TSH-binding Inhibitory Immunoglobulin Research Articles

Treatment of Pretibial Myxedema (PTM) with Topical Steroid Ointment Application with Sealing Cover (Steroid Occlusive Dressing Technique: Steroid ODT) in Graves' Patients

Localized pretibial myxedema (PTM) is a sign of Graves' disease. A 53-year-old man with Graves' disease was admitted with the development of PTM following radioisotope (131)I treatment for Graves' hyperthyroidism. TSH receptor antibody (TRAb) titer was also increased after (131)I treatment. TRAb was measured as thyroid stimulating antibody (TSAb) or TSH-binding inhibitory immunoglobulin (TBII). PTM was noted several months after (131)I treatment. The PTM-development seems to be associated with the increased TRAb-activities. The localized pretibial myxedema was effectively treated with topical steroid (triamcinolone acetonide) ointment application with sealing cover (steroid occlusive dressing technique: steroid ODT). We also report our experience of PTM-treatment with steroid ODT in 5 other PTM patients with positive TRAb. PTM was successfully treated with steroid ODT in two patients. In these two patients, the treatment was started within several months of the appearance of PTM. In the other 4 patients, the treatment was started 5-10 years after the appearance of PTM without any beneficial effects. Early detection and early treatment are necessary for the remission of PTM.

Thyroid Function in Japanese Adults as Assessed by a General Health Checkup System in Relation with Thyroid-Related Antibodies and Other Clinical Parameters

A limited number of epidemiological studies have attempted to assess thyroid function in the general population of iodine-sufficient countries. The aim of the present study was to determine the underlying thyroid diseases responsible for abnormal thyroid function detected by a general health checkup system in Japan, and to characterize the lipid metabolism in subjects found to have thyroid dysfunction. Serum thyrotropin (TSH), free thyroxine, anti-thyroglobulin antibodies (TgAb), anti-thyroid peroxidase antibodies (TPOAb), and TSH-binding inhibitor immunoglobulins (TBII) were determined in 1818 Japanese adults (804 men and 1014 women; mean age 51.3 +/- 9.0 years) who undertook a general health checkup. Of the 1818 examinees, 12 (0.7%) had overt hypothyroidism (OH), 105 (5.8%) subclinical hypothyroidism, 13 (0.7%) overt thyrotoxicosis, and 39 (2.1%) subclinical thyrotoxicosis. TgAb or TPOAb tests were positive in 17.7% of men and 31.4% of women. The prevalence of positive tests for TgAb or TPOAb was 14.8% for men and 23.4% for women without palpable goiter. Positive tests for TgAb, TPOAb, TBII, and a palpable goiter were more common in subjects with abnormal thyroid function tests than in subjects with normal thyroid function. At the time that abnormal thyroid function test results were first obtained, the signs of thyrotoxicosis were mild or even absent in all 13 subjects with overt thyrotoxicosis, 8 of whom had Graves' disease and 5 of whom had painless thyroiditis. Of the 12 patients with OH, only 2 patients had a palpable goiter. In the OH group, TgAb tests were positive in eight, TPOAb tests were positive in eight, and TBII tests were positive in two. The prevalence of disturbed lipid metabolism, when adjusted for age, was significantly higher in the subclinical hypothyroidism group than in normal controls (p < 0.001; odds ratio, 1.67; 95% confidence interval, 1.10-2.51). In Japanese adults who chose to be screened by a general health checkup system, the prevalence of abnormal thyroid function was nearly 10%. In a high percentage of these patients, abnormal thyroid function could not be detected by their history or physical examination. Just a physical examination without thyroid function tests, particularly serum TSH levels, was not adequate even when performed by a thyroid specialist.

Remission rate and remission predictors of Graves disease in children and adolescents

Purpose:Medical therapy is the initial treatment for children with Graves disease to avoid complications of other treatments. However, optimal treatment for childhood Graves disease is controversial because most patients require relatively long periods of medical therapy and relapse is common after medication discontinuation. Therefore, this study aimed to search clinical or biochemical characteristics that could be used as remission predictors in Graves disease. Methods:We retrospectively studied children diagnosed with Graves disease, treated with anti-thyroid agents, and observed for at least 3 years. Patients were categorized into remission and non-remission groups, and the groups were compared to determine the variables that were predictive of achieving remission. Results:Sixty-four patients were enrolled, of which 37 (57.8%) achieved remission and 27 (42.2%) could not achieve remission until the last visit. Normalization of thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII) after treatment was faster in the remission group than in the non-remission group (remission group, 15.5112.07 vs. non-remission group, 41.6935.70 months). Thyrotropin-releasing hormone (TRH) stimulation tests were performed in 28 patients. Only 2 (8.3%) of 26 patients who showed normal or hyper-response in TRH stimulation test relapsed. Binary logistic regression analysis identified rapid achievement of TBII normalization after treatment as a significant predictor of remission. Six percent of patients achieved remission within 3 years and 55.8% achieved it within 6 years. Conclusion:Rapid achievement of TBII normalization can be a predictor of remission in childhood Graves disease. The TRH stimulation test can be a predictor of maintenance of remission.

Age and stress as determinants of the severity of hyperthyroidism caused by Graves' disease in newly diagnosed patients

The evidence that stress may provoke Graves' hyperthyroidism in genetically susceptible subjects is substantial. Whether exposure to stress is related to the severity of thyrotoxicosis has not been studied. Advancing age is associated with not only less severe Graves' hyperthyroidism but also self-reported stress. We tested the hypothesis whether advancing age is associated with less exposure to stress, resulting in a lower immunological response, and less severe Graves' hyperthyroidism. Cross-sectional multicenter study. Two hundred and sixty-three consecutive untreated patients with a first episode of Graves' hyperthyroidism were included. The severity of Graves' hyperthyroidism was evaluated biochemically (freeT(4)-index and freeT(3)-index, thyrotropin-binding inhibitory immunoglobulin (TBII)) and clinically by the hyperthyroid symptom scale score (HSS score). Stress exposure was quantitated by three questionnaires. Advancing age was associated with less severe Graves' hyperthyroidism, both biochemically by lower serum freeT(3)-index and freeT(4)-index (P<0.01), lower serum TBII (P=0.05), and clinically by lower HSS scores (P=0.04) and smaller goiter size (P<0.01). FreeT(3)-index and freeT(4)-index were directly associated with HSS scores (P<0.01). Stress scores were associated with HSS scores (P<0.01) but not with biochemical severity of Graves' hyperthyroidism. Advancing age was associated with lower scores for stress exposure. Multivariate regression analysis showed that HSS score was independently related to the tendency to report negative feelings (P<0.01) but not to other stress scores and also not to age. Advancing age is associated with less exposure to stress, lower serum TBII and less severe clinical and biochemical Graves' hyperthyroidism. Because no direct relationship exists between stress exposure and TBII or freeT(3)-index and freeT(4)-index, we reject our hypothesis that less stress is causally related to biochemically less severe Graves' hyperthyroidism in old age. HSS score is primarily determined by negative feelings and not by age.

Frequency and characteristics of TBII‐seronegative patients in a population with untreated Graves’ hyperthyroidism: a prospective study

It is claimed that second generation thyrotropin-binding inhibitory immunoglobulin (TBII) assays have a very high sensitivity for the diagnosis of Graves' hyperthyroidism (GH). However, studies evaluating the accuracy of TBII have been retrospective in nature and/or GH had not been diagnosed independently of TBII. The aim of the present study, therefore, was to prospectively evaluate the frequency and characteristics of TBII-seronegative patients in a population of untreated GH diagnosed independent of serum TBII. Prospective multicentre observational study. A total of 259 consecutive untreated patients with a first episode of GH, diagnosed independent of serum TBII. TBII levels were measured by second generation assay and correlated to thyroid function, clinical characteristics and exposure to environmental factors. Serum TBII was positive in 245 (94.6%) patients and negative (< 2 IU/l) in 14 (5.4%) patients. TBII-seronegative patients had lower fT4 (median 42.5 vs. 53.9 pmol/l, P = 0.02), T3 (median 3.55 vs. 4.90 nmol/l, P < 0.01) and fT3-index (median 4.30 vs. 6.27, P < 0.01) compared to TBII-seropositive patients. None of the TBII-seronegative patients had TSH-receptor activating mutations, Graves' orbitopathy or pretibial myxedema. Serum TBII was positively correlated to free T3 (fT3)-index and free T4 (fT4)-index (P < 0.01), goitre size (P < 0.01) and the prevalence of Graves' orbitopathy (P < 0.01). There were no significant differences between TBII-seropositive and TBII-seronegative patients in environmental factors. The prevalence of TBII-seronegativity in untreated patients with GH is 5.4% using a second generation assay. TBII-seronegative patients have biochemically less severe thyrotoxicosis and no Graves' orbitopathy. TBII-seronegative and TBII-seropositive patients apparently belong to the same population of GH, albeit the severity of the autoimmune attack is less in TBII-seronegative patients.

Rituximab in relapsing Graves' disease, a phase II study

Conventional therapies for Graves' disease, consisting of medical therapy or radioiodine are unsatisfactory, because of limited efficacy and adverse events. Interventions aimed at the underlying autoimmune pathogenesis of Graves' disease may be worthwhile to explore. We therefore performed a prospective, 26-week phase II study with open-ended observational extension to assess the efficacy of rituximab in patients with recurrent Graves' disease. We performed a prospective, 26-week phase II study with open-ended observations. Thirteen patients with relapsing Graves' disease (9 females and 4 males, age 39.5+/-9.5 years) received 2 dosages of rituximab 1000 mg i.v. with a 2-week interval. Before administration and on several periods after the administration of TSH, free thyroxine (FT(4)), thyrotropin binding inhibitory immunoglobulins (TBII) and the proportion of CD19 and MS4A1 positive peripheral blood mononuclear cells were measured. The proportion of MS4A1 positive lymphocytes decreased in all patients from 5.8% at baseline to 1.4% at 26 weeks (P=0.007). Four patients with high initial FT(4) levels did not respond to treatment. All remaining patients had a decrease in FT(4) levels at 26 weeks (P=0.001) and an increase in TSH levels (P=0.011). TBII decreased in all remaining patients (P=0.003). At a follow-up time of 14-27 months, nine of these patients were still euthyroid with normal FT(4) (P<0.001) and TSH levels (P=0.008). The present study results suggest a beneficial role of rituximab in mild relapsing Graves' disease. A subsequent randomized controlled trial with rituximab is recommended.

In vitro production of interferon-gamma by peripheral blood from patients with Graves' disease, Hashimoto's thyroiditis and rheumatoid arthritis

The production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells (PBMC), CD4 cells, or CD8 cells in response to interleukin-2 (IL-2) stimulation has been studied; the samples were obtained from 12 healthy control subjects, 19 patients with Graves' disease (10 hyperthyroid and nine euthyroid), 13 patients with Hashimoto's thyroiditis (four hypothyroid and nine euthyroid), and 15 patients with rheumatoid arthritis (11 active and four inactive). A dose of IL-2 (25 U/ml) was utilized to induce IFN-gamma by PBMC from all four groups. The incremental increase in IFN-gamma values (with IL-2 stimulation minus without stimulation) was significantly less in PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis than that in PBMC from control subjects. The values from PBMC in patients with Graves' disease in a euthyroid state were below normal but greater than those from patients with Graves' disease in a hyperthyroid state. The incremental increase in IFN-gamma values from Graves' disease PBMC correlated with the serum TSH values (r = 0.622, P less than 0.01), but not with thyroid autoantibodies (anti-thyroid microsomal antibodies, anti-thyroid microsomal antibodies, nor TSH-binding inhibitory immunoglobulin activities). The incremental increase in IFN-gamma from PBMC from both control subjects and Graves' disease was correlated with that from CD4 cells (r = 0.711, P less than 0.01), but not with that from CD8 cells. The production of IFN-gamma in response to IL-2 from PBMC in Graves' disease correlated inversely with thyroid function, appearing to reflect the very effect of hyperthyroidism in this process. The precise explanation of these phenomena remains unclear. The decreased response of IFN-gamma to IL-2 stimulation by PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis seems to be a non-specific phenomenon occurring in both organ specific autoimmune disease and systemic autoimmune disease. It may be due to a down-regulation in autoimmune disease of CD4 cells in response to IL-2, a decreased level of IL-2 cellular receptors or a decreased receptor affinity, associated increased soluble IL-2 receptors, or a defect of the intra-CD4 cellular IL-2 signal to produce or release IFN-gamma in the conditions studied.

Clinical Usefulness of the Second Generation TSH-Binding Inhibitory Immunoglobulin Assay Using Recombinant Human TSH Receptor in Patients with Graves' Disease

Background and Aim: Detection of TSH receptor antibody in patients with Graves' disease (GD) has been widely used in clinical practice. This has been performed mostly by commercial radio-receptor assays that measure TSH-binding inhibitory immunoglobulin (TBII) with using porcine TSH receptor as the ligand. To increase the sensitivity of the assay, many research groups have tried to replace the porcine source of TSH receptor with recombinant human TSH receptor. In this study we evaluated the clinical usefulness of the second generation TBII assay, which uses recombinant human TSH receptor, for making the diagnosis of GD, as compared to the conventional TBII assay. Materials and Methods: We obtained sera from 76 patients with newly diagnosed or relapsing GD without or with less than 4 weeks of antithyroid drugs, and 54 patients with Hashimoto's thyroiditis who had not received thyroid hormone treatment or quit thyroid hormone more than 3 months before. TBII was measured by using both the conventional porcine TBII assay (pTBII) and the human recombinant TBII assay (hTBII). TBII was also measured in the sera from 66 healthy controls. Results: The cut-off values of the pTBII and hTBII assay were defined as two geometric standard deviations from the geometric mean of the values in healthy controls, and these values were 10.8 IU/L and 1.0 IU/L, respectively. The sensitivity was 62% (47/76) for pTB II, as compared to 100% (76/76) for the hTBII, for diagnosing GD. Of the 54 patients with Hashimoto's thyroiditis, 3 (5.6%) and 7 (13.0%) patients had positive pTBII and positive hTBII, respectively. Conclusions: These data showed that the hTBII assay was a comparable method in terms of the sensitivity for the diagnosis of GD, as compared to the pTBII assay. It can be suggested that this new hTBII assay, rather than the pTBII assay, should be more widely used as the first line diagnostic test for GD. (J Korean Endocr Soc 23:179~185, 2008)

A Case of Painful Graves' Disease

Graves’ disease rarely presents as pain and tenderness of goiter, with only a few cases reported in the literature. We describe a case of painful Graves’ disease presenting as 2 episodes of painful goiter. A-25-yr-old male was referred to our hospital because of pain in the anterior neck, palpitations, and muscle weakness. His heart rate was 122 beat/min and body temperature was normal. The thyroid gland was enlarged and tender. His thyroid function test showed thyrotoxicosis with high TSH binding inhibitory immunoglobulin (TBII) and thyroid peroxidase antibody (TPO Ab). A 99mTc-pertechnate thyroid scan showed diffuse increased uptake with no focal defects. He was started on propranolol, methimazole, Lugol’s solution, and prednisolone. He was discharged 7 days later with improved painful symptoms. The prednisolone was tapered out for 2 months. Eight months after the initial pain, he experienced one more episode of thyroid pain and hyperthyroidism, with an increase in TBII. He was treated with methimazole and prednisolone, and responded well. (J Korean Endocr Soc 23:337~341, 2008)

Serum Concentrations of Adiponectin in Patients with Hyperthyroidism before and after Control of Thyroid Function

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. 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. Any change in BMI was strongly correlated with changes in serum-adiponectin levels (r = -0.789, p<0.001). Any change in serum FT4 was also correlated with changes in BMI and serum adiponectin levels (r = -0.254, p = 0.05 and r = 0.501, p = 0.029 respectively). After controlling for BMI changes, we found correlation also between serum FT4 and adiponectin (r = 0.29, p = 0.005). Multivariate-regression analysis still revealed BMI to be a statistically strong predictor for serum-adiponectin level (p<0.001). However, that analysis also revealed thyroid function level as another predictor (p = 0.029). Although BMI is the best predictor of adiponectin, that thyroid hormone might influence circulating levels of adiponectin.

The Prevalence of Transient Thyrotoxicosis after Antithyroid Drug Therapy in Patients with Graves' Disease

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.

Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from Graves’ disease

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. 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. TBF was significantly higher in Graves' disease (mean +/- 1SD: 14.9 +/- 6.4%, P < 0.0001) than in painless thyroiditis (0.8 +/- 0.5%), subacute thyroiditis (0.9 +/- 0.7%) and in normal controls (0.8 +/- 0.5%). All patients with Graves' disease had TBF values of more than 4% and all patients with painless thyroiditis and subacute thyroiditis had TBF values less than 4%. TBF values significantly correlated with values of radioactive iodine uptake (RAIU) either at 3 h (r = 0.492, P < 0.01) or 24 h (r = 0.762, P < 0.001) within the Graves' disease and painless thyroiditis groups. There was no relationship between TBF values and thyroid volumes or values of TBII in the Graves' disease group. All patients with Graves' disease had positive TBII of 15% or more. Three of 28 patients with painless thyroiditis and one of 30 patients with subacute thyroiditis had positive TBII. TBF was quantitatively measured by power Doppler ultrasonography and was more effective than TBII for differentiation between destruction-induced thyrotoxicosis (painless or subacute thyroiditis) and Graves' thyrotoxicosis. TBF values of less than 4% in untreated thyrotoxic patients are laboratory signals of destruction-induced thyrotoxicosis and if these are determined, the radioactive iodine uptake test can be omitted for differential diagnosis of these two types of thyrotoxicosis.

Continued Suppression of Serum TSH Level May Be Attributed to TSH Receptor Antibody Activity As Well As the Severity of Thyrotoxicosis and the Time to Recovery of Thyroid Hormone in Treated Euthyroid Graves' Patients

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

Differential Susceptibility of BALB/c and BALB/cBy Mice to Graves' Hyperthyroidism

BALB/c mice are susceptible to the induction of Graves' hyperthyroidism. To investigate the susceptibility of BALB/c substrains of mice to the induction of hyperthyroidism, we immunized BALB/cJ and BALB/cByJ mice with an adenovirus expressing amino acid residues 1-289 of thyrotropin receptor (TSHR). The data presented in this article showed that 17 of 26 (65%) BALB/c and only 4 of 30 (13%) BALB/cBy mice developed hyperthyroidism. Hyperthyroid mice displayed characteristics of Graves' disease, such as thyroid-stimulating antibodies and enlarged thyroid glands. To explore the differences in the susceptibility of these substrains for hyperthyroidism, we examined the TSHR antibodies in three different assays. The TSHR antibodies determined in a radioreceptor assay (TSH binding inhibitory immunoglobulins) were similar in both of these BALB/c substrains. The TSHR antibody titers of total IgG, IgG1, and IgG2a were measured by an enzyme-linked immunosorbent assay and were found to be similar in these mice. There were no significant differences between these two groups of mice in the thyroid-stimulating antibody activity. However, BALB/cBy mice had significantly higher TSH-blocking antibody activity compared to BALB/c mice. TSHR-specific proliferation of splenocytes and secretion of cytokines interferon-gamma and interleukin-4 by spleen cells were comparable in both the groups. BALB/cJ and BALB/cByJ mice both belong to same MHC haplotype, H-2(d), but differ in the Qa-2 region of class Ib molecule. This report shows the importance of other genes, such as Qa-2 region of class Ib molecule in addition to MHC class II, in the susceptibility of Graves' hyperthyroidism.

HLA-DPB1*0202 Is Associated with a Predictor of Good Prognosis of Graves’ Disease in the Japanese

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.

Analysis of the Factors Associated with Tc-99m Pertechnetate Uptake in Thyrotoxicosis and Graves' Disease

To determine the factors associated with 20 minute Tc-99m pertechnetate thyroid uptake, we examined all patients in whom thyrotoxicosis was diagnosed at Chiba-Hokusoh Hospital, Nippon Medical School from 2001 April through 2003 March. Patients with thyrotoxicosis diagnosed during this period were 57 with Graves' disease (76%), 11 with transient hyperthyroxinemia (TH)(14.7%), and 7 with subacute thyroiditis (SAT)(9.3%). The uptake of Tc-99m ranged from 0.97% to 40.1% in Graves' disease and from 0.15% to 0.8% in TH. Although TH may include spontaneous resolution of Graves' disease as well as painless thyroiditis, no treatment was necessary for these patients. Uptake in all patients with SAT was less than 0.5%. There were significant correlations between the level of Tc-99m uptake and the levels of free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH)-binding inhibitory immunoglobulin (TBII), and thyroid stimulating antibody (TSAb) in patients with Graves' disease. Older patients with Graves' disease showed lower uptake than did younger patients. Both Tc-99m pertechnetate uptake and TBII levels, but not fT3, fT4 or TSAb levels, at the beginning of antithyroid drug treatment correlated significantly with the duration of treatment until the daily dose of methimazole reached 5 mg. These data suggest that Tc-99m pertechnetate uptake reflects the severity of Graves' disease and its response to the medical treatment and that antithyroid drug therapy is not necessary when the uptake is less than 0.9%.

Successful Use of Iodine and Levothyroxine to Treat Graves' Disease in a Pregnant Patient with Allergy to Antithyroid Drugs and High Thyrotropin-Binding Inhibitor Immunoglobulin After Radioiodine Therapy

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.

Graves’ Disease and Stiff-Person (Stiff-Man) Syndrome: Case Report and Literature Review

To report an association between two autoimmune conditions, Graves' disease and stiff-person (stiff-man) syndrome, and discuss the relevant literature. We present a case of a 52-year-old white woman with stiff-person syndrome who also had Graves' disease, discuss her management, and review the related literature. Pertinent published reports from 1950 through 2004 were researched with use of MEDLINE and PubMed, and cross-references to other articles were reviewed. A 52-year-old white woman presented with symptoms of hyperthyroidism due to Graves' disease. Laboratory data were as follows: thyrotropin <0.005 m IU/mL, thyroxine 11.1 microg/dL, free thyroxine index (FTI) 10.7, and triiodothyronine 170 ng/dL. Thyroid-stimulating immunoglobulins (TSI) and thyrotropin-binding inhibitory immunoglobulins (TBII) were positive at 1,986% and 82.5 U/L, respectively. The hyperthyroidism was treated with propranolol. She had a long-standing history of musculoskeletal complaints and was ultimately diagnosed with stiff-person syndrome. During her thyroid evaluation, she had severe neurologic deterioration that necessitated hospitalization and treatment with clonazepam, baclofen, intravenous immunoglobulin, and subsequently prednisone and azathioprine for appreciable symptomatic relief. The aggressive immunosuppression had a profound effect on her symptoms of hyperthyroidism, results of thyroid function tests, and thyrotropin receptor antibodies (TRABs). Thyrotropin was 0.52 microIU/mL, thyroxine was 6.9 microg/dL, and FTI was 5.7. The TSI decreased from 1,986% to 248%, and her TBII normalized from 82.5 U/L to <5 U/L. She was clinically and biochemically euthyroid at last follow-up in May 2004. This case illustrates the association between TRAB-positive Graves' disease and stiff-person syndrome and the improvement of Graves' disease with immunosuppressive therapy.

Assays for Thyroid-stimulating Antibodies and Thyrotropin-binding Inhibitory Immunoglobulins in Children with Graves' Disease

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.

Effect of High Dose Methylprednisolone Pulse Therapy Followed by Oral Prednisolone Administration on the Production of Anti-TSH Receptor Antibodies and Clinical Outcome in Graves' Disease

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 (p<0.001), 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 (p<0.001), but increased again at 12 to 24 months (p<0.05). 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.