Oxidative stress peripheral parameters in Graves' disease: the effect of methimazole treatment in patients with and without infiltrative ophthalmopathy
Introduction
Graves' disease is an autoimmune disorder of the thyroid gland characterized by production of TSH receptor-stimulating autoantibodies [1], resulting in hyperthyroidism. Infiltrative ophthalmopathy, present in 3–5% of Graves' patients, is considered to be an inflammatory disorder that has an autoimmune background [2]. The autoimmune process is induced presumably due to the sharing of antigenic epitopes (e.g., TSH receptor [3]) by thyroid and retroocular tissues [4]. Activated T lymphocytes stimulate proliferation of orbital fibroblasts as well as synthesis of glycosaminoglycans via a cytokine network [5], which leads to extraocular muscle enlargement and clinically overt ophthalmopathy development. Later on, inflammatory changes typical of an active phase are replaced by fibrotic lesions (an inactive phase) [6].
Thyroid hormones accelerate the basal metabolic rate and oxidative metabolism by mitochondrial enzyme induction. Hyperthyroidism enhances reactive oxygen species (ROS) generation and produces changes in various tissue antioxidant systems, which participate in the development of hyperthyroidism-induced tissue damage [7], [8]. On the other hand, there is growing evidence that oxidative stress plays an important role in the pathogenesis of autoimmune disorders [9]. Experimental data suggest that the presence of oxidative stress and initiation of the immune response in Graves' disease may be closely related [10]. So far only a few experimental studies have documented ROS involvement in the pathogenesis of the infiltrative eye changes in Graves' disease. Burch et al. [11] showed anti-TSH receptor antibodies reacted with superoxide dismutase (SOD) in orbital fibroblasts, which revealed a homologous fragment with the TSH receptor. They proved that there was a higher prevalence of anti-SOD antibodies in Graves' patients compared to controls. An observation that appears particularly interesting is that ROS stimulate proliferation of retroocular fibroblasts from patients with Graves' ophthalmopathy, which would otherwise be inhibited by methimazole [12]. Thyrostatics also inhibit ROS-induced expression of a 72-kDa heat shock protein in Graves' retroocular fibroblasts [13]. However, little is known about peripheral ROS metabolism in patients with Graves' ophthalmopathy. In clinical practice, it is very difficult and complex to analyze parameters involved in the pathological process of retroorbital tissues. Thus, identifying the orbital inflammation peripheral markers in Graves' patients could give a valuable tool for diagnosis and follow-up of immunosuppressive treatment. The aim of the study was to determine the influence of hyperthyroidism and methimazole treatment on blood extracellular indices of ROS generation and free radical scavenging in patients with Graves' disease, with and without infiltrative ophthalmopathy.
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Subjects
The study was performed on three groups of subjects. Group A was comprised of 22 patients (15 females and 7 males, aged 48.4 ± 10.3, mean ± SD) with newly diagnosed and untreated hyperthyroidism due to Graves' disease, which had manifested in untreated, advanced eye changes in classes 3b–5 according to the American Thyroid Association (ATA) classification [14] for no longer than 3 months (an ophthalmopathy group). These individuals revealed high values (≥4) of a Clinical Activity Score (4.9 ±
Results
The fT4, fT3, and TSH concentrations were within the normal population range for the control subjects. In all hyperthyroid patients before therapy, the fT4 and fT3 levels were significantly higher and the TSH level was significantly lower in comparison to the controls (Table 1). Achievement of stable euthyroidism during methimazole treatment was confirmed by normalization of fT4, fT3, and TSH concentrations.
The changes of free radical activity markers are shown in Table 2. H2O2, ROOH and TBARS
Discussion
It is well known that oxidative stress with subsequent antioxidant defense mobilization is present at sites of inflammation [22]. Local inflammatory processes may also influence peripheral blood markers of ROS metabolism [23], [24], [25], [26], [27], [28]. The present work proves the difference of oxidative stress peripheral parameters in Graves' disease patients with and without infiltrative ophthalmopathy, after having achieved normalization of elevated thyroid hormone levels by methimazole
Acknowledgment
This study was supported by a grant obtained from the Polish Scientific Research Committee (No. 4 PO5B 073 18).
References (43)
- et al.
Diagnostic evaluation of Graves' ophthalmopathy
Endocrinol. Metab. Clin. North Am.
(1988) - et al.
Thyroid-associated ophthalmopathy: pathogenesis and clinical management
Baillière's Clin. Endocrinol. Metab.
(1995) - et al.
Superoxide radical production stimulates retroocular fibroblast proliferation in Graves' ophthalmopathy
Exp. Eye Res.
(1997) - et al.
Microsomal lipid peroxidation
Methods Enzymol.
(1978) - et al.
Measurement of plasma hydroperoxide concentrations by the ferrous oxidation-xylenol orange assay in conjunction with triphenylphosphine
Anal. Biochem.
(1994) - et al.
Protection of phagocytic leukocytes by endogenous glutathione: studies in a family with glutathione reductase deficiency
Blood
(1979) A simple method for determination of serum catalase activity and revision of reference range
Clin. Chim. Acta
(1991)- et al.
Role of free radicals in human disease: an overview
Methods Enzymol.
(1990) - et al.
The evaluation of autoantibodies against oxidatively modified low-density lipoprotein (LDL), susceptibility of LDL to oxidation, serum lipids and lipid hydroperoxide levels, total antioxidant status, antioxidant enzyme activities, and endothelial dysfunction in patients with Behcet's disease
Clin. Biochem.
(2002) - et al.
Effect of corticosteroids and eicosapentaenoic acid/docosahexaenoic acid on pro-oxidant and anti-oxidant status and metabolism of essential fatty acids in patients with glomerular disorders
Prostaglandins Leukot. Essent. Fat. Acids
(2001)
Free radical activity and antioxidant defense mechanisms in patients with hyperthyroidism due to Graves' disease during therapy
Clin. Chim. Acta
Lipid peroxidation in erythrocytes
Chem. Phys. Lipids
Antioxidant status in experimental hyperthyroidism: effect of vitamin E supplementation
Clin. Chim. Acta
Comparative study of superoxide dismutase activity, catalase and glutathione peroxidase levels in erythrocytes of different animals
Biochem. Biophys. Res. Commun.
The effect of methimazole on the oxidant and antioxidant system in patients with hyperthyroidism
Pharmacol. Res.
Ceruloplasmin and vitamin E levels in toxic multinodular goiter
Nutrition Res.
Role of the immune system in the control of the thyroid function
Thyrotropin receptor expression in Graves' orbital adipose/connective tissues: potential autoantigen in Graves' ophthalmopathy
J. Clin. Endocrinol. Metab.
Stimulation of glycosaminoglycan production in cultured human retroocular fibroblasts
Invest. Ophthalmol. Visual Sci.
Pathogenesis of Graves' ophthalmopathy
N. Engl. J. Med.
Superoxide radical generation, NADPH oxidase activity and cytochrome P-450 content of rat liver microsomal fractions in an experimental hyperthyroid state: relation to lipid peroxidation
Endocrinology
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