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Transcript
CONFERENCIAS versus hydrocortisone treatment in late-onset adrenal hyperplasia. J Clin Endocrinol Metab. 1990; 70:642-6. 34. Feldman, S.; Billaud, L.; Thalabard, J.C.; Raux- G R AV E S ’ O P H T H A L M O PAT H Y Armin E. Heufelder Division of Endocrinology, The Eliscourt Clinical Center and Medical Faculty, Technical University of Munich, Germany Graves’ ophthalmopathy (GO) results from a complex interplay of genetic, immunological, hormonal and environmental factors. Various genes, including those coding for HLA, may determine a patient’s susceptibility to the disease and its severity, but in addition, environmental factors such as stress and smoking may determine its course. Once established, the inflammatory process within the orbital tissues takes on a momentum of its own. Based on the current state of knowledge, the following working scheme for the pathogenesis of GO is proposed: Against the background of a permissive immunogenetic milieu, macrophages and dendritic cells appear to initiate the immune process in a nonspecific manner by reacting to an environmental (e.g. microbial) insult. These cells can efficiently take up antigen, travel to regional lymphoid tissues and present antigenic peptides to T cells, thereby sensitizing T and B cells to proliferate, to expand in an antigen-specific manner, and to recirculate, ready to release abundant quantities of chemokines (RANTES) and proinflammatory cytokines (IL-1, TNFalpha, IFNgamma). These compounds facilitate upregulation of various adhesion- and co-stimulatory molecules, which act to prepare the orbital microvascular endothelium for recruitment and efflux of circulating T cells that carry a restricted repertoire of V genes and have been primed to cross-react between intrathyroidal and orbital antigenic epitopes. Infiltration of T cells into orbital connective tissue and extraocular muscle is perpetuated by preadipocytes and fibroblasts, which act as target and effector cells of the orbital immune process. This includes preadipocyte fibroblasts present 15 Demay, M.C.; Mowszowicz, I.; Kuttenn, F.; Mauvais-Jarvis, P. Fertility in women with lateonset adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992; 74:635-9. in the perimysium of extraocular muscles, which do not appear to be immunologically or metabolically different from those located in the orbital connective tissue. Differentiation of preadipocytes into adipocytes is mediated, at least in part, by nuclear transcription factors (PPARs, NFκB) and accompanied by increased expression of the TSH receptor, which appears to facilitate the orbital immune process and its consequences, stimulation of adipogenesis and accumulation of hydrophilic glycosaminoglycans (GAG). Both endogenous (high TSH receptor antibodies) and exogenous factors (e.g. smoking) may act as amplifiers in this process. Once adipogenesis and GAG deposition have exceeded a critical stage, mechanical complications may occur within the confines of the bony orbits, resulting in impairment of arterial blood supply and venous drainage, tissue hypoxia, oxidative tissue injury, extraocular muscle dysfunction and optic nerve compromize. Unless relieved early and efficiently by spontaneous autodecompression or therapeutic interventions such as immunomodulatory measures or surgical decompression, permanent tissue changes will ensue, causing restriction of extraocular muscles, connective tissue fibrosis and optic nerve damage. Clinically, close follow-up in all patients with Graves’ disease and early recognition of GO are mandatory. Much emphasis should be placed on preventing GO by early identification of patients with Graves’ disease who are at high risk of GO. Once active progressive GO has been documented, conventional therapy (oral or intravenous glucocorticosteroids, surgical decompression of the orbits, radiotherapy) should be administered early on to arrest orbital inflammation in its earliest stages before irreversible changes have occurred. Novel therapeutic approaches such as long-acting octreotide, antioxidants, methotrexate, biologicals or B-cell directed strategies are now under study to assess their role in the treatment of GO.