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Kim et al., Seoul, Korea, studied 2 groups of patients with Graves' disease
who had thyroid stimulating antibodies (TSAb) in their serum. TSAb of group
A (n = 45) did not react with a mutated transfected TSH receptor in Chinese
hamster ovary cells, although they reacted when the wild (= normal) type
receptor was transfected. TSAb of group B (n = 21) did also react with
the mutated transfected TSH receptor. Patients of group A and B were comparable
with regard to age, sex, goiter size, prevalence of ophthalmopathy, initial
thyroid function parameters, and prevalence of titer of thyroid autoantibodies
including TSH binding inhibiting immunoglobulin activities (TBBI). It appeared
that 22/37 patients in group A but only 1/18patients of group B failed
to respond to antithyroid drugs. The authors conclude among other things
that heterogeneity in epitopes for TSAb may be responsible for differences
in the natural course of the disease or in response to drug therapy.
Schumm-Draeger et al., Frankfurt/Main, Germany, injected the nude mouse xenotransplantation model with lymphocytes isolated from the thyroid after thyroidectomy and from peripheral blood from 10 patients with Graves' disease, toxic nodular goiter, and toxic adenoma. The nude mice were already bearing transplants of normal thyroid tissue. Only lymphocytes derived from the thyroid gland from patients with Graves' disease were able to induce thyroid hyperfunction in the mice as reflected by increased levels of newly synthesized T4 and of antibodies against the TSH receptor. It is concluded that intrathyroidal lymphocytes of patients with Graves' disease play an important role in the development of thyroid hyperfunction. Several studies were reported regarding different regiments of medical treatment of Graves' disease in relation to recurrence rates. Thus, Doufas et al., Athens, Greece, studied the effects of T4 or T3 administration on recurrence rate after 50 patients with Graves' disease were treated with a final dose of 5 mg carbimazole and 25 ug T3 daily for 18 months. Patients were followed for 12 months and were treated either with 100 ug T4, 25 ug T3 daily, or placebo. The recurrence rate was 13/20 (65%), 5/14 (35%), and 5/16 (31%) respectively. It is concluded that thyroid hormone treatment after discontinuation of medical treatment, in particular T4 treatment, does not improve recurrence rate as has been suggested previously by others. Meng et al., Greifswald, Germany, studied the recurrence rate after treatment of 2 groups of patients with Graves' disease, treated daily either with 40 mg methimazole + T4 or with only a maintenance dose of methimazole of 10 mg. These 2 groups were studied prospectively and the relapse rate after 2 years was 49 and 47% respectively. A retrospective study was also conducted in 2 similar groups except that the group with combined treatment continued with T4 substitution after discontinuation of methimazole. In this group recurrence rate was 45% versus 49% in the methimazole only group. The number of patients in each group was at least 70. These studies again argue against a beneficial effect of additional T4 treatment during or after discontinuation of methimazole with regard to recurrence rate. McIver et al., Edinburgh, Scotland, performed an open prospective randomized trial of either carbimazole alone in maintenance dose to keep TSH in the normal range or 40 mg methimazole per day in combination with T4. Patients were treated for 18 months and followed for a further 3 years. No differences in relapse rate were seen. (Comment: These studies in combination with others show that, in the absence or presence of T4 treatment during and/or after methimazole no differences exist in recurrence rates in patients with Graves' disease. These studies are in contrast with those of Hashizume et al., N Engl J Med 324:947,1991, who showed that additional T4 treatment favourably influences prognosis. This discrepancy can at present not be explained but is maybe due to differences in genetics?) Studies were also reported regarding the question whether high or low dose methimazole could influence the autoimmune process in Graves'disease. Paschke et al., Brussels, Belgium, related intrathyroidal methimazole concentrations to local autoimmune processes in thyroids of patients operated for relapsing Graves' disease. They could not find any relationship between methimazole concentrations and any parameter of autoimmunity. In line with these findings is the follow-up report of Reinwein et al., Essen, Germany, who reported further on an earlier multicenter study from 7 European countries (J Clin Endocrinol Metab 76:1516-1521, 1993) on relapse rate in two groups of patients (in total 199 patients), one group treated with 10 mg methimazole daily, and the other with 40 mg methimazole daily (both without T4 substitution). The two groups of patients were followed after discontinuation of therapy for 3 and 4 years respectively. Again no difference, either in clinical or immunological course of Graves' disease was found between these two groups. From the same multicenter study Benker et al., Essen, Germany, determined factors that are important in the initial response of Graves' disease to methimazole treatment,i.e. the duration to achieve euthyroidism. The study involved 509 patients. It was found that daily methimazole dose, pretreatment serum T3 level, and goiter size are the main determinants of the initial therapeutic response. It should be noted that these studies were done in countries with subnormal to low-normal iodine intake. Azizi, Teheran, Iran, studied the effect of methimazole (20 mg daily for 1 month, subsequently 10 mg daily for a 2nd month) in 21 patients with optimal iodine intake (range in urine 10.2-35.0 ug/dl) and in 15 patients with low iodine intake (2.3-9.5 pg/dl). The effect of methimazole on decrease of serum T4 and T3 parameters was more pronounced in patients on low iodine intake, showing (again) that methimazole exerts more effect if iodine stores in the thyroid are low. Fukata et al., Kobe, Japan and Los Angeles, CA, USA, reported on 12 patients with so-called painful Graves' disease characterized by a painful thyroid gland, signs of inflammation like fever, increased erythrocyte sedimentation rate, and positive C-reacting protein, however with increased 24h radioiodine uptake, and no cytological findings of subacute thyroiditis. One to five episodes of severe pain and tenderness were experienced per patient and 9/12 developed hypothyroidism, having all strong positive anti-TG and antimicrosomal antibodies titers. Two out of the 3 patients, who did not develop hypothyroidism, had no thyroid autoantibodies in the serum. Treatment with glucocorticoids relieved symptoms but did not affect outcome of the disease. (Comment: These are very peculiar cases, in that the picture resembles very much subacute thyroiditis, except that in contrast to this entity the present patients did show uptake of radioactive iodine in the thyroid. Another difference between the 2 entities is that 10 of the present patients showed strong positive antithyroid antibody titers whereas this seldomly occurs in subacute thyroiditis. Last but not least, in all of the present patients positive TBII levels were present in the serum. It is not known if these patients also had ophthalmopathy.) Murakami et al., Kobe, Japan, studied the prognostic significance of thyroglobulin serum levels with regard to remission rate in patients treated for Graves' disease with methimazole. The study was conducted in 45 patients after discontinuation of antithyroid drugs for at least 3 months. Thirty-five patients had normal serum TG and 10 patients high TG levels. In 29/35 (85%) of normal TG patients remission remained for at least 1 year, whereas this was only the case in 3/10 (30 %) of high TG patients. It is concluded that a normal serum TG after antithyroid treatment is a prognostic favourable sign with regard to remission rate, even despite an enlarged thyroid gland. Kawauchi et al., Tokyo, Japan, published the first report of a 45 year old woman with Graves' disease who is treated with ultrasound guided percutaneous ethanol injection after euthyroidism was achieved by administration of antithyroid drugs. She was injected 4 times in a period of 3 weeks. In total 26 ml ethanol was injected. There was a temporal increase in thyroid hormone level for 2 weeks after which a return into the normal range was seen, despite discontinuation of antithyroid drug treatment prior to ethanol injection. No major side effects were seen. Fiore et al., Pisa, Italy, studied the possible relationship between stress and the development of Graves' disease in 41 patients suffering from panic attacks for a mean period of 10 years. They found an increased tendency for humoral thyroid autoimmunity as compared to the general population, however, no evidence was found for a higher prevalence of Graves' disease. It is not known so far if there is a genetic link between panic disorders and thyroid autoimmunity or that the psychiatric condition is the cause of the autoimmune derangement. (Comment: Although the relationship between emotional stress and the development of Graves' disease has been already studied since 1860 and many reports have been published on the subject, we have the feeling that not even a small step has been made towards its solution). Several studies were reported on the genetic aspects of Graves' disease, done in the United Kingdom by Ratanachaiyavong et al., in Denmark by Lavard et al., and in Mexico by Gomez et al. The results again show a polygenic role in its etiology and differences in linkage studies between different populations. Taniyama et al., Tokyo, Japan, measured thyroid artery blood flow using ultrasound pulse Doppler in 24 patients with Graves' disease who were euthyroid by minimal antithyroid drug treatment. Blood flow was measured just before discontinuation of drug treatment. Of 15/24 patients who remained euthyroid for at least after 1 year, only 3 had a mean velocity of more than 20 cm/sec, whereas 7 out of 9 patients with a recurrence within one year also had a mean velocity higher than 20 cm/sec. These results were independent of the T3 suppression test data. It is concluded that measurement of artery blood flow has predictive value towards remission rate. (Comment: As artery blood flow may be related to thyroid volume, and it is known that thyroid volume also has predictive value towards remission rate. We would be interested to know if in these patients blood flow is related to thyroid volume.) Noh et al., Chiba, Japan, studied the presence of TSH binding inhibiting immunoglobulins (TBII) present in 73 samples of umbilical cord blood of neonates, born to mothers who were euthyroid but underwent subtotal thyroidectomy for Graves' disease in the past. They could not find any correlationship between TBII levels and FT4 in these neonates. They conclude that the normal thyroid gland of the neonate does not react to TSH receptor antibodies. (Comment: As it is not known to what extent these TBII had any TSH receptor stimulating activity, the conclusion of the authors should be questioned.) Gomi et al., Tokyo, Japan, studied TBII activity in 18 women in remission after surgery for Graves' disease from the onset of conception until 1 year after delivery. During pregnancy TBII levels decreased in 11/18 and increased in 4/18. Most levels increased after delivery, but subsequently declined to levels that were not significantly different from those at the time of conception. These findings suggested that pregnancy has no significant permanent influence on the course of treated Graves' disease in this group of patients. Fukao et al., Sagamihara, Japan, studied mental status and stressful events in 52 patients using antithyroid drugs in whom TSH receptor antibodies did not decrease during therapy, in 16 patients in whom TSH receptor antibodies did decrease during therapy, and in 14 patients in remission after medical therapy. They found a higher frequency of mental disorders, like depression, hypochondriasis, psychasthenia, and schizophrenia in the patient groups notably in those on treatment without a decrease in TSH receptor antibodies. Intensity of daily stress was more in treated groups than the remission group and in controls. The authors conclude that mental disorders are more frequently present in patients with Graves' disease. (Comment: It would be interesting to know what the psychological test results would be in first degree relatives (without thyroid autoimmunity) of patients with Graves'disease.) Kasuga et al., Matsumoto, Japan, studied thyroid and immunological status in 176 patients who underwent subtotal thyroidectomy for Graves' disease between 1970 and 1979. Patients were re-examined in 1984 and 1992. 50/79 patients, being all euthyroid in 1984, were still euthyroid in 1992. 17/79 of these patients became latent hypothyroid after 1984, 7/79 overt hypothyroid, and 5/79 overt hyperthyroid. TPO and TGAb vary frequently, in that patients who were positive in 1984 became negative after wards, and vice versa. No significant differences were found with regard to percentages of CD3-, CD4-, and CD8positive cells between different patient groups and versus controls. |
