Thyroid hormone modulates insulin-like growth factor-I(IGF-I) and IGF-binding protein-3, without mediation by growth hormone, in patients with autoimmune thyroid diseases.

The expression and synthesis of insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 (IGFBP-3) are regulated by various hormones and nutritional conditions. We evaluated the effects of thyroid hormones on serum levels of IGF-I and IGFBP-3 levels in patients with autoimmune thyroid diseases including 54 patients with Graves' disease and 17 patients with Hashimoto's thyroiditis, and in 32 healthy age-matched control subjects. Patients were subdivided into hyperthyroid, euthyroid and hypothyroid groups that were untreated, or were treated with methylmercaptoimidazole (MMI) or L-thyroxine (L-T4). Serum levels of growth hormone (GH), IGF-I and IGFBP-3 were determined by radioimmunoassay. Serum GH levels did not differ significantly between the hyperthyroid and the age-matched euthyroid patients with Graves' disease. The serum levels of IGF-I and IGFBP-3 showed a significant positive correlation in the patients (R=0.616, P<0.001). The levels of both IGF-I and IFGBP-3 were significantly higher in the hyperthyroid patients with Graves' disease or in those with Hashimoto's thyroiditis induced by excess L-T4 administration than in control subjects. Patients with hypothyroid Graves' disease induced by the excess administration of MMI showed significantly lower IGFBP-3 levels as compared to those in healthy controls (P<0.05). Levels of IGFBP-3, but not IGF-I levels, showed a significant positive correlation with the levels of free T4 and free T3. In Graves' disease, levels of TPOAb, but not of TRAb, showed a significant positive correlation with IGFBP-3. We conclude that in patients with autoimmune thyroid diseases, thyroid hormone modulates the synthesis and/or the secretion of IGF-I and IGFBP-3, and this function is not mediated by GH.     

Detection of the novel autoantibody (anti-UACA antibody) in patients with Graves' disease

Uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) is an autoantigen in patients with panuveitis such as Vogt-Koyanagi-Harada disease. The prevalence of IgG anti-UACA antibodies in patients with uveitis is significantly higher than healthy controls, suggesting its potential role as an autoantigen. Originally, UACA was cloned from dog thyroid tissue following TSH stimulation. So, we presumed UACA could be a novel autoantigen in autoimmune thyroid diseases. We measured serum anti-UACA antibody titer using ELISA in patients with autoimmune thyroid diseases (Graves' disease, Hashimoto's thyroiditis, subacute thyroiditis, and silent thyroiditis). The prevalence of anti-UACA antibodies in Graves' disease group was significantly higher than that in healthy group (15% vs. 0%). Moreover, the prevalence of anti-UACA antibodies in Graves' ophthalmopathy was significantly higher than that in Graves' patients without ophthalmopathy (29% vs. 11%). Especially, 75% of severe ocular myopathy cases showed high UACA titer. Immunohistochemical analysis revealed that UACA protein is expressed in eye muscles as well as human thyroid follicular cells. Taken together, UACA is a novel candidate for eye muscle autoantigens in thyroid-associated ophthalmopathy.     

Serum IL-18 levels are not increased in patients with untreated Graves' ophthalmopathy.

OBJECTIVE: Cytokines play an important role in autoimmune thyroid diseases, and serum levels may reflect the activity of the immune process. This is particularly interesting in Graves' ophthalmopathy, where a reliable serum activity marker is warranted. Interleukin-18 (IL-18) is a potent Th1 cytokine, known to induce interferon (IFN)-gamma and the aim of this study was to evaluate serum IL-18 levels in Graves' ophthalmopathy. METHODS: Serum IL-18 was measured by ELISA in 52 patients with untreated Graves' ophthalmopathy (who all had been rendered euthyroid with antithyroid drugs), 52 healthy controls matched for sex, age, and smoking habits, and 15 euthyroid patients who had been treated for Graves' hyperthyroidism and ophthalmopathy in the past. RESULTS: Serum IL-18 (median values in pg/ml with range) levels did not differ between the untreated Graves' ophthalmopathy patients-226 (61-704) pg/ml, matched healthy controls-194 (17-802) pg/ml, and Graves' ophthalmopathy patients treated in the past-146 (0-608) pg/ml. No correlation was observed between serum IL-18 levels and thyroid function or antithyroid antibodies. There was no correlation between serum IL-18 levels and smoking habits. CONCLUSION: We conclude that Graves' ophthalmopathy does not affect serum IL-18.     

Analysis of Fas, FasL and Caspase-8 expression in thyroid gland in young patients with immune and non-immune thyroid diseases

INTRODUCTION: Apoptosis, programmed cell death is a regulating mechanism enabling the removal of superabundantly produced and unnecessary at the certain moment cells. Disturbances of the apoptosis regulation contribute to the pathogenesis of many diseases, including autoimmune thyroid disorders. The aim of this study was to estimate expression of proapoptotic Fas/FasL and caspase-8 in thyroid tissues in patients with Graves' disease (GD), non-toxic nodular goiter (NTNG) and Hashimoto's thyroiditis (HT). MATERIAL AND METHODS: Inclusion criteria of Graves' patients were: large goiter, ophthalmopathy, TRAb > 5 U/L, positive titre of anti-TPO and anti-TG antibodies and concentration of TSH < 0.45 microIU/mL for more the 2-3 months from an onset of the disease. Isolated thyrocytes were identified by indirect method: in the first stage mouse monoclonal antibodies (mAbs) anti-TPO were bound to rabbit anti-mouse antibodies IgG (Fab')2 labeled FITC. To obtained cellular suspension mAbs directed against apoptotic Fas/FasL molecules labeled with PE (Phycoerythrin) was added. All investigations were performed on Coulter EPICS XL flow cytometer. Detection of apoptotic proteins was confirmed by Western Blot and immunohistochemistry methods using mAbs in DAB chromogene visuality and marked by Mayer's haematoxylin. Evaluation of caspase-8 expression in thyroid follicular cells was performed by Western Blot test. RESULTS: The analysis of Fas and FasL expression on surface of thyroid follicular cells was higher in patients with Hashimoto's thyroiditis (38%, 26%) in comparison with patients with Graves' disease (18%, 14%). In case of patients with Hashimoto's thyroiditis significantly lower percentage of thyroid tissue infiltrating immune Fas+ (13%) and FasL+ (22%) T cells in comparison with Graves' patients (33%, 43% respectively) was observed . Identification of proapoptotic Fas and FasL molecules in the thyroid follicular cells revealed higher expression of both proteins in patients with GD (++,++) and HT (+++; +++, respectively) in comparison with NTNG patients (+/0; +/0). Caspase-8 expression was detected in band 55 kDa using Western Blot test in patients with thyroid autoimmune diseases. CONCLUSIONS: We conclude that alteration in the expression of proapoptotic proteins in thyroid follicular cells may play a role in pathogenesis of thyroid autoimmune disorders. In addition, suppression of apoptosis in Graves' disease led to increased proliferation of thyroid follicular cells which is responsible for goiter formation.     

CTLA4 gene polymorphisms in children and adolescents with autoimmune thyroid diseases

Two common forms of autoimmune thyroid diseases are Graves' disease and Hashimoto's thyroiditis. Cytotoxic T lymphocyte antigen 4 (CTLA4) encoded by the CTLA4 gene on chromosome 2q33 plays a role in susceptibility to Graves' disease and is probably important also for Hashimoto's thyroiditis as well as for the other endocrine autoimmune disorders. The CTLA4 locus is the only nonhuman leukocyte antigen locus that has been found in association with Graves' disease repeatedly. Particularly, association of three polymorphic markers of CTLA4 gene, namely, C(-318)T, A49G, and (AT)n dinucleotide repeat, with Graves' disease was demonstrated in most of the population-based investigations. On the other hand, there are few studies to reveal the association of these markers with Hashimoto's thyroiditis. A49G polymorphism was proposed to be associated with Hashimoto's thyroiditis, and C(-318)T was suggested to be not associated. The patient groups consisted of 88 patients (10 males and 78 females; mean age: 14.5 +/- 3.2 years [4.6-21.0 years]) with a previous diagnosis of Hashimoto's thyroiditis and 112 euthyroid volunteers (51 males and 61 females; mean age: 14.1 +/- 2.9 years [5.2-18 years]). The frequency of A/G (A49G) genotype was high and statistically significant in patients with Hashimoto's thyroiditis in comparison with the control group. Although the frequency of C/T [C(-318)T] genotype is not significantly high in children with Hashimoto's thyroiditis according to the control group, the risk of Hashimoto's thyroiditis in A/G genotype group was 4.66 times greater than the group with A/A genotype. In this study, we documented that the A49G polymorphism might increase the susceptibility for Hashimoto's thyroiditis.     

Increase in autorosette-forming lymphocytes in thyroid diseases

A subpopulation of lymphocytes forming rosettes with autologous erythrocytes was studied on peripheral blood and thyroid tissues obtained from the patients with various thyroid diseases. The mean (+/-S.D.) percentage of autorosette-forming cells (ARFC) was 10.1(+/-5.5)% in the peripheral blood from patients with hyperthyroid Graves' disease, which was higher than that in normal subjects (5.6 +/- 2.8%), while the levels of ARFC in the peripheral blood from euthyroid patients with Graves' disease under treatment and Hashimoto's thyroiditis did not significantly differ from the normal level. The mean percentages of ARFC in the thyroid tissues from patients with Graves' disease and Hashimoto's thyroiditis were 14.7(+/-8.5) and 13.3(+/-7.8)%, respectively, which were higher than those in the peripheral blood from the same patients. Most of these cases with abnormally high levels of ARFC were accompanied with the abnormally low T cell to B cell ratios. The microscopic examination of the cytological materials from these patients showed an increased number of large stimulated lymphoid cells or lymphoblasts as compared with those who had few ARFC. These results suggest an increase in an activated T cell subset in the circulation and/or in the thyroid tissue, which is probably caused by active immune response to some stimuli.     

Isolation and characterization of mononuclear cells from various thyroid tissue specimens

Extensive studies of humoral and cell mediated autoimmune responses to thyroid antigens have been performed in order to understand the underlying mechanisms of autoimmune thyroid disorders. Very little is known, however, about the nature of the lymphocyte subpopulations in the thyroid gland and their possible involvement in the pathogenesis of thyroid diseases. We have developed a Percoll gradient technique to separate mononuclear cells from thyroid cells of resected thyroid glands. Thyroid tissue was minced, incubated with Dispase and passed through a tissue sieve. The filtrate was layered onto a four step discontinuous Percoll gradient (densities 1.140, 1.077, 1.061, 1.030 g/ml). Thyroid cells appeared in band II and mononuclear cells in band III. Mononuclear cells were characterized using the monoclonal antibodies OKT-3, OKT-8, OKI-a and OKM-1, and the levels of these populations in peripheral blood and thyroid tissue compared. Patients have been classified by conventional clinical, immunological and histological criteria. The studies involved thyroid tissues from 8 patients with euthyroid nodular goitre, 7 patients with Graves' disease and 1 with Hashimoto's thyroiditis. In the thyroid tissue of non-autoimmune thyroid diseases we find significantly less OKT-3+ cells compared to peripheral blood. In thyroid tissue of autoimmune thyroid diseases there are significantly less OKT-8+ cells compared to peripheral blood. These preliminary results might be linked to the hypothesis of decreased suppressor T-cell activity in autoimmune thyroid disease.     

Immunological abnormality of peripheral blood B cells in patients with autoimmune thyroid disease

We investigated the response to immunoglobulin G-secreting cells (ISC) by peripheral blood mononuclear cells (PB-MNC) and purified B cells following stimulation with Staphylococcus aureus Cowan 1 (SAC) or with B cell stimulatory factor 2 (interleukin 6: IL-6), using the reverse hemolytic plaque assay in an attempt to clarify the immunological functions of peripheral blood B cells in patients with autoimmune thyroid disease (AITD). ISC response by PB-MNC following stimulation with SAC was significantly decreased in patients in the hyperthyroid state of Graves' disease and Hashimoto's thyroiditis as compared with that of normal controls. The difference in SAC-response was not significant between patients with euthyroid state of Graves' disease and normal controls. ISC response by PB-MNC following stimulation with SAC exhibited a reciprocal relationship to TRAb in patients with Graves' disease. Using purified B cells, some spontaneous ISC response without SAC stimulation was observed in patients in the hyperthyroid state of Graves' disease and Hashimoto's thyroiditis. This spontaneous ISC response was further enhanced by IL-6. These results suggest that in organ-specific autoimmune diseases such as AITD, immunological abnormalities exist in B cells and some B cells are nonspecifically activated in the immunologically active state.     

Etiopathogenesis of Graves' disease

Graves' disease is an autoimmune disorder, caused by thyroid-stimulating antibodies, which bind to and activate the thyrotropin receptor on thyroid cells, inducing the synthesis and release of thyroid hormones. It is a polygenic and multifactorial disease that develops as a result of complex interaction between genetic susceptibility and environmental and/or endogenous factors. Graves' disease differs from other autoimmune diseases of the thyroid by specific clinical features, including hyperthyroidism, vascular goitre, ophthalmopathy and--less commonly--infiltrative dermopathy. This article discusses current theories, regarding the etiology and pathogenesis of Graves' disease, including possible predisposing factors, autoimmune aspects of Graves' disease, ophthalmopathy, and dermopathy.     

Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity in patients with Graves' disease, subacute thyroiditis, and silent thyroiditis: a longitudinal study.

Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity was measured longitudinally in 12 patients with Graves' disease, 5 patients with subacute thyroiditis, and 1 patient with silent thyroiditis, and compared with that of 36 normal controls. The patients with Graves' disease and subacute thyroiditis were treated with anti-thyroid drug (methimazole or propylthiouracil) and prednisolone, respectively. On the other hand, no treatment was given to the patient with silent thyroiditis. Since two patients with Graves' disease clearly showed transient deterioration of the thyroid function during the treatment period, data from these two patients were separately investigated. Urinary levels of NAG in the remaining ten patients with Graves' disease before, 1, 3, 6 and 12 months after the treatment were 15.59 +/- 7.93 (SD), 8.96 +/- 6.82, 4.39 +/- 2.33, 3.46 +/- 2.24, and 3.63 +/- 2.38 U/g.creatinine (g.Cr.), respectively. Those obtained before, 1 and 3 months after the treatment were significantly higher than those of the controls (2.85 +/- 1.12 U/g.Cr.). Free thyroid hormone levels became normal or low 3 months after the treatment. The two Graves' patients mentioned above showed a transient increase in urinary NAG with concomitant changes in free thyroid hormone levels. Urinary NAG levels in the patients with subacute thyroiditis before, 2, 4, and 6 weeks after the treatment were 16.56 +/- 10.97, 6.76 +/- 2.79, 3.14 +/- 0.48 and 3.70 +/- 1.44 U/g.Cr., respectively. Those obtained before and 2 weeks after the treatment were significantly higher than those of the controls. Free thyroid hormones were normal 2 weeks after therapy. Urinary NAG in the patient with silent thyroiditis was 9.60 U/g.Cr. on the first visit and gradually decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated prolactin to cortisol ratio and polyclonal autoimmune activation in Hashimoto's thyroiditis.

Cortisol and prolactin, which are considered to have an immunomodulatory effect, and selected autoantibodies were determined in Hashimoto's thyroiditis. 37 patients (8 males and 29 females) (54 +/- 13.8 years) and an equal number of sex- and age-matched normal subjects (52.6 +/- 14.2 years) were studied. None of the 74 subjects suffered from any other immunological, infectious, hepatic, renal or malignant diseases. Patients with Hashimoto's thyroiditis exhibited significantly higher (p < 0.016) prolactin values (14.0 +/- 3.8 ng/ml) than did control subjects (6.5 +/- 1.3 ng/ml). In contrast, cortisol levels were lower in Hashimoto's thyroiditis (13.5 +/- 3.2 microg/dl) vs. normal state (16.0 +/- 1.13 microg/dl), (p < 0.05). The prevalence of anti-TPO and anti-Tg antibodies was 100 % and 43 % in the patients with Hashimoto's disease. In contrast, no subject of the control group was positive for anti-TPO, although 9 subjects (24 %) were positive for anti-Tg autoantibodies. The percentage of positive autoantibodies to nucleus, smooth-muscle, and parietal cells in the patients (36.0, 10.9 and 18.5 %, respectively) was higher than that in healthy group (11.0 and 0 % respectively). Notably, neither group was positive for antibodies against double-stranded DNA or mitochondria. In conclusion, our results provide evidence for a polyclonal activity in Hashimoto's thyroiditis, an organ-specific autoimmune disease, associated with an altered prolactin-adrenocortical status. Such information should initiate longitudinal studies to clarify the exact time sequence of these events related to the disease's activity.     

Encephalopathy associated with autoimmune thyroid disease in patients with Graves' disease: clinical manifestations,follow-up,and outcomes

Background  

The encephalopathy associated with autoimmune thyroid disease (EAATD) is characterized by neurological/psychiatric symptoms, high levels of anti-thyroid antibodies, increased cerebrospinal fluid protein concentration, non-specific electroencephalogram abnormalities, and responsiveness to the corticosteroid treatment in patients with an autoimmune thyroid disease. Almost all EAATD patients are affected by Hashimoto's thyroiditis (HT), although fourteen EAATD patients with Graves' disease (GD) have been also reported.     

The thyroid "microsomal" antigen is an epitope on the thyrotropin receptor

Antimicrosomal antibodies are present in the sera of most patients with autoimmune thyroiditis, and Graves' disease. It has, in general, been difficult to separate antimicrosomal activity from that directed against the thyrotropin (TSH) receptor in Graves' IgG preparations. The "microsomal" antigen has been localized to the endoplasmic reticulum and microfollicular aspect of thyrocytes; its structure is however unknown. In an attempt to identify the thyroid microsomal antigen, we studied the interaction of Hashimoto's IgG with high microsomal antibody titre and negative for thyroglobulin with purified thyroid plasma and light microsomal membranes. We allowed Hashimoto's, Graves', and control IgGs to bind to protein blots of thyroid plasma membranes resolved on SDS-PAGE under non-reducing conditions. All seven Hashimoto's IgG at a concentration of 2 mg/ml interacted with an M approximately 197,000 polypeptide corresponding to the TSH holoreceptor. By contrast to Graves' IgG (which were positive at 1 mg/ml), however, this binding was not blocked by pretreatment of the protein blots with TSH. Normal IgGs showed no binding at concentrations of up to 2 mg/ml. Both Hashimoto's and Graves' IgG interacted with TSH-affinity column-purified receptor preparations. Two of the Hashimoto's IgGs induced adenylate cyclase activation in thyroid plasma membranes, three inhibited TSH-stimulated enzyme activation, and two were without effect. Two classes of autoantibodies, other than TSH receptor directed, were encountered; one class raised to antigens common to all seven patients and another class unique to individual patients, eg, Mr 210,000 and Mr 20,000 polypeptides. We propose that the TSH receptor has multiple epitopes (functional domains), and the one to which antimicrosomal antibody bind is likely to be spatially separated from that with which Graves' IgG and TSH interact. Differences in affinity or number of sites allows for the demonstration of Graves' IgG against a background of antimicrosomal antibody.     

Oxidation products and antioxidant markers in plasma of patients with Graves' disease and toxic multinodular goiter: effect of methimazole treatment

Oxidative stress plays an important role in hyperthyroidism-induced tissue damage, as well as in development of autoimmune disorders. To clarify influence of thyroid metabolic status and autoimmune factors on blood extracellular indices of reactive oxygen species (ROS) generation and free radical scavenging in hyperthyroidism, we studied patients with newly diagnosed and untreated Graves' disease without infiltrative ophthalmopathy (17 female and 8 male, aged 41.8±8.9) and toxic multinodular goiter (15 female and 9 male, aged 48.4±10.1) under the same antithyroid treatment protocol. Initially and after achievement of stable euthyroidism with methimazole, plasma levels of hydrogen peroxide (H₂O₂), lipid hydroperoxides (ROOH) and ceruloplasmin (CP) and serum concentrations of thiobarbituric acid-reacting substances (TBARS) were determined. Similarly, activities of plasma superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were assayed. The results were compared to those of age- and sex-matched controls. Average duration of hyperthyroidism and treatment period were similar in both patients groups. H₂O₂, ROOH and TBARS concentrations were significantly higher in hyperthyroid patients compared to controls. Hyperthyroidism caused an evident increase in SOD and CAT activities and CP level, as well as a decrease in GPx and GR activities. Achievement of euthyroidism resulted in normalization of all analyzed parameters in both hyperthyroid patients groups. These findings suggest that the changes in blood extracellular indices of oxidative stress and free radical scavenging in hyperthyroid patients are influenced by thyroid metabolic status, and are not directly dependent on autoimmune factors present in Graves' disease.     

Immunoglobulin G subclasses of anti-thyroid peroxidase autoantibodies in human autoimmune thyroid diseases

A distribution of immunoglobulin G (IgG) subclass of anti-thyroid peroxidase (TPO) autoantibodies was studied to know whether anti-TPO autoantibodies are closely implicated in the pathogenesis of human autoimmune thyroid diseases. As a result of analyzing 14 patients' sera, 7 with Graves' disease and 7 with Hashimoto's thyroiditis, anti-TPO autoantibodies were found to consist of mainly IgG1 subclass. Percentages of both IgG1 and IgG2 subclasses in IgG class of autoantibodies corresponded to those in the normal serum composition, whereas IgG3 subclass was scarcely contained in anti-TPO autoantibodies and IgG4 subclass markedly increased. It was thought that anti-TPO autoantibodies had a capability to lyse thyroid follicular cells by the mechanism of antibody-dependent complement-mediated cytolysis, because IgG1 and IgG2 subclasses of antibodies can fix complement and TPO locates in apical membrane surface of thyroid follicular cells. Comparing Graves' disease with Hashimoto's thyroiditis, mean percentages of both IgG1 and IgG2 subclasses of 2 groups were statistically different. Namely, sera of patients with Graves' disease had higher and lower mean percentages of IgG1 and IgG2 subclasses of autoantibodies, respectively, than those with Hashimoto's thyroiditis, though no plausible explanation for these differences can be offered at the present time.     

Expression and distribution of S-100 protein, CD83 and apoptosis-related proteins (Fas, FasL and Bcl-2) in thyroid tissues of autoimmune thyroid diseases

Previous studies have shown that dendritic cells (DCs) and apoptosis-related proteins play a critical role in the pathogenesis of autoimmune thyroid diseases (ATD).This study was designed to investigate the expression and distribution of S-100 protein, CD83 and apoptosis-related proteins (Fas, FasL and Bcl-2) in the thyroid tissues of ATD and their role in ATD pathogenesis as determined by immunochemical staing techniques and other methods. Pathological tissues of 30 patients with Hashimoto's thyroiditis (HT), 30 patients with Graves' disease (GD) and 30 cases of thyroid follicular adenoma (TFA, as control) were used for this study. A higher expression of S-100 in HT (4.2+/-3.1%) and GD (3.9+/-2.8%) vs TFA (0.95+/-0.64%) (p<0.001). was observed as well as a higher expression of CD83 in HT (22.58+/-13.96% and GD (29.92+/-14.43%) vs TFA (5.19+/-8.08%) (p<0.001). HT thyrocytes adjacent to thyroid infiltrating lymphocytes (TILs) showed greater increases in the levels of Fas and FasL than did the GD thyrocytes while HT TILs exhibited lower expression of Fas and FasL than did the GD TILs. GD thyrocytes expressed increased levels of the antiapoptotic protein Bcl-2 as compared to the low levels detected in HT thyrocytes. An opposite pattern was observed in the TILs in GD (low expression of Bcl-2) and HT (high expression of Bcl-2). The findings suggest that the high expression of DC markers is related to the pathogenesis of HT and GD. Up-regulation of both the number and matured functions of DCs may lead to the presentation of more antigens to lymphocytes which are related to the development of autoimmune thyroid diseases. The regulation of Fas/FasL/Bcl-2 in GD favors apoptosis of infiltrating lymphocytes and thyrocyte survival. The regulation of Fas/FasL/Bcl-2 in HT may promote thyrocyte apoptosis leading to hypothyroidism.     

Primary malignant lymphoma of the thyroid in a patient with long-standing Graves' disease

We have recently encountered a patient with rapidly enlarging thyroid masses histologically diagnosed as diffuse histiocytic lymphoma which developed in the active course of Graves' disease. The primary thyroid lymphoma has been in complete remission after local radiation therapy. The association of Hashimoto's thyroiditis and thyroid lymphoma has well been recognized. Meanwhile, data have accumulated to demonstrate that Hashimoto's thyroiditis and Graves' disease share possible similar causal immunological abnormalities and are closely related entities. However, the association of Graves' disease and primary thyroid lymphoma has never been reported, as far as we know. Therefore, this case may be the first one that supports the natural concept that thyroid lymphoma develops from pre-existing Graves' disease secondary to the similar immunological abnormalities in Hashimoto's thyroiditis.     

Similarity and dissimilarity between clinical and laboratory findings, especially anti-thyrotropin receptor antibody in ophthalmic Graves' disease without persistent hyperthyroidism and hyperthyroid Graves' disease

The aim of this study was to investigate thyroid states, significance of anti-TSH receptor antibodies and the clinical courses of patients with euthyroid Graves' ophthalmopathy. The clinical and laboratory finding of 30 patients with euthyroid Graves' ophthalmopathy were briefly as follows: 1) normal sized thyroid or small goiter; 2) negative or weakly positive thyrotropin binding inhibitor immunoglobulin (TBII); 3) normal thyroid [99 m-Tc] pertechnetate uptake; and 4) frequent observations of low serum TSH values. Besides TBII, thyroid stimulating antibody (TSAb) was measured under low salt and isotonic conditions using FRTL-5 rat thyroid cells. Both TBII and TSAb titers were lower in euthyroid Graves' ophthalmopathy than in hyperthyroid Graves' disease. Serum TSH levels frequently became low in patients considered as euthyroid upon the first examination as well as in Graves' patients in remission, reflecting preceding or mild hyperthyroidism. In follow-up studies, these patients with mildly elevated thyroid hormone levels and low TSH levels seldom reached a state of persistent hyperthyroidism, when TBII was negative or only weakly positive.     

Anterior pituitary cell antibodies detected in Hashimoto's thyroiditis and Graves' disease

An immunofluorescence study using unfixed cryostat sections of rat pituitary glands was carried out on sera from 34 patients with Hashimoto's thyroiditis, 28 patients with Graves' disease, 10 patients with thyroid adenoma and 50 healthy subjects. After absorption of sera with rat liver tissues, 19 of 34 patients retained reactivity to anterior pituitary cell antibodies (PCA, 55.8%). On the other hand, immunofluorescence in anterior pituitary cells was faint and detected in only 2 of 28 patients with Graves' disease (7.1%) after absorption of their sera with rat liver aceton powder. A similar result was also obtained when PCA were compared in the sera of Hashimoto's thyroiditis and Graves' disease with high titers of thyroid microsomal autoantibodies. PCA were detected neither in the sera of patients with thyroid adenoma nor in the healthy subjects. The present study suggests that PCA were considerably more prevalent in Hashimoto's thyroiditis than in Graves' disease.     

Changes in adipocyte hormones leptin, resistin, and adiponectin in thyroid dysfunction

Thyroid hormones as well as the recently discovered secretory products of adipose tissue adiponectin and resistin take part in energy metabolism. To study the changes in the adipocyte hormones with changes in the thyroid functional status, we measured adiponectin, resistin, and leptin in 69 subjects with Graves' disease before and 32 patients at follow up after treatment for hyperthyroidism at hypothyroid state. Concentrations of serum adiponectin and resistin were higher in hyperthyroid state than in hypothyroid state (adiponectin: 5.73 +/- 1.1 vs. 3.0 +/- 0.5 ng/ml, P = 0.03) (resistin: 6.378 +/- 0.6 vs. 5.81 +/- 0.57 ng/ml, P < 0.0001). Resistin levels correlate positively with free t4(r = 0.37, P < 0.01), free t3 levels(r = 0.33, P < 0.01) and negatively with TSH(r = -0.22, P < 0.05). Adiponectin levels correlate with free t4(r = 0.33, P < 0.01) and free t3 (r = 0.44, P < 0.01). Though the adiponectin levels did not correlate with leptin or resistin levels, strong positive correlation of both resistin and adiponectin with thyroid hormones is noted. Serum levels of leptin did not change with change in the thyroid functional status (leptin: 53.38 +/- 2.47 vs. 55.10 +/- 2.58 NS). Leptin levels did not correlate with resistin and adiponectin. We conclude that thyroid function has effect on adipocyte hormones adiponectin and resistin but not leptin.