TSH-receptor autoantibodies - differentiation of hyperthyroidism between Graves' disease and toxic multinodular goitre.

Previous studies indicate pre-existing subclinical Graves' disease in many patients with the scintigraphic diagnosis of toxic multinodular goitre type A, equivalent to the in Germany so-called disseminated thyroid autonomy. Furthermore, after radioiodine treatment an increase or the induction of TSH-receptor antibodies (TRAb) in patients with Graves' disease or toxic multinodular goitre has been repeatedly reported. The distinction between both hyperthyroid conditions, Graves' disease and toxic multinodular goitre type A, depends on the diagnostic power of the TSH-receptor antibody determination. Bioassays using CHO cell lines expressing the hTSH-receptor or a new TBII assay based on competitive binding to recombinant human TSH-receptor showed a higher sensitivity for the detection of TSH-receptor antibodies in patients with Graves' disease than previous assays using solubilized porcine epithelial cell membranes. In up to 50 % of patients with toxic multinodular goitre A without antithyroid drug pretreatment TSH-receptor antibodies were detectable with a high correlation between thyroid-stimulating antibodies in the bioassay and the h-TBII assay. Moreover, in a recent study the development of TSH-receptor antibodies after radioiodine treatment was detectable in 36 % of patients with toxic multinodular goitre type A, whereas TSH-receptor antibodies were not detectable in patients with toxic multinodular goitre type B or in patients with toxic adenoma. In conclusion, thyroid-stimulating antibodies in a bioassay or TSH-receptor antibodies detected with the h-TBII assay have the highest diagnostic power to differentiate Graves' disease from toxic multinodular goitre. Because of its less cumbersome assay technique the h-TBII should be performed in all patients with hyperthyroidism to differentiate Graves' disease from non-autoimmune hyperthyroidism such as toxic multinodular goitre to select the appropriate therapy for these patients.     

The usefulness of conventional and echo colour Doppler sonography in the differential diagnosis of toxic multinodular goitres

OBJECTIVE: To assess the potential role of conventional sonography and colour flow Doppler (CFD) sonography (CFDS) in the differential diagnosis of toxic multinodular goitres. SUBJECTS AND METHODS: We investigated 55 patients with untreated hyperthyroidism (24 with typical toxic diffuse goitre of Graves' disease (Group A); 26 with multinodular goitre (Group B); and five with single toxic adenoma (Group C); 22 euthyroid subjects (12 with non-toxic multinodular goitre (Group D) and ten normal subjects (Group E)) were included as controls. In all cases free thyroxine, free tri-iodothyronine, TSH, TSH receptor antibodies (TRAb), anti-thyroperoxidase antibody, anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies were determined and a [(99m)Tc]pertechnetate thyroid scan was performed. RESULTS: Patients with toxic multinodular goitre displayed two different CFDS patterns: 18 patients (Group B-1) had nodules with normal vascularity surrounded by diffuse parenchymal hypoechogenicity with markedly increased CFD signal and maximal peak systolic velocity (PSV) (a pattern similar to Group A patients with Graves' disease); eight patients (Group B-2) had increased intra- and perinodular CFD signal and PSV with normal extranodular vascularity (a pattern similar to that found in Group C patients with single toxic adenoma). Patients of Group B-1 showed a proportion of clinically evident thyroid ophthalmopathy, positive TRAb and other thyroid autoantibodies similar to that observed in Group A patients, while no evidence of thyroid autoimmunity was found in Group B-2. Sixteen out of 18 (89%) patients from Group B-1 displayed a scintiscan pattern of diffuse uneven radionuclide distribution, while seven out of eight (87.5%) of those from Group B-2 had localized uptake in multiple discrete nodules. Taken together, these data strongly suggest that Group B-1 mostly represents patients with the multinodular variant of Graves' disease, while Group B-2 represents patients with non-autoimmune toxic multinodular goitre. CONCLUSIONS: This study shows that combined conventional sonography and CFDS may easily distinguish nodular variants of Graves' disease from non-autoimmune forms of toxic multinodular goitre and confirms the clinical usefulness of this technique in the first-line evaluation of hyperthyroid patients.     

Relevance of cause of hyperthyroidism in determining its management

We analyzed the relapse rates of hyperthyroidism and prevalence rates of hypothyroidism after partial thyroidectomy and radio-iodine therapy in patients with Graves' disease and toxic multinodular goitre. In achieving euthyroidism, partial thyroidectomy was more effective in patients with Graves' disease (P less than 0.02). In patients with toxic multinodular goitre, radio-iodine therapy was more successful (P less than 0.05). Relapse of hyperthyroidism occurred more often in the radio-iodine group (P less than 0.02), mainly in patients with Graves' disease, and was seen sooner after radio-iodine therapy than after surgery (P less than 0.0001). Patients with toxic multinodular goitre, developed hypothyroidism more often after partial thyroidectomy than after 131I (P less than 0.01). In contrast, in patients with Graves' disease, hypothyroidism occurred more often after radio-iodine therapy than in the toxic multinodular goitre group (P less than 0.02). We conclude that the cause of hyperthyroidism strongly influences the efficacy of the therapeutic regimen.     

HYPERTHYROIDISM AND THYROID CANCER

Ten of 502 patients presenting with thyroid cancer were hyperthyroid due to Graves' disease (4 patients), multinodular goitre (3), an autonomous functioning nodule (1) and a large functioning tumour (2). In addition eight patients had a past history of Graves' disease and four of hyperthyroidism associated with multinodular goitre. Mortality in patients with Graves' disease and with multinodular goitre appeared similar to that of other patients of comparable age. Both patients with large functioning tumours died from progressive disease. Concentration 131I by tumour metastases was present in one patient with active Graves' disease who had a high serum concentration of TSH-receptor binding antibodies, indicating that these antibodies may chronically stimulate tumour function. The potential for 131I concentration by tumour when TSH secretion is suppressed should therefore be determined in patients with Graves' disease and if demonstrable tumour function is present, reflecting stimulation by Graves' immunoglobulins, then elimination of tumour remnants is particularly important.     

Goitre size and outcome of medical treatment of Graves' disease

One hundred and twenty-four patients with newly diagnosed hyperthyroidism received a combined thionamid-thyroxine medical therapy for approximately 2 years. According to the estimated goitre size before therapy and the type of goitre the patients were divided into 4 groups: Graves' disease no goitre (n = 19), Graves' disease small goitre (n = 57), Graves' disease medium or large goitre (n = 23), multinodular goitre (n = 25). The median follow-up period after cessation of medication was 64 (range 11-141) months. The remission rates in the different groups during follow-up were calculated using life table analysis. Graves' patients with no goitre or a small goitre had a significantly better outcome (remission % after 5 years 82.5 +/- 15.4 (SE) and 71.5 +/- 7.8, respectively) than Graves' patients with a medium size or large goitre (remission % after 5 years 37.0 +/- 11.1)(P less than 0.025). Most patients with multinodular goitre had a relapse within the first year after stop of medication (remission % after 5 years 15.5 +/- 10.1). Hence patients with Graves' disease having a small thyroid gland should be treated medically while surgery or radioiodine may be a more reasonable choice in Graves' patients with medium size or large goitres. Medically treated patients with toxic multinodular goitres have a very small chance of prolonged remission if medication is stopped.     

Use of the 2nd generation TRAK human assay did not improve prediction of relapse after antithyroid medical therapy of Graves' disease

OBJECTIVE: Antithyroid drug treatment (ATD) is used world-wide in the treatment of thyrotoxicosis in patients with Graves' disease (GD). The main problem is a relapse rate of 30 to 50% within 2 years after the treatment has stopped. The measurement of thyrotropin receptor antibodies (TRAb) in serum has been used to confirm the diagnosis of GD in selected patients with a diagnostic specificity of 70 to 90%. However, in predicting the recurrence of thyrotoxicosis after discontinuing ATD it has been of little value. The aim of this study was to evaluate the ability of TRAb measured by the more sensitive recombinant human TSH receptor method to predict risk of recurrence of GD after discontinuing ATD. MATERIALS, PATIENTS AND METHODS: One hundred and twenty nine patients with newly diagnosed GD were included. Of these, 58 had relapse of hyperthyroidism in a follow-up of at least 11 months (median 18 months, range 11-49) after discontinuing ATD. In 122 Graves' patients TRAb were measured at the time of diagnosis and in all patients when discontinuing ATD by a competitive radioreceptor assay using recombinant human TSH receptors (TRAK human assay). RESULTS: We found an increased diagnostic specificity (99%) compared with the old TRAK porcine assay. The predictive values of a positive and negative test in relation to the prediction of a relapse of GD were found to be only 55% and 62% respectively when using a cut-off level of 1.5 IU/l, and the predictive value of a positive test decreased to 49% and of a negative test to 60% at a lower cut-off limit (1 IU/l). CONCLUSION: Our study confirms that the new TRAK human assay had a superior diagnostic sensitivity in comparison with the old TRAK porcine assay. Despite the higher diagnostic sensitivity of the TRAK human method, we could not find any improvement of predictive values for relapse of hyperthyroidism in the measurement of TRAb at the end of ATD.     

促甲状腺激素受体抗体放射受体分析法的建立及其临床应用

用0.5％ Triton X-100一次增溶猪甲状腺细胞膜,用固相Iodogen法标记bTSH再经受体亲合纯化获得了高比生物活性的可溶性TSH受体和~(125)I-bTSH,建立了TRAb放射受体分析法。制备的TSH受体和~(125)I-bTSH的结合可被非标记bTSH和Graves病患者血清中的TRAb呈剂量依赖性抑制。TRAb平均抑制率分别为15.4％和90.6％时,批间变异系数相应为12.6％和3.1％。试验和临床应用结果表明,本方法灵敏度高、特异性强、重复性好,且操作简便、快速,适于临床常规应用。     

Long-term follow-up study of radioiodine treatment of hyperthyroidism

OBJECTIVE: To determine the cumulative incidence of hypothyroidism during long-term follow-up in patients treated for hyperthyroidism by radioactive iodine (131)I (RAI) therapy, the significance of clinical factors in predicting the development of hypothyroidism, and the outcome after a fixed 7 mCi (259 MBq) dose of RAI. DESIGN: Prospective cohort study of patients treated for hyperthyroidism by RAI. PATIENTS AND MEASUREMENTS: Since 1965, details on 2043 patients treated by RAI therapy in Tampere University Hospital were entered into a computerized register. Following RAI treatment, thyroid status was monitored every 1-3 months during the first year, and subsequently at 1-3-year intervals until June 2002 or until the patient died or moved out of the Tampere University Hospital district. results The cumulative incidence of hypothyroidism in patients with Graves' disease and toxic multinodular goitre at 1, 10 and 25 years was 24%vs. 4%, 59%vs. 15% and 82%vs. 32%, respectively. In a Cox regression model, previous partial thyroidectomy [risk ratio (RR) = 1.63 in patients with Graves' disease and RR = 1.59 in those with toxic multinodular goitre] and age at the first RAI treatment (RR = 0.998 and RR = 0.996 per year) were statistically significantly associated with the development of hypothyroidism both in patients with Graves' disease and in those with toxic multinodular goitre. Antithyroid medication preceding RAI therapy (RR = 0.47) decreased and female gender (RR = 1.53) increased the risk of hypothyroidism only in patients with Graves' disease. Administration of a single dose of RAI resulted in the control of hyperthyroidism in 75% of patients, while two to six RAI treatments were needed in 25% of patients to achieve either a hypothyroid or a euthyroid state in both groups. None of the clinical factors studied was associated with the remission rate either in patients with Graves' disease or in those with toxic multinodular goitre. The remission rate did not differ between the patients who received a dose of RAI calculated according to the uptake of RAI and thyroid size and those who received an empirical dose of RAI. The fixed 7 mCi (259 MBq) dose of RAI cured 80% of patients. CONCLUSION: RAI treatment is effective in treating hyperthyroidism in patients with Graves' disease, but hypothyroidism will develop in 82% of patients in 25 years. Because the development of hypothyroidism seems to be inevitable and unpredictable by any clinical factors, the objective of RAI treatment should be to minimize the persistence of hyperthyroidism with the simplest possible form of treatment. We recommend a fixed 7 mCi dose of RAI to be used as the first empirical dose in the treatment of hyperthyroidism, at least in Graves' disease.     

Incidence of radioiodine induced Graves' disease in patients with multinodular toxic goiter.

In this study, we assessed the incidence of Graves' disease (GD) following radioiodine therapy (RIT) in a large cohort of well characterized patients with autonomy in comparison to the clinical course of control patients with thyroidal autonomy not definitively treated with (131)I or surgery. 622 consecutive patients were treated with (131)I for autonomy (unifocal: n = 321; multifocal: n = 199; disseminated: n = 102) and followed up for at least 6 months post RIT. 108 consecutive patients with autonomy not definitively treated (unifocal: n = 49; multifocal: n = 42; disseminated: n = 11) followed up for at least 6 months served as controls. Initial evaluation and follow-up included determination of FT3, FT4, TSH, autoantibodies against the thyroid peroxidase (anti-TPO) and TSH-receptor antibodies (TRAb) by highly sensitive radio receptor-assay, quantitative thyroid scintigraphy and sonography. After 6 months, GD was newly diagnosed in 1/321 patients with unifocal autonomy, in 1/199 patients with multifocal autonomy and in 0/108 control patients. In patients with disseminated autonomy (group C), GD was diagnosed significantly more often compared to the other groups (5/102 patients; 4,1 %; p < 0.05). In conclusion, RIT may induce Graves' disease in a few cases with toxic multinodular goiter. The incidence in this population is small. Compared with patients suffering from uni- or multifocal autonomy, subjects with disseminated autonomy have a more than tenfold higher risk for the development of GD.     

Appearance of anti TSH-receptor antibodies and clinical Graves' disease after radioiodine therapy for hyperfunctioning thyroid adenoma

Radioiodine treatment use is frequent in patients with benign hyperfunctioning thyroid diseases and the side-effects are rare. In this paper we described the appearance of TSH-receptor antibodies and the concomitant development of persistent hyperthyroidism in a patient with hyperfunctioning thyroid adenoma after 131I treatment. A 70-year-old man presented a hyperfunctioning thyroid adenoma with suppressed uptake in the adjacent normal gland. Antibodies against the thyroglobulin (TgAb), thyroid peroxidase (TPOAb) and TSH-receptor (TRAb) were absent. One year after remission by radioiodine therapy the patient developed severe and persistent hyperthyroidism associated with diffuse 131I uptake in the gland. TgAb and TPOAb remained absent, but TRAb were present. Although spontaneous development of Graves' disease cannot be excluded, the time sequence and the negative familial and personal history for autoimmune diseases suggest a possible connection between the two phenomena. The release of TSH-receptor antigen from follicular cells damaged by 131I may have triggered the autoimmune response turning a toxic nodular goiter patient into a Graves' disease patient.     

TSH-receptor antibody measurement in patients with various thyrotoxicosis and Hashimoto's thyroiditis: a comparison of two two-step assays,coated plate ELISA using porcine TSH-receptor and coated tube radioassay using human recombinant TSH-receptor

The aim of this study was to compare two two-step assays, a new coated plate (CP) ELISA assay (TRAb ELISA) using purified porcine TSH-receptors (pTSH-R) and a coated tube assay (CT) using recombinant human TSH-receptors (hTSH-R) (DYNO(R) test TRAK human). The same serum samples were used for the determination by both assays in patients with 100 untreated Graves' disease (GD), 30 silent thyroiditis (ST), 10 subacute thyroiditis (SAT) and 87 Hashimoto's thyroiditis (HT). In sera from patients with untreated GD, pTBII and hTBII were positive in nearly all cases except the same one, whereas the thirty sera from the ST had positive values of pTBII in one case and of hTBII in 4 cases. In the one ST case of both pTBII and hTBII positive, hyperthyroidism developed following ST, although the remaining ST cases including the three hTBII-positive cases were not followed by hyperthyroidism after ST attack. A positive value of hTBII was observed in one of 10 patients with SAT, whereas none of them was pTBII positive. In the 87 patients with HT, positive values of pTBII were recognized in 9 patients, whereas hTBII is positive in 10 patients. Serum TSAb and TSBAb activities were analyzed in the hTBII positive 7 patients. As a result, TSAb was all positive except one and TSBAb positive in 4 cases. Since there is no significant difference in the sensitivity and specificity between the two assays in the differentiation of thyrotoxicosis as well as the frequency of finding positive values in patients with HT, it is reasonable to conclude that the clear advantage of sensitivity for clinical application in the new CP and CT assays may be derived from the coated plate or coated tube assay itself, which probably excludes the effect of anti-TSH antibodies and HAMA, and is unrelated to the use of human or porcine TSH-receptors.     

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.     

THE CIRCADIAN VARIATION OF THYROTROPHIN IN PATIENTS WITH PRIMARY THYROIDAL DISEASE

We have used a highly sensitive immunochemiluminometric assay (ICMA) for human TSH to study the effect of thyroid status on the circadian variation in TSH levels. Three subjects with Graves' disease, three with toxic multinodular goitre and three with euthyroid multinodular goitre were sampled every hour for 24 h. The results obtained were compared to those from five euthyroid control subjects. It was found that some patients with hyperthyroidism and suppressed basal TSH levels exhibited a 24 h secretory pattern similar to that seen in normal subjects with peak TSH levels occurring at night. In addition two subjects with a euthyroid multinodular goitre demonstrated levels of TSH below the normal range despite being clinically and biochemically euthyroid. TSH suppression in these subjects is probably related to some degree of thyroid autonomy and possible development of hyperthyroidism in the future.     

The role of circulating immune complexes in the pathogenesis of Graves' disease

It has recently been reported that many immunological abnormalities including the presence of TSH-receptor antibody (TRAb) were found in Graves' disease (GD). Circulating immune complexes (CIC) have also been detected in the serum of patients with GD as observed in systemic lupus erythematosus, which is thought to be a typical model of immune complex disease. The role of CIC in pathogenesis of hyperthyroidism, however, remains to be elucidated. Therefore, to clarify pathophysiological functions of CIC in GD, the levels of it in those patients were compared with their symptoms, those of TRAb, and lymphoblastogenesis (LBG) induced by phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM). The subjects were forty patients with GD without any medication, one hundred and nine patients with GD on medication with methimazole (MMI), and fifteen healthy volunteers. CIC was measured by three different methods; polyethyleneglycol precipitation method (PEG), Clq binding assay (Clq), and Protein A binding assay (PA). The normal range was estimated with the mean plus or minus two times the standard deviation of normal controls. In untreated GD, CIC determined by PEG, Clq and PA widely distributed from normal range to high levels. The positive rates of CIC determined by PEG, Clq, PA, and any one method of these three were 17.5%, 22.5%, 30.0% and 52.5%, respectively. LBG using incorporation of tritiated thymidine showed the decreases in PHA and Con A, and the increases in PWM in patients with GD. The positive rates of CIC determined by PEG and PA were significantly higher in patients without goiter or with small one than those with large one (p less than 0.05). CIC measured by all three of PEG, Clq and PA showed negative correlation with TRAb significantly (p less than 0.05, p less than 0.01, p less than 0.01, respectively). On the other hand, CIC measured by Clq showed significant negative correlation with serum thyroxine concentration (p less than 0.01). The levels of CIC, TRAb and PWM-induced LBG decreased following the tapering dose of MMI sufficient to keep patients in euthyroid state. In consequence, there were no longer any correlations between CIC and TRAb after thyroid function was normalized. These observations suggest that CIC's which have huge molecular weight or have ability to bind Fc receptor on K cell, macrophage, neutrophil, and other immune cells may be one of the factors to inhibit the goitrogenic action of TRAb, and that CIC's which have ability to activate the complement system may be one of the factors to inhibit the stimulation of secretion of thyroid hormone by TRAb.(ABSTRACT TRUNCATED AT 400 WORDS)     

Diagnostic imaging work up in multi-nodular goiter

Ultrasound, scintigraphy and sonographically guided fine-needle biopsy are the cornerstones in the diagnostic work-up multinodular goitre. Subsequent decisions for adequate treatments should be based on accurate tests to avoid unnecessary intervention. Especially in areas with endemic goitre a preselection of patients for the most effective procedure e.g. surgical or medical treatment is mandatory. Autoimmune hyperthyroidism (Graves' disease), solitary hyperfunctioning thyroid nodules and toxic multinodular goitre (Plummer's disease) constitute a clear indication for radioiodine treatment in many cases. Recently, there is an emerging role for I-131 in the treatment for so called subclinical hyperthyroidism caused by either of three first entities and for patients with non-toxic goitre, in whom surgery is not an option. These patients with large non toxic goitre encompass a group of patients who are euthyroid but may benefit from diminishment of thyroid volume. We review the spectrum of diagnostic tests and provide some recommendations regarding (nuclear medicine) therapy.     

Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves' disease (GD): an international multicentre trial

Background  Most recently, a new rapid and fully automated electrochemiluminescence immunoassay for the determination of TSH receptor autoantibodies (TRAb) based on the ability of TRAb to inhibit the binding of a human thyroid-stimulating monoclonal antibody (M22) has been established.
Objective  To evaluate this assay system in clinical routine based on an international multicentre trial and to compare the results with other established TRAb assays.
Patients and measurements  Totally 508 Graves' disease (GD), 142 autoimmune thyroiditis, 107 subacute thyroiditis, 109 nonautoimmune nodular goitre, 23 thyroid cancer patients and 446 normal controls were retrospectively evaluated.
Results  ROC plot analysis revealed an area under curve of 0·99 (95% CI: 0·99–1·0) indicating a high assay sensitivity and specificity. The highest sensitivity (99%) and specificity (99%) was seen at a cut-off level of 1·75 IU/l. Here, the calculated positive predictive value was 95%, whereas the negative predictive value was 100%. Applying the ROC plot-derived cut-off of 1·75 IU/l we found a sensitivity for TRAb positivity within the group of newly diagnosed GD patients of 97% which is in accordance to the sum of different nonautomated porcine TSH receptor-based assays with a sensitivity of 94% indicating an excellent analytical performance of the new assay format. Detailed comparison of the automated and the sum of manual assays revealed a near identical specificity.
Conclusion  Our results demonstrate that this new assay system has a high sensitivity for detecting GD and specificity for discriminating from other thyroid diseases. This assay may represent the future technology for rapid fully automated TRAb detection.     

促甲状腺激素受体抗体检测的临床意义

50年前人们发现了促甲状腺激素受体抗体(TRAb),随着对促甲状腺激素受体(TSHR)结构和功能认识的不断更新,加之TSHR信号转导和与TRAb相互作用的逐步阐明,人们对TRAb及其临床应用的认识得到了进一步提高.TRAb的检测在Graves病(GD)及Graves眼病的诊断中有重要作用,并有效预测GD经抗甲状腺药物或放射性碘治疗后复发.其亦可应用于近期服碘的孕妇和乳母,因为甲状腺扫描对她们来说是禁忌的.另外,TRAb有助于胎儿、新生儿甲状腺功能亢进及其他类型的甲状腺毒症的诊断和鉴别诊断.目前,已有文献报道TRAb阳性的GD患者发生甲状腺肿瘤及不良预后之间的可能联系,但尚需更多的前瞻性研究来证实.

Abstract：

It has been 50 years since the discovery of thyrotropin receptor autoantibody (TRAb). Advances in the knowledge of thyrotropin receptor ( TSHR) structure and function, combined with the elucidation of TSHR signaling and TSHR-autoantibody interaction have greatly facilitated our understanding of TRAb and their clinical applications. Measurement of TRAb activity plays an important role in the diagnosis of Graves' disease ( GD) and Graves' opthalmopathy. It has also been well recognized that TRAb is an effective predictor of GD relapse or remission after antithyroid drug and radioactive iodine treatment. TRAb test is of particular help in pregnant women and lactating mothers with recent iodine load, where radioactive iodine or technetium tests are contraindicated. In addition, it is useful in the diagnosis and differential diagnosis of fetal and neonatal hyperthyroidism as well as some rare forms of thyrotoxicosis in clinical practice. Accumulating evidence also indicates the possible correlation between thyroid cancer occurring in GD patients with positive TRAb and adverse outcomes. However, further innovation and standardization of TRAb tests are required to help pave the way for clinical applications.     

Mitral valve prolapse in hyperthyroidism of two different origins.

The prevalence of mitral valve prolapse was investigated in 126 patients with hyperthyroidism due to Graves' disease or toxic nodular goitre and that of hyperthyroidism in 64 patients with mitral valve prolapse. One hundred and eleven asymptomatic healthy subjects comprised a control group. The patients with hyperthyroidism were divided into those with Graves' disease and those with toxic nodular goitre. Of the group as whole, 12 (9.5%) patients had mitral valve prolapse compared with six (5.4%) in the control group, but the difference was not statistically significant. The prevalence of mitral valve prolapse in the patients with toxic goitre was also not significantly different from that in the controls. When the prevalence in the group with Graves' disease was compared with that in the control group (16.3% vs 5.4%) the difference was significant. Only one patient with mitral valve prolapse had hyperthyroidism.     

促甲状腺激素受体抗体检测的临床意义

50年前人们发现了促甲状腺激素受体抗体(TRAb),随着对促甲状腺激素受体(TSHR)结构和功能认识的不断更新,加之TSHR信号转导和与TRAb相互作用的逐步阐明,人们对TRAb及其临床应用的认识得到了进一步提高.TRAb的检测在Graves病(GD)及Graves眼病的诊断中有重要作用,并有效预测GD经抗甲状腺药物或放射性碘治疗后复发.其亦可应用于近期服碘的孕妇和乳母,因为甲状腺扫描对她们来说是禁忌的.另外,TRAb有助于胎儿、新生儿甲状腺功能亢进及其他类型的甲状腺毒症的诊断和鉴别诊断.目前,已有文献报道TRAb阳性的GD患者发生甲状腺肿瘤及不良预后之间的可能联系,但尚需更多的前瞻性研究来证实.     

Mitral valve prolapse in hyperthyroidism of two different origins

The prevalence of mitral valve prolapse was investigated in 126 patients with hyperthyroidism due to Graves' disease or toxic nodular goitre and that of hyperthyroidism in 64 patients with mitral valve prolapse. One hundred and eleven asymptomatic healthy subjects comprised a control group. The patients with hyperthyroidism were divided into those with Graves' disease and those with toxic nodular goitre. Of the group as whole, 12 (9.5%) patients had mitral valve prolapse compared with six (5.4%) in the control group, but the difference was not statistically significant. The prevalence of mitral valve prolapse in the patients with toxic goitre was also not significantly different from that in the controls. When the prevalence in the group with Graves' disease was compared with that in the control group (16.3% vs 5.4%) the difference was significant. Only one patient with mitral valve prolapse had hyperthyroidism.