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.     

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.     

EFFECT OF RADIOIODINE ON STIMULATORY ACTIVITY OF GRAVES'IMMUNOGLOBULINS

The effects of ¹³¹I therapy on the activity of thyroid stimulating antibody (TSAb) and thyrotrophin binding inhibiting immunoglobulin (TBII) in nineteen patients with Graves’disease have been studied. Prior to ¹³¹I administration TSAb was detected in 84%, and TBII in 68% of patients. Following ¹³¹I administration TSAb and TBII were detectable in 100% of patients. The elevation 3 months after treatment of the means of both the TSAb and TBII indices for the group of nineteen patients was highly significant compared with pre treatment values. All the patients went into remission during the course of the study and the TSAb index declined in all patients, becoming undetectable in eleven; TBII also declined in most patients but remained detectable in thirteen. The study furthermore afforded the opportunity for a direct comparison of binding with stimulatory activity. These results show that after ¹³¹I therapy for Graves’hyperthyroidism there is a transient increase in TSAb as well as TBII, followed by a decline, and that the measurement of binding and stimulatory activities are in good general agreement.     

A study of untreated Graves' patients with undetectable TSH binding inhibitor immunoglobulins and the effect of anti-thyroid drugs

OBJECTIVE We previously reported the clinical characteristics of Graves' disease with undetectable TSH binding inhibitor immunoglobulins (TBII) at first visit, but a study of the prognosis of untreated TBII negative patients with anti-thyroid drug medication has never been undertaken. The aim of this paper is to study the difference between negative and positive TBll Graves' disease in relation to the effect of anti-thyroid drug treatment. PATIENTS From January 1986 to April 1991,1545 patients with untreated Graves' disease were referred to Kuma Hospital, Kobe, Japan. Of these, 94 TRAb negative patients were identified. Another 83 TRAb positive patients were randomly selected from the other Graves' disease patients and served as a comparison group. Fifty-six of the 94 patients in the TBII negative group and 52 of the 83 patients in the TBII positive group completed treatment with methimazole only. MEASUREMENTS The trial was conducted as a retrospective study with a maximum treatment period of 36 months and a follow-up period of a further 12 months. From the original pool of patients, we classified 56 TBII negative patients into two groups according to the clinical course taken; Group A in whom TBII remained undetectable throughout methimazole treatment (9 men and 34 women, age 37.2 ± 2.2 years), and Group B who became TBII positive (4 men and 9 women, 31.2 ± 44 years). Fifty-two TBII positive patients served as the comparison Group C (8 men and 44 women, age 38.1 ± 2.0 years). RESULTS Serum free T4 and free T3 levels in groups A and B were significantly lower before treatment than those of Group C (P < 0.001). The thyroid volumes of Group A and B patients were significantly smaller than those of Group C (P < 0.01). The level of TBII in Groups A and B was significantly lower than that in Group C (8.3 ± 0.7 and 8.8·1.1 vs 57.0 ± 28%, respectively, P < 0.001). The level of thyroid stimulating antibody (TSAb) in Groups A and B was significantly lower than that in Group C (478 ± 71.0 and 761 ± 140.3 vs 2143 ± 280%, respectively, P < 0.01), and there were no significant differences in TSAb activities between Groups A and B. The remission rates in Groups A, B and C were 77.4, 36.4 and 36.5%, respectively. These data Indicate that Group A has a good prognosis, but Group B has the same prognosis as Group C. CONCLUSION We conclude that patients In whom TSH binding inhibitor Immunoglobulins remained negative have a much better prognosis than TSH binding inhibitor immunoglobulins positive patients or those who become TSH binding inhibitor immunoglobulins positive, having been initially negative.     

PRODUCTION OF NON-STIMULATORY IMMUNOGLOBULINS THAT INHIBIT TSH BINDING IN Graves'' DISEASE AFTER RADIOIODINE ADMINISTRATION

The effect of a single dose of ¹³¹I upon thyroid stimulating immunoglobulins has been studied in twenty-two patients with Graves' disease. The thyroid stimulating immunoglobulins were assessed by parallel measurements of thyrotrophin receptor binding inhibitory immunoglobulins (TBII) and of thyroid adenylate cyclase stimulating immunoglobulins (TACSI) in serum by radioreceptor assay and stimulation of adenylate cyclase respectively. Prior to ¹³¹I therapy TBII were present in fourteen and TACSI in sixteen patients; seventeen were positive in one of the assays and thirteen in both assays. After radioiodine the level of both TACSI and TBII increased in most patients, but in six patients ¹³¹I therapy appeared to lead to a dissociation between the TBII and TACSI. After 12 months, nine patients were still positive in both assays, and twenty-one in one of the assays. In total, five patients developed hypothyroidism within 1 year after radioiodine. The TBII levels were significantly higher both before and 3 months after therapy in these patients than in those who remained euthyroid. Two of the hypothyroid patients developed non-stimulatory TSH binding inhibitory antibodies. The present study thus confirms that radioiodine therapy is followed by an increase of TBII and TACSI in most patients with Graves' disease. The level of TBII can probably provide a marker for development of hypothyroidism following ¹³¹I therapy and might be involved in its pathogenesis.     

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.     

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.     

Metastatic thyroid cancer presenting as thyrotoxicosis: report of three cases

Three patients with metastatic thyroid follicular carcinoma developed thyrotoxicosis. Two had mild T3 toxicosis without detectable TSH binding inhibitor immunoglobulins (TBII) or thyroid stimulating antibodies (TSAb). Considerable concentration of ¹³¹***I by tumours occurred, although serum TSH was undetectable. The third patient developed thyrotoxicosis several months after treatment with ¹³¹I had commenced and this was associated with concurrent increase in both TBII (90%; normal, less than 11%) and TSAb (2100%). We conclude that thyrotoxicosis in patients with metastatic thyroid carcinoma may result from a large bulk of tumour functioning either autonomously or after stimulation by TSH receptor antibodies.     

Influence of compensated radioiodine therapy on thyroid volume and incidence of hypothyroidism in Graves' disease

Abstract. Objectives . To investigate the long-term effect of radioactive iodine (¹³¹I) on thyroid function and size in patients with Graves' disease. Setting . Out-patient clinic in Herlev Hospital. Subjects . One hundred and seventeen consecutive patients (104 women) with Graves' disease selected for ¹³¹I treatment and followed for a minimum of 12 months (range 1–10 years, median 5 years). Interventions . ¹³¹I dose was calculated based on thyroid volume and 24-h ¹³¹I uptake. Main outcome measures . Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 0.75, 1.5, 3, 6 and 12 months after treatment, and then once a year were investigated. Results . Seventy-eight patients were cured by one ¹³¹I dose and 30 by two doses, while the remaining nine patients received additional doses (range one to five doses, median one dose). Within one year, 25% developed hypothyroidism, and hereafter, hypothyroidism developed at a constant rate of 3% per year independent of antithyroid pretreatment. The cumulative 10-year risk of hypothyroidism was 60%. Initial median thyroid volume was 33 mL (range 9–106 mL). At 12 months after the last ¹³¹I dose, median thyroid volume was reduced to 14 mL (range 6–36 mL) (P < 0.00001). The median reduction being 58% (range 0–80%,), hereafter no further reduction occurred. A significant reduction in thyroid volume was also noted in patients needing subsequent ¹³¹I doses and in those developing hypothyroidism within the first year. Conclusions . ¹³¹I normalizes thyroid volume in patients with Graves' disease. Hypothyroidism seems an inevitable end result of this treatment. The present study suggests that it will be impossible to modify ¹³¹I therapy in a way to achieve both early control of hyperthyroidism and a low incidence of hypothyroidism.     

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 postoperative 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.     

Paired determination of thyroid-stimulating and TSH-binding inhibitory activities in patients with Graves' disease during antithyroid drug treatment

Sequential changes in thyroid-stimulating antibodies (TSAb) and TSH-binding inhibitor immunoglobulins (TBII) during antithyroid drug treatment were studied in 17 patients with Graves' disease. Before treatment, TSAb and TBII were detected in 17 (100%) and 13 (76.5%) patients, respectively, with a significant correlation between the two activities (r = 0.600, n = 17, P less than 0.02). In 9 patients who became euthyroid as early as after 1-4 months of treatment, the TSAb and TBII activities both gradually decreased, and there was a good correlation between the changes of these activities during treatment. Among the 7 patients in whom small changes in TSAb and TBII activities were observed, 4 showed poor control of the thyrotoxicosis during the whole observation period (7 months-2 years). One patient who showed a marked dissociation between the changes in TSAb and TBII activities developed hypothyroidism, when his TBII became remarkably high. These potent TBII inhibited cAMP production induced by bTSH. These findings indicate that 1) changes in TSAb and TBII activities reflect the clinical course of hyperthyroidism in most patients with Graves' disease, and 2) development of a blocking-type of TBII may induce hypothyroidism in some patients after the treatment.     

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.     

血清甲状腺自身抗体、碘摄入量与Graves病发病及临床转归的关系

目的探讨血清甲状腺刺激性抗体（TSAb）、甲状腺刺激阻断性抗体（TSBAb）等甲状腺自身抗体、碘摄入量与Graves病（GD）甲状腺功能亢进症（甲亢）发病和转归的关系。方法测定3个不同碘摄入量地区63例临床甲亢患者的血清TSAb、TSBAb、促甲状腺激素结合抑制免疫球蛋白（TBⅡ）、甲状腺过氧化物酶抗体（TPOAb）和甲状腺球蛋白抗体（TGAb）,2年后随访。TSAb和TSBAb采用转染了重组人促甲状腺素受体的中国仓鼠卵巢细胞（rhTSHR—CHO细胞）生物法测定。结果初访GD甲亢患者TSAb、TBⅡ和TSBAb的阳性率分别为80．9％、61．7％和6．4％,TSAb和TBⅡ任-抗体阳性率为91．5％,显著高于对照组。TSAb和TBⅡ的一致率为59．6％。GD甲亢患者TSAb与TBⅡ（r=0．407）、甲状腺球蛋白（r=0、301）、甲状腺体积（r=0．317）正相关。初访碘过量地区GD甲亢患者TSAb阳性率（91．7％）显著高于轻度碘缺乏地区（66．7％）,3个地区GD患者TBⅡ、TPOAb、TGAb阳性率、活性和甲状腺体积无统计学差异。随访时患者分为甲状腺功能恢复组（G1）和未恢复组（G2）。G1组TSAb活性和甲状腺体积显著下降。当TPOAb滴度显著增高,且随访时继续保持高滴度时,甲状腺功能不易恢复。此时TSAb对甲状腺功能的影响降为次要因素。结论TSAb对GD甲亢的诊断和判断临床转归的意义大于TBⅡ,联合应用二者能提高GD甲亢患者促甲状腺激素受体抗体的检出率;GD甲亢的转归与TSAb、TPOAb浓度和甲状腺体积有关。     

Remission of Graves' hyperthyroidism predicted by smooth decreases of thyroid-stimulating antibody and thyrotropin-binding inhibitor immunoglobulin during antithyroid drug treatment.

It is important to know whether a patient with Graves' disease will get into remission or not during antithyroid drug (ATD) treatment. Thyrotropin (TSH) receptor antibodies (TRAb) cause Graves' disease. Thyroid-stimulating antibody (TSAb) and TSH-binding inhibitor immunoglobulin (TBII) have been measured as TRAb to diagnose Graves' disease and to follow Graves' patients. Smooth decreases of TSAb and TBII during ATD treatment predict the remission of Graves' hyperthyroidism. We followed serial changes of TSAb and TBII in 58 Graves' patients before, during, and after ATD treatment; TSAb was measured as a stimulator assay, using porcine thyroid cells, and TBII as a receptor assay. Patterns of TSAb and TBII changes during ATD treatment differ from one patient to another. TSAb and TBII activities decreased and disappeared in 52 (group A) but continued to be high in the other 6 (group B); 39 of the 52 group A patients achieved remission, but all of the 6 group B patients with persistently positive TSAb and TBII continued to have hyperthyroidism. No differences in the initial TSAb and TBII activities were noted between the 52 group A patients and the 6 group B patients. Of the 52 group A patients in whom TSAb and TBII had disappeared, 44 had smooth decreases of TSAb and TBII (group A1), and 8 had complex changes of TSAb and/or TBII (group A2); 36 of the 44 group A1 patients (82%) but only 3 of the 8 group A2 patients (37%) continued to be in remission more than 1 year after ATD discontinuation. The number of remission in group A1 was significantly larger than that in group A2. No differences in the initial TSAb and TBII activities were noted between group A1 and group A2. More than 80% of group A1 patients, who had smooth decreases of TSAb and TBII, continued to be in remission longer than 1 year. We demonstrated that smooth decreases of TSAb and TBII during ATD treatment predicted the remission of Graves' hyperthyroidism. The Graves' patients can be classified into A1, A2, and B groups according to the patterns of TSAb and TBII changes during ATD treatment. Group A1 patients, who had smooth decreases of TSAb and TBII, had higher rate of remission than the others. Smooth decreases of TSAb and TBII during the early phase of ATD treatment are a reliable predictor of the remission.     

Immunoglobulins of untreated Graves' patients with or without thyrotropin receptor antibody (determined by porcine thyrocytes) universally elicit potent thyroid hormone-releasing activity in cultured human thyroid follicles.

Thyrotropin receptor antibody (TRAb), comprising thyrotropin binding inhibitor immunoglobulin (TBII) and thyroid-stimulating antibody (TSAb), both of which are conventionally determined using porcine thyrocytes in Japan, is not always positive in patients with untreated Graves' disease. To elucidate whether immunoglobulin G (IgG) obtained from TBII/TSAb-positive (+) or negative (-) Graves' disease patients are responsible for hyperthyroidism, we investigated the thyroid hormone-releasing activity (THRA) of these IgGs in human thyroid follicles in suspension culture, in which bovine thyrotropin (bTSH) is detectable even at 0.1 microU/mL. Human thyroid follicles, obtained from Graves' disease patients by subtotal thyroidectomy, were cultured in serum-free F-12/RPMI-1640 medium supplemented with bTSH or purified Graves' IgGs. After preculturing for 3 days, 125I was added, and after an additional 3 days of culture, 1251 incorporated into the thyroid follicles and organic 125I released into the culture medium (mainly 1251 -T4 + 125I-T3) were counted. Seventy TBII(+)/TSAb( + )-, 3 TBII( + )/TSAb( - )-, and 3 TBII( - )/TSAb( + )- patients with untreated Graves' disease were all positive for THRA, which became undetectable in spontaneous remission obtained after several years of medical treatment. The THRA was equivalent to 0.8-230 microU/mL bTSH. Furthermore, 2 TBII(-)/TSAb(-) patients were significantly positive for THRA. This TBII(-)/TSAb(-)IgG stimulated human thyrocytes to produce cyclic adenosine monophosphate (cAMP), and this was partially inhibited by antihuman IgG antibody. The THRA induced by TBII(+)/TSAb(+) IgGs as well as TBII(-)/TSAb(-) IgG was inhibited by blocking-type TRAb obtained from TBII(+) patients with myxedema. There was a significant correlation between THRA and TSAb. These in vitro findings suggest that all IgGs obtained from untreated Graves' patients (n = 78) elicit potent THRA in human thyroid follicles in suspension culture. Because the TBII(-)/TSAb(-) IgGs can stimulate cAMP production in human but not in porcine thyrocytes, they probably recognize epitope(s) of TSH-binding sites specific to the human thyrotropin (hTSH) receptor. Furthermore, we have demonstrated that the thyroid gland of hyperthyroid Graves' patients is stimulated by IgG(s) equivalent to at least 0.8 microU/mL bTSH (about 5 microU/mL hTSH) in vitro.     

LACK OF EFFECT OF SOMATOSTATIN ON THYROID GLAND FUNCTION IN GRAVES' DISEASE

Five women with Graves' disease, 26–52 years of age, with serum concentrations of triiodothyronine (T3) 4·8–9·2 nmol/l and thyroxine (T4) 200–320 nmol/l were studied. A 26 h infusion of cyclic somatostatin (Bachem), 6 mg in isotonic saline solution was administered. Radioactive iodine i.v. (¹²⁵I or ¹³¹I) was given immediately after the start of this infusion. Serum T3, T4 and conversion rate (CR%= PBRI: total RI × 100) were determined four times during the infusion, then daily for a week. The same studies, related to an injection of radioiodine, were performed during a control week when no somatostatin was administered. Arginine-stimulated insulin and growth hormone (hGH) concentrations were considerably lowered by the somatostatin infusion. No difference in serum T3, T4 or CR between the week that started with somatostatin infusion and the control week was observed. Twelve-26 h after the somatostatin infusion started, all patients experienced gastrointestinal symptoms, which lasted 2–6 h after somatostatin withdrawal. Somatostatin in the dose given does not inhibit thyroid gland function in 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.     

Standardized radioiodine therapy in Graves' disease: the persistent effect of thyroid weight and radioiodine uptake on outcome

Abstract. Objective. To assess the incidence of hypothyroidism, euthyroidism, and recurrent hyperthyroidism following a standard dose of Na¹³¹I (3.7 MBq or 100 μCi) per g thyroid tissue, adjusted for radioiodine tracer uptake. Design. A single-centre prospective follow-up study from January 1990 to December 1992. Setting. Academic Hospital in Utrecht, the Netherlands. Subjects. Newly diagnosed patients with Graves' disease (n = 148). Interventions. Radioiodine treatment at a standard dose of 3.7 MBq or 100 μCi per g thyroid tissue. Main outcome measures. Confidence interval testing of resulting thyroid status, defined by biochemical criteria. Results. The overall cure rate was 70% (103 of 148 subjects), confidence interval (CI) 62–77%. A 90% incidence of hypothyroidism was found in patients with a small thyroid (less than 20 g). Recurrent hyperthyroidism was found significantly more often in subjects with a thyroid weight exceeding 60 g compared to those who had a thyroid of 9–59 g. More recurrences were found in subjects in the highest tertile of a 24-h radioiodine uptake test (> 80% uptake) compared to those in the lowest tertile (< 60% uptake). Conclusions. No uniform treatment results expressed per thyroid weight category were obtained, in spite of standardizing the treatment Na¹³¹I dose (3.7 MBq per g thyroid). Graves' patients with a thyroid smaller than 20 g and those with less than 60% 24-h radioiodine uptake have a 50–90% chance of hypothyroidism at the 12-month follow-up.     

Appearance of thyroid stimulating antibody and Graves' disease after radioiodine therapy for toxic nodular goitre

A patient with toxic nodular goitre is described in whom radioiodine (¹³¹I) therapy paradoxically induced typical Graves' disease. This patient had a goitre with two autonomously functioning nodules suppressing uptake by the remainder of the gland. Circulating thyroid peroxidase antibody indicated the coexistence of focal lymphocytic thyroiditis. Radioiodine therapy was followed by the development of severe and persistent Graves' hyperthyroidism associated with diffuse ¹³¹I uptake by the gland. A second administration of ¹³¹I produced a further worsening of hyperthyroidism, and the appearance of ophthalmopathy. TSH-receptor antibody and thyroid stimulating antibody were undetectable before ¹³¹I, appeared after the first administration of radioiodine, and showed a further increase after the second dose of ¹³¹I. We suggest that, in a patient genetically susceptible to thyroid autoimmunity, the release of TSH-receptor antigenic components from follicular cells damaged by radioiodine therapy triggered an autoimmune response to the TSH-receptor, thus turning a toxic nodular goitre into Graves' disease.     

The occurrence of thyrotropin binding-inhibiting immunoglobulins and thyroid-stimulating antibodies in patients with silent thyroiditis

Silent (painless) thyroiditis has been recognized as a clinical entity for over a decade and is characterized by spontaneously resolving thyrotoxicosis. Its etiology is uncertain; however, a few reports have indicated the occurrence of TSH binding-inhibiting immunoglobulins (TBII) and thyroid-stimulating antibodies (TSAb) in some of the patients. The present study was undertaken to evaluate thyroid function and the occurrence of TBII and TSAb and thyroid autoantibodies (antithyroglobulin and antimicrosomal) in 53 patients with silent thyroiditis during the course of their disease. The patients were divided into 2 major groups: I) those who developed transient hypothyroidism and II) those who did not. All patients initially had significantly increased concentrations of serum T4, free T4, and free T3, suppressed TSH levels, and decreased thyroid radioiodine uptake. TBII and TSAb were initially positive in 8 (15.1%) and 10 patients (18.9%), respectively. Forty patients were available for follow-up. TBII was positive in 6 of 24 (25.0%), and TSAb was positive in 8 of 24 (33.3%) of the patients who developed transient hypothyroidism during the course of their disease. Among the patients who did not become hypothyroid at any time, TBII was positive in only 2 of 16 (12.5%), and none of the patients became TSAb positive. The findings indicate that increased TSAb and TBII activity may be detected in patients with silent thyroiditis and, when present, are associated with transient hypothyroidism during the course of the disease.