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.

Effects of thyroid hormone on carbonic anhydrase I gene expression in human erythroid cells.

Individuals with hyperthyroidism exhibit concentrations of carbonic anhydrase I (CAI) in red blood cells that reflect the integrated serum thyroid hormone concentration over the preceding few months. Furthermore, triiodothyronine T3, at a physiological free concentration, decreases the CAI concentration in both human erythroleukemic YN-1 cells and burst-forming unit-erythroid (BFU-E)-derived cells. In the present study, the effect of T3 on CAI mRNA levels in various human erythroleukemic cell lines (YN-1, HEL and KU-812) and BFU-E-derived cells was studied. Northern analysis of RNA extracted from erythroid cells revealed a CAI mRNA of 1.5 kilobases. T3 significantly decreased the levels of CAI mRNA in YN-1 and BFU-E-derived cells in a dose-dependent manner. Incubation of T3-stimulated cells with actinomycin D prevented the decrease in CAI mRNA levels. By contrast, T3 had no effect on either the concentrations of CAI or the levels of CAI mRNA in HEL and KU-812 cells. These results suggest that YN-1 and BFU-E-derived cells may be useful models for investigating T3 actions on CAI mRNA in human cells.

Hyperthyroid Graves' disease and primary hypothyroidism caused by TSH receptor antibodies in monozygotic twins: case reports.

A 33-year-old woman with signs and symptoms of hypothyroidism, including increased thyroid stimulating blocking antibody (TSBAb) activity, was referred for treatment by her local physician. Her monozygote twin was treated for hyperthyroid Graves' disease 10 years earlier. This case of hyperthyroidism and hypothyroidism in identical twins suggests the involvement of environmental factors in the pathogenesis of autoimmune thyroid diseases.

Role of thyroid-stimulating blocking antibody in patients who developed hypothyroidism within one year after 131I treatment for Graves' disease.

OBJECTIVE: We recently reported that thyroid-stimulating blocking antibody (TSBAb) may not contribute to the development of hypothyroidism more than six years after 131I treatment. In the present study, we attempted to determine whether hypothyroidism that develops within a shorter period of time following 131I therapy is associated with TSBAb. DESIGN: Retrospective study. PATIENTS: Sera were obtained from 8 patients who developed hypothyroidism within 6 months after 131I therapy (Group 1), 8 patients who became euthyroid one year after 131I therapy (Group 2), and 7 patients who developed transient hypothyroidism (Group 3). MEASUREMENTS: Thyroid stimulating antibody (TSAb) activity was measured as the amount of cyclic adenosine monophosphate (cAMP) produced by cultured FRTL-5 cells, and TSBAb activity as the inhibition of cAMP produced in response to 100 mU/l bovine TSH. RESULTS: At about 3 months after 131I treatment, TSAb activity increased significantly in Groups 2 and 3, but did not change in Group 1. In contrast, TSBAb activity in Group 1 increased significantly and was positive in 6 patients at that time. At 12-18 months after 131I treatment, TSBAb activity tended to decrease and remained positive in 3 patients but became negative in 3 patients. It did not change in the patients in Groups 2 and 3. The patients in Group 1 were treated with levothyroxine, 75-125 micrograms/day. Levothyroxine was discontinued in the 3 patients whose TSBAb activity disappeared. Two of them remained euthyroid, and 1 became hypothyroid. CONCLUSION: Results indicate that the hypothyroidism that develops within a short time after 131I treatment may be caused by TSBAb activity. Thyroid function may be recovered when TSBAb activity disappears.

Failure in detection of Epstein-Barr virus and cytomegalovirus in specimen obtained by fine needle aspiration biopsy of thyroid in patients with subacute thyroiditis.

To study the possible role of viral infection in the etiology of subacute thyroiditis (SAT), we measured serum virus-specific antibodies to measles, rubella, mumps, type I herpes, chicken pox, human parvovirus B19 and cytomegalovirus (CMV) in 10 patients with SAT during the course of illness. In spite of the presence of IgG to each virus in more than 70% of patients, no significant changes in the IgG titers were observed except those to measles, rubella, chicken pox or CMV in only 10% of patients, respectively. Then we examined the presence of virus DNA in specimens of 9 patients with SAT obtained by fine-needle aspiration biopsy (FNAB) of the thyroid. DNA was amplified to detect that of Epstein-Barr virus and CMV by polymerase chain reaction. However, none of them were detected in all the specimens. Whereas previous studies suggest the involvement of viral infection in the pathogenesis of SAT, we failed to demonstrate significant changes in serum antiviral antibody titers or to detect viral DNA in the specimens obtained by FNAB of the thyroid. Thus further studies are clearly required to establish the definite role of viral infection in the pathogenesis of SAT.

Measurement of red blood cell zinc concentration with Zn-test kit: discrimination between hyperthyroid Graves' disease and transient thyrotoxicosis.

We have previously reported in patients with hyperthyroidism that the red blood cell (RBC) zinc (Zn) concentration reflects the mean thyroid hormone concentration over the preceding months. In the present study, the concentration of RBC Zn was measured by a simple and easy method with a Zn-test Wako kit. Within-run and between-run precision were 1.4% and 1.3%, respectively. The relationship between RBC concentration and dilution was linear. The average recovery was 103%. A good correlation (r=0.97) was obtained between this method and atomic absorption spectrophotometry. The mean concentration of RBC Zn in 39 euthyroid controls was 12.6 +/- 1.3 mg/l, ranging from 10.4 to 15.1 mg/l. The RBC Zn concentrations in 38 patients with Graves' disease, in 10 patients with silent thyroiditis and in 3 patients with gestational thyrotoxicosis were 7.3 +/- 1.6 (3.2-9.8), 12.0 +/- 1.6 (9.5-14.2) and 11.8 +/- 1.7 (10.5-13.7) mg/l, respectively. The concentration of RBC Zn was able to differentiate hyperthyroid Graves' disease from transient thyrotoxicosis except in 1 case and was a better index than TSH-binding inhibitory immunoglobulin. These results indicate that measuring RBC Zn with the Zinc-test Wako kit is very useful in differentiating hyperthyroid Graves' disease from transient thyrotoxicosis.

The development of transient hypothyroidism after iodine-131 treatment in hyperthyroid patients with Graves' disease: prevalence, mechanism and prognosis.

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

Relationship between thyroid-stimulating antibodies and thyrotropin-binding inhibitory immunoglobulins years after administration of radioiodine for Graves' disease: retrospective clinical survey.

Thyroid-stimulating antibody (TSAb) activity and the TSH-binding inhibitory immunoglobulin (TBII) index were assessed in 158 patients with Graves' disease who had been treated with 131I 6-14 years earlier. Twenty-one patients (13%) were still hyperthyroid, 45 (28%) were euthyroid, 44 (28%) were subclinically hypothyroid, and 48 (30%) were overtly hypothyroid. Positive results were obtained in 10 (48%) of the 21 patients with hyperthyroidism for both TSAb and TBII assays, and in 3 patients (14%) in one of the assays. In contrast, only two (5%) patients with subclinical hypothyroidism and 1 (2%) patient with overt hypothyroidism tested positive in both assays, and 11 (25%) subclinically hypothyroid patients and 15 (31%) overtly hypothyroid patients tested positive in one of the assays. The correlation coefficients between TSAb and TBII were 0.88 (p < 0.01) in hyperthyroid patients, 0.49 (p < 0.01) in euthyroid patients, 0.34 (p < 0.05) in subclinically hypothyroid patients, and 0.12 (p > 0.05) in patients with overt hypothyroidism. Findings indicate the presence of long-term changes in the population of TSH receptor antibodies years after 131I treatment, which may influence thyroid function.

Effects of thyroid hormone on carbonic anhydrase I concentration in human erythroid burst-forming unit-derived cells.

Individuals with hyperthyroidism exhibit red blood cell concentrations of carbonic anhydrase I (CAI) that reflect the integrated serum thyroid hormone concentration over the preceding few months. Furthermore, T3, at a physiological free concentration, decreases the CAI concentration in human erythroleukemic YN-1 cells. The effect of T3 on CAI concentration in burst-forming unit-erythroid (BFU-E)- derived cells, obtained by culturing peripheral blood mononuclear cells with various cytokines, including erythropoietin, has now been investigated. BFU-E-derived cells contained a high concentration of CAI (mean +/- SE, 4.8 +/- 0.8 x 10(-12) mol/10(6) cells; n = 8). The CAI in BFU-E-derived cells was immunologically identical to that present in mature red blood cells. T3 decreased the CAI concentration in BFU-E-derived cells in a dose-dependent manner (28%, 47% and 75% decreases at 3 x 10(-10), 1 x 10(-9), and 3 x 10(-9) mol/liter T3, respectively). These results suggest that BFU-E-derived cells may be used to study the effect of T3 on human red blood cell CAI. This system may prove useful in the tissue diagnosis of resistance to thyroid hormone.

Thyroid hormone regulates rat placental type III iodothyronine deiodinase activity by inducing kinetic changes different from those in the same isozyme in rat brain.

The kinetics of type III iodothyronine deiodinase (5-D) in rat placenta and brain and the role of phospholipids in enzyme activity were determined. Pregnant Sprague-Dawley rats were given either vehicle (control group) or T4 (15 micrograms/100 g bw/day; hyperthyroid group) from the 14th to the 21st day of gestation. Mitochondrial-microsomal fractions of the placenta and brain were used as the source of T4 5-D. Placental T4 5-D activity in the hyperthyroid group was increased when determined at 13 nM T4, but it was not significantly different from the control value when assayed at 1.3 microM T4. In contrast, T4 5-D in the brain was significantly increased in the hyperthyroid group regardless of the substrate concentration. Hyperthyroid rats showed decreased Km for placental 5-D and increased Vmax for brain 5-D. CM-Sephadex chromatography of solubilized placental microsomes was performed to determine whether phospholipids cause a reduction in the Km of placental 5-D in hyperthyroid rats. T3 5-D activity was undetectable unless protein-containing fractions were combined with phospholipid-containing fractions in the reaction mixture. Kinetic studies revealed that phospholipids had no effects on either Km or Vmax of placental T3 5-D. These data indicate that 5-D activity in the rat placenta is increased in hyperthyroidism with different kinetic changes from those in the brain, and that phospholipids have no effects on the kinetic parameters of placental 5-D whereas they are essential for the enzyme activity.

Intercellular adhesion molecule-1 (ICAM-1) in the sera of patients with Graves' disease: correlation with disease activity and treatment status.

Intercellular adhesion molecule (ICAM-1), a ligand for lymphocyte function-associated antigen-1 (LFA-1), plays an important role in a variety of immune-mediated mechanisms such as lymphocyte attachment to cultured Graves' thyroid cells. We report the detection of a soluble form of the ICAM-1 molecule (sICAM-1) in sera from patients with Graves' disease (GD) and other thyroid disorders. The mean (+/- SD) sICAM-1 concentration in 28 euthyroid control subjects was 1931 +/- 681 pmol/L. The mean sICAM-1 concentration in 25 untreated hyperthyroid patients with GD was significantly elevated (3065 +/- 890 pmol/L), and decreased significantly (2489 +/- 845 pmol/L) after treatment with antithyroid drugs and/or 131I. Of 14 GD patients who had been in remission following administration of antithyroid drugs, 12 had recurrent disease. In 10 of the 12 patients in whom GD recurred, the sICAM-1 concentration (3807 +/- 796 pmol/L) increased significantly. The mean sICAM-1 concentration in patients with hypothyroidism due to chronic thyroiditis (n = 15:2895 +/- 569 pmol/L) was significantly elevated over that of control subjects, and not different from untreated hyperthyroid patients. The mean sICAM-1 concentration in patients with subacute thyroiditis (n = 13: 3036 +/- 441 pmol/L) was significantly elevated, while the mean sICAM-1 concentration in patients with nodular goiter (n = 10: 2318 +/- 490 pmol/L) was within the normal range. These results indicate that mean serum sICAM-1 concentration was significantly elevated in patients with untreated GD, and it decreased after treatment and increased at the time of recurrence. Therefore, the elevated serum concentration of sICAM-1 in patient with GD probably reflects ongoing immune processes.

Novel sensing system for glucose based on the complex formation between phenylborate and fluorescent diol compounds.

From the standpoints of long-term stability and simple handling, a glucose sensor composed of totally synthetic sensing moieties should be of great advantage. This study was performed to demonstrate the feasibility of a novel glucose sensing system in an aqueous milieu based on a change in the fluorescence on competitive binding between a fluorescent diol compound and glucose toward a phenylborate compound. 6,7-Dihydroxy-4-methyl-coumarin (DHMC) was selected as a fluorophore, and 3-propionamidophenylboronic acid (PAPBA) as a phenylborate compound. The relationship between the glucose concentration and fluorescence intensity was linear in the range of 0 to 500 mg/dl of glucose. The availability of various derivatives of DHMC and phenylborate compounds allows the incorporation of these functionalities on the tip of an optical fiber to construct an opto-sensing system for glucose.

Long-term effects of radioiodine on thyrotrophin receptor antibodies in Graves' disease.

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.