Cholesterol Serum Levels and Use of Statins in Graves' Orbitopathy: A New Starting Point for the Therapy

Abstract

Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO.

Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves’ Ophthalmopathy to Parenteral Corticosteroids

“…Elevated LDLc levels have been hypothesized to increase the influx of free fatty acids into the liver causing the production of reactive oxygen radical species (ROS) and the secretion of interleukin-6 (IL-6). The increase in IL-6 activity within the orbital environment can promote greater secretion of insulin growth factor 1 (IGF-1) by orbital fibroblasts of GO patients and improve the proliferation of fibroblasts and the expansion of soft orbital tissues favoring IGF-1R -TSHR crosstalk (8,(27)(28)(29). These studies raise the need to investigate the impact of LDLc levels on the GO response to immunosuppressive therapy.…”

Oxidative Stress in Graves Disease and Graves Orbitopathy

“…Although GD affects primarily the thyroid, extrathyroidal manifestations, i.e., Graves orbitopathy (GO), pretibial myxoedema, and acropachy [2][3][4][5], can be observed. Graves hyperthyroidism (GH) is due to autoantibodies against the thyroid-stimulating hormone receptor (TSH-R), which bind to the TSH-R, leading to thyrocyte proliferation and hyperfunction [6]. However, the etiopathogenesis is likely multifactorial, and the complex pathogenetic interplay includes, among others, oxidative stress [4,6].…”

“…Graves hyperthyroidism (GH) is due to autoantibodies against the thyroid-stimulating hormone receptor (TSH-R), which bind to the TSH-R, leading to thyrocyte proliferation and hyperfunction [6]. However, the etiopathogenesis is likely multifactorial, and the complex pathogenetic interplay includes, among others, oxidative stress [4,6].…”

“…The pathogenesis of GO is autoimmune due to both humoral and cellular immunity against the TSH-R and possibly other autoantigens expressed by thyrocytes and orbital fibroblasts (OFs). The ultimate pathogenetic mechanisms are not completely clear, but the most popular hypothesis is that autoreactive T lymphocytes infiltrate orbital tissues, triggering, together with autoantibodies, the release of inflammatory agents, including chemokines, cytokines, growth factors, and oxygen reactive species, resulting in fibroblast proliferation, differentiation into adipocytes, and enhanced release of glycosami-Eur Thyroid J 2020;9(suppl 1):40-50 DOI: 10.1159/000509615 noglycans, especially hyaluronic acid (HA) [1,6]. The process ultimately results in orbital fat expansion and extraocular muscle enlargement, the orbital remodeling typical of GO.…”

“…In this regard, a number of antioxidant agents, among which are selenium and selenoproteins, have been proposed to have a therapeutic action. In addition, statins (3-hydroxy-3-methylglutarylcoenzyme reductase inhibitors), because of their anti-oxidative actions, might also be considered for GO treatment [6].…”