two entities. Patients and measurements One hundred and fourteen untreated patients with thyrotoxicosis (56 Graves’ disease, 28 painless thyroiditis, 30 subacute thyroiditis) and 25 normal controls were examined. Serum levels of freeT4 (FT4), freeT3 (FT3) and TSH were measured by chemiluminescent immunoassay, and anti-TSH receptor antibodies (TSH-binding inhibitory immunoglobulin, TBII) were measured by enzyme-linked immunosorbent assay. Thyroid volume and blood flow (TBF) were measured quantitatively by ultrasonography. Results TBF was significantly higher in Graves’ disease (mean ± 1SD: 14·9 ± 6·4%, P

We encountered a 55-year-old female patient with Hashimoto's thyroiditis who showed persistent fever, and could not find any source of fever other than the large nontender goiter. Her fever continued with positive CRP for 6 months. Although we did not assume that the inflammation was related to Hashimoto's thyroiditis, total thyroidectomy was performed for cosmetic reasons; however, fever was resolved immediately after thyroidectomy. Pathological diagnosis was Hashimoto's chronic thyroiditis. Immunohistochemical staining showed that the follicular cells were positive for IL-1alpha, IL-1beta, and TNF-alpha. We believed that fever was induced by inflammatory cytokines produced in thyroid. The case indicated that Hashimoto's thyroiditis with nontender goiter could cause idiopathic fever.

Recently, non-high-density lipoprotein cholesterol (non-HDL-C), a measure of total cholesterol minus HDL-C, has emerged as a predictor of cardiovascular disease.We evaluated the effect of L-T4 replacement on non-HDL-C levels in patients with primary hypothyroidism.Thirteen patients with overt hypothyroidism and 26 patients with subclinical hypothyroidism participated in the study. The lipid profiles, including non-HDL-C, were measured in patients with hypothyroidism before and 3 months after L-T4 replacement was started.After L-T4 replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein (a) [Lp(a)], were significantly decreased in patients with overt hypothyroidism. In patients with subclinical hypothyroidism, the serum concentrations of total cholesterol, non-HDL-C, remnant-like particle cholesterol, and apolipoprotein B (Apo B) were significantly decreased, whereas no significant changes in the serum concentrations of low-density lipoprotein cholesterol, HDL-C, triglycerides, apolipoprotein A-I, and Lp(a) were observed. In all 39 patients, the reduction in the non-HDL-C levels correlated with the reduction in the low-density lipoprotein cholesterol, remnant-like particle cholesterol, and Apo B levels. However, the reduction in the non-HDL-C levels did not correlate with the reduction in the HDL-C, Lp(a), and apolipoprotein A-I levels.This study is the first to show that L-T4 replacement may reduce serum concentrations of non-HDL-C in patients with hypothyroidism. The study also suggests that such altered serum concentrations of non-HDL-C in hypothyroidism may be related to the disturbed metabolism of low-density lipoprotein, remnant lipoprotein, and Apo B.

Whereas most patients with Graves’ disease (GD) have antibodies against the thyrotropin receptor, which are measured as thyrotropin-binding inhibitory immunoglobulin (TBII), the TBII of 10% or less of Japanese patients with GD is undetectable at the first visit and throughout the entire clinical course, and these patients tend to respond well to medications and follow the better clinical course. Therefore, the absence of TBII at the first visit may be a predictor of good prognosis. Ninety-seven patients with GD who had remained TBII negative for at least 2 years from the onset, as well as 142 typical TBII-positive GD patients, were examined to reveal the HLA-linked immunogenetic background for this predictor. Compared with a healthy control population, the frequencies of HLA-A*0206 (OR = 2.17, p = 9.73 × 10 −4 ) and DPB1*0501 (OR = 3.26, p = 3.31 × 10 −7 ) carriers were increased in the typical patients, whereas those of HLA-A*0201 (OR = 2.16, p = 1.92 × 10 −3 ), A*0207 (OR = 3.19, p = 7.17 × 10 −4 ), and DPB1*0202 (OR = 3.13, p = 3.97 × 10 −4 ) were increased in the TBII-negative group. These two patient groups were associated with similar HLA-A alleles and different HLA-DPB1 alleles, suggesting the presence of two genetic factors for GD within the HLA region; one is HLA-A linked and may be related to thyroid organ specificity, the other is HLA-DP linked and may control the severity of autoimmunity.

We report four cases of Graves' disease that developed after painful Hashimoto's thyroiditis. All were middle-aged women, who had high titers of anti-thyroid antibodies and thyrotoxicosis at the onset of painful Hashimoto's thyroiditis. After 2 to 7 years, they developed Graves' disease with positive antibody against the thyrotropin receptor. Their clinical courses of Graves' disease went favorably due to the treatment with antithyroid drug or radioactive iodine therapy. Painful Hashimoto's thyroiditis is an atypical variant of Hashimoto's thyroiditis and is one form of destructive thyroiditis. Thyroid damage due to painful Hashimoto's thyroiditis may be associated with the development of Graves' disease.

Benign thyroid teratomas are rare in adolescents and adults. We report on three cases of benign thyroid teratomas that presented as painful tumors in the neck after puberty. The tumor adjacent to the thyroid in each case showed rapid enlargement with predominant cystic lesions within several months. Ultrasonography and computed tomography revealed few findings suggesting the origin of the tumor. Cytological examination and culture of the aspirate failed to show cells originating from the thyroid or infectious findings, but revealed a small population of columnar epithelial cells or squamous epithelial cells. Chemical analysis of the aspirate showed levels of pancreatic enzymes higher than those in serum. The accumulation of cystic fluid in each case was refractory to drainage treatment or percutaneous ethanol injection therapy. The patients subsequently underwent resection of the tumor, and microscopic examination revealed various types of tissue including pancreas, adipose, cartilage, muscle, and skin, and the cystic wall was lined by gastric, intestinal, respiratory, and stratified squamous epithelium. Surgical resection was curative, and subsequent histologic examination revealed mature benign teratomas of the thyroid. The main characteristic of our cases presented the painful tumors due to the enlarged cystic formation lined by a variety of different types of epithelium, which agreed with previous cases of benign thyroid teratomas in adolescents and adults.

A case of thyrotoxicosis caused by acute suppurative thyroiditis after repeated fine-needle aspiration (FNA) is described. A 39-year-old woman with atopic dermatitis showed rapid enlargement of a left thyroid cyst after a third FNA. She had a high fever, painful swelling of the left thyroid, and elevated thyroid hormone levels. Ultrasonography revealed abscess formation in the left thyroid cyst. The cytologic examination of an FNA specimen showed abundant neutrophils, and culture of the aspirate yielded Staphylococcus aureus. Because antibiotic treatment for 1 month failed to improve the inflammatory findings, the patient subsequently underwent left thyroid lobectomy, which resulted in the normalization of thyroid function and the resolution of inflammation. Thyroid infection had possibly been induced by needle-track seeding, because atopic skin favors colonization by S. aureus because of local immunologic deficiency. FNA is a useful and safe technique for aspirating fluid from thyroid cysts, but special care is required in patients with atopic dermatatis to avoid bacterial infection.

Pseudomalabsorption of levothyroxine is a factitious disorder. Despite the administration of large doses of levothyroxine, patients with this disorder show hypothyroidism due to noncompliance. These patients are different from the patients with simple noncompliance in that they have a psychiatric disorder. Because their psychological identities are rooted in their being a “patient,” they go to great lengths to become and stay a patient. We report a case of pseudomalabsorption of levothyroxine. A 28-year-old woman was referred to us because she was believed to have unusual malabsorption of levothyroxine. We diagnosed the patient as having this factitious disorder, and as treatment, had her visit a hospital twice a week to take medicine under the observation of nurses so that she would not lose her status as a “patient.” Her serum free T4 level normalized during three years with twice weekly dosing of thyroxine after hospital discharge. Our approach could be a therapeutic choice for this intractable disorder. To our knowledge, this is the first report of successful management of a patient with pseudomalabsorption of levothyroxine.

Summary objectives Remnant-like particles (RLPs) reflect chylomicron remnants and very-low-density lipoprotein remnants, which are most likely to be atherogenic particles. To investigate the effect of thyroxine replacement on the metabolism of RLPs in hypothyroidism, we measured serum concentrations of RLPs during an oral fat-loading test in patients with hypothyroidism before and after thyroxine replacement. patients and methods Thirteen patients with hypothyroidism, having serum-free thyroxine (FT4) of 4·25 ± 2·23 pmol/l (mean ± SD) and TSH of 72·5 ± 27·7 mU/l, participated in the study. Two-hundred grams of cream containing 32·9% of fat were given to each patient followed by blood draws every 2 h for 8 h. The patients became euthyroid after 3 months of T4 replacement, and the fat-loading tests were then repeated. results Fasting levels of serum total cholesterol and low-density lipoprotein cholesterol were remarkably decreased after T4 therapy (P

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.

Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigen. The cytotoxic T-lymphocyte antigen-4 ( CTLA4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. Recently, AITD susceptibility in the Caucasians was mapped to the 6.1-kb 3'UTR of the CTLA4 gene, in which the three single-nucleotide polymorphisms (SNPs) CT60, JO31, and JO30 were strongly associated with AITD. In order to determine the association of the CTLA4 gene with AITD in the Japanese, case-control association analysis for the four SNPs of the CTLA4 gene using 380 AITD patients and 266 healthy controls was done. Among the SNPs examined, the SNP JO31 was most significantly associated with AITD in the Japanese, whereas the association of the JO30 with AITD was not observed. The frequency of the disease-susceptible G allele of the JO31 of the Japanese control was higher than that of the Caucasians (67.1% vs 50.2%); however, the G allele of the JO31 was associated with Graves' disease (GD) (67.1% vs 76.3%, P=0.0013) and AITD in the Japanese (67.1% vs 74.2%, P=0.0055). Furthermore, the G allele of the JO31 was associated with the increased risk for GD [ P=0.0051, odds ratio (OR)=1.7] and AITD ( P=0.016, OR=1.5) in a dominant model. These results suggested that the CTLA4 gene is involved in the susceptibility for GD and AITD in the Japanese.

Apolipoprotein B-48 (ApoB-48) is a constituent of chylomicrons and chylomicron remnants, and is thought to be one of the risk factors for atherosclerosis. We evaluated the effect of L-thyroxine (L-T(4)) replacement on serum ApoB-48 levels in patients with primary hypothyroidism. Eighteen patients with overt hypothyroidism (OH) and 18 patients with subclinical hypothyroidism (SH) participated in the study. The lipid profiles, including ApoB-48, were measured in patients with hypothyroidism before and 3 months after L-T(4) replacement. After L-T(4) replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein(a) (Lp(a)), were significantly decreased in patients with OH. In patents with SH, the serum levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), apolipoprotein B (ApoB), and ApoB-48 decreased significantly after L-T(4) replacement. The serum levels of triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA-1), and Lp(a) did not change significantly. In all 36 patients, the reduction in the ApoB-48 levels correlated significantly with the reduction in TSH levels (r = 0.39, P

ObjectiveThyroidal production of triiodothyronine (T3) is absent in patients who have undergone total thyroidectomy. Therefore, relative T3 deficiency may occur during postoperative levothyroxine (l-T4) therapy. The objective of this study was to evaluate how the individual serum T3 level changes between preoperative native thyroid function and postoperative l-T4 therapy.MethodsWe retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T4 (FT4), free T3 (FT3), and TSH levels measured preoperatively were compared with those levels measured on postoperative l-T4 therapy.ResultsSerum TSH levels during postoperative l-T4 therapy were significantly decreased compared with native TSH levels (P4 levels were significantly increased (P3 levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT3 levels significantly higher than the native levels (P3 levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT3 levels (PConclusionsSerum FT3 levels during postoperative l-T4 therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of l-T4 is required to achieve the preoperative native serum T3 levels in postoperative l-T4 therapy.

We report two cases of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma with associated amyloid protein deposition. While other primary thyroid neoplasms sush as medullary carcinoma and plasmacytoma with associated amyloid protein are known to occur and have been previously described by fine-needle aspiration cytology (FNAC), to our knowledge, the current cases are the first of thyroid MALT lymphoma with amyloid deposition to be detailed in the cytopathology literature. Case 1 was a 73-year-old female with chronic thyroiditis. FNAC suspected MALT lymphoma. The amyloid material was not noticed, nevertheless it existed. Case 2 was a 71-year-old female with a nodule of the thyroid. Malignant lymphoma and medullary carcinoma were suspected by FNAC. The possibility of medullary carcinoma was excluded by a measurement of serum calcitonin and carcinoembryonic antigen. After follow-up for two years, the nodule was diagnosed as MALT lymphoma associated with plasma cell differentiation and amyloidosis by the fourth FNAC. When we encounter small round cell tumors associated with amyloid in thyroid FNAC, we should consider not only medullary carcinoma but also MALT lymphoma.

Polycystic thyroid disease (PCTD) is characterized by multiple thyroid cysts detected by ultrasonography, the absence of thyroid autoantibodies, and susceptibility to the development of hypothyroidism due to a high iodine intake. It is necessary to obtain histopathological information on PCTD in order to clarify the cause of hypothyroidism. We retrospectively reviewed three patients with PCTD and small papillary thyroid cancer who underwent thyroidectomy. We observed the thyroid tissues pathologically in areas with and without multiple cysts, and compared them with those of multinodular goiter with cysts. In the patients with PCTD, there were multiple enlarged follicles that resembled enlarged normal follicles and differed from those found in multinodular goiter in terms of their shape. Huge follicles corresponded to the cysts that were detected by ultrasonography. Each follicle contained colloid. Follicular cells in enlarged follicles comprised low cuboidal epithelium that appeared normal. These findings were common in the 3 patients with PCTD. In Conclusion the PCTD patients had multiple enlarged follicles that seemed to decrease the total number of follicular cells, and may be a cause of hypothyroidism. We believe that PCTD is a new entity of thyroid disease based on the pathological findings.

Postpartum thyroiditis is defined as an exacerbation of autoimmune thyroiditis during the postpartum period (1). Patients do not develop thyroid autoimmunity at the onset of postpartum thyroiditis, but have ‘subclinical autoimmune thyroiditis’ beforehand which is exacerbated after delivery. Typically an exacerbation induces destructive thyrotoxicosis followed by transient hypothyroidism. However, various types of thyroid dysfunction may occur, including Graves’ disease. Therefore, any kind of thyroid dysfunction observed during the postpartum period, is referred to as ‘postpartum thyroid dysfunction’.

Background Hb Himeji is variant hemoglobin associated with increased glycation in a mutated β chain. We measured HbA1c using various methods in a family with Hb Himeji. Methods The proband was a 42-y female. While receiving treatment for Graves' disease, an oral glucose tolerance test showed normal glucose tolerance, but HbA1c by enzymatic assay was abnormally elevated (11.6%). Hemoglobin gene analysis identified Hb Himeji [β140 (H18) Ala → Asp]. Results HbA1c values measured by high-performance liquid chromatography (HPLC; HLC-723G8 and HA-8160 instruments), immunoassay, enzymatic assay, affinity method, and electrospray ionization/mass spectrometry were 3.2%, 5.2%, 11.5%, 9.7%, 7.2%, and 9.6%, respectively. Glycation product of the variant hemoglobin measured by HPLC, using HLC-723G8 and HA-8160, was 9.1% and 4.5%, respectively. The proband's father with type 2 diabetes was the first reported case of Hb Himeji. HbA1c by affinity method was markedly elevated (18.0%), but it was 5.3% by HPLC. The proband's two sisters also had Hb Himeji variant and similar method-dependent discrepancies in HbA1c values were observed. Conclusions In the patients with Hb Himeji, discrepancies occur between plasma glucose and HbA1c with all measurement methods because of differences in HPLC mobility, increased glycation, and antigenic changes of the variant β chain.

We previously reported that multiple thyroid cysts may be a cause of hypothyroidism in patients with a relatively high iodine intake and we termed it polycystic thyroid disease (PCTD). The aim of this study was to investigate the prevalence of PCTD in patients who visited our thyroid center. We hypothesized that patients with PCTD are not rare in a region with a high iodine intake.We retrospectively studied the cause of hypothyroidism based on medical histories and ultrasonography in new patients to our hospital from April 2008 to March 2009 whose serum tests for antithyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb) were negative. Serum thyroid hormones, thyrotropin (TSH), TgAb, and TPOAb were measured in 8243 patients. Patients with four or more thyroid cysts, negative tests for TgAb and TPOAb, no evidence for thyroid diseases other than their thyroid cysts, and no exposure to thyroid-perturbing influences were defined as having PCTD.Three hundred seven patients had overt hypothyroidism (TSH level above 10.0 μU/mL and free thyroxine level below 0.7 ng/dL), of whom 71 patients were both TgAb and TPOAb negative. There were 546 patients with subclinical hypothyroidism (TSH level above 5.0 μU/mL and normal free thyroxine), of whom 193 patients were both TgAb and TPOAb negative. There were 24 patients with overt hypothyroidism and PCTD, accounting for 7.8% (24/307) of all causes of overt hypothyroidism. There were 42 patients with subclinical hypothyroidism and PCTD, accounting for 7.7% (42/543) of all causes of subclinical hypothyroidism. PCTD was more common among elderly people than young people.PCTD appears to be a minor but not negligible cause of hypothyroidism, at least in iodine-rich regions. PCTD with hypothyroidism may have been misdiagnosed as thyroid antibody-negative Hashimoto's thyroiditis in many reports.

The prevalence of menstrual disturbances, including secondary amenorrhea, hypomenorrhea, oligomenorrhea, hypermenorrhea, polymenorrhea and irregular menstrual cycle were prospectively examined in 586 patients with hyperthyroidism due to Graves' disease, 111 with hypothyroidism, 558 with euthyroid chronic thyroiditis, 202 with painless thyroiditis and 595 with thyroid tumor. In the overall patient group, the prevalence did not different from that in 105 healthy controls. However, patients with severe hyperthyroidism showed a higher prevalence of secondary amenorrhea (2.5%) and hypomenorrhea (3.7%) than those (0.2% and 0.9%, respectively) with mild or moderate hyperthyroidism. Moreover, patients with severe hypothyroidism had a higher prevalence (34.8%) of menstrual disturbances than mild-moderate cases (10.2%). Menstrual disturbances in thyroid dysfunction were less frequent than previously thought.

Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves' disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission.A total of 134 untreated patients with Graves' disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation.Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography.After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P0.05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P0.05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance.Combined treatment with MMI and KI improved the short-term control of Graves' hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.

Somatic mutations of the thyrotropin receptor (TSHR) gene and the gene encoding the alpha subunit of the stimulatory GTP-binding protein (Gsalpha) are the main cause for autonomously functioning thyroid nodules (AFTN) in iodine-deficient regions of the world. In iodine-sufficient regions, including Japan, the genetic relevance of AFTN is unclear. In a series of 45 Japanese subjects with AFTN, exons 9 and 10 of the TSHR and exons 7-10 of Gsalpha , where the activating mutations have been found, were analyzed using direct sequencing. We found 29 somatic mutations: 22 in the TSHR gene and 7 in the Gsalpha gene. The most frequent mutation in TSHR was Met453Thr (10 cases), followed by clustered residues from codons 630 through 633 on TSHR (7 cases). Mutations of Gsalpha were detected at codon 201 in 5 cases and at codon 227 in 2 cases. No patients had coexistent TSHR and Gsalpha mutations in the same nodule. All mutated residues but one, which was deleted at codon 403 on the TSHR gene, are constitutively active. The prevalences of a germline polymorphism of Asp727Glu on the TSHR gene and incidental papillary thyroid carcinoma in thyroid surgical specimens were similar to those reported in other studies. In the present study, more than half of the cases with AFTN had a somatic activating mutation either of the TSHR or Gsalpha gene, despite their high iodine intake.

Antithyroid drugs (ATDs) are prescribed as the initial therapy for the majority of patients with Graves' disease in many areas of the world. Although, it is well known that agranulocytosis is one of the most serious side effects of ATDs, there has not yet been any conclusive evidence that the prevalence of agranulocytosis induced by ATDs is dose related. This study was performed to determine if the prevalence of agranulocytosis is different depending on the starting dosage of ATDs in patients with Graves' disease.Until 1996, we had typically prescribed 30 mg/d of methimazole (MMI) as the initial dosage for the treatment of Graves' disease at our institution. We changed the initial MMI dosage to 15 mg/d as a general rule in 1997. As a consequence, we acquired two groups of patients with Graves' disease who received different dosages of MMI. We retrospectively compared the prevalence of MMI-induced agranulocytosis in patients who received 15 mg/d of MMI to those who received 30 mg/d of MMI.There were 2087 subjects treated with 30 mg/d of MMI and 2739 treated with 15 mg/d of MMI. The prevalence of agranulocytosis in the 30 mg/d group was significantly higher than in the 15 mg/d group (0.814% vs. 0.219%, respectively, p0.01). The prevalence of agranulocytosis plus neutropenia in the 30 mg/d group was also significantly higher than in the 15 mg/d group (1.581% vs. 0.474%, respectively, p0.001).It is very likely that MMI-induced agranulocytosis occurs with a larger dosage of MMI and is dose related. Considering both the effectiveness and the risk of serious side effects, we recommend 15 mg/d of MMI as the starting dosage for the treatment of Graves' disease.

The effect of constant rich iodine intake, especially during pregnancy, has not been well understood.The objective was to examine urinary iodine excretion and thyroid function in early pregnancy in Japanese healthy women. We also studied fetal maturation and child development in these women.This study was an observational, prospective study conducted at a maternity hospital.Subjects were 622 pregnant women who visited a maternity hospital consecutively in early gestation. Subjects with positive thyroid antibodies were excluded, and finally 514 subjects were examined. Offspring subjects were infants born to the maternal subjects.Thyroid function, serum thyroperoxidase antibodies, and urinary concentrations of iodine were measured at the initial obstetrical visit. The fetal maturation scores estimated by the Dubowitz and Ballard methods in newly born infants were assessed. A child developmental test was performed using the Enjoji Scale up to 12 months of age.The distribution of urinary iodine concentrations was large, and the average was extremely high. There were significant positive correlations between urinary iodine and serum TSH (r = 0.1326; P0.005). Serum TSH during early pregnancy in mothers had no relevance to parameters in neonates, scores of fetal maturation, or child developmental testing in their infants.Iodine excess during early pregnancy seems to have no adverse effects on the fetus in healthy Japanese women. To avoid hypothyroidism, reducing excess dietary iodine intake to moderate intake may be beneficial for pregnant woman in Japan.

Subacute thyroiditis (SAT) has been rarely reported to coexist with thyroid carcinomas. The objective of the study was to assess sequential ultrasonographic and histopathological findings of SAT in the context of complicating thyroid carcinomas.Of 1152 patients with SAT who visited our thyroid clinic at Kuma Hospital from 1996 through 2006, 5 cases complicated by papillary carcinoma underwent surgical resection 3-16 months after SAT onset. Ultrasonographic examinations and thyroid function tests were performed in all patients at onset of SAT and just before surgery. Sequential histopathological features of regenerated thyroid and carcinoma involvement were evaluated.Heterogenous areas with microcalcifications in the thyroid or lymphadenopathy in three patients were clues for the nodular involvement with papillary carcinoma on the initial ultrasonographic examination. In contrast, diffuse hypoechoic change in the thyroid in two patients made it impossible to differentiate nodular involvement from inflammatory lesion. Histopathological examination of surgical specimens showed granulomatous and fibrotic changes. These were present about 3 months from SAT onset, and residual fibrosis remained several additional months, in the condition of no inflammatory hypoechoic lesions. In the areas of papillary carcinoma overlapping with transient inflammatory involvement, some lymphocytes and fibrotic changes were present in the stroma of papillary foci, but no granulomatous formation was present in any sections. Continuity with fibrosis around regenerated follicular cells was absent. The degree of lymphoid infiltrate and fibrotic change in the papillary carcinoma was not dependent on periods between SAT onset and the resection.SAT may produce ultrasound changes that obscure the coexistence of papillary carcinoma, but affects no lymphoid infiltrate and fibrotic changes involved in carcinoma throughout the clinical course. We recommend that patients with SAT have ultrasonography after they recover. Further workup, including cytological examination of hypoechoic regions, should be performed if they are present as measuring 1 cm or larger.

To describe the first adult case of large goiter associated with a novel R1110Q mutation in the dual oxidase 2 (DUOX2) gene. She was initially euthyroid, and developed hypothyroidism later in her forties. DUOX2 is an essential enzyme in iodine organification of thyroid hormone biosynthesis. Only infant cases of congenital hypothyroidism due to mutations of the DUOX2 gene have been reported. Biallelic mutation of DUOX2 is thought to lead to total iodine organification defect. PATIENTS AND MEASUREMENT: This 57-year-old woman became first aware of goiter around the age of 20 years. Since the goiter had enlarged gradually, she consulted us at the age of 32 years. Goiter was soft, and thyroid function was normal. Antithyroid antibodies were negative. Both physical and mental development was normal. Three of her nine siblings and her mother had large goiters. At the age of 44 years, thyroid function demonstrated subclinical hypothyroidism. She started to take levo-thyroxine at a dose of 100 mug/day to reduce goiter. At the age of 56 years, goiter size remained the same. The perchlorate discharge rate was 72.8%, suggesting partial iodine organification defect. Thus, thyroid peroxidase (TPO) gene and DUOX2 gene were analyzed.There was no mutation in the TPO gene, but a novel homozygous mutation (R1110Q) in the DUOX2 gene was identified. The same heterozygous mutation was detected in her two sons and two grandchildren. This mutation was not detected in 104 control alleles and was located at a site differing from any other reported mutations in the DUOX2 gene.This homozygous missense mutation can be associated with thyroid dysfunction and goiter formation of an enlarged thyroid gland.

Constitutively activating germline mutations of the thyrotropin receptor (TSHR) gene have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. We describe here a Japanese kindred with two affected individuals who showed overt hyperthyroidism and mild goiter in the absence of TSHR antibodies. A novel heterozygous germline point mutation, identified in both individuals, resulted in an amino acid substitution of aspartic acid for tyrosine at codon 617 (Asp617Tyr) in the third intracellular loop of the TSHR. Screening of 7 additional family members led to the identification of the same mutation in 4 relatives: 1 had undergone thyroidectomy due to hyperthyroidism but 3 were asymptomatic with subclinical hyperthyroidism. In vitro functional studies of the Asp617Tyr TSHR demonstrated a constitutive activation of the cyclic adenosine monophosphate pathway, but not of the inositol phosphate cascade, with data similar to those of Asp619Gly, the first constitutively activating mutant TSHR identified. Treatment with inorganic iodine for 7 months successfully relieved all symptoms of hyperthyroidism in both patients.

When the liver function tests are aggravated after starting antithyroid drugs (ATDs) in Graves' hyperthyroidism, discontinuation of ATDs is generally considered. However, a question arises whether such aggravation constitutes an adverse effect of the drugs or not.The aim of this study was to clarify the influence of thyrotoxicosis on liver function tests, comparing the results with those in thyrotoxicosis induced by painless thyroiditis.We prospectively studied liver biochemical tests in 30 patients with Graves' disease and in 27 patients with painless thyroiditis.Twenty-three (76.7%) untreated Graves' disease patients and 14 (51.9%) untreated painless thyroiditis patients were found to have at least one liver function test abnormality. One month after starting ATD therapy in patients with Graves' disease, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations from initial values were observed in 16 (53.3%). Similar elevations of AST and ALT from initial values at 1 month were observed in 10 (37.0%) and 7 (25.9%) patients with painless thyroiditis, respectively. Alkaline phosphatase (ALP) increased gradually after starting ATD therapy and maintained an elevated value for 3-5 months in Graves' disease. In painless thyroiditis, ALP also increased gradually, similarly to that in Graves' disease, but changes were mild. Elevation of ALT after 1 month of ATD therapy in Graves' disease was significantly higher in patients whose estimated disease duration was 6 months or more compared to those with duration of less than 6 months. Elevated AST and ALT at 1 month after ATD therapy decreased to normal ranges, even though patients were receiving the same ATDs in Graves' disease.Similar serial changes in liver function tests in both Graves' disease and painless thyroiditis strongly suggest that increases of AST and ALT after starting ATD therapy may not be due to ATD side effects but may be induced by changes in thyroid function.

Constitutively activating thyrotropin receptor (TSHR) germline mutations have been identified as a molecular cause of congenital hyperthyroidism. We here describe a Japanese woman who had presented with severe hyperthyroidism and advanced bone age as a neonate. She underwent neurosurgical intervention for craniosynostosis, and presented with perodactylia and mild mental retardation with hydrocephalus. Hyperthyroidism has been refractory to antithyroid drug therapy in the absence of antithyrotropin receptor antibodies during follow-up of 20 years, resulting in an enlarged goiter. Analysis of the patient's genomic DNA showed a heterozygous thymine-to-adenine point mutation in exon 10 of TSHR at position 1535 which was not present in the parents' DNA. This mutation, changing leucine to glutamine in codon 512 in the third transmembrane region, was previously identified as a somatic mutation in toxic thyroid nodules and was shown to increase basal cAMP production in vitro. To our knowledge, this is the first report of a germline mutation of TSHR causing sporadic congenital nonautoimmune hyperthyroidism in a Japanese patient.

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.

Little is known about the immunosuppressive effect of glucocorticoids on TSH receptor antibodies. We observed the long-term prognosis and serum TSH binding inhibitor immunoglobulin (TBII) levels in patients with Graves' ophthalmopathy who had received intravenous methylprednisolone pulse therapy (pulse therapy) followed by oral prednisolone administration in order to ascertain how long the immunosuppressive effect of glucocorticoids continued. This is the first report on the effect of pulse therapy on Graves' disease outcome. We observed 67 patients who were treated by antithyroid drugs (ATD) alone for 2 years after pulse therapy. TBII was evaluated before and 3, 6, 12, 18, and 24 months after pulse therapy. The mean TBII decreased significantly 3 months after pulse therapy (p0.001), and was maintained until 24 months. There were 24 patients whose TBII was positive (15%) at 24 months, in whom the mean TBII decreased significantly 3 to 6 months after pulse therapy (p0.001), but increased again at 12 to 24 months (p0.05). Thus, the immunosuppressive effect of glucocorticoids may be lost at 12 months after pulse therapy in these patients. The remission rate in the pulse therapy group was 40.98%, and that of the control patient group was 48.57%. There was no significant difference between the two. These results suggest that the immunosuppressive effect of pulse therapy was temporary, and that pulse therapy did not increase remission rate of Graves' disease.

High titer of thyrotropin-binding inhibitor immunoglobulin (TBII) in patients with Graves' disease can cause fetal hyperthyroidism during pregnancy. Prevention of fetal hyperthyroidism by administration of antithyroid drug (ATD) and levothyroxine (LT(4)) to pregnant patients who previously received ablative therapy has been reported. We administered iodine and LT(4) to a patient during gestation, because she had a severe adverse reaction to ATD. Although gestation proceeded normally, the infant showed transient neonatal hyperthyroidism right after birth. We believe that the fetus would have developed hyperthyroidism if we had not administered iodine to the mother. Administration of iodine and LT(4) to a pregnant patient with Graves' disease showing a high TBII after ablative therapy should be considered in rare patients with allergy to ATD.

Painful Hashimoto's thyroiditis is an atypical variant of Hashimoto's thyroiditis characterized by thyroid pain and fever. In patients with this condition, anti-inflammatory agents are not always effective as in those with subacute thyroiditis. Therefore, long-term pain management is an important issue. We report herein four cases of painful Hashimoto's thyroiditis requiring total thyroidectomy to relieve thyroid pain and histologic findings of the thyroid gland. All patients had high titers of anti-thyroperoxidase (TPO) and thyroglobulin antibodies. Three were hypothyroid, and the other was euthyroid. During the first visit, four patients had fever and/or thyroid pain with elevated C-reactive protein or erythrocyte sedimentation rate, and they were treated with oral corticosteroids given continuously or intermittently for 9 to 48 months. Because a reduction or discontinuation of corticosteroids caused recurrent painful attacks, the decision was made to perform surgery. After total thyroidectomy, their symptoms disappeared. The histopathologic characteristics of these hypothyroid cases were advanced fibrosis and destructive thyroid architecture. One euthyroid case showed a mild fibrous change and the presence of foreign body type giant cells. In conclusion, total thyroidectomy is the effective and reliable treatment for patients with recurrent painful Hashimoto's thyroiditis. Pathologic characteristics include advanced fibrosis and destructive thyroid architecture.

The weight-reducing herbal medicines "Dream Shape" and "Ever Youth" became available in Japan in 2000. Herein, we describe 12 patients who developed thyrotoxicosis after taking them. The thyroid hormone content of 1 capsule or tablet of herbal medicine, measured following Pronase digestion and ethanol extraction, was approximately 1 mug of triiodothyronine and 3 to 4 mug of thyroxine. Two of us took 10 capsules or tablets of Dream Shape or Ever Youth, and changes in thyroid hormone levels were observed during the first 24 hours. Serum free triiodothyronine levels began to rise 2 hours after ingestion and reached peak levels at 4 to 8 hours; changes in free thyroxine and thyrotropin levels were small during the first 24 hours. Similar herbal medicines may have been distributed to other countries via the Internet. Resultant factitious thyrotoxicosis can create diagnostic and therapeutic confusion, particularly in patients with thyroid disease.