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Determination of free thyroid hormones and their binding proteins in a patient with severe hyperthyroidism (thyroid storm?) and thyroid encephalopathy.

A patient with severe hyperthyroidism (thyroid storm?) and thyroid encephalopathy is described. During her illness only a slightly raised level of total thyroxine and a normal level of total triiodothyronine was found in contrast with very high levels of free thyroid hormones. Very low levels of thyroxine binding globulin, albumin and low levels of thyroxine binding prealbumin in contrast with nearly normal values of T3 resin uptake were observed. All parameters of thyroid function returned to normal after therapy.

Adult

Thyroid-specific T cells in the normal Wistar rat. II. T cell clones interact with cloned wistar rat thyroid cells and provide direct evidence for autoantigen presentation by thyroid epithelial cells.

Strains of rat differ in their susceptibility to experimental autoimmune thyroiditis (EAT). We recently observed that the normal Wistar rat has lymph node (LN) T cells which recognize the newly available cloned Wistar thyroid cell line (WRT) and/or rat thyroglobulin (rTg). We have now cloned thyroid-specific T cells and characterized their interaction with the WRT target cell. Twenty-three T cell clones were tested for their reactivity to syngeneic thymocytes, WRT cells alone, or WRT cells with thymocytes. All the clones were of the CD4+CD8- phenotype. Seven of 23 T cell clones proliferated in the presence of WRT cells alone or with the combination of WRT cells and thymocytes, exhibiting stimulation indices of 1.5 to 5. In all but one of the T cell clones responding to WRT cells alone was there no evidence that the additional presence of thymocytes supplied a stronger "second" proliferative signal than the WRT cells. These WRT-reactive clones which were able to be more extensively characterized were MHC class II restricted, secreted rat interferon (IFN)-gamma in response to WRT cell exposure, and one clone showed cross-reactivity with rTg antigen. Induction of WRT cell MHC class II antigen by prior treatment with IFN-gamma failed to further enhance the WRT cell-induced T cell proliferation. These data provide the first evidence for direct antigen presentation by thyroid epithelial cells (TECs) in the absence of other antigen-presenting cells. Furthermore, they provide evidence that TECs are able to provide the appropriate "second" signals required for T cell activation and successful autoantigen presentation.

Animals

Estimation of thyroid gland activity in the Snell dwarf mouse by ultrastructural observation of the thyroid gland, measurement of plasma thyroxine concentration and thyroid hormone binding capacity.

An ultrastructural study of the thyroid gland of the Snell dwarf mouse showed cellular activity to be very low. Follicle cell diameters were significantly lower than in controls whilst the nucleocytoplasmic ratio was significantly higher. The observed cellular activity of the thyroid cells was associated with circulating levels of thyroxine which were found to be significantly lower than in controls. Measurement of the free thyroxine index showed very little free hormone available for tissue uptake. No differences in thyroid function due to age or sex in the dwarf mice were seen. Possible endocrine imbalances contributing to the low thyroid activity in the Snell dwarf mouse are discussed.

Animals

The relationships between serum T3 index, thyroid volume, and thyroid stimulating, TSH receptor binding and thyroid growth stimulating antibodies in untreated Graves' disease.

This study represents an international double-blind collaborative study of abnormal immunoglobulin activity in untreated Graves' disease. Laboratories in two countries participated in a comparison of thyrotrophin binding inhibiting (TBII), thyroid stimulating (TSAb), and growth stimulating (TGI) immunoglobulins with clinical data, including ultrasonically measured thyroid size. The correlation between TGI and thyroid volume (n = 25, Rs = 0.54, P less than 0.05) and the fact that 9 of 10 patients with high range TGI values had large goitres establish the relationship between TGI and goitre, confirming that the in-vitro activity of these antibodies is related to an in-vivo action. In addition, both TBII and TSAb correlated with serum free T3 indices (TBII: n = 60, Rs = 0.46, P less than 0.001, and TSAb: n = 60, Rs = 0.64, P less than 0.001). Moreover, both TBII and TSAb correlated with thyroid volume (TBII: n = 60, Rs = 0.37, P less than 0.01, and TSAb: n = 60, Rs = 0.41, P less than 0.01) suggesting that these antibodies are also important in development of goitre in Graves' disease. Finally, some correlation between the antibodies was observed. TBII correlated with TSAb (n = 60, Rs = 0.47, P less than 0.001), and in the 16 patients with positive TGI results, this activity correlated with TBII (Rs = 0.54, P less than 0.05), but not with TSAb. Also some cases were found with corresponding high range TBII and TGI, while negative for TSAb, suggesting a close relationship between the in-vitro measurement of TSH binding and TGI.

Adult

Thyroid disease in middle-aged and elderly Swedish women: thyroid-related hormones, thyroid dysfunction and goitre in relation to age and smoking.

The prevalence of thyroid disease and the concentration of thyroid hormones and thyrotropin were studied in a random population sample of 1154 women, aged 50-72 years, with special reference to the effect of age and smoking. The prevalence of spontaneous hypothyroidism was 3.3% (previously unknown overt and mild disease 1.3%) and the prevalence of hyperthyroidism was 2.5% (previously unknown disease 0.2%). Clinically suspected hyper- or hypothyroidism (very weak to strong) was recorded in 288 women, but was only verified in three cases. The prevalence of visible and palpable thyroid enlargement was 2.1% and 13-14%, respectively. Total thyroxine concentrations increased and free tri-iodothyronine levels decreased significantly with age (P less than 0.001). The serum thyrotropin concentrations were lower in smoking women than in non-smokers in the 50- and 58-year age groups (P less than 0.05). There was no increase in the prevalence of thyroid disease or goitre in the women who were smokers at the time of the study.

Age Factors

Basal and thyroid hormone receptor auxiliary protein-enhanced binding of thyroid hormone receptor isoforms to native thyroid hormone response elements.

There are three known isoforms of the rat thyroid hormone receptor, TR alpha-1, TR beta-1, and TR beta-2. The first two are expressed in all tissues, whereas TR beta-2 appears to be expressed only in the pituitary. The differences in the roles of the three receptor isoforms are unknown, but may involve preferential interaction with different subsets of thyroid hormone-regulated genes in different tissues. We tested the binding of the three TR isoforms to putative thyroid hormone response elements (TREs) from genes that are expressed in the pituitary or other tissues and are regulated by thyroid hormone. In vitro translated 35S-labeled rat TR alpha-1, rat TR beta-2, and human TR beta-1 receptors were bound to a battery of biotinylated synthetic deoxyribonucleotides containing naturally occurring putative TREs from genes expressed either in only pituitary (rat glycoprotein hormone alpha-subunit, TSH beta-subunit, and GH) or in nonpituitary (rat alpha-myosin heavy chain, malic enzyme, and Moloney murine leukemia virus promoter) tissues. All three receptor forms bound to each of the TREs. TR beta-2 did not show preferential binding to TREs of pituitary-specific genes compared to TR beta-1. Additionally, TR alpha-1 had a similar TRE-binding pattern as the TR beta s, except for possibly less binding to rat glycoprotein hormone alpha-subunit TRE. Finally, rat pituitary and liver nuclear extracts enhanced TR binding to TREs, with the greatest enhancement seen with the alpha-subunit TRE. These studies suggest that all TR isoforms bind similarly to native TREs. Also, TR binding to TREs can be differentially enhanced by interactions with nuclear proteins.

Animals

Evidence that both long-acting thyroid stimulator and long-acting thyroid stimulator-protector stimulate the human thyroid gland.

Thyroid-stimulating immunoglobulins were prepared from two potent sera, one contained long-acting thyroid stimulator (LATS) and the other contained both LATS and LATS-protector (LATS-P). The potencies of the immunoglobulin G (IgG) preparations were estimated in the McKenzie assay. The accumulation of cyclic AMP in mouse thyroid lobes was stimulated only by LATS--IgG; LATS-P--IgG was inactive. In contrast, both LATS-IgG and LATS-P--IgG were equally effective in slices of human thyroid.

Animals

High potential to tumor necrosis factor alpha (TNF-alpha) production of thyroid infiltrating T lymphocytes in Hashimoto's thyroiditis: a peculiar feature of destructive thyroid autoimmunity.

T lymphocytes present in thyroid infiltrates of 6 patients with Hashimoto's thyroiditis (HT) and of 4 patients with Graves' disease (GD) were analyzed at clonal level and their profiles of mitogen-induced lymphokine secretion were characterized. Production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma) was measured in culture supernatants of a total number of 332 T cell clones (TCC) from HT, of 269 TCC from GD infiltrates and of 266 control TCC derived from normal lymphoid tissues. No significant difference was found in the ability to produce IL-2 between TCC from HT or GD infiltrates and control TCC. The proportion of HT- or GD-derived TCC able to produce IL-4 was extremely low (4 and 5%, respectively) in comparison with controls (19%). In contrast, the proportion of interferon-gamma (IFN-gamma)-producing (IFN-P) TCC derived from either HT (87%) or GD (80%) infiltrates was much higher (p less than 0.0005) than that found in controls (59%). In addition, most of IFN-P TCC from either HT or GD usually released higher amounts (p less than 0.002) of IFN-gamma than did control clones. No significant difference was found between GD infiltrates and controls in the proportions of TCC able to secrete TNF-alpha (39% and 47%, respectively), whereas the proportion of TNF-alpha-producing (TNF-P) TCC derived from HT (78%) was significantly higher (p less than 0.0001). In addition, most of both CD8 and CD4 TCC from HT released higher amounts of TNF-alpha than did TNF-P clones from controls or GD. These data suggest that T cells present in autoimmune thyroid infiltrates share a number of functions, such as high production of IFN-gamma, but differ with regard to their ability to secrete TNF-alpha, which is peculiar of most T cells present in the thyroid of HT patients.

Antigens, Differentiation, T-Lymphocyte

Seronegative Hashimoto thyroiditis with thyroid autoantibody production localized to the thyroid.

A patient without serologic evidence of an autoimmune disorder had a thyroidectomy for neck compression caused by her goiter. Histologic examination of the gland revealed pathologic changes compatible with Hashimoto disease, and lymphocytes isolated from her thyroid gland were transformed into lymphoblastoid cells in vitro by Epstein-Barr virus in the presence of cyclosporine. These cells produced antibodies against thyroglobulin, thyroid microsome, thyrocyte membrane, and thyrotropin, whereas lymphoblastoid cells produced from the patient's peripheral blood lymphocytes showed no antithyroid activity. Several human monoclonal antibodies were produced from the intrathyroidal lymphocytes by fusion with the SHM-D33 heteromyeloma, and the resulting cell lines produced antibodies with high-affinity binding specific for thyroid antigens. These studies show that lymphocytes capable of producing antithyroid antibodies can be present in the thyroid glands of patients with Hashimoto disease without evidence of a peripheral immune response, thus indicating that Hashimoto disease can exist as an organ-restricted autoimmune disorder.

Adipose Tissue

Pituitary-thyroid interaction: effects of thyroid hormone, non thyroidal illness and various agents on TSH secretion.

Recent developments in thyroid hormone metabolism have helped to understand the complex events which characterize the regulation of TSH secretion. Plasma T3 concentration as well as intrapituitary T3 generation from T4, exert a profound effect on TSH synthesis and release. Pituitary Type II deiodinase differs from Type I deiodinase found in other tissue such as liver and kidney, and in fact different conditions such as hypothyroidism and hyperthyroidism affect these enzymes in opposite direction. Thyroid hormones exert other effects on the pituitary such as increased synthesis of substance P, increased synthesis of GH, and decreased TRH receptors, TRH also modifies its own receptors in the pituitary and exerts modulatory effects on TSH molecule. Patients with non thyroidal illness may display TSH molecules with decreased biological activity. Various agents used in every day praxis may alter TSH and thyroid secretion. The physician must be aware of changes in order to avoid diagnostic pitfalls.

Animals

Thyroid iodine content and serum thyroid hormone levels in autoimmune thyroiditis: effect of iodide supplementation.

The relationship between thyroid iodine content (TIC) measured by x-ray fluorescence and serum TSH, T4, and T3 levels was investigated under iodide supplementation (0.5 mg/day for 1 to 9 mo). In five euthyroid control patients, whose TIC ranged from 2.5 to 14 mg, the TIC increased from 1.5 to 4 mg after 4 wk of treatment and had a tendency to plateau when the treatment was pursued. No significant changes in serum T4, T3, and TSH levels have been observed in these control subjects. Fourteen patients with autoimmune thyroiditis with low TIC (0-5 mg) were also studied. In six patients, the TIC increased significantly (3-10 mg over initial value after 3-7 mo of treatment). In parallel, there was a significant increase in serum T4 levels (35-150% over initial value) while T3 levels were modified in only two patients. In five patients serum TSH level decreased and was two- to seven-fold lower than before treatment whatever was its initial value; however, the spectrum of changes varied among patients from slight increase to a complete normalization of hormonosynthesis. In the eight other patients, iodide supplementation aggravated the thyroid disorders during the first months of treatment. The thyroid hormone blood levels dropped significantly in six patients (percent decrease below initial value: 20-100%) and was unchanged in the two others. An increase in the TSH blood level (X2-6) was observed in all patients except one. Concomitantly, the iodine stores were progressively depleted in three patients, unchanged in three and increased in two. When iodide treatment was pursued, an escape from this organification block was observed in two patients.

Adult

Influence of thyroid substitution therapy and thyroid autoantibodies on the value of serum thyroglobulin in recurring thyroid cancer.

The study was performed to evaluate the influence of thyroxine substitution therapy and the presence of thyroglobulin antibodies (TgAb) on the usefulness of serum thyroglobulin (Tg) measurements in the follow-up of patients treated for well differentiated thyroid carcinoma. Seventy-two consecutive patients with differentiated thyroid cancer and eight with medullary carcinoma as well as controls were studied on one or more occasions and blood was drawn for measurement of serum Tg, TgAb, TSH and thyroid hormones. In 23 patients the hormonal substitution was withdrawn and 3-4 weeks later new blood samples and a 131I scintigraphy was performed. Eighteen patients were shown to have recurrence or metastases. Four of these had TgAb, two had normal Tg values, and the remaining 12 had extremely elevated levels. Those with TgAb and normal Tg values all had high Tg levels off thyroxine substitution. The 54 patients without evidence of recurrence had low levels of serum Tg except for one with highly elevated values. Based on the results from this and other studies is concluded that serum Tg is an important adjunct in the follow-up of patients with well differentiated thyroid carcinoma, but certain limiting factors have to be taken into account, i.e., the radicality of surgery, the sufficiency of the substitution, the presence of TgAb and the method for measurement of Tg.

Adolescent

Differential effects of methylmercuric chloride and mercuric chloride on the histochemistry of rat thyroid peroxidase and the thyroid peroxidase activity of isolated pig thyroid cells.

This study was designed to characterize the interaction of CH3HgCl or HgCl2 with thyroid peroxidase (TPO). Two types of experiments were performed. First, the thyroids from rats that were given 5.6 mg/kg/day of either CH3HgCl or HgCl2 for 2 weeks by intubation were subjected to histochemical treatment and then to electron microscopy. TPO activities in all cell compartments were inhibited by HgCl2 but not by CH3HgCl. Morphological observation showed that taller epithelia were induced by HgCl2, whereas flattened epithelia forming large follicles were induced by CH3HgCl. The serum thyrotropin level was substantially lowered by CH3HgCl but was unchanged by HgCl2. Second, the guaiacol oxidation by TPO in isolated and ruptured pig thyroid cells was spectrophotometrically monitored in the presence of either CH3HgCl or HgCl2. The TPO was not inhibited by CH3HgCl but was inhibited by HgCl2. These results indicated that CH3HgCl induced a hypothyroid state without affecting TPO, whereas HgCl2 inhibited TPO and induced a hypertropic state owing to compensation for loss of enzyme activity, and that the lack of inhibitory activity of CH3HgCl was not due to the inability to penetrate the cells. Therefore, there appeared to be a differential interaction of organic and inorganic forms of mercurials with the thyroid.

3,3'-Diaminobenzidine

Alterations of serum concentrations of thyroid hormones and sex hormone-binding globulin, nuclear binding of tri-iodothyronine and thyroid hormone-stimulated cellular uptake of oxygen and glucose in mononuclear blood cells from patients with non-thyroidal illness.

Nuclear tri-iodothyronine (T3) binding and thyroid hormone-stimulated oxygen consumption and glucose uptake were examined in mononuclear blood cells from patients with non-thyroidal illness (NTI) in which serum T3 was significantly (P less than 0.05) depressed (0.62 +/- 0.12 (S.D.) nmol/l) compared with healthy control subjects (1.45 +/- 0.30 nmol/l). Neither serum TSH nor sex hormone-binding globulin differed from that of the control group. Nuclear T3 binding capacity was increased (P less than 0.05) in patients with NTI (10.1 +/- 3.0 fmol/100 micrograms DNA) compared with controls (2.5 +/- 0.9 fmol/100 micrograms DNA). Unstimulated glucose uptake was increased in cells from patients with NTI (2.03 +/- 0.49 mmol/l per mg DNA per h, P less than 0.01) compared with controls (1.13 +/- 0.20 mmol/l per mg DNA per h). Thyroxine-stimulated glucose uptake (stimulated glucose uptake--unstimulated glucose uptake) was increased in cells from patients with NTI (2.06 +/- 1.67 mmol/l per mg DNA per h, P less than 0.01) compared with controls (0.26 +/- 0.12 mmol/l per mg DNA per h), and T3-stimulated glucose uptake was also increased in cells from patients with NTI (1.34 +/- 0.81 mmol/l per mg DNA per h, P less than 0.05) compared with controls (0.24 +/- 0.10 mmol/l per mg DNA per h). In contrast, neither unstimulated nor thyroid hormone-stimulated oxygen consumption differed. We conclude that both increased nuclear T3 binding and increased thyroid hormone-induced glucose uptake may represent counter-regulatory mechanisms which tend to maintain intracellular homeostasis.

Adult

Detection of thyroid-stimulating antibodies in thyroid diseases, employing rat thyroid fragment perifusion.

The technique of perifusing rat thyroid fragments was used to investigate the presence of thyroid-stimulating antibodies (TSAb) in the sera of 48 patients. Response to IgG was measured by determining the mean rate of release of T4 (R) during a 30-min perifusion and the secretion peak (Imax) by means of samples taken every 5 min. Values found to be above the mean + 2 SD of the control values of R or Imax were considered to be positive. TSAb were found in all the 17 patients with untreated Graves' disease (GD) and in the 2 treated with antithyroid drugs, but not in the 3 who had undergone surgery or 131I treatment or in the 2 on corticosteroid treatment. TSAb were also found in 2 out of 3 patients with untreated nodular toxic goiter (UNTG) and in 6 out of 8 with diffuse nontoxic goiter (DNG) but at lower levels. In the untreated GD group, R and Imax correlated significantly with the corresponding IgG concentrations (from 90 to 800 micrograms/ml), suggesting TSAb activity which can be compared from one patient to another. TSAb activity did not correlate with thyroid function tests in any group. In all the groups it induced an early secretion peak followed by a decreasing response throughout the stimulation period, as was previously found with 65 mIU/ml TSH. The specificity of this technique was verified by five different control methods: the perifusion technique was checked by using KRBG buffer alone; sera were studied from a group of healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Hyperthyroidism with potent thyroid-stimulation-blocking antibodies and negative thyroid-stimulating antibodies after subtotal thyroidectomy for Graves' disease with follicular thyroid carcinoma.

A 39-year-old woman with Graves' disease associated with follicular thyroid carcinoma underwent subtotal thyroidectomy. TSH-binding inhibitor immunoglobulins (TBII) were positive, whereas thyroid-stimulating antibodies (TSAb) and thyroid-stimulation-blocking antibodies (TSBAb) were both negative before the operation. After the operation, TBII markedly increased above the pretreatment value. TSBAb became positive 3 months after the operation and then their activity increased, while TSAb remained negative after the operation. Subtotal thyroidectomy may have influenced the development of TSBAb in this patient. Irrespective of these findings, the patient became hyperthyroid again several months after the operation.

Adenocarcinoma

Studies of CD4+ (helper/inducer) T lymphocytes in autoimmune thyroid disease: demonstration of specific induction in response to thyroid peroxidase (TPO) in vitro and its relationship with thyroid status in vivo.

We have studied by flow cytometric analysis the antigen specific activation of CD4+ (helper/inducer) T lymphocytes by purified human thyroid peroxidase (TPO). Peripheral blood mononuclear cells were obtained from 26 patients with Graves' disease (GD), 16 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), and 14 normal subjects (N). Cells were cultured for 7 days in the presence or absence of TPO at final concentrations of 3, 30, and 300 ng/mL. When harvested, cells were reacted with an FITC-conjugated anti-CD4 and a PE-conjugated anti-HLA-DR murine monoclonal antibodies. The percentage of HLA-DR+ CD4+ cells (activated CD4+ cells) was determined by a flow cytometer. In the absence of TPO, CD4+ cells had been activated without any specific stimulant. This is known as the autologous mixed lymphocyte reaction (AMLR). In the AMLR, CD4+ cells from GD and HT were less activated compared to those from NG and N. Results of TPO-specific activation were expressed as an incremental increase of activated CD4+ cells (II) (percentage of activated CD4+ cells cultured with TPO minus percentage of activated CD4+ cells cultured without TPO). II of N, GD, HT, and NG were 0.37 +/- 0.21, 2.20 +/- 0.45,** 2.0 +/- 0.66,* and 0.35 +/- 0.27 (mean +/- SEM), respectively (**p less than 0.01; *p less than 0.05 vs N). When patients were further subdivided, the highest mean II was found in patients with hyperthyroid GD (p less than 0.01), followed by euthyroid HT (p less than 0.05) and euthyroid GD (p less than 0.05), however there was no significant difference between hypothyroid HT and N. In conclusion (1) AMLR reactivity of CD4+ cells from GD and HT was impaired, (2) however, CD4+ cells from both GD and HT were significantly more induced by TPO compared to N, and (3) this induction depends, in part, on the in vivo thyroid status.

Adolescent

[Thyroid functions in nonthyroidal illness: specific changes in serum levels of thyroid hormones related in illness and the correlation between thyrotropin and free thyroid hormones in patients with nonthyroidal illnesses].

In order to assess the thyroid function of patients with nonthyroidal illness, 292 patients with nonthyroidal illness were employed in the present study. These patients were then subdivided into 6 groups according to their original illness. The groups consisted of patients with malignant illnesses (19 males and 10 females; mean age of 59.7 yr.), with chronic hepatitis (14 males and 8 females; mean age of 55.2 yr.), with liver cirrhosis (5 males and 6 females, mean age of 60.4 yr.), with uremia who had been receiving constant hemodialysis 2 approximately 3 times per week (52 males and 38 females; mean age of 48.1 yr.), with diabetes mellitus (50 males and 43 females; mean age of 52.3 yr.) and with cerebrovascular accident (21 males and 26 females; mean age of 74.9 yr.). In addition, 34 healthy persons (15 males and 19 females; mean age of 41.6 yr.) were also employed as controls. Because the differences between mean ages in these groups were significant, the relationship between age and thyroid function was examined. Significant positive correlations between age and total thyroxine (TT4) (r = 0.19; p less than 0.01), and reverse triiodothyronine (rT3) (r = 0.175; p less than 0.01) were found. A negative correlation was also found between age and total triiodothyronine (TT3) (r = 0.231; p less than 0.01). The serum levels of rT3 were elevated in patients with neoplasma and liver cirrhosis but significantly low in patients with uremia. These characteristic findings were correlated with the severity of each original disease such as % motarity, serum levels of cholinesterase, blood urea nitrogens and the blood sugar control in the diabetics. In these circumstances, multiple correlation analyses were performed in order to assess whether there might exist a negative feedback mechanism between thyrotropin and FT4/FT3. The highest partial correlation coefficient was obtained between thyrotropin and FT4. It might, therefore, be concluded that in patients with a nonthyroidal illness, decreased levels of serum thyroid hormones indicate not only the severity of the illness but also the supposed presence of a hypothyroid state.

Adult