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

Giulia Lanzolla,Federica Sileo,Ilaria Ionni,Guia Vannucchi,Irene Campi,Elisa Lazzaroni,Michele Marinò

doi:10.3389/fendo.2019.00933

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.

Highlights

Graves’ orbitopathy (GO) is a disfiguring syndrome observed in patients with autoimmune thyroid diseases, especially Graves’ disease (GD)
Inhibition of HMG-CoA leads to leak of cathepsin B (CATH-B) and L (CATH-L) from lysosomes, thereby enhancing apoptosis [67], and inducing the autophagy flux. These findings suggest that statins influence autophagic events acting on the coregulation of apoptosis and unfolded protein response (UPR) [67]
The studies available so fare are quite few, no randomized clinical trial are available, because of which the role of statins, and of cholesterol in Graves’ Orbitopathy (GO) must be considered still preliminary. Both basic and clinical findings regarding the effects of statins on GO are encouraging and deserve to be better investigated

Summary

INTRODUCTION

Graves’ orbitopathy (GO) is a disfiguring syndrome observed in patients with autoimmune thyroid diseases, especially Graves’ disease (GD). Autophagy may influence the differentiation of OFs into mature adipocytes [69], and the early autophagic flux can trigger the cell death-cascade in several cell types, including fibroblasts and monocytoid cells [70] Based on these assumptions, the association between statin treatment and an altered autophagy due to a severe reduction of protein prenylation, reflecting blocking of the mevalonate pathway, may be a potential explanation for their protective effect on GO. These data suggest the possibility that cholesterol is a possible GO risk factor, and that it may be associated with more active forms of the eye disease In confirmation of these data, in a recent retrospective study, it was reported that patients with GO had higher LDL-cholesterol and total cholesterol compared with patients affected with GD without GO.

STRENGTHS AND LIMITATIONS

Findings

CONCLUSIONS