Mechanistic Pathways of Selenium in the Treatment of Graves' Disease and Graves' Orbitopathy.

Based on the role of oxidative stress in the pathogenesis of Graves' hyperthyroidism and Graves' orbitopathy, the use of the antioxidant agent selenium has been proposed and several studies on the subject have been conducted, both in vitro and in vivo. Whereas a true benefit related to the use of selenium in patients with Graves' hyperthyroidism has been questioned, its use in patients with mild Graves' orbitopathy is generally believed to be beneficial because of which selenium has entered in the clinical practice for this eye condition.

Antioxidant Actions of Selenium in Orbital Fibroblasts: A Basis for the Effects of Selenium in Graves' Orbitopathy.

BACKGROUND: A recent clinical trial has shown a beneficial effect of the antioxidant agent selenium in Graves' orbitopathy (GO). In order to shed light on the cellular mechanisms on which selenium may act, this study investigated its effects in cultured orbital fibroblasts. METHODS: Primary cultures of orbital fibroblasts from six GO patients and six control subjects were established. Cells were treated with H2O2 to induce oxidative stress, after pre-incubation with selenium-(methyl)selenocysteine (SeMCys). The following assays were performed: glutathione disulfide (GSSG), as a measure of oxidative stress, glutathione peroxidase (GPX) activity, cell proliferation, hyaluronic acid (HA), and pro-inflammatory cytokines. RESULTS: H2O2 induced an increase in cell GSSG and fibroblast proliferation, which were reduced by SeMCys. Incubation of H2O2-treated cells with SeMCys was followed by an increase in glutathione peroxidase activity, one of the antioxidant enzymes into which selenium is incorporated. At the concentrations used (5 µM), H2O2 did not significantly affect HA release, but it was reduced by SeMCys. H2O2 determined an increase in endogenous cytokines involved in the response to oxidative stress and GO pathogenesis, namely tumor necrosis factor alpha, interleukin 1 beta, and interferon gamma. The increases in tumor necrosis factor alpha and interferon gamma were blocked by SeMCys. While the effects of SeMCys on oxidative stress and cytokines were similar in GO and control fibroblasts, they were exclusive to GO fibroblasts in terms of inhibiting proliferation and HA secretion. CONCLUSIONS: Selenium, in the form of SeMCys, abolishes some of the effects of oxidative stress in orbital fibroblasts, namely increased proliferation and secretion of pro-inflammatory cytokines. SeMCys reduces HA release in GO fibroblasts in a manner that seems at least in part independent from H2O2-induced oxidative stress. Some effects of SeMCys are specific for GO fibroblasts. These findings reveal some cellular mechanisms by which selenium may act in patients with GO.

VARIABLES AFFECTING THE LONG-TERM OUTCOME OF GRAVES ORBITOPATHY FOLLOWING HIGH-DOSE INTRAVENOUS GLUCOCORTICOID PULSE THERAPY IN PATIENTS NOT TREATED WITH ORBITAL RADIOTHERAPY.

OBJECTIVE: Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC. METHODS: We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time. RESULTS: GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders. CONCLUSION: Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments. ABBREVIATIONS: ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy 131I = radioactive iodine iv = intravenous ivGC = high-dose intravenous glucocorticoid pulse therapy MMI = methimazole OD = orbital decompression ORT = orbital radiotherapy TRAb = antithyroid-stimulating hormone receptor antibodies.

Age and Dose Are Major Risk Factors for Liver Damage Associated with Intravenous Glucocorticoid Pulse Therapy for Graves' Orbitopathy.

BACKGROUND: High-dose intravenous glucocorticoid (ivGC) pulse therapy, which is commonly used for Graves' orbitopathy (GO), has been associated with acute liver damage (ALD), resulting in a fatal outcome in a few cases. No certain risk factors for ALD have been established. Consequently, a large retrospective cohort study was performed. METHODS: The relationship between ALD and several potential risk factors was assessed in 1076 consecutive patients with GO given ivGC. ALD was defined as an increase of alanine aminotransferase ≥300 IU/L. RESULTS: Fourteen cases of ALD were recorded, resulting in a morbidity of 1.3%. Thirteen patients recovered and one died, resulting in a mortality of 0.09%. There was a significant, positive correlation of ALD with age and methylprednisolone acetate (MPA) cumulative dose, and ALD was more common (relative risk [RR]=2.8; p=0.05) in patients aged ≥53 years (9/420; 2.14%) than in those aged <53 years (5/656; 0.76%). In patients aged ≥53 years, there was a significant positive correlation of ALD with MPA cumulative dose, and with MPA dose per infusion. Thus, the frequency of ALD in this age group was greater (RR=3.48; p=0.04) in patients with a MPA dose per infusion ≥0.7 g (5/111, 4.5% vs. 4/308, 1.29%). Regardless of age, no cases of ALD were observed for MPA doses per infusion <0.57 g. CONCLUSIONS: Age and MPA dose are significant risk factors for ALD, with the following practical implications. First, the total MPA cumulative dose should not exceed 8.5 g (the average dose in patients without ALD). Second, in patients aged ≥53 years, selection and observation should be quite strict. However, being aged ≥53 years should not be seen as an absolute contraindication to ivGC, especially in patients with severe GO, considering that the risk of ALD, although statistically significant, was relatively low. Third, the MPA dose should not exceed 0.57 g per infusion, a measure to be applied regardless of age.

PREGO (presentation of Graves' orbitopathy) study: changes in referral patterns to European Group On Graves' Orbitopathy (EUGOGO) centres over the period from 2000 to 2012.

BACKGROUND/AIMS: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time. METHODS: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000. RESULTS: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01). CONCLUSIONS: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

Treatment options for Graves' orbitopathy.

INTRODUCTION: Treatment of Graves' orbitopathy (GO) is a difficult challenge and should be performed through a multidisciplinary approach. AREAS COVERED: This review covers the current treatment of hyperthyroidism and its effect on the course of GO. Treatment options for GO, according to its severity and activity, are discussed. EXPERT OPINION: In hyperthyroid patients, euthyroidism should be restored with antithyroid drug (ATD) therapy. High-dose i.v. glucocorticoids (ivGC) should be immediately given to patients with optic neuropathy, and orbital decompression should be performed in non-responders. Permanent treatment of hyperthyroidism (by radioiodine or surgery) should be planned in patients with moderate-to-severe and active GO, followed by a course of ivGC associated with orbital radiotherapy, particularly when eye muscle involvement is present. Patients should be carefully evaluated for liver, cardio- and cerebrovascular risk factors. Rehabilitative surgery (orbital decompression, squint and eyelid surgery) should be considered when GO is inactive, or to improve the results of medical therapy. In patients with mild GO long-term ATD therapy and a 6-month course of selenium should be used. Ablative therapy should be considered in patients with poorly controlled hyperthyroidism or persistently elevated thyroid-stimulating hormone (TSH) receptor antibody levels. Oral GC should be given to patients with risk factors or active GO, if radioiodine is used.

Oxidative stress in graves' disease.

Increased reactive oxygen species (ROS) generation and the consequent oxidative damage are involved in the development of several diseases, including autoimmune diseases. Graves' disease is an autoimmune disorder characterized by hyperthyroidism and, less frequently, orbitopathy. Hyperthyroidism is characterized by increased oxidative stress. Untreated hyperthyroidism is associated with an increase of several parameters of oxidative stress and in most studies (but not all) by an increase of antioxidant defense enzymes. Restoration of euthyroidism with antithyroid drug is associated with a reversal of the biochemical abnormalities associated with oxidative stress. Animal and human studies suggest that increased ROS may directly contribute to some clinical manifestation of the disease, including orbitopathy. Antioxidants administered alone improve some clinical signs and symptoms of hyperthyroidism and, when associated with antithyroid drugs, induce a more rapid control of clinical manifestations and a faster achievement of euthyroidism. A large randomized clinical trial has shown that antioxidant supplementation (selenium) may also be beneficial for mild Graves' orbitopathy.