Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?

OBJECTIVE A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with ‘burned-out’ disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse. DESIGN Longitudinal prospective study of previously untreated patients with GD. PATIENTS Thirty-nine consecutive patients aged 10–72 years were treated with methimazole (MMI) for 12–24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal. MEASUREMENTS Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal. RESULTS Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1±1.1 vs 2±0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month. CONCLUSIONS Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.     

Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy

BACKGROUND: CXCL10 plays an important role in the initial phases of Graves' disease (GD) and autoimmune thyroiditis (AT); however, until now, CXCL10 serum levels (sCXCL10) in patients with GD have never been evaluated in relation to thyroid function and treatment. OBJECTIVE: To evaluate sCXCL10 in GD. DESIGN: Cross-sectional. PATIENTS: One hundred and three GD, 164 AT, 20 nontoxic multinodular goitre (NTMNG), 16 toxic nodular goitre (TNG) patients and 70 healthy controls (age- and sex-matched). MEASUREMENTS: We measured sCXCL10 in patients and controls, to relate this parameter to the clinical phenotype. RESULTS: Mean sCXCL10 in GD and AT patients were comparable (122+/-81 and 133+/-102 pg/ml) and significantly higher (P<0.01) than in controls or NTMNG patients (73+/- 32 and 76+/- 25 pg/ml, respectively). Hyperthyroid GD had significantly higher sCXCL10 than euthyroid or hypothyroid GD (145+/- 92, 107+/- 56 and 105+/- 46 pg/ml, respectively; P=0.01). GD patients with untreated hyperthyroidism had higher sCXCL10 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment (166+/-125, 124+/- 41 and 94+/- 35 pg/ml, respectively; P=0.006). Comparable sCXCL10 levels were observed in newly diagnosed untreated hyperthyroid GD patients with respect to untreated patients with relapse of hyperthyroidism after a previous MMI course (176+/-125, 155+/- 97 pg/ml, respectively). GD had similar sCXCL10 to AT and higher than TNG patients or controls (all age- and sex-matched) (144+/- 81, 149+/- 114, 101+/- 27 and 86+/- 44 pg/ml, respectively; P=0.02). CONCLUSIONS: sCXCL10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. The reduction in sCXCL10 in treated patients with GD may be related to the immunomodulatory effects of MMI.     

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.     

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.     

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.     

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.     

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.     

血清TRAb水平在Graves’病诊治中的意义

目的探讨促甲状腺激素受体抗体（TRAb）在Graves’病诊断、治疗及复发监测中的意义。方法电化学发光法测定Graves’病患者治疗前及治疗中TRAb的浓度,绘制ROC曲线,比较治疗前后和复发前后TRAb浓度的变化。结果 ROC曲线下面积为0.931、cut-off值为1.67 IU/L,此时对Graves’病诊断的敏感度为94%、特异性为85%。治疗前后及复发前后TRAb浓度的变化有统计学意义（P〈0.05）。结论电化学发光法测定TRAb是一种快速、敏感性和特异性较高的方法 ,有助于临床对Graves’病诊断、疗效观察和停药复发监测。     

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.     

Impact of smoking on the course of Graves' disease after withdrawal of antithyroid drugs.

Cigarette smoking has been reported to alter relapse rate in patients with Graves' disease (GD). However, the predictive effect of smoking in GD patients after withdrawal of antithyroid drug treatment (ATDT) is still controversial. A prospective multicenter trial has previously identified smoking as an independent risk factor for relapse. Based on this study, the present paper gives a more detailed analysis of the impact of smoking on the long-term course of GD after ATDT withdrawal. To this end, 86 smokers and 177 non-smokers were followed during two years after ATDT cessation. At the end of ATDT (visit 1) and four weeks later (visit 2) smokers had significant higher TSH receptor antibody (TRAb) levels than non-smokers (10.0 IU/L+/-1.6; mean+/-SEM vs. 6.4 IU/L+/-0.9; 11.0 IU/L+/-1.8 vs. 6.8 IU/L+/-0.8, p < 0.01, respectively). During follow-up, Kaplan Meier analysis showed a significantly higher relapse rate in smokers than non-smokers. A subset of GD patients with TRAb levels >10 IU/L had the highest risk to develop relapse during follow-up. Among them, smokers more often relapsed than non-smokers irrespective of TRAb levels, p < 0.01. Thus, in smokers with TRAb levels > or =10 IU/L the predictive values of a positive and negative test for relapse was 68% and 73%, respectively (specificity 95%). In conclusion, we identified two effects by which smoking alters the course of GD. First, smoking is implicated to elevate TRAb levels and therefore increase the risk for relapse during follow-up. Second, smoking is an independent risk factor to worsen the clinical course of both, GD patients with low and high immunological risk to experience relapse after a successful outcome of ATDT. Thus, our data suggest that smoking has modifying immunological consequences and an adverse impact on the course of GD after withdrawal of ATDT. Therefore, patients should be encouraged to stop smoking.     

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.     

Therapy of Graves' disease with sodium ipodate is associated with a high recurrence rate of hyperthyroidism.

To evaluate the long-term efficacy of sodium ipodate (IPO) in the treatment of hyperthyroid Graves' disease, we studied 12 consecutive patients with Graves' hyperthyroidism treated only with 500 mg IPO po daily for several weeks to 22 months. Serum thyroid hormone concentrations markedly decreased and serum free T3 values normalized in all patients within 7 days of therapy. Five patients (42%, Group 1) were euthyroid after 6 weeks of IPO treatment and remained so until IPO was discontinued after 22 months. Recurrence of hyperthyroidism after drug withdrawal occurred in only one of these Group 1 patients, who was promptly responsive to a second course of IPO. In contrast, seven of 12 patients (58%, Group 2) relapsed with recurrent hyperthyroidism between 14 and 42 days of IPO therapy. After IPO was withdrawn, these Group 2 patients were treated with methimazole (20-30 mg/day, initial dose), but the therapeutic response was poor and delayed. Two patients were still hyperthyroid after 6 months of methimazole treatment. Elevated serum FT3 concentrations were observed in the Group 2 patients at 21 days following the early normalization of serum FT3 concentrations. No changes in serum thyroglobulin and thyroid microsomal and TSH-receptor autoantibody titers were observed in either groups during IPO therapy. In conclusion, the results of the present study demonstrate that IPO rapidly restores euthyroidism, but its prolonged administration is associated with a high rate of relapse of hyperthyroidism and a poor response to subsequent methimazole treatment and that long-term IPO administration does not affect humoral markers of thyroid autoimmunity.     

Serum paraoxonase activity before and after treatment of thyrotoxicosis

OBJECTIVE: Antioxidant effects of paraoxonase, a high density lipoprotein (HDL)-associated enzyme that inhibits low density lipoprotein cholesterol (LDL-C) oxidation in human serum, have been reported. Patients with thyroid dysfunction are more susceptible to oxidative stress, and may show enhanced LDL-C oxidation. The purpose of this study was to evaluate serum paraoxonase activity in patients with hyperthyroidism before and after treatment with methimazole (MMI). DESIGN AND PATIENTS: Twenty-four hyperthyroid patients (15 women and nine men, aged 43.0 +/- 12.9 years) and 23 age- and sex-matched healthy controls were studied. Serum paraoxonase activity, lipid, lipoprotein and apolipoprotein levels were measured in fasting samples. Patients were treated with MMI 20-30 mg daily for the first month, and 5-10 mg daily thereafter, and re-evaluated after 6-9 months of treatment. RESULTS: Significantly lower serum paraoxonase activity was present in hyperthyroid patients before treatment compared with the controls (43.4 +/- 21.9 vs. 72.6 +/- 41.2 U/ml, P < 0.005). After a mean follow-up of 7.3 months, 15 patients became euthyroid (treated) and nine were still hyperthyroid. After follow-up, serum paraoxonase activity had increased to 62.2 +/- 37.4 U/ml in those who became euthyroid (P < 0.05 compared with baseline). In patients who were still hyperthyroid serum paraoxonase was unchanged from baseline, at 43.2 +/- 23.2 U/ml. CONCLUSION: Serum paraoxonase is reduced in patients with hyperthyroidism and reverts to normal after euthyroidism is attained. Reduced serum paraoxonase activity in thyrotoxicosis might predispose lipids to oxidation.     

PROLONGED TREATMENT OF HYPERTHYROIDISM WITH SODIUM TYROPANOATE, AN ORAL CHOLECYSTOGRAPHIC AGENT: A RE-EVALUATION OF ITS CLINICAL UTILITY

To re-evaluate the clinical utility of the prolonged management of hyperthyroidism with sodium tyropanoate (TP), an oral cholecystographic agent, we studied the changes in the scoring of thyrotoxic signs and symptoms (thyrotoxic index; TI), serum concentrations and binding of thyroid hormone, and circulating TSH receptor antibodies (TRAb) in two groups of patients with Graves' disease; seven patients (TP group) received TP (1.5 g daily) alone for 14 weeks, and six patients (TP + MMI group) received methimazole (MMI; 30 mg daily) in addition to TP for 8 weeks and MMI alone thereafter. In the TP group, the TI reduced significantly, but it failed to reach a euthyroid level in all except one. Serum total T4 (TT4), free T4 (FT4), and T3 uptake (T3U) values declined by the third week of treatment, but an 'escape' occurred thereafter. Serum rT3 and T4 binding globulin (TBG) levels were increased. The TRAb titres were increased slightly but significantly. Serum T3 levels fell within a week but remained higher than normal during the treatment. In the TP + MMI group, all patients achieved a normal TI by the end of the treatment. Serum TT4, FT4 and T3U fell more significantly than those in the TP group, indicating no escape from the effect of TP. The serum TRAb decreased significantly. Serum T3 levels showed a greater reduction than those in the TP group, and remained decreased even after withdrawal of TP. In a further 9 patients receiving TP alone for 4-14 weeks (7.3 +/- 5.0 weeks on the average), TP was withdrawn and replaced by MMI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum concentrations of proinflammatory cytokines in Graves' disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking

OBJECTIVE: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb). SUBJECTS: We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers. RESULTS: Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking. CONCLUSIONS: Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.     

Transition of nodular toxic goiter to autoimmune hyperthyroidism triggered by 131I therapy.

The use of 131I treatment in nodular toxic goiter is widely accepted. In this article, we describe transition of nodular toxic goiter into an autoimmune toxic goiter with development of thyrotropin receptor antibodies (TRAb) as a side effect of 131I treatment. In this retrospective study, 149 patients with nodular toxic goiter (100 with multinodular goiter, 49 with a solitary autonomously functioning toxic nodule) were studied. Of these 149 patients 100 became permanently euthryoid after 1 dose of 131I, and due to persistent hyperthyroidism, 32 patients needed 2-5 doses to became euthyroid. After becoming euthyroid, none of these 132 patients had relapse of hyperthyroidism in the follow-up period. Based on evaluation of the thyroid hormone variables, 17 of 149 patients had a distinctly different pattern in the changes in thyroid hormones. They developed an increase in FT4I 3-6 months posttreatment after an initial fall in FT4I. Twelve of these 17 patients were treated with antithyroid drugs before the initial 131I dose. On samples of frozen sera (-20 degrees C) anti-thyroid peroxidase (TPO) and TRAb were followed for 6 months after 131I treatment in these 17 patients. A similar follow-up was done in 20 patients (10 with and 10 without antithyroid drug pretreatment), randomly selected from the patients who did not relapse. In the remaining 112 patients, anti-TPO and TRAb levels were measured only before the 131I treatment. Of the 17 patients with relapse, 6 developed TRAb concomitant with recurrence of hyperthyroidism (4% of the study group). In 5 of the 17 patients TRAb values remained absent throughout the follow-up period. The remaining 6 patients had elevated TRAb values before 131I treatment. Among the 132 patients who did not relapse, an additional 7 cases with presence of TRAb were found. A total of 9% of the study group was found to have TRAb before 131I pretreatment. Anti-TPO was found in 20 of 149 patients (13%) before 131I treatment. Complications, either hypothyroidism or TRAb-associated hyperthyroidism, were seen in 8 of 20 patients (40%) with anti-TPO before 131I treatment, compared to 9 of 129 (7%) without (p<0.005). In conclusion, TRAb and a Graves' like hyperthyroidism can be triggered by 131I treatment in patients with nodular toxic goiter. The presence of anti-TPO seem to be a marker of an increased risk of development of TRAb-associated hyperthyroidism as well as hypothyroidism, but both side effects can be seen despite the absence of anti-TPO autoantibodies.     

B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study

CONTEXT: Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might be of benefit in GD. OBJECTIVE/DESIGN: The objective of this prospective, controlled, nonrandomized study was to investigate the effect of RTX in GD. SETTING/PATIENTS: We studied 20 outpatients referred to a university clinic with newly diagnosed (four with relapse) untreated GD. Ten received RTX (+RTX), whereas 10 did not (-RTX). INTERVENTION: The patients received methimazole (MMI) for a median of 102 d (+RTX) and 110 d (-RTX) before the study. Patients in the +RTX group received 375 mg RTX/m(2) iv on d 1, 8, 15, and 22, and all patients were withdrawn from methimazole (MMI) at d 22. MAIN OUTCOME MEASURES: We measured time to relapse of hyperthyroidism and changes in autoantibody levels. RESULTS: Four patients in the +RTX group remained in remission with a median follow-up of 705 d (range, 435-904 d), whereas all the patients in the -RTX group had relapsed by d 393 (P < 0.05). All of the patients in remission had initial TRAb levels below 5 IU/liter (normal, <0.7 IU/liter). However, none of the five patients in the -RTX group with correspondingly low TRAb levels were in remission (P < 0.01). RTX treatment did not affect autoantibody levels to a greater extent than did MMI monotherapy. Two patients received glucocorticoids for joint pain after RTX therapy. CONCLUSIONS: RTX treatment may induce sustained remission in patients with GD with low TRAb levels. However, RTX did not affect autoantibody levels and seems ineffective in patients with high TRAb levels. At present, high cost, low efficacy, and potential side effects do not support use in uncomplicated GD.     

Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves' hyperthyroidism

OBJECTIVE: The present study was to compare the efficacy of a single daily dose of methimazole (MMI) and propylthiouracil (PTU) in the treatment of Graves' hyperthyroidism. BACKGROUND: Antithyroid drugs, MMI and PTU, are widely used in the treatment of hyperthyroidism. Previous studies in the treatment of hyperthyroidism with a single daily dose of antithyroid drugs have demonstrated a more favourable result with MMI. However, the efficacy of a single daily dose of PTU was inconsistent. In this study, we examined the therapeutic efficacy of single daily doses of MMI and PTU on the change of thyroid hormones and thyrotropin receptor antibodies (TRAb) levels. METHODS: Thirty patients with newly diagnosed Graves' hyperthyroidism were randomly divided into two groups, each receiving a single dose of either 15 mg MMI or 150 mg PTU daily for 12 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), total thyroxine (TT4), thyrotropin (TSH), free thyroxine (FT4), and TRAb levels at baseline and at the end of 4, 8 and 12 weeks during the study period. RESULTS: There was no significant difference in baseline thyroid function parameters. Serum TT3, TT4 and FT4 levels in the MMI-treated group were significantly lower than those of the PTU-treated group after 4 weeks and through the end of the study. MMI also has superior effect on reducing serum TRAb levels than PTU after 8 weeks and at the end of the study. CONCLUSION: During the 12-week treatment of Graves' hyperthyroidism, a single daily dose of 15 mg MMI was much more effective in the induction of euthyroidism than a single daily dose of 150 mg PTU. In the doses used in this study, MMI is preferable to PTU when a once-daily regimen of antithyroid drug is considered for the treatment of Graves' hyperthyroidism.     

Circulating soluble Fas ligand correlates with disease activity in Graves' hyperthyroidism

Apoptosis of thyrocytes may play an important role in the pathogenesis of autoimmune thyroiditis. Meanwhile, the Fas/Fas ligand (FasL) apoptosis pathway has received much attention in physiological homeostasis and immune regulation in various thyroid diseases, including Graves' hyperthyroidism (GD). FasL is a type II membrane protein of the tumor necrosis factor family, and induces apoptosis when it binds to Fas. Soluble FasL (sFasL) may also exert cytotoxic activity against Fas-expressing cells by producing trimerization of Fas molecule, but soluble Fas (sFas) is an apoptotic inhibitor. To determine the role of circulating sFas/sFasL in modulating disease activity of GD, we examined the circulating levels of sFas/sFasL in GD patients with various levels of anti-thyrotropin-stimulating hormone (TSH) receptor antibodies (TRAb). Serum samples were obtained from 22 consecutive untreated hyperthyroid GD patients with higher TRAb level (63.8% +/- 12.5%, group I) and 22 treated euthyroid GD patients, who were in a state of disease remission, with lower TRAb level (7.9% +/-5.9%, group II). The levels of sFas were significantly higher in group I (1.56 +/- 0.26 ng/mL) than in group II (0.76 +/- 0.26 ng/mL, P <.01). The levels of sFasL were also significantly higher in group I patients (0.153 +/- 0.018 ng/mL) than in group II patients (0.126 +/- 0.012 ng/mL, P <.01). A significant correlation was found between sFasL levels and TRAb activity in all GD patients (r = 0.69, P <.01). Because changes in sFasL levels and TRAb levels occur in parallel, increased serum sFasL in patients with GD may contribute to homeostasis in the thyroid. Serum sFasL may be considered to be a candidate marker for evaluating disease aggression or regression in GD.