Indicators of oxidative stress and tissue hypoxia in various phases of Graves’ orbitopathy activity

Graves’ orbitopathy (GO) is an extrathyroid complication of thyroid dysfunction characterized by chronic autoimmune inflammation of soft retrobulbar tissues. The data on the role of oxidative and hypoxic stress in GO are heterogeneous, which necessitates further research.
The aim of the study. To evaluate the indicators of oxidative stress and tissue hypoxia at various phases of Graves’ orbitopathy activity.
Material and methods. Examination of patients with GO (n = 32), with autoimmune thyroid pathology (n = 18) and healthy individuals (n = 15) was performed. The study included ophthalmological examination and blood sampling to determine the concentration of antibodies to the thyroid-stimulating hormone receptor, interleukin 17A (IL-17A), hypoxia inducible factor 1a (HIF-1a), TBK-active products and calculation of total antioxidant activity.
Results. An increase in the concentration of TBK-active products in the clinical group was revealed compared with the control (p < 0.001). The total antioxidant activity was reduced at all phases of GO activity than in the control (p < 0.001). The level of HIF-1α did not differ in the study groups (H = 3.29; p = 0.51). Direct moderate correlations were found between the concentration of IL-17A and the level of TBA-active substances (p = 0.001), as well as inverse moderate correlations with the value of total antioxidant activity (p = 0.007). The activity of GO had weak correlations with total antioxidant activity (p < 0.001). Significant correlations between indicators of oxidative stress and tissue hypoxia were not found.
Conclusion. In GO, regardless of the activity phase, there is an imbalance between the parameters of the “lipid peroxidation – antioxidant protection” system, which is manifested by an increase in TBA-active substances while reducing the total antioxidant activity. The indicators of tissue hypoxia did not differ in the study groups. The revealed correlations between the autoimmune inflammation activity in the orbit and oxidative stress emphasize the pathogenetic conditionality of the antioxidant drugs appointment in the therapy of GO.

1. Zheng J, Duan H, You S, Liang B, Chen Y, Huang H. Research progress on the pathogenesis of Graves’ ophthalmopathy: Based on immunity, noncoding RNA and exosomes. Front Immunol. 2022; 13: 952954. doi: 10.3389/fimmu.2022.952954

2. Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020; 16(2): 104-116. doi: 10.1038/s41574-019-0305-4

3. Hoang TD, Stocker DJ, Chou EL, Burch HB. 2022 update on clinical management of Graves disease and thyroid eye disease. Endocrinol Metab Clin North Am. 2022; 51(2): 287-304. doi: 10.1016/j.ecl.2021.12.004

4. Taskina ES, Kharintseva SV. Morphofunctional characteristics and immunological regulation of the orbital fibroblasts function in endocrine ophthalmopathy. Clinical and Experimental Thyroidology. 2018; 14(4): 183-191. (In Russ.). doi: 10.14341/ket10147

5. Longo CM, Higgins PJ. Molecular biomarkers of Graves’ ophthalmopathy. Exp Mol Pathol. 2019; 106: 1-6. doi: 10.1016/j.yexmp.2018.11.004

6. Charinzeva SV, Taskina ES. The role of interleukins 17, 23 and antibodies to the thyroid-stimulating hormone receptor in the pathogenesis of endocrine ophthalmopathy. Clinical and Experimental Thyroidology. 2018; 14(2): 72-80. (In Russ.). doi: 10.14341/ket9703

7. Hou TY, Wu SB, Kau HC, Tsai CC. The role of oxidative stress and therapeutic potential of antioxidants in Graves’ ophthalmopathy. Biomedicines. 2021; 9(12): 1871. doi: 10.3390/biomedicines9121871

8. Görtz GE, Philipp S, Bruderek K, Jesenek C, Horstmann M, Henning Y, et al. Macrophage-orbital fibroblast interaction and hypoxia promote inflammation and adipogenesis in Graves’ orbitopathy. Endocrinology. 2022; 164(2): bqac203. doi: 10.1210/endocr/bqac203

9. Werner SC. Modification of the classification of the eye changes of Graves’ disease. Am J Ophthalmol. 1977; 83(5): 725-727. doi: 10.1016/0002-9394(77)90140-4

10. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velazquez-Villoria A, Galofre JC. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015; 2015: 249125. doi: 10.1155/2015/249125

11. Mourits MP, Koornneef L, Wiersinga WM. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: A novel approach. Br J Ophthalmol. 1989; 73(8): 639-644. doi: 10.1136/bjo.73.8.639

12. Alekseev VV, Karpishchenko AI. Medical laboratory technologies: Guideline to clinical and laboratory diagnostics. 3rd edition, revised and enlarged. Moscow: GEOTAR-Media; 2013; 2. (In Russ.).

13. Promyshlov MSh, Demchuk ML. A modified method of determination of the total serum antioxidant activity. Voprosy meditsinskoi khimii. 1990; 36(4): 90-92. (In Russ.).

14. Mudrov VA. Statistical analysis algorithms of quantitative features in biomedical research using the SPSS software package. Transbaikalian Medical Bulletin. 2020; 1: 140-150. (In Russ.) doi: 10.52485/19986173_2020_1_140

15. Lanzolla G, Marcocci C, Marinò M. Antioxidant therapy in Graves’ orbitopathy. Front Endocrinol (Lausanne). 2020; 11: 608733. doi: 10.3389/fendo.2020.608733

16. Wang F, Li C, Li S, Cui L, Zhao J, Liao L. Selenium and thyroid diseases. Front Endocrinol (Lausanne). 2023; 14: 1133000. doi: 10.3389/fendo.2023.1133000

17. Liu CT, Yen JJ, Brown DA, Song YC, Chu MY, Hung YH, et al. Targeting Nrf2 with 3H-1,2-dithiole-3-thione to moderate OXPHOS-driven oxidative stress attenuates IL-17A-induced psoriasis. Biomed Pharmacother. 2023; 159: 114294. doi: 10.1016/j.biopha.2023.114294

18. Gross CJ, Mishra R, Schneider KS, Medard G, Wettmarshausen J, Dittlein DC, et al. K(+) efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity. 2016; 45(4): 761-773. doi: 10.1016/j.immuni.2016.08.010

19. Mogilenko DA, Haas JT, L’Homme L, Fleury S, Quemener S, Levavasseur M, et al. Metabolic and innate immune cues merge into a specific inflammatory response via the UPR. Cell. 2019; 177(5): 1201-1216 e19. doi: 10.1016/j.cell.2019.03.018

20. Ece H, Mehmet E, Cigir BA, Yavuz D, Muammer K, Cumhur G, et al. Serum 8-OHdG and HIF-1α levels: Do they affect the development of malignancy in patients with hypoactive thyroid nodules? Contemp Oncol (Pozn). 2013; 17(1): 51-57. doi: 10.5114/wo.2013.33774

21. Görtz GE, Horstmann M, Aniol B, Reyes BD, Fandrey J, Eckstein A, et al. Hypoxia-dependent HIF-1 activation impacts on tissue remodeling in Graves’ ophthalmopathy-implications for smoking. J Clin Endocrinol Metab. 2016; 101: 4834-4842. doi: 10.1210/jc.2016-1279

22. Malkov MI, Lee CT, Taylor CT. Regulation of the hypoxiainducible factor (HIF) by pro-inflammatory cytokines. Cells. 2021; 10: 2340. doi: 10.3390/cells10092340