Gutenberg University Medical Center

Mainz, Germany

Gutenberg University Medical Center

Mainz, Germany
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Marcocci C.,University of Pisa | Kahaly G.J.,Gutenberg University Medical Center | Krassas G.E.,Panagia General Hospital | Bartalena L.,University of Insubria | And 7 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 μg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P = 0.01) and slowed the progression of Graves' orbitopathy (P = 0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.) Copyright © 2011 Massachusetts Medical Society.


Biondi B.,University of Naples Federico II | Kahaly G.J.,Gutenberg University Medical Center
Nature Reviews Endocrinology | Year: 2010

Various clinical disorders can cause hyperthyroidism, the effects of which vary according to the patient's age, severity of clinical presentation and association with other comorbidities. Hyperthyroidism is associated with increased morbidity and mortality from cardiovascular disease, although whether the risk of specific cardiovascular complications is related to the etiology of hyperthyroidism is unknown. This article will focus on patients with Graves disease, toxic adenoma and toxic multinodular goiter, and will compare the cardiovascular risks associated with these diseases. Patients with toxic multinodular goiter have a higher cardiovascular risk than do patients with Graves disease, although cardiovascular complications in both groups are differentially influenced by the patient's age and the cause of hyperthyroidism. Atrial fibrillation, atrial enlargement and congestive heart failure are important cardiac complications of hyperthyroidism and are prevalent in patients aged ≥60 years with toxic multinodular goiter, particularly in those with underlying cardiac disease. An increased risk of stroke is common in patients >65 years of age with atrial fibrillation. Graves disease is linked with autoimmune complications, such as cardiac valve involvement, pulmonary arterial hypertension and specific cardiomyopathy. Consequently, the etiology of hyperthyroidism must be established to enable correct treatment of the disease and the cardiovascular complications. © 2010 Macmillan Publishers Limited. All rights reserved.


Li Y.,Diagnostic Hybrids | Kim J.,Diagnostic Hybrids | Diana T.,Gutenberg University Medical Center | Klasen R.,Diagnostic Hybrids | And 2 more authors.
Clinical and Experimental Immunology | Year: 2013

Summary: Autoantibodies to the thyrotrophin (TSH) receptor (anti-TSHR) are unique, in that they are involved directly in the pathophysiology of certain autoimmune thyroid diseases (AITD). Thyroid-stimulating antibodies (TSAb) act as agonists that activate the thyroid gland and cause Graves' disease. Other anti-TSHR antibodies block TSH and can cause hypothyroidism. Thyroid-blocking antibodies (TBAb) have not been studied as extensively as TSAb. We developed a TBAb bioassay based on a cell line that expresses a chimeric TSHR. The 50% inhibitory concentration of the chimeric Chinese hamster ovary (CHO)-Luc cells was more than five-fold lower compared with the wild-type CHO-Luc cells. We tested the performance of this bioassay using a thyroid-blocking monoclonal antibody K1-70, established an assay cut-off and detected TBAb in 15 of 50 (30%) patients with AITD. Interestingly, the assay detects both TSAb and TBAb and measures the net activity of a mixture of both types of antibodies. There was a high correlation (R2 0·9, P<0·0001) between the results of the TSAb assay and the negative percentage inhibition of the TBAb assay. The TBAb bioassay was approximately 20-fold more sensitive than a commercially available TSHR binding assay (TRAb). In contrast to TRAb, sera with high levels of TBAb activity were able to be diluted several hundred-fold and still exhibit blocking activity above the cut-off level. Thus, this TBAb bioassay provides a useful tool for measuring the activity of anti-TSHR antibodies and may help clinicians to characterize the diverse clinical presentations of patients with AITD. © 2013 British Society for Immunology, Clinical and Experimental Immunology.


Lytton S.D.,Gutenberg University Medical Center | Ponto K.A.,Gutenberg University Medical Center | Kanitz M.,Gutenberg University Medical Center | Matheis N.,Gutenberg University Medical Center | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Immunoglobulins stimulating the TSH receptor (TSI) influence thyroid function and likely mediate extrathyroidal manifestations of Graves' disease (GD). Objectives: The aim of this study was to assess the clinical relevance of TSI in GD patients with or without Graves' orbitopathy (GO), to correlate the TSI levels with activity/severity of GO, and to compare the sensitivity/specificity of a novel TSI bioassay with TSH receptor (TSH-R) binding methods (TRAb). Design: TSI were tested in two reporter cell lines designed to measure Igs binding the TSH-R and transmitting signals for cAMP/CREB/cAMP regulatory element complex-dependent activation of luciferase gene expression. Responsiveness to TSI of the novel chimeric (Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R) was compared with the wild-type (wt) TSH-R. Results: All hyperthyroid GD/GO patients were TSI-positive. TSI were detected in 150 of 155 (97%, Mc4) and 148 of 155 (95%, wt) GO patients, in six of 45 (13%, Mc4) and 20 of 45 (44%, wt) mostly treated GD subjects, and in 0 of 40 (Mc4) and one of 40 (wt) controls. Serum TSI titers were 3- and 8-fold higher inGOvs. GD and control, respectively. All patients with diplopiaandoptic neuropathy and smokers were TSI-positive. TSI strongly correlated with GO activity (r = 0.87 and r = 0.7; both P < 0.001) and severity (r = 0.87 and r = 0.72; both P < 0.001) in the Mc4 and wt bioassays, respectively. Clinical sensitivity (97 vs. 77%; P < 0.001) and specificity (89 vs. 43%; P < 0.001) of the Mc4/TSI were greater than TRAb in GO. All 11 of 200 (5.5%) TSI-positive/TRAb-negative patients had GO, whereas all seven of 200 (3.5%) TSI-negative/TRAb-positive subjects had GD only. Conclusion: The novel Mc4/TSI is a functional indicator of GO activity and severity. Copyright © 2010 by The Endocrine Society.


Muller-Forell W.,Gutenberg University Medical Center | Kahaly G.J.,Gutenberg University Medical Center
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2012

Neuroimaging of Graves' orbitopathy (GO) plays an important role in the differential diagnosis and interdisciplinary management of patients with GO. Orbital imaging is required in unclear or asymmetric proptosis, in suspected optic neuropathy and prior to decompression surgery. Especially computed tomography and magnetic resonance (MR) imaging show the actual objective morphological findings, quantitative MR imaging giving additional information concerning the acuteness or chronicity of the disease. Major morphological diagnostic criteria include a spindle like spreading of the rectus muscles without involvement of the tendon, a compression of the optic nerve in the orbital apex (crowded orbital apex syndrome) and the absence of any space occupying intraorbital process. A longer lasting course of the disease may lead to a corresponding impression of the lamina papyracae, the normally parallel configured medial wall of the orbit, similar to a spontaneous decompression. © 2011 Elsevier Ltd. All rights reserved.


Zang S.,Gutenberg University Medical Center | Ponto K.A.,Gutenberg University Medical Center | Kahaly G.J.,Gutenberg University Medical Center
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: The administration of iv glucocorticoid pulses has been advocated as a treatment approach for patients with inflammatory and moderate to severe Graves' orbitopathy (GO). This review offers an update on this controversial regimen. Evidence Acquisition: PubMed and the MeSH-Database were searched (with no temporal limit) for the following topics: management of active and severe GO; glucocorticoid therapy of GO; iv glucocorticoid administration; mechanism and pharmacokinetics of iv glucocorticoids; and adverse events, morbidity, and mortality of iv glucocorticoids. The articles were evaluated according to their setting and study design. Evidence Synthesis: All randomized and uncontrolled trials, consensus statement, systematic reviews, and meta-analyses dealing with the efficacy and morbidity of iv glucocorticoids in GO were identified. Conclusions: The current first-line treatment for active, moderate-to-severe GO is a 12-wk course of high-dose iv glucocorticoid pulses. The response rate of this regimen is approximately 80%. Intravenous glucocorticoids have a statistically significant advantage over oral treatment and cause significantly fewer adverse events. However, major side effects related to preexisting diseases, administered dose, and treatment schedule have been reported. The morbidity and mortality of iv glucocorticoid therapy are 6.5 and 0.6%, respectively. Thus, careful patient selection is warranted. Before iv glucocorticoid administration, patients should be screened for recent hepatitis, liver dysfunction, cardiovascular morbidity, severe hypertension, inadequately managed diabetes, and glaucoma. The cumulative dose should not exceed 8 g, and with the exception of sight-threatening GO the single doses preferably should not be administered on consecutive days. Monthly monitoring during subsequent treatment is warranted. Copyright © 2011 by The Endocrine Society.


Zang S.,Gutenberg University Medical Center | Kahaly G.J.,Gutenberg University Medical Center
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2011

Steroids act via suppression of the immune system in two different ways: a genomic and a non-genomic pathway. While the non-genomic pathway appears to be responsible for the quick effects only a few minutes after application, the genomic pathway determines the long-time effects. Since decades, systemic steroids have been applied in the management of severe Graves' orbitopathy (GO). In GO, steroids effectively modulate both the effector cells as well as the orbital targets cells, i.e. fibroblasts and pre-adipocytes. They inhibit the release of inflammatory mediators i.e. cytokines and prostaglandins. Also, systemic steroids significantly reduce the titer of the disease relevant thyroid-stimulating immunoglobulins. A few studies only, dealing with difference in mechanisms depending on the way of administration (intravenous, oral or peribulbar) are available. Efficacy of the three ways of application is statistically different. The systemic administration of steroids has a higher efficacy than the local peribulbar application. Furthermore, evidence based and compared to the oral form, the intravenous steroid administration shows both a significantly higher response rate as well as markedly less adverse events. Thus, high dose intravenous steroid pulses are currently considered the first line-reatment for active and severe GO. © 2011 Bentham Science Publishers Ltd.


Lytton S.D.,Gutenberg University Medical Center | Kahaly G.J.,Gutenberg University Medical Center
Autoimmunity Reviews | Year: 2010

Immunoglobulins in patients with Graves' disease (GD) that modulate the thyroid stimulating hormone receptor (TSH-R) do so via stimulating cAMP dependent signals (TSI), blocking TSH or inhibition of TSH-receptor activation (TBI) or inducing apoptotic signals. These functional immunoglobulins represent powerful biomarkers of anti-self reactivity in the thyroid and systemic tissues that harbor TSH-R expressing target cells. TSI on thyrocytes induce hyperthyroidism, and TSI on TSH-R fibroblasts of orbital muscles, skin and heart provoke the release of cytokines and antigen-specific T-cell responses leading to systemic inflammation. Bioassays of anti-TSH-R autoantibodies provide decisive information on GD activity. This review examines the past and present bioassays in GD. The critical goal of cell-based anti-TSH-R autoantibody bioassays, to identify the pathogenic immunoglobulins in GD under robust and standardized conditions suitable for routine clinical laboratory practice, is discussed. © 2010 Elsevier B.V.


Dittmar M.,Gutenberg University Medical Center | Dittmar M.,University of Kiel | Woletz K.,Gutenberg University Medical Center | Kahaly G.J.,Gutenberg University Medical Center
Hormone and Metabolic Research | Year: 2013

The enzyme DNASE1 plays an important role in the hydrolysis of double-stranded DNA and might be related to autoimmunity. Therefore, the authors hypothesized that patients with autoimmune thyroid disease show a reduced expression of the DNASE1 gene. DNASE1 mRNA was quantitatively analyzed in 20 patients (10 with Hashimoto's thyroiditis and 10 with Graves' disease) and 20 age- and sex-matched healthy controls by real-time reverse transcription PCR in a lightcycler using SYBR-Green-format. For relative quantification, the mRNA ratio of the DNASE1 gene to the house keeping gene β2-MICROGLOBULIN was used. The house keeping gene was proved not to be regulated by autoimmune thyroid disease. The interassay coefficient of variation for patients and controls was 22.2% and 15.6%, respectively, suggesting good reproducibility of measurements. The mean expression of the DNASE1 mRNA in patients was 0.52±0.22 (range 0.18-0.99) and in controls 0.95±0.22 (0.66-1.43). The expression level of the DNASE1 gene was strongly decreased in patients, amounting only 54.7% of that in controls (p<0.001). The lowered expression level in patients was not related to age or sex. This study demonstrated for the first time a downregulation of the DNASE1 mRNA expression in patients with autoimmune thyroid disease. This might result in degrading less DNA from dying cells, thereby promoting the development of thyroid autoimmunity. © Georg Thieme Verlag KG Stuttgart · New York.


Ponto K.A.,Gutenberg University Medical Center
Thyroid : official journal of the American Thyroid Association | Year: 2010

BACKGROUND: Autoimmunity against the thyrotropin receptor (TSH-R) is a key pathogenic element in Graves' disease (GD) and the autoimmune aberration may be modified by antithyroid treatment. An association between radioactive iodine (RAI) therapy for GD and the development or worsening of Graves' orbitopathy (GO) is widely quoted. RAI-associated leakage of thyroid antigen(s) leads to an increased production of TSH-R antibodies that may initiate the eye injury. SUMMARY: RAI therapy leads to prolonged worsening of autoimmunity against the TSH-R, and the number of patients entering remission of TSH-R autoimmunity is considerably lower than with other antithyroid therapies. Scientific evidence has indicated that RAI treatment for GD is associated with increased risk of occurrence or progression of GO compared with antithyroid drugs (ATD) and thyroid surgery. The risks of developing new GO or worsening of preexisting GO is around 20% after RAI and around 5% after ATD. The risk of developing severe GO after RAI is around 7%. Smoking, high levels of pretreatment serum triiodothyronine, and post-RAI hypothyroidism are associated with increased risk of GO, whereas a high TSH-R autoantibody titer is an independent risk factor for the progression of GO. In patients with mild preexisting GO, steroid prophylaxis is effective in preventing deterioration of GO. Also, routine use of prophylactic oral steroids with RAI therapy should be considered in GD patients without overt GO, but even more so in those at higher risks of eye complications such as smokers, old men, and those with severe hyperthyroidism or high TSH-R antibody titers. CONCLUSION: In contrast to ATD, remission of TSH-R autoimmunity after RAI therapy is less common, and RAI for GD is associated with definite increased risk of GO. Oral steroids are beneficial for patients with preexisting GO, particularly smokers.

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