THYROID STIMULATING ANTIBODIES (TSAb) IN PATIENTS WITH GRAVES' DISEASE UNDERGOING ANTITHYROID DRUG TREATMENT: INDICATORS OF ACTIVITY OF DISEASE

Thyroid-stimulating antibodies (TSAb) were studied in patients with Graves' disease using a method based on cAMP production in isolated human thyroid membranes. Stimulation was detected in forty-one (82%) of fifty patients with untreated Graves' disease. In these subjects, the TSAb levels were correlated with the thyroid hormone levels. Among twenty patients treated for 1–2 months with carbimazole, 16 (80%) had positive TSAb. During prolonged treatment TSAb gradually diminished and finally normalized. In fifteen patients, it was possible to compare TSAb levels after cessation of previous medical therapy with TSAb levels at relapse. In nine of these patients, an increase of the TSAb level within the normal range at the time of relapse was found, in four the litres were positive. The results indicate that positive TSAb litres are markers of active Graves' disease and suggest that in such patients antithyroid therapy should be continued. A normal TSAb titre after anti-thyroid therapy does not exclude the possibility of relapse.     

Immunological findings and thyroid function of untreated Graves' disease patients with undetectable TSH-binding inhibitor immunoglobulin

OBJECTIVE TSH-binding inhibitory immunoglobulin (TBII) is undetectable in about 10% of untreated Graves' disease patients, but the clinical characteristics and immunological significance of this finding are unknown. In this study we evaluated the clinical characteristics of TBII negative Graves' disease. PATIENTS We examined TBII in 1048 untreated patients at Kuma hospital from 1986 to 1990 and found 69 TBII undetectable patients (12 men and 57 women, mean age ± SEM 35 ± 2 years, group A). MEASUREMENTS We compared the clinical characteristics and immunological findings of group A with 57 untreated TBII detectable Graves' patients who were selected randomly (11 men and 46 women, mean age ±SEM 40 ±2 years, group B). T4, TSH, FT4, FT3, 1231 thyroid uptake, TBII, thyroid stimulating antibodies (TSAb) and the volume of the thyroid using ultrasonography were measured at the first visit. RESULTS Serum T4, FT4 and FT3 levels in group A were significantly lower than those in group B (P<0 001). The values of TSAb in group A were significantly lower than those in group B (593±67 (mean±SE) vs 2143±280%, respectively, P < 0001). The 1231 thyroid uptake in group A was significantly lower than that in group B (53 1 ±11 vs 61 -4±14%, respectively, P<0.01).The thyroid volume in group A was significantly smaller than that in group B (391 ±3 0 vs 51 3±3 3 ml, respectively, P<0 01). TSAb was undetectable in about 10% (6) of the TBII negative untreated Graves' patients at their first visit. CONCLUSION In the present study, untreated TBII negative patients with Graves' disease were characterized by mild elevation of thyroid hormones, mildly elevated ¹²³l uptake, weak TSAb activities and small goitres. The finding of both TBII and TSAb negative titres in untreated Graves' disease patients was also confirmed.     

HYPOTHYROIDISM AND GRAVES' DISEASE AFTER MANTLE IRRADIATION: A FOLLOW UP STUDY

Abstract Fifty of 66 patients whose thyroid function had previously been assessed 7–139 months after irradiation for Hodgkin's disease were re-evaluated 35 ± 3 months later. They could be divided into three groups: those whose thyroid function had been normal in the first study (N= 26), those who had had asymptomatic impaired thyroid reserve (N= 19), and those in whom evidence of Graves' disease had developed (N= 5). The 26 patients who had been euthyroid when first studied had developed significant increases in mean throid-stimulating hormone (TSH) levels basal and following thyrotrophin releasing hormone) without changes in mean free thyroxine index (FTI). In three of these patients, each studied within six years of irradiation, basal TSH had risen to hypothyroid levels. There were no significant changes in mean FTI or basal and peak TSH in 19 patients who had demonstrated impaired thyroid reserve in the first study. The cumulative incidence of impaired thyroid reserve in the total cohort is now 30/66 (45%) but only one of these 30 has developed clinical hypothyroidism. Five patients developed evidence of Graves' disease. Two patients with thyrotoxicosis and one with euthyroid Graves' disease were found in the initial study. On re-evaluation, a third patient had developed frank thyrotoxicosis and another euthyroid Graves' disease, giving a cumulative incidence of Graves' disease of 5/66 (7%). Three of these five were HLA-DR3 and three had measurable thyrotrophin binding inhibiting immunoglobulins. We conclude that impaired thyroid reserve continues to develop within six years of mantle irradiation in adults but once established appears to remain stable. There also appears to be a high incidence of Graves' disease after mantle irradiation.     

The Birmingham pituitary database: auditing the outcome of the treatment of acromegaly

OBJECTIVE Graves' disease is recognized as an organ-specific autoimmune disorder caused by the presence of TSH receptor antibodies. The long-term effects of ¹³¹I treatment for Graves' disease on TSH receptor antibodies have not previously been studied. We have measured the TSH-binding Inhibitory immunoglobulin (TBII) Index and thyroid stimulating antibody (TSAb) activity in patients with Graves' disease following treatment with ¹³¹I. DESIGN A retrospective study. PATIENTS Two hundred and twenty-five patients with Graves' disease who were treated with ¹³¹I 1–13 years earlier were studied (1 year: 27 patients; 2–5 years: 42 patients; 6–9 years: 79 patients; 10–13 years: 77 patients). MEASUREMENTS The TBII index was measured as the percentage ¹²⁵I-TSH bound to pig thyroid membranes and TSAb activity as the amount of cAMP produced by cultured FRTL-5 cells. RESULTS TBII was detected in 78% of patients prior to ¹³¹I administration. Following ¹³¹I administration, the Incidence of positive TBII was 85% at the end of the first year decreasing to 40,19 and 17% at 2–5,6–9 and 10–13 years, respectively. The frequency of a positive TSAb was 74% at the end of the first year, and also decreased to 49, 27 and 29% at 2–5, 6–9 and 10–13 years, respectively. At more than 2 years after ¹³¹I therapy, the frequencies of hyperthyroidism In TBII and TSAb positive patients were 42% (19/45) and 30% (19/63), respectively, which were significantly higher than those In TBII and TSAb negative patients (8%: 12/153 and 8%:11/131, respectively). The frequency of hyperthyroidism after ¹³¹I treatment in patients with negative TBII before treatment (7%: 2/29) was significantly lower than that (29%: 30/102) In patients with positive TBII before treatment. CONCLUSIONS These results indicate that (1) the TBII Index and TSAb activity decreased over a period of more than 2 years after ¹³¹I therapy for Graves' disease, and (2) the TBII index before treatment may influence the long-term outcome of ¹³¹I therapy.     

Prediction of post-partum Graves' thyrotoxicosis by measurement of thyroid stimulating antibody in early pregnancy

OBJECTIVE Autoimmune thyroid diseases often occur after delivery. However, it has been difficult to predict who will develop Graves' thyrotoxicosis after delivery. We tried to establish a systematic method for predicting postpartum onset of Graves' thyrotoxicosis. DESIGN We followed up the pregnant women with antithyroid microsomal antibody (MCAb) from early pregnancy to the post-partum period and analysed the relation between the activities of thyroid stimulating antibodies (TSAb) in early pregnancy and post-partum occurrence of Graves' disease. PATIENTS Seventy-one women with positive MCAb in early pregnancy were studied. They were randomly selected from 262 MCAb-positive subjects found in 3405 consecutive early pregnant women who attended our maternity clinic during the last ten years. MEASUREMENTS MCAb was measured with a commercially available agglutination kit. For 71 MCAb-positive subjects, TSH-binding inhibitory immunoglobulin (TBII) and TSAb were measured in early pregnancy, and serially until 6 months after delivery for the subjects with either positive TBII or TSAb. Thyroid function and goitre size were recorded at every observation. RESULTS Among the 71 subjects, 7 showed positive TSAb in early pregnancy without any thyroid dysfunction; all 7 developed thyroid dysfunction in the post-partum period. Five of them (70% of TSAb-positive subjects) developed Graves' disease, two showing persistence and three transiently. None of 64 TSAb-negative subjects developed Graves' thyrotoxicosis, though 44 developed various types of thyroid dysfunction as a result of postpartum autoimmune thyroiditis. CONCLUSION The Individuals at high risk of post-partum onset of Graves' thyrotoxicosis can be found early in their pregnancy by the detection of TSAb. Overall occurrence of post-partum Graves' disease in the general population is estimated above 0–54%, that is, one in 200 post-partum women may develop Graves' thyrotoxicosis, although thyrotoxicosis may be transient in half of the patients.     

Prediction of the Course of Graves' Disease after Medical Antithyroid Treatment

ABSTRACT The course of thyrotoxicosis in 33 patients with Graves' disease was evaluated clinically and biochemically (free thyroxine index, serum triiodothyronine, thyroid stimulating antibodies, (TSAb), thyroid stimulating hormone binding inhibiting immunoglobulins (TBII)). Relapse of the disease was found to be correlated to anamnestic information of thyrotoxicosis among first degree relatives (predictive value 90%) and to concomitantly raised levels of TSAb and TBII at the start of treatment (predictive value 71%). Mean duration of treatment of patients with long-lasting remission was 16.8 months. When comparing various information used to predict relapse of Graves' disease, anamnestic information of familial predisposition to thyrotoxicosis carries the highest predictive value.     

A long-term follow-up study of patients with non-toxic diffuse goitre in Japan

OBJECTIVE Although non-toxic diffuse goitre is a common disorder, little is known of the clinical course of patients. We therefore decided to investigate the long-term clinical outcome of patients with non-toxic diffuse goitre. DESIGN A retrospective study. PATIENTS Of 850 patients with non-toxic diffuse goitre who met our criteria and were seen in our thyroid clinic between 1977 and 1985, 108 who had been followed for from 5 to 14 years (mean 8 years) were entered in this study. All patients fulfilled our criteria having soft diffuse goitres, normal serum TSH and T4 concentrations, and undetectable antithyroglobulin and antithyroid microsomal antibodies. MEASUREMENTS A family history of thyroid disease was obtained and the occurrence of Graves' ophthalmopathy was noted. Serum TSH and T4 concentrations, and antithyroglobulin and antithyroid microsomal antibodies were measured during the follow-up period. Thyroidal radioactive iodine uptake (RAIU), serum free T4 and free T3 concentrations, and TSH binding inhibitory immunoglobulin (TBII) activities were determined in all patients who were subsequently found to have abnormal serum TSH or T4 concentrations or signs of Graves' ophthalmopathy. RESULTS Thirty-six of the 108 patients (33%) had a family history of autoimmune thyroid disease. Elevated serum T4 or free T4 concentrations and depressed serum TSH concentrations were found in six patients during the follow-up period. Hyperthyroid Graves' disease was diagnosed in four of the six patients, subacute thyroiditis in one, and transient post-partum thyrotoxicosis in one. Hypothyroidism was found in one patient who was diagnosed as having transient post-partum hypothyroidism. Euthyroid Graves' disease was diagnosed in one patient. Furthermore, six of these eight patients had a family history of autoimmune thyroid disease in first-degree relatives. CONCLUSION During a prolonged follow-up period of patients with non-toxic diffuse goitre, Graves' disease was found in five of 108 patients (four hyperthyroid Graves' and one euthyroid Graves'), post-partum thyroid dysfunction in two, and subacute thyroiditis in one. Six of these eight patients had a family history of autoimmune thyroid disease in first-degree relatives. Long-term follow-up is necessary for patients with non-toxic diffuse goitre, especially those who have a family history of autoimmune thyroid disease.     

Measurement of thyroid stimulating immunoglobulins in a new cell line transfected with a functional human TSH receptor (JPO9 cells), compared with an assay using FRTL-5 cells

OBJECTIVES Most bioassays used to measure thyroid stimulating antibodies (TSAb) rely on the ability of patient sera to generate cAMP in cultured cells of non-human origin. The cell line most commonly used has been the rat thyroid cell line, FRTL-5. Recently, a new cell line (JPO9) possessing a transfected human TSH receptor has been developed. The aim of this study was to evaluate the JPO9 cells by comparing them with the widely used FRTL-5 cells, using the method of ³H-adenine incorporation for the direct measurement of intracellular cAMP. DESIGN The ability of patient sera to generate cAMP production in JPO9 and FRTL-5 cells was used as the index of thyroid stimulation. The specificity of the assay was determined using sera from patients with autoimmune thyroid and non-thyroid autoimmune diseases. PATIENTS We studied sera from 28 patients with newly diagnosed Graves' disease, 72 patients with Graves' disease at various stages of treatment, 8 patients with Hashimoto's thyroiditis, 40 patients with a variety of non-thyroid autoimmune diseases and 42 control subjects. MEASUREMENTS The intracellular ³H-cAMP generated in JPO9 cells following preincubation with ³H-adenine and subsequent incubation with patient or control sera, was used as a measure for TSAb. The results obtained with these cells were compared to those obtained with the widely used FRTL-5 cells and they were also correlated with the measurement of TSH binding inhibitory immunoglobulins by a conventional radioreceptor assay. RESULTS JPO9 cells were more sensitive and had a wider range of response to bovine TSH (bTSH) than had FRTL-5 cells (10^-7-10^-2 U/ml compared to 10^-5-10^-3 U/ml respectively). Unlike FRTL-5 cells, JPO9 cells respond well to unmodified serum and grow constitutively in the absence of TSH, thereby not requiring TSH deprivation prior to assay. The TSAb values obtained with both cell lines correlated well (r= 0·87). The JPO9 cells responded specifically to Graves' sera (23 out of 28 newly diagnosed patients were positive), whereas no patients with Hashimoto's thyroiditis and only 4 of 40 patients with non-thyroid autoimmune diseases gave low positive results for the presence of TSAb. CONCLUSIONS The JPO9 cells provide similar diagnostic information to FRTL-5 cells in patients with autoimmune thyroid disease. However, because they are more sensitive, grow faster, have less fastidious growth requirements and respond to unextracted sera, compared to FRTL-5 cells, we conclude that the JPO9 cells are preferable for the measurement of TSAb.     

Thyroid-stimulating antibodies in patients with autoimmune disorders.

A radioreceptor assay was used to measure thyroid-stimulating antibody (TSAb) in 1) patients with Graves' disease with untreated hyperthyroidism, selected for absence of clinically significant eye disease; 2) patients with Graves' ophthalmopathy, with and without previously treated hyperthyroidism; 3) patients with other thyroid disorders; 4) patients with other autoimmune disorders; and 5) normal subjects. TSAb was detected in 14 of 15 (93%) patients with Graves' hyperthyroidism and in 10 of 16 (63%) patients with Graves' ophthalmopathy. Of the patients with Graves' ophthalmopathy, TSAb was detected in 9 of 10 patients who had once been hyperthyroid and in only 1 of 6 patients who had never been hyperthyroid (euthyroid Graves' disease). TSAb was detected in 1 patient with idiopathic Addison's disease (autoimmune adrenalitis) and in 1 patient with juvenile diabetes mellitus (both of whom were euthyroid), and borderline levels were found in 1 patient with Sj?gren's syndrome and 1 patient with methyldopa-induced antired blood cell antibodies. TSAb was not detected in normal subjects or patients with other thyroid disorders. The conclusions are: 1) the test is very useful in the diagnosis of Graves' disease; 2) Graves' eye disease may be a frequently associated but separate disorder; and 3) because TSAb may be present in some euthyroid patients with other autoimmune disorders, TSAb production may occur primarily because of a disorder in the immune system.     

Increased incidence of hypothyroidism in primary biliary cirrhosis

We examined the thyroid status of 58 patients with primary biliary cirrhosis (PBC) using total serum thyroxin, thyroid hormone binding ratio, free thyroxin index, serum TSH, antithyroglobulin, and antimicrosomal antibodies. Seven patients were known to be hypothyroid prior to the diagnosis of PBC. Six additional patients were found to have biochemical evidence of hypothyroidism. The prevalence of hypothyroidism was 12% if we include only those six PBC patients with newly diagnosed hypothyroidism or 22% if we include all 13 patients. Five of the 58 patients had evidence for an elevation of thyroid hormone binding capacity. Three hypothyroid patients had normal total thyroxins with low thyroid hormone binding ratios. Two euthyroid patients had elevated total T ₄ s with low thyroid hormone binding ratio and normal FTI. The prevalence of positive antimicrosomal antibodies was 34%, including 11 euthyroid PBC patients. The prevalence of positive antithyroglobulin antibodies was 20% including five euthyroid patients. There was no association between HLA DR3 or DR5 and the patients with hypothyroidism and/ or antithyroid antibodies. Because fatigue, lethargy, and anorexia as well as hypercholesterolemia are common features of both hypothyroidism and PBC, patients with PBC should be screened for evidence of thyroid dysfunction. Thyroid disease may precede the diagnosis of PBC by several years. Therefore, the development of cholestatic liver disease in a patient with known autoimmune thyroiditis should arouse suspicion of PBC.     

Role of thyrotropin receptor antibodies in the development of hyperthyroidism: follow-up studies on nine patients with Graves' disease

TSH binding inhibitor immunoglobulin (TBII) and thyroid-stimulating antibody (TSAb) activities were measured serially for 4-32 months in nine patients before and during development of hyperthyroidism due to Graves' disease. Initially, all were euthyroid, seven had thyroid enlargement, one had proptosis, and seven had high serum titers of antithyroid microsomal antibodies. The occurrence of hyperthyroidism was preceded by detection of both TBII and TSAb in four patients and detection of TSAb alone in four patients. One patient had neither TBII nor TSAb when euthyroid. The mean initial TBII and TSAb activities were 10.2 +/- 15.2% (+/- SD) and 2677 +/- 4620%, respectively, when these patients were euthyroid. When they became hyperthyroid, both TBII and TSAb activities increased in all patients. At that time, TBII was detected in all but one (eight of nine subjects; 88.9%), with a mean activity of 58.8 +/- 23.4% (+/- SD), and TSAb was detected in all nine patients, with a mean value of 4508 +/- 4429%. These findings not only indicate the crucial role of TSH receptor antibodies in the development of hyperthyroidism due to Graves' disease, but also suggest that a certain period of subclinical Graves' disease exists before the onset of overt hyperthyroidism in most patients, in the sense that they have TSH receptor antibodies, especially TSAb, in their serum even though they are euthyroid.     

Thyroid-stimulating antibody in a patient with euthyroid Graves' disease

We report an 11-year-old girl with euthyroid Graves' disease. She was referred to our clinic because of left exophthalmos without other symptoms suggestive of hyperthyroidism. Her serum concentration of free thyroxine (FT4) and free triiodothyronine (FT3) were normal, but thyroid-stimulating hormone (TSH) was below normal and impaired TSH response to TSH releasing hormone (TRH) was found. Although the sera were positive for anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb), both titers were not as high as usually observed in Graves' disease. Three months later, she developed hyperthyroidism and was treated with propylthiouracil. Within 2 weeks of the initiation of therapy, all symptoms except exophthalmos disappeared, and after 2 months of treatment TRAb was negative though TSAb remained positive. TSAb is therefore a good indicator to use in the diagnosis and follow-up of euthyroid Graves' disease and should be measured in patients with exophthalmos of unknown origin, even in children.     

THYROTROPHIN RESPONSE TO THYROTROPHIN-RELEASING HORMONE IN OPHTHALMIC GRAVES'' DISEASE: CORRELATION WITH OTHER ASPECTS OF THYROID FUNCTION, THYROID SUPPRESSIBILITY AND ACTIVITY OF EYE SIGNS

Thirty-four patients with ophthalmic Graves' disease were investigated by routine thyroid function tests, by measurement of the serum thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) and by measurement of the serum triiodothyronine (T₃) levels. The patients could be divided into four groups according to their response to TRH—normal, impaired, absent and exaggerated. Those with normal responses had routine thyroid function tests and serum T₃ levels which in general did not differ from normal control values. Those with impaired and with absent responses showed routine thyroid function tests which approached the hyperthyroid range together with significant elevation of serum T₃ levels. It is suggested that they might represent examples of ‘subclinical T₃ thyrotoxicosis’. Patients with exaggerated responses had routine thyroid function tests near the lower end of the normal range and could be regarded as suffering from ‘subclinical hypothyroidism’. There was a good correlation between a normal TRH response and normal thyroid suppressibility by T₃, and between impaired and absent responses and impaired thyroid suppressibility. It is evident that the TRH test which is safer, shorter and more convenient, can replace the T₃ suppression test in routine clinical practice. The response to TRH also provided information on the activity of the eye signs, a normal response was associated with improving eye signs whereas impaired, absent or exaggerated responses were associated with static signs or actual deterioration. The TRH test is of value in the diagnosis of unilateral exophthalmos since about three-quarters of the patients in this series showed some abnormality. The wide range of TRH response and of circulating thyroid hormone levels is to be expected since the thyroid is not subject to the normal finely-balanced negative feed-back mechanism via TSH.     

Effects of Betamethasone on Serum lodothyronines and Thyroid Hormone-binding Proteins in Graves' Disease

ABSTRACT The influence of betamethasone on iodothyronines and their binding proteins in serum was studied in 18 patients with Graves' disease. Betamethasone, 6 mg daily, was given orally for 5 days. Serum triiodothyronine (T₃) concentration decreased, reverse triiodothyronine increased, while thyroxine (T₄) and thyroid-stimulating hormone were unchanged. Thyroxine-binding globulin (TBG) decreased and thyroxine-binding prealbumin increased. In accordance with the decrease in TBG, the in vitro T₃ uptake increased and out of the indirect measures of the free thyroid hormones, the free T₄ index increased and the free T₃ index decreased. We suggest that the decrease in serum T₃ during betamethasone administration supports the view of glucocorticoids being benefical as additional treatment in some patients with thyrotoxic crisis.     

A novel mutation causing complete deficiency of thyroxine binding globulin

OBJECTIVE Recovery of thyroid function in patients following hypothyroidism induced by ¹³¹I therapy for Graves' disease has been described, but only a few detailed clinical and biochemical studies of this phenomenon (transient hypothyroidism) have been published. The prevalence, mechanism, and final outcome of transient hypothyroidism in 260 patients with Graves’ disease treated with ¹³¹I was studied. DESIGN A retrospective study. PATIENTS Two hundred sixty patients with Graves' disease, treated with ¹³¹I between 1 and 15 years previously, were categorized into 4 groups according to their thyroid function during and 1 year after therapy (Group 1: permanent hypothyroidism, 28 patients; Group 2: transient hypothyroidism, 39 patients; Group 3: euthyroidism without transient hypothyroidism, 83 patients; Group 4: hyperthyroidism, 110 patients). MEASUREMENTS We compared total T4, total T3, TSH, anti-thyroglobulin (TGHA) and anti-microsomal (MCHA) antibodies, the TSH-binding inhibitory immunoglobulin (TBII) index, thyroid weight, dose of ¹³¹I, and 24-hour ¹³¹I uptake as pretreatment variables. The mean time for permanent hypothyroidism to develop was estimated by the Kaplan–Meier product limit method. The TBII index and thyroid stimulating antibody (TSAb) activity were measured in seven patients from Group 1 and in nine patients from Group 2 at the time that they became hypothyroid. RESULTS Hypothyroidism developing within 12 months of therapy was transient in 58% (39/67) of patients. No pretreatment variables were found to differ between patients with and without transient hypothyroidism. The mean estimated time between therapy and the development of permanent hypothyroidism was 96 months in Group 2; this time interval was significantly shorter than 126 months in Group 3 and 129 months in Group 4 (P<0.05, P<0.01, respectively). TSAb activity was > 500% in 78% (7/9) of patients from Group 2, which was significantly higher than that found (14%, 1/7) in Group 1. CONCLUSIONS These results indicate that (1) more than half the patients who developed hypothyroidism within 6 months after ¹³¹I treatment for Graves' disease recovered spontaneously, (2) TSAb activity might play some role in the recovery of transient hypothyroidism, and (3) the development of transient hypothyroidism may influence long-term thyroid function.     

The mechanism of spontaneous hypothyroidism in patients with Graves' disease after antithyroid drug treatment

The natural course of Graves' disease results in hypothyroidism in up to 20% of patients previously treated with antithyroid drugs. The precise mechanisms are not known, although autoimmune destruction of thyroid tissue has been proposed. We studied sequentially obtained serum samples from three patients with hyperthyroid Graves' disease previously treated with an antithyroid drug who became hypothyroid to determine possible causes of their hypothyroidism. Antithyroglobulin and antithyroid microsomal autoantibodies, TSH binding inhibitory immunoglobulin (TBII), thyroid-stimulating antibody (TSAb), and thyroid stimulation-blocking activity were measured. Autoantibodies were markedly elevated throughout the clinical course in all three patients. Patient 1 had no TBII and blocking activity and extremely high TSAb when she was euthyroid as well as hypothyroid. Hypothyroidism was probably the result of autoimmune thyroid destruction. In patient 2, TSAb disappeared, and TBII and blocking activity increased markedly when she developed hypothyroidism, which thus appeared to result from blocking antibodies. Patient 3 had intermittent periods of hyper- and hypothyroidism before becoming and remaining euthyroid. While initially hypothyroid, TBII was weakly positive, and TSAb was strongly positive; subsequently, when hyperthyroidism recurred, TBII and TSAb were strongly positive. Hypothyroidism appeared to result from focal autoimmune thyroiditis. Patients with hyperthyroid Graves' disease may develop hypothyroidism later by different means. Autoimmune thyroiditis, diffuse or focal, with thyroid destruction is one mechanism. The appearance of antibodies that block TSH stimulation may be another.     

ON THE EFFECT OF THYROTROPIN AND IMMUNOGLOBULINS RELATED TO GRAVES'' DISEASE ON THYROTROPIN SYNTHESIS AND SECRETION

The effect of exogenous thyroxine (T₄), thyrotropin (TSH), long acting thyroid stimulator (LATS), immunoglobulin G fractions from (a) thyrotoxic sera without LATS and (b) sera from patients with ophthalmic Graves' disease, upon serum TSH concentration and pituitary TSH content has been investigated in the guinea-pig. Pituitary TSH content was significantly lower in animals injected with T₄ (1.80 mU), TSH (2.80 mU) and LATS (3.20 mU) than that in the controls (6.40 mU). Thyroidectomy caused a significant elevation in serum TSH concentration (22.30 mU/dl vs 6.67 in sham operated controls) but no significant alteration in pituitary TSH content (4.40 mU vs 3.80 mU in sham operated controls). TSH injections in thyroidectomised animals induced a significant increase in serum TSH concentration (31.60 mU/dl) and the pituitary TSH content (6.50 mU). Two out of four IgG samples from patients with ophthalmic Graves' disease caused a fall in serum TSH concentration (12.90 and 14.40 mU/dl) with a concomitant rise in pituitary TSH content (9.00 and 9.30 mU) in thyroidectomized animals. It is concluded (1) that exogenous TSH induces an enhanced TSH synthesis and release in thyroidectomised guinea-pigs which suggests the presence of a positive ‘short loop’ feedback for TSH and (2) that IgG fractions from some sera of ophthalmic Graves' disease may have the ability to inhibit TSH release from the pituitary. This inhibitory effect, hitherto not described, may be responsible for the diminished TRH induced TSH release in some patients with euthyroid Graves' disease.     

Serial changes in thyroid-stimulating antibody and thyrotropin binding inhibitor immunoglobulin at the time of postpartum occurrence of thyrotoxicosis in Graves' disease

Thyroid-stimulating antibody (TSAb) and TSH binding inhibitor immunoglobulin (TBII) were measured serially in 10 patients with Graves' disease at the time of postpartum onset (n = 2) or relapse (n = 8) of Graves' thyrotoxicosis and in 5 patients with Graves' disease who were in remission and had no postpartum relapse of Graves' thyrotoxicosis. TSAb was measured by a sensitive cAMP accumulation assay using FRTL-5 cells, and TBII was determined by radioreceptor assay. In no patient with either recurrent or new onset postpartum hyperthyroidism did the serum free T3 index (FT3I) rise before the free T4 index (FT4I). Of the 10 patients who had postpartum thyrotoxicosis, concomitant increases in serum FT4I and FT3I, and TSAb and TBII were observed in only 1 patient. Increases in TSAb and TBII after those in FT4I and FT3I occurred in 6 patients. In 1 patient, an increase in TBII was associated with the occurrence of thyrotoxicosis, but TSAb increased 1 month later. In the other 2 patients, a TSAb increase was followed by the development of thyrotoxicosis, but TBII increased later. In 3 of these 10 patients, the increased serum FT4I and FT3I values decreased spontaneously, whereas the TSAb and TBII levels increased continuously. No positive test or increase in TSAb or TBII was found in the 5 patients with Graves' disease who did not have a postpartum relapse of thyrotoxicosis. These data indicate that postpartum initiation of Graves' thyrotoxicosis is not always associated with an increase in circulating anti-TSH receptor antibodies and that such parameters are poor indicators of thyroid function. Intrathyroidal humoral or cell-mediated immunological mechanisms may also be involved in mediating thyrotoxicosis in Graves' disease.     

Islet cell and glutamic acid decarboxylase antibodies in hyperthyroid patients: at diagnosis and following treatment

Objectives. To study the frequency of islet cell (ICA) and glutamic acid decarboxylase (GAD-Ab) antibodies in patients with hyperthyroidism of different types at diagnosis before treatment and in the euthyroid state following treatment. Setting. Department of Endocrinology, Malmö University Hospital, Malmö, Sweden. Subjects and design. Blood samples were collected at diagnosis from 129 hyperthyroid patients, and about 6 months later, from 78 of the patients (euthyroid state). Ninety-two patients had Graves' disease (69 females and 23 males, median age 49 years, range 17–85 years), and 37 patients had toxic nodular goitre/solitary toxic adenoma (34 females and three males, median age 69 years, range 24–86 years). Interventions. Most patients were treated by radioactive iodine following the first blood sample. Main outcome measures. ICA and GAD-Ab in serum. Results. At diagnosis of Graves' disease, ICA were detected in two out of 92 (2.2%) patients, two out of 85 (2.4%) without diabetes mellitus and in the euthyroid state in one patient. None of the patients with toxic nodular goitre/solitary toxic adenoma had detectable ICA. At diagnosis of Graves' disease, GAD65-Ab as well as GAD67-Ab were detected in 11 out of 85 (13%) patients without diabetes. As many as six out of 11 GAD67-Ab-positive patients were GAD65-Ab negative. In the euthyroid state, GAD65-Ab were found in six out of 51 (12%) and GAD67-Ab in eight out of 51 (16%) of the non-diabetic Graves' disease patients. The frequencies of GAD65-Ab and GAD67-Ab in toxic nodular goitre/solitary toxic adenoma, diabetes excluded, were 3 and 0%, respectively, in the hyperthyroid state. Conclusion . The frequency of ICA in patients with hyperthyroidism is not increased as compared to the background population. GAD-Ab seems to be associated with Graves' disease and not with hyperthyroidism. The presence of GAD67-Ab in GAD65-Ab negative sera from patients with Graves' disease indicates autoreactivity against a specific GAD67 epitope.     

The Oral TRH Stimulation Test

ABSTRACT. We have developed a 28-hour TRH stimulation test based on the FT₃I response to repeated oral TRH stimulation. The normal FT₃I response in 15 controls was ±40 arb.U. Twenty-five euthyroid patients with multinodular goitre were studied. Fourteen had normal FT₃I responses and normal basal levels of serum T₄, FT₄I, serum T₃ and FT₃I. Eleven patients had FT₃I responses below 20 arb. U. Although the patients' individual basal values of serum T₄, FT₄I, serum T₃ and FT₃I were within the normal range, the median values of FT₄I, serum T₃ and FT₃I were significantly elevated compared to the controls, suggesting that these patients were in a “pretoxic” condition. This assumption seems to be supported by the fact that 3 of these patients subsequently became frankly hyperthyroid, whereas all patients with normal FT₃I response remained euthyroid. A comparison between the TSH response to i.v. TRH and the FT₃I response to oral TRH showed concordance in 21 of the 25 patients studied.