Graves病患者药物治疗复发的相关因素分析

目的 回顾抗甲状腺药物(ATD)治疗的初发Graves病(GD)患者的临床资料,观察各临床特征对ATD治疗转归的影响,以评价GD复发的影响因素.方法 收集204例初发GD甲亢患者的临床资料.根据ATD治疗结果分为有效组和失败组,失败组包括停药复发和未能停药两个亚组,比较各因素对ATD治疗转归的影响.结果 204例初发GD患者中94例(46.1%)治疗有效,110例(53.9%)治疗失败.与有效组比较,失败组发病年龄小[(31.0±12.2)岁比(36.3±14.0)岁,P=0.004],发病初游离T3水平高[(25.60±9.52)pmol/L比(19.16±6.38)pmol/L,P=0.001],FT3/FT4比值大[(4.87±1.21)比(3.86±0.98),P=0.001],促甲状腺素受体抗体(TRAb)水平高[(57.3±18.4)%比(29.6±14.9)%,P=0.001].logistic分析显示,发病初甲状腺大小、FT3/FT4比值、TRAb水平是药物治疗失败的独立影响因素.复发亚组停药时,甲状腺明显肿大、伴有眼征的患者比率高.治疗过程中甲状腺激素正常3、6、9、12个月时,复发亚组中超敏促甲状腺素(TSH)受抑制患者的比率均明显多于有效组(P=0.001).结论 (1)治疗前甲状腺明显肿大、TRAb水平高、FT3/FT4比值大的患者,药物治疗反应差;(2)停药时甲状腺明显肿大、伴有眼病者,停药后复发率高;(3)经治疗甲状腺激素正常、TSH延迟恢复或仍受抑制者复发率高.     

Graves病患者甲状腺激素水平正常后sTSH长期抑制机制的探讨

目的 探讨临床上部分Graves病(GD)患者经抗甲状腺药物(ATD)治疗后甲状腺激素水平达到正常,但促甲状腺素(TSH)仍长期处于被抑制状态的机制.方法 入选初发122例GD甲亢患者,予以初始等效剂量的ATD治疗,每月随访时根据甲状腺功能测定的结果酌情减量,并适时添加左旋甲状腺素(L-T4).当甲状腺激素(FT3、FT4)水平持续正常3个月即达随访标准,复查FT3、FT4、sTSH、TSH受体抗体(TRAb),并根据TRAb是否阳性分组比较.结果 122例GD甲亢患者经(7.1±1.1)个月的ATD治疗后,甲状腺激素水平均已经达到正常3个月.随访时,58例TRAb转为阴性,64例TRAb持续阳性.两组甲状腺激素水平无差异, TRAb阳性组的sTSH水平明显低于阴性组[0.044 mIU/L(0.001～4.163 mIU/L) vs 1.749 mIU/L(0.079～4.646 mIU/L),P＜0.01];血清sTSH水平与TRAb呈明显负相关(r=-0.539,P＜0.01),与FT3、FT4、年龄、病程、治疗时间、L-T4剂量、L-T4添加时间等均无相关性.结论 药物治疗过程中,甲状腺激素水平正常的GD患者,其TSH水平长期受抑制的原因与高水平TRAb相关,可能由于TRAb直接与垂体内TSH受体结合,通过超短环反馈抑制TSH的分泌所致.     

Graves病131I治疗前和治疗一年中促甲状腺素受体抗体水平的动态变化

对157例Graves病131I门诊治疗的病例进行回顾性研究.按131I治疗1年后甲状腺功能状态分成3组:缓解组(FT3、FT4)、部分缓解组(FT3、FT3未降至正常范围)、甲减组(FT3、FT3低于正常).治疗前促甲状腺素受体抗体(TRAb)的阳性率为88.5%.131I治疗后,TRAb在3～6个月时达高峰,之后逐渐下降.甲状腺重量、显著升高的TRAb(≥405 U/L)、FT3、FT3水平是评估预后的指标.     

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.     

Graves病患者甲状腺功能改变与细胞免疫相关分析

目的探讨Graves病患者甲状腺功能与机体的细胞免疫间的关系。方法（1）采用流式细胞仪检测20例高功能Graves病患者和20例健康对照组的T淋巴细胞亚群和CD8-／IFN-γT（Th1）细胞和CD8-／IL-4＋T（Th2）细胞的百分含量。（2）化学发光法检测FT3、FT4、s-TSH,放射免疫法检测TRAb、TGAb、TMAb。（3）应用逐步回归分析,以FT3、FT4、8-TSH为因变量,CD4T细胞、CD8T细胞、CD4＋／CD8＋T细胞比值、Th2细胞百分含量、Th1细胞百分含量、Th1／Th2比值、TRAb、TGAb、TMAb滴度为自变量进行分析。结果（1）Graves病患者的FT3,s—TSH、TRAb、TGAb、TMAb滴度均较正常对照组明显增高（P〈0．01）。（2）Graves病患者较正常人群CD4＋T细胞和CD4＋／CD8＋T细胞比值增高;Th2百分含量增高;而CD8＋T细胞、Th1细胞及Th1／Th2细胞比值下降（P均〈0．05）。（3）CD4／CD8＋T细胞比值、Th1／Th2细胞比值以及TRAb、TGAb、TMAb成为影响FT3、FT4、TSH变化的重要因素。结论Graves病患者机体的T细胞免疫调节失衡不仅参与疾病的发生和发展,还影响了甲状腺激素功能。CD4＋／CD8＋T细胞比值、Th1／Th2比值可作为临床治疗的监测高功能Graves病活动及疗效的指标。     

Performance of a third‐generation TSH‐receptor antibody in a UK clinic

Background UK national guidelines recommend the measurement of TSH receptor antibodies (TRAb) in certain clinical scenarios. A commercial third‐generation TRAb autoantibody M22‐biotin ELISA assay was introduced in May 2008 in our centre. Objective To evaluate the diagnostic performance of a TRAb assay in a retrospective and subsequently a prospective cohort in a UK centre. Design A retrospective review of patients with thyroid disease followed by a prospective observational study in consecutive patients with newly found suppressed serum thyrotrophin (TSH). Patients and Measurements Medical records of 200 consecutive patients with thyroid disorders who had TRAb measured since the introduction of the assay. In a prospective study 44 patients with newly identified hyperthyroidism (TSH < 0·02 mIU/l) had sera assayed for TRAb prior to their clinic appointment at which a final diagnosis was sought. Results In the retrospective cohort, the manufacturer’s cut‐off point of TRAb ≥0·4 U/l resulted in a positive predictive value (PPV) of 95%, sensitivity 85%, specificity 94% and negative predictive value (NVP) 79% to diagnose Graves’ disease using defined criteria. Receiver operating characteristic (ROC) analysis determined an optimal cut‐off point of TRAb ≥3·5 U/l with a 100% specificity to exclude patients without Graves’ disease at the cost though of a lower sensitivity (43%). In the prospective study, the sensitivity, PPV, specificity and NPV were all 96% using the ≥0·4 U/l cut‐off. When combining hyperthyroid patients from both cohorts the assay sensitivity and specificity at ≥0·4 U/l cut‐off were 95% and 92% respectively. A positive TRAb result increased the probability of Graves’ disease for a particular patient by 25–35% and only six (2·5%) patients had a diagnosis of hyperthyroidism of uncertain aetiology after TRAb testing. Conclusions The assay studied specifically identifies patients with Graves’ disease. It is a reliable tool in the initial clinical assessment to determine the aetiology of hyperthyroidism and has the potential for cost‐savings.     

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.     

Thyroid function in breast-fed infants is not affected by methimazole-induced maternal hypothyroidism: results of a retrospective study

For many years, breast-feeding was forbidden if methimazole (MMI) was being used. However, a few studies have demonstrated the relative safety of MMI. The purpose of this study was to evaluate thyroid function of breast-fed infants whose lactating mothers became hypothyroid while taking methimazole. Between 1990 and 2001, 134 thyrotoxic lactating mothers received MMI while breast-feeding. MMI therapy was initiated between 2-8 months postpartum, 10-30 mg for the first month and 5-10 mg from the second until the twelfth month. In 16 mothers, TSH was increased at the end of one month of MMI therapy (Group 1). Infants of 18 mothers whose serum TSH was normal at the end of the first month were included as controls (Group 2). Mothers and their infants were clinically evaluated and serum T4, T3 and TSH were measured before and at 1, 2, 4, 8 and 12 months after MMI therapy. Serum MMI was measured in 8 infants 2 h after breast-feeding. Mean +/- SD of FT4I and FT3I were not statistically different between the two groups of mothers before MMI therapy. In all 34 mothers thyroid indices decreased one month after MMI therapy; FT4I: Group 1 from 19.8 +/- 4.3 to 6.0 +/- 4.8 (p<0.001) and Group 2 from 20.3 +/- 4.7 to 11.4 +/- 4.1 (p<0.001); FT3I: Group 1 from 602 +/- 56 to 146 +/- 52 (p<0.001) and Group 2 from 562 +/- 42 to 186 +/- 39 (p<0.001). The difference in FT4I, FT3I and TSH (20 +/- 18 vs 2.1 +/- 1.1 mU/l, p<0.001) between the 2 groups was significant at the end of the first month of MMI therapy. There was no significant difference in thyroid function of infants of these two groups one month after MMI therapy and all tests remained within the normal range during 12 months of treatment of their lactating mothers. Serum MMI levels were less than 0.03 in 6 and 0.03 and 0.035 microg/ml in the other 2 infants. The results further indicate the safety of MMI therapy in breast-feeding thyrotoxic women.     

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)     

Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves' hyperthyroidism

We compared the effects of high and low dosages of antithyroid drugs in 113 patients with Graves' hyperthyroidism. The patients were randomly divided into 2 groups. In group A, 65 patients received either methimazole (MMI): 60 +/- 14.5 mg/day (mean +/- SD); range 40-100 mg/day, or propylthiouracil (PTU): 693 +/- 173 mg/day; range 500-1200 mg/day. These high doses were maintained throughout treatment with later addition of 50-75 micrograms T3 daily. Forty eight patients (group B) were treated with lower doses of MMI or PTU without thyroid hormone addition. The maintenance dose of MMI was 13.6 +/- 7 mg/day (range 5-25 mg/day) and that of PTU was 180 +/- 58 mg/day (range 100-300 mg/day). The treatment period was 15.1 +/- 4.2 (range 10-30) months for group A and 13.5 +/- 2.2 (range 12-20) months for group B. Remission occurred in 75.4% patients from group A and in 41.6% patients from group B (P less than 0.001). The mean follow-up was 42 +/- 14 months (17-81 months). The free T4 index (FT4I) in group A remained below the normal range during treatment. The mean FT4I, obtained during the course of treatment, of patients who went into remission from group A was significantly (P less than 0.001) lower than in relapsed patients (4.8 vs. 6.5). Moreover, there was an inverse correlation between mean FT4I and maintenance daily dose of either MMI (r = -0.567; P less than 0.001), or PTU (r = -0.379; P less than 0.01). A fall in microsomal antibody (MCHA) titer occurred mainly in remission patients, and was more significant (P less than 0.05) in group A patients. In contrast, 11 (7 from group B) of the 16 patients with an increase of microsomal antibody levels relapsed. The frequency of negative tests of thyroid-stimulating antibody was higher in group A patients (71%) than in group B (29%) at the end of therapy (P less than 0.01). No correlation was found between thyroid T3 suppressibility and either mean FT4I or thyroid-stimulatory antibody activity during treatment. Our findings show that patients treated with high doses of PTU or MMI throughout treatment have a higher remission rate when compared to those treated with a more conventional regimen. These results support the hypothesis that large antithyroid drug doses may have greater immunosuppressive effects than low dosage regimens. Furthermore, a high dosage regimen could permit the restoration of the immune surveillance mechanisms and, thus, lasting remission of Graves' disease.     

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.     

Serum thyroid-stimulating antibody, thyroglobulin levels, and thyroid suppressibility measurement as predictors of the outcome of combined methimazole and triiodothyronine therapy in Graves' disease.

The value of the criteria used to anticipate the outcome of treatment of Graves' hyperthyroid patients with methimazole (MMI) remains controversial. We have reported that high MMI doses combined with T3 administration was correlated with higher remission rates. In this study, we used the lowest MMI dose able to control the hyperthyroidism, keeping the free T4 index (FT4I) values below the normal range throughout treatment, and compared the results with patients treated with a high MMI regimen. Both groups received T3. We also evaluated the usefulness of goiter size, serum thyroid-stimulating antibody (TSAb: adenylate cyclase stimulation in human thyroid membrane), thyroglobulin (Tg) levels, and the T3 suppressibility of 24 h RAIU as prognostic markers for the outcome of Graves' disease therapy. Twenty-four Graves' hyperthyroid patients were treated with high MMI dose (mean +/- SD 60 +/- 19, range 40-120 mg daily), and 25 patients received low MMI dose (17 +/- 4.3, 5-20 mg daily). T3, 75 micrograms daily, was given to both groups of patients for 15 +/- 4 (13-22) months of treatment. After cessation of drug therapy, 31 patients (63%) remained euthyroid for 18 +/- 3 (13-49) months of follow-up, 15 (62.5%) and 16 (64%) patients in the high and low dose groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

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。     

Cost-effectiveness of the clinical treatment of Grave's disease in a public University Hospital: a retrospective analysis and prospective projection for a therapeutic approach

The aim of the present study was to evaluate a new proposal for increasing compliance to the clinical management of patients with Graves' disease (GD) in a large and public University Hospital. The patients were carefully selected (no previous GD treatment, goiter volume less than 6 mL must be living in the metro area of S?o Paulo), received medication at no cost, were contacted frequently by the social worker and alerted for the date of consultation and only referred to a single endocrinologist during all phases of treatment. We recruited 229 patients with GD that were initially treated with methimazole (MMI--60 mg q.d) in a single daily dose followed by a combination of MMI (20 mg) plus L-T4 (100 microg) daily for 24 months. Only 83 patients (36.2%) completed the protocol and were subdivided in: Group 1 (n= 34) that were in remission for 3 years after discontinuation of the MMI and Group 2 (n= 49) that presented recurrence of GD between 2 and 36 months without MMI. Predictive factors associated with remission were: decrease of the glandular volume, serum TG< 40 ng/mL and normal TRAb values. We concluded that in spite of a careful protocol planned to increase compliance, more than 60% of patients with GD did not complete the therapeutic trial and were referred for radioiodine treatment. The solution for this low therapeutic success for GD should be the possible identification of factors that would indicate patients that are not inclined to follow a long period of clinical therapy.     

Graves病甲状腺功能亢进症性肝损害的相关因素分析

目的 探讨影响Graves病甲状腺功能亢进症(甲亢)性肝功能损害的相关因素.方法 回顾性分析天津医科大学总医院2013年1月至2015年12月收治的Graves病住院患者254例,根据肝功能将患者分为Graves病甲亢性肝损害组(A组,n=159)和甲亢肝功能正常组(B组,n=95),比较两组的基础代谢率(BMR)、甲状腺重量、FT3、FT4、促甲状腺激素(TSH)、TSH受体抗体(TRAb)、甲状腺球蛋白抗体(TgAb)、甲状腺过氧化物酶抗体(TPOAb).采用Pearson相关性分析甲状腺重量、BMR、FT3、FT4、TRAb与甲亢性肝损害的相关性,应用Logistic回归分析甲亢性肝损害的独立危险因素.结果 A组的甲状腺重量、BMR、FT3、FT4、TRAb、TPOAb均高于B组,而TSH低于B组(t或z=-4.720～-2.276,P均＜0.05).Pearson相关性分析显示,甲状腺重量、BMR、FT3、FT4、TRAb与甲亢性肝损害的发生呈正相关(r=0.157～ 0.270,P均＜0.05).Logistic回归分析显示,FT3(OR=1.052,95％ CI:1.001～1.105)、BMR(OR=1.019,9.5％ CI:1.006 ～ 1,033)是Graves病甲亢性肝损害发生的独立危险因素(P均＜0.05).结论 Graves病甲亢性肝损害与FT3、FT4、TRAb、BMR、甲状腺重量有关.其中FT3、BMR为甲亢性肝损害发生的独立危险因素.     

血清游离三碘甲状腺原氨酸游离甲状腺素及两者比值在甲状腺毒症病因鉴别诊断中的价值

目的 探讨游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)及FT3/FT4值在甲状腺毒症病因鉴别诊断中的价值,为甲状腺毒症病因鉴别提供一项简单实用的临床参考指标.方法 回顾性分析2017年10月至2019年11月在中南大学湘雅医院新诊断的326例甲状腺毒症患者的临床资料,根据病因分为Graves病组(203例)和...     

Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease

CONTEXT: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat hyperthyroidism caused by Graves' disease (GD), there is still no clear conclusion about the choice of drug or appropriate initial doses. OBJECTIVE: The aim of the study was to compare the MMI 30 mg/d treatment with the PTU 300 mg/d and MMI 15 mg/d treatment in terms of efficacy and adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Patients newly diagnosed with GD were randomly assigned to one of the three treatment regimens in a prospective study at four Japanese hospitals. MAIN OUTCOME MEASURES: Percentages of patients with normal serum free T(4) (FT4) or free T(3) (FT3) and frequency of adverse effects were measured at 4, 8, and 12 wk. RESULTS: MMI 30 mg/d normalized FT4 in more patients than PTU 300 mg/d and MMI 15 mg/d for the whole group (240 patients) at 12 wk (96.5 vs. 78.3%; P = 0.001; and 86.2%, P = 0.023, respectively). When patients were divided into two groups by initial FT4, in the group of the patients with severe hyperthyroidism (FT4, 7 ng/dl or more, 64 patients) MMI 30 mg/d normalized FT4 more effectively than PTU 300 mg/d at 8 and 12 wk and MMI 15 mg/d at 8 wk, respectively (P < 0.05). No remarkable difference between the treatments was observed in patients with initial FT4 less than 7 ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with PTU and significantly lower with MMI 15 mg/d compared with MMI 30 mg/d. CONCLUSIONS: MMI 15 mg/d is suitable for mild and moderate GD, whereas MMI 30 mg/d is advisable for severe cases. PTU is not recommended for initial use.     

Thyroid function in breast-fed infants whose mothers take high doses of methimazole

Recently, a few studies have shown the safety of methimazole (MMI) therapy of thyrotoxic lactating mothers on thyroid function of their infants. However, it is not known whether the effect of moderately high doses of MMI therapy on lactating mothers can be dangerous for breast-fed infants. Eighty-eight thyrotoxic lactating mothers and their infants were studied. 46 received 20 mg MMI and 42 were given 30 mg MMI during the first month, 10 mg for the second and 5-10 mg for additional 10 months of therapy. Serum T4, T3 and TSH concentrations and in hyperthyroid MMI treated mothers and their RT3U were measured in hyperthyroid MMI treated mothers and their infants, before and at 1, 2, 6, and 12 months after initiation of therapy. Serum MMI was measured in the infants of thyrotoxic mothers taking 20-30 mg MMI. Mean+/-SD of free T4 index (FT4I) in thyrotoxic mothers treated with 20 and 30 mg MMI for one month decreased from 20.1+/-4.2 to 9.7+/-1.5 (p<0.001) and from 20.6+/-4.8 to 8.6+/-3.0 (p<0.001), respectively. Values for free T3 index (FT3I) decreased from 587+/-53 to 180+/-39 (p<0.001) and from 610+/-49 to 151+/-31 (p<0.001) in those treated with 20 and 30 mg MMI, respectively. By the end of one month 5 had elevated FT4I or FT3I or both and 12 had elevated TSH. The dose of MMI was adjusted and thyroid function remained normal up to 12 months of MMI therapy in thyrotoxic lactating mothers. Serum T4, T3 and TSH concentrations of breast-fed infants were normal before and up to 12 months of MMI therapy of their breast-feeding mothers. The lowest T4 and T3 and the highest TSH values were 101 nmol/l, 1.8 nmol/l and 4.1 mU/l, respectively. Serum MMI levels were <0.03 in 7 and 0.03, 0.034 and 0.035 microg/ml in the other 3 infants. We conclude that the treatment of hyperthyroid lactating mothers with doses of 20-30 mg MMI day does not cause deleterious effects on thyroid function of their breast-fed infants.     

Practical treatment with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease

Although many researchers have reported clinical and laboratory parameters for prediction of remission in Graves' disease during or after anti-thyroid drug therapy, there is no reliable one to assure the complete remission. We prospectively examined a practical therapy with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease. Fifty-seven patients with Graves' disease were treated with anti-thyroid drugs at the initial dose of 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU). Then, doses were gradually decreased, and finally discontinued when the patients were able to maintain euthyroid (normal FT4 and TSH) for at least 6 months with the minimum maintenance dose (MMI 5 mg every other day or PTU 50 mg every other day). After discontinuation of drugs, FT4, FT3, TSH and TSH-binding inhibitory immunoglobulin (TBII) were measured every one to two months for the first 6 months and every 3-4 months for the next 18 months to confirm continuous remission. After 2 years of drug cessation, 46 (81%) of 57 patients were in remission and the other 11 patients had relapsed into thyrotoxicosis. At the time of drug discontinuation, the serum concentration of FT4, FT3 and TSH, titers of anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies, goiter size were not different between the remission and relapse groups. At the time of drug cessation, the activities of TBII and thyroid-stimulating antibodies (TSAb) overlapped between the two groups, although they were significantly lower in the remission group than in the relapse group (p<0.01). Forty percent (4/10) of TBII positive patients and 71% (23/32) of TSAb positive patients continued to be in remission. On the other hand, thyrotoxicosis relapsed in 5 (11%) of 47 TBII negative and 2 (8%) of 25 TSAb negative patients. These data indicate that minimum maintenance therapy to keep euthyroid (normal FT4 and TSH) for 6 months is a practical measure for 81% prediction of remission in Graves' disease. The measurement of TBII or TSAb gave little additional information for predicting remission.     

Thyroid function and intellectual development of infants nursed by mothers taking methimazole

For many years, breast-feeding was forbidden if antithyroid drugs were being used. Recently, limited studies have shown the relative safety of propylthiouracil and methimazole (MMI). It is not known whether MMI therapy of lactating mothers for 1 yr is safe for breast-fed infants and does not cause alterations in thyroid function and intellectual development. Between 1988 and 1998, 139 thyrotoxic lactating mothers and their infants were studied. Fifty-one thyrotoxic lactating mothers were treated with MMI during pregnancy, and MMI was continued during breast-feeding. Eighty-eight mothers were given 10 mg MMI (n 46) or 20 mg MMI (n = 42) daily for 1 month, 10 mg daily for the second month, and 5-10 mg daily thereafter. Serum T4, T3, and TSH concentrations were measured in thyrotoxic lactating mothers and their infants, before and at 1, 2, 4, 8, and 12 months. Serum MMI was measured in the infants of thyrotoxic lactating mothers taking 20 mg MMI. Thyroid function, urinary iodine, thyroid antibodies, intelligence quotient (IQ), verbal and functional components (Wechsler and Goodenough tests) were performed on 14 children of thyrotoxic lactating mothers between 48 and 74 months of age and on 17 controls. Mean +/- SD of FT4I in thyrotoxic lactating mothers treated with 10 mg MMI for 1 month decreased from 19.4 +/- 4.1 to 11.6 +/- 4.4 and from 20.5 +/- 4.7 to 9.8 +/- 1.5 when treated with 20 mg MMI. Values for FT3I decreased from 462 +/- 52 to 194 +/- 52 with 10 mg MMI and from 481 +/- 92 to 171 +/- 38 with 20 mg MMI. FT4I and FT3I were normal from the third to the twelfth months. In all infants FT4I, FT3I, and TSH concentrations were normal before and up to 12 months of MMI therapy in their lactating mothers. The lowest T4 and T3 values were 108 and 1.87 nmol/L, and the highest TSH value was 4.0 mU/L. Serum MMI levels in infants were less than 0.03 microg/mL. Six mothers receiving 20 mg MMI had increased serum TSH concentrations ranging from 26-135 mU/L after 1 month of treatment. Their infants were euthyroid with serum TSH values less than 2.6 mU/L. At 48-74 months of age, height, weight, FT4I, FT3I, TSH, and antithyroid antibody titers were not different than controls. The mean IQ was 107 +/- 14 vs. 106 +/- 16 (Goodenough test) and 103 +/- 10 vs. 103 +/- 16 (Wechsler test) for infants of thyrotoxic lactating mothers and control infants, respectively. Similarly, there was no difference in verbal and performance IQ and their components between infants of thyrotoxic lactating mothers and control children. No deleterious effects occur in thyroid function and physical and intellectual development of breast-fed infants whose lactating mothers were treated with doses of MMI up to 20 mg daily.