Prediction of remission after antithyroid drug treatment in Graves' disease.

A prospective study was carried out to determine the factors which influence response to antithyroid drug treatment in Graves' disease and to assess their predictive value. Eleven variables were included in the assessment and were subjected to discriminant analysis, log rank test and "survival" analysis. The patients were observed for a considerable period (mean duration 51 months). Carbimazole (mean total dose 8 g) was given in combination with thyroxine for an average of eight months to 72 patients. Thirty-five patients relapsed and 37 remain in remission. Thyrotrophin binding inhibiting immunoglobulins (TBII) were detectable in 74 per cent of patients at diagnosis and thyroid stimulating antibodies detectable in 70 per cent. At the end of treatment thyrotrophin binding inhibiting immunoglobulins and thyroid stimulating antibodies were present in 36 and 27 per cent of patients respectively. Levels of thyrotrophin binding inhibiting immunoglobulins were significantly higher both before and after treatment in the group who relapsed, but were not of prognostic significance in an individual patient unless the value was extremely high (TBII index greater than 70). The presence of thyroid stimulating antibodies was of no value in predicting outcome. HLA typing confirmed the known association of Graves' disease with HLA B8 and HLA DR3 but neither of these antigens conferred and increased likelihood of relapse. The likelihood of relapse is shown to be directly related to the severity of the disease at the time of diagnosis, as measured by the serum total T3, and to the size of the thyroid gland; it is not affected by age, family history of thyroid disease or ophthalmopathy. The data indicate that antithyroid drug treatment can be expected to induce long-term remission in patients with mild disease (T3 less than 5 nmol/l) and small thyroids; carbimazole at this dose level is inappropriate for patients with severe disease (T3 greater than 9 nmol/) and large goitres.

Antibodies that block stimulation by TSH or TSAb of thyroid hormone secretion in primary hypothyroidism.

Antibodies that inhibit the stimulation of the thyroid by TSH have been studied in 63 patients with primary hypothyroidism of whom 34 had thyroid atrophy and 29 goitrous Hashimoto's thyroiditis. The method used measured the secretion of tri-iodothyronine (T3) from porcine thyroid slices incubated in vitro. The aims of the study were to assess the frequency and clinical correlates of blocking antibodies in an unselected series of patients, to establish their IgG nature and to examine their action in relation to the TSH receptor. Blocking antibodies were found in 25% of patients and occurred in association with both atrophic (32%) and goitrous (17%) hypothyroidism. These antibodies did not bind TSH (with one exception) nor did they inhibit binding of TSH to its receptor (also with one exception). Blocking-antibody activity was abolished by treatment of the serum with anti-hIgG or with protein A, and the activity was purified from serum by affinity chromatography on protein A sepharose-4B, thus establishing the IgG nature of the antibodies. The stimulation of T3 secretion by thyroid-stimulating antibodies was also blocked and in one case, where IgG did not block stimulation by bTSH, stimulation by hTSH was blocked. Antibodies blocking the action of TSH probably represent an important mechanism in the pathogenesis of primary hypothyroidism in some patients.

The effect of subtotal thyroidectomy with propranolol preparation on antibody activity in Graves' disease.

The effect of subtotal thyroidectomy on thyroid stimulating antibodies (TSAb), thyrotrophin binding inhibitory immunoglobulins (TBII) and antimicrosomal antibodies (MsAb) was studied in 26 patients with Graves' hyperthyroidism treated pre-operatively with propranolol, but without antithyroid drugs. Following surgery, two patients relapsed in the first year and eight patients became hypothyroid. Eighteen patients (69%) had detectable TSAb at entry and no significant change in titre was seen during propranolol therapy. Following surgery TSAb levels fell within 24 h in eight patients, and at 6 weeks only seven patients had detectable TSAb. TSAb were still detectable in seven patients at 6 months. TSAb activity did not predict the late relapses. TBII were present in 13 patients (50%) before surgery and titres remained unchanged in all but two patients during the immediate postoperative period. At 6 weeks TBII had disappeared from the serum of only three patients. During the early post-operative period TBII became transiently detectable in five of the 13 patients initially TBII negative. The two patients who subsequently relapsed remained TBII positive throughout. Microsomal antibodies were present in the sera of 22 patients (85%). Surgery was followed by a decline in titre, which was substantial in only six of 13 patients studied in detail. Thus, in 92% patients hyperthyroidism was successfully eradicated. Propranolol treatment had no effect on antibody activity. TSAb and TBII disappeared from the circulation in 61% and 46% patients, respectively. These data are compatible with the concept that lymphocytes within the thyroid are the major site of TSAb production but other important sites for synthesis of thyroidal autoantibodies probably exist. Although outcome from surgery could not be accurately predicted from TSAb or TBII status either pre- or post-operatively, the two patients who relapsed had the most severe disturbances of thyroid autoimmunity; all patients in whom initially detectable TSAb or TBII disappeared remained in remission.

Myxoedema followed by TSAb-induced hyperthyroidism: report of 2 cases.

The development of spontaneous hyperthyroidism following primary hypothyroidism is an unusual occurrence. We report two cases of confirmed primary hypothyroidism who subsequently became hyperthyroid. Thyroid stimulating antibodies were present in the sera of both patients during the hyperthyroid state. The significance of this sequence of events is discussed and a possible explanation proposed.

Blocking activity to action of thyroid stimulating hormone in serum from patients with primary hypothyroidism.

Spontaneous primary hypothyroidism in adults is usually associated with autoimmune thyroiditis. The hypothesis that hypothyroidism may result from the presence in serum of a factor that blocks stimulation of the thyroid by thyroid stimulating hormone was examined. Serum samples were collected from 28 patients with recently diagnosed primary hypothyroidism. After removal of endogenous thyroid stimulating hormone the effect of the serum on secretion of triiodothyronine induced by thyroid stimulating hormone or thyroid stimulating antibodies was examined in thyroid slices incubated in vitro. Serum samples from six of the patients demonstrated significant blocking of the stimulation by bovine thyroid stimulating hormone. Inhibition of the stimulatory action of thyroid stimulating antibodies was also exhibited by serum samples with blocking activity. It is concluded that in some patients with primary hypothyroidism a serum factor, which is probably an IgG, exists that can block the thyroid response to thyroid stimulating hormone and thyroid stimulating antibodies; it may represent an important mechanism in the pathogenesis of hypothyroidism.

Evidence that thyroid-stimulating antibody is produced in the thyroid gland.

The hyperthyroidism in Graves' disease results from the action of thyroid-stimulating antibodies (TSAb). The thyroid gland in Graves' disease shows diffuse lymphocytic infiltration, and after removal of the gland antibody titres usually decline and patients go into remission. It is postulated that the lymphocytes in the thyroid may be an important site of TSAb production. 10 patients with Graves' disease and 8 patients with other thyroid disorders were studied. Blood was taken during operation, but before thyroid mobilisation, from the thyroid vein and simultaneously from a peripheral vein. In patients with Graves' disease the concentration of TSAb activity in the thyroid vein was much greater than that in the peripheral vein. TSAb was not detected in either peripheral vein or thyroid vein samples in the other patients. The increase in TSAb concentration in the thyroid vein indicates production of antibodies by lymphocytes within the thyroid and could explain why removal of the thyroid results in disappearance of TSAb from the circulation.