Elsevier

Clinical Biochemistry

Volume 38, Issue 1, January 2005, Pages 13-18
Clinical Biochemistry

Oxidative stress peripheral parameters in Graves' disease: the effect of methimazole treatment in patients with and without infiltrative ophthalmopathy

https://doi.org/10.1016/j.clinbiochem.2004.09.015Get rights and content

Abstract

Objectives:

The study was designed to estimate the influence of hyperthyroidism and antithyroid treatment on oxidative stress peripheral parameters in Graves' disease patients with and without infiltrative ophthalmopathy.

Design and methods:

Free radical generation and scavenging plasma indices were determined in 47 patients with hyperthyroidism due to Graves' disease (22 with and 25 without infiltrative ophthalmopathy), as well as in 24 healthy volunteers after euthyroidism achievement with methimazole.

Results:

In the hyperthyroid patients, hydrogen peroxide, lipid hydroperoxides, thiobarbituric acid-reacting substances, ceruloplasmin, superoxide dismutase, and catalase were increased. Glutathione peroxidase and glutathione reductase, however, were reduced. Methimazole treatment resulted in all markers being normalized in the patients without infiltrative ophthalmopathy, yet oxidative stress was still present in the ophthalmopathy group.

Conclusion:

We suggest that apart from the thyroid metabolic status influence, it is orbital inflammation that triggers changes in blood extracellular indices of reactive oxygen species metabolism.

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.

Section snippets

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).

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