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Oxidative Stress Change by Systemic Corticosteroid Treatment Among Patients Having Active Graves Ophthalmopathy
Chieh-Chih Tsai, MD;
Shu-Ching Kao, MD;
Ching-Yu Cheng, MD, MPH;
Hui-Chuan Kau, MD, MS;
Wen-Ming Hsu, MD;
Cheng-Feng Lee, PhD;
Yau-Huei Wei, PhD
Arch Ophthalmol. 2007;125(12):1652-1656.
ABSTRACT
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Objectives To measure the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in patients having active Graves ophthalmopathy (GO) and to compare this oxidative stress biomarker and the clinical evolution of patients after systemic corticosteroid treatment.
Methods In 8 euthyroid patients having active GO, we determined the 8-OHdG levels in urine before, during, and after intensive corticosteroid therapy. Clinical activity and ophthalmopathy index scores were assessed. Nine age- and sex-matched healthy volunteers served as control subjects.
Results The mean 8-OHdG level was statistically significantly increased in patients having active GO compared with that of controls (17.47 vs 5.97 ng/mg of creatinine, P < .001). During and after maximal systemic corticosteroid treatment, patients had statistically significantly lower mean 8-OHdG levels (7.19 and 10.18 ng/mg of creatinine, respectively) compared with the mean level before treatment. These changes were accompanied by decreases in clinical activity and ophthalmopathy index scores. The urinary 8-OHdG levels were subsequently elevated in 2 patients having recurrent active GO when corticosteroid therapy was tapered or withdrawn.
Conclusions Oxidative stress may have a role in the pathogenesis of GO. Urinary 8-OHdG level can be used not only as a noninvasive biomarker of oxidative stress in patients having GO but also as an objective and quantitative parameter in the follow-up of patients during immunosuppressive treatment.
INTRODUCTION
Graves ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves disease, is considered an inflammatory disorder of autoimmune background.1-2 Many researchers have tried to identify a causative antigen or antibody in an effort to unravel the pathogenesis of the disease, but this has remained controversial.3-5 Recent studies6-7 implicate a change in reactive oxygen species (ROS) metabolism in the pathogenesis of several autoimmune disorders, including Graves disease. Graves disease is characterized by overproduction of thyroid hormones due to continuous stimulation of the thyrotropin receptor by thyroid-stimulating autoantibodies. Thyroid hormones can accelerate the basal metabolic rate and oxidative metabolism by induction of mitochondrial enzymes, which causes a hypermetabolic state with increased generation of ROS.8-9 There is growing evidence of an imbalance between prooxidant-antioxidant status and increased free radical–mediated oxidative stress in patients having Graves disease.6-12 Bednarek et al7 found that increased ROS generation and scavenging plasma indexes in patients having Graves disease with hyperthyroid state can be normalized with the antithyroid agent methimazole except in those with infiltrative GO, suggesting that, apart from the effect of the thyroid metabolic status, orbital inflammation may also trigger changes in extracellular indexes of ROS metabolism in blood. However, the contribution of ROS to the ocular changes in Graves disease is poorly understood.
This study was undertaken to investigate the effect of corticosteroid treatment on the oxidative stress status in patients having GO. Systemic corticosteroids are a fundamental therapeutic tool for active GO, and their use is associated with interference in the formation of ROS or an effect on ROS scavenging enzymes.13-14 Among the various types of oxidative damage in cellular structures or biomolecules induced by ROS, 8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidative products of DNA and represents a noninvasive and sensitive biomarker of oxidative stress.15 In this study, we measured the 8-OHdG levels in urine of patients having active GO treated with systemic corticosteroids with an aim to determine whether 8-OHdG level could be used as a biomarker in the management of GO.
METHODS
PATIENTS
Between June 1, 2006, and May 31, 2007, all patients who had developed ocular signs during the past 6 months and demonstrated active GO with a clinical activity score (CAS) of 4 or higher16 at the beginning of therapy and who underwent systemic corticosteroid therapy at Taipei Veterans General Hospital were prospectively recruited for the study. Before inclusion in the study, euthyroidism in all patients having GO was achieved by medication (antithyroid drugs only, including carbimazole, methimazole, and propylthiouracil, or combined with thyroxine sodium) for at least 6 months. None were treated with radioactive iodine. The diagnosis of GO was based on the criteria proposed by Bartley and Gorman.17 Computed tomography of the orbit and Hertel exophthalmometry were performed to help confirm the diagnosis of GO. Control subjects were recruited from age-matched and sex-matched healthy persons who were enrolled when they attended their routine physical examinations. Exclusion criteria were pregnancy, alcohol drinking, any ocular diseases other than GO, regular drug ingestion or antioxidant use, and GO with a history of surgical decompression, systemic corticosteroid therapy, or radiation therapy, as well as individuals with chronic or acute disease such as cancer, hypertension, hyperlipidemia, diabetes mellitus, and diseases of the lung, liver, or kidney or other endocrine, immunologic, or inflammatory disorders. The study was approved by the institutional review board of Taipei Veterans General Hospital, and patients gave informed consent for their participation.
TREATMENT, FOLLOW-UP, AND URINE COLLECTION
In the GO group, systemic corticosteroid therapy was oral prednisolone (0.75 mg/kg of body weight daily) administered for 4 weeks and then tapered slowly to discontinuation at approximately 3 months. All patients underwent ophthalmologic investigation, including assessment of clinical activity and severity of GO and collection of urine before, during (4 weeks after treatment initiation), and after intensive corticosteroid treatment. Graves ophthalmopathy activity was scored according to the CAS suggested by Mourits et al,18 ranging from 0 to 10 points. Severity of GO was scored using the ophthalmopathy index (OI),19 based on the NOSPECS mnemonic (composed of the first character describing each grade) classification ranging from 0 to 15 points (0-3 points were given for each ocular change based on the severity of sight loss, proptosis, and soft-tissue, extraocular muscle, and corneal involvement). The definition of proptosis was adjusted according to racial/ethnic variation, and the mean ± SD exophthalmos value among Taiwanese healthy adults is 13.91 ± 2.33 mm.20 Urine samples were also obtained from the control subjects. Smokers were requested to abstain from smoking overnight before urine collection.21
DETERMINATION OF 8-OHDG LEVEL IN URINE
Urine specimens were centrifuged at 4000g for 10 minutes, and the supernatant was stored at –70°C until the enzyme-linked immunosorbent assay (ELISA) analysis. The amount of 8-OHdG in urine was measured using an ELISA kit (8-OHdG check; Japan Institute for the Control of Aging, Fukuroi, Japan). Assays were performed according to the manufacturer's instructions. The specificity of the assay has been established, and the detection range was 0.5 to 200 ng/mL. The urinary 8-OHdG level in each subject was corrected by the creatinine level in urine and is expressed in nanograms per milligram of creatinine.
STATISTICAL ANALYSIS
Statistical analysis was performed using commercially available software (STATA; StataCorp, College Station, Texas). Data obtained are expressed as mean ± SD. Normality of these data was assessed using the Shapiro-Wilk test. Comparisons of 8-OHdG levels between patients having GO and the control group were performed using the unpaired t test, and the effect of treatment in the GO group was evaluated using the paired t test. P < .05 was considered statistically significant.
RESULTS
Nine patients met the inclusion criteria; however, 1 patient withdrew because of intolerance of oral prednisolone. Data obtained from 8 patients (Table 1) and 9 control subjects (Table 2) were analyzed. No statistically significant differences in age (P =.90), sex (P > .99), or smoking status (P > .99) were observed between the groups.
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Table 1. Characteristics and Urinary 8-Hydroxy-2'-Deoxyguanosine (8-OHdG) Levels Among Patients Having Active Graves Ophthalmopathy
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Table 2. Smoking Status and Urinary 8-Hydroxy-2'-Deoxyguanosine (8-OHdG) Levels Among Control Subjects
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In patients having active GO before therapy, the mean urinary 8-OHdG level (17.47 ng/mg of creatinine) was statistically significantly higher than that of controls (5.97 ng/mg of creatinine) (P < .001). In the GO group, the changes in urinary 8-OHdG level, CAS, and OI after treatment are given in Table 3. The mean 8-OHdG level in urine was statistically significantly decreased among patients during maximal systemic corticosteroid treatment (7.19 ng/mg of creatinine, P =.002) and after completion of treatment (10.18 ng/mg of creatinine, P =.01) compared with that before therapy (Figure). However, there was no statistically significant difference in the mean 8-OHdG level among the patients during maximal systemic corticosteroid therapy vs after treatment (P = .07). The mean CAS of patients statistically significantly decreased from 4.88 before therapy to 2.25 (P < .001) during maximal systemic corticosteroid treatment and to 1.86 (P < .001) after completion of treatment. The mean OI of patients statistically significantly decreased from 5.50 before therapy to 3.00 (P =.002) during maximal systemic corticosteroid treatment and to 2.43 (P =.001) after completion of treatment. Recurrence of active GO was noted in patient 3 (Table 1) when prednisolone therapy was tapered and in patient 4 when the drug was withdrawn for 1 month. The urinary 8-OHdG levels were elevated to 17.31 and 14.35 ng/mg of creatinine in patients 3 and 4, respectively. Both patients subsequently received further intravenous corticosteroid therapy and combined orbital radiation therapy.
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Table 3. Changes in Urinary 8-Hydroxy-2'-Deoxyguanosine (8-OHdG) Levels, Clinical Activity Scores, and Ophthalmopathy Indexes Among Patients Having Active Graves Ophthalmopathya
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Figure. The mean ± SD changes in urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels among patients having Graves ophthalmopathy treated with systemic corticosteroids.
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COMMENT
Oxidative stress has been associated with the development of different degenerative,22 neoplastic,23 and inflammatory24 diseases. As a reliable biomarker of oxidative DNA damage, higher 8-OHdG levels have been observed in various ocular diseases such as trabecular meshwork in patients having glaucoma,25 Eales disease,26 and pterygium tissue.27 To our knowledge, this is the first study to explore increased 8-OHdG levels in urine of patients having active GO and to disclose the alleviation of this biomarker of oxidative DNA damage after treatment with systemic corticosteroids.
Graves ophthalmopathy, as a primary feature of Graves disease, is a disfiguring and potentially sight-threatening disorder that profoundly affects the person's quality of life. Although several new treatments have been proposed, progress in the management of GO has been slow. Early intervention with novel therapy requires vast knowledge of the disease mechanisms. Many attempts have been made to understand the pathophysiology and pathogenesis of GO,28-31 but the findings are unclear. Graves ophthalmopathy may be caused by a complex interplay of endogenous and environmental factors, which may be associated with ROS. In vitro findings suggest that interleukin 1β, an important cytokine, participates in the autoimmune response of GO and causes an increase in oxygen-free radical production by orbital fibroblasts, as well as that superoxide dismutase and catalase could partially block the accumulation of glycosaminoglycans induced by this cytokine.32 In addition, in patients having GO, superoxide anions have been shown to stimulate proliferation of orbital fibroblasts, which could be inhibited by methimazole or nicotinamide.33-34 In an in vivo study,35 extracellular indexes of ROS metabolism in blood were also found to increase in patients having infiltrative GO. In the present study, we further revealed increased oxidative DNA damage in patients having active GO compared with controls. To eliminate the effect of abnormal levels of thyroid hormones, only the patients having GO achieving stable euthyroidism for at least 6 months were included in this study. Therefore, it is rational to propose that ongoing orbital inflammation triggered changes in the levels of ROS, which caused subsequent free radical–mediated oxidative stress in these patients. Bednarek et al35 reported that intensive corticosteroid therapy resulted in normalization of peripheral markers for ROS metabolism and restoration of these markers, along with activation of antioxidant defense systems after withdrawal of corticosteroid therapy. In our study, we demonstrated a similar reduction in oxidative DNA damage after systemic corticosteroid treatment. After withdrawal of corticosteroid therapy, the mean urinary 8-OHdG level was statistically significantly lower than that before therapy but was slightly increased compared with that during intensive corticosteroid therapy. This indicates an imbalance between the elevated ROS level and the antioxidant capacity after withdrawal of corticosteroid therapy. In a small case series, the use of oral antioxidants showed encouraging results in the treatment of mild and moderately severe GO.36 Therefore, based on the results of the present work and previous findings, antioxidant supplementation may be potentially beneficial for these patients after withdrawal of corticosteroid therapy.
Apart from GO, other factors might have been responsible for the increased levels of 8-OHdG.21 Among other factors, cigarette smoking, which is considered to be the most important known environmental factor associated with GO occurrence and morbidity, may enhance the generation of ROS37 and reduce the endogenous levels of antioxidants.38 Patient 3 in our study (Table 1), who had recurrent active GO during tapering of corticosteroid therapy, is a smoker, and his urinary 8-OHdG level was elevated almost to the previous level while receiving systemic corticosteroid therapy. The other smoker with GO (patient 1) had a urinary 8-OHdG level that was more than 4-fold higher than the mean 8-OHdG level of the controls. This suggests that smoking may have a role in the oxidative stress of patients having GO, at least in perpetuating ongoing oxidative damage.
The natural history of GO often includes an initial active phase of progressive exacerbation, followed by regression to a static and inactive phase with residual morbidity of the disease.39-40 In this regard, management of GO should rely on the assessment of 2 different features, namely, the severity and activity of the disease. Many indicators of disease severity and activity have been proposed; it is possible that a combination of different variables may better define and characterize the disease condition.40 In the present study, not only the urinary 8-OHdG level but also the CAS and OI were improved during and after systemic corticosteroid treatment. In addition, the urinary 8-OHdG levels were subsequently elevated in 2 patients having recurrent active GO when corticosteroid therapy was tapered or withdrawn, suggesting that the urinary 8-OHdG level can be used as a valuable variable in the assessment of GO and may potentially help clinicians decide whether a patient requires treatment.
Based on the findings of the present work and previous studies,32-36,41 oxidative stress represents an important pathogenic factor in GO, at least in perpetuating ongoing reactions. However, because of limited cases in this study, more studies are warranted to provide additional information about the precise effect of 8-OHdG level on the natural history of the disease.
In conclusion, we demonstrated that the urinary 8-OHdG level is increased in patients having active GO and that successful management of GO with corticosteroids is associated with a decrease in this oxidative stress marker. The 8-OHdG level in urine is not only a noninvasive biomarker of oxidative stress in patients having GO but also an objective and quantitative variable for the follow-up of immunosuppressive treatment of the disease.
AUTHOR INFORMATION
Correspondence: Yau-Huei Wei, PhD, Department of Biochemistry and Molecular Biology, National Yang-Ming University, 155 Li-Nong St, Section 2, Taipei 112, Taiwan (joeman{at}ym.edu.tw).
Submitted for Publication: May 31, 2007; final revision received July 21, 2007; accepted July 27, 2007.
Financial Disclosure: None reported.
Funding/Support: This study was supported by grant 95-2314-B-075-058 from the National Science Council of Taiwan (Dr Tsai) and by grant V96-B1-002 from Taipei Veterans General Hospital (Dr Tsai).
Additional Contributions: Shi-Bei Wu, MS, and Chun-Yi Liu, MS, at the Department of Biochemistry and Molecular Biology, National Yang-Ming University, provided technical assistance.
Author Affiliations: Department of Ophthalmology, Taipei Veterans General Hospital (Drs Tsai, Kao, Cheng, and Hsu), and Institute of Clinical Medicine (Dr Tsai) and Departments of Ophthalmology (Drs Tsai, Kao, Cheng, Kau, and Hsu) and Biochemistry and Molecular Biology (Drs Lee and Wei), National Yang-Ming University; and Department of Ophthalmology, Koo Foundation Sun Yat-Sen Cancer Center (Dr Kau), Taipei, Taiwan; and Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, and Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland (Dr Cheng).
REFERENCES
| |
1. Kazim M, Goldberg RA, Smith TJ. Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy. Arch Ophthalmol. 2002;120(3):380-386.
FREE FULL TEXT
2. Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves' disease and ophthalmopathy. Endocr Rev. 2003;24(6):802-835.
FREE FULL TEXT
3. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med. 1993;329(20):1468-1475.
FREE FULL TEXT
4. Bahn RS. Pathophysiology of Graves' ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab. 2003;88(5):1939-1946.
FREE FULL TEXT
5. Smith TJ, Koumas L, Gagnon A; et al. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2002;87(1):385-392.
FREE FULL TEXT
6. Ademo lu E, Ozbey N, Erbil Y. Determination of oxidative stress in thyroid tissue and plasma of patients with Graves' disease. Eur J Intern Med. 2006;17(8):545-550.
FULL TEXT
|
ISI
| PUBMED
7. 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(1):13-18.
FULL TEXT
|
ISI
| PUBMED
8. Mano T, Sinohara R, Sawai Y; et al. Effects of thyroid hormone on coenzyme Q and other free radical scavengers in rat heart muscle. J Endocrinol. 1995;145(1):131-136.
FREE FULL TEXT
9. Asayama K, Kato K. Oxidative muscular injury and its relevance to hyperthyroidism Free Radic Biol Med. 1990;8(3):293-303.
FULL TEXT
|
ISI
| PUBMED
10. Videla LA, Sir T, Wolff C. Increased lipid peroxidation in hyperthyroid patients: suppression by propylthiouracil treatment. Free Radic Res Commun. 1988;5(1):1-10.
ISI
| PUBMED
11. Venditti P, Balestrini M, Di Meo S, De Leo T. Effect of thyroid state on lipid peroxidation, antioxidant defenses, and susceptibility to oxidative stress in rat tissues. J Endocrinol. 1997;155(1):151-157.
FREE FULL TEXT
12. Abalovich M, Llesuy S, Gutierrez S, Repetto M. Peripheral parameters of oxidative stress in Graves' disease: the effects of methimazole and 131 iodine treatments. Clin Endocrinol (Oxf). 2003;59(3):321-327.
FULL TEXT
| PUBMED
13. Whitehouse MW, Cleland LG. Reactive oxygen species and drug therapy for inflammatory diseases. Agents Actions Suppl. 1985;17:177-188.
PUBMED
14. Youssef AA, Baron DN. Leucocyte superoxide dismutase in rheumatoid arthritis. Ann Rheum Dis. 1983;42(5):558-562.
FREE FULL TEXT
15. Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res. 1997;387(3):147-163.
FULL TEXT
|
ISI
| PUBMED
16. Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf). 1997;47(1):9-14.
FULL TEXT
| PUBMED
17. Bartley GB, Gorman CA. Diagnostic criteria for Graves' ophthalmopathy. Am J Ophthalmol. 1995;119(6):792-795.
ISI
| PUBMED
18. Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73(8):639-644.
FREE FULL TEXT
19. Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A. Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves' ophthalmopathy is more effective than radiotherapy alone: results of a prospective randomized study. J Endocrinol Invest. 1991;14(10):853-860.
ISI
| PUBMED
20. Tsai CC, Kau HC, Kao SC, Hsu WM. Exophthalmos of patients with Graves' disease in Chinese of Taiwan. Eye. 2006;20(5):569-573.
FULL TEXT
|
ISI
| PUBMED
21. Loft S, Vistisen K, Ewertz M, Tjonneland A, Overvad K, Poulsen HE. Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: influence of smoking, gender and body mass index. Carcinogenesis. 1992;13(12):2241-2247.
FREE FULL TEXT
22. Giacosa A, Filiberti R. Free radicals, oxidative damage and degenerative diseases. Eur J Cancer Prev. 1996;5(5):307-312.
FULL TEXT
|
ISI
| PUBMED
23. Floyd RA. The role of 8-hydroxyguanine in carcinogenesis. Carcinogenesis. 1990;11(9):1447-1450.
FREE FULL TEXT
24. Kato J, Kobune M, Nakamura T; et al. Normalization of elevated hepatic 8-hydroxy-2'-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. Cancer Res. 2001;61(24):8697-8702.
FREE FULL TEXT
25. Saccà SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123(4):458-463.
FREE FULL TEXT
26. Rajesh M, Ramesh A, Ravi PE; et al. Accumulation of 8-hydroxydeoxyguanosine and its relationship with antioxidant parameters in patients with Eales' disease: implications for antioxidant therapy. Curr Eye Res. 2003;27(2):103-110.
FULL TEXT
|
ISI
| PUBMED
27. Kau HC, Tsai CC, Lee CF, Kao SC, Hsu WM, Wei YH. Increased oxidative DNA damage, 8-hydroxydeoxyquanosine, in human pterygium. Eye. 2006;20(7):826-831.
FULL TEXT
|
ISI
| PUBMED
28. Smith TJ, Wang HS, Evans CH. Leukoregulin is a potent inducer of hyaluronan synthesis in cultured human orbital fibroblasts. Am J Physiol. 1995;268(2 pt 1):C382-C388.
ISI
| PUBMED
29. Smith TJ. The putative role of fibroblasts in the pathogenesis of Graves' disease: evidence for the involvement of the insulin-like growth factor–1 receptor in fibroblast activation. Autoimmunity. 2003;36(6-7):409-415.
FULL TEXT
|
ISI
| PUBMED
30. Chen B, Tsui S, Smith TJ. IL-1β induces IL-6 expression in human orbital fibroblasts: identification of an anatomic-site specific phenotypic attribute relevant to thyroid-associated ophthalmopathy. J Immunol. 2005;175(2):1310-1319.
FREE FULL TEXT
31. Tsai CC, Kau HC, Kao SC; et al. Pulsatile ocular blood flow in patients with Graves' ophthalmopathy. Eye. 2005;19(2):159-162.
FULL TEXT
|
ISI
| PUBMED
32. Lu R, Wang P, Wartofsky L; et al. Oxygen free radicals in interleukin-1β–induced glycosaminoglycan production by retro-ocular fibroblasts from normal subjects and Graves' ophthalmopathy patients. Thyroid. 1999;9(3):297-303.
ISI
| PUBMED
33. Burch HB, Lahiri S, Bahn RS, Barnes S. Superoxide radical production stimulates retroocular fibroblast proliferation in Graves' ophthalmopathy. Exp Eye Res. 1997;65(2):311-316.
FULL TEXT
|
ISI
| PUBMED
34. Hiromatsu Y, Yang D, Miyake I; et al. Nicotinamide decreases cytokine-induced activation of orbital fibroblasts from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 1998;83(1):121-124.
FREE FULL TEXT
35. Bednarek J, Wysocki H, Sowinski J. Peripheral parameters of oxidative stress in patients with infiltrative Graves' ophthalmopathy treated with corticosteroids. Immunol Lett. 2004;93(2-3):227-232.
FULL TEXT
|
ISI
| PUBMED
36. Bouzas EA, Karadimas P, Mastorakos G, Koutras DA. Antioxidant agents in the treatment of Graves' ophthalmopathy. Am J Ophthalmol. 2000;129(5):618-622.
FULL TEXT
|
ISI
| PUBMED
37. Ludwig PW, Hoidal JR. Alterations in leukocyte oxidative metabolism in cigarette smokers. Am Rev Respir Dis. 1982;126(6):977-980.
ISI
| PUBMED
38. Marangon K, Herbeth B, Lecomte E; et al. Diet, antioxidant status, and smoking habits in French men. Am J Clin Nutr. 1998;67(2):231-239.
ABSTRACT
39. Wiersinga W, Prummel MF. Retrobulbar radiation in Graves' ophthalmopathy. J Clin Endocrinol Metab. 1995;80(2):345-347.
ISI
| PUBMED
40. Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: reality and perspectives. Endocr Rev. 2000;21(2):168-199.
FREE FULL TEXT
41. Bartalena L, Tanda ML, Piantanida E, Lai A. Oxidative stress and Graves' ophthalmopathy: in vitro studies and therapeutic implications. Biofactors. 2003;19(3-4):155-163.
ISI
| PUBMED
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