Treatment of neonatal hyperthyroidism due to Graves' disease with sodium ipodate

We describe the effect of administration of repeated doses of sodium ipodate in a newborn infant with hyperthyroidism due to transient Graves' disease. Pretreatment (day 3) serum T4 and T3 concentrations were 49 micrograms/dl and 590 ng/dl, respectively. With 24 h after the first dose of ipodate, serum T3 fell by 40%, and it subsequently ranged from 209-278 ng/dl throughout the 39-day ipodate treatment period. Serum T4 also decreased after ipodate administration to 69% and 41% of the pretreatment value after 72 h and 7 days of treatment, respectively; values thereafter during treatment ranged from 19-22 micrograms/dl. These plateau values are in the upper range of normal for the neonatal period. Rapid clinical improvement occurred as the hyperiodothyroninemia abated. Serum rT3 concentrations increased from 468-672 ng/dl to greater than 1400 ng/dl 24 h after each ipodate dose. Thyroid-stimulating immunoglobulin was present in maternal and cord sera, and the half-life of serum thyroid-stimulating immunoglobulin in the infant was approximately 12 days. Antithyroglobulin and antimicrosomal antibodies were present in the infant at 10 days of age, and the titers decreased progressively thereafter; the half-life for the antimicrosomal antibody titer was 3 weeks. The data suggest that sodium ipodate can be useful for treatment of neonatal hyperthyroidism due to Graves' disease.     

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

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 After IPO was withdrawn, these Group 2 patients were treated with methimazole (20-30 mg/day, initial dose), but the therapeutic response was poor and delayed.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

Further studies on the long-term treatment of Graves' hyperthyroidism with ipodate: assessment of a minimal effective dose.

We have previously described that sodium ipodate (500 mg/day, p.o.) is effective in normalizing serum T3 and T4 levels in most patients with Graves' hyperthyroidism. In this study, we examined serum T3, T4, and rT3 levels in 14 hyperthyroid patients with Graves' disease during treatment with a lower dose (500 mg, every other day, p.o.) of sodium ipodate for a period of 3-30 weeks (mean 15.5 weeks). Three types of responses were observed. In group I (4 patients), both serum T3 and T4 were in the normal range at the end of treatment [baseline: mean +/- SEM T3, 6.8 +/- 0.96 nmol/L (normal 0.92-3.0)] and T4 [256 +/- 44 nmol/L (normal 62-167); post-ipodate: T3, 2.0 +/- 0.46 nmol/L and T4 107 +/- 28 nmol/L]. In group II (n = 5), either serum T3 (3 patients) or serum T4 (2 patients) did not become normal (baseline: T3 7.7 +/- 1.1 and T4 228 +/- 3.9; post-ipodate: T3 2.9 +/- 0.57 and T4 188 +/- 27 nmol/L). In group III (5 patients), neither serum T3 nor serum T4 returned to normal following ipodate treatment (baseline: T3 11.9 +/- 1.8 and T4 260 +/- 23; post-ipodate: T3 7.5 +/- 0.49 and T4 322 +/- 17 nmol/L). The mean serum rT3 concentration increased during ipodate treatment to a peak value of 100% above baseline and remained elevated (20-75% above baseline) throughout the study. Some improvement in hyperthyroidism was suggested by increase in body weight during ipodate treatment in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long term treatment of Graves' disease with iopanoic acid (Telepaque)

To investigate the long term utility of the cholecystographic contrast agent iopanoic acid (Telepaque) for treatment of Graves' hyperthyroidism, we studied 40 patients treated with 500 mg, orally, daily for 1-12 months. We measured thyroid size; body weight; serum T3, T4, and free T4 concentrations; and antithyroglobulin and antimicrosomal antibody levels at monthly intervals. Based on the effects of the therapy, the patients were divided into 3 groups: 6 patients had excellent responses with return of serum thyroid hormone levels to normal (group A); 12 patients had fair responses, but 1 thyroid hormone test remained elevated (group B); and 22 patients had minimal benefit (group C) with only slight clinical improvement and transient reduction of serum T3 concentration. Mean serum T3 levels decreased significantly after 1 month of therapy in all 3 groups and became normal in groups A and B, but the reduction in group C was not sustained. Mean serum T4 and free T4 levels remained above normal during the course of therapy in groups B and C. Sixty-eight percent of patients in group C had large goiters compared with 33% of group A and 25% of group B, and those in group C tended to have more severe biochemical hyperthyroidism initially. There were no significant changes in antibody titers during therapy. These data indicate that iopanoic acid is not effective therapy for many hyperthyroid patients.     

Resistant hyperthyroidism induced by sodium iopodate used as treatment for Graves' disease

Sodium iopodate has recently been advocated for long-term control of hyperthyroidism in Graves' disease. Its advantages over conventional therapy are a rapid fall in thyroid hormones and control of symptoms with a simple dosage regime. We report a case in which severe resistant hyperthyroidism developed during treatment of Graves' disease with sodium iopodate. Sodium iopodate may not be suitable for long-term use in all patients with Graves' disease.     

Relationship between Graves' ophthalmopathy and type of treatment of Graves' hyperthyroidism.

The relationship between the treatment of Graves' hyperthyroidism and the course of ophthalmopathy is rather unclear. Antithyroid drugs may improve eye manifestations, possibly by restoring normal thyroid function and reducing orbit-directed autoimmune reactions, whereas ophthalmopathy may worsen after radioiodine administration or thyroidectomy. This might occur because of a treatment-related release of thyroid antigens and activation of the autoimmune response that might involve the orbit. On the other hand, some authors suggest that complete thyroid ablation, either by radioiodine or surgery, might be beneficial for ophthalmopathy. However, reported effects of radioiodine and thyroidectomy on Graves' ophthalmopathy are conflicting. This may be due, at least in part, to the retrospective feature of most studies and the lack of precise evaluation of ocular involvement. Two prospective studies were performed in which patients with Graves' disease with mild or no ophthalmopathy were randomly assigned to treatment by radioiodine or subtotal thyroidectomy alone or in association with systemic glucocorticoids. Both treatments were followed by a progression of pre-existing mild ophthalmopathy in a substantial proportion of cases: glucocorticoids prevented such an exacerbation. Ophthalmopathy did not develop in patients without clinical evidence of eye disease prior to therapy. Therefore, it is recommended that a course of glucocorticoids be instituted concomitantly with radioiodine therapy or thyroidectomy in Graves' patients with some degree of ocular involvement.     

Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves' disease

Graves' hyperthyroid patients were treated daily for 10 days with 1 g sodium ipodate, a cholecystographic agent which exerts a blocking effect on the peripheral conversion of T4 to T3, or with 12 drops of saturated solution of potassium iodide (SSKI). Serum concentrations of free T4 (FT4) and free T3 (FT3) were measured before, during and 5 and 10 days after the administration of each drug. Sodium ipodate treatment induced a rapid decrement of serum FT4 concentrations which declined from 48.9 +/- 6.6 pg/ml to 26.0 +/- 2.7 pg/ml. In these patients serum FT3 concentrations declined from 12.4 +/- 2.0 pg/ml to 2.5 +/- 0.4 pg/ml. Ten days after sodium ipodate withdrawal, serum FT4 and FT3 concentrations returned to baseline values. In patients treated with SSKI serum FT4 concentrations declined from 51.1 +/- 8.8 pg/ml to 11.3 +/- 1.4 pg/ml and FT3 from 15.7 +/- 2 pg/ml to 2.6 +/- 0.3 pg/ml. Moreover, after therapy interruption serum free thyroid hormone concentrations returned to baseline values in these patients. Serum FT4 pattern during the study was not different between the two groups of subjects whereas serum FT3 concentrations were significantly lower in patients treated with sodium ipodate. These findings indicate that SSKI and sodium ipodate are effective in inducing a rapid decrement of serum free thyroid hormone concentrations. Therefore the employment of these drugs may be useful in the treatment of patients with thyroid storm and those undergoing thyroidectomy.     

Graves' animal models of Graves' hyperthyroidism.

Fifty years after the discovery of thyroid autoimmunity, several animal models of Graves' hyperthyroidism are now available. All are inducible types, and diseases are elicited by injecting living cells (professional or nonprofessional antigen-presenting cells) expressing the recombinant thyrotropin receptor (TSHR) or by DNA vaccination with TSHR cDNA in plasmid or adenovirus vectors. Thus most Graves' models are attributed to the cloning of the TSHR cDNA and involve in vivo expression of the TSHR. These breakthroughs have provided us important insights into our understanding of the pathogenesis of Graves' disease, and also indispensable means to exploring the possibility of development of novel therapeutic modalities. In particular, recent studies have begun to scrutinize the genetic factors contributing to the susceptibility to this ailment, and to delineate the roles for central and peripheral tolerance and also for fine balance between autoreactive effector T cells and regulatory T cells in the pathophysiology of anti-TSHR autoimmunity and Graves' hyperthyroidism. Moreover, preliminary, but novel, therapeutic approaches have also been started to treat experimental hyperthyroidism.     

Management of Graves' hyperthyroidism

Management of Graves' disease hyperthyroidism, a life-long disease, hinges on a clear strategy and involves the patient's understanding and adherence. Antithyroid drug treatment is difficult to adapt to each patient's need; so far, the more efficient use of antithyroid drug remains on long-term courses of 18 months or more. Although a picture is evolving of patients more likely to go into remission after the medical treatment, its characteristics are not yet reliable. Radical (ablative) treatments are often necessary. In general, surgery might appear less appealing than 131I irradiation which, as compared to surgery, carries only the risk of later hypothyroidism. It is hoped that basic as well as clinical research is able to generate innovative, better adapted, and pathophysiologically oriented new therapeutic means.     

Long term thyroid function after subtotal thyroidectomy for Graves' disease

Between 1973 and 1980, 93 patients with Graves' disease underwent subtotal thyroidectomy by the same surgeon (the size of thyroid remnant was 4 g per side). No case of operative mortality, no case of thyroid storm nor of surgical complications occurred. Three months after surgery 40% of patients were euthyroid, 25% had overt hypothyroidism, 35% had subclinical hypothyroidism. In the following yr important variations of thyroid function were observed. The number of patients with subclinical hypothyroidism decreased slowly (22% and 9% at 3 and 6 yr, respectively), and some became euthyroid, some hypothyroid, others relapsed. Seven patients had recurrent hyperthyroidism. In particular at 3 yr 45% of patients were euthyroid, 28% had overt hypothyroidism, 22% had subclinical hypothyroidism, 4% had recurrence; at 6 yr 56% were euthyroid, 32% had overt hypothyroidism, 9% had subclinical hypothyroidism, 3% had recurrence. Four out of the 8 patients operated under 20-yr-old became hypothyroid in comparison with only 2 out of the 15 patients over 50-yr-old. Relapses were present only in patients operated at less than 40-yr and only in females. No correlation was found between thyroid lymphocytic infiltration and thyroid function after surgery, nor between the presence of antithyroid antibodies and hypothyroidism. All cases who relapsed had high TMA titers both before and after operation. This study confirms the need for accurate follow-up after subtotal thyroidectomy for Graves' disease.     

Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves' hyperthyroidism

Effectiveness of radioiodine for Graves' hyperthyroidism depends also on its intrathyroidal persistence. The latter is enhanced by lithium by blocking iodine release from the thyroid. One hundred ten patients with Graves' hyperthyroidism were randomly assigned to treatment with radioiodine or radioiodine plus lithium, stratified according to goiter size (< or =40 or >40 mL) and evaluated for changes in thyroid function and goiter size, at monthly intervals, for 12 months. Cure of hyperthyroidism occurred in 33 of 46 patients (72%) treated with radioiodine and in 45 of 54 patients (83%) treated with radioiodine plus lithium. The probability of curing hyperthyroidism was higher and its control prompter (P = 0.02) in the radioiodine-plus-lithium group. Patients with < or =40-mL goiters had similar persistence of hyperthyroidism (13%), but lithium-treated patients had hyperthyroidism controlled earlier (P = 0.04). Among patients with >40-mL goiters, hyperthyroidism was cured in 6 of 15 patients (40%) treated with radioiodine alone and in 12 of 16 patients (75%) treated with radioiodine plus lithium (P = 0.07), and cure occurred earlier in the latter (P = 0.05). Goiters shrank in both groups (P < 0.0001), more effectively and promptly (P < 0.0005) in the radioiodine-plus-lithium group. Serum free T4 and T3 levels increased shortly after therapy only in the radioiodine group (P < 0.01). Lithium carbonate enhances the effectiveness of radioiodine therapy, in terms of prompter control of hyperthyroidism, in patients with small or large goiters. In the latter group, lithium also increases the rate of permanent control of hyperthyroidism.     

Animal models of Graves' hyperthyroidism

Graves' disease is a common organ-specific autoimmune disease characterized by overstimulation of the thyroid gland with agonistic anti-thyrotropin (TSH) receptor autoantibodies, which leads to hyperthyroidism and diffuse hyperplasia of the thyroid gland. Several groups including us have recently established several animal models of Graves' hyperthyroidism using novel immunization approaches, such as in vivo expression of the TSH receptor by injecting syngeneic living cells co-expressing the TSH receptor, the major histocompatibility complex (MHC) class II antigen and a costimulatory molecule, or genetic immunization using plasmid or adenovirus vectors coding the TSH receptor. This breakthrough has made it possible for us to study the pathogenesis of Graves' disease in more detail and has provided important insights into our understanding of disease pathogenesis. The important new findings that have emerged include: (i) the shed A subunit being the major autoantigen for TSAb, (ii) the significant role played by dendritic cells (DCs) as professional antigen-presenting cells in initiating disease development, (iii) contribution of MHC and particularly non-MHC genetic backgrounds in disease susceptibility, and (iv) influence of some particular infectious pathogens on disease development. However, the data regarding Th1/Th2 balance of TSH receptor-specific immune response or the association of Graves' hyperthyroidism with intrathyroidal lymphocytic infiltration are rather inconsistent. Future studies with these models will hopefully lead to better understanding of disease pathogenesis and help develop novel strategies for treatment and ultimately prevention of Graves' disease in humans.     

抗甲状腺药物或~(131)Ⅰ治疗Graves甲亢与甲状腺相关眼病的关系

甲状腺功能亢进症(甲亢)的治疗方式可能影响甲状腺相关眼病(TAO)的发病及病程.近期对过去一些随机对照研究所作的系统综述显示,与药物相比,放射性碘治疗肯定是TAO发生与加重的危险因子.然而,由于缺少大型的随机试验,TAO的诊断标准也不统一,因此很难作出结论.     

Age and gender predict the outcome of treatment for Graves' hyperthyroidism

The response to treatment in Graves' hyperthyroidism is unpredictable, and factors postulated to predict outcome have not generally proved clinically useful or been widely adopted in clinical practice. We audited outcome in 536 patients with Graves' hyperthyroidism presenting consecutively to determine whether simple clinical features predict disease presentation and response to treatment. At presentation males had slightly more severe biochemical hyperthyroidism [free T4: males, 64.3 +/- 3.0 pmol/L (mean +/- SE); females, 61.3 +/- 1.7 (P = 0.45); free T3: males, 24.3 +/- 1.5 pmol/L; females, 21.0 +/- 0.6, (P = 0.04)]. Patients less than 40 yr at diagnosis had more severe hyperthyroidism than patients more than 40 yr old [free T4: <40 yr, 64.3 +/- 2.0; >40 yr, 56.7 +/- 2.3 (P = 0.02); free T3: <40 yr, 22.8 +/- 0.8; >40 yr, 19.0 +/- 0.9 (P = 0.003)]. Males had a lower remission rate than females after a course of antithyroid medication [19.6% vs. 40%; odds ratio, 0.37; 95% confidence interval (CI), 0.17-0.79; P < 0.01]. Similarly, patients aged less than 40 yr had a lower remission rate than older patients (32.6% vs. 47.8%; odds ratio, 0.53; 95% CI, 0.32-0.87; P = 0.01). One dose of radioiodine cured hyperthyroidism in fewer males than females (47% vs. 74%; P < 0.0001). Logistic regression analysis demonstrated male sex (odds ratio, 2.80; 95% CI, 1.31-5.98; P = 0.008), serum free T4 concentration at diagnosis (odds ratio, 1.02; 95% CI, 1.0-1.04; P = 0.01), and dose of radioiodine administered (odds ratio, 0.99; 95% CI, 0.99-1.00; P = 0.001) were contributing factors associated with failure to respond to a single dose of radioiodine. As males and younger patients are more likely to fail to respond to medical treatment, and male patients are likewise less likely to respond to a single dose of radioiodine, we suggest that those groups with low remission rates should be offered definitive treatment with radioiodine or surgery soon after presentation and that the value of higher initial doses of radioiodine in males be evaluated.     

Long term effects of the treatment of the Graves' disease by 4 different therapeutics (author's transl)

166 patients suffering of Graves' disease have been treated between 1967 and 1971 with 4 different methods (Carbimazole alone, Carbimazole + Surgery, 131 I, 131 I + Carbimazole between 10th and 50th days). The choice was conducted by the volume of the gland and the age of the patient. Isotope was calculated to deliver 7 000 rads in 76 cases and 10 000 rads in 17 more severe cases (cardiothyreosis). 129 patients were submitted to a long term follow up. Medical treatment gave euthyroidism in 34/47 after a mean duration of 8 months. 1/3 to 1/2 of the patients relapsed between 1 to 9 years. Surgical treatment was successful in 25/26 after a total period of 5,5 months. 8 relapsed and 3 became hypothyroid. Relapses were more frequent after bilateral subtotal thyroidectomy than after total lobectomy + subtotal contralateral lobectomy. Isotope gave a complete cure in 14 patients (delay 4,1 months) and in 34, a complementary treatment was necessary (delay 13,5 months). Relapses (12/94) were detected in general after 2 years. The results were the same after 7 000 ans 10 000 rads doses and in the patient receiving, or not, systematically carbimazole. The treatment of Graves' disease is long and difficult. An excellent result is obtained only in half of the cases. 1/3 of these good results needs less than 6 months and 2/3 12 months. A thyroid of less than 40 g include after surgical treatment or after isotopic irradiation an increasing risk of hypothyroidism.     

Long term treatment of severe asthma with subcutaneous terbutaline

We have investigated the use of subcutaneous terbutaline in 17 patients with brittle asthma and five patients with chronic severe asthma. Twelve of the 17 patients with brittle asthma improved both subjectively and objectively (mean lowest daily PEF rising from 142 litres/min to 297 litres/min), with reduction in oral steroid dose, nebulized beta-agonist dose and number of hospital admissions. Both continuous infusion and 6-hourly divided dose regimens were equally effective. Only one of the five with chronic severe asthma showed any lasting response. Eighteen patients have continued to use subcutaneous terbutaline over long periods (2-40 months). Overall 11 patients suffered side-effects of usually minor degree, although one patient had to withdraw because of the development of painful subcutaneous nodules. We conclude that subcutaneous terbutaline delivered by infusion or by intermittent injections is a useful addition to the therapy of some patients with brittle asthma.