Serum thyroglobulin changes in patients with Graves' disease treated with long term antithyroid drug therapy

In 29 patients with thyrotoxic Graves' disease treated with conventional long term antithyroid drug therapy, serum thyroglobulin (Tg) was serially determined by RIA and compared with clinical course, goiter shrinkage, and 131I uptake suppression. Those subjects with Tg autoantibody-negative sera comprised 46% of the patients with Graves' disease. They were divided into a remission group (G I) and an exacerbation group (G II). G I was subdivided into G Ia, who were in remission for 7-40 months, and G Ib, who relapsed more than 15 months after therapy. G II was still on therapy 27-62 months after its initiation, because these subjects exacerbated on reduction of the drugs. Goiter shrinkage occurred in 60% and 0%, and 131I uptakes were suppressed by T3 in 50% and 0% in G I and G II, respectively. Serum Tg in G I declined progressively and reached 48 +/- 5 (+/-SE) ng/ml on discontinuation of therapy, in sharp contrast with serum Tg in G II which remained high throughout (154 +/- 29 ng/ml at the last examination; P less than 0.001). Results of goiter shrinkage, 131I uptake suppressibility, and serum Tg levels were similar in G Ia and G Ib on cessation of therapy. Serum Tg levels less than 68 or more than 140 ng/ml on discontinuation of therapy were helpful in predicting the outcome of therapy. On the other hand, Tg levels were low and goiters were small in size in euthyroid Graves' disease. Tg levels were not clearly correlated with goiter weight or serum T4 and T3 levels before treatment. In conclusion, serial determinations of serum Tg reflect thyroid activity and provide information useful in the decision to discontinue therapy and observation after that.     

Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves' disease

OBJECTIVE: To investigate the effect of different antithyroid drug (ATD) regimens on relapse rates of Graves' disease, and to look for predictors of relapse. DESIGN AND METHODS: In a prospective two-way factorial randomized clinical trial, 218 patients with Graves' disease were assigned to ATD combined with l-thyroxine (l-T(4)) or ATD alone for 12 Months. After discontinuation of antithyroid therapy, each group was stratified to either 12 Months further treatment with l-T(4) or no treatment. Clinical and biochemical assessments were carried out before treatment, after 3 and 6 weeks, and every third Month for 12 Months. If the patients lacked symptoms of relapse, laboratory tests were performed every third Month for the second Year, and thereafter annually. RESULTS: The proportion of all patients with relapse was 47.7% 2 Years after withdrawal of ATD. There was no difference in relapse rates between the treatment groups (P=0.217, log--rank test). Smokers had a higher relapse rate than non-smokers (58.4% vs 38.8%, P=0.009). Patients who were thyrotropin-receptor antibody (TRAb) positive after 12 Months of antithyroid therapy had a higher relapse rate than those who were negative (72.5% vs 36.8%, P<0.0001). Similarly, relapse was more frequent (55.5%) in patients having large goiter compared with subjects with small goiter (36.3%, P=0.0007). CONCLUSIONS: Relapse rates of Graves' disease were independent of ATD regimen whether followed by l-T(4) therapy or not. Smoking, large goiter and presence of TRAb at the end of ATD therapy were strong predictors of relapse.     

Clinical significance of assay of thyroid-stimulating antibody in Graves' disease

We correlated thyroid-stimulating antibody (direct thyroid stimulation method) with the clinical course of 187 patients with Graves' disease. Of 64 patients with newly diagnosed hyperthyroidism, 59 were positive; 36 of 38 patients tested early in therapy were positive. Twenty-eight patients received antithyroid drug therapy, and thyroid-stimulating antibody was measured at cessation of therapy; 13 patients, negative in the assay, remained in remission, and of 15 relapsed cases 12 were positive. Of 57 patients previously treated by various means for hyperthyroidism, 34 were positive, and they primarily had had relapse after initial treatment, then ablative therapy causing hypothyroidism. Six of 10 patients with euthyroid ophthalmopathy had a positive assay and an abnormal thyrotropin-releasing hormone (TRH) test or thyroid suppression test; the four negative patients had a normal TRH test. Thus measurement of thyroid-stimulating antibody appears effectively to reflect activity of the underlying disturbance in Graves' disease.     

Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease

In Hashimoto's thyroiditis, Fas-induced apoptosis is one of the mechanisms leading to cell destruction, whereas thyroid tissue in Graves' disease is prevented from it. The soluble form of the Fas molecule produced by alternative splicing prevents from apoptosis. We measured soluble Fas in the sera of 112 patients with Graves' disease, 21 patients with toxic goiter, and 24 patients with subclinical hyperthyroidism due to suppressive therapy with levothyroxine after near-total resection of the thyroid gland for nodular goiter. Soluble Fas was increased in thyrotoxic patients, toxic goiter, and patients with subclinical hyperthyroidism. Decreased levels of soluble Fas were found in euthyroid patients with Graves' disease after surgery, whereas soluble Fas was normal in euthyroid patients with Graves' disease receiving antithyroid drug treatment and in patients in stable remission. There was a good correlation between soluble Fas with free T(3) (r = 0.6) and free T(4) (r = 0.5). Our results show that soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.     

Differences between changes in serum thyrotropin-binding inhibitory antibodies and thyroid-stimulating antibodies in the course of antithyroid drug therapy for Graves' disease.

There has recently been controversy regarding whether the measurement of thyrotropin-binding inhibitory antibodies (TBIAb) is useful in the management of Graves' disease. Another method of assessing Graves' disease by measuring adenylate cyclase activity in thyroid cells, known as thyroid-stimulating antibodies (TSAb), differs from TBIAb not only in terms of assay but also in immunoglobulin type according to recent studies. In this study, the concentrations of TBIAb and TSAb were compared in serial serum samples collected from 29 patients with Graves' hyperthyroidism during 12 months of antithyroid drug therapy. Before therapy, there was a correlation between TBIAb and TSAb (r = 0.59). The radioactive iodine uptake (RAIU) was not significantly correlated with either TBIAb or TSAb (r = 0.20 and r = 0.29, respectively), and the serum free thyroxine (FT4) concentration was also not significantly correlated with either TBIAb or TSAb (r = 0.06 and r = 0.22, respectively). In patients with Graves' ophthalmopathy, TSAb levels were higher than in patients without ophthalmopathy (1015%+/-851% vs. 456%+/-323%, p<0.01), but the TBIAb levels were not significantly different. After antithyroid treatment, TBIAb did not decrease significantly (from 42.1%+/-20.8% to 20.5%+/-19.5%, p = 0.29). On the other hand, TSAb was significantly decreased after 12 months of treatment (from 649%+/-611% to 294%+/-205%, p< 0.05). These findings indicate that TBIAb and TSAb are not identical, and that TSAb has a closer relationship to thyroid function than TBIAb. In the clinical setting, determination of the serum TSAb level may provide a more accurate index of the thyroid status in Graves' disease patients receiving antithyroid therapy.     

Toxic multinodular goiter: a variant of autoimmune hyperthyroidism

The aim of this study was to examine whether at least a subgroup of patients with toxic multinodular goiter may have autoimmune thyroid disease. Thyroid-stimulating immunoglobulin (TSI) activity, measured by a sensitive bioassay employing cultured human thyroid cells, was determined in patients with toxic multinodular goiter and other thyroid disorders. All patients with active Graves' disease (n = 47) had detectable serum TSI activity, whereas TSI was undetectable in patients with thyroid disease not believed to be of autoimmune origin: toxic adenoma (n = 13), cold nodule (n = 5), and nontoxic goiter (n = 19), with a single exception in the latter group. Toxic multinodular goiter (n = 26) was diagnosed based on clinical and laboratory evidence of hyperthyroidism associated with a multinodular goiter on palpation and scintiscan. The toxic multinodular goiter group was then subclassified according to scintiscan pattern (type A, diffuse but uneven distribution of technetium uptake; type B, multiple discrete nodules of varying size and function). All but 1 of the 11 TSI-positive toxic multinodular goiter patients had a type A scintiscan pattern. The patients with the type A scintiscan pattern were younger and more often had elevated antithyroid antibody titers, ophthalmopathy, and concurrent development of goiter and hyperthyroidism (rather than long-standing goiter preceding hyperthyroidism) compared to the type B patients. Thus, a subgroup of patients with clinically defined toxic multinodular goiter (type A) probably have autoimmune hyperthyroidism (a variant of Graves' disease), while in another subgroup (type B) hyperthyroidism is not related to an autoimmune etiology (a variant of toxic adenoma).     

Evaluation of the medical treatment of Graves' disease (GD)

The treatment of Graves' disease (GD) with antithyroid drugs (ATD) leads to remission of the disease in approximately half of patients treated for at least six months, and the overall relapse rate is high, ranging from 60% to 80%. The presence of prognostic features for achieving a remission after medical treatment is a matter of discussion in the literature. The aim of this study is to evaluate the effect of different ATD regimens available in Brazil (propylthiouracil--PTU and methimazole--MMI) on remission and relapse rates of GD, as well as to determine possible predictors of remission and relapse of the disease and the side effects profile. We reviewed the records from all patients submitted to medical treatment of GD (and with no report of prior treatment of the disease) for at least six months and followed for at least 12 months after the drug withdrawal at Hospital Universitário Clementino Fraga Filho (HUCFF), between October 1978 and August 2003. We identified 127 patients, with the age ranging from 18 to 88 years (mean 39.3 +/- 12.8). Remission was observed in 58 patients (45.7%) and relapse occurred in 31 (53.4%), at a mean period of 14.5 +/- 16.1 months. We verified that the duration of symptoms before the beginning of medical treatment, age and gender did not influence the rate of remission and the relapse risk, whereas the presence of large goiter size (> 40 grams), Graves' ophthalmopathy and use of high daily doses of ATD (> or = 600 mg of propylthiouracil/60 mg of methimazole MMI) were associated with a decreased remission rate. Moreover, patients who presented a TSH measurement < 0.4 microIU/mL between 4 to 5 weeks after the drug withdrawal showed an increased relapse cumulative probability. In conclusion, our results confirms that lasting remission rate of GD treated with ATD is relatively low. We concluded that the combination of goiter size > 40 g, ophthalmopathy, and use of daily doses of PTU > or = 600 mg or MMI > or = 60 mg was vigorously related to lack of remission of GD. Furthermore, TSH measurement between 4 to 5 weeks after the drug withdrawal seems to be a useful tool to determine the remission chance and the relapse risk of the disease.     

Relationship between thyroid status and Graves' disease-specific immunoglobulins.

The prevalence of TSI in Graves' disease was investigated with a radioligand receptor assay using human thyroid membranes and highly purified labeled porcine TSH or bovine TSH in 110 patients before treatment and in 39 patients after successful treatment with antithyroid drugs. In 11 patients, the assay was performed before, during, and after therapy. The results in the radioligand receptor assay were compared to thyroid function tests (TRH test, free T4 index, serum %3 level, and thyroid suppression test). Normal IgG inhibits nonspecifically, but dose dependently, the binding of [125I]TSH to thyroid membranes. IgG samples from patients were only considered to be positive if they reduced the binding of the labeled hormone below the mean value minus 2 SD of the controls. TSI activity was found in 50% of the patients with untreated diffuse toxic goiter, in 3 out of 27 cases who regained suppressible thyroid function, and in 5 out of 12 cases who were off therapy for more than 6 weeks and showed normal TRH tests and normal hormone levels but in whom the suppression test was not performed. Our data cannot prove the hypothesis that only humoral antibodies are responsible for the thyroid stimulation in Graves' disease, but of course they cannot exclude it; furthermore, they suggest the existence of antibodies which bind to the human thyroid cell membrane without necessarily stimulating thyroid cellular activity.     

Antithyroid drug and Graves' hyperthyroidism. Significance of treatment duration and TRAb determination on lasting remission.

OBJECTIVE: To investigate the significance of treatment with antithyroid drugs longer than 12 months on lasting remission in Graves' hyperthyroid patients, and to study clinical and laboratory parameters of prognostic value. PATIENTS: Fifty-two untreated Graves' hyperthyroid patients were assigned at random to two therapeutic groups. They were treated with carbimazole during 12 and 24 months in Group I (n = 28) and Group II (n = 24), respectively. MEASUREMENTS: Serum levels of FT4, T3, sTSH and TSH receptor antibody (TRAb) were measured before starting treatment and at regular intervals during treatment and follow-up after drug withdrawal. We compared the relapse rate in both groups of patients, at short (2-yr) and long-term (5-yr) periods after drug withdrawal. Also, we compared clinical and biochemical parameters between patients who stayed in remission and who had relapse. RESULTS: At the end of the short-term period, relapse had occurred in 13 (46.4%) Group I patients and in 13 (54.1%) Group II patients, p = 0.36. At the end of the long-term period, relapse had occurred in 24 (85.7%) Group I and 20 (83.3%) Group II patients, p = 0.78. No difference could be observed between patients who had stayed in remission and who had suffered relapse, within the 5-yr follow-up period regarding to goiter size, frequency of ophthalmopathy, TSH and TRAb levels. CONCLUSIONS: The high relapse rate observed could be due to high iodine intake in our country. In this study and in a review of the available data, we have been unable to find any rational basis for courses of antithyroid drugs longer than twelve months for the treatment of Graves' hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prediction of relapse after antithyroid drug therapy of Graves' disease: value of color Doppler sonography.

Opinions differ regarding the indications for antithyroid drugs, radioiodine and surgery in patients with Graves' disease because the likelihood of long-term remission after medical treatment cannot be predicted. The aim of this study was to assess the value of quantifying thyroid blood flow in an attempt to predict outcome following withdrawal of antithyroid drug therapy. Spectral Doppler recordings were obtained from the thyroid arteries in 24 patients with Graves' disease at the time of diagnosis. Thyroid blood flow levels measured at the time of diagnosis of Graves' disease were correlated with outcome following withdrawal of medical treatment (mean duration of treatment: 14 months). Clinical follow-up for at least 18 months (range: 18 - 39 months) after antithyroid drug withdrawal was possible in 13 patients (12 women). Mean peak systolic velocity and volume flow rate values as well as thyroid volume measured at the time of diagnosis were significantly higher (139 cm/s, SD 46; 195 ml/min, SD 170; 52 ml, SD 18) in patients who relapsed after drug treatment compared with patients in remission (71 cm/s, SD 27; 67 ml/min, SD 61; 25 ml, SD 13). The correlation between thyroid blood flow measurements and thyroid volume was high (r = 0.79 - 0.96). Recurrence of disease could be predicted with a sensitivity of 71 % and a specificity of 100 % based on thyroid blood flow measurements. This preliminary data suggest that quantification of thyroid blood flow by means of Doppler sonography might be a useful tool to predict the outcome of Graves' disease following withdrawal of medical treatment and could be helpful in finding the adequate kind of therapy.     

Recurrence of hyperthyroidism in multinodular goiter after long-term drug therapy: a comparison with Graves' disease.

The chance of permanent remission after prolonged drug therapy was investigated in 41 patients with toxic multinodular goiter. For purposes of comparison a group of 41 patients with Graves' disease was also studied. After euthyroidism was achieved all patients received a combination of thionamide and thyroxine for at least 12 months. The minimum follow-up period was 2 yr. Relapse of thyrotoxicosis occurred in 95.1% of patients with toxic multinodular goiter and 34.1% of patients with Graves' disease (p < 0.001). It is concluded that for patients with toxic multinodular goiter early radioiodine therapy or surgery is preferred since prolonged drug therapy seldom produces permanent remission.     

Hyperthyroidism due to Graves' disease and due to autonomous goiter

An attempt was made to classify 326 patients with hyperthyroidism due to Graves' disease and due to autonomous goiter in an area of endemic iodine deficient goiter using the following two sets of criteria: Primary criteria: the presence of endocrine ophthalmopathy (Graves' disease) and the absence of endocrine ophthalmopathy and the absence of microsomal antibodies greater than or equal to 1:1600 (autonomous goiter). Sixty-nine percent of the patients could be divided in the two groups with the aid of these criteria. Secondary criteria: age greater than 50 years, presence of a goiter, presence of thyroid nodules, activity distribution in the scan, iodine intake determined by iodine excretion in the urine. These criteria had to be applied in the 31% of the patients who could not be divided into one of the two groups using the primary criteria. The secondary criteria were accumulative. Using these criteria 55% of the 326 patients were classified as having Graves' disease and 45% as having autonomous goiter. The probability of correct grouping when both primary and secondary criteria were applied was estimated to be 90% compared to 54% when we used only the classical terms, i.e. endocrine ophthalmopathy and diffuse goiter on the one hand and multinodular goiter without endocrine ophthalmopathy on the other hand. In a second group of 120 hyperthyroid patients classified in this way, thyrotropin displacing activity was determined independently. Its prevalence was 79% in patients classified as having Graves' disease but only 3% in those classified as having autonomous goiter. The prevalence of TDA observed in patients who presumably had autonomous goiter was in the same range as in the following groups: 45 normal individuals; 126 patients with euthyroid goiter; and in 112 patients with euthyroid and hyperthyroid autonomous adenoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in thyroid-stimulating immunoglobulins during antithyroid therapy

Thyroid-stimulating immunoglobulin (TSI) activity was measured by radioreceptor assay in sera from patients with Graves' disease, Hashimoto's thyroiditis, and thyroid cancer. In untreated Graves' disease (47 cases), TSI index was significantly lower [76.7 +/- 1.4 (SE)] than the average of a normal control group (30 cases; 94.4 +/- 1.9). In untreated Hashimoto's thyroiditis (25 cases), it was also significantly lower (83.0 +/- 2.4). In patients with thyroid cancer (19 cases), there was no significant difference from normal controls. After 131I treatment, the TSI index in Graves' disease decreased during 2--4 months, then increased and reached normal levels in 1 yr. During propylthiouracil treatment, the TSI index increased and reached a normal level in 5--6 months without the decreasing phase seen after 131I treatment. Free T4 index values were gradually decreased by both treatments. There was no significant relationship between TSI index and thyroid antibodies (microsomal antibodies and thyroglobulin antibodies) in untreated Graves' disease or Hashimoto's thyroiditis. It is concluded that 1) in the sera of patients with Graves' disease and Hashimoto's thyroiditis, there are immunoglobulin Gs that can displace TSH binding to thyroid membranes; 2) these immunoglobulins Gs are different from the classic antithyroid antibodies; and 3) 131T treatment of Graves' disease may enhance TSI production during the first 1--2 months after therapy.     

Surgical treatment of Graves' disease in children.

Thyroidectomy may be indicated in children with Graves' disease who have adverse reactions to antithyroid drugs or who relapse after antithyroid drug therapy. We investigated the characteristics of childhood Graves' disease from the standpoint of surgical outcome. Between 1989 and 1998, 1897 patients with Graves' disease underwent thyroidectomy and their thyroid function could be evaluated 2 to 3 years after thyroidectomy. The patients were divided into three groups according to age at thyroidectomy: 74 patients were 15 years old or less (children), 345 patients 16 to 20 years of age (adolescents), and 1478 patients 21 years of age or more (adults). The children included higher proportions of patients who had a large goiter (> 100 g), high thyrotropin-binding inhibitory immunoglobulin (TBII) level (> 50%), and small remnant thyroid (< 4 g). At 2 to 3 years after thyroidectomy, the overt recurrence rate of the children, adolescents, and adults was 9.5%, 4.9%, and 5%, respectively. The cumulative recurrence-free rate of the children, adolescents, and adults at 5 years after thyroidectomy was 82%, 90%, and 92%, respectively. Surgical complications were more frequently observed in children. Considering the aggressiveness of childhood Graves' disease, subtotal thyroidectomy with thyroid remnant less than 3 g is the procedure of choice for preventing recurrent hyperthyroidism.     

Graves病药物治疗停药复发相关因素分析

目的 探讨甲状腺刺激性抗体(TSAb)水平和甲状腺体积等相关因素对Graves病患者抗甲状腺药物治疗停药后复发的预测价值.方法 71例Graves病患者经抗甲状腺药物正规治疗(2.8±1.4)年后停药,随访(22±6.0)个月.对停药后复发与未复发组的年龄、性别及停药时的TSAb活性、甲状腺体积和甲状腺功能指标等进行分析比较.应用表达重组人促甲状腺激素受体的人胚肾(HEK-hTSHR)细胞测定TSAb活性.结果 71例患者随访期间有11例(15.5%)复发,治疗停药时TSAb阳性患者复发率(42.9%,6/14)显著高于阴性患者(8.8%,5/57,X2=9.97,P<0.01).停药时甲状腺正常体积、Ⅰ度肿大、Ⅱ度肿大复发比率分别为6.25%、12.2%、35.7%.复发组患者停药时TSAb活性、阳性率以及甲状腺体积均显著高于未复发组(P<0.05或P<0.01).结论 Graves病患者抗甲状腺药物治疗终止时TSAb活性和甲状腺大小是Graves病停药后复发的有效预测因子.     

A sensitive and practical assay for thyroid-stimulating antibodies using crude immunoglobulin fractions precipitated with polyethylene glycol

A simple, sensitive, and practical assay for thyroid-stimulating autoantibodies (TSAb) was developed in which cryopreserved porcine thyroid cells were incubated with crude immunoglobulin fractions sedimented from serum with polyethylene glycol. In the assay, 1.4- to 2.0-fold and 6- to 12-fold increases in cAMP released into Hank's medium without NaCl were found at 1 and 10 microU/ml bovine TSH, respectively. TSAb were detected in 41 (97.6%) of 42 patients with untreated hyperthyroid Graves' disease, 29 (55.8%) of 52 patients with hyperthyroid Graves' disease who were euthyroid while taking antithyroid drugs, 22 (78.6%) of 28 patients with euthyroid Graves' disease, and none of the patients with simple goiter, adenomatous goiter, thyroid adenoma, or thyroid cancer tested. TSAb activities measured using porcine thyroid cells significantly correlated with those measured using human thyroid adenoma cells (r = 0.908; n = 46; P less than 0.001). Thyroid-stimulating activity was also detected in 11 (28.9%) of 38 patients with Hashimoto's thyroiditis. However, the activity was considered to be due to TSH in the patients' sera, because it was completely abolished by pretreatment with anti-TSH antibodies. Serum TSH concentrations lower than 50 microU/ml did not affect the assay result. In Graves' disease after cessation of antithyroid drugs, 85.7% (12 of 14) of TSAb-positive patients relapsed, while 77.8% (14 of 18) of TSAb-negative patients remained in remission. Thus, the assessment of TSAb was useful as an index to predict prognosis.     

Similar effects of thionamide drugs and perchlorate on thyroid-stimulating immunoglobulins in Graves' disease: evidence against an immunosuppressive action of thionamide drugs

Previous studies have shown that serum titers of thyroid-specific antibodies such as thyroid-stimulating immunoglobulins (TSI), TSH-displacing antibodies (TDA), or microsomal antibodies (MAb) decrease in patients with Graves' disease during therapy with thionamide drugs (TD). In keeping with some in vitro results it was postulated that TD have an immunosuppressive action which may be partly responsible for the beneficial effects. To further elucidate this theory, we compared the changes in TSI during treatment with TD such as methimazole (MMI) and propylthiouracil (PTU) as well as with perchlorate (PC), an unrelated compound with a different mode of therapeutic action. Of 69 patients with hyperthyroidism due to Graves' disease, serum from 62 (90%) was positive for TSI, as measured by cAMP accumulation in a thyroid tissue culture assay. Six patients had to be excluded due to noncompliance. Of the remaining 56 patients, those 41 subjects (73%) with good control of the disease were followed up to 24 months during dose-adjusted antithyroid treatment. All patients with an uncomplicated course of treatment had a decline in the initially increased TSI values on either drug regimen. Five of 10 patients receiving PTU and 8 of 13 patients receiving MMI reached normal TSI levels; so did 11 of 18 patients receiving PC. There was no individual correlation between TSI decrease and drug dosages or the serum T4 and T3 levels. In all 3 groups, however, a decrease in mean T4 and T3 levels preceded the fall in TSI. By grouping the patients according to whether they had more than a 20% decrease in the initial TSI values after either 2 months or more than 4 months of treatment, it could be shown that the late responders had significantly higher T4 and T3 levels after 2 months of treatment. The similar patterns of change in TSI during treatment with TD and PC are strong evidence against an immunosuppressive effect of TD. If any direct interference occurs, a toxic effect on intrathyroidal lymphocytes by intrathyroidal drug accumulation could be the cause of the disappearance of TSI with both drug types. On the other hand, the data provide indirect evidence for the theory that the restoration of the euthyroid state is the cause of decreasing TSI levels and normalization of the immune regulation in many patients during treatment with antithyroid drugs.     

HLA-DR3 and HLA-DR5 associated thyrotoxicosis--two different types of toxic diffuse goiter

One hundred fifty patients with toxic and scintigraphically diffuse goiter were HLA typed (A, B, C, DR). One group consisted of 101 patients with concomitant Graves' ophthalmopathy and/or TSH-binding inhibiting antibodies (TBIAb). Forty nine patients had neither ophthalmopathy nor TBIAb. The former group showed a higher prevalence of HLA-B8 and DR3 compared to a normal control group. The latter group showed a higher frequency of HLA-DR5, whereas the HLA-B8 and DR3 antigens were slightly below normal prevalence. These data indicate an immunogenetic heterogeneity in patients with toxic diffuse goiter. A group of 47 hyperthyroid patients with single autonomous thyroid adenoma had no increased prevalence of any HLA-antigens. Patients with long term remission did not show an altered prevalence of any of the HLA antigens compared to controls. In contrast, patients with Graves' ophthalmopathy and/or TBIAb activity who relapsed had a significantly higher prevalence of HLA-B8 DR3, whereas patients without TBIAb and eye signs who relapsed had a significantly higher prevalence of HLA-DR5 than the control group.     

Reduction of the risk of relapse after withdrawal of medical therapy for Graves' disease.

It has been a continuing challenge to try and identify those patients with hyperthyroid Graves' disease likely to remain in remission after an antithyroid drug course or to manage the medical treatment so as to increase the chance of remission. On average, the overall relapse rate is approximately 50% and any significant reduction of this figure would be of practical as well as theoretical value. The numerous controlled prospective studies performed in many parts of the world, with varying iodine intakes, have all confirmed that the main initial features related to the subsequent risk of relapse are: young age, male gender, goiter larger than 40 mL, hypoechogenic and hypervascular gland, high level of anti-thyrotropin receptor antibody (TRAb), detected either with radioreceptor assay (TBII: >40 U/L) or the biologic stimulation assay (thyroid-stimulating antibodies [TSAb]; >300%), severity of hyperthyroidism, and possibly the presence of ophthalmopathy. Alone, each of these has a low predictive value, but together they allow evaluation of the risk of relapse, thus helping treatment choice. As to the modalities of antithyroid drug treatment, dose of the drug or addition of levothyroxine does not affect posttreatment outcome. In contrast, significantly fewer relapses occur for drug courses longer than at least 1 year. Persistence of high levels of TRAb after medical treatment is strongly predictive of relapse but this is of limited value because in most patients, TRAb levels are low or even undetectable at the end of treatment, which does not indicate for further outcome. Smoking is a significant independent risk factor for relapse. In conclusion, reduction of the risk of relapse in patients with medically treated hyperthyroid Graves' disease relies on clinical competence and appropriate management taking into account an array of factors none of which alone has definite predictive value.     

Syndrome of persisting thyroid stimulating immunoglobulins and growth promotion of goiter combined with low thyroxine and high triiodothyronine serum levels in drug treated Graves' disease

Among 48 Graves' patients treated with antithyroid drugs there were 8 patients with a further growth of an already enlarged goiter and a persistence of thyroid stimulating immunoglobulins (TSI). TSI activity did not persist in a comparison group of patients with less severe initial symptoms and an uncomplicated course during a similar regimen of drug treatment. Thyrotoxicosis was difficult to control in this subgroup of patients as low serum T4 was accompanied by borderline high T3 levels although TSH in serum remained undetectable. In spite of comparable low doses of antithyroid drugs serum T4 in the complicated group remained significantly lower (58 +/= 15 nmol/I SD vs. 97 +/- 19 nmol/I SD, p less than 0,001) and serum T3 stayed significantly higher (3,66 +/- 0,49 nmol/I SD vs. 2,15 +/- 0,50 nmol/I SD, p less than 0,001) than in the group with uncomplicated treatment. It is discussed that the promotion of goiter growth could be due to growth stimulating antibodies, and that a local intrathyroidal iodide depletion during antithyroid drug treatment might cause the shift from T4 to T3 production in this entity of Graves' patients.