Antithyroid drug therapy for Graves' hyperthyroidism: is long-term administration of a small maintenance dose necessary?

This retrospective study serves as an inquiry into the common practice of long-term administration of small maintenance doses of either methyl-mercaptoimidazole (MMI) or propylthiouracil (PTU) to Graves' hyperthyroid patients who became euthyroid with primary large doses of the same drugs. One hundred and two patients with Graves' hyperthyroidism treated with antithyroid drug (ATD) were studied. Sixty-one were treated with conventional long term therapy and 41 were treated with short-term therapy. Small maintenance doses of ATDs were not administered to the short-term therapy patients. The duration of long-term therapy was 28.6 +/- 20.2 months (from 12 to 48 months) and that of short-term therapy was 8.4 +/- 1.8 months (from 5 to 11). Post therapy and follow-up observation continued for 19.0 +/- 2.7 months (16-25 months) in both long-term and short-term patients. Of the 61 long-term therapy patients, 20 were relapsed and 41 (67.2%) continue to remain in remission. So too, of the 41 short-term therapy patients, 14 relapsed and 27 (65.9%) still remain in remission. There was no statistical difference between the long-term and short-term therapy group in age, sex, duration of symptoms before diagnosis, antithyroid antibodies, radioactive iodine uptake, free thyroid hormone levels or goiter size before treatment or in TBII levels at cessation of ATD. It is concluded that 'short-term ATD therapy' without a maintenance dose is sufficient and saves several months of the patient's and clinician's time.     

The distribution of the major peripheral blood T, B and NK cell subsets does not predict the clinical outcome of Graves' disease patients after methimazole therapy

Biological markers capable of predicting the clinical outcome of antithyroid drug therapy could be clinically useful in selecting the modality of treatment for Graves' disease, but at present they are unavailable. In the present study we prospectively explore the value of 22 different peripheral blood T, B and NK lymphocyte subsets to predict remission and relapse in a group of 42 Graves' disease patients. Eighteen patients were studied at diagnosis, before treatment, and 24 during antithyroid drug therapy. All cases were followed-up for at least one year after finishing an 18 month cycle of methimazole therapy. The combination of flow cytometry and 3- color immunofluorescence did not reveal significant differences in the distribution of the major peripheral blood T, B and NK cell subsets between the relapsed patients and those in remission, both in the groups studied at diagnosis and in those analyzed during the cycle of antithyroid drug therapy. In our search for a prognostic marker for relapse prediction we found that some lymphoid subpopulations such as total B cells, total NK and NK CD8+ cells showed high sensitivity (88-100%). In turn, other subsets such as TCD8+, total T and B cells expressing the CD25 antigen displayed high specificity (77-88%).     

Serum free triiodothyronine to free thyroxine ratio enables early prediction of the outcome of antithyroid drug therapy in patients with Graves' hyperthyroidism.

This study scrutinizes the correlation between serum free triiodothyronine (FT3) to free thyroxine (FT4) ratios and the eventual outcome of antithyroid drug (ATD) therapy in patients with Graves' disease. Forty-four patients with Graves' thyrotoxicosis were treated with methylmercaptoimidazole (methimazole). During the follow-up, 16 patients relapsed in the short period of one to five months after cessation of the drug (relapse group), and 28 patients remained in remission when checked at 12 to 20 months after treatment (remission group). Serum FT3 to FT4 ratios [(pg/ml/ng/dl) x 10] were less than 55 throughout ATD therapy in 27 of the 28 remission patients whereas the ratios of the relapse group exceeded 55 from the early phase of methimazole treatment in 10 of 16 patients. In eight of these 10 patients the increased ratios were detected within three months of therapy (1 month, 3 patients; 2 months, 4 patients; 3 months, 1 patient). The ratios for the remaining two patients rose above 55 at the fifth and sixth months. There was no statistical difference between the remission and relapse groups in the FT3 to FT4 ratios either before nor at the completion of the treatment. However, a clear difference could be measured at a point during the therapy. Those in whom this difference was pronounced later underwent relapse.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the ratio of T3 release stimulating antibodies to TSH-binding inhibiting antibodies during the course of Graves' disease

The mechanisms leading to a remission of Graves' hyperthyroidism are still unknown. One possibility would be that autoantibodies raised during the course of disease could change the composition of the autoantibody spectrum in such a way to counterbalance the action of stimulatory autoantibodies, thereby resulting in an induction of remission. Therefore, in the present study using a rigorous methodological approach we have characterized the portion of T3 release stimulating autoantibodies among the total body of TSH receptor antibodies, i.e. the TSAb/TBII ratio, over the course of a 12 month antithyroid therapy in 25 patients with Graves' hyperthyroidism. Further, we have evaluated the relation of the alteration of the antibody spectrum to the course of disease. The TSAb/TBII ratio was indeed found to be subject to considerable changes. The observed shift in the antibody composition was more often in favor of a relative increase in stimulatory inactive TBII. Nevertheless, the clinical course of patients showing a persistence of TBII despite the decline or even absence of TSAb proved to be variable. In conclusion, our data indicate that the spectrum of autoantibodies may change over the course of antithyroid therapy owing mostly to a relative rise in stimulatory less active autoantibodies. This phenomenon, however, is apparently not closely related to the course of disease.     

Long term antithyroid drug therapy for intractable cases of Graves' disease.

Among the 504 patients with Graves' disease in whom the author initiated antithyroid drug therapy between 1956 and 1968 are 14 to whom the administration of antithyroid drug has been continued for 8 to 21 years because of recurrence shortly after the discontinuation of drugs. During these periods, no side effects were observed and three patients went into complete remission after 8, 9 and 20 years of antithyroid drug administration, respectively. It is suggested therefore that the long term administration of antithryoid drugs can be a useful treatment for intractable cases.     

Studies on the T3 suppression test by the 24-hour thyroidal 131I uptake in patients with Graves' disease: comparison of the effects of propylthiouracil and methylmercaptoimidazole

The T3 suppression test by the 24-hr thyroidal 131I uptake was reevaluated in patients with Graves' disease before and after withdrawal of antithyroid drug. Fifty patients had been treated with propylthiouracil (PTU) or methylmercaptoimidazole (MMI) for 12 to 70 months. They were prescribed a maintenance dose of antithyroid drug (PTU, 50 mg/day; MMI, 5 mg/day) at the time of investigation and regarded as euthyroid on the basis of serum T3, T4 and TSH levels. Each patient was given 75 micrograms T3 daily for 8 days in conjunction with PTU or MMI. The 24-hr thyroidal 131I uptake was then measured (post T3 uptake). In 30 patients whose post T3 uptake was below 35%, treatment was stopped and the T3 suppression test was repeated at one and 3 months later. During the two-year follow up, 24 remained well, while 6 relapsed within 4 to 12 months. In patients with sustained remission, the post T3 uptake was significantly lower in the MMI-treated group (13 cases, 7.7 +/- 1.0%) than in the PTU-treated group (11 cases, 18.6 +/- 1.9%). MMI withdrawal produced a marked rebound in the post T3 uptake, whereas none of the patients showed the rebound after PTU withdrawal. In patients who relapsed later, there was no difference in the post T3 uptake during treatment and the rebound occurred in the both groups following goitrogen withdrawal. Serum T3, T4 and TSH levels were within normal ranges at one and 3 months after cessation of antithyroid drug. From the results of the present study, it is concluded that criteria for T3 suppressibility by the 24-hr uptake should be determined by the antithyroid drug employed and by the time of investigation. There is a dissociation in the post T3 uptake values following withdrawal of the two different antithyroid drugs.     

The management of hyperthyroidism due to Graves' disease in Japan in 1988. The Japan Thyroid Association

The management of hyperthyroidism due to Graves' disease in Japan was the subject of a survey of the members of the Japan Thyroid Association (JTA), and the results were compared to those of the European Thyroid Association (ETA). In the questionnaire, in vivo and in vitro diagnostic procedures, the choice of treatment and the details of the treatment for a patient with typical, moderate and uncomplicated hyperthyroidism due to Graves' disease was at first asked, and eight variations with a single alternative were proposed to evaluate how each alternative would affect the choice of treatment. For the diagnostic procedures, thyroid uptake/scintigraphy was carried out by approximately 60% of the respondents and the isotope mainly used was 123I. The number of in vitro tests used for diagnosis averaged 8.1 +/- 1.8 tests. Measurements of basal TSH and free T4 were the most frequent tests performed to confirm the diagnosis of hyperthyroidism (94 and 80%, respectively). Determinations of microsomal, thyroglobulin and TSH-receptor autoantibodies were also employed by many respondents (96, 96 and 77%, respectively). On the other hand, the free T4 index and TRH test were less frequently employed. In the treatment of these patients, antithyroid drug treatment was the first choice, and surgery was not, in general, regarded as a primary therapy except in a patient with a large goiter. The frequency of the respondents who advocated radioiodine therapy was considerably higher for patients with recurrences and old age. No respondents proposed radioiodine therapy for young patients. Specialists tended to favor their own specialist treatment regimens. The initial dose of antithyroid drugs was reduced according to thyroid function, and withdrawal of antithyroid drug treatment was determined by some specific criteria (basal TSH in supersensitive assays, TSH-receptor autoantibodies, T3 suppression test, etc.). The aim of radioiodine therapy and surgery was to restore euthyroidism. The significant differences between the results from the JTA and those from the ETA were as follows; radionuclide used for thyroid uptake/scintigraphy was mainly 123I in Japan, but 131I in Europe, the number of diagnostic studies in Japan was more than that in Europe, and the dosage of antithyroid drugs was reduced according to thyroid function and discontinued based on certain specific criteria in Japan, but after fixed periods in Europe. These results may represent actual trends in how hyperthyroidism due to Graves' disease is managed in specialist clinics in Japan today and the differences between the JTA and the ETA.     

Relationship among thyrotropin (TSH), thyroid stimulating immunoglobulins, and results of triiodothyronine (T3) suppression test in patients with Graves' disease

To investigate the relationship between TSH and abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease in whom normal thyroid hormone levels in the serum were maintained by antithyroid drug therapy and in patients with euthyroid Graves' disease, determinations were made of the TSH concentration, action of thyroid stimulating immunoglobulins (TSAb and TBII), and T3 suppression. Out of thirty-three patients with hyperthyroid Graves' disease, twelve patients with subnormal TSH levels were all non-suppressible according to the T3 suppression test results and the detectability of TSAb and/or TBII was as high as 75%. In three out of five patients with euthyroid Graves' disease, the serum TSH level was subnormal. All three showed non-suppressibility in the T3 suppression test and positive action of either TSAb or TBII. One of them became clinically thyrotoxic when the TSAb activity was further increased and TBII became positive, and was therefore diagnosed as having hyperthyroid Graves' disease. The present findings suggest that there are still abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease who have low TSH, even if their thyroid hormone concentrations remain normal. Moreover, it is likely that some of the patients with euthyroid Graves' disease are actually in a state of subclinical hyperthyroidism because of the presence of abnormal thyroid stimulator(s).     

Closer correlation between serum triiodothyronine and basal metabolic rate during antithyroid drug treatment in patients with Graves' disease.

The correlations between serum triidothyronine (T3), thyroxine (T4), 131I-triiodothyronine resin sponge uptake (RT3U) or free thyroxine index (T7) and the basal metabolic rate (BMR) during antithyroid drug treatment in 86 patients with Graves' disease were investigated. Although serum T3, T4, RT3U and T7 during therapy with MMI showed significant positive correlations with BMR, the coefficient of correlation (r = 0.6088, P less than 0.001) between T3 and BMR was the highest of all. While the normal range of BMR in control subjects was between -1.9 and +14.9 (the range of mean +/- SD), the corresponding values of T3, T4, RT3U and T7 calculated from the regression lines, ranged from 94.2 to 184.0 ng/dl, from 5.32 to 8.75 microgram/dl, from 26.5 to 28.9% and from 1.57 to 2.47 respectively. On the other hand, when the corresponding values of BMR to normal values of T3 (100-170 ng/dl), T4 (7.6-12.2 microgram/dl), RT3U (26.7-36.5% and T7 (2.29-3.49) in control subjects were calculated from the regression lines, the range of value obtained from the regression line of T3 coincided better with normal value of BMR in control subjects that those calculated from other regression lines (T4, RT3U and T7). These results suggest that serum T3 level would be a better index of evaluation of the thyroid function that T4 or RT3U in patients with Graves' disease under antithyroid drug treatment.     

Does Graves' disease during puberty influence adult bone mineral density?

AIM: To evaluate the bone mineral density at lumbar spine and at femoral neck in a group of young adults in whom Graves' disease developed during childhood and adolescence. PATIENTS AND METHODS: We examined 28 patients (5 male, 23 female, age 20.9 +/- 3.3 years) who were 11.8 +/- 2.9 years old at the onset of Graves' disease. They were treated either with methimazole (14 patients) or with methimazole plus l-thyroxine (14 patients). At the time of the investigation, 13 patients were considered cured following antithyroid treatment, 2 were still on antithyroid drugs, 3 were on replacement therapy with l-thyroxine because of hypothyroidism, and 10, treated either surgically or with (131)I, were on replacement therapy. The bone mineral density was measured at the lumbar spine (L2-L4) and at the femoral neck, using dual-energy X-ray absorptiometry. RESULTS: The spinal bone mineral density SD score was -0.28 +/- 1.02, the femoral neck bone mineral density SD score was 0.36 +/- 1.02, and both were not different from zero (NS). We did not find any correlation between the bone mineral density of the femoral neck and that of the lumbar spine and the clinical parameters. CONCLUSION: Graves' disease, beginning in childhood and adolescence, when appropriately treated, does not affect attainment of peak bone mass.     

Changes in thyrotropin binding inhibitor immunoglobulin (TBII) concentration before and after various treatments in a patient with infiltrative Graves' ophthalmopathy

In a patient with active Graves' disease an infiltrative ophthalmopathy developed during antithyroid drug therapy. Her eye symptoms were effectively treated with a large dose of prednisolone (PD), plasma exchanges (PE), cyclophosphamide, orbital irradiation, antithyroid drug and a supplemental dose of triiodothyronine. Before, during and after these treatments thyrotropin binding inhibitor immunoglobulin (TBII) activities in a unit serum immunoglobulin (IgG) were measured after adjusting the IgG concentration by adding normal IgG. Relative TBII concentrations were calculated by extrapolating individual data on a standard curve constructed from serial dilutions of the most potent IgG. Approximately a 5 fold increase in the TBII concentration was observed during the 2 months of progression of the ophthalmopathy, while TBII activity revealed only a 13.3% increase. After treatment TBII concentrations decreased gradually showing a close relation with the severity of the eye symptoms. Every PE was found to remove 48.5 +/- 7.9 (s.e.m.) % of TBII. After PE TBII returned to the preexchange level very rapidly and then overshot it in 2 to 3 weeks. Sixty mg of PD failed to prevent the overshoot but a 100 mg initial dose of PD after 5 PEs inhibited it to some extent. The effectiveness of combined therapy with PE, PD and cyclophosphamide appeared to confirm a role of humoral factors in the pathogenesis of Graves' ophthalmopathy. Serial determinations of TBII in a relative concentration were considered quite useful in analyzing the effectiveness of treatment in Graves' ophthalmopathy.     

Angiotensin-converting enzyme and anorexia nervosa

Angiotensin-converting enzyme (ACE) activity was measured in 10 patients with anorexia nervosa, 6 with hyperthyroid Graves' disease, and 7 with primary hypothyroidism. Patients with anorexia nervosa had a low serum ACE activity (9.8 +/- 2.2 IU/l), as compared to findings in normal subjects (13.4 +/- 3.5 IU/l) (P less than 0.05). Patients with hyperthyroid Graves' disease had high serum ACE activity (23.7 +/- 5.8 IU/l), as compared to levels in normal subjects (P less than 0.01), and patients with primary hypothyroidism tended to have low serum ACE activity (10.1 +/- 1.8 IU/l), compared to the normal subjects (P less than 0.1). Following weight gain (before; 71.3 +/- 10.2% of ideal body weight, after; 88.7 +/- 5.6% of ideal body weight), serum ACE activity in patients with anorexia nervosa reverted to within the normal range (13.8 +/- 3.5 IU/l), and serum T3 concentration was restored to the normal range (before; 0.7 +/- 0.2 ng/ml, after; 1.1 +/- 0.3 ng/ml). In these patients, ACE activity correlated with the per cent of ideal body weight (P less than 0.05). These data suggest that, in underweight subjects with anorexia nervosa, decreased serum ACE activities may relate to emaciation.     

Mapping of a linear autoantigenic epitope within the human thyroid peroxidase using recombinant DNA techniques.

Autoantibodies directed against the thyroid peroxidase (TPO), the thyroid microsomal antigen, are widely used to diagnose human autoimmune thyroid disease. A cloned 3.088 kb cDNA coding for the entire mature human TPO was isolated from a cDNA library derived from a pathological thyroid gland of a Graves' disease patient and used further to generate a so-called TPO epitope cDNA library in order to map linear autoantigenic epitopes involving a recombinant molecular biology approach. The TPO epitope cDNA library consisting of randomly fragmented cDNA sequences inserted in the expression vector pGEX-2T was expressed in Escherichia coli and screened with characterized anti-TPO autoantisera from Hashimoto's disease patients. All the sera were positively tested with a purified thyroid microsomal antigen fraction (TMA/TPO). Only about 1% of examined autoantisera were able to recognize bacterial expressed recombinant TPO representing sequential antigenic determinants. A corresponding autoantigenic epitope with 61 amino acids in length was located at the C-terminus of human TPO.     

Optimization and clinical assessment of a radioreceptor assay for thyrotropin-binding inhibitor immunoglobulins

We tried to improve the sensitivity of a radioreceptor assay for thyrotropin-binding inhibitor immunoglobulins (TBII) by modifying assay conditions. About a twofold increase in sensitivity without a loss of reproducibility was obtained by prolonging the incubation of the receptors with test serum from 15 to 120 min before the addition of 125I-labeled thyrotropin. In 20 untreated, 49 treated patients with Graves' disease and 19 patients with euthyroid Graves' disease, TBII activities obtained using 120 min preincubation were significantly higher than those obtained using 15 min preincubation (p less than 0.005). No significant increase in TBII activities was observed in the presence of sera from patients with primary hypothyroidism (n = 17), simple goiter (n = 7), adenomatous goiter (n = 11), thyroid adenoma (n = 11) or cancer (n = 12). TBII were detectable in 15 (47%) of 32 triiodothyronine-nonsuppressible Graves' patients who were receiving maintenance antithyroid drug therapy using 120 min preincubation, while they were positive in only 6 patients (19%) using 15 min preincubation. The assay using a longer preincubation period was found to be sensitive, specific and useful for diagnosis and follow-up of Graves' disease.     

Short and long term effects of radioiodine and antithyroid drugs on T4 binding proteins, free T4 and T3, during Graves' disease therapy.

Ninety five patients with Graves' disease were studied before and at three months intervals after antithyroid drugs (ATD) (31 cases) or radioiodine (64 cases) therapy until recovery. Before treatment, the T4 maxima binding capacity of TBPA was significantly decreased 253.5 +/- 11.4 mug/100 ml)(mean + se) (control values: 287 +/- 10.4 mug/100 ml) (alpha = 0.04), especially in 53.7% of patients (m = 177 +/- 8 mug/100 ml). The mean of TBG (m = 20.7 +/- 0.9 mug/100 ml) was not different from euthyroid subjects (m = 19.7 +/- 1.7 mug/100 ml) except in 51.2% of patients who had a low TBG (m = 14.3 +/- 1.1 mug/100 ml). An inverse linear correlation was found between TBG-DFT4 (alpha = 0.05) and DF T 3 (alpha = 0.002), TBPA-log DF T4 (alpha = 0.05) but not between TBG and TBPA. The physiological relationship between DFT3, DFT4, TT3, TBG and TBPA was studied in vitro; after adding increased quantities of T4 to a pool of sera collected from eu, hypo or hyperthyroid patients, DFT4, DFT3, FT3 index increased in linear positive relationship with TT4 concentrations, the kinetic of this phenomena was inversely correlated with T4 maximal binding capacity of TBG or TBPA for T4. Addition of T3 to the same sera did not show any effect on the previous parameters. DFT3 depended on the level of T4 in serum more than T3 concentration and was in inverse relationship with the maximal binding capacity of TBG. This data might explain the paradoxal normal or slightly increased values of DFT3 found in T3 thyrotoxicosis. In patients treated with ATD or radioiodine, TBPA but not TBG increased significantly on year after. However, in subjects with an initial very low TGB or TBPA, this phenomenon occurred on the third month after radioiodine or ATD. During the same period, DF T4 and DF T3 were inversely correlated to TBG and TBPA. In conclusion, important changes in T4 binding proteins and free fractions of thyroid hormones were observed in Graves' disease but were corrected by antithyroid therapy. All these data were in good agreement with the normalisation of thyroid function.     

Serum concentrations of 3, 3'-diiodothyronine, 3', 5'-diiodothyronine, and 3, 5-diiodothyronine in altered thyroid states

To investigate the thyroid hormone metabolism in altered states of thyroid function, serum concentrations of 3, 3'-diiodothyronine (3, 3'-T2), 3', 5'-T2 and 3, 5-T2 as well as T4, T3 and rT3 were determined by specific radioimmunoassays in 17 hyperthyroid and 10 hypothyroid patients, before and during the treatment. Serum T4, T3, rT3, 3, 3'-T2 and 3', 5'-T2 concentrations were all higher in the hyperthyroid patients than in age-matched controls and decreased to the normal ranges within 3 to 4 months following treatment with antithyroid drugs. In the hypothyroid patients, these iodothyronine concentrations were lower than in age-matched controls and returned to the normal ranges after 2 to 3 months treatment with T4. In contrast, serum 3, 5-T2 concentrations in hyperthyroid patients (mean +/- SE : 4.0 +/- 0.5 ng/dl) were not significantly different from those in controls (3.9 +/ 0.4 ng/dl), although they tended to decrease in 3 of 6 patients after the antithyroid drug therapy. Serum 3, 5-T2 levels in the hypothyroid patients (3.8 +/- 0.6 ng/dl) were also within the normal range and showed no significant change following the T4 replacement therapy. However, serum 3, 5-T2 as well as 3, 3'T2 concentrations rose significantly with a marked rise in serum T3 following T3 administration, 75 micrograms/day for 7 days, in Graves' patients in euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Predicting a relapse of Graves' hyperthyroidism in adults during the early phase of treatment with anti-thyroid drugs

INTRODUCTION: The long-term effectiveness of anti-thyroid drugs (ATD) in the treatment of Graves' hyperthyroidism (GH) is still unsatisfactory and difficult to predict. The aim of this study was to evaluate the usefulness of a determination of serum level of thyrotropin-binding inhibiting immunoglobulins (second generation TBII assay) in predicting the possibility of relapse in the early phase of pharmacological treatment. MATERIAL AND METHODS: We investigated 37 patients within the 20-60 age range with the first occurrence of GH. All patients were treated with thiamazole for 12 months. Clinical assessment, ultrasound estimation of thyroid volume and determination of serum thyrotropin, free thyroxine, free triiodothyronine, thyroid autoantibodies and TBII levels were carried out at the onset and after 1, 3, 6, 9 and 12 months of ATD treatment. RESULTS: The mean follow-up period after ATD withdrawal was 27.24 +/- 5.81 months. Of 37 patients 12 (32%) had a relapse of hyperthyroidism (mean time 8.17 +/- 6.91 months after drug withdrawal). The difference in TBII levels between the relapse and the remission group was found to be significant after the first month of therapy until the end of ATD treatment. We observed that patients with TBII above 14 IU/L after 3 months and above 8 IU/L after 6 months of therapy relapsed more frequently than patients with lower levels (sensitivity 50% and specificity 92 and 96%, respectively). CONCLUSIONS: The study confirmed that TBII estimation in the early phase of ATD could be useful in the proper planning of GH therapy and early qualification to more radical treatment (radioiodine or surgery).     

Are pituitary and thyroid function tests useful for the monitoring of antithyroid drug treatment and the post therapeutic control of Graves' disease?

The control of Graves' disease patients treated with antithyroid drugs (ATD) involves monitoring the dose of ATD, the duration of therapy and the prediction of the long-term outcome of the disease. The sequential follow-up of free thyroid hormones and ultrasensitive TSH (USTSH) helps in monitoring of ATD therapy, except in patients complemented with thyroid hormones. The normalization of early thyroid uptake of radioiodine or pertechnetate, which seems to be closely related to circulating thyroid-stimulating immunoglobulins, confirms the remission that leads to stopping ATD therapy. The raise of plasma USTSH in a normal range within the six months following ATD withdrawal is another indicator of remission. However, the post therapeutic course of Graves' patients remains unpredictable: late relapses and hypothyroidism may occur despite the normalization of the pituitary-thyroid axis, leading to a yearly clinical control with USTSH evaluation.     

Serum IL-18 levels are not increased in patients with untreated Graves' ophthalmopathy.

OBJECTIVE: Cytokines play an important role in autoimmune thyroid diseases, and serum levels may reflect the activity of the immune process. This is particularly interesting in Graves' ophthalmopathy, where a reliable serum activity marker is warranted. Interleukin-18 (IL-18) is a potent Th1 cytokine, known to induce interferon (IFN)-gamma and the aim of this study was to evaluate serum IL-18 levels in Graves' ophthalmopathy. METHODS: Serum IL-18 was measured by ELISA in 52 patients with untreated Graves' ophthalmopathy (who all had been rendered euthyroid with antithyroid drugs), 52 healthy controls matched for sex, age, and smoking habits, and 15 euthyroid patients who had been treated for Graves' hyperthyroidism and ophthalmopathy in the past. RESULTS: Serum IL-18 (median values in pg/ml with range) levels did not differ between the untreated Graves' ophthalmopathy patients-226 (61-704) pg/ml, matched healthy controls-194 (17-802) pg/ml, and Graves' ophthalmopathy patients treated in the past-146 (0-608) pg/ml. No correlation was observed between serum IL-18 levels and thyroid function or antithyroid antibodies. There was no correlation between serum IL-18 levels and smoking habits. CONCLUSION: We conclude that Graves' ophthalmopathy does not affect serum IL-18.     

Comparison of LATS activity and TSH receptor antibody in Graves' disease

TSH-receptor antibody (TRAb) activity and LATS activity of Graves' sera were compared. All of 50 LATS-positive cases were TRAb positive, although only 63% of LATS-negative cases were TRAb positive. Binding of 125I-TSH to the TSH receptors was inhibited dose-dependently by LATS-immunoglobulin. However, no correlation between TRAb activity and LATS activity was observed. TRAb was positive in 2 LATS-positive cases even when the symptoms of hyperthyroidism were controlled by treatment (antithyroid or radioisotope). The positive TRAb was not changed in 4 Graves' disease patients whose LATS activity had disappeared following antithyroid treatment. These clinical studies show that TRAb is more sensitive than LATS and suggest that LATS may be one of a heterogenous population of antibodies to the TSH receptor in Graves' disease.