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.     

Does lats cause hyperthyroidism in Graves' disease? : (A review biased toward the affirmative)

The long-acting thyroid stimulator (LATS) is now accepted as a feature of Graves' disease, and a great deal is known about its biochemical characteristics and its mode of action on the thyroid. Briefly, it is an IgG that directly influences thyroid gland function; its action involves stimulation of adenyl cyclase and enhanced production of 3′, 5′ cyclic adenosine monophosphate in the thyroid. It has an effect on at least one other extrathyroid tissue, adipose tissue, as shown by increased lipolysis in guinea pig epididymal fat that is incubated with LATS. While these facts are all well established, little is known about factors controlling the production of LATS, and its precise role in Graves' disease is much debated. The relationship of LATS to features of Graves' disease, apart from hyperthyroidism, is probably quite indirect; indeed, there may be in the syndrome one or more other immunoglobulins that have more significance than LATS has for pretibial myxedema (dermopathy) and ophthalmopathy. Although LATS is said to occur in a majority of patients with hyperthyroidism of Graves' disease when concentrates of IgG are tested, even tenfold concentration has failed to show 100% positive results. This fact has raised doubts about the colse pathogenetic relationship of LATS to hyperthyroidism. Moreover, a few patients have been reported to have LATS in blood but to have suppressible (with thyroid hormone) thyroid function. Therefore, LATS as the sole cause of hyperthyroidism is a theory that is now difficult to uphold. The existence of a permissive factor that facilitates its action on the thyroid is one postulate that may reconcile the apparent discrepancies.     

促甲状腺激素受体抗体的检测及其在Graves病诊疗中的价值

血清促甲状腺激素受体抗体(TRAb)是Graves病的特征性抗体,伴随生物检验技术的进步,TSAb的检测方法历经了三代发展.目前的多数研究证实,检测TRAb不仅有助于判断甲状腺毒症发生的原因、评估甲状腺功能、制定诊疗方案,同时对Graves病的相关疾病如Graves眼病、胫前黏液性水肿、肝功能损害病情的评估有重要意义,通过监测TRAb可以一定程度上控制Graves病及其并发症的加重或者复发.检测有Graves病病史的孕妇血清TRAb对安全妊娠也有意义.将目前TRAb的检测方法及其临床意义的研究进展作一综述,有助于临床医师通过TRAb做出决策并提高临床疗效.     

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.     

Immunoglobulin class and subclass distribution of eye muscle and fibroblast antibodies in patients with thyroid-associated ophthalmopathy

OBJECTIVES The investigation of the antibody response in thyroid-associated ophthalmopathy (TAO) using different antigens and assays has given inconsistent results. We have analysed antibodies against eye muscle and control antigens in a large group of TAO patients to assess whether specific eye muscle antibodies exist in TAO. We have also evaluated the presence of IgA and IgM class antibodies and examined IgG subclass distribution. DESIGN Sera were obtained from all patients (TAO, Graves' disease without ophthalmopathy and Hashimoto's thyroiditis) within one year of diagnosis. Sera were also collected from healthy controls, with no family history of autoimmune thyroid disease. PATIENTS Thirty-eight patients had Graves' disease with Grade III or greater TAO; 15 patients had Graves' disease without ophthalmopathy and nine had Hashimoto's thyroiditis without any eye signs. The control group consisted of 14 subjects. MEASUREMENTS Antibodies against porcine eye and skeletal muscle, human eye (membrane and soluble antigen) and skeletal muscle, human thyroid microsomal and thyroglobulin antigens and dermal and orbital fibroblast antigens were assessed using ELISA. Antibody isotypes and IgG subclasses were studied for porcine and human eye muscle antibodies. Eye muscle (porcine and human) and orbital fibroblast antibodies were further analysed by immunoblotting. RESULTS There were no significant differences in the ability of either IgG or IgA in sera from the different groups to bind porcine and human eye muscle antigens. There was a significant correlation (P < 0·0001) between the binding to porcine eye muscle and skeletal muscle antigens (for both IgG and IgA). There was no difference between sera from TAO patients and control subjects in their binding to eye muscle fibroblasts for both IgG and IgA antibodies. However, IgA antibody activity against dermal fibroblasts differed significantly between TAO patients and controls (P <0·05). By immunoblotting, the frequency of IgA antibodies recognizing 21 kDa (40% of patients) and 62 kDa (52%) bands in porcine eye muscle blots and 20, 24 and 38 kDa bands in blots of human eye muscle (soluble) antigen differed significantly between patients with TAO and controls (P <0·05 in all cases). IgG antibodies recognizing 80 and 92 kDa bands in blots of the subcellular membrane antigen prepared from orbital fibroblasts were found more frequently in patients with TAO compared with controls (P <0·05 in both cases). CONCLUSIONS We found no evidence that eye muscle membrane or fibroblast antibodies are present in a significant proportion of TAO patients, using ELISAs based on antigens prepared from several sources. We have also failed to demonstrate the presence of previously described specific, TAO-associated antibodies, including those directed against a 64 kDa protein in eye muscle and a 23 kDa protein in fibroblasts. IgA class antibodies reactive with orbital components appeared to be more strongly associated with TAO than those of the IgG class, though even this relationship is weak. These results suggest that antibodies are of secondary importance in the pathogenesis of TAO, which is most likely a T cell-mediated disorder.     

Euthyroid Graves' disease showing no thyroid abnormalities except positive thyroid-stimulating antibody (TSAb): two case reports

Abstract. We report two cases of euthyroid Graves' disease in women who had ophthalmopathy without previous history of hyperthyroidism. Enlargement of extraocular muscles was observed by magnetic resonance imaging (MRI). The patients had no thyroid enlargement and their serum concentrations of free T₄, free T₃, and TSH were normal. The sera were negative for antithyroid microsomal and thyrogobulin antibodies, and anti-TSH receptor antibodies measured by radioreceptor assay. T₃ suppression test results were normal. Only thyroid-stimulating antibody (TSAb) measured by sensitive bioassay was positive. These findings indicate that sensitive TSAb is the most useful laboratory test in the diagnosis of euthyroid Graves' disease.     

FAILURE OF HAEMAGGLUTINATION AND IMMUNOFLUORESCENCE METHODS TO DETECT SERUM ORBITAL ANTIBODIES IN PATIENTS WITH GRAVES' OPHTHALMOPATHY

Serum antibodies against human, bovine, and guinea-pig, orbital antigens were tested for in patients with Graves' ophthalmopathy using haemagglutination and immunofluorescence techniques. Although low titres of antibodies were demonstrated in a small proportion of patients with Graves' ophthalmopathy, the prevalence was similar to that for normal subjects using both tests. The significance of these findings and the evidence for a role of autoantibodies in the pathogenesis of Graves' ophthalmopathy are discussed.     

The role of TSH receptor antibodies in the management of Graves' disease

The central role of thyrotropin receptor antibodies (TRAbs) in the pathogenesis of Graves' disease has been recognised for several decades. However, the practical application of testing for TRAbs in clinical decision making remains the subject of controversy. The diagnosis of Graves' disease can be made in most cases simply based on a patient's clinical presentation. The TRAb test is therefore of most value in ambiguous clinical scenarios such as in the differential diagnosis of unilateral exophthalmos, euthyroid Graves' ophthalmopathy, subclinical hyperthyroidism, thyrotoxicosis associated with hyperemesis gravidarum, amiodarone-induced thyrotoxicosis and painless thyroiditis. It may also have a role in predicting the risk of a recurrence of Graves' disease following a course of antithyroid drug treatment. One further clinical utility of the TRAb test is in pregnancy where antibody titre measured during the third trimester is used to predict the risk of neonatal thyroid dysfunction. The TRAb titre not only aids in clinching a difficult diagnosis but can also help guide treatment in some patients. Although the TRAb assay has become more affordable in recent years, cost remains an important factor when considering its use routinely. Nonetheless, this is an underutilised blood test that could augment standard endocrine investigations in the differential diagnosis of hyperthyroidism.     

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.     

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.     

Hyperthyroid Graves' disease without detectable thyrotropin receptor antibodies.

TSH receptor antibodies are generally held responsible for the stimulation of the thyroid that characterizes patients with Graves' disease. Here, we describe nine patients with hyperthyroidism (triiodothyronine 4.9, 3.2-6.7 nmol/L; median, range) who were referred for radioiodine treatment and who had increased thyroid radioiodine uptake values but lacked TSH receptor antibodies determined by a radioreceptor assay. Furthermore, when serum immunoglobulins were studied in a bioassay based on a rat thyroid cell line (FRTL-5), no evidence of stimulant activity was observed. Subsequent to radioiodine therapy, TSH receptor antibodies appeared in all nine patients. The antibodies competed for TSH in the radioreceptor assay and, of the eight patient samples studied with the bioassay, six stimulated cAMP production whereas another two blocked the latter. The results show that a small proportion of patients with active hyperthyroid Graves' disease, in this study 9 out of 130 cases, do not have detectable TSH receptor stimulatory antibodies. A local production of antibodies within the thyroid can be suggested, although a more likely explanation might be that the thyroid in Graves' disease is activated also by other mechanisms than antibody-dependent ones.     

Graves' dermopathy and acropachy are markers of severe Graves' ophthalmopathy.

It is generally considered that thyroid dermopathy and acropachy almost always occur with Graves' ophthalmopathy and that these two extrathyroidal manifestations are indicators of severe autoimmune disease and hence of more severe ophthalmopathy. However, documentation of these anecdotal impressions is needed. We assessed the presence of optic neuropathy and frequency of orbital decompression in 2 referral cohorts: 40 patients with acropachy and dermopathy (acropachy group) and 138 patients with Graves' dermopathy and no acropachy (dermopathy group). We compared those cohorts with a cohort of 114 patients who had ophthalmopathy without dermopathy and acropachy (control group). We considered optic neuropathy and the need for orbital decompression to be indicators of severe Graves' ophthalmopathy. The frequency of orbital decompression was significantly higher in the dermopathy group than in the control group (odds ratio, 3.55) and even higher in the acropachy group (odds ratios: 20.68 for acropachy group compared with control group; 5.83 for acropachy group compared with dermopathy group). The same trend occurred with optic neuropathy but was not statistically significant (alpha = 0.05; p = 0.07). Five patients were exceptions: they had definite Graves' dermopathy without clinically obvious ophthalmopathy. In conclusion, dermopathy and acropachy appear to be markers of severe ophthalmopathy. Occasionally, however, Graves' dermopathy occurs without clinical ophthalmopathy.     

Treatment of Graves' Ophthalmopathy with Cyclosporin A

ABSTRACT Six patients with Graves' ophthalmopathy (2 with acute and 4 with chronic alterations) were treated with cyclosporin A (10 mg/kg/day) for 5 weeks. This treatment had no effect on either the ocular manifestations (protrusion, eye muscle function) or subjective well-being of the patients. In contrast, creatinine clearance decreased from 83.5 to 55.5 ml/min during treatment, but normalized (94.9 ml/min) after cessation of the drug. A transient increase in serum 4-androstenedione was observed in 3 patients. We conclude that cyclosporin A has no convincing effect in the treatment of Graves' ophthalmopathy, but rather exerts serious renal effects.     

Development of severe thyroid-associated ophthalmopathy in a patient with disseminated thyroid cancer treated with recombinant human thyrotropin/radioiodine and retinoic acid.

We present a case in which a patient with disseminated well-differentiated papillary thyroid cancer developed severe thyroid-associated ophthalmopathy. Eight years after initial surgery and ablative radioiodine therapy the patient was found to have multiple pulmonary metastases. The metastases showed poor uptake of radioiodine. An attempt was made to use 13-cis-retinoic acid in order to achieve a redifferentiation of the thyroid cancer cells before recombinant human thyrotropin (rhTSH) stimulated radioiodine therapy. The treatment did not improve the uptake of radioiodine. However, approximately 2 weeks after completion of the treatment the patient experienced discomfort in her eyes and then over the next months she developed a severe ophthalmopathy. The analyses of TSH receptor antibodies and S-thyroglobulin simultaneously showed a pronounced increase. An association between therapy given and severe ophthalmopathy cannot be excluded.     

Anti-cardiolipin antibodies in autoimmune thyroid diseases

OBJECTIVE In recent years anti-phospholipid antibodies have gained much attention since they are frequently associated with thrombosis, recurrent abortion, and thrombocytopenia. Besides disease-specific autoantibodies, other autoantibodies reactive with both organ and non-organ specific autoantigens have been found in patients with autoimmune thyroid diseases. Therefore the objective of this study was to evaluate the presence and significance of anti-phospholipid antibodies in untreated patients with different forms of autoimmune thyroid diseases. PATIENTS AND METHODS Thirty-one patients (26 females, five males; mean age 42.5 years) affected by different autoimmune thyroid diseases were studied. Fourteen patients were affected by Graves' disease, eight by silent thyroiditis, five by Hashimoto's thyroiditis. Four patients with Graves' disease in remission were also evaluated. Anti-cardiolipin antibodies were detected by enzyme linked immunosorbent assay. In five Graves' disease patients anti-cardiolipin antibodies were evaluated before and after 3 months of therapy with methimazole. RESULTS Seventeen out of 31 patients were positive for IgG and/or IgM anti-cardiolipin antibodies, the highest levels occurring in three Graves' disease patients with severe thyrotoxicosis. In four of five Graves' patients evaluated before and after methimazole therapy, anti-cardiolipin antibodies decreased following treatment. None of the patients with increased IgG and/or IgM anti-cardiolipin antibodies showed clinical manifestations of the anti-phospholipid syndrome during our observation which ranged from 1 to 5 years. CONCLUSIONS Our results showed an increased incidence of anti-cardiolipin antibodies in patients affected by autoimmune thyroid diseases. However, these autoantibodies seem merely to represent a non-specific marker of immune dysregulation.     

THE SPECIES SPECIFICITY OF TSH RECEPTOR BINDING ANTIBODIES AS MEASURED BY RADIORECEPTOR ASSAY

The species specificity of TSH binding inhibitory antibodies was compared for patients with untreated Graves' hyperthyroidism, past Graves' hyper-thyroidism, active ophthalmopathy with past hyperthyroidism, and subacute thyroiditis, by measuring inhibition of TSH binding to plasma membranes prepared from human, guinea-pig, calf, pig, and dog thyroid glands in a radioreceptor assay. Results were expressed as TSH binding inhibition indices (TBII). Broad species reactivity was demonstrated. This was greatest with pig and least with guinea-pig thyroid membranes. Immunoglobulin (Ig) from patients in whom strongly positive tests with human thyroid preparations were demonstrated were usually strongly positive with all other species tested, whereas Ig from patients which were less strongly positive with human were, generally, also less positive with the other species. There was a tendency for greater species reactivity of TSH binding inhibiting antibodies from patients with treated Graves' hyperthyroidism (with or without eye disease) than of those from untreated patients with Graves' hyperthyroidism or subacute thyroiditis. Combining the data from all groups, correlation between TBII for human membranes and those of other species was best for dog and least for guinea-pig. It is concluded that the TSH binding inhibiting antibody is a polyclonal antibody against a single antigen at or near the TSH receptor, and that the degree of reactivity with its antigen in other species depends, mainly, on the amount of antibody present in the serum.     

Significance of antibodies reactive with a 64 kDa eye muscle membrane antigen in patients with thyroid autoimmunity.

SDS-polyacrylamide gel electrophoresis and Western blotting for antibodies reactive with a 64 kDa protein in pig eye muscle membrane was carried out in patients with lid lag and retraction, but no other signs of ophthalmopathy, associated with thyroid disease or nonimmunologic goiter and in patients with Graves' hyperthyroidism without ophthalmopathy who were studied prospectively to determine the relationship of eye muscle antibodies to clinical features of the ophthalmopathy as they appeared in this group of predisposed patients. Seventy-one percent of euthyroid patients with lid lag and retraction but no established ophthalmopathy had detectable serum antibodies to a 64 kDa eye muscle membrane protein. Much smaller proportions had antibodies to proteins of other MW. In normal subjects with previously detectable antibodies to a 64 kDa protein, serum titers, determined by carrying out immunoblotting at serum dilutions of 1:25-1:6400, were low (< or = 1:100) in all cases tested. On the other hand, titers were higher (1:200-1:6400) in 16 of 22 patients with established ophthalmopathy and in 5 of 7 patients with lid lag and retraction tested. Titers tended to be lower in patients with ophthalmopathy of > or = 3 years duration than in those of < or = 1 year duration. Antibody titers were low (1:25) in 6 of 7 patients with Graves' hyperthyroidism without evident eye disease tested. Antibodies to a 64 kDa eye muscle membrane protein were predictive of the development of ophthalmopathy in patients with Graves' hyperthyroidism studied prospectively for periods of 8-42 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presence of antibodies in the sera of patients with Graves' disease recognizing a 23 kilodalton fibroblast protein

We examined whether antibodies (present in sera from patients with Graves' disease) might be directed against a connective tissue cellular component of the anatomical regions affected in the peripheral manifestations of that disease. Accordingly, we performed immunoblot analyses of cultured retroocular and pretibial fibroblasts. Retroocular connective tissue was obtained during orbital decompression surgery (n = 7) and at autopsy from normal individuals (n = 2). Pretibial skin biopsies were obtained from patients with pretibial dermopathy (n = 3) and at autopsy (n = 2). In addition, biopsies from other regions [extraocular muscle (n = 6), thyroid (n = 2), and abdominal skin (n = 3)] were also collected at surgery or autopsy. Serum samples were obtained from patients with severe Graves' ophthalmopathy (n = 31), hyperthyroid Graves' disease without overt ophthalmopathy (n = 13), nodular thyroid disease (n = 7), Hashimoto's thyroiditis (n = 7), rheumatoid arthritis (n = 5), and systemic lupus erythematosus (n = 3) and from normal individuals (n = 33). Electrophoresed fibroblast proteins were immunoblotted with 1:100 dilutions of sera using an antihuman immunoglobulin G-alkaline phosphatase conjugate. Antibodies against a 23kDa fibroblast protein were present in the sera from 24 of 44 (56%) of patients with Graves' disease with or without ophthalmopathy, 0 of 7 nodular thyroid disease, 0 of 7 Hashimoto's thyroiditis, 0 of 5 rheumatoid arthritis, 0 of 3 systemic lupus erythematosus, and 5 of 33 (15%) normal subjects. Significant differences in the observed frequency of antibodies existed between the Graves' disease group and the normal control group (P less than 0.01) or those patients with the other conditions (P less than 0.01). This 23kDa antigen was apparent in fibroblasts derived from individuals with Graves' disease as well as normal individuals and was present in fibroblasts from all anatomical sites studied. It was the sole protein uniquely recognized by sera from patients with Graves' disease. However, this serum reactivity did not appear to be related to the presence of clinically overt ophthalmopathy or pretibial dermopathy. Subcellular localization studies disclosed that the antigen was present in the supernatant but not the pellet resulting from a 100,000 x g centrifugation of whole cell sonicates. Antibodies against a 23kDa fibroblast protein are present in the majority of sera from patients with Graves' disease and rarely in sera from either normal individuals or those with other thyroid disorders or autoimmune diseases. Our results suggest the possibility that antibodies directed against this fibroblast antigen may be related to the developm     

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.     

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.