Selenium has been proposed for the management of thyroid diseases, including Graves’ disease(GD), Graves’ Orbitopathy (GO), and chronic autoimmune thyroiditis. The efficacy of selenium in GD and GO is based on its anti-oxidant properties, being oxidative stress involved in the pathogenesis of both conditions .

GD is an autoimmune disease with a prevalence of ~1% , which affects mainly the thyroid.Extrathyroidal manifestations, including GO, pretibial myxedema, and acropachy, can be observed to various extents . The major pathogenetic mechanism of GD is the stimulation of the thyroid stimulating hormone receptor (TSH-R) by autoantibodies that bind to it and promote thyrocyte proliferation and activity, resulting in thyroid hyperfunction . The symptoms of thyrotoxicosis are often nonspecific, so patients with GD may present in various ways. Heat intolerance, tachycardia, inappropriate feelings of anxiety and apprehension, hyperactivity and weight loss are common. A diffuse goiter can be visible or palpable, with a systolic phase bruit found over it. Systolic blood pressure may be elevated, and hepatomegaly or splenomegaly may be observed . The complex pathogenetic interplay of GD includes, among others, oxidative stress, because of which selenium and other antioxidant agents have been proposed for the management of Graves’ hyperthyroidism (GH). In this paper we review the role of oxidative stress in GH, as well as the most significant studies on the use of selenium in the management of patients with GH and GO. The molecular mechanisms by which the disruption of the cell redox state plays a role in the pathogenesis of GO, as well as the potential beneficial effect of other antioxidant agents in patients with GO, are largely discussed in another review article in this issue of the journal.

硒被建议用于治疗甲状腺疾病，包括Graves病（GD）、Graves眼病（GO）和慢性自身免疫性甲状腺炎。硒对GD和GO的疗效基于其抗氧化特性，氧化应激参与了两种疾病的发病机制。

GD是一种自身免疫性疾病，患病率约为1%，主要影响甲状腺。甲状腺外表现，包括观察到不同程度的GO、胫前粘液水肿和肢端肥大症的表现。GD的主要发病机制是神经刺激促甲状腺激素受体（TSH-R）通过自身抗体与之结合，促进甲状腺细胞增殖和活性，导致甲状腺功能亢进症。甲状腺毒症通常是非特异性的，因此GD患者可能以多种方式出现。热不耐受、心动过速、不适当的焦虑和恐惧感、多动症和体重减轻是常见的。弥漫性甲状腺肿可见或可触及，其上可见收缩期杂音。收缩压可能升高，并可观察到肝肿大或脾肿大。GD的复杂致病相互作用包括氧化应激，因此硒和其他抗氧化剂被提议用于治疗Graves'甲（GD）。在本文中，我们回顾了氧化应激在GD的作用，以及硒在GD和GO患者治疗中的最重要的研究。本期杂志的另一篇综述文章主要讨论了细胞氧化还原状态的破坏在GO发病机制中所起的作用的分子机制，以及其他抗氧化剂对GO患者的潜在有益作用。

Over the last few years, in addition to the most common treatment for the management of moderate-to-severe and active GO, namely high dose oral and intravenous glucocorticoids (GC), orbital irradiation and surgical procedures , other medications have been proven effective to various extents, including rituximab , the recently FDA- approved teprotumumab, mycophenolate , and tocilizumab. Until recently, the treatment of mild GO was typically limited to local measures (19 but ~15% of patients GO progress to an extent that requires specific treatments .In general, major treatments are not recommended for mild GO, unless there is a sufficient impairment in the quality of life,which justifies the risk of GC-related adverse events . In view of the role of oxidative stress in GO,antioxidant supplements have been proposed as a possible therapeutic approach, and basic and clinical studies have investigated the effect of selenium, due to its antioxidant and immunomodulating actions.

在过去的几年里，除了治疗中重度和活动性GO的最常见的治疗方法，即大剂量口服和静脉注射糖皮质激素（GC）、眼眶照射和外科手术，其他药物已被证明在不同程度上有效，包括利妥昔单抗，最近FDA批准了替普妥单抗、霉酚酸酯和托昔单抗。直到最近，轻度GO的治疗通常仅限于局部措施15%的患者进展到需要特殊治疗的程度。一般来说，不建议对轻度GO进行主要治疗，除非生活质量有足够的损害，证明了糖皮质激素相关不良事件的风险 鉴于氧化应激在GO中的作用，抗氧化补充剂被认为是一种可能的治疗方法，基础和临床研究也探讨了硒的抗氧化和免疫调节作用。

A couple of in vitro studies have provided evidence for a beneficial effect of selenium in primary cultures of orbital fibroblasts (OFs) (Table 2). In a first study ,after induction of oxidative stress by treating OFs with H2O2,GPX activity, glutathione disulfide (GSSG), cell proliferation,HA and pro-inflammatory cytokines were measured, in the presence or absence of selenium-(Methyl)-selenocysteine (SeMCys). H2O2 induced oxidative stress in OFs, reflected by a dose-dependent increase in GSSG, a known measure of cell response to ROS (Figure 1). SeMCys reduced the effects of H2O2 , providing evidence for an antioxidant action of selenium in OFs. The effect of selenium was observed in OFs from both GO patients and control subjects, which should not be seen as a limitation for its clinical use. Thus, in the same study the authors reported that proliferation of OFs, as well as the production of HA, were significantly greater in GO than in control fibroblasts. Moreover, SeMCys significantly reduced cell proliferation and hyaluronic acid (HA) release in GO OFs, whereas no effects were observed in control OFs . These findings might suggest that fibroblasts from GO patients are somehow different, leading to a different response to oxidative stress and selenium activity.
In a subsequent study, the same authors reported a dual effect of H2O2 on cell proliferation, depending on dose used. At low concentrations, H2O2 promoted cell proliferation,whereas at high concentration progressively decreased cell vitality and cell proliferation. The effects of both high and low dose H2O2 were inhibited by SeMCys which, interestingly,inhibited HA synthesis in GO, but not in control fibroblasts, even though H2O2 did not affect HA release . This observation suggests that selenium may influence HA release,at least in part, regardless of the oxidative stress induced by H2O2 , through mechanisms that are still to be clarified.Furthermore, a reduction in the release of pro-inflammatory cytokines induced by low dose H2O2 , namely interferon-g(IFNg) and TNFa, was found in both GO and control OFs treated with SeMCys , contributing the beneficial effects of selenium in GO OFs.

一些体外研究提供了硒对眼眶成纤维细胞（OFs）原代培养有益的证据。在第一项研究中，通过通过H2O2处理OFs诱导氧化应激后，在存在或不存在硒代蛋氨酸或硒代半胱氨酸的情况下，测定GPX活性、谷胱甘肽二硫（GSSG）、细胞增殖、HA和促炎细胞因子。H2O2在OFs中诱导氧化应激，反映为GSSG的剂量依赖性增加，GSSG是细胞对ROS反应的已知量度。

硒代半胱氨酸降低了H2O2的影响，为硒在OFs中的抗氧化作用提供了证据。硒代半胱氨酸显著降低了GO OFs的细胞增殖和透明质酸（HA）释放，而对照OFs没有观察到效果。这些发现可能表明GO患者的成纤维细胞在某种程度上不同，导致对氧化应激和硒活性的不同反应。在随后的一项研究中，同样的作者报道了H2O2对细胞增殖的双重影响，这取决于所用的剂量。低浓度H2O2促进细胞增殖，高浓度H2O2则逐渐降低细胞活力和细胞增殖。高剂量和低剂量H2O2的作用均被半胱氨酸抑制，有趣的是，半胱氨酸抑制了GO中的HA合成，但在对照成纤维细胞中不起作用，即使H2O2不影响HA的释放。此外，减少低剂量H2O2(即干扰素g)诱导的促炎细胞因子的释放(IFNG)和TNFa，在GO和Control OFs中都有发现，SeMCys处理促进了硒在GO OFs中的有益作用。