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CONFERENCIAS
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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
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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.