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We report high resolution sonographic (7.5 MHz) findings in four cases of undifferentiated carcinoma of the thyroid gland. Sonographic findings in these four cases included poorly marginated, hypoechoic masses associated with calcifications, and invasion of adjacent cervical structures. A knowledge of the sonographic features of undifferentiated carcinoma of the thyroid gland is of clinical importance, since the tumour has a grave prognosis, quite different from the relatively favourable prognosis of well differentiated thyroid carcinoma.

A 48-year-old woman with diffuse goiter presented with typical symptoms and signs of thyrotoxicosis. Thyroid scanning with I-123 revealed a localized accumulation of the radionuclide in the left lobe which corresponded to a small nodule later detected by ultrasonography, with suppression of the remaining tissues. Owing to the overall reduced radioactivity in the thyroid, she was suspected of having silent thyroiditis causing thyrotoxicosis. Meanwhile, the thyrotoxicosis subsided concurrently with an increase in radioactivity in the extranodular area that had initially been suppressed. The histology of thyroid tissues obtained at the time of operation revealed follicular adenoma or hyperplasia in the area of the localized I-123 uptake and findings similar to those in Hashimoto’s thyroiditis in the remaining tissues, supporting our clinical diagnosis of silent thyroiditis together with a functioning nodule.

We found familial thyroid ectopy in a mother and son, each of whom had an anterior neck mass corresponding to a perihyoid ectopic thyroid. In addition, technetium scintigraphy revealed another focus of aberrant uptake at their tongue roots. Neither patient showed hypothyroid symptoms or abnormal biochemical data other than a mildly elevated TSH level in the son. No other member of the family had a thyroid disorder. To our knowledge this is the first documented instance of familial thyroid ectopy in multiple sites. The observed similarity in distribution of ectopic tissue suggests a hereditary pathogenic factor.

Cystic thyroid lesions are generally considered to be benign and managed by repeated aspiration and/or biopsy. We report characteristic sonographic signs in eight cases of cystic papillary carcinomas of the thyroid gland. In all eight cases, ultrasonography (US) revealed mostly cystic lesions with solid excrescences protruding into the cyst. These nodules contained multiple punctate echogenic foci suggesting calcification. In three of these cases the initial fine needle aspiration biopsy was negative. The 'calcified nodule in cyst' sign was found to be very specific for cystic thyroid carcinoma in a review of the ultrasound findings in 115 patients with nodular thyroid lesions. Careful evaluation and/or surgery should be recommended in patients who have such characteristic sonographic findings even if the fine needle aspiration result is negative.

A new and practical assay was developed using cultured FRTL-5 cells for simultaneous assessment of TS-ab and TSH-binding inhibitor immunoglobulin, allowing direct comparison of these two activities under the same conditions. Subsequent to the TS-ab assay in which extracellular cAMP concentration in Hanks' medium without NaCl was determined, [125I]bTSH in this medium was added to observe the ability of serum Ig to inhibit the binding of [125I]bTSH to FRTL-5 cells. We found a much higher specific binding of [125I]bTSH to FRTL-5 cells and a much greater inhibition of [125I]bTSH binding to the cells exposed to Graves' Ig in hypotonic NaCl-free than in NaCl containing Hanks' medium, indicating that the binding of both TSH and Graves' Ig to the TSH receptor was salt-sensitive. The inhibitory activity of [125I]bTSH binding to the cells was 0.2±4.6% (mean ±sd) in 45 normals. Inter-assay coefficients of variation in two positive controls with the mean values of 18.0 and 65.8% were 15.8 and 16.5%, respectively. Among 46 patients with untreated hyperthyroidism owing to Graves' disease, 45 (97.8%) were positive for TS-ab; 35 (76.1%) and 40 (87.0%) were positive for TSH-binding inhibitor in Ig assays using FRTL-5 cells and solubilized porcine thyroid membranes, respectively. TS-ab activities correlated less closely with TSH-binding inhibitory activities determined using FRTL-5 cells (r=0.576, p

Major two functions that a PACS workstation is considered to be equipped with are 1) efficient retrieval of image data and 2) supporting or consultation of writing reports, as radiologists have to diagnose increasing number of digital images in routine clinical studies. The authors developed a prototype PACS workstation with high speed image retrieving architecture and computer aided diagnosis and reporting function by using an artificial intelligence technology (AIPACS workstation). When physician selects the patient and his studies, the system performs feature extraction and generates diagnostic report by the inference engine with backward reasoning using the knowledge installed as production rules. Clinical application to the system for thyroid diagnosis showed good correlation with the diagnosis done by the physician.© (1990) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Although abnormal thyroid-stimulating and -blocking antibodies have been demonstrated in hyperthyroid and hypothyroid patients with autoimmune thyroid disorders, a direct correlation is not always observed. Thyroid-stimulating antibody, thyrotropinbinding inhibitory immunoglobulin, and thyroid-stimulating blocking antibody levels were determined in three hypothyroid patients who subsequently developed hyperthyroidism. Thyroid-stimulating antibodies levels were normal in one, elevated in another, and unmeasured in the third hypothyroid patient, but became elevated in all patients with the onset of hyperthyroidism. There was discordance, however, in one patient who had markedly elevated thyroid-stimulating antibodies and TSH-binding inhibitory immunoglobulin levels when she was hypothyroid. The data indicate that thyroidal responses to the abnormal stimulating antibodies may differ among patients with autoimmune thyroid disease.

A case report of three patients with primary hypothyroidism who had potent TSH-binding inhibitor immunoglobulins (TBII) and both thyroid stimulating (TSAb) and thyroid stimulation-blocking antibodies (TSBAb) has been described. Two patients displayed symptoms and signs indistinguishable from those in primary myxoedema (cases 1 and 2), and another patient had a history of Graves' disease (case 3). TBII, TSAb and TSBAb activities were 90.0, 1084.2 and 94.5% in case 1, 91.5, 826.6 and 95.8% in case 2, 76.0, 230.0 and 95.0% in case 3, respectively (normal range, less than 11.0%, less than 145.0 and less than 22.0%, respectively. The results indicate that both stimulating and blocking types of TSH-receptor antibodies exist in these patients. The possible mechanism whereby hypothyroidism developed has been discussed.

Fifteen patients with subacute thyroiditis were studied with thyroid sonography. There were local hypoechoic areas in all patients during the active phase of the disease. Among 6 patients who underwent follow-up studies during the course of treatment, 3 had recurrence or aggravation of clinical symptoms such as painful swelling of the thyroid region, which was associated with, and sometimes preceded by, spread or reappearance of the sonographic abnormality. All 6 patients showed complete disappearance of the hypoechoic area when they were in remission. The thyroid sonography is useful not only for the initial diagnosis but also for the follow-up of these patients during the course of the disease.

A 55 year-old female had suffered from 3 consecutive diseases for a year. The diseases were ulcerative colitis, primary hypothyroidism and idiopathic thrombocytopenic purpura, and had been treated with L-thyroxine (50 micrograms daily) and betamethasone (0.5 to 1.5 mg daily). On examination, the thyroid gland was not palpable at all, thyroid 99 mTc pertechnetate uptake was 0%, and an echogram revealed the existence of an atrophic gland. Thyrotropin binding inhibitor immunoglobulin (TBII) in the serum was elevated to 58.0% and her IgG almost completely inhibited the in vitro cAMP increase due to bTSH. After 5 months TBII turned out to be negative and the inhibitory IgG activity was reduced significantly. The thyroid gland also became visible scintigraphically. Thyroid medication was then stopped. Four months after the cessation of thyroxine, she felt quite well and her thyroid functions remained within the normal ranges. Antibody to Yersinia enterocolitica was positive at a low titer (X20) in the early stages, but elevated reciprocally with the fall in TBII and finally reached X320. In conclusion, evidence of the disappearance of blocking type TBII from the serum was demonstrated for the first time. Steroid might have caused some favorable effects, and this clinical report indicates the possibility that remission of hypothyroidism due to blocking type TBII can be expected.

We have attempted to clarify the mechanism whereby the sensitivity to detect thyroid stimulating antibodies by use of cultured thyroid cells is enhanced when sodium chloride is removed from isotonic medium. Preexposure of cultured porcine thyroid cells to 10−4 mol/l cycloheximide increased the subsequent cAMP response to TSab stimulation in isotonic NaCl medium, but not in hypotonic NaCl-free medium. Crude membrane fractions from porcine thyroid tissues were incubated with 6 Graves' IgGs in NaCl or NaCl-free medium at 37°C for 1 h, centrifuged, washed, added [125I]TSH, and incubated for another hour. The result of the 'residual TBII assay' indicated that all 6 IgGs exhibited greater inhibition of [125I]TSH binding to the membranes when pre-incubated under hypotonic than isotonic conditions. When cultured porcine thyroid cells were incubated with 7 TSab samples in NaCl or NaCl-free medium depleted with 3-isobutyl-1-methylxantine at 37°C for 1 h, washed, added the NaCl-free medium containing 3-isobutyl-1-methylxanthine, and incubated for another 2 h, the use of NaCl-free medium during the pre-incubation resulted in greater increase in cAMP elicited by all 7 samples. In summary, 1) an inhibitory mechanism upon adenylate cyclase seems to be involved under isotonic conditions and may require new protein synthesis; 2) the binding of TSH receptor antibodies to the TSH receptor increases when NaCl is removed from isotonic medium, and 3) these factors are considered responsible for the enhanced sensitivity under hypotonic conditions.

In an assay for thyroid-stimulating antibodies, in which FRTL-5 thyroid cells were incubated with crude immunoglobulin (Ig) fractions precipitated from serum with 15% polyethylene glycol, significant increase in cAMP production was elicited by the samples from 25 (35.7%) out of 70 pregnant women. The highest value was 529.5%. There was a close correlation between thyroid stimulating activities and serum hCG concentrations (r = 0.708, P less than 0.001). When 125I-hCG was added to serum from pregnant women, about 20% of the radioactivity was incorporated into the Ig fractions. hCG preparations within a range of concentrations of 30-300 IU/m elicited 2.3-16.5 times increase in cAMP in a dose-dependent manner. Nine pregnant women with serum TSH concentrations less than the lower limit of the normal range (less than 0.25 mU/l) displayed significantly higher values for both thyroid stimulating activities and serum hCG concentrations (P less than 0.001, respectively) compared with those who had normal TSH levels in serum. These data suggest that hCG or its variant may stimulate the thyroid sufficiently to suppress secretion of TSH from the pituitary in some pregnant women.

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.

Antibodies against thyroxine (T4) and/or triiodothyronine (T3) were detected in 3 patients with Hashimoto's thyroiditis. One of the patients had both anti-T4 and anti-T3 antibodies and the other 2 patients had only anti-T3 antibody. Serum T4 or T3 antibodies and the other 2 patients had only anti-T3 antibody. Serum T4 or T3 values measured by the single antibody radioimmunoassay (RIA), were low or nil in these patients. One patient was mildly hypothyroid. The other 2 patients were clinically euthyroid, but they were considered latent hypothyroid because of a slight elevation in serum TSH. On extraction of the sera with ethanol, high or normal values of T3 were obtained in all cases. Recovery of T4 or T3 added to the patients' sera determined by RIA was significantly low. The binding of [125I]T4 or [125I]T3 to the patients' sera was demonstrated by the polyethylene glycol method and by using RIA kits without adding the antibody provided. The binding activity was localized in the IgG fraction by column chromatography and by immunoprecipitation. T4- or T3-binding protein in two sera migrated in the gammaglobulin region on paper electrophoresis and was found in 7S fraction on Sephadex G-200 chromatography. In one serum containing both anti-T4 and anti-T3 antibodies, the association constants (Ka) for binding of T4 and T3 were 3.8 x 10(8) l/mol and 1.7 x 10(8) l/mol, respectively. The binding capacities in the serum were 8.2 microgram of T4 and 1.9 microgram of T3 per 100 ml of serum. For two sera containing anti-T3 antibody, Ka were 5.5 x 10(8) l/mol and 7.4 x 10(10) l/mol, and the binding capacities were 0.6 microgram/100 ml serum and 0.7 microgram/100 ml serum respectively. The clinical significance of these antibodies is discussed.

Binding of immunoglobulin G (IgG) to Triton-solubilized fat cell membranes crosslinked with 125I-TSH was studied by an indirect immunoprecipitation method. Guinea pig fat cell membranes (FCM) containing TSH receptors with an association constant of 1.92 X 10(9) M-1 were first reacted with 125I-TSH, then treated with a crosslinker, dissuccinimidyl suberate. The dissociation of 125I-TSH from the crosslinked 125I-TSH-FCM complexes due to the addition of 100 mU/ml unlabeled TSH was 9.0%, while it was 33% without the treatment. To the Triton-solubilized FCM crosslinked with 125I-TSH, 50 micrograms each of IgG from 20 normal controls, 20 patients with Graves' disease and 20 with Hashimoto's disease was added and precipitation was effected by adding anti-human IgG. In patients with Graves' disease, 125I-TSH-FCM complexes immunoprecipitated ranged from 1.10 to 4.18% with an average of 2.4 +/- 0.99 (S. D.) % which was significantly higher than those in normal controls (1.6 +/- 0.29%). The values in the patients with Hashimoto's disease averaged 1.7 +/- 0.53 (S. D.) which did not differ significantly from those of controls. The value did not correlate with either TSH-binding inhibiting activities or titers of anti-microsomal antibodies. These data suggest the presence of TSH-receptor antibodies which react with antigens other than TSH-binding sites in the patients with Graves' disease.

A 23-year-old female who developed thyrotoxic Graves' disease following primary hypothyroidism was reported. She presented with symptoms of hypothyroidism and slight exophthalmos. After primary hypothyroidism was confirmed, she was treated with T4 in a dose of 50 micrograms/d. Two months after delivery, 1 year after the initial diagnosis of hypothyroidism, hyperthyroidism developed while she was taking T4. Graves' disease was confirmed by persistent thyrotoxicosis, high 99mTc thyroidal uptake, negative T3 suppressibility and detection of TSH-receptor antibodies. During the hypothyroid phase, TSH-binding inhibitory immunoglobulins (TBII) could not be detected, while thyroid stimulating antibodies (TSAb) were positive showing between 5.8 and 9.0 fold increases in the amount of cAMP produced in cultured porcine thyroid cells. Her IgG did not inhibit TSH-induced cAMP increase in vitro. When she developed hyperthyroidism, TSAb activity became more potent (31.7 fold increase in cAMP) and TBII became positive (+61.3%).

To elucidate the relationship between the mother's TSH-receptor antibody activities and the status of thyroid dysfunction in their offspring, blood was taken from 5 mothers with chronic thyroiditis with potent thyrotropin (TSH)-receptor blocking activity, and the potency of TBII and TSBAb activity was assayed more quantitatively. In those mothers whose infants suffered from neonatal hypothyroidism, the 50% inhibition of binding of labeled TSH to its receptors was obtained at more than 30 to 50-fold dilution, while in those mothers whose infants had transiently increased TSH or were euthyroid, the titers were of less than 30-fold dilution. Similarly, in those mother whose infants suffered from neonatal hypothyroidism, the 50% inhibition of TSH-induced cAMP accumulation was obtained at approximately 400 to 3000-fold dilution, while in those mothers whose infants had transiently increased TSH or were euthyroid, the titers were of less than 50-fold dilution. On the other hand TBII activity was much less potent in serum from patients with Graves' disease. These results suggested that the titration of serum with dilution to obtain 50% inhibition of labelled TSH binding to its receptor may be the simplest way to predict thyroid dysfunction of the newborn infants born to mothers with chronic thyroiditis.

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 < 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.

The TSH receptor from human thyroid plasma membranes has been solubilized in 10 mm Tris/HCl, 50 mm NaCl, pH 7.4 containing 0.5% triton X-100. Binding of [125I]TSH to the soluble receptor showed rapid and reversible kinetics and reached a maximum within 30 min at 37°C, by 1 h at 25°C and by 24 h at 4°C. Optimal pH was 7.4. The soluble receptor retained specificity with cross-reactivity only to crude hCG (0.03%). Scatchard plots were curvilinear, indicating the presence of at least two binding sites. The high affinity site showed an affinity constant of 1.1 × 109 m−1 with binding capacity of 1.3 × 10−10 m/mg protein. TSH-binding inhibitor immunoglobulins from patients with Graves' disease inhibited [125I]TSH binding to the soluble receptor in a dose-dependent manner. NaCl inhibited the TSH binding and this was ascribed to the decrease in the receptor capacity. Trypsin, neuraminidase and phospholipase C treatment of the solubilized receptor had no effect on TSH binding. The apparent molecular weight of the receptor, determined by gel filtration on Sepharose® 6B, was approximately 300 000.

IN 1960, Sutherland et al.1 reported on children with familial nongoitrous cretinism born of a hypothyroid mother with Hashimoto's disease. Subsequently, Goldsmith et al.2 studied this family in de...

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.

The pituitary functions were tested in two males with the typical clinical pictures of hypogonadism. The secretions of ACTH, TSH, GH and prolactin in these patients were maintained within normal limits, whereas they had markedly diminished LH and FSH levels in plasma. Plasma LH and FSH responses to the intravenous injection of 100 mug LH-RH were absent or limited. After 7-day treatment with intravenous infusion of 400 mug LH-RH, they showed normal or improved responses to the intravenous injection of 100 mug LH-RH. Thus, the diagnosis of isolated gonadotropin deficiency due to a hypothalamic lesion was established. Initially, the standard LH-RH test (100 mug intravenous injection) did not elicit a rise in plasma GH levels. However, it was of interest that after the repeated stimulation by 400 mug LH-RH, GH response to the intravenous injection of 100 mug LH-RH was observed in both patients.

We report a 48-year-old woman who developed hyperthyroidism following primary hypothyroidism. The serum T4 level was initially low and serum TSH level was high with clinical signs of hypothyroidism. The thyroid gland was not enlarged. Therapy with L-T4 was started. Three years later she developed hyperthyroidism; serum free T4 increased to 29.1 pmol/l after cessation of L-T4 therapy. The 123I thyroid uptake was increased with no suppression by exogenous T3. When she was hypothyroid, the activity of thyroid stimulating antibodies (TSAb) in serum measured by cyclic AMP production in cultured porcine thyroid cells were negative at 93.4% (normal less than 140%), while thyroid stimulation-blocking antibodies (TSBAb) determined by inhibition of TSH-induced cyclic AMP increase were positive at 96.1% (normal less than 40%). When hyperthyroidism subsequently occurred, TSBAb became negative (30.9%), while TSBAb became positive (163.3%). The findings indicate that hypothyroidism due to the potent TSBAb activity is not always persistent, but can be changed when various types of thyroid-relating antibodies change in the course of the disease.

In frozen sections of thyroid glands with Hashimoto's thyroiditis (HT) and Graves' disease (GD), infiltrating lymphocytes were tested for their expression of HLA-DR antigens as a marker of in situ activation. In a combination of indirect immunoperoxidase and direct immunofluorescence staining, most of the immunoglobulin D positive mature B cells were found to be DR positive (DR+) in both diseases. In HT, sizable portions of both helper/inducer T (Leu3+) and suppressor/cytotoxic T (Leu2+) cells were DR+ in interfollicular regions as well as in lymphocyte clusters and lymphoid follicles. In GD, the proportion of DR+ cells in the interfollicular Leu2+ population was significantly lower than that of HT. DR+ thyrocytes were seen in all 14 cases of HT and in 14 out of 16 cases of GD, especially in the vicinity of lymphocyte aggregates. The extent of their DR expression was not correlated with the percentage of DR+ cells in either T subset. These results indicate that a significant portion of infiltrating T cells are activated in autoimmune thyroid diseases, and there may be bidirectional interaction between DR+ thyrocytes and DR+ T cells. The difference in frequency of Leu2+ DR+ cells may account for the difference between the immunopathological features of HT and GD.

A radioreceptor assay of TSH using Triton-solubilized human thyroid receptors was applied to the detection of TSH-binding inhibitor immunoglobulins (TBII). In 26 untreated patients with Graves' disease, 20 (76.9%) were found positive in this assay, while 18 (69.2%) cases were found positive by the conventional assay using human thyroid particulate receptors. In 25 patients with goitrous Hashimoto's thyroiditis, 2 (8.0%) were found positive by the assay using soluble receptor, while 3 (12.0%) were found positive by the conventional one. A significant correlation was found between TBII activities in the patients with untreated Graves' disease detected by these two assay systems (r=0.69; n=26; p less than 0.001). These data support the concept that TBII are antibodies against the TSH receptor or its closely related structures.

Clinical usefulness of thyroid-stimulating antibodies (TSab) and TSH-binding inhibitor immunoglobulins (TBII) for predicting the prognosis in patients with Graves' disease after cessation of antithyroid drug treatment was evaluated, and compared with that of T3 suppression test and goitre size. Among 46 patients who had been euthyroid on a maintenance dose of antithyroid drugs for at least one year and had discontinued taking medicine, 16 relapsed within one year (group 1), 7 relapsed later than 1 year (group 2), and 23 patients remained in remission for more than 1 year (group 3). Incidence of TSab, TBII, T3 nonsuppressibility and large goitre (transverse diameter longer than means of the values for the 46 patients: ≥ 4.36 cm in females; ≥ 4.74 cm in males) determined at the time of discontinuation of treatment was 87.5% (14/16), 56.3% (9/16), 78.6% (11/14) and 81.3% (13/16) in group 1; 66.7% (4/6), 28.6% (2/7), 50.0% (3/6), and 57.1% (4/7) in group 2, and 56.5% (13/23), 24.1% (5/23), 35.7% (8/23), and 26.1% (6/23) in group 3, respectively. All relapsed patients showed remarkable increases in both TSab and TBII activities at the time of relapse. High incidence of TSab in patients remaining in remission suggests that a reduced functional reserve of the thyroid, probably owing to destructive changes and/or shrinkage of the gland, may cause impaired responses to TSab and is involved in the cause of remission. Development of blocking type of TBII was not considered to be a cause of remission. Remission was predictable in all patients with any two of the indices such as negative TSab, positive T3 suppressibility, and small goitre.

Magnetic resonance (MR) imaging was performed in eight healthy volunteers and 30 patients with histologically and endocrinologically proved thyroid diseases. The use of a surface coil greatly improved spatial resolution, and normal anatomic structures were well demonstrated. In thyroid tumors, the margin, pseudocapsule, and lymph nodes were easily detected. Smooth margins, lobulated margins, and pseudocapsules were found in both adenoma and papillary carcinoma, whereas unclear margins were found only in papillary carcinoma. An unclear margin between the tumor and adjacent normal thyroid tissue seemed to reflect an ill-defined tumor border on gross pathologic examination. Metastatic lymph nodes as small as 3 mm were seen. Identification of small vessels enabled detection of dilated vessels in thyroid parenchyma in patients with Graves disease. Hemorrhage (hemorrhagic degeneration) was often found in adenoma, papillary carcinoma, and adenomatous goiter, resulting in variable signal intensity.

Blood was taken from 56 selected newborn babies whose mothers had Graves' disease, to assess the relation between their thyroid function and the presence of thyrotropin (TSH) binding inhibitor immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) in maternal serum. All the mothers of the thyrotoxic babies had both these TSH receptor antibodies in their serum. However, most of the mothers whose thyroid function had been well controlled in pregnancy gave birth to normal babies. 15 babies had a transient syndrome of low serum thyroxine (T4) and free T4 with normal TSH and this tended to be associated with TSH receptor antibodies in maternal serum (TBII 9/15, TSAb 4/15). 2 infants had transient hyperthyroxinaemia without hyperthyroidism and both their mothers showed strong TSAb activity without TBII activity.

Fat cell TSH receptor-related antibodies were detected by immunoprecipitation of 125I-TSH-receptor complexes and the nature of the antibodies was analyzed. To 125I-TSH prebound to Triton-solubilized receptors from guinea pig fat tissues, 50 micrograms of immunoglobulin G (IgG) was added and precipitation was effected by the addition of antihuman IgG. Immunoprecipitation values in 13 patients with Graves' disease were significantly (p less than 0.05) higher than those in 11 normal subjects. No significant increase in the values was seen in 8 patients with Hashimoto's disease. No correlation was observed between immunoprecipitation values and titers of antimicrosomal and antithyroglobulin antibodies. Neither was there any correlation between the values and TSH-binding inhibitor immunoglobulins (TBII) detected by the radioreceptor assay. The IgG fractions positive for the immunoprecipitation antibody were found to be poor human thyroid stimulators (HTS) relative to their TBII activities. And a highly significant correlation was observed between TBII and HTS activities among IgGs without detectable antibody by immunoprecipitation (r=0.907; p less than 0.005; n=7). These findings 1) demonstrate that immunoprecipitation assay using fat cell TSH receptor may detect TSH receptor-related antibodies different from TBII in patients with Graves' disease and 2) suggest the antibodies may recognize determinants on the receptor or its vicinity that do not participate in the binding of TSH or thyroid stimulating antibody, and may interfere with thyroidal response to these stimulators.

The present studies were undertaken to delineate the role of sialic acid residues in the two subunits of hCG in relation to its hormonal activity. Sialic acid was removed by treatment of the individual subunits or intact hCG with insolubilized neuraminidase. Desialylated variants of hCG were obtained by combining an asialo subunit (as alpha or as beta) with its complementary intact or desialylated subunit. When tested in the hCG receptor assay using a rat testis fraction, none of the hCG variants exhibited any loss of activity compared with that of intact purified hCG. In in vitro bioassays that employed cAMP and testosterone generation in rat Leydig cells as indices of response, intact hCG and as alpha in combination with intact beta (as alpha-beta) were equipotent. In contrast, intact alpha-subunit combined with as beta (alpha-as beta) and desialylated intact hCG (asialo-hCG) showed activity that at the highest concentration of each tested (20 ng/ml) was no more than half of that evoked by intact hCG. In a TSH receptor assay in human thyroid membranes, loss of sialic acid from either one or both hCG subunits resulted in enhancement of binding affinity; the rank order of decreasing potency was asialo-hCG, alpha-as beta, as alpha-beta. However, despite their enhanced binding affinity, and like intact hCG itself, none of the variants elicited a cAMP response in either human thyroid membranes or cultured human thyroid cells. Rather, asialo-hCG and alpha-as beta, but not intact hCG and as alpha-beta, were effective antagonists of the stimulatory response induced by bovine TSH in thyroid cells. These findings indicate that desialylation of hCG enhances its binding affinity for hCG receptors in testis and, much more so, for TSH receptors in human thyroid. Desialylation also changes hCG from a full agonist to a partial agonist in testis and from a nonagonist to an antagonist in human thyroid. In all cases, sialic acid in the beta-subunit of hCG appears to have a predominant role in these effects.

We tried to improve the sensitivity of a radioreceptor assay for thyrotropin-binding inhibitor immunoglobulins (TBII) by modifying assay conditions. About a twofold increase in sensitivity without a loss of reproducibility was obtained by prolonging the incubation of the receptors with test serum from 15 to 120 min before the addition of 125I-labeled thyrotropin. In 20 untreated, 49 treated patients with Graves' disease and 19 patients with euthyroid Graves' disease, TBII activities obtained using 120 min preincubation were significantly higher than those obtained using 15 min preincubation (p less than 0.005). No significant increase in TBII activities was observed in the presence of sera from patients with primary hypothyroidism (n = 17), simple goiter (n = 7), adenomatous goiter (n = 11), thyroid adenoma (n = 11) or cancer (n = 12). TBII were detectable in 15 (47%) of 32 triiodothyronine-nonsuppressible Graves' patients who were receiving maintenance antithyroid drug therapy using 120 min preincubation, while they were positive in only 6 patients (19%) using 15 min preincubation. The assay using a longer preincubation period was found to be sensitive, specific and useful for diagnosis and follow-up of Graves' disease.

We describe autoantibodies against iodinated gastrin in a patient with Graves' disease. Values for serum gastrin differed in this case, depending on which of two different radioimmunoassay (RIA) kits was used. RIA with the dextran-coated charcoal method for separation of free tracer gastrin gave a value less than 9.5 pmol/L, whereas the value by a RIA kit by the double-antibody method was 318 pmol/L. The patient's serum contained a binding protein for 125I-labeled gastrin, as detected by Sephadex G-200 column chromatography. The IgG fraction was responsible for the ability of serum to bind 125I-labeled gastrin. Interestingly, of the two possible forms of iodinated gastrins, monoiodinated (MIT) and diiodinated (DIT) tyrosine-125I-labeled gastrin, only the latter bound to patient's IgG. Furthermore, DIT-gastrin, but not gastrin or MIT-gastrin, inhibited the binding of DIT-125I-labeled gastrin. The patient's serum evidently contains autoantibodies against DIT-gastrin that interfere with RIA of gastrin.

Thyroid imaging using TI-201 was useful to visualize the normal thyroid tissue, which was not visualized by conventional imaging using I-123 or Tc-99m, in three patients with toxic nodular goiter.

We have developed a new method for assessing the bioactivity of thyrotropin (TSH) in human serum by measuring cAMP production in FRTL-5 thyroid cells as an index of stimulation. To eliminate serum inhibitors of the cAMP response to TSH, we purified samples by mixing them with anti-TSH antibodies coupled to magnetizable particles. This method of immunoaffinity purification was simple and suitable for the measurement of a large number of samples. The detection limit of the bioassay was 3.13 milli-int. units of human TSH per liter. Intra-assay and interassay coefficients of variation ranged from 5.4 to 8.6% and from 12.6 to 21.5%, respectively. The concentrations of bioassayable TSH closely correlated with those of immunoassayable TSH, both in the immunoaffinity-purified samples (r = 0.946, P less than 0.001) and in the serum samples (r = 0.945, P less than 0.001) from 14 euthyroid subjects and 53 hypothyroid patients with Hashimoto's thyroiditis. The bioactivity-to-immunoactivity ratio was almost constant (0.84 +/- 0.30; mean +/- SD) over the range of concentrations of immunoassayable TSH in serum, 6.3 to 177 milli-int. units/L. We also demonstrate that the technique is applicable to measurements of bioactivities of circulating forms of immunoreactive TSH in different pathophysiological conditions.

We studied antibody-dependent mononuclear cell-mediated growth inhibition of thyroid cells in 18 untreated patients with Graves' disease, 18 patients with chronic thyroiditis, and 15 normal subjects by measuring the ability of their sera to inhibit [3H]thymidine incorporation into DNA in a rat thyroid cell line, FRTL-5, in the presence of normal mononuclear cells. [3H]thymidine incorporation was significantly inhibited in the presence of sera from patients with Graves' disease and chronic thyroiditis (P 3H]thymidine incorporation and the titre of anti-microsomal antibodies (P 3H]thymidine incorporation was significantly abolished when serum pre-absorbed with human thyroid membranes was used (P 3H]thymidine incorporation significantly correlated with those obtained by using IgG fractions (P

We studied thyroid growth-blocking activity in immunoglobulin G (IgG) fractions of serum from 24 patients with primary myxedema, 24 patients with goitrous Hashimoto's thyroiditis, and 18 normal subjects by measuring the ability of their IgG to inhibit TSH-induced [3H]thymidine incorporation into DNA in a rat thyroid cell line, FRTL-5. Both groups of patients were receiving T4 when studied. [3H]Thymidine incorporation induced by 0.1 mU/ml bovine TSH was significantly inhibited by the addition of 2 mg/ml IgG from patients with primary myxedema (P less than 0.01), while it was not affected by IgG from the normal subjects or 23 of the 24 patients with goitrous Hashimoto's thyroiditis. IgG from patients with primary myxedema also inhibited the [3H]thymidine incorporation induced by Graves' IgG, but not that induced by forskolin, cholera toxin, (Bu)2cAMP or phorbol-12-myristate-13-acetate. The inhibition of TSH-induced [3H]thymidine incorporation by IgGs from patients with primary myxedema was significantly correlated with their inhibitory activities against both TSH-induced cAMP generation and TSH binding (P less than 0.001). These data indicate that these growth-blocking antibodies are directed against the TSH receptor and might be one of the causes of the thyroid atrophy in patients with primary myxedema.

By using an assay measuring cAMP production in FRTL-5 thyroid cells, thyroid stimulating antibodies (TSab) were detected in all of 15 patients with euthyroid Graves' disease (EG) and of 26 patients with hyperthyroid Graves' disease (HG). There was no significant difference between TSab activities in EG and in HG. In an effort to elucidate why EG patients remain euthyroid in spite of having TSab, we investigated the effect of the patient's crude immunoglobulin fractions on 125I uptake in FRTL-5 thyroid cells, one of the indices of stimulation subsequent to cAMP production. The 125I uptake stimulating (IUS) activity was positive in 46.7% (7/15) of EG patients and 88.5% (23/26) of HG patients, being significantly lower in the former than in the latter (P < 0.02). Although the IUS activities significantly correlated with TSab activities in 41 patients with EG and HG (r = 0.784, P < 0.001), the ratio of IUS to TSab in EG tended to be lower than that in HG. TSH-binding inhibitor immunoglobulins (TBII) activities in EG patients were negative or weakly positive, being significantly lower than those in HG patients (P < 0.001). Thus, the ratios of TBII to both TSab and IUS activities were significantly higher in HG than in EG (P < 0.01, P < 0.001, respectively). The in vitro IUS activities also correlated with TBII activities (r = 0.441, P < 0.001) and in vivo 99mTc thyroid uptake (r = 0.401, P < 0.001) in both EG and HG patients. The EG patients with positive IUS activities displayed smaller goitre size and lower 99m thyroid uptake in comparison to 19 HG patients with a similar range of IUS activities. There was a good correlation between thyroid weight and 99mTc thyroid uptake (r = 0.827, P < 0.001). In conclusion, lower IUS activity and/or smaller goitre size in EG than in HG, which may lead to lower thyroidal uptake of 99mTc and presumably radioiodine in vivo, might be a factor responsible for keeping EG patients euthyroid despite the presence of TSab.

We studied the effects of crude immunoglobulin (Ig) fractions of serum from patients with goitrous and atrophic autoimmune thyroiditis on TSH-, thyroid-stimulating immunoglobulin (TSI)-, forskolin-, and dibutyryl cAMP-stimulated 125I uptake by FRTL-5 thyroid cells. TSH-stimulated 125I uptake was inhibited by the Ig fractions from 15 patients with atrophic thyroiditis who had serum TSH binding inhibitor Igs (TBII), 10 (62.5%) of 16 TBII-negative patients with atrophic thyroiditis, 7 (43.8%) of 16 hypothyroid patients with goitrous thyroiditis who had no TBII activity, and only 2 (15.4%) of 13 euthyroid patients with goitrous thyroiditis who were negative for TBII. The mean inhibition of TSH-stimulated 125I uptake produced by the crude Igs from the former 3 groups of hypothyroid patients was statistically significant (P less than 0.001, P less than 0.001, and P less than 0.01, respectively) and correlated closely with the ability of the Ig fractions to inhibit TSI-stimulated 125I uptake (r = 0.882) and TSH-stimulated cAMP accumulation (r = 0.929). The inhibition of TSH- or TSI-stimulated 125I uptake by Ig samples containing TBII correlated significantly with the TBII activities. On the other hand, in the presence of Igs from TBII-negative hypothyroid patients, the inhibition of TSH-stimulated 125I uptake correlated significantly with that of forskolin-stimulated 125I uptake (r = 0.685). Although 6 (12.8%) of 47 Ig samples from hypothyroid patients inhibited dibutyryl cAMP-stimulated 125I uptake, the activities were marginal. These findings suggest that at least 2 types of antibodies are involved in the inhibition of TSH- or TSI-stimulated 125I uptake: 1 being a competitive inhibitor of TSH binding to its receptors, and another exerting influence on a step subsequent to TSH or TSI binding, presumably through adenylate cyclase inhibition.

We correlated scintigraphy and histological findings in 40 cases of nodular goiter in which two or more kinds of scintigraphy were performed preoperatively. 201Tl scintigraphy for imaging thyroid carcinoma showed a diagnostic agreement of 80% for thyroid lesions and 82% for metastatic lesions in the cervical lymph nodes. These agreements were higher than with 99mTc-bleomycin scintigraphy. Thus, 201Tl scan can be used to evaluate 'cold' thyroid nodules and to visualize metastatic lesions. 201Tl scan was also found valuable as a diagnostic measure for local recurrence of thyroid carcinoma. However, there were a few false-positive and false-negative results.

Seventeen patients with moderately severe ophthalmopathy due to Graves' disease were treated by cobalt or supervoltage radiotherapy. All patients complained of diplopia. The mean proptosis value was 21.4 mm. Three patients (18%) showed good response, 7 (41%) moderate and 7 minimal or no response. Improvement was noted mainly in soft tissue changes and diplopia, while proptosis decreased in only 5 patients. All except one patient who had marked extraocular muscle involvement revealed by computed tomography responded to treatment. These data indicate that radiotherapy may be indicated in patients with progressive ophthalmopathy, especially in those who are associated with extraocular muscle enlargement.