Methylprednisolone increases plasma leptin levels in Graves' hyperthyroidism patients with active Graves' ophthalmopathy.

Whether leptin, a product of the ob gene, can be stimulated by glucocorticoid administration has been an issue of controversy. We investigated the effect of intravenous administration of methylprednisolone (500 mg/day x 3 days) on plasma levels of leptin in 16 patients (female/male = 11/5) with Graves' hyperthyroidism and active ophthalmopathy who received pulse therapy. Significant elevation of plasma leptin levels started at the eighth hour (13.9+/-1.8 ng/mL, p=0.042) and lasted until the 72nd hour (21.2+/-5.0 ng/mL, p=0.009), as compared with basal levels (8.8+/-1.2 ng/mL). When methylprednisolone was replaced with oral prednisolone (10 mg three times per day x 2 weeks), no difference in plasma leptin levels was noted compared with basal measurement. Under methylprednisolone administration, a significant suppression of tumor necrosis factor-alpha began at the 24th hour (8.1+/-1.3 pg/mL, p=0.004) and lasted until the 48th hour (8.1+/-1.0 pg/mL, p=0.008), as compared with basal measurement (12.5+/-1.5 pg/mL). Compared with basal levels (93+/-2 mg/dL), significant elevation in the plasma glucose level started at the third hour (135+/-10 mg/dL, p=0.000) and lasted until the 72nd hour (110+/-4 mg/dL, p=0.019). The timing of serum insulin elevation approximated that of plasma glucose (3 hours: 14+/-3 microU/mL, p=0.006) and lasted until the end of prednisolone administration (2 weeks: 12+/-2 microU/mL, p=0.044), when compared with basal levels (14+/-3 microU/mL). We concluded that the parental administration of pharmacological doses of methylprednisolone to patients with Graves' hyperthyroidism could acutely raise their plasma level of leptin.     

Correlation between serum osteoprotegerin and biomarkers of bone metabolism during anti-thyroid treatment in patients with Graves' disease

Bone turnover is increased in favor of resorption in hyperthyroid patients. We aimed to examine whether osteoprotegerin (OPG), which has an inhibitory effect on osteoclasts, is correlated with any biomarkers for bone turnover in Graves' disease. Twenty-one patients with Graves' disease were examined in this study, before and after treatment. Briefly, OPG, calcium, phosphorus, PTH, free T3, free T4, TSH, TSH receptor antibody and TSH-stimulating antibody were measured. Elevated serum OPG levels were decreased in accordance with anti-thyroid treatment. This change of OPG level was associated with thyroid hormone free T4 (r = 0.175, p = 0.038) but not with free T3 (r = 0.164, p = 0.052) and TSH (r = 0.046, p = 0.59). Additionally, there was a negative correlation between OPG and PTH (r = -0.37, p = 0.0001). In stepwise regression analysis, the change in serum OPG levels during anti-thyroid treatment was significantly and independently associated with PTH (F ratio = 24.4, p < 0.0001). Our findings suggest that OPG may prevent excessive bone loss in the hyperthyroid state in accordance with the change of biomarkers for bone turnover.     

Improvement of immunologic abnormalities associated with hyperthyroidism of Graves' disease during methimazole treatment

In an attempt to study the effects of methimazole treatment on immunologic abnormality of hyperthyroidism of Graves' disease, TSH receptor antibody (TRab), anti-DNA antibody and HLA-DR were measured in untreated patients with hyperthyroidism of Graves' disease and treated patients with methimazole for 2 years, using peripheral blood. In untreated patients, all 3 parameters elevated above normal. Three parameters decreased 2 years after methimazole treatment, but the magnitude of decrease was more in T3-suppressible patients than in T3-unsuppressible patients. However, both anti-DNA antibody and HLA-DR were significantly more in T3-suppressible patients than in normal subjects. It is suggested that immunologic abnormalities should largely be improved before remission of Graves' disease can be obtained.     

Intravenous methylprednisolone in the treatment of Graves' ophthalmopathy.

Eleven euthyroid patients with severe Graves'' eye disease were treated with intravenous methylprednisolone and followed up for six months or more by ophthalmological assessment, orbital computed tomography (CT), photographs, and antibody measurements. Papilloedema resolved in the single patient in whom it was present; visual acuity was abnormal in seven eyes initially and in only one eye after treatment; the intraocular pressure differential, which reflects muscle dysfunction, was initially abnormal in 18 eyes but showed a progressive and distinct improvement; nine patients showed substantial improvement in inflammatory signs. Exophthalmos improved early after treatment, but this improvement was not maintained. Orbital CT showed a pronounced reduction in the bulk of eye muscles after treatment in eight of nine patients. Autoantibodies to the thyroid stimulating hormone receptor declined. Adverse effects were trivial. Thus eight patients showed a clear response to intravenous methylprednisolone as judged by ophthalmic assessment and CT scan. The two patients who showed little response and one who had none all had a long history (more than a year) of ophthalmopathy. Results were better than those with oral steroids and adverse effects less. Treatment of Graves'' eye disease is more likely to be effective if given early; patients should be referred promptly to specialist centres, where treatment with intravenous methylprednisolone should be considered.     

Analysis of early results of combined treatment with glucocorticoids and telecobalt therapy for Graves' disease ophthalmopathy]

Early results of combined use of glucocorticoid administration and irradiation with radioactive cobalt for treatment of oedematous-infiltrative ophthalmopathy associated with Graves' disease have been analyzed in a group of 33 patients including 28 women and 5 men of age between 25 and 66 years (mean age 47.3 years). The combined therapy was a modification of the original method of Bartalena et al. which consisted in the gradual increase of the initial dose of glucocorticoids and prolongation of the period of administration of the drug. The ophthalmic lesions were assessed by thorough ophthalmologic examination and classified according to Werner. The ophthalmopathy index was calculated according to Donaldson. Satisfactory results of treatment have been obtained in 32 patients, with 9 patients being completely relieved from any objective or subjective ophthalmic symptoms (very good results), and 23 patients having still small afflictions originating from the soft tissues of the eye socket, exophthalmos, diplopia during marginal vision and a decreased visual acuity (good results). The clinical recovery was mostly connected with the improvement in the condition of soft tissues of the eye socket, cornea and external ocular muscles and, to a smaller extent, exophthalmos which persisted to some degree and acuity of vision not always attaining normal values. In one person the results of treatment were unsatisfactory despite some improvement. Very good and good results obtained in 97% of patients indicate that the administration of glucocorticoids combined with the irradiation of retrobulbar tissues with radioactive cobalt can now be regarded as the most effective method of treatment of the progressive oedematous-infiltrative ophthalmopathy.     

Mechanisms of immune damage in Graves' ophthalmopathy

We have studied the role of immunologically mediated cytotoxicity in the orbital tissue damage of Graves' ophthalmopathy. Antibody-dependent cell-mediated cytotoxicity (ADCC) against eye muscle (EM) cells and orbital fibroblasts (OF) was demonstrated in a small proportion of patients, all of whom had severe, recent disease. Antibody-mediated (complement-dependent) cytotoxicity against OF was found in only a few patients. No patients showed lysis above background with EM targets. ADCC activity against OF was absorbed by preincubation of serum with thyroid cells, eye muscle cells, and orbital fibroblasts, as well as thyroid, eye muscle and orbital connective tissue membranes. Both EM and OF were able to express class II MHC HLA-DR antigens when stimulated by gamma interferon, phytohemagglutinin or activated T lymphocytes. DR-positive target cells were much more susceptible to lysis, in both ADCC and lymphocyte-mediated cytotoxicity, than DR negative cells. When DR-positive OF and EM were used as targets in ADCC assays, the degree of lysis determined as 51Cr release given by serum from patients with Graves' ophthalmopathy was enhanced, but only in those patients showing positive tests with DR-negative targets. Intrathyroidal T lymphocytes obtained from a patient with Graves' ophthalmopathy were more cytotoxic against DR-positive OF and EM than equal numbers of her peripheral blood T lymphocytes. Antibody-dependent cell-mediated cytotoxicity and lymphocyte-mediated cytotoxicity against orbital fibroblasts and eye muscle cells are thus associated with target cell HLA-DR antigen expression and are likely to be mechanisms for in vivo tissue damage in Graves' ophthalmopathy. The identity of the mononuclear cell subpopulation effecting cell-mediated cytotoxicity against orbital target cells, and the possible significance of reaction of cytotoxic antibodies against orbital, thyroid-shared antigens are unclear.     

Serum hyaluronan concentration determined by radiometric assay in patients with pretibial myxedema and Graves' ophthalmopathy

The serum concentration of hyaluronan (HA) was measured by radiometric assay in patients with pretibial myxedema (PTM) and Graves' ophthalmopathy (GO). The mean HA concentration in the patients (n = 8) was 21.2 +/- 15.3 (mean +/- SD) microgram/l, while that of Graves' disease without skin or eye involvement (n = 7) was 23.5 +/- 11.0 (mean +/- SD) microgram/l and that of the control (n = 8) was 25.5 +/- 16.4 (mean +/- SD) microgram/l. We conclude that local accumulation of glycosaminoglycan in PTM or GO is not associated with an increase in the serum HA concentration.     

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.     

The management of hyperthyroidism due to Graves' disease in Japan in 1988. The Japan Thyroid Association

The management of hyperthyroidism due to Graves' disease in Japan was the subject of a survey of the members of the Japan Thyroid Association (JTA), and the results were compared to those of the European Thyroid Association (ETA). In the questionnaire, in vivo and in vitro diagnostic procedures, the choice of treatment and the details of the treatment for a patient with typical, moderate and uncomplicated hyperthyroidism due to Graves' disease was at first asked, and eight variations with a single alternative were proposed to evaluate how each alternative would affect the choice of treatment. For the diagnostic procedures, thyroid uptake/scintigraphy was carried out by approximately 60% of the respondents and the isotope mainly used was 123I. The number of in vitro tests used for diagnosis averaged 8.1 +/- 1.8 tests. Measurements of basal TSH and free T4 were the most frequent tests performed to confirm the diagnosis of hyperthyroidism (94 and 80%, respectively). Determinations of microsomal, thyroglobulin and TSH-receptor autoantibodies were also employed by many respondents (96, 96 and 77%, respectively). On the other hand, the free T4 index and TRH test were less frequently employed. In the treatment of these patients, antithyroid drug treatment was the first choice, and surgery was not, in general, regarded as a primary therapy except in a patient with a large goiter. The frequency of the respondents who advocated radioiodine therapy was considerably higher for patients with recurrences and old age. No respondents proposed radioiodine therapy for young patients. Specialists tended to favor their own specialist treatment regimens. The initial dose of antithyroid drugs was reduced according to thyroid function, and withdrawal of antithyroid drug treatment was determined by some specific criteria (basal TSH in supersensitive assays, TSH-receptor autoantibodies, T3 suppression test, etc.). The aim of radioiodine therapy and surgery was to restore euthyroidism. The significant differences between the results from the JTA and those from the ETA were as follows; radionuclide used for thyroid uptake/scintigraphy was mainly 123I in Japan, but 131I in Europe, the number of diagnostic studies in Japan was more than that in Europe, and the dosage of antithyroid drugs was reduced according to thyroid function and discontinued based on certain specific criteria in Japan, but after fixed periods in Europe. These results may represent actual trends in how hyperthyroidism due to Graves' disease is managed in specialist clinics in Japan today and the differences between the JTA and the ETA.     

Autoimmune diabetes mellitus, Hodgkin's disease and Graves' ophthalmopathy in a patient with 8.1 ancestral haplotype.

In this report, we describe the case of a 43-year-old woman affected by type 1 diabetes mellitus diagnosed 8 years before, who developed Graves' disease 2 years after chemotherapy and mantle radiotherapy treatment for Hodgkin's disease. Bilateral Graves' ophthalmopathy appeared four months before our observations. Intravenous methyl-prednisolone therapy was started, but was interrupted due to severe metabolic failure. Autoantibodies (anti-islet cells, anti-thyroid, thyroid-stimulating, non-organ-specific) were positive. Since the clinical picture suggested a genetic immunological ground predisposing to autoimmunity, we evaluated her HLA haplotype. Genomic typing of the patient permitted identification of the 8.1 ancestral haplotype, a Caucasoid haplotype unique in its association with many immunopathological diseases. Moreover, we also observed a haplotype unusual in Caucasians, trans DRB1*1101, DQA1*0103, DQB1*0603. To our knowledge, HLA-related genetic risk of developing thyroid autoimmunity after neck irradiation has never been studied. Although we cannot confirm a direct association between the 8.1 ancestral haplotype or DRB1*1101, DQA1*0103, DQB1*0603 and the diseases described, we suggest considering immunological parameters and HLA typing in candidate patients for mantle radiation therapy for Hodgkin's disease or other tumors. HLA haplotype determination could be useful in identifying the patients at raised risk of developing autoimmune diseases after irradiation, thus permitting a more appropriate follow-up schedule.     

Ultrasonographic thyroid volume as a reliable prognostic index of radioiodine-131 treatment outcome in Graves' disease hyperthyroidism.

OBJECTIVE: We studied the relationship between thyroid volume, thyroid function and immunological markers of Graves' disease (GD) to determine prognostic factors of treatment response to low-dose radioiodine-131 (131I). MATERIAL AND METHODS: A prospective study of 40 patients with GD hyperthyroidism treated with 131I (141 +/- 85MBq) and 10 GD patients who went spontaneously into remission (controls). Free T4, total T3 and basal TSH levels, TSH-receptor antibodies (TRAb) and anti-thyroid peroxidase antibodies (TPOAb) were studied. Thyroid volume was determined by ultrasonography. Logistic regression models were used to predict the probability of final thyroid status. Receiver-operating characteristics (ROC) curves and Hosmer Lemeshow tests were used to evaluate the final statistical models. RESULTS: Of 40 patients treated with 131I, 16 became euthyroid, 12 hyperthyroid and 12 hypothyroid at 12 months. Median thyroid volume was reduced from 24.8 ml before to 8.5 ml at 12 months (p<0.001). In 10 control patients, the median reduction was from 16.6 ml to 11.3 ml (p=0.029). Thyroid volume reduction was lower in the hyperthyroid than in the euthyroid group, but higher in the hypothyroid group. Thyroid volume at baseline and at 3 months predicted hyperthyroidism outcome with a cut-off of 45 ml and 24.4 ml, respectively (odds ratio 1.074, p=0.003, ROC curve 0.78 and odds ratio 1.182, p=0.012, ROC curve 0.86 respectively). Thyroid volume at 6 months differentiated the hyperthyroid group with a cut-off of 17 ml. Thyroid volume at 3 and 6 months with a cut-off of 8.5 ml and 9.3 ml respectively, predicts permanent hypothyroidism outcome (odds ratio 0.768 and 0.685, p=0.012 and p=0.008, ROC curve 0.89 and 0.88, respectively). Changes in thyroid echogenicity and TRAb and TPOAb levels did not show any predictive value in the follow-up after 131I therapeutic outcome. CONCLUSION: The study shows that the ultrasonographic thyroid volume at 3 and 6 months after low-dose 131I treatment for GD hyperthyroidism could be a reliable prognostic factor of thyroid function outcome in the first year after treatment, and also reveals that the changes in the thyroid echogenicity and in the immunological markers of GD have no prognostic value.     

Plasma atrial natriuretic peptide, plasma renin activity and aldosterone during treatment of hyperthyroidism due to Graves' disease

Plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and aldosterone were consecutively measured during methimazole treatment in patients with hyperthyroidism due to Graves' disease. ANP values of untreated hyperthyroid patients varied greatly from patient to patient, but decreased progressively with a decrease of serum thyroid hormone concentration during methimazole treatment. PRA was elevated in hyperthyroid patients but less aldosterone was secreted as evidenced by lower aldosterone/PRA ratio in these patients than in normal subjects and in hypertensive patients treated with thiazide. In addition, aldosterone/PRA ratio increased progressively with a decrease of ANP during methimazole treatment. The data indicated that ANP secretion was increased and ANP thus secreted depressed aldosterone secretion in hyperthyroid patients. Propranolol depressed pulse rate but failed to affect ANP secretion. It is suggested that thyroid hormone specifically acts on myocytes to stimulate ANP secretion but physiologic significance of such increased ANP secretion remains to be solved.     

Serum Th1 and Th2 profile cytokine level changes in patients with Graves' ophthalmopathy treated with corticosteroids.

The aim of this study was to estimate the influence of corticosteroids on Th1 and Th2 serum cytokine balance in patients with GO: IFNgamma, TNFalpha, IL-4 and IL-10. Further, we tested the hypothesis of an up-regulation of Th2 immune response during successful treatment with corticosteroids to explain their beneficial effect in Graves' ophthalmopathy. Serum cytokines were detected in three groups of subjects: 20 patients with Graves' disease without ophthalmopathy (Gd), 16 patients with clinical symptoms of ophthalmopathy (GO) (CAS over 3 points, last consultation record for GO less than a year old) and 16 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) (2 series, 3 g each time) and subsequent treatment with oral prednisone (60 mg per day) in a tapering schedule. The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and at the end of corticosteroid therapy. The levels of IFNgamma, TNFalpha, IL-4 and IL-10 in the serum were determined using ELISA. Statistical significance was estimated by the Mann-Whitney U-test. Our findings show a deviation to systemic Th2 profile cytokines in Graves' disease. In patients with GO, we found a significantly increased serum IL-10 concentration. In corticosteroid-responsive patients, the balance of serum cytokines IL-4/IFNgamma, IL-4/TNFalpha, IL-10/IFNgamma and IL-10/TNFalpha increased and remained upregulated until the end of the study. In non-responders, the balance of serum cytokines studied increased after methylprednisolone but declined markedly during continuation of the therapy with prednisone. In summary, our results show that efficient corticosteroid therapy may be related to its influence on Th2/Th1 profile cytokine balance. The upregulation of serum IL-4 and IL-10 during successful treatment with corticosteroids indicate the possibility of using these cytokines as predictors of the beneficial effect of corticosteroids in Graves' ophthalmopathy.     

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.     

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.