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Oxidative stress is involved in the pathogenesis of Graves hyperthyroidism (GH) and Graves orbitopathy (GO) and an antioxidant approach has been proposed for both. In GH, a disbalance of the cell redox state is associated with thyroid hyperfunction and antithyroid medications may reduce oxidative stress. Tissue hypoxia participates in the pathogenesis of GO, and oxygen free radicals are involved in the typical changes of orbital tissues as reported by in vitro and clinical studies. Antioxidant agents, especially selenium, have been proposed as a therapeutic option for GH and GO. A clinical study regarding the use of selenium in mild GO has provided evidence for a beneficial effect in the short term, even though its beneficial effects in the long term are still to be investigated. In addition to selenium, a protective role of other antioxidant agents, i.e., quercetin, enalapril, vitamin C, N-acetyl-L-cysteine and melatonin has been suggested by in vitro studies, although clinical studies are lacking. Here, we review the role of oxidative stress and antioxidant agents in GH and GO.
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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.
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Background: Graves’ orbitopathy (GO) is believed to be the consequence of autoimmunity against antigens that are present both in the thyroid and orbital tissues. Massive release of thyroid antigens causes the appearance or deterioration of GO in patients with Graves’ hyperthyroidism (GH), as it occurs following radioiodine treatment. In theory, a similar release of autoantigens may occur at the eye level, for example due to an orbital trauma or surgical manipulation. To our knowledge, this is the first report of a case of de novo appearance of GO and then GH after an eye trauma, possibly reflecting spreading of autoantigens and activation of the immune system against shared orbital and thyroid antigens. Case Report: An otherwise healthy, 57-year-old man presented 6 months after the appearance of a monolateral right orbitopathy, which occurred 40 days after a trauma in the ipsilateral eye. His thyroid function was normal, with positive serum anti-TSH receptor autoantibodies. The thyroid was normal on ultrasound. A month later he developed hyperthyroidism and orbitopathy in the left eye. Discussion: The development of GO after an eye trauma may reflect tissue damage with release of autoantigens and consequent autoimmunity in a predisposed individual (our patient had a familial history of autoimmune thyroid disease). The subsequent development of hyperthyroidism is in keeping with the hypothesis that GH and GO are due to autoimmunity against antigens present both in the thyroid and in orbital tissues.
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Background: Selenium (Se) is a trace element that plays key roles in thyroid physiology. Se deficiency is associated with increased risk of thyroid disease. Some evidence suggests that Se supplementation may be beneficial in autoimmune thyroid disease (either hypo- or hyperthyroidism). Objectives: We sought to examine the use of Se in daily clinical practice among Italian endocrinologists. Methods: Members of the Associazione Medici Endocrinologi (AME) were invited to participate in a web-based survey investigating the use of Se in different clinical conditions. Results: A total of 815 individuals (43.2% of AME members) participated in the survey, 778 of whom completed all of the sections. Among these respondents, 85.2% considered using Se for thyroid disease (58.1% rarely/occasionally and 27.1% often/always), and 79.4% prescribed Se for chronic autoimmune thyroiditis (AIT) (39.1% sometimes and 40.3% often/always). About two thirds of the respondents considered Se use in cases of subclinical autoimmune hypothyroidism, and about 40% had suggested Se use for patients with AIT who were planning pregnancy or already pregnant. About one fourth of the respondents had used Se for mild Graves' orbitopathy. Regarding the suggested daily dosage of Se, 60% of the respondents answered 100-200 µg, 20-30% recommended <100 µg, and 10-20% recommended >200 µg. Conclusions: Se use is widely considered in daily clinical practice. Moreover, Se supplementation is often used or suggested for purposes extending beyond those supported by evidence-based medicine. Ongoing studies will better clarify how Se treatment can be properly utilized in thyroid disease management.
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Introduction: In the last few years, immune checkpoint inhibitors (ICPis) have become a common treatment of cancer. ICPis are associated with peculiar immune side effects, termed immune-related adverse events (irAEs). Thyroid disfunction is a common irAE, but clinical manifestation, severity, and pathogenesis can be variable. While destructive thyroiditis and hypothyroidism are the most common thyroid irAEs induced by ICPis, autoimmune hyperthyroidism (Graves’ disease) is rare. We describe a case of a Graves’ disease induced by anti-PD-1 therapy and we review the previous reports on this issue. Case Presentation: A 51-year-old man developed an overt autoimmune hyperthyroidism 2 months after he had started nivolumab (anti-PD-1) therapy for a metastatic non-small cell lung cancer. Although TSH-receptor autoantibodies (TRAb) were negative, the persistence of hyperthyroidism, the hypervascular pattern at thyroid ultrasound, and the high uptake at thyroid scintigraphy were all features suggestive of Graves’ disease. Methimazole was started with the prompt restoration of euthyroidism. TRAb remained undetectable during the entire follow-up. Conclusions: Autoimmune hyperthyroidism can be induced by anti-PD-1 treatment. TRAb were negative in both cases of nivolumab-induced Graves’ disease described to date. A correct differential diagnosis between destructive thyroiditis and autoimmune hyperthyroidism is crucial for the appropriate treatment.
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Background: The pathogenesis of the extrathyroidal manifestations of Graves’ disease (GD) is not fully clarified. According to the most common hypothesis, they would reflect an autoimmune reaction against antigens constitutively expressed by the thyroid and by the extrathyroidal affected tissues. According to another hypothesis, the so-called Kriss’ hypothesis, soluble autoantigens released from the thyroid would reach the affected tissues, where they would become the target of the immune system. In this regard, a shift in gravity during sleep may favour antigen deposition. Case Report: A 59-year old man with GD came to our observation because of a dermopathy. He had been treated with radioactive iodine for Graves’ hyperthyroidism and with glucocorticoids and orbital decompression for a bilateral Graves’ orbitopathy (GO). The patient complained of a monolateral, untreated dermopathy, affecting the left leg and hand. At physical examination the skin of the left pretibial area and of the dorsal surface of the left hand appeared red and thickened, with an orange peel aspect. Interestingly, the patient reported that he usually slept laying on the left side of his body. Discussion: The observation of a patient with a monolateral dermopathy somehow reports to the Kriss’ hypothesis, especially in view of the patient’s habit of sleeping on the same side as dermopathy was present. Of course, this does not represent a proof that the Kriss’ hypothesis is correct, but it carries an element in favour of it. The fact that GO was bilateral is somehow against it, but does not exclude this possibility.
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Objectives: There is a general belief that Graves’ orbitopathy (GO) is a “chronic” disease, namely that patients’ eyes do not return to how they were before GO appeared. Here, we investigate this issue from both the patient’s and the physician’s point of view. Study Design: We studied the disappearance of GO, regardless of treatment, in all consecutive patients with a GO history of at least 10 years who came for a follow-up visit over a period of 5 years. Patients underwent an ophthalmological examination and were asked to answer a questionnaire on self-perception related to GO. Results: We studied 99 consecutive patients with a GO duration ≥10 years. Between the first and the last observation, patients received several types of treatment for their thyroid disease and/or for GO. At the end of follow-up, GO was considered disappeared based on objective criteria in 8 patients (∼8%) and based on subjective criteria in 24 patients (∼24%). When we considered both subjective and objective criteria, only 2 patients (∼2%) had all criteria fulfilled and could be considered as GO-free. Conclusions: GO is a chronic disease in the vast majority of patients. Even after a very long time since its onset, complete disappearance is rare, although a minority of patients believe they do not have GO anymore and an even lower proportion do not have relevant GO signs. Our findings have obvious implications in patient management and counseling.
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Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.
