The effects of long-term antithyroid drug treatment on serum reverse T3 in patients with Graves' disease

The effects of long-term treatment with antithyroid drugs, carbimazole (CMI) or propylthiouracil (PTU), on serum reverse triiodothyronine (rT3) levels were studied in 23 patients with Graves' disease. Nineteen patients were given CMI and four PTU for a minimum of six months. After one month of treatment the serum levels of thyroxine (T4), triiodothyronine (T3) and rT3 had normalized in both groups. When L-thyroxine was added to the regimens after two months of therapy, both serum T4 and rT3 levels increased, whereas serum T3 level continued to fall. The serum levels of rT3 seemed to be dependent on and followed the T4 levels so closely that determinations of rT3 in the medical management of patients with Graves' disease will be of little clinical use.     

甲状腺球蛋白基因外显子33单核苷酸多态性与Graves病停药后复发的相关性分析

目的:探究甲状腺球蛋白基因外显子33单核苷酸多态性(E33SNP)与Graves病(GD)复发的相关性,为临床预测GD抗甲状腺药物(ATD)治疗后的复发提供合理性依据。方法:选取健康对照者232例以及GD治疗后停药的患者243例,且根据GD停药患者的复发情况将观察组分为A、B、C 3个亚组:77例治疗后1年内复发者为A组,86例治疗后1~2年内复发者为B组,80例治疗后2年内未复发者为C组。利用RT-PCR检测对照组和观察组的E33SNP进行分型,对比分析对照组和观察组不同基因型的比率及观察组不同甲状腺球蛋白基因型患者的游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺激素(TSH)和促甲状腺激素受体抗体(TRAb)水平,以及眼征、甲状腺肿大程度等临床资料,且对观察组不同基因型患者在治疗后2年内的累积有效率进行对比分析。结果:观察组与对照组E33SNP的基因型差异无统计学显著性,但观察组各个亚组间E33SNP基因型差异具有统计学显著性(P0.05)。对观察组的A、B、C 3个亚组间不同基因型患者各项甲状腺功能相关指标进行对比分析表明,不同基因型患者的TSH、FT3、FT4水平及甲状腺肿大程度的差异无统计学显著性,而TRAb水平和眼征发生率的差异具有统计学显著性(P0.05)。此外,E33SNP T/T型GD患者ATD治疗后2年内的累积有效率为61.8%,E33SNP T/C型患者为42.6%,E33SNP C/C型患者为21.3%,差异具有统计学显著性(P0.05)。结论:E33SNP C/C型GD患者停药后的TRAb水平以及眼征发生率明显偏高,在ATD治疗后更加容易复发,E33SNP T/T型患者则呈现相反的趋势,复发率明显偏低,因此E33SNP C/C型GD患者采用其它治疗方式或者联合治疗方式可能更加合理。     

Remission of Graves' disease with hyperthyroidism by a combination of glucocorticoids and antithyroid drugs

The possibility of inducing long-term or permanent remission of Graves disease with hyperthyroidism from combination therapy with glucocorticoids and antithyroid drugs is considered. A case report is presented in support of this hypothesis.     

Anomalies of cellular immunity in Graves' disease treated by synthetic antithyroid drugs: effects on prognosis

The involvement of humoral immunity mechanism in etiology of Graves' disease was observed for the first time in 1956. Twenty years later cellular auto-immune dysfunction was also described. To day, there is evidence for suppressor T cell deficiency and decrease in T suppressor lymphocytes in Graves' disease and cell mediated immunity might be one of the most important point in the pathogenesis of Graves disease. For the future, cellular auto-immune dysfunction might be used to predict the evolution of the disease and to choice the best therapeutic scheme.     

Relapses after thionamide therapy for Graves' disease

Between 1969 and 1979 a course of either propylthiouracil or carbimazole was given to 102 patients with Graves' disease. Ten of the patients discontinued the therapy because of adverse reactions or persisting symptoms, and 40 relapsed at some time after cessation of the therapy, giving a proportion of total failures of 49%. The proportion of such failures increased from 45% in 1969-72 to 57% in 1973-79. The probability of relapse was significantly higher in 1973-79 than in the earlier period (p less than 0.01). Patients aged 30-39 years had the highest proportion of failures (55%), but the mean time until relapse (6 months) was shortest in patients older than that. Adverse reactions--agranulocytosis, leukopenia, urticaria and elevated serum levels of liver enzymes--were seen in 12 patients. Six patients developed hypothyroidism after a mean time of 3.5 years after termination of thionamide therapy.     

Activated T cells in Graves' disease before treatment

The aim of this study was the definition of abnormalities occurring within T-cell subsets of thyrotoxic Graves' patients before treatment. Special emphasis was placed on the enumeration of activated T cells using a number of new monoclonal antibodies. Lymphocytes from 22 Graves' disease patients were examined. The total number, the percentage of 'helper/inducer' and 'suppressor/cytotoxic' positive cells were evaluated using the antibodies T3, T4 and UCHT4, whereas the cells with killer activity were defined by H25. Activated T cells were detected using the antibodies DA6.231, DA6.164, and L243 which bind different epitopes of the beta chains of class II surface antigens and 4F2, which binds a 120,000 molecular weight glycoprotein. The results show no significant change in the total T, helper or suppressor cell phenotype, but an increase in the killer cell percentage was noted. Of those patients tested, 19 of 22 showed an increase in activated T cells, 18 of 22 patients showed a significant increase of T cells bearing class II antigens, 11 of 22 showed an increase of T cells staining with another activated T cell antibody, 4F2. The anti-DR antibodies expressed different binding characteristics, the most striking difference being seen between the antibodies DA6.231 and L243. The results of this study suggest an heterogeneity of the immune response, or differences in activation stage in patients with Graves' disease before therapeutic intervention. An important role for these cells in the pathogenesis of this disorder can be inferred.     

Graves' disease. Clinical features and treatment results

In the last years the diagnosis of Grave's disease has become easier and accelerated due to new laboratory and instrumental tests. The therapeutic possibilities improved also by using antithyroidal drugs, surgery and radioiodine application subsequently. In a retrospective study 278 outpatients with Graves disease, treated and controlled by our centre for thyroid diseases in 1992-1999, were investigated to evaluate the initial and leading subjective symptoms which led the patients to seek medical help ("guide symptoms"). These obtained guide symptoms were compared with the objective "clinical signs" observed at the beginning of the disease. Weight loss turned out to be the most frequent (26%) guide symptom, whereas tachycardia (> 90 beats/min) and moist skin were the most frequently observed clinical signs (71 and 61% respectively). The beginning of therapy, dosage of drugs, length of application and results of treatment are critically evaluated, with special emphasis on the rate and time of remission, on the frequency of recurrences and on the success of additional treatments such as surgery and/or radioiodine application. Pharmacological treatment alone induced a persistent remission (at least 6 months of euthyroidism) in 156 patients (in 113 after the first and in 43 after the 2nd drug trial). Surgery was successful in 46, radioiodine application in 40 patients. The sequential use of drug therapy, surgery and radioiodine as it is performed in our institution leads to a permanent remission in 242 of 278 (= 87%) patients.     

Long-term ECG recordings in hyperthyroid patients before and after antithyroid treatment

Heart rate and heart rhythm were studied in 19 hyperthyroid patients before and after antithyroid treatment inducing a euthyroid state. The mean 24-hour heart rate in patients with sinus rhythm and without drugs influencing heart rate was 100 beats/min before and 80 after antithyroid treatment. The difference was greatest in the sleeping hours. The heart rate, especially in the sleeping hours, correlated significantly with serum triiodothyronine but not with serum thyroxine concentrations.     

The behaviour of suppressor-inducer T cells following treatment for Graves' disease

The expression of surface markers of T cell subsets in the peripheral blood of 30 Graves' disease patients was investigated pre and post therapy using two colour flow cytometry. Reduced numbers of total, helper/inducer and suppressor/cytotoxic T cells were found in untreated Graves' patients. Numbers of suppressor-inducer T cells which are associated with maintaining the normal immune response, did not differ significantly between untreated Graves' patients and controls. Although 8 weeks' Carbimazole therapy reversed the changes in total, helper/inducer and suppressor/cytotoxic T cells, PTU or 131I therapy did not. While suppressor-inducer T cell numbers were not affected by Carbimazole or PTU therapy, 131I treatment caused a decrease in suppressor-inducer T cell numbers.     

Color Doppler imaging of the superior ophthalmic vein in patients with Graves' orbitopathy before and after treatment of congestive disease

OBJECTIVE:

To compare superior ophthalmic vein blood flow parameters measured with color Doppler imaging in patients with congestive Graves'' orbitopathy before and after treatment and in normal controls.

METHODS:

Twenty-two orbits from 12 patients with Graves'' orbitopathy in the congestive stage and 32 orbits from 16 normal controls underwent color Doppler imaging studies. Color Doppler imaging was repeated after treatment in the group of patients with Graves'' orbitopathy, which included orbital decompression in 16 orbits and corticosteroids in six orbits. The findings for each group were compared.

RESULTS:

In the group of orbits with congestive disease, superior ophthalmic vein flow was detected in 17 orbits (anteroposteriorally in 13 and in the opposite direction in four) and was undetectable in five. After treatment, superior ophthalmic vein flow was detected and anteroposterior in 21 and undetected in one orbit. In normals, superior ophthalmic vein flow was detected anteroposterior in 29 orbits and undetectable in three orbits, indicating a significant difference between groups. There was also a significant difference between controls and congestive Graves'' orbits and between congestive orbits before and after treatment, but not between controls and patients after treatment. A comparison of superior ophthalmic vein flow parameters revealed a significant difference between the groups. The superior ophthalmic vein flow was significantly reduced in the congestive stage compared with the flow parameters following treatment and in the untreated controls.

CONCLUSIONS:

Superior ophthalmic vein flow was significantly reduced in the orbits affected with congestive Graves'' orbitopathy and returned to normal following treatment. Congestion appears to be a contributing pathogenic factor in the active inflammatory stage of Graves'' orbitopathy.     

Diagnosis and classification of Graves' disease

Graves' disease (GD) is an autoimmune disorder involving the thyroid gland, typically characterized by the presence of circulating autoantibodies that bind to and stimulate the thyroid hormone receptor (TSHR), resulting in hyperthyroidism and goiter. Organs other than the thyroid can also be affected, leading to the extrathyroidal manifestations of GD, namely Graves' ophthalmopathy, which is observed in ~ 50% of patients, and Graves' dermopathy and acropachy, which are quite rare. Presumably, the extrathyroidal manifestations of GD are due to autoimmunity against antigens common to the thyroid and other affected organs. Although its exact etiology remains to be completely understood, GD is believed to result from a complex interaction between genetic susceptibility and environmental factors. Clinically, GD is characterized by the manifestations of thyrotoxicosis as well as by its extrathyroidal features when present, the latter making the diagnosis almost unmistakable. In the absence of ophthalmopathy, the diagnosis is generally based on the association of hyperthyroidism and usually diffuse goiter confirmed with serum anti-TSHR autoantibodies (TRAbs). Hyperthyroidism is generally treated with anti-thyroid drugs, but a common long term treatment strategy in patients relapsing after a course of anti-thyroid drugs (60-70%), implies the use of radioactive iodine or surgery.     

Short-term antithyroid drug therapy for the thyrotoxicosis of Graves's disease.

We investigated whether thyrotoxic patients treated with short-term antithyroid therapy would achieve prolonged remissions. Thirty-one previously untreated and nine previously treated patients with thyrotoxic Graves's disease received a single daily dose of methimazole or propylthiouracil. The drug was stopped at, or shortly after, the time they became euthyroid. Twelve of the 31 previously untreated patients remained in remission for 29 +/- 3.5 months (mean +/- S.E.) after treatment for 4.5 +/- 0.3 months. Four of the nine previously treated have remained in remission of 13.0 +/- 2.1 months after treatment for 3.0 +/- 0.3 months. Of various possibilities analyzed, only a small goiter at the onset of therapy and tri-iodothyronine toxicosis were significantly favorable prognostic indicators that a remission would be maintained. The lasting remission rate is as good when antithyroid drugs are stopped as soon as the patient is euthyroid as when they are continued for one year or more.