The Effect of Immunosuppression on Selected Antioxidant Parameters in Patients with Graves’ Disease with Active Thyroid-Associated Orbitopathy

Abstract

Background and Study Aims Thyroid-associated orbitopathy, the most common extrathyroidal manifestation of Graves’ disease, is an autoimmune inflammation of orbital soft tissue. We report the study assessing the effect of immunosuppressive treatment with methylprednisolone on selected antioxidant parameters in patients with Graves’ disease with active thyroid-associated orbitopathy.

Patients and Methods Activity and serum levels of selected antioxidant parameters as well as lipid peroxidation products were determined in a group of 56 patients with active thyroid-associated orbitopathy at three time-points: at baseline, after the discontinuation of intravenous methylprednisolone treatment and at 3 months after the discontinuation of additional oral methylprednisolone treatment. A control group consisted of 20 healthy age- and sex-matched volunteers.

Results We found an increased activity of superoxide dismutase and glutathione peroxidase and increased serum levels of uric acid, malondialdehyde and conjugated dienes, as well as a reduced activity of paraoxonase-1 and reduced serum vitamin C level in the study group at baseline. Systemic intravenous and oral methylprednisolone therapy led to normalization of activity and concentration of the most studied parameters.

Conclusion Results of our study confirmed that oxidative stress is one of the factors involved in the pathogenesis of thyroid-associated orbitopathy and the methyloprednisolone treatment is effective in reducing both clinical symptoms and oxidative stress in patients with this disease.

Key words

Graves’ orbitopathy - corticosteroids - antioxidant parameters - lipid peroxidation products - oxidative stress 

Publication History

Received: 25 March 2020
Received: 22 September 2020

Accepted: 29 September 2020

Article published online:
06 November 2020

• References

• 1 Wall JR, Lahooti H. Pathogenesis of thyroid eye disease - does autoimmunity against the TSH receptor explain all cases?. Endokrynol Pol 2010; 61: 222-227
• 2 Effraimidis G, Wiersinga WM. Mechanisms in endocrinology: autoimmune thyroid disease: Old and new players. Eur J Endocrinol 2014; 170: 241-252
• 3 Dong YH, Fu DG. Autoimmune thyroid disease: Mechanism, genetics and current knowledge. Eur Rev Med Pharmacol Sci 2014; 18: 3611-3618
• 4 Piantanida E, Tanda ML, Lai A. et al. Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 2013; 36: 444-449
• 5 Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc 1994; 92: 477-588
• 6 Marcocci C, Bartalena L, Bogazzi F. et al. Studies on the occurrence of opthalmopathy in Graves’ disease. Acta Endocrinol (Copenh) 1989; 120: 473-478
• 7 Burch HB, Wartofsky L. Graves’ ophthalmopathy: Current concepts regarding pathogenesis and management. Endocr Rev 1993; 14: 747-793
• 8 Eckstein AK, Johnson KT, Thanos M. et al. Current insights into the pathogenesis of Graves’ orbitopathy. Horm Metab Res 2009; 41: 456-464
• 9 Smith TJ, Hegedus L, Douglas RS. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 291-302
• 10 Moshkelgosha S, So P-W, Deasy N. et al. Cutting Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a Preclinical Female Mouse Model of Graves’ Orbitopathy Induced by Thyrotropin Receptor Plasmid-in Vivo Electroporation. Endocrinology 2013; 154: 3008-3015
• 11 Bahn RS. News and Views: At Long Last, an Animal Model of Graves’ Orbitopathy. Endocrinology 2013; 154: 2989-2991
• 12 Krieger CC, Neumann S, Place RF. et al. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobulins. J Clin Endocrinol Metab 2015; 100: 1071-1077
• 13 Mikozami T, Salvi M, Wall JR. Eye muscle antibodies in Graves’ ophthalmopathy: Pathogenic or secondary epiphenomenon?. J Endocrinol Invest 2004; 27: 221-229
• 14 Gopinath B, Musselman R, Adams CL. et al. Study of serum antibodies against three eye muscle antigens and the connective tissue antigen collagen XIII in patients with Graves’ disease with and without ophthalmopathy: Correlation with clinical features. Thyroid 2006; 16: 967-974
• 15 Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010; 362: 726-738
• 16 Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev 1994; 74: 139-162
• 17 Burch HB, Lahiri S, Bahn RS. et al. Superoxide radical production stimulates retroocular fibroblast proliferation in Graves’ ophthalmopathy. Exp Eye Res 1997; 65: 311-316
• 18 Murrell GAC, Francis MJO, Bromley L. Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 1990; 265: 659-665
• 19 Bednarek J, Wysocki H, Sowiński J. Peripheral parameters of oxidative stress in patients with infiltrative Graves’ ophthalmopathy treated with corticosteroids. Immunol Lett 2004; 93: 227-232
• 20 Rabinowitz MP, Carrasco JR. Update on advanced imaging options for thyroid-associated orbitopathy. Saudi J Ophthalmol 2012; 26: 385-392
• 21 Tortora F, Mario Cirillo M, Ferrara M. et al. Disease Activity in Graves’ Ophthalmopathy: Diagnosis with Orbital MR Imaging and Correlation with Clinical Score. Neuroradiol J 2013; 26: 555-564
• 22 Bartalena L, Baldeschi L, Boboridis K. et al. European Group on Graves’ Orbitopathy (EUGOGO). The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. Eur Thyroid J 2016; 5: 9-26
• 23 Benzie JF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 1996; 239: 70-76
• 24 Oyangui Y. Revaluation of assay methods and establishment of kit for superoxide dismutase. Anal Biochem 1984; 142: 290-296
• 25 Paglia D, Valentine W. Studies on the quantities and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin 1967; 70: 158-169
• 26 Eckerson HW, Romson J, Wyte C. et al. The human serum paraoxonase polymorphism: Identification of phenotypes by their response to salts. Am J Hum Genet 1983; 35: 214-227
• 27 Wielkoszyński T. Spectrophotometric method of determination L-ascorbic acid concentration in biological material. Diagn Lab 2001; 37 (Supl 2): 172
• 28 Wąsowicz W, Nève J, Peretz A. Optimized steps in fluorometric determination of thiobarbituric acid-reactive substances in serum: importance of extraction pH and influence of sample preservation and storage. Clin Chem 1993; 39: 2522-2526
• 29 Corongiu FP, Banni S, Dessi MA. Conjugated dienes detected in tissue lipid extracts by second derivative spectrophotometry. Free Radic Biol Med 1989; 7: 183-186
• 30 Kajdaniuk D, Marek B, Borgiel-Marek H. et al. Transforming growth factor beta1 (TGF beta 1) in physiology and pathophysiology. Endokrynol Pol 2013; 64: 384-396
• 31 Nowak M, Marek B, Karpe J. et al. Serum concentration of VEGF and PDGF-AA in patients with active thyroid orbitopathy before and after immunosuppressive therapy. Exp Clin Endocrinol Diabetes 2014; 122: 582-586
• 32 Nowak M, Siemińska L, Karpe J. et al. Serum concentrations of HGF and IL-8 in patients with active Graves’ orbitopathy before and after methylprednisolone therapy. J Endocrinol Invest 2016; 39: 63-72
• 33 Bednarek J, Wysocki H, Sowinski J. Oxidative stress peripheral parameters in Graves’ disease: The effect of methimazole treatment in patients with and without infiltrative ophthalmopathy. Clin Biochem 2005; 38: 13-18
• 34 Hondur A, Konuk O, Dincel AS. et al. Oxidative stress and antioxidant activity in orbital fibroadipose tissue in Graves’ ophthalmopathy. Curr Eye Res 2008; 33: 421-427
• 35 Choi W, Li Y, Ji YS. et al. Oxidative stress markers in tears of patients with Graves’ orbitopathy and their correlation with clinical activity score. BMC. Ophthalmol 2018; 18: 303-309
• 36 Hübner G, Meng W, Meisel P. et al. Behavior of the erythrocyte glucose-6-phosphate dehydrogenase in patients with functional thyroid disorders and in hyperthyroxinemic rats. Z Gesamte Inn Med 1979; 34: 386-389
• 37 Wilson R, Chopra M, Bradley H. et al. Free radicals and Graves’ disease: The effects of therapy. Clin Endocrinol 1989; 30: 429-433
• 38 Rotondo Dottore G, Ionni I, Menconi F. et al. Antioxidant Effects of β-Carotene, but Not of Retinol and Vitamin E, in Orbital Fibroblasts From Patients With Graves’ Orbitopathy (GO). J Endocrinol Invest 2018; 41: 815-820
• 39 Rotondo Dottore G, Leo M, Casini G. et al. Antioxidant actions of selenium in orbital fibroblasts: a basis for the effects of selenium in Graves’ orbitopathy. Thyroid 2017; 27: 271-278
• 40 Botta R, Lisi S, Marcocci C. et al. Enalapril reduces proliferation and hyaluronic acid release in orbital fibroblasts. Thyroid 2013; 23: 92-96
• 41 Lisi S, Botta R, Lemmi M. et al. Quercetin decreases proliferation of orbital fibroblasts and their release of hyaluronic acid. J Endocrinol Invest 2011; 34: 521-527
• 42 Marcocci C, Bartalena L. Role of oxidative stress and selenium in Graves’ hyperthyroidism and orbitopathy. J Endocrinol Invest 2013; 36: 15-20
• 43 Marcocci C, Kahaly GJ, Krassas GE. et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 2011; 364: 1920-1931
• 44 Tsai CC, Wu SB, Cheng CY. et al. Increased oxidative DNA damage, lipid peroxidation, and reactive oxygen species in cultured orbital fibroblasts from patients with Graves ophthalmopathy: Evidence that oxidative stress has a role in this disorder. Eye 2010; 24: 1520-1525
• 45 Tsai CC, Cheng CY, Liu CY. et al. Oxidative stress in patients with Graves’ ophthalmopathy: relationship between oxidative DNA damage and clinical evolution. Eye 2009; 23: 1725-1730
• 46 Acarsu E, Buyukhatipoglu H, Aktaran S. et al. Effects of pulse methylprednisolone and oral methylprednisolone treatments on serum levels of oxidative stress markers in Graves’ ophthalmopathy. Clin Endocrinol 2011; 74: 118-124
• 47 Tsai CC, Kao SC, Cheng CY. et al. Oxidative stress change by systemic corticosteroid treatment among patients having active Graves ophthalmopathy. Arch Ophthalmol 2007; 125: 1652-1656
• 48 Rajkovic MG, Rumora L, Barisic K. The paraoxonase 1, 2 and 3 in humans. Biochem Med 2011; 21: 122-130
• 49 Emin O, Hasan A, Rusen DM. Plasma paraoxonase, oxidative status level and their relationship with asthma control test in children with asthma. Allergol Immunopathol (Madr) 2015; 43: 346-352
• 50 Azizi F, Raiszadeh F, Solati M. et al. Serum paraoxonase 1 activity is decreased in thyroid dysfunction. J Endocrinol Invest 2003; 26: 703-709
• 51 Raiszadeh F, Solati M, Etemadi A. et al. Serum paraoxonase activity before and after treatment of thyrotoxicosis. Clin Endocrinol (Oxf) 2004; 60: 75-80
• 52 Baskol G, Dolbun Seçkin K, Bayram F. et al. Investigation of serum paraoxonase-1 activity and lipid levels in patients with hyperthyroidism. Turk J Med Sci 2012; 42 (Suppl. 01) 1166-1171
• 53 Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 1986; 314: 892-902
• 54 Rotondo Dotore G, Ionni I, Menconi F. et al. Action of bioavailable antioxidants in orbital fibroblasts from patients with Graves’ orbitopathy (GO): A new frontier for GO treatment?. J Endocrinol Invest 2018; 41: 193-201
• 55 Ames BN, Cathcart R, Schwiers E. et al. Uric acid provides an antioxidant defense in humans against oxidant and radical-caused aging and cancer: hypothesis. Proc Natl Acad Sci USA 1981; 78: 6858-6862
• 56 Frei B, Stocker R, Ames BN. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA 1988; 85: 9748-9752
• 57 Pasalic D, Marinkovic N, Feher-Turkovic N. Uric acid as one of the important factors in multifactorial disorders – facts and controversies. Biochem Med 2012; 22: 63-75
• 58 Waring WS, Webb DJ, Maxwell SR. Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers. J Cardiovasc Pharmacol 2001; 38: 365-371
• 59 Bouzas EA, Karadimas P, Mastorakos G. et al. Antioxidant agents in the treatment of Graves’ ophthalmopathy. Am J Ophthalmol 2000; 129: 618-622
• 60 Karasek D, Cibickova L, Karhanova M. et al. Clinical and immunological changes in patients with active moderate-to-severe Graves’ orbitopathy treated with very low-dose rituximab. Endokrynol Pol 2017; 68: 498-504
• 61 Russell DJ, Wagner LH, Seiff SR. Tocilizumab as a steroid sparing agent for the treatment of Graves’ orbitopathy. Am J Ophthalmol Case Rep 2017; 7: 146-148
• 62 Swierkot M, Kulawik G, Sarnat-Kucharczyk M. et al. Long-term remission of steroid-resistant Graves’ orbitopathy after administration of anti-thymocyte globulin – description of the first case. Endokrynol Pol 2020; 71: 198-199