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.     

Binding of immunoglobulin G from patients with autoimmune thyroid diseases to solubilized guinea pig fat cell membranes crosslinked with 125I-TSH

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.     

Surgical correction of exophthalmos secondary to Graves' disease

Graves' disease has been recorded in the medical literature for more than 150 years. Despite introduction of iodine into the diet, Graves' disease still remains the most important disorder of the thyroid gland. Clinically, Graves' disease is a multisystem disorder of unknown etiology characterized by the clinical triad of infiltrative pretibial dermopathy, thyroid glandular hyperplasia, and ophthalmopathy. Expansion of the bony orbital volume is an effective method of treating moderate to severe exophthalmos. Our experience with a simplified version of a three-wall orbital decompression to correct exophthalmos secondary to Graves' disease is presented.     

Relationship among thyrotropin (TSH), thyroid stimulating immunoglobulins, and results of triiodothyronine (T3) suppression test in patients with Graves' disease

To investigate the relationship between TSH and abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease in whom normal thyroid hormone levels in the serum were maintained by antithyroid drug therapy and in patients with euthyroid Graves' disease, determinations were made of the TSH concentration, action of thyroid stimulating immunoglobulins (TSAb and TBII), and T3 suppression. Out of thirty-three patients with hyperthyroid Graves' disease, twelve patients with subnormal TSH levels were all non-suppressible according to the T3 suppression test results and the detectability of TSAb and/or TBII was as high as 75%. In three out of five patients with euthyroid Graves' disease, the serum TSH level was subnormal. All three showed non-suppressibility in the T3 suppression test and positive action of either TSAb or TBII. One of them became clinically thyrotoxic when the TSAb activity was further increased and TBII became positive, and was therefore diagnosed as having hyperthyroid Graves' disease. The present findings suggest that there are still abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease who have low TSH, even if their thyroid hormone concentrations remain normal. Moreover, it is likely that some of the patients with euthyroid Graves' disease are actually in a state of subclinical hyperthyroidism because of the presence of abnormal thyroid stimulator(s).     

Two cases of anorexia nervosa associated with Graves' disease

In this report on two cases of anorexia nervosa associated with Graves' disease, metabolism and the relationship between the two illness are considered. Case 1 was a 25-year-old female. Anorexia was associated with a stressful life situation following marriage. One year after the onset of anorexia, her condition was diagnosed as Graves' disease. In spite of high levels of serum thyroid hormone, she did not show the clinical signs and symptoms of hyperthyroidism. The hypermetabolic state of Graves' disease seems to be suppressed by the hypometabolism of anorexia. Case 2 was a 17-year-old female whose body weight, due to anorexia, at one time had decreased from 55 kg to 35.2 kg. A rebound from anorexia to bulimia increased her body weight to 80 kg in spite of an association with the hypermetabolic state of Graves' disease. In light of the abovementioned cases, it seems that the clinical picture of Graves' disease is usually hidden by the clinical symptoms of anorexia nervosa.     

HLA haplotypes and susceptibility to Graves' disease.

Graves' disease is a polygenic disease in which the HLA cluster could play a role. The purpose of our study is to identify HLA haplotypes in a family with closely related susceptibility to Graves' disease and foresee the risk of disease in the youngest daughter. The family studied had included the father (47 years), mother (46 years) and 3 daughters (18, 17 and 13 years). The mother and 2 eldest daughters were affected by Graves' disease. HLA-A, -B, -C, -DR and -DQ were performed with standard microlymphotoxicity techniques. A mother's role in passing susceptibility to Graves' disease to daughters is undisputed; it seems to be due to the B35 HLA allele. Also, the third daughter (at 15 years) has an HLA B35 allele, and actually has an incipient humoral hyperthyroidism.     

Studies on the association of NIDDM in Japanese patients with hyperthyroid Graves' disease.

We attempted to analyze the association of hyperthyroid Graves' disease with non-insulin-dependent diabetes mellitus (NIDDM). Forty-nine patients (23 males and 26 females; 7.6%) of a total of 647 patients with hyperthyroid Graves' disease had NIDDM, several years before or after Graves' disease was diagnosed. Only 1 patient had insulin-dependent diabetes mellitus. Compared with the general Japanese population (n = 9,133), the incidence of NIDDM (n = 348; 3.9%) in patients with Graves' disease was higher in all age groups. Only 4 patients (8.2%) of the 49 hyperthyroid patients with NIDDM had a history of being overweight (body mass index > 25). In contrast, 276 (79.9%) of the 348 diabetic patients were currently or previously overweight. Moreover, the incidence of a family history of diabetes (13 of the 49 hyperthyroid Graves' patients with NIDDM; 26.5%) was also lower in the patients with NIDDM in the general Japanese population (50% incidence). The male:female ration in patients with Graves' disease and NIDDM was 1:1.1; much different from that in the total Graves' disease population (1:4.1). Analysis of the HLA loci A, B, C, DR and DQ (35 determinations) in 35 hyperthyroid patients with NIDDM and in 386 subjects from the general population revealed a highly significant difference between them in the incidence of HLA-Cw4, -DR2, -DQw1, -DQw3 and -DQw4. This study suggests that there was an association of Graves' disease with NIDDM. A significant association of HLA-DR and -DQ loci was observed in hyperthyroid Graves' patients with NIDDM.     

Incidental thyroid carcinoma in thyrotoxic patients treated by surgery

BACKGROUND AND AIMS: Thyroid malignancy detected incidentally in patients who are operated for thyrotoxicosis has been reported at different rates. The aim of this study was to investigate the rate of incidental thyroid carcinoma in thyrotoxic patients managed with surgery in our institution. METHODS: Of the 375 thyrotoxic patients who had thyroid surgery between the years of 1997-2004, 70.7% were females and 29.3% were males. Among thyrotoxic patients 65.3% (n=245) had toxic multinodular goiter (TMG), 16.8% (n=63) had toxic adenoma (TA) and 17.9% (n=67) had Graves' disease. RESULTS: Twenty-six (6.9%) of all thyrotoxic patients had thyroid carcinoma. Eighteen (7.3%) of TMG, 4 (6.3%) of TA and 4 (6%) of Graves' disease patients had thyroid carcinoma. Histologic examination revealed 18 papillary (9 microscopic), 5 follicular, 2 hurthle cell and 1 anaplastic carcinoma. CONCLUSION: In our study, incidental thyroid carcinoma was found in 6.9% of subjects with thyrotoxicosis. Papillary thyroid microcarcinomas constituted 34.6% (26/9) of these newly diagnosed thyroid carcinomas. The incidence of thyroid carcinoma was not higher in subjects with Graves' disease compared to TMG and TA. The rate of incidental thyroid carcinoma in subjects with thyrotoxicosis treated with surgery was similar to previous studies reported from different countries.     

Japanese Graves' disease: association with HLA-Bw46

HLA-A, -B, and -C antigen frequency of 61 Japanese patients with Graves' disease, and HLA-DR and -DQ frequency of 53 patients with it were compared that of 1,998 controls. The prevalence of Bw46 was significantly higher in patients with Graves' disease (23.0% vs 8.4%, Pc less than 0.003). The result was quite different from previous reports on Japanese Graves' disease.     

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.     

Association analysis of vitamin D receptor gene polymorphisms with bone mineral density in young women with Graves' disease

Graves' (GD) hyperthyroidism induces accelerated bone turnover that leads to decreased bone mineral density (BMD). The role of the VDR gene in predisposition to primary osteoporosis has been recognized. Recent studies show associations between the VDR gene polymorphisms and susceptibility to autoimmune diseases. Here we analyzed if VDR gene polymorphisms: BsmI, ApaI, TaqI, and FokI may predispose women with Graves' hyperthyroidism to BMD reduction or to disease development. The subjects were 75 premenopausal female Polish patients with GD and 163 healthy women. The genotyping was performed by the use of the restriction fragment length polymorphism analysis (RFLP). We studied the association of the VDR polymorphisms and their haplotypes with patients' BMD and also SNPs and haplotypes association with Graves' disease. We found a strong linkage disequilibrium for the BsmI, ApaI, and TaqI polymorphims that formed three most frequent haplotypes in Graves' women: baT (47.9%), BAt (34.9%), and bAT (16.4%). We did not show statistically significant association of analyzed VDR polymorphisms or haplotypes with decreased bone mineral density in Graves' patients. However, the presence of F allele had a weak tendency to be associated with Graves' disease (with OR=1.93; 95% CI: 0.97-3.84; p=0.058). In conclusion: VDR gene polymorphisms do not predict the risk of decreased BMD in Polish women with Graves'. It may be speculated that the F allele carriers of the VDR-FokI polymorphism are predisposed to Graves' disease development.     

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.     

Enhanced prednisolone elimination: a possible cause for failure of glucocorticoid therapy in Graves' ophthalmopathy

This study was undertaken to determine the pharmacokinetics of intravenous prednisolone in patients with Graves' eye disease. 6 women with Graves' ophthalmopathy treated with prednisolone for severe endocrine exophthalmos were compared with 6 healthy female volunteers. All subjects with Graves' disease had been taking carbimazole and I-thyroxine as concurrent drugs for at least 4 months prior to study day. All subjects were euthyroid. Each subject received .54 mg/kg prednisolone as an i.v. bolus. Plasma concentrations for total and unbound prednisolone were determined by HPLC and equilibrium dialysis. Significant increase (p less than .01) in clearance values and significant decreases in half-life times (p less than .01) were found for both total and unbound prednisolone in women with Graves' disease compared with the control subjects. Volumes of distribution at steady-state were unchanged in both groups. The data suggest that patients with Graves' ophthalmopathy show an enhanced elimination for prednisolone and that is why they may need higher doses of corticoid although the function of the thyroid gland is euthyroid.     

Plasma atrial natriuretic peptide in patients with Graves' disease

In order to clarify the effect of thyroid hormone on the plasma atrial natriuretic peptide (ANP) concentration, 14 patients with Graves' disease and 6 normal control subjects were studied. They were all under constant sodium intake because dietary sodium is known to affect the amount of plasma ANP. Sodium intake remained constant at 171 mEq daily for five consecutive days at which time the ANP concentration was measured. Graves' disease patients were tested both before and after surgery. The preoperative, hyperthyroid ANP level concentration in Graves' disease patients was 6.7 +/- 2.3 fmol/ml compared to a significantly lower level of 4.2 +/- 1.4 fmol/in normal control subjects. Seven days after surgery when Graves' disease patients became euthyroid their ANP markedly decreased to 4.2 +/- 2.9 fmol/ml. In the present study we were able to confirm that under a constant sodium diet, high plasma ANP in patients with Graves' disease was reduced after surgery when they became euthyroid. Results also suggest that high circulating ANP might play an important role in sodium and water metabolism and hemodynamic changes in hyperthyroidism.     

Ciclosporine and Graves' ophthalmopathy

The pharmacological treatment of Graves' ophthalmopathy remains unsatisfactory due to the limited efficacy and severe side effects of the available drugs. Ciclosporine, an immunosuppressive drug has recently been used with the aim of controlling the autoimmune process considered to be responsible for the disease. This paper reviews the data obtained with ciclosporine in comparison with those previously reported with corticosteroids.     

Signaling pathways involved in thyroid hyperfunction and growth in Graves' disease.

The elucidation of the multiple signaling cascades coupled to the TSH receptor has offered new approaches in the understanding of the pathogenesis of Graves' disease. Here we review findings showing that immunoglobulins from Graves' patients are heterogeneous, bind to different epitopes and, similarly to TSH, activate different signaling pathways, including adenylyl cyclase, phospholipase C and phospholipase A2. Evidence that the multiplicity of signals correlates with the different manifestations of the disease is also summarized. We believe that the dissection of the molecular mechanisms involved in the pathogenesis of Graves' disease offers the basis for developing novel therapeutical approaches to this disease.     

Graves' disease presented as painful goiter

Pain in the thyroid gland is rarely present in Graves' disease. We describe a 32-year-old female hyperthyroid Graves' disease patient with an initial manifestation of painful goiter. On physical examination, the thyroid gland was diffusely enlarged and tender. The laboratory examinations showed high serum thyroid hormone and low thyrotropin values. Serum inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate, were elevated. Thyroid ultrasound revealed multiple focal hypoechoic areas. All these findings gave an initial impression of an acute inflammatory and destructive process in the thyroid gland. However, subsequent thyroid scintigraphy demonstrated a diffuse radioactive iodide uptake pattern with positive serum thyrotropin receptor antibodies. Fine-needle aspiration cytology showed only the presence of lymphocytes. She was diagnosed as having Graves' disease and was treated with propylthiouracil, and prednisolone was given for neck pain. Within a few days, the thyroid tenderness dramatically improved, and the erythrocyte sedimentation rate progressively normalized. However, follow-up thyroid function tests still showed high serum thyroid hormone levels. The possible etiologies of a painful thyroid gland in Graves' disease will be discussed.     

Thyrotropin receptor non-mediated thyroid stimulating immunoglobulin in Graves' disease.

There exists a consensus that hyperthyroid Graves' disease is caused by thyrotropin receptor (TSH-R) autoantibodies. To test the possibility that the TSH-R is the sole antigen for thyroid stimulating antibodies (TSAb), we compared bioactivities of Graves' IgGs between non-thyroid mammalian cells transfected with human TSH-R cDNA and the reference thyroid bioassay. A Graves' IgG with TSH-binding inhibitor immunoglobulin (TBII) activity (89%) markedly stimulated cAMP formation in both CHO-K1 cells transfected with TSH-R cDNA (340 microU/ml of TSH equivalent) and rat thyroid cells, FRTL-5, (410 microU/ml of TSH equivalent). In contrast, a TBII negative (-1.5%) IgG from another patient with Graves' disease showed a strong thyroid stimulating activity (87 microU/ml of TSH equivalent) when FRTL-5 cells were used for the assay. But no stimulating activity was observed in this IgG when CHO-K1 cells transfected with TSH-R cDNA were used, suggesting a possible existence of TSH-R non-mediated thyroid stimulating immunoglobulin in some cases of Graves' disease.     

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.