Thyroid Stimulating Antibody Values Research Articles

Differential Evolution of Thyroid Peroxidase and Thyrotropin Receptor Antibodies in Graves' Disease: Thyroid Peroxidase Antibody Activity Reverts to Pretreatment Level After Carbimazole Withdrawal

In this study, we compared the evolution of thyroid peroxidase antibody (TPOAb) and thyroid-stimulating antibody (TSAb) activities before, during, and after treatment of Graves' disease (GD) with carbimazole. TPOAb and TSAb were measured in sera from 75 patients with GD, during an 18-month block-replace regimen and after drug withdrawal (12, 24, and 36 months). At diagnosis, TPOAb were present in 85% of the patients versus 99% for TSAb. During the treatment, TPOAb values and prevalence significantly decreased, as observed with TSAb. After drug withdrawal, TPOAb levels increased once again to reach the pretreatment values, whereas TSAb remained unchanged. TPOAb values and prevalence at drug withdrawal were not significantly different between patients who remained euthyroid and those who had a relapse of hyperthyroidism. In contrast, TSAb values and prevalence were higher at drug withdrawal in relapse patients. In conclusion, TPOAb and TSAb changes are similar during GD treatment by carbimazole but diverge after drug withdrawal. TPOAb might reflect autoimmune perturbations independently of the clinical status and of the thyroid-stimulating activity.

Clinical validity of a new commercial method for detection of TSH-receptor binding antibodies in sera from patients with Graves’ disease treated with antithyroid drugs

In this work, we compared the activities of TSH binding inhibitory immunoglobulin (TBII) results obtained with a new human TBII assay (h-TBII) using the human recombinant TSH receptor with thyroid stimulating antibodies (TSAbs). Sera were obtained from 90 patients with Graves’ disease before and after therapy with carbimazole (1-methyl-2-thio-3-carbethoxyimidazole). Before treatment, h-TBII were detected in 89/90 patients (98.9%) whereas TSAb activity was positive in 88/90 patients (97.7%). The two parameters fell during therapy. At the end of treatment, only h-TBII levels were significantly different between patients in remission and those in relapse ( Z=−2.212; P=0.0270). The relapse rate in the patients with positive antibodies at drug withdrawal was significantly increased ( χ 2=6.057; P=0.0139 for h-TBII and χ 2=8.988; P=0.0021 for TSAb). Most of patients (76%) relapsed during the 2 years following drug withdrawal. h-TBII or TSAb values were positive in 84.6% or in 80.8% of patients at the time of relapse. There was a significant correlation between the two antibody measurement methods before treatment, at drug withdrawal and at the time of relapse. These results indicate that the new TBII assay using human TSH receptor is as sensitive as the TSAb assay. Because of its much easier performance, it may advantageously replace TSAb measurement especially for the Graves’ disease diagnosis and in the prediction of short-term relapse at the end of treatment.

Clinical value of a new TSH binding inihibitory activity assay using human TSH receptors in the follow‐up of antithyroid drug treated Graves' disease. Comparison with thyroid stimulating antibody bioassay

First, to evaluate the performance level of a new TSH binding inhibitory antibody assay using human recombinant TSH receptors (h-TBII) in comparison with a thyroid stimulating antibody (TSAb) bioassay performed before, at the end of treatment (18 months) and after antithyroid drug withdrawal in Graves' disease patients; second, to assess the accuracy with which h-TBII levels could predict relapse and remission. Retrospective study on serum samples of Graves' disease patients treated by antithyroid drugs for 18 months. Serum samples from 140 patients (27 men and 113 women; median age 42 years) with recent onset hyperthyroidism due to Graves' disease were retrospectively tested for h-TBII at diagnosis, at 18 months and for 76 of them 6, 12, 24 and 36 months after drug withdrawal or at relapse. TSAb were also evaluated at each time. Thyroid blocking antibodies (TBAb) were measured in sera positive for h-TBII and negative for TSAb. h-TBII levels were measured with a radioreceptor assay using the human recombinant TSH receptor (DYNOtest TRAK human from B.R.A.H.M.S. Diagnostica, Berlin, Germany). TSAb and TBAb levels were assayed in thyrocyte cultures. At diagnosis, high levels of h-TBII were found in 138 of 140 patients with Graves' disease (98.6%). High TSAb values were also detected in the same 138 patients. The h-TBII and TSAb values were significantly correlated (r = 0.582, p < 0.0001). At 18 months, h-TBII were found in 48 of the 140 patients (34%) and TSAb in 43 patients (31%). The h-TBII and TSAb values were significantly correlated (r = 0.618, p < 0.0001) and fell significantly between diagnosis and 18 months (Z = - 9.84, p < 0.0001 and Z = - 9.19, p < 0.0001). TBAb were found in two of the 11 sera positive for h-TBII and negative for TSAb. At diagnosis, the median levels of h-TBII and TSAb were not significantly different between the patients who relapsed within the 3 years after the withdrawal of treatment (n = 60) and those who did not (n = 80) (Z = - 1.1, ns; Z = - 0.216, ns). At 18 months, the prevalences of h-TBII and TSAb were significantly increased in patients who relapsed compared to those who remained in remission at 3 years (60% vs. 15%, chi2 = 30.8, p < 0.0001 and 55% vs. 13%, chi2 = 29.1, p < 0.0001, respectively). h-TBII and TSAb median levels were also significantly increased in patients who relapsed compared to the others (Z = - 4,8, p < 0.0001; Z = - 3,01, P < 0.005). Among the 60 patients who relapsed, 36 (60%) displayed h-TBII and 33 (55%) TSAb at 18 months. The majority of patients who relapsed during the 2 years following the end of treatment, in contrast to those who relapsed later, were positive for h-TBII (67% vs. 27%, chi2 = 6.01, p = 0.035). Seventeen of the 18 tested patients who relapsed were negative for h-TBII at 18 months, were then positive for h-TBII at the time of relapse, whereas 15 of them were still negative, 6-12 months before the relapse. Among the 80 patients who remained in remission at 3 years, only 10 (13%) displayed TSAb and 12 (15%) h-TBII at 18 months. In 10 of these 12 patients who were further evaluated for h-TBII positivity, h-TBII fell to control levels during the 3 years following the end of treatment. The new h-TBII assay is a simple and rapid method with a performance level similar to that of TSAb determination. Its sensitivity is close to 100% at diagnosis. In the whole group, TBII level analysis is relevant as a predictor for short time relapse. However, some of the patients are "misclassified", due to the inter-individual variability in the time course of h-TBII activity. Our results confirm that, in addition to h-TBII, even when measured with a highly sensitive test, the concomitant analysis of other clinical and/or biological parameters is necessary to improve the prediction of treatment outcome.

Use of Chinese hamster ovary cell lines transfected with cloned human thyrotropin receptor for the measurement of thyroid-stimulating antibodies: advantages and difficulties

We compared the activities of thyroid-stimulating antibodies (TSAb) as measured with two cell lines (JP26 and JP26/26) transfected with cloned human thyrotropin (TSH) receptor and the values for TSAb measured on human thyrocytes cultures. Sera were obtained from patients with Graves’ disease, before, during and after therapy with carbimazole (1-methyl-2-thio-3-carbethoxyimidazole). The activities of TSAb performed with the three assays correlated significantly. The TSAb technique using JP26/26 cells was as sensitive as the method performed on human thyrocyte cultures since positive TSAb values were found in 45 out of 47 (95.7%) newly diagnosed patients, in 100% of patients who relapsed after drug withdrawal and in none in remission. When the JP26 cell line was used, sensitivity decreased as the detection rate was only 53.2 and 55.5% before treatment and in case of relapse, respectively. The TSH receptors analysis showed a receptor density two times higher for JP26/26 than for JP26. JP26/26 cells provide similar diagnostic information on human thyrocytes in patients with Graves’ disease. Moreover with these cells, the procedure for cell culture is less cumbersome and precision is better. However, rigorous culture conditions are required to maintain TSH receptor expression in transfected cells.

Clinical course and thyroid stimulating hormone (TSH) receptor antibodies during surgical treatment of Graves' disease.

This study assessed the results of surgical treatment for Graves' disease in our hospital and examined the relationship between the values of thyroid stimulating hormone (TSH) receptor antibodies and postoperative thyroid function. From 1983 to 1988, subtotal thyroidectomy was performed in 313 patients with Graves' disease. The follow-up rate was 89.1% (278 of 313 patients). Thirteen (4.2%) patients required methimazole postoperatively for hyperthyroidism and 23 (7.3%) patients required L-thyroxine postoperatively for hypothyroidism. The relationship between the postoperative thyroid function and TSH receptor antibodies was examined. The pre-operative thyrotropin binding inhibitory immunoglobulin (TBII) value had no relationship to postoperative thyroid function. Only in the patients who were hyperthyroid postoperatively did the TBII value remain elevated, but the value decreased gradually in patients who were not hyperthyroid postoperatively. In 43 of 94 patients whose pre-operative TBII values were high, the postoperative TBII value normalized. The higher the preoperative TBII value, the longer time was required for it to normalize postoperatively. The postoperative thyroid stimulating antibody (TSAb) values were higher in patients who remained hyperthyroid than in the patients who were not hyperthyroid. In the patients who remained hyperthyroid postoperatively, there was a significant correlation between the postoperative TBII value and the TSAB value. In the patients who were hypothyroid postoperatively, the TSBAb values were negative. In patients undergoing surgical treatment of Graves' disease, the postoperative TBII and TSAb values were related to postoperative hyperthyroidism. The TSBAb value had no relationship to postoperative hypothyroidism.

Development of Spontaneous Hypothyroidism in Patients with Graves' Disease Treated with Antithyroidal Drugs: Clinical, Immunological, and Histological Findings in 26 Patients

Graves' disease may result eventually in hypothyroidism in approximately 5-20% of patients. In a few such patients hypothyroidism was associated with TSH-blocking antibodies, but whether the frequency of TSH-blocking antibodies in such patients is as high as it is (21%) in patients with primary myxedema is not known. This study was undertaken to determine the presence of various immunoglobulins [TSH binding inhibitor immunoglobulins, thyroid-stimulating antibodies (TSAb), and TSH-blocking antibodies] in 26 patients with Graves' disease who developed hypothyroidism from 0.5-10 yr or more after discontinuation of antithyroid drug therapy. Eight of the 26 patients (31%) had TSH-blocking antibodies, 16 (61%) had TSAb, and 14 (54%) had thyroid hormone binding inhibitor immunoglobulins. Thyroid needle biopsies were performed in 9 patients. Three of 5 patients who had subclinical hypothyroidism had chronic lymphocytic thyroiditis, and all had positive TSAb titers. Three patients had the fibrous variant of chronic lymphocytic thyroiditis; their TSAb values were 902%, 431%, and 1290%. One patient had follicular hyperplasia. We conclude that TSH-blocking antibodies may account for hypothyroidism in approximately one third of patients with Graves' disease who were previously treated with antithyroid drugs, and that autoimmune thyroiditis is comparable for the hypothyroidism in the remaining two thirds of Graves' disease patients.

T Lymphocyte Subsets at Various Stages of Hyperthyroid Graves' Disease: Effect of Carbimazole Treatment and Relationship with Thyroid-Stimulating Antibody Levels or HLA Status

Markers of autoimmunity in hyperthyroid Graves' disease were studied at various stages of the disease in connection with HLA status. The 148 patients studied were included in a long term prospective evaluation of antithyroid drug treatment. The proportions of total T lymphocytes and OKT4 and OKT8 positive cells in peripheral blood and circulating thyroid-stimulating antibodies were determined before treatment (M0; 46 patients), after 6 (M6; 50 patients), and 18 months (M18; 22 patients) of carbimazole treatment, at relapse (15 patients) and after 2 yr of euthyroidism after drug withdrawal (remission; 23 patients). Twenty-seven patients were sequentially studied between M0 and M6, and M6 and M18. As compared to matched normal subjects, the mean proportion of OKT8 positive cells was significantly decreased in every group of patients, even in those in remission, and the mean OKT4/OKT8 cell ratios were increased in all groups except the patients in remission. However, OKT4/OKT8 cell ratios in individual M0 patients were widely distributed, being normal in 50%. No correlation was found between the proportions of T cell subsets and thyroid-stimulating antibody values, and the two measures varied independently in patients studied sequentially. OKT8 lymphocyte subset was dependent on HLA status. In DR3-positive patients, the mean OKT4/OKT8 cell ratio was high at all stages of the study; in DR3-negative patients it decreased significantly at M18 and was normal in those patients who had a remission. However, in the DR3-positive and -negative groups of patients, the mean OKT4/OKT8 ratios at M0 and at relapse were similar. In conclusion, the proportions of circulating OKT8 positive lymphocytes reflect only poorly the activity of the immune abnormalities in Graves' disease, but do correlate with HLA-DR3 status.

Thyroid-stimulating antibody (TSAb) of Graves' disease

The current knowledge of thyroid-stimulating antibody (TSAb) and its significance in Graves' disease is reviewed under 4 headings. 1) Methods of assay; these are categorized as thyroid-stimulation or thyrotropin-receptor-modulation type methods. The latter are convenient but non-specific and the former are inconvenient but specific. The use of guinea pig fat cell membranes as a source of receptor for thyrotropin may improve the specificity of the thyrotropin-binding inhibition (TBI) system. 2) Immunochemistry of TSAb; evidence for the restricted heterogeneity, or oligoclonality, of the antibody as it occurs in some sera, viz. selected for the very high titer, includes a relatively constant pI on isoelectric focussing, restriction to IgG1 and having only λ or k as the light chain. 3) Are antibodies other than TSAb pathogenic in hyperthyroidism? data are provided indicating the presence in one serum of an antibody that inhibits the action of TSAb in vitro . Clinically this novel antibody caused delayed onset of neonatal hyperthyroidism in 2 children. The prevalence of the antibody and its general clinical significance are unknown, but ways of testing for its presence are reviewed. 4) Clinical significance of the assay of TSAb; TSAb occurs in at least 90% of patients but should not be necessary for the diagnosis of Graves' disease. Its persistence at the end of a course of antithyroid drugs predicates relapse; a high level on first diagnosis may forecast such persistence and be an indication for ablative therapy for hyperthyroidism. A high level of TSAb in the third trimester of pregnancy is a reliable index of neonatal hyperthyroidism. It should be recognized that there is a marked tendency for TSAb values to fall throughout the course of pregnancy.