Usefulness of the 2nd generation assay for anti-TSH receptor antibodies to differentiate relapse of Graves' thyrotoxicosis from development of painless thyroiditis after antithyroid drug treatment for Graves' disease

After antithyroid drug (ATD) treatment for Graves' disease, either a relapse of Graves' thyrotoxicosis or painless thyroiditis can develop. It is important to differentiate these two types of thyrotoxicosis because of the difference in required therapy. However, differentiation of thyrotoxicosis is usually difficult without radioactive iodine uptake (RAIU) which is not available in general practice. We investigated the clinical usefulness of the 2nd generation assay for anti-TSH receptor antibodies (TRAb) to differentiate these two types of thyrotoxicosis after ATD treatment for Graves' disease. We recruited 26 patients who developed thyrotoxicosis after ATD treatment for Graves' disease. These patients once became negative for TRAb and seemed to be in remission after ATD treatment. Upon development of thyrotoxicosis after ATD treatment, TSH, free T4, free T3 and TRAb were measured. TRAb were measured by the 2nd generation assay using recombinant human TSH receptors instead of porcine TSH receptors. Fourteen patients relapsed into Graves' thyrotoxicosis and 12 patients developed painless thyroiditis. Twelve (85.7%) of 14 patients with relapse of Graves' thyrotoxicosis were positive for TRAb. Eleven (91.7%) of 12 patients with development of painless thyroiditis after ATD treatment for Graves' disease were negative for TRAb. Levels of TRAb were significantly different between patients with relapse of Graves' thyrotoxicosis (4.86 +/- 6.45 IU/L) and those with painless thyroiditis (0.62 +/- 0.61 IU/L) (P<0.001). The 2nd generation assay for TRAb was useful to differentiate relapse of Graves' thyrotoxicosis from development of painless thyroiditis in patients who seemed to be in remission after ATD treatment for Graves' disease.     

Evaluation of serum basal thyrotrophin levels and thyrotrophin receptor antibody activities as prognostic markers for discontinuation of antithyroid drug treatment in patients with Graves'' disease

OBJECTIVE: We evaluated whether antithyroid drug treatment could be terminated more appropriately when both the serum basal thyrotrophin (TSH) level and TSH receptor antibody activity have become normal. DESIGN: This was a prospective randomized study of patients with Graves' disease followed for a mean of 28 months after the withdrawal of antithyroid drug treatment. PATIENTS AND INTERVENTIONS: A total of 174 patients with hyperthyroid Graves' disease were entered consecutively into this study, 11 of whom were subsequently excluded. One hundred and sixty-three patients were divided randomly into two groups having different criteria for the discontinuation of the antithyroid drug. Group 1 consisted of 79 patients whose antithyroid drug treatment was discontinued if both their serum TSH level and thyrotrophin binding inhibitor immunoglobulin (TBII) activity normalized. Group 2 consisted of 84 patients who were treated for 24 months irrespective of their serum TSH level and TBII activity. All patients were treated initially with 400 mg/day of propylthiouracil followed by decreasing doses that maintained a euthyroid state. MEASUREMENTS: Serum basal TSH levels and TBII activities were measured using a radioimmunometric assay and a radioreceptor assay, respectively, every 2 months during the antithyroid drug treatment. RESULTS: The remission rate of Group 1 (51.9%) was not significantly different from that (63.1%) of Group 2. The mean duration of treatment in Group 1 was 10.2 +/- 4.5 months (range 5-24, median 10). Median duration of treatment in Group 1 was 14 months shorter than in Group 2. In Group 1, the relapse rate was independent of the duration of the treatment. Further, the mean duration of treatment in the relapsed patients was not significantly different from that for patients who went into remission (9.9 +/- 3.8 vs 10.7 +/- 5.7 months; P greater than 0.1). In Group 2, the relapse rate was dependent on the time when both the serum TSH level and TBII activity were normalized (chi 2 = 27.0, d.f. = 4; P less than 0.001). When both the serum TSH level and TBII activity were normalized, the relapse rate of Group 2 was not significantly different from that of Group I for treatment periods of 6-12 months (25 vs 24.2%, P greater than 0.1), 12-18 months (33.3 vs 40%, P greater than 0.1), and 18-24 months (46.2 vs 50%, P greater than 0.1). However, the relapse rate of Group 2 was significantly lower than that of Group 1 when there was only a 6-month treatment period (5.6 vs 42.9%, P less than 0.05). Of the clinical and laboratory parameters measured, male sex, change of goitre size during treatment, and TSH levels and TBII values at the end of treatment, were of prognostic significance in predicting a relapse. CONCLUSION: The present study suggests that antithyroid drugs treatment can be terminated more appropriately when both the serum TSH level and TBII activity are made normal, thus avoiding prolonged and unnecessary drug treatment.     

Antithyrotropin receptor antibodies in a series of Basedow's disease

Thyrotrophin binding inhibiting immunoglobulins (TBII) were tested in 40 Graves' disease patients with hyperthyreosis, by an isotopic receptor assay (TRAK-Assay Behring). The samples were taken before, during and at the end of the hyperthyroid treatment. TRAb were present in serum of 86.67% of the patients before the treatment and in none of the 20 healthy control volunteers. There was no correlation between TRAb values and either the clinical signes of the disease neither the other thyroidal antibodies. After discontinuation of the antithyroid therapy (18 to 24 months after the onset) TRAb were negative in 71.4% of the patients; among this group 33% had a late relapse of the disease. In the positive TRAb group after discontinuation of the antithyroid therapy, 83.3% had a relapse of the disease and this relapse occurred shortly. There is a significant correlation between the TRAb values and the occurrence of relapse. In conclusion, TRAb values at the end of hyperthyroid treatment in Graves' disease patients seems to be a useful predictor value of the clinical course of the disease. This may be also a good help in the decision to continue or discontinue antithyroid therapy in Graves' disease patients with hyperthyreosis.     

Remission of Graves' hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene

We studied whether a patient with Graves' disease will go into remission during antithyroid drug (ATD) treatment. Remission of Graves' hyperthyroidism is predicted by a smooth decrease in TSH receptor antibody (TRAb) during ATD treatment. Cytotoxic T cell lymphocyte-associated molecule-4 (CTLA-4) may play an important role in the development of Graves' hyperthyroidism and in its remission. We studied A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene in 144 Japanese Graves' patients. We intended to reveal the possible association of CTLA-4 gene polymorphism with the remission of Graves' hyperthyroidism. All patients with Graves' disease were treated with ATD. Thyroid-stimulating antibody and TSH binding inhibitory Ig were measured as TRAb. We analyzed CTLA-4 genotypes and alleles with PCR. We calculated the frequencies of CTLA-4 genotypes and alleles. A significant increase in the frequency of the G allele was seen in Graves' patients compared with controls (P = 0.0095). Graves' patients were divided into three groups (A, B, and C) according to time of TRAb disappearance after the start of ATD treatment. In group A patients TRAb had disappeared within 1 yr after the start of ATD treatment, in group B TRAb had disappeared between the beginning of the second year and the end of the fifth year of treatment, and in group C TRAb continued to be positive after 5 yr of ATD treatment. The frequencies of the GG genotype and the G allele were significantly higher in group C patients with persistently positive TRAb over 5 yr of ATD treatment than in the other groups (P < 0.0001). Group C patients did not have the AA genotype. The periods of time until remission were significantly shorter in the AA genotype. Graves' patients with the G allele need to continue ATD treatment for longer periods.     

Sensitive thyrotropin and thyrotropin-receptor antibody determinations one month after discontinuation of antithyroid drug treatment as predictors of relapse in Graves' disease.

OBJECTIVE: After primary successful antithyroid drug treatment (ATDT), Graves' disease has a relapse rate of 30% to 50%. Previous studies have evaluated age, gender, goiter volume, smoking habits, and the presence of thyrotropin-receptor antibodies (TRAb) as predictive markers to facilitate an individualized patient management. Despite higher sensitivity and specificity of the new second generation human TSH-receptor assay, the predictive value of TRAb for relapse of hyperthyroidism is still controversial. In a recent prospective multicenter study we have previously shown that suppressed or low TSH values predict both early (persistence) and late relapse of Graves' disease. We now present a more detailed analysis of the predictive value of TSH and TRAb for recurrent hyperthyroidism. METHODS: Four weeks after withdrawal of ATDT, 96 patients were available for thyroid function tests, including a sensitive third-generation TSH assay and a second-generation recombinant TSH receptor assay. Relapse of Graves' disease was evaluated for a total follow-up of 2 years. RESULTS: Within 2 years, 47 of 96 patients (49%) developed relapse of hyperthyroidism. Nine patients relapsed within the first 4 weeks after withdrawal of ATDT and were thus considered to have persistent Graves' disease. Ten of 15 other patients with TSH levels below 0.3 mU/L without overt hyperthyroidism relapsed within 2 years. Twenty-five of 65 patients with normal TSH (0.3-3.0 mU/L) and 3 of 4 patients with TSH values above 3 mU/L also had recurrent hyperthyroidism. After ATDT cessation, TSH had a positive predictive value of 70% and a negative predictive value of 62% (specificity 85%) for relapse of Graves 'disease. Mean TRAb levels in the group of patients with relapse were significantly higher (11.1 IU/L +/- 0.17) than TRAb values in the remission group (4.5 IU/L +/- 0.6), p < 0.001. Using a cutoff value of 1.5 IU/L, TRAb had low positive and negative predictive values of 49% and 54%, respectively (specificity, 14%), but with a cutoff level of 10 IU/L, predictive values improved to 83% and 62%, respectively (specificity, 92%). Combination of TSH and TRAb determinations did not further improve prediction of relapse. Other factors such as gender, age, goiter volume, smoking habits, presence of thyroid-associated ophthalmopathy, and urinary iodine excretion did not show a significant influence on relapse rate. CONCLUSION: Low TSH values 4 weeks after ATDT withdrawal predict relapse of Graves' disease, both early (persistence) and, to a lesser extend, within 2 years of follow-up. Also, TRAb above 10 IU/L found in a small subset of patients, correlated with a higher relapse rate.     

Reduction of the risk of relapse after withdrawal of medical therapy for Graves' disease.

It has been a continuing challenge to try and identify those patients with hyperthyroid Graves' disease likely to remain in remission after an antithyroid drug course or to manage the medical treatment so as to increase the chance of remission. On average, the overall relapse rate is approximately 50% and any significant reduction of this figure would be of practical as well as theoretical value. The numerous controlled prospective studies performed in many parts of the world, with varying iodine intakes, have all confirmed that the main initial features related to the subsequent risk of relapse are: young age, male gender, goiter larger than 40 mL, hypoechogenic and hypervascular gland, high level of anti-thyrotropin receptor antibody (TRAb), detected either with radioreceptor assay (TBII: >40 U/L) or the biologic stimulation assay (thyroid-stimulating antibodies [TSAb]; >300%), severity of hyperthyroidism, and possibly the presence of ophthalmopathy. Alone, each of these has a low predictive value, but together they allow evaluation of the risk of relapse, thus helping treatment choice. As to the modalities of antithyroid drug treatment, dose of the drug or addition of levothyroxine does not affect posttreatment outcome. In contrast, significantly fewer relapses occur for drug courses longer than at least 1 year. Persistence of high levels of TRAb after medical treatment is strongly predictive of relapse but this is of limited value because in most patients, TRAb levels are low or even undetectable at the end of treatment, which does not indicate for further outcome. Smoking is a significant independent risk factor for relapse. In conclusion, reduction of the risk of relapse in patients with medically treated hyperthyroid Graves' disease relies on clinical competence and appropriate management taking into account an array of factors none of which alone has definite predictive value.     

Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves' disease

OBJECTIVE: To investigate the effect of different antithyroid drug (ATD) regimens on relapse rates of Graves' disease, and to look for predictors of relapse. DESIGN AND METHODS: In a prospective two-way factorial randomized clinical trial, 218 patients with Graves' disease were assigned to ATD combined with l-thyroxine (l-T(4)) or ATD alone for 12 Months. After discontinuation of antithyroid therapy, each group was stratified to either 12 Months further treatment with l-T(4) or no treatment. Clinical and biochemical assessments were carried out before treatment, after 3 and 6 weeks, and every third Month for 12 Months. If the patients lacked symptoms of relapse, laboratory tests were performed every third Month for the second Year, and thereafter annually. RESULTS: The proportion of all patients with relapse was 47.7% 2 Years after withdrawal of ATD. There was no difference in relapse rates between the treatment groups (P=0.217, log--rank test). Smokers had a higher relapse rate than non-smokers (58.4% vs 38.8%, P=0.009). Patients who were thyrotropin-receptor antibody (TRAb) positive after 12 Months of antithyroid therapy had a higher relapse rate than those who were negative (72.5% vs 36.8%, P<0.0001). Similarly, relapse was more frequent (55.5%) in patients having large goiter compared with subjects with small goiter (36.3%, P=0.0007). CONCLUSIONS: Relapse rates of Graves' disease were independent of ATD regimen whether followed by l-T(4) therapy or not. Smoking, large goiter and presence of TRAb at the end of ATD therapy were strong predictors of relapse.     

A possible role of immunoglobulin E in patients with hyperthyroid Graves' disease.

To investigate the possible participation of immunoglobulin E (IgE) in the autoimmune process of Graves' disease, incidence of elevation of serum IgE level, TSH receptor antibody (TRAb), and thyroid status were studied in 66 patients with hyperthyroid Graves' disease, 54 patients with Hashimoto's thyroiditis, 19 patients with bronchial asthma, and 15 patients with pollen allergy. In hyperthyroid Graves' patients, elevation of serum IgE levels (> or = 170 U/mL) was found in 19 of 66 patients (29%), 11 of whom had hereditary and/or allergic conditions. Elevations of serum IgE levels were found in 63% of patients with bronchial asthma and in 40% of patients with pollen allergy. Mean values of serum IgE were the same in patients with hyperthyroid Graves' disease and with bronchial asthma. During methimazole treatment TRAb decreased without fluctuation of IgE levels in both groups. The decrease in TRAb was significantly greater in patients with normal IgE than in patients with IgE elevation. After prednisone administration, reduction in TRAb was greater in patients with normal IgE than that in patients with IgE elevation. High incidence of IgE elevation in hyperthyroid Graves' disease and slower reduction in TRAb in association with IgE elevation suggest a difference in the autoimmune processes in Graves' disease with and without elevation of IgE.     

TSH receptor antibody measurements and prediction of remission in Graves' disease patients treated with minimum maintenance doses of antithyroid drugs

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

Clinical studies on abnormal thyroid stimulators in patients with Graves' disease. II. Clinical significance of measuring TSAb and TBII in patients with euthyroid Graves' disease and patients with hyperthyroid Graves' disease during antithyroid drug treatment

To evaluate the clinical significance of TBII and TSAb activities in euthyroid and hyperthyroid Graves' disease, these two activities were measured in 8 patients with euthyroid Graves' disease and 29 patients with hyperthyroid Graves' disease during treatment with antithyroid drugs. In 8 patients with euthyroid Graves' disease, TBII activity was detectable only in one patient and TSAb activity detected in 3 patients, these detectabilities being much lower than those in hyperthyroid Graves' disease. However, 2 of 4 patients who had either TSAb or TBII came to have both activities, and one of them became overt hyperthyroid. In patients with hyperthyroid Graves' disease, detectabilities of these activities became lower as they became euthyroid with antithyroid drug treatment, but TSAb tended to be higher than TBII when they remained euthyroid for more than 4 months. Although the majority of the patients who had TSAb and/or TBII activities were T3 non-suppressible, patients with no TSAb and TBII activities did not necessarily show remission of the disease. The present results suggest that patients with euthyroid Graves' disease with both TBII and TSAb may be apt to become hyperthyroid, and that TSAb and TBII activities and T3 suppressibility may not be a definite criteria for the remission of Graves' disease.     

Prognostic value of thyrotrophin binding inhibiting immunoglobulins (TBII) in longterm antithyroid treatment, 131I therapy given in combination with carbimazole and in euthyroid ophthalmopathy

Thyrotrophin binding inhibiting immunoglobulins (TBII) were measured in 27 patients with Graves' disease during and after longterm antithyroid treatment. The median observation period after treatment was 24 months. During the first 6 months of treatment the TBII index increased significantly in both the relapse and the remission group, but during the rest of the treatment and the observation no further change was observed. Patients with a TBII index below 0.35 at drug withdrawal (n = 8) all relapsed and patients with values above 1.00 (n = 5) all stayed in remission. There was a significant correlation between the TBII index at drug withdrawal and the time elapsed before a relapse. Graves' disease was treated with 131I in combination with carbimazole in 22 patients. The TBII index of these patients decreased after 131I and increased towards normal values during longterm observation of median 33 months. Of 4 patients with euthyroid ophthalmopathy one was TBII positive. This patient became overt hyperthyroid after an observation period of two years of prednisone treatment. It is concluded, that the TBII index is of some prognostic value after longterm antithyroid treatment, but is of no clinical importance following 131I treatment.     

Remission of Graves' hyperthyroidism predicted by smooth decreases of thyroid-stimulating antibody and thyrotropin-binding inhibitor immunoglobulin during antithyroid drug treatment.

It is important to know whether a patient with Graves' disease will get into remission or not during antithyroid drug (ATD) treatment. Thyrotropin (TSH) receptor antibodies (TRAb) cause Graves' disease. Thyroid-stimulating antibody (TSAb) and TSH-binding inhibitor immunoglobulin (TBII) have been measured as TRAb to diagnose Graves' disease and to follow Graves' patients. Smooth decreases of TSAb and TBII during ATD treatment predict the remission of Graves' hyperthyroidism. We followed serial changes of TSAb and TBII in 58 Graves' patients before, during, and after ATD treatment; TSAb was measured as a stimulator assay, using porcine thyroid cells, and TBII as a receptor assay. Patterns of TSAb and TBII changes during ATD treatment differ from one patient to another. TSAb and TBII activities decreased and disappeared in 52 (group A) but continued to be high in the other 6 (group B); 39 of the 52 group A patients achieved remission, but all of the 6 group B patients with persistently positive TSAb and TBII continued to have hyperthyroidism. No differences in the initial TSAb and TBII activities were noted between the 52 group A patients and the 6 group B patients. Of the 52 group A patients in whom TSAb and TBII had disappeared, 44 had smooth decreases of TSAb and TBII (group A1), and 8 had complex changes of TSAb and/or TBII (group A2); 36 of the 44 group A1 patients (82%) but only 3 of the 8 group A2 patients (37%) continued to be in remission more than 1 year after ATD discontinuation. The number of remission in group A1 was significantly larger than that in group A2. No differences in the initial TSAb and TBII activities were noted between group A1 and group A2. More than 80% of group A1 patients, who had smooth decreases of TSAb and TBII, continued to be in remission longer than 1 year. We demonstrated that smooth decreases of TSAb and TBII during ATD treatment predicted the remission of Graves' hyperthyroidism. The Graves' patients can be classified into A1, A2, and B groups according to the patterns of TSAb and TBII changes during ATD treatment. Group A1 patients, who had smooth decreases of TSAb and TBII, had higher rate of remission than the others. Smooth decreases of TSAb and TBII during the early phase of ATD treatment are a reliable predictor of the remission.     

Serum thyrotropin receptor antibodies concentrations in patients with Graves' disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period.

AIM AND METHODS: We performed a quantitative retrospective analysis of serum thyrotropin receptor antibody (TRAb) concentrations measured by a second-generation radioreceptor assay in 58 patients with Graves' disease (GD) at the onset of the disease, at the end of 18 month methimazole (MMI) treatment, and after MMI withdrawal in order to evaluate the correlation between the presence of these antibodies and the relapse of hyperthyroidism. Sixty healthy subjects were enrolled as a control group. RESULTS: Before MMI treatment the best cutoff TRAb value for identifying patients with GD was 1.45 UI/L (specificity, 100%; sensitivity, 98.3%). At the end of MMI treatment, serum TRAb concentrations were significantly lower (p < 0.001) than those measured at baseline, but they were still significantly higher (p < 0.001) than those found in the control subjects. At the end of MMI treatment, 44 patients (75.9%) had positive TRAb values (>1.45 UI/L). After MMI withdrawal (median, 15 months), 34 patients (58.6%) became hyperthyroid, 4 patients (6.9%) became hypothyroid, and 20 patients (34.5%) remained euthyroid. There was a significant correlation between serum TRAb concentrations at the end of MMI treatment and the percentage of patients who became hyperthyroid (r: 0.56; p < 0.001) and the time of appearance of hyperthyroidism (r: -0.38; p = 0.03). All 4 patients with TRAb values below 0.9 UI/L at the end of MMI treatment remained euthyroid throughout the follow-up period. Among the 27 patients who had serum TRAb values higher than 4.4 UI/L, 23 developed hyperthyroidism and 4 hypothyroidism. The TRAb values between 0.9 and 4.4 UI/L did not discriminate between the 27 patients (46.6%) who remained euthyroid from those who had relapse of hyperthyroidism. Thus a different TRAb end of treatment cutoff was calculated to identify patients who became again hyperthyroid. This TRAb cutoff value was 3.85 UI/L (sensitivity, 85.3%; specificity, 96.5%). All but 1 patient who had serum TRAb values above 3.85 UI/L became hyperthyroid after MMI was withdrawn (positive predictive value, 96.7%). In these patients, relapse of hyperthyroidism was independent of the changes in serum TRAb concentrations (r: 0.27; p = 0.15) and occurred after a median period of 8 weeks (range, 4-48). Hyperthyroidism also developed in 5 of 24 patients who had serum TRAb concentrations lower than 3.85 UI/L at the end of MMI treatment. In these 5 patients the relapse of hyperthyroidism occurred after a median period of 56 weeks (range, 24-120) and was always accompanied by an increase in serum TRAb concentrations. CONCLUSIONS: TRAb persist in the blood of most patients with GD after 18 months of MMI treatment. Both the frequency and the time of appearance of hyperthyroidism are closely correlated with serum TRAb concentrations at the end of MMI treatment. Our data would suggest that TRAb maintain stimulating activity after a full course of MMI treatment in the large majority of patients with GD. However, it is likely that the potency of these antibodies and/or the thyroid response to them change during treatment, as suggested by the different values measured in euthyroid control subjects and in euthyroid patients after MMI treatment.     

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.     

Discordant hypothyroxinemia and hypertriiodothyroninemia in treated patients with hyperthyroid Graves' disease

Hypothyroxinemia and hypertriiodothyroninemia may occur in the course of antithyroid drug or 131I treatment for hyperthyroid Graves' disease. To determine the frequency of combined high serum T3 and low serum T4 concentrations during such treatment and to assess the clinical significance of its recognition, we reviewed 60 patients treated for hyperthyroid Graves' disease with antithyroid drugs (n = 43) or radioactive iodine (n = 17). Six of these patients (10%) were found to have high serum T3 and low serum T4 concentrations during therapy. Four were receiving antithyroid drugs, and 2 had received radioactive iodine. At the time this abnormality occurred, 4 patients were euthyroid, 1 was hypothyroid, and 1 was hyperthyroid. The serum TSH concentration was increased in 2, at the upper limit of normal in 1, and undetectable in 3 patients. In 2 clinically euthyroid patients, these biochemical findings resolved spontaneously. After discontinuation or reduction in the dose of antithyroid drug, clinical and chemical euthyroidism was restored in 2 additional patients with previously elevated TSH levels. In 2 patients, both of whom previously had undetectable serum TSH levels, clinical hyperthyroidism persisted or recurred, and additional therapy was required. No patient developed permanent hypothyroidism during the period of follow-up (1-22 months). An additional 19 of the 60 patients (32%) had an elevated serum T3 level with a normal serum T4 concentration during the course of follow-up. Among these 19 patients, the magnitude of serum T3 elevation was not different between clinically euthyroid (n = 13) and hyperthyroid (n = 6) patients. We conclude that discordance of serum T4 and T3 concentrations is frequently encountered in patients with hyperthyroid Graves' disease during or after therapy. In such patients, the low serum T4 level does not predict hypothyroidism, nor does a high serum T3 level predict hyperthyroidism. Furthermore, the serum T3 concentration in these patients correlates poorly with their clinical thyroid status.     

Clinical experience with a human thyroid cell bioassay for thyroid-stimulating immunoglobulin

A sensitive, specific, and practical bioassay for thyroid-stimulating immunoglobulin (TSI) is now available for clinical use. Fifty-seven of 61 patients with untreated hyperthyroid Graves' disease were TSI positive (sensitivity, 93%). TSI was undetectable in all normal subjects and in patients with Hashimoto's thyroiditis (without concurrent Graves' ophthalmopathy), nontoxic goiter, and toxic nodular goiter (specificity, 100%). The prevalence of TSI in serum declined after therapy, particularly during methimazole or propylthiouracil treatment. TSI correlated well with relapse or remission after antithyroid drug therapy. All 12 patients who were TSI negative at the time of discontinuing antithyroid drug therapy remained in remission (average follow-up of 10 months). TSI values in Graves' disease correlated better with thyroid dysfunction than with ophthalmopathy. Prenatal TSI activity tended to be higher in mothers of infants who developed neonatal Graves' disease than in at-risk mothers who delivered normal infants. However, there was considerable overlap between the two groups.     

Prognostic value of thyrotropin receptor antibodies (TRAb) in Graves' disease: a 120 months prospective study

In most trials, at least 30-60% of patients with Graves' disease treated with antithyroid drugs relapse within 2 years after therapy withdrawal. At present, there are no prognostic parameters available early in treatment to indicate patients likely to achieve long-term remission. Because thyrotropin receptor autoantibodies (TRAb) are specific for Graves' disease, we evaluated the ability of their levels and of their rate of change to predict long-term prognosis. In our study 216 consecutive patients with newly diagnosed Graves' disease started a therapy with methimazole. Patients were treated until they achieved euthyroidism and TRAb were measured at 6-month intervals throughout a follow up of 120 months. Our study demonstrated that at the onset of hyperthyroidism patients' age, sex, fT4 levels and goiter size had no prognostic value in predicting long-term prognosis (respectively p = 0.79; p = 0.98; p = 0.83; p = 0.89). On the contrary, at the time of diagnosis TRAb titer was a good predictor of the final outcome (p<0.001); a titer equal to (or) more than 46.5 UI/L could identify patients who had never achieved long-term remission with a sensitivity of 52% and a specificity of 78%. Also fall rate of TRAb at 6 months of follow up and after therapy withdrawal were useful to predict the final outcome (p<0.001). At 6 months of follow up the time of therapy withdrawal, a decrease of TRAb lower than 52.3% or even its increase could identify patients who had never achieved permanent remission with a sensitivity of 55% and a specificity of 79.1%. No single parameter among TRAb, satisfactory identified a sub-set of patients who achieved long remission. Accordingly to our data, the best result in predicting long term remission is probably given by the presence of at least one of the two features evaluated at 6 months (TRAb titer and/or percentage of TRAb fall rate), with a sensitivity of 63% and specificity of 88%. TRAb titers evaluated both at the onset of hyperthyroidism that at 6 months of therapy or their rate of fall at 6 months and at ATD withdrawal are predictors of outcome. However, the presence of at least one, between titers of TRAb or their rate of fall at six months, resulted to be the best predictor of remission with the higher sensitivity and specificity.     

Standardized grey scale ultrasonography in Graves' disease: correlation to autoimmune activity.

OBJECTIVE: Graves' disease leads to thyroid enlargement and to reduction of tissue echogenicity. Our purpose was to correlate grey scale ultrasonography of the thyroid gland with clinical and laboratory findings in patients with Graves' disease. DESIGN: Fifty-three patients with Graves'disease were included in our study, 100 euthyroid volunteers served as control group. Free thyroxine (FT(4)), TSH and TRAb (TSH receptor antibodies) values were measured and correlated with sonographic echogenicity of the thyroid gland. METHODS: All patients and control persons underwent ultrasonographical histogram analyses under standardized conditions. Mean densities of the thyroid tissues were determined in grey scales (GWE). RESULTS: Compared with controls with homogeneous thyroid lobes of normal size (25.6 +/- 2.0GWE, mean +/- S.D.) echogenicity in patients with Graves' disease was significantly lower (21.3 +/- 3. 3GWE, mean +/- S.D., P < 0.0001). Among the patients with Graves' disease significant differences of thyroid echo levels were revealed for patients with suppressed (20.4 +/- 3.1 GWE, mean +/- S.D., n=34) and normalized TSH values (22.5 +/- 3.6GWE, mean +/- S.D., n=19, P < 0.02). Significantly lower echogenicities were also measured in cases of persistent elevated TRAb levels (19.9 +/- 2.9GWE, mean +/- S.D., n=31) in comparison with normal TRAb levels (22.9 +/- 3.5 GWE, mean +/- S.D., n=22, P < 0.0015). No correlation could be verified between echogenicity and either still elevated or already normalized FT(4) values or the thyroid volume. In coincidence of hyperthyroidism and Graves' ophthalmopathy (19.7 +/- 3.5GWE, mean +/- S.D., n=23) significantly lower echogenicity was measured than in the absence of ophthalmological symptoms (22.3 +/- 3.3GWE, mean +/- S.D., n=30, P < 0.016). Patients needing active antithyroid drug treatment revealed significantly lower thyroid echogenicity (20.3 +/- 3.1 GWE, mean +/- S.D., n=40) than patients in remission (23.7 +/- 3.4 GWE, mean +/- S.D., n=13, P < 0.001). Statistical evaluation was carried out using Student's t-test. CONCLUSIONS: Standardized grey scale histogram analysis allows for supplementary judgements of thyroid function and degree of autoimmune activity in Graves' disease. Whether these values help to estimate the risk of recurrence of hyperthyroidism after withdrawal of antithyroid medication should be evaluated in a prospective study.     

血清TSH受体抗体检测对预测Graves病复发的意义

采用酶免疫法(EIA)测定和观察Graves病人血清TSH受体抗体(TRAb)在用他巴唑治疗过程中的变化并对部分病例停药后随访2年的结果表明,(1)治疗1年时血清TRAb持续存在的患者具有反覆发作的倾向。(2)停药时TRAb阳性是患者尚未达到免疫学缓解、可能在近期内复发的重要标志。     

A sensitive and practical assay for thyroid-stimulating antibodies using crude immunoglobulin fractions precipitated with polyethylene glycol

A simple, sensitive, and practical assay for thyroid-stimulating autoantibodies (TSAb) was developed in which cryopreserved porcine thyroid cells were incubated with crude immunoglobulin fractions sedimented from serum with polyethylene glycol. In the assay, 1.4- to 2.0-fold and 6- to 12-fold increases in cAMP released into Hank's medium without NaCl were found at 1 and 10 microU/ml bovine TSH, respectively. TSAb were detected in 41 (97.6%) of 42 patients with untreated hyperthyroid Graves' disease, 29 (55.8%) of 52 patients with hyperthyroid Graves' disease who were euthyroid while taking antithyroid drugs, 22 (78.6%) of 28 patients with euthyroid Graves' disease, and none of the patients with simple goiter, adenomatous goiter, thyroid adenoma, or thyroid cancer tested. TSAb activities measured using porcine thyroid cells significantly correlated with those measured using human thyroid adenoma cells (r = 0.908; n = 46; P less than 0.001). Thyroid-stimulating activity was also detected in 11 (28.9%) of 38 patients with Hashimoto's thyroiditis. However, the activity was considered to be due to TSH in the patients' sera, because it was completely abolished by pretreatment with anti-TSH antibodies. Serum TSH concentrations lower than 50 microU/ml did not affect the assay result. In Graves' disease after cessation of antithyroid drugs, 85.7% (12 of 14) of TSAb-positive patients relapsed, while 77.8% (14 of 18) of TSAb-negative patients remained in remission. Thus, the assessment of TSAb was useful as an index to predict prognosis.