Thyroid-stimulating antibody is related to Graves' ophthalmopathy, but thyrotropin-binding inhibitor immunoglobulin is related to hyperthyroidism in patients with Graves' disease.

We investigated the relationship between thyroid function or ophthalmopathy of Graves' disease and thyrotropin receptor antibodies (TRAb) in 155 untreated patients with Graves' hyperthyroidism. All patients were examined by ophthalmologists, and underwent computed tomography of the orbit and measurement of serum free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin-binding inhibitor immunoglobulin (TBII), and thyroid stimulating antibodies (TSAb). Patients were divided into three groups according to the presence of orbital fat increase (OFI) and extraocular muscle enlargement (EME): 57 patients without OFI and EMO formed the no Graves' ophthalmopathy (NGO) group; 55 patients with OFI but without EMO formed the OF group; 43 patients with EME with or without OFI formed the EM group. The FT3, FT4, and thyroid weight increased in the order of the EME, NGO, and OFI groups. TSAb increased in the order of the NGO, OFI, and EME groups, and TSAb was significantly greater in the EME and OFI than in the NGO group. TBII was not significantly different among the three groups, but was lower in EME than NGO. There was a significant positive correlation between TBII and FT3 or FT4 in all patients combined as well as in all three groups, but correlation between TSAb and FT3 or FT4 was very weak in all groups, and that between TSAb and FT3 was not significant in the EM group In the relationship between ophthalmopathy and TRAb, the sum of the scores of eyelid swelling, proptosis, and extraocular muscle enlargement was taken as a measure of the overall severity of the Graves' ophthalmopathy (GO). TSAb was significantly correlated with the GO score, but there was no correlation between TBII and GO scores. In conclusion, TSAb was correlated with ophthalmopathy but TBII was related to hyperthyroidism.     

Clinical studies on abnormal thyroid stimulators in patients with Graves' disease. II. Clinical significance of measuring TSAb and TBII in patients with euthyroid Graves' disease and patients with hyperthyroid Graves' disease during antithyroid drug treatment

To evaluate the clinical significance of TBII and TSAb activities in euthyroid and hyperthyroid Graves' disease, these two activities were measured in 8 patients with euthyroid Graves' disease and 29 patients with hyperthyroid Graves' disease during treatment with antithyroid drugs. In 8 patients with euthyroid Graves' disease, TBII activity was detectable only in one patient and TSAb activity detected in 3 patients, these detectabilities being much lower than those in hyperthyroid Graves' disease. However, 2 of 4 patients who had either TSAb or TBII came to have both activities, and one of them became overt hyperthyroid. In patients with hyperthyroid Graves' disease, detectabilities of these activities became lower as they became euthyroid with antithyroid drug treatment, but TSAb tended to be higher than TBII when they remained euthyroid for more than 4 months. Although the majority of the patients who had TSAb and/or TBII activities were T3 non-suppressible, patients with no TSAb and TBII activities did not necessarily show remission of the disease. The present results suggest that patients with euthyroid Graves' disease with both TBII and TSAb may be apt to become hyperthyroid, and that TSAb and TBII activities and T3 suppressibility may not be a definite criteria for the remission of Graves' disease.     

Increased retinal blood flow in patients with Graves' disease: influence of thyroid function and ophthalmopathy

OBJECTIVE: Graves' ophthalmopathy (GO), resulting from the inflammation of retro-orbital tissue, is one of the major complications of Graves' disease (GD). We investigated the clinical usefulness of the measurement of retinal blood flow (RBF) in the evaluation of GO and its activity. MEASUREMENT: RBF was quantitated by pulsed Doppler mode at just below the branch of central retinal artery, from which the resistance index (RI) was calculated. PATIENTS: Forty-seven euthyroid GD patients and 70 gender- and age-matched normal controls were measured for RI to investigate the effect of GO on RBF. To investigate the effect of hyperthyroidism, 20 GD patients were measured for RI changes during antithyroid drug (ATD) therapy. Furthermore, 17 GD patients with clinically overt GO were measured for RI changes during treatment with glucocorticoid plus retro-orbital radiation. RESULTS: RI and exophthalmos showed a significant positive correlation in 47 treated euthyroid GD patients without clinically overt GO (r=0.307, P<0.05), but not in 70 age- and sex-matched normal subjects (r=0.185, P=0.161). Furthermore, RI, but not exophthalmos, significantly correlated with serum TSH receptor antibodies, an indicator for the disease activity of GO. ATD therapy significantly reduced RI in GD patients from 0.719+/-0.041 in the hyperthyroid state to 0.661+/-0.051 in the euthyroid state, but not to the levels observed in normal subjects having the similar exophthalmos (0.640+/-0.049). The fractional reduction of RI during ATD therapy significantly correlated with those of pulse pressure and ultrasonographic distensibility in carotid artery, but not with those of serum vascular injury markers. In 17 GD patients with clinically overt GO, all four patients having adipose tissue enlargement but not extraocular muscle hypertrophy (inactive GO) showed RI within the mean +/- 1 s.d. for treated GD patients without GO. In the other 13 GD patients having extraocular muscle hypertrophy (active GO), four and eight patients showed RI outside mean +/- 2 s.d. and mean +/- 1 s.d. respectively. Treatment with glucocorticoid plus radiation moved RI in 8 out of 10 patients toward the mean values of GD patients without GO, in spite of little improvement of exophthalmos. CONCLUSIONS: It was suggested that GD patients showed altered retinal hemodynamics, possibly resulting either from the cardiovascular effect of hyperthyroidism or from retro-orbital inflammation, particularly in extraocular muscle.     

Studies of immunoreactivity to human lacrimal gland fractions in patients with ophthalmic Graves' disease.

In vitro evidence for immunoreactivity against human lacrimal gland fractions was sought in patients with ophthalmic Graves' disease. There was no significant increase in interstitial lymphoid tissue on lacrimal gland biopsy. Serum antibodies against lacrimal fractions were not detected using the indirect immunofluorescent technique. Using the tanned cell hemagglutination test with lacrimal antigen, antibodies were detected in 2 of 15 patients with eye disease, 2 of 15 hyperthyroid patients without eye disease, and 2 of 20 normal subjects. Macrophage inhibitory factor (MIF) production in response to human lacrimal extract was not demonstrated in any of 11 patients with eye disease tested. On the other hand, MIF was demonstrated in 2 of 10 patients with Graves' disease selected for absence of eye disease. Significant peripheral blood lymphocyte transformation in response to human lacrimal extract, or a soluble or membrane fraction, was demonstrated in 9 of 22 patients tested; in 6 of 21 patients to extract, in 3 of 21 patients to a soluble fraction and in 7 of 10 patients to a membrane fraction. The possible significance of lacrimal gland inflammation and role(s) in the pathogenesis of ophthalmic Graves' disease are discussed.     

STUDIES ON THYROTROPHIN RECEPTOR ANTIBODIES IN PATIENTS WITH EUTHYROID GRAVES'' DISEASE

Thyroid stimulating antibodies (TSAb) and TSH-binding inhibitor immunoglobulins (TBII) were assessed in 30 patients with euthyroid Graves' disease. TSAb were detected in 24 cases (80.0%), the incidence being not significantly different from that in hyperthyroid Graves' disease (29/30, 97.6%). On the other hand, the incidence of TBII in patients with euthyroid Graves' disease (12/30, 40.0%) was significantly lower than that in patients with hyperthyroid Graves' disease (30/30, 100.0%). The mean TSAb and TBII activities in the euthyroid patients were significantly lower than in the hyperthyroid patients (P less than 0.005 and P less than 0.001, respectively). Both TBII and, more closely, TSAb activities correlated with T3-nonsuppressibility and inhibition of serum TSH response to TRH stimulation. The findings supported the stimulation in vivo of the thyroid by these antibodies. Both antithyroglobulin and antimicrosomal antibody titres in euthyroid Graves' disease were significantly lower than in hyperthyroid Graves' disease (P less than 0.05, P less than 0.01, respectively). Goitre size was significantly smaller (P less than 0.001), and 99mTc thyroid uptake was significantly lower (P less than 0.001) in the euthyroid than in the hyperthyroid group. Thus, the reduced mass of thyroid tissues responding to the stimulators was considered to be one of the factors responsible for the euthyroidism despite the presence of TSAb. The high incidence of TSAb and relatively low incidence of TBII in euthyroid Graves' disease indicate that the presence of TSAb does not necessarily lead to hyperthyroidism and that the development of overt thyrotoxicosis may require augmentation of both TSAb and TBII.     

Effect of plasmapheresis and steroid treatment on thyrotropin binding inhibitory immunoglobulins in a patient with exophthalmos and a patient with pretibial myxedema

The effect of prednisone treatment and plasmapheresis was studied in two patients with Graves' disease complicated by severe exophthalmos and/or pretibial myxedema. Titers of Thyrotropin Binding Inhibitory Immunoglobulins (TBII), Long Acting Thyroid Stimulator (LATS), antithyroid antibodies, and serum gammaglobulin concentrations, as well as clinical changes in exophthalmos and pretibial myxedema, were observed during the course of treatment. Steroid treatment lowered all of the abnormal antibody titers. Plasmapheresis did not change the TBII activity when determined using a fixed amount of immunoglobulin G fraction. However, serum gammaglobulin concentration was reduced by plasmapheresis, and therefore, total TBII activity in a unit of serum was reduced. Plasmapheresis also partially and temporarily resolved the pretibial myxedema, whereas no significant change in exophthalmos was observed. These results suggest that both steroid and plasmapheresis treatment are useful for lowering abnormal antibody titers in sera of patients with Graves' disease, and that plasmapheresis can be of some value in the treatment of pretibial myxedema.     

Immunoglobulin G4-positive staining of orbital lesions in thyroid eye disease: Report of two cases

We report two cases with immunoglobulin G4 (IgG4)-positive staining of orbital lesions and thyroid eye disease (TED). Case 1 was a 63-year-old male with right upper eyelid swelling due to right lacrimal gland enlargement. Case 2 was a 49-year-old male with bilateral proptosis due to multiple orbital masses. Both the biopsied right lacrimal gland in Case 1 and the orbital masses on both sides in Case 2 showed infiltration of immunoglobulin-G4-positive plasma cells.     

EFFECTS OF RADIOIODINE ON THYROTROPHIN BINDING INHIBITING IMMUNOGLOBULINS IN GRAVES''DISEASE

We have studied the effects of 131I therapy on thyrotrophin binding inhibiting immunoglobulins (TBII) in fifty-five patients with Graves' disease and five patients with toxic multinodular goitre (MNG). A group of forty patients with Graves' disease and four patients with toxic MNG were treated with drugs and acted as controls. In 78% of patients treated with 131I there was a marked increase in the serum TBII activity during the 3 months following therapy, whereas drug-treated patient showed a decrease (77%) or no change in TBII activity over the same period. TBII activity was not detectable in patients with toxic MNG before or after drug or 131I therapy. Consideration of the mechanisms involved in the changes in serum TBII activity after 131I treatment or during drug treatment provide insight into the basic defects responsible for the development of hyperthyroid Graves' disease and suggest that both the thyroid and immune system are involved.     

Extraocular muscle antibodies and the occurrence of ophthalmopathy in Graves' disease

OBJECTIVE: The aim of this study was twofold: first to investigate the presence of extraocular muscle antibodies (EMAb) in sera of Graves' patients with ophthalmopathy characterized by clinical extraocular muscle (EM) involvement; second to evaluate in Graves' patients without ophthalmopathy whether longitudinal variations of EMAb have a predictive role for the development of eye disease. PATIENTS: We evaluated sera of Graves' patients previously tested for G2sAb and FpAb; in particular, sera of 32 patients with moderate or severe ophthalmopathy and EM involvement: 18 with active disease (group 1), 14 with inactive disease (group 2). Moreover, we evaluated longitudinally sera of 19 Graves' patients without ophthalmopathy previously tested for anti-GS2 (G2sAb) and antiflavoprotein antibodies (FpAb; group 3). During the 18-month follow-up, four of them did not develop ophthalmopathy (group 3a), and 15 did: seven developed eye disease (group 3b) with clinical EM involvement. In particular, moderate disease and clinical activity score (CAS) >/= 4 in four of them, severe ophthalmopathy and CAS /= 4 without EM involvement (group 3c). MEASUREMENTS: EMAb were evaluated in all samples by indirect immunofluorescence method. RESULTS: EMAb were detected in 13 out of 18 patients (72.2%) in group 1 (titre 1/32-1/128) and in five out of 14 patients (35.7%) in group 2 (titre 1/2-1/8). As regards to group 3, at the start of the study EMAb were detected in 13 out of 19 patients (72%) at titres 1/2-1/8; during the follow-up they became or persisted negative in all patients in group 3a, while they increased at titres ranging from 1/64 to 1/128 in all patients in group 3b before the onset of ophthalmopathy. Finally, in group 3c, four patients showed a mild increase (1/8-1/16) of EMAb before the onset of eye disease, while four patients were negative during the entire follow-up. CONCLUSIONS: Our results indicate that EMAb are a good marker of ophthalmopathy with EM involvement and their titre is higher in patients with active than in those with inactive disease. Thus, even if our results must be confirmed on a larger cohort of patients, the increase of EMAb in patients with Graves' disease could be considered as a risk factor for the development of ophthalmopathy with subclinical/clinical EM impairment. In this connection we propose the evaluation of EMAb, in Graves' patients with subclinical and clinical ophthalmopathy, as a simple and sensitive marker of the EM inflammatory process.     

Pathogenesis of Graves' ophthalmopathy: the role of autoantibodies.

The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within orbital tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage.     

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.     

The prevalence and clinical significance of blocking thyrotropin receptor antibodies in untreated hyperthyroid Graves' disease.

The goal of this study was to evaluate the clinical significance of the blocking thyrotropin receptor antibodies (TSHRAb) in Graves' disease. The amount of blocking and stimulating TSHRAb were measured in 200 patients with untreated hyperthyroid Graves' disease using several cell lines carrying different TSHR chimera. Stimulating TSHRAb were measured in Chinese hamster ovary (CHO) cells with wild-type human TSHR (CHO-hTSHR) or a TSHR chimera with residues 90-165 (Mc2) or 8-165 (Mc1+2) substituted by equivalent residues of rat luteinizing hormone/chorionic gonadotrophin (LH/CG) receptor or in FRTL-5 cells. Blocking TSHRAb were measured in Mc2 cells. The activities of different TSHRAb were assessed and clinical features were compared to patients who were positive or negative for blocking TSHRAb antibodies. Blocking TSHRAbs were detected in 18.5% of patients (37/200) with hyperthyroid Graves' disease. Patients with blocking antibodies had significantly lower mean stimulating TSHRAb activities than those without blocking antibodies in wild-type CHO-hTSHR cells (301 +/- 179 vs. 446% +/- 537%, p = 0.005). Mean stimulating TSHRAb activities measured by FRTL-5, Mc1+2, or Mc2 cells and mean thyrotropin receptor inhibitor immunoglobulin (TBII) activities were not different between the two groups. The patients with blocking antibodies were not different from those without blocking antibodies in age, gender ratio, initial serum free thyroxine (T4) levels, or goiter size. However, the prevalence of exophthalmos was higher (35.1% vs. 17.5%, p = 0.024) in the patients with blocking antibodies than those without. In summary, the presence of blocking TSHRAb is not rare in patients with hyperthyroid Graves' disease when measured with chimeric receptor expressing cells. Blocking TSHRAb in Graves' sera do not strongly antagonize the action of stimulating TSHRAb in vivo, but could be a major factor responsible for underestimation of stimulating TSHRAb activities measured by CHO-hTSHR. The association of blocking TSHRAb with ophthalmopathy suggests that the TSHRAb repertoire of Graves' patients is different in those who do and who do not have ophthalmopathy.     

Antithyroid drugs inhibit radioiodine-induced increases in thyroid autoantibodies in hyperthyroid Graves' disease.

Methimazole (MMI) has been reported to affect prognosis in hyperthyroid Graves' disease patients treated with radioiodine (131I). In the present study, serum concentrations of thyroxine (T4), triiodothyronine (T3), thyroglobulin (Tg), thyrotropin-binding inhibitory immunoglobulin (TBII), thyroglobulin antibody (TgAb), and thyroid-peroxidase antibody (TPOAb) were measured serially for 1 year in patients with Graves' disease after 131I treatment either given alone (group 1, 41 patients) or followed by an antithyroid drug (group 2, 19 patients). The effect of antithyroid drugs on these parameters was analyzed retrospectively. Mean serum concentrations of T4 and T3 both decreased to normal within 3 months after 131I treatment in both groups. Serum Tg concentrations in group 1 showed significant transient increases (about four times the basal value) 1 month after 131I administration. Titers of TBII, TgAb, and TPOAb in group 1 also increased transiently after 131I treatment, with the maximum increase at 3 months. Antithyroid drugs significantly lessened 131I-induced increases in serum concentrations of Tg and all thyroid autoantibodies tested. One year after 131I treatment, 33 of 41 patients (80%) were euthyroid or hypothyroid in group 1; this was true for only 4 of 19 group II patients (22%). The results indicate that administering antithyroid drugs after 131I treatment reduced 131I-induced damage to the thyroid and reduced therapeutic efficacy of 131I in hyperthyroidism. Drug treatment also inhibited release of Tg and blunted 131I-induced increases in titers of thyroid autoantibodies.     

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.     

Delayed hypersensitivity in Graves' disease and exophthalmos: identification of thyroglobulin in normal human orbital muscle.

Patients with Graves' disease and exophthalmos demonstrate delayed hypersensitivity to antigens present in extracts of certain normal human tissue; namely,thyroid gland and retroorbital tissue. The delayed hypersensitivity can be assayed in vitro by quantitating the amount of a lymphokine, migration inhibition factor (MIF), which is produced when T lymphocytes of patients with Graves' disease and exophthalmos are exposed to these antigens. In the present report, a partial purification is described for the retro-orbital tissue antigen which is responsible for the positive leucocyte migration inhibition factor assay (MIF assay) exhibited by a sensitized lymphocytes of these patients. The purified retro-orbital tissue antigen preparation demonstrates a 50- to 150-fold higher specific activity over crude homogenates in its ability to act as an antigen in the MIF assay of exophthalmic patients. Immunodiffusion, ultracentrifugation, and disc electrophoretic data indicate that this purified antigen preparation, obtained from normal human, retro-orbital tissue, contains thyroglobulin or a derivative of thyroglobulin; immunofluorescence studies localize the anti-thyroglobulin reactive material to the plasma membranes of extraocular muscle fibers of normal individuals. On the basis of these data it is concluded that thyroglobulin or a derivative of the thyroglobulin molecule is present in the orbital muscle of normal individuals. Since thyroglobulin purified from normal human thyroid glands and the purified retro-orbital tissue preparation are nearly equivalent as antigens in the MIF assay of exophthalmic patients, we conclude that thyroglobulin or an antigenic component of the thyroglobulin molecule is one of the antigens to which patients with Graves' disease and exophthalmos demonstrate delayed hypersensitivity.     

Studies on the radioreceptor assay of TSH: the properties of TSH-binding inhibitor immunoglobulins (TBII) in patients with Graves' disease (author's transl)]

In the radioreceptor assay system for TSH, serum immunoglobulin G (IgG) from some patients with Graves' disease has been shown to inhibit the binding of labelled TSH to its receptor sites. In order to clarify the properties of these TSH-binding inhibitor immunoglobulins (TBII) in patients with Graves' disease, TBII were measured in sera from 31 untreated and 51 131I-treated patients, and their relation to clinical and laboratory findings was studied. TBII were detected in 18 (60%) out of 31 patients with untreated Graves' disease. TBII levels in these patients correlated well with thyroidal 99mTc uptake at 30 min and also with the grade of epithelial hyperplasia of thyroid follicles. There was no significant correlation between TBII and serum T3, serum T4, free T4 index, antibody titers against thyroglobulin and microsomes, or association of exophthalmos. There were many patients with Graves' disease whose sera contained high TBII levels but no detectable bioassayable thyroid-stimulating activity (LATS), and in these patients a close correlation was observed between serum levels of TBII and bioassayable LATS-protector activity. In patients with Graves' disease who had been treated by 131I from 5 to 17 years before, the incidence of TBII was very low at 20% (10/51). All except two cases having TBII were found to be still thyrotoxic. Thus, TBII were detected in 8 out of 10 thyrotoxic patients and in only 2 out of 18 euthyroid and none of 23 hypothyroid patients. These findings suggest that TBII in patients with Graves' disease were in close association with human thyroid stimulating activity, and that TBII might be useful as an indicator for checking the effectiveness of the treatment.     

Luekocyte adherence inhibition in response to human orbital and lacrimal extracts in patients with Graves' ophthalmopathy

Leukocyte adherence inhibition (LAI) may be a test for cell-mediated immunity or cytophilic antibodies. LAI tests were carried out on patients with Graves' ophthalmopathy, using normal human lacrimal gland, orbital fat, and eye muscle extracts as antigens. The results were expressed as % LAI. The percentage leukocyte adherence inhibition in tests from patients and normal subjects were not significantly different for any preparation (Mann-Whitney tests). Taking the upper limit of normal as the mean % LAI + 2SD for normal subjects, tests were positive, to eye muscle extract, in only one patient whilst borderline inhibition, in response to eye muscle and fat extracts respectively, was demonstrated in two patients. All three had active disease. LAI tests may be positive only during the acute stage of Graves' ophthalmopathy. The significance of these findings in respect to the pathogenesis of Graves' ophthalmopathy is discussed.     

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.     

A case of hypothyroid Graves' disease following external radiation therapy to the cervical region

A case of hypothyroid Graves' disease occurred following external radiation therapy to the cervical region is described. Severe hypothyroidism developed in a 56-year-old man 6 months after external radiation therapy for submandibular cancer. Serological evaluation of thyroid autoimmunity revealed the presence of antithyroid antibodies and thyrotropin-binding inhibitory immunogloblins (TBII). Diplopia, limitation of downward gaze, and palpebral edema developed 2 years after levothyroxine replacement therapy. Ocular magnetic resonance imaging revealed marked hypertrophy of the bilateral extraocular muscles with signal hyperintensity on T2-weighted images. This infiltrative ophthalmopathy showed marked improvement after additional treatment with high-dose methylprednisolone and orbital radiation, in parallel with a decrease in TBII. These results suggest that radiation-associated thyroidal injury might be associated with the etiology of hypothyroid Graves' disease.     

An elevation of serum immunoglobulin E provides a new aspect of hyperthyroid Graves' disease

In hyperthyroid Graves' disease, short-term methimazole is sufficient to induce lasting remission in some patients, but even long-term treatment fails to do so in others. We have evaluated the role of autoimmune abnormalities in the helper T cell type 2 (TH2)-interleukin-13 (IL-13)-TSH receptor system in maintaining hyperthyroidism by comparing IgE levels in patients with various thyroid diseases. One hundred and ninety-three patients with hyperthyroid Graves' disease were treated with methimazole, and blood samples were obtained to measure serum levels of T4, T3, TSH, thyroglobulin, antimicrosomal antibody, TSH binding inhibitory Ig (TBII), thyroid-stimulating antibody, thyroid stimulation-blocking antibody, IgE, interferon-gamma, IL-4, and IL-13. Elevation of serum IgE (> or = 170 U/mL) was found in 35.5% of patients with hyperthyroid Graves' disease, and serum levels of T4, T:1, antimicrosomal antibody, and TBII were significantly greater in patients with IgE elevation than in those with normal serum IgE. During methimazole treatment, there was a parallel decrease in the serum T4 concentration in the presence or absence of an IgE elevation. However, there was a significantly smaller decrease in TBII in patients with elevated IgE than in those with normal IgE. As a result, the remission rate was significantly greater in patients with normal IgE than in those with IgE elevation. Serum levels of IL-13 were elevated in 64.7% of patients with IgE elevation in the absence of detectable TH1 marker, interferon-gamma. These findings suggest that in one third of patients with hyperthyroid Graves' disease, TH2 cells are stimulated and secrete excess amounts of IL-13, which subsequently stimulates B cells to synthesize more TSH receptor antibody and IgE, so that during methimazole treatment TBII decreases less in patients with IgE elevation, producing a lower remission rate.