Topic: GRAVES- ORBITOPATHY
Title: Smoking and thyroid-associated ophthalmopathy: a novel explanation of the biological link.
Authors: Cawood TJ, Moriarty P, O- Farrelly C, & O-Shea D.
Reference: Journal of Clinical Endocrinology and Metabolism 92: 59-64, 2007
Cigarette smoking is the most important risk factor associated with the occurrence and/or progression of Graves- orbitopathy (GO).
The objective of this study was to assess in vitro whether cigarette smoke extract (CSE) affected the activity of orbital fibroblasts and differentiation of preadipocyte fibroblasts into adipocytes.
Material & Methods
Orbital fibroblasts obtained at surgery (for orbital decompression) for severe Graves- orbitopathy (GO) were exposed to different concentrations of CSE (4 cigarettes smoked through a 30 ml culture medium, giving a concentration of smoke-derived constituents 40 times higher than that contained in the blood of 20-cigarette/day smokers) and/or interleukin-1 (IL-1). Intercellular adhesion molecule-1 (ICAM-1) expression was measured by flow cytometry, and glycosaminoglycans (GAG) were assayed in culture medium. Degree of adipogenesis was also quantified.
CSE did not affect ICAM-1 expression, while it caused a marked increase in GAG production. Both CSE and IL-1 increased adipogenesis, their effect being synergistic. Adipogenesis could be inhibited to a large extent by the addition of anti-IL-1 antibody to the culture medium.
These studies show an in vitro mechanism whereby cigarette smoking can be linked to the occurrence and progression of GO.
Graves- orbitopathy (GO) derives from a complex interplay between poorly defined endogenous factors and better defined environmental factors. The latter, currently believed to play a major role in the occurrence of eye disease, include thyroid dysfunction per se , radioiodine therapy for hyperthyroidism, and most importantly, cigarette smoking. The prevalence of smokers is much higher in Graves- patients with associated GO than in those without GO. Smoking is associated with an increased risk of GO occurrence in Graves- disease. Smokers have a higher likelihood to develop more severe forms of GO. Smoking reduces the efficacy of glucocorticoids and orbital radiotherapy for moderate to severe GO. To refrain from smoking seems to decrease the risk of developing diplopia and proptosis, although controlled studies on this issue are lacking. The mechanisms whereby smoking may exert these effects on the eye are unclear. In addition to direct irritation effects of smoking, smoke-induced hypoxia and increased oxygen free-radical concentration in the retro-orbital space might lead to increased production and release of cytokines, which play a major role, at least in the maintenance of ongoing orbital immune reactions.
This study, using an interesting in vitro system, demonstrated that cigarette smoke extracts (CSE) stimulated orbital fibroblasts to produce glycosaminoglycans (GAG) which, in view of their hydrophilic properties, are important for the occurrence of mechanical expressions of eye disease, such as oedema, extra-ocular muscle swelling, and proptosis. In addition, CSE stimulated the differentiation and proliferation of adipocytes, another important feature of GO. Interestingly, this effect was synergistic with that exerted by IL-1, and could be abolished to a large extent by addition of anti-IL-1 antibody. On the one hand, this may suggest that cigarette smoking probably requires the pre-existence of inflammatory reactions in the orbit to express its deleterious potential for the orbitopathy. On the other hand, IL-1 might represent a future therapeutic target for the management of GO. The present in vitro study reinforces the concept, already based on multiple epidemiologic and clinical studies, that withdrawal of smoking is an important measure to adopt in patients with Graves- disease. Summary and commentary prepared by Luigi Bartalena ) Present summary and commentary are related to the Chapter N- 12 (Section 2) of TDM Full paper obtainable at http://jcem.endojournals.org/cgi/reprint/92/1/59