Non-suppressed thyroidal radioactive iodine uptake (RAIU) in thyrotoxic phase in a case of subacute thyroiditis with thyroid-stimulating antibodies (TSAb).

In this paper, we report a 49-year-old female with subacute thyroiditis who had thyroid-stimulating antibodies (TSAb) and thyroid-stimulation-blocking antibodies (TSBAb) in serum. Although she was in the thyrotoxic phase and TSH was suppressed in May, 1990, her radioactive iodine uptake (RAIU) was not suppressed (35.5%) and a thyroid scan disclosed a diffuse goiter with no defect. Serum assays revealed the presence of TSAb, but TSBAb were negative. In August, 1990, the right lobe became undetectable by thyroid scan when the RAIU was 20.7% with the TSH level remaining suppressed. At that time, TSAb were negative, while TSBAb were positive. When the RAIU was 31.1% in October, 1990, both thyroid lobes became visible and the TSH level was normalized. TSBAb became negative, and although TSAb reappeared it later became undetectable. These results indicate that the changes in the patient's thyroid scan and RAIU were attributable to the presence of TSAb.     

Development of chicken antibodies toward the human thyrotropin receptor peptides and their bioactivities.

We have synthesized four peptides (P2, P4, E3 and P1) corresponding to different segments of human thyrotropin (TSH) receptor. We have obtained antibodies by immunizing them to chickens, and antibodies are evaluated for their thyroid stimulating antibody (TSAb), thyroid stimulation blocking antibody (TSBAb) and TSH-binding inhibitor immunoglobulin (TBII) activities. None of the antibodies had TSAb activity. Antibodies against human TSH receptor specific region such as P2 and P4 (P2: No. 372-397, P4: No. 341-358) had TSBAb and TBII activities. Anti-E3 antibody (E3: the third putative extracellular loop, No. 649-661) had only TSBAb activity. Anti-P1 antibody (P1: high homology with pig LH/CG receptor, No. 398-417), however, had none. These results suggest that anti-TSH receptor antibodies to different antigenic epitopes show heterogeneity in their biological activities.     

TSBAb (TSH-stimulation blocking antibody) and TSAb (thyroid stimulating antibody) in TSBAb-positive patients with hypothyroidism and Graves' patients with hyperthyroidism.

There are two types of TSH receptor antibodies (TRAb); thyroid stimulating antibody (TSAb) and TSH-stimulation blocking antibody (TSBAb). TSAb causes Graves' hyperthyroidism. TSBAb causes hypothyroidism. Both TSAb and TSBAb block TSH-binding to thyroid cells as TSH receptor antibodies (TRAb). TSBAb-positive patients with hypothyroidism and Graves' patients with hyperthyroidism may have both TSBAb and TSAb. We studied TSBAb and TSAb in 43 TSBAb-positive patients with hypothyroidism and in 55 untreated Graves' patients with hyperthyroidism. TSBAb-activities were expressed as percentage inhibition of bovine (b) TSH-stimulated cAMP production by test IgG. Two formulas were used to calculate TSBAb-activities; TSBAb-A (%) = [1 - (c - b)/(a - b)] x 100 and TSBAb-B (%) = [1 - (c - d)/(a - b)] x 100, where a: cAMP generated in the presence of normal IgG and bTSH, b: cAMP generated in the presence of normal IgG, c: cAMP generated in the presence of test IgG and bTSH, and d: cAMP generated in the presence of test IgG. TSAb (%) = [d/b] x 100. All of the 43 TSBAb-positive patients with hypothyroidism had strongly positive TSBAb-A and -B. Some of them had weakly positive TSAb (<240%). All 55 untreated Graves' patients had positive TSAb (205-2509%). Some of them had both TSAb and TSBAb. TSBAb-positive patients with hypothyroidism had a limited distribution of TSBAb- and TSAb-activities (TSBAb-A + 75 - + 103%, TSBAb-B + 87 - + 106%, TSAb 92-240%), but Graves' patients with hyperthyroidsim had a wide distribution of TSAb- and TSBAb-activities (TSAb 205-2509%, TSBAb-A - 158 - + 43%, TSBAb-B - 14 - + 164%). TSBAb-A ignores TSAb activity in serum, and might give low TSBAb activity. However, TSBAb-A clearly differentiates TSBAb-positive patients with hypothyroidism from Graves' patients with hyperthyroidism; thus, we favor TSBAb-A over TSBAb-B. Some of TSBAb-positive patients with hypothyroidism and Graves' patients with hyperthyroidism have both TSBAb and TSAb.     

Activity of thyroid stimulating antibody and thyroid stimulation blocking antibody determined by radioiodine uptake into FRTL-5 cells

To investigate the pathophysiology of patients with autoimmune thyroid diseases, we measured serum thyroid stimulating antibody (TSAb) activity and thyroid stimulation blocking antibody (TSBAb) activity by determining the radioiodine (125I) uptake into FRTL-5 cells. FRTL-5 cells were pre-incubated for seven days with 5H medium and then incubated for 48 hours with patients' crude IgG prepared by polyethylene glycol precipitation. In order to measure TSBAb, 10 microU/ml TSH was also added. 125I was added one hour before the end of the 48 hour incubation period. After the incubation, the medium was aspirated, and the radioactivity in the cells was counted. In patients with untreated hyperthyroid Graves' disease, TSAb was detectable in 18 of 20 patients, the detectability being 90%, and activity showed a statistically significant positive correlation with TSAb activity determined by c-AMP accumulation. Out of 41 patients with hypothyroidism, TSBAb determined by 125I uptake was positive in six cases, the detectability being 14.6%. The inhibition of 125I uptake by one of these six IgGs was suggested to be at the TSH receptor level because it inhibited TSH induced c-AMP accumulation and showed positive thyrotropin binding inhibitor immunoglobulin (TBI I) activity, but did not inhibit the forskolin- and (Bu)2cAMP-induced 125I uptake. Inhibition of another IgG was suggested at the post-receptor level because it did not inhibit TSH induced cAMP accumulation and showed negative TBI I activity, but inhibited forskolin- and (Bu)2cAMP-induced 125I uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sensitive assay to detect thyroid stimulating antibody (TSAb) in the presence of thyroid stimulation blocking antibody (TSBAb) in serum.

The detection of thyroid stimulating antibody (TSAb) activity in the presence of thyroid stimulation blocking antibody (TSBAb) in Graves' serum is difficult because TSBAb blocks TSAb activity. We recently demonstrated that polyethylene glycol (PEG) augments TSAb activity in porcine thyroid cells (PTC) assay. This PEG-induced augmentation makes it possible to develop a sensitive assay to detect TSAb in the presence of TSBAb. We studied the effects of PEG on TSAb- and TSBAb-activities in PTC using 4 different preparations of the samples; (1) crude IgG using PEG 22.5% precipitated fraction (PF) from Graves' serum (0.2 ml), (2) crude IgG using PEG 12.5% PF, (3) serum (50 microl), and (4) serum (50 microl) in the presence of 5% PEG (final). When the effects of PEG on TSAb activity using crude IgG were examined, PEG 22.5% PF showed significantly higher TSAb activity than PEG 12.5% PF as reported previously. The augmentative effect of PEG on TSAb activity was also observed by the addition of 5% PEG to serum. We also demonstrated that PEG augmented TSAb-activities even in TSBAb-positive serum by two methods (crude IgG using PEG 22.5% PF and the addition of 5% PEG to serum). TSBAb activities were expressed by two calculation methods (A= [1 - (a - b)/(c - d) x 100] and B = [1 - (a - d)/(c - d) x 100], where a is cAMP produced in the presence of bTSH and patient's IgG, b is cAMP produced in the presence of patient's IgG, c is cAMP produced in the presence of bTSH and normal IgG, and d is cAMP produced in the presence of normal IgG). In the presence of TSAb, the values of A method were always higher than those of B method, since TSAb stimulated cAMP synthesis. We have developed two sensitive methods to detect TSAb even in the presence of TSBAb in serum using PEG; 1) incubation of crude IgG using PEG 22.5% PF from serum (0.2 ml), and 2) co-incubation of 5 % PEG with test serum (50 microl).     

Lack of interaction in recombinant human FSH receptor and both TSAb and TSBAb

Since cross-reactivity of TSH with the human FSH receptor has been reported, in this study we tested the effect of thyroid-stimulating antibody (TSAb) and thyroid stimulation-blocking antibody (TSBAb) on Chinese hamster ovary cells expressing human FSH receptor (CHO-hFSH-R cells). We examined the TSBAb activity of sera from hypothyroid patients who had a positive TBII to determine whether these sera also block the effect of FSH on CHO-hFSH-R cells. Although human FSH I-3 (0.25-16 ng/ml) stimulated the production of intracellular cAMP in CHO-hFSH-R cells with dose-responsive manner, neither TSAb nor TSBAb had such an effect on the cells.     

Métastase rénale d’un carcinome vésiculaire de la thyroïde révélée par le balayage du corps entier à l’iode 131

Distant metastasis of differentiated thyroid carcinoma generally affect lung and/or bone tissue. Renal metastasis from thyroid carcinoma is extremely rare. We report a case of renal metastasis from a follicular thyroid carcinoma in a 55-year-old man, occuring 11 years after total thyroidectomy, fortuitously discovered on a whole body scan carried out after 131-iodine therapy for neck recurrence of disease. Salient features of our clinical case are the fortuitous mode of discovery the unilateral localization of metastases and especially the long time interval which separates its detection from that of the primitive tumour. This case report exemplifies the useful role of the whole body scan carried out after 131-iodine therapy better adapted to reveal often undetectable occult metastases with low dose, but also to ensure a regular and protracted follow-up of patients treated for differentiated thyroid carcinoma.     

NLR、PLR与分化型甲状腺癌术后131I清甲效果的关系及其预测价值分析

摘要 目的：探讨中性粒细胞/淋巴细胞比值（NLR）、血小板/淋巴细胞比值（PLR）与分化型甲状腺癌（DTC）术后碘131（¹³¹I）清甲治疗效果的关系及对DTC术后¹³¹I清甲效果的预测价值。方法：选择2019年3月至2021年12月在江苏大学附属徐州医院行甲状腺切除术且术后进行¹³¹I清甲治疗的DTC患者150例为研究对象,根据¹³¹I清甲治疗效果分为清甲成功组（107例）和清甲未成功组（43例）,通过检查血常规获得中性粒细胞计数、血小板计数、淋巴细胞计数并计算NLR、PLR,比较两组NLR、PLR;采用单因素及多因素logistics回归模型分析¹³¹I清甲疗效的影响因素,采用受试者工作特征曲线（ROC）分析NLR、PLR对¹³¹I清甲治疗效果的预测价值。结果：清甲成功组NLR、PLR低于清甲未成功组（P＜0.05）,单因素分析显示清甲成功组促甲状腺激素（TSH）高于清甲未成功组,甲状腺球蛋白（Tg）水平低于清甲未成功组,清甲成功组病灶最大径小于清甲未成功组（P＜0.05）;多因素logistics回归分析显示,高NLR、PLR、Tg是¹³¹I清甲治疗失败的独立危险因素（P＜0.05）;NLR、PLR及联合检测预测¹³¹I清甲治疗效果的ROC曲线下面积（AUC）分别为0.760、0.732、0.829,NLR与PLR联合检测的AUC高于二者单独检测。结论：高NLR、PLR是DTC术后¹³¹I清甲未成功的独立危险因素,早期检测NLR、PLR对DTC术后¹³¹I清甲治疗效果具有较好的预测价值。     

Treatment with sorafenib in advanced thyroid cancer - a case report

Papillary thyroid cancer (PTC) usually has a good prognosis. The treatment, including total thyroidectomy and complementary radioiodine (RAI) therapy, gives complete remission in 90% of patients. However, in 10% of subjects with metastatic disease, the prognosis is poor. In the group of patients with disease progression and no 131I uptake, searching for new therapeutic modalities before all tyrosine kinase inhibitors and other antiangiogenic agents is necessary. The study presents the case of a 55-year-old male with advanced PTC /pT3mNxMo/ diagnosed in 1993. Primary treatment by total thyroidectomy and 131I ablation led to complete remission. In 2000 local as well as lymph node recurrence was diagnosed and successively treated by surgery. In 2006 an increasing serum thyroglobulin level was noted and a single lung metastasis was diagnosed and operated on. In 2007 new foci in CNS and vertebral column with no 131I uptake were stated. Further progression (bones, CNS, and pterygoid muscle) was confirmed by PET-CT. The patient underwent neurosurgical metastasectomy twice and palliative CNS and vertebra's radiotherapy. Liver metastases were diagnosed in 2009. Treatment with increasing doses of thalidomide (up to 800 mg/d) was administered for 3 months with a good tolerance; however, the therapy was withdrawn due to cancer progression. Next, sorafenib (800 mg/d) was given for 16 weeks. Radiological examination performed after 16 weeks confirmed stable disease, whereas 2 months later, after sorafenib withdrawal due to lack of treatment possibility, further progression was observed. Metronomic chemotherapy with Adriamycin was instituted which gave disease stabilization for 6 months. The patient died with advanced disseminated disease due to pulmonary embolism. We present this case to document no adverse effects of therapy with sorafenib in a patient with brain DTC metastases. Sorafenib therapy was only short-term, but no progression occurred in this time.     

Detection of thyroid-stimulating antibody in patients with inflammatory thyrotoxicosis.

The detection of thyrotropin-binding inhibitory immunoglobulins (TBII) and/or thyroid-stimulating antibody (TSAb) has been reported in some patients with painless thyroiditis (PT) or subacute thyroiditis (SAT). However, its mechanism is unknown. TBII and TSAb measured using cultured FRTL-5 thyroid cells were evaluated in 18 patients with PT, 11 patients with SAT and a patient with SAT-like symptoms. In PT, we detected both TBII and TSAb activities in only 1 patient. This case had first come to our attention with subclinical hypothyroidism and had already had weakly positive TSAb activity (205.9%) 1 year before the present onset of PT. This patient had a transient thyrotoxicosis with a low uptake (24 h) of 123I (4.3%) and 821.0% TSAb activity, and subsequently developed a transient subclinical hypothyroidism. Even after 2 years, she still had positive TSAb activity (382.3%). In SAT, TBII and TSAb activities were not detected during the courses of any patients. A patient with transient thyrotoxicosis, who had a high uptake (30 min) of 99mTc (5.6%) and SAT-like symptoms (painful tenderness on right thyroid lobe and markedly accelerated erythrocyte sedimentation rate), showed positive activities of TBII (34.9%) and TSAb activity (1,366.9%). Histological findings by thyroid needle biopsy performed in the thyrotoxic phase showed coexistence of granulomatous inflammatory changes and hyperplasia with papillary folds of some residual follicular cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunoglobulins from Graves' disease patients interact with different sites on TSH receptor/LH-CG receptor chimeras than either TSH or immunoglobulins from idiopathic myxedema patients

To examine the identity of binding sites for thyrotropin (TSH) and thyroid stimulating antibodies (TSAbs) associated with Graves' disease, we constructed eight human TSH receptor/rat LH-CG receptor chimeras. Substitution of amino acid residues 8-165 of the TSH receptor with the corresponding LH-CG receptor segment (Mc1 + 2) results in a chimera which retains high affinity TSH binding and the cAMP response to TSH but loses both the cAMP response to Graves' IgG and Graves' IgG inhibition of TSH binding. Two of three IgGs from idiopathic myxedema patients which contain thyroid stimulation blocking antibodies (TSBAbs) still, however, react with this chimera. Chimeras which substitute residues 90-165 (Mc2) and 261-370 (Mc4) retain the ability to interact with TSH, Graves' IgG, and idiopathic myxedema IgG. The data thus suggest that residues 8-165 contain an epitope specific for TSAbs and that TSH receptor determinants important for the activities of TSAbs and TSH are not identical. Further, binding sites for TSBAbs in idiopathic myxedema may be different from receptor binding sites for both Graves' IgG TSAb as well as TSH and may be different in individual patients.     

Rabbit antibodies toward extracellular loops of the membrane spanning region of human thyrotropin receptor possess thyroid stimulating activities.

We have synthesized three different peptides, E1 (amino acid residues 478-497), E2 (amino acid residues 561-580) and E3 (amino acid residues 649-652), corresponding to the first, the second and the third extracellular loops of the membrane spanning region of human thyrotropin receptor (TSH-R), respectively. We have produced rabbit antibodies toward these peptides and evaluated their thyroid stimulating antibody (TSAb) and TSH-binding inhibitor immunoglobulin (TBII) activities. Although only slight TSAb activity was observed in E1 antibodies, E2 and E3 antibodies possessed strong TSAb activities, the values of which were 1118% and 910%, respectively. None of these antibody had TBII activities. These results suggest that antibodies against the extracellular loops of the TSH-R can stimulate cAMP formation in thyroid cells and that these regions may be one of the candidates for the epitope against autoantibodies from patients with Graves' disease.     

Graves Ophthalmopathy After Radiation Treatment of Thyroid Cancer

ObjectiveTo describe a patient with metastatic thyroid cancer who developed Graves ophthalmopathy after treatment with radioiodine (I 131) and external beam radiation.MethodsWe present a case report that includes clinical, laboratory, and radiologic findings and a brief review of the literature.ResultsA 49-year-old woman who had had a total thyroidectomy and neck dissection followed by I 131 treatment 5 years earlier for papillary thyroid cancer presented for follow-up management after recent neck dissection for recurrent disease. Because she had thyroglobulin antibodies, she was again treated with I 131 after preparation with recombinant human thyroid-stimulating hormone. A post-treatment scan revealed uptake in the right iliac crest. A fludeoxyglucose F 18 positron emission tomography/computed tomography fusion scan revealed osseous metastases in the right pelvis, and external beam radiotherapy was delivered to this area. Approximately 5 months later, she developed periocular swelling and excessive tearing. Magnetic resonance imaging of the orbits revealed enlargement of the extraocular muscles. Serum thyroid-stimulating immunoglobulins were greatly elevated.ConclusionThis case corroborates an earlier report to suggest that radiation-associated thyroid injury in a patient with thyroid cancer may be followed by Graves ophthalmopathy and appearance of thyroid-stimulating immune-globulins in the serum. (Endocr Pract. 2008;14:419-421)     

Rabbit antibodies against two different extracellular domains of human thyrotropin receptor possess thyroid stimulating activities

We have produced rabbit antibodies against synthetic peptides corresponding to the mid-region (amino acid residues 172-202, C peptide) and to the unique segment near the transmembrane region (amino acid residues 341-370, P peptide) in the extracellular component of the human thyrotropin (TSH) receptor and evaluated their biological activities. Both anti-C peptide antibodies raised in two rabbits showed strong thyroid stimulating activities (TSAb) (4127% and 2548%). Anti-P peptide antibodies raised in two rabbits were also strongly positive for TSAb activities (359% and 3468%). However, none of these antibodies had TSH-binding inhibitor immunoglobulin (TBII) activities. These results suggest that the domains responsible for TSAb are likely to span the entire extracellular component of the TSH receptor.     

Clinical usefulness of TSAb assay with high polyethylene glycol concentrations.

We previously demonstrated the stimulatory effect of polyethylene glycol (PEG) on thyroid-stimulating antibody (TSAb)-IgG-stimulated cAMP production (thyroid stimulating (TS) index) in porcine thyroid cell (PTC) assay. In the present study the clinical usefulness of the practical method using high PEG concentrations was examined. TS activity using PEG 22.5% precipitated fraction (PF) was significantly higher compared to standard TSAb activity using 12.5% PF from TSAb-positive serum, but the maximum TS activity was observed with PEG 12.5% PF + 4% PEG or PEG 22.5% PF + 2% PEG. In all cases of untreated Graves' patients, TSAb activity determined by PEG 22.5% PF was higher compared to standard TSAb activity using PEG 12. 5% PF from test serum, but the highest TSAb activity was observed by PEG 12.5% PF + 4% PEG without increased cAMP production to normal serum. TSAb was positive in 85% (40/47), 98% (46/47) and 100% (47/47) of untreated Graves' patients by the method of PEG 12.5% PF, PEG 22.5% PF and PEG 12.5% + 4% PEG, respectively. Increased TSAb activity by PEG 12.5% PF + 4% PEG method was also observed even if the standard TSAb activity using PEG 12.5% PF method was negative in the euthyroid states of Graves' patients during antithyroid drug therapy. The stimulatory effect of PEG on TS activity was not found in other thyroidal diseases [thyroiditis chronica (with high serum TSH), thyroid stimulation-blocking antibody (TSBAb)-positive sera (with low serum TSH), adenomatous goiter, subacute thyroiditis, and thyroid cancer]. The stimulatory effect of 5% PEG on TS activity produced directly by small amounts of Graves' serum (50 microl) was also found, although the sensitivity was lower than with PEG-precipitated IgG from 0.2 ml serum. The clinical usefulness of the sensitive TSAb assay using PEG-precipitated IgG or direct serum assay in the presence of high PEG concentrations was demonstrated.     

Sleep Quality of Patients with Differentiated Thyroid Cancer

Objective

We aimed to measure prevalence of sleep disturbance in patients with differentiated thyroid cancer (DTC) by calculating Pittsburgh Sleep Quality Index (PSQI), and compare these data with patients with benign thyroid nodules or normal participants.

Methods

Three groups of patients participated in this cross-sectional study. In the first group, 162 patients with DTC received total thyroidectomy, and then ¹³¹I therapy. The second group consisted of 84 patients with benign thyroid nodules, who received partial thyroidectomy. The third group was 78 normal healthy control cases. PSQI was used to assess the sleep quality. Inter-group differences were analyzed by Kruskal-Wallis test or independent samples T test. χ² test was also used to check prevalence differences of poor sleep quality among the groups. Differences of PSQI score and poor sleep quality prevalence before and after ¹³¹I therapy in the same group of DTC participants were analyzed by paired T test and Mcnemar''s test.

Results

Higher PSQI score (7.59 ± 4.21) and higher rate of poor sleep quality (54.32%) were shown in DTC patients than in any other group. After ¹³¹I therapy, PSQI score and prevalence of poor sleep quality in DTC patients increased significantly to 8.78 ± 4.72 and 70.99%. Then DTC patients were divided into two subgroups based on their metastatic status. DTC patients with metastasis (87/162 cases, 53.70%) had significantly higher PSQI score (10.87 ± 5.18) and higher prevalence of poor sleep quality (79.31%).

Conclusion

DTC patients suffer from sleep disturbance, ¹³¹I therapy and awareness of metastatic status could worsen sleep problem. Psychological fear of cancer, nuclear medicine therapy and metastasis could be one major underlying reason. Longitude and interventional studies are necessary for further investigations.     

A case of Graves' disease with false hyperthyrotropinemia who developed silent thyroiditis.

We encountered a patient who developed silent thyroiditis during the course of Graves' disease. The diagnosis of silent thyroiditis was made on the basis of a low thyroidal 131I uptake, no response to the thyrotropin releasing hormone (TRH) test, and subsequent hypothyroidism despite the presence of high titers of thyrotropin (TSH) receptor antibody (TRAb) and thyroid stimulating antibody (TSAb). The patient, in addition, had a discrepancy between serum TSH and thyroid hormone values. This was due to the presence of interfering substances that react to mouse IgG in the sera since serum TSH levels were decreased in a dose dependent manner by the addition of increasing amounts of mouse IgG to the sera. It should therefore be noted that silent thyroiditis can develop in patients with Graves' disease. Furthermore, clinicians should be aware that two-site immunoassay kits that use mouse monoclonal antibodies are subject to interference by some substances, possibly antibodies which react to mouse IgG.     

Onset of subacute aggravation of chronic thyroiditis followed immediately by transient hypothyroidism during antithyroid drug therapy for Graves' hyperthyroidism.

A 56-year-old man presented with clinical and biochemical hyperthyroidism with high thyroid 99mTc uptake, positive result for antimicrosomal antibody (MCHA; 1:8,100) and markedly high activities of thyrotropin-binding inhibitory immunoglobulin (TBII; 90.0%) and thyroid-stimulating antibody (TSAb; 2,400%). Fifty days after the initiation of antithyroid drug therapy, he developed a painful tender enlarged thyroid and an accelerated erythrocyte sedimentation rate (ESR), which were followed immediately by hypothyroidism with a transient increase in MCHA titer (peak; 1:218,700) despite of maintenance of high TBII and TSAb activities. Two and a half months after the recovery from hypothyroidism, recurrent hyperfunction was observed with further elevation of TSAb activity (4,643%). After about 2 weeks, recurrences of a painful tender enlarged thyroid and an accelerated ESR, which were followed by abrupt progression to hypothyroidism, were found. Specimens obtained when he had still slightly tender goiter after the first and second episodes of neck pain showed microscopically extremely extended interstitial fibrosis with collapsed follicles and moderate lymphocytic infiltration. Thyroid-stimulation-blocking antibody was not detected at either onset of hypothyroidism. Thus, it is possible that Graves' disease, subacute aggravation of chronic thyroiditis and hypothyroidism coexist in the same individual. In such patients, thyroid status may be determined by the degree of each of the stimulating factors (TSH, TSAb and/or unknown factors) and suppressive or destructive factors (humoral and/or cellular) and may be changed in a very short interval.     

Thyroid stimulating immunoglobulins in patients in long-term remission after Graves' disease

Thyroid stimulating antibodies (TSAb) and thyrotropin binding inhibiting immunoglobulins (TBII) were measured in 32 patients with Graves' disease who had been in remission for at least two years after treatment was been stopped. Seventeen patients had been treated with antithyroid drugs, and 15 patients with 131Iodine. In the first group 3 of 17 patients had TSAb and one TBII, whereas in the second group 4 of 15 patients had TSAb and two TBII. One patient from each group had inhibiting TSAb. During the follow-up one patient from each group relapsed, whereas 5 patients from the second group developed myxoedema. No relationship between the clinical outcome and TSAb and TBII was found.     

Identification of separate determinants on the thyrotropin receptor reactive with Graves' thyroid-stimulating antibodies and with thyroid-stimulating blocking antibodies in idiopathic myxedema: these determinants have no homologous sequence on gonadotropin receptors.

Deletions, substitutions, or mutations of the rat TSH receptor extracellular domain between residues 20 and 107 (all residue numbers are determined by counting from the methionine start site) have been made by site-directed mutagenesis of receptor cDNA. After transfection in Cos-7 cells, constructs were evaluated for their ability to bind [125I]TSH or respond to TSH and thyroid-stimulating antibodies (TSAbs) from Graves' patients in assays measuring cAMP levels of the transfected cells. Assay results were compared to results from Cos-7 cells transfected with wild-type receptor constructs or vector alone. We identify threonine-40 as a TSAb-specific site whose mutation to asparagine, but not alanine, reduces TSAb activity 10-fold, but only minimally affects TSH-increased cAMP levels. We show that thyroid-stimulating blocking antibodies (TSBAbs), which block TSH or TSAb activity and are found in hypothyroid patients with idiopathic myxedema, continue to inhibit TSH-stimulated cAMP levels when threonine-40 is mutated to asparagine or alanine, suggesting that TSBAbs interact with different TSH receptor epitopes than the TSAb autoantibodies in Graves' patients. This is confirmed by the demonstration that these TSBAbs interact with high affinity TSH-binding sites previously identified at tyrosine-385 or at residues 295-306 of the extracellular domain of the TSH receptor. This is evidenced by a loss in the ability of TSBAbs to inhibit TSAb activity when these residues are mutated or deleted, respectively. Since the TSAb and TSBAb epitopes are in regions of the extracellular domain of the TSH receptor that have no homology in gonadotropin receptors, these data explain at least in part the organ-specific nature of TSH receptor autoantibodies in autoimmune thyroid disease. Data are additionally provided which indicate that residues 30-37 and 42-45, which flank the TSAb epitope at threonine-40, appear to be ligand interaction sites more important for high affinity TSH binding than for the ability of TSH to increase cAMP levels and that cysteine-41 is critical for TSH receptor conformation and expression on the surface of the cell. Thus, despite unchanged maximal values for TSH-increased cAMP levels, substitution of residues 42-45 or deletion of residues 30-37 results in receptors, which, by comparison to wild-type constructs, exhibit significantly worsened Kd values for TSH binding than EC50 values for TSH- or TSAb-increased cAMP activity.(ABSTRACT TRUNCATED AT 400 WORDS)