Clinical implications of somatostatin-receptor scintigraphy in ophthalmic Graves' disease.

Abstract

The eye complications associated most typically withhyperthyroidism caused by Graves’ disease range fromdiscomfort and lid retraction to disfiguring proptosis,diplopia and sight loss (1, 2). Usually called Graves’ophthalmopathy, this condition is better termedthyroid-associated ophthalmopathy (TAO), emphasis-ing the wide spectrum of thyroid disorders in thesepatients. TAO is one of the most difficult autoimmunedisorders to investigate; it is characterised by enlarge-ment of the extraocular muscles and an increase inthe retrobulbar fat, which cause eye proptosis, themain clinical manifestation of the disease (Table 1).Involvement of the cornea, the optic nerve and orbitalsoft tissues may occur during the natural course ofthe disease (3).An exact in vivo characterisation of the underlyingpatho-physiological mechanism of TAO has remaineddifficult because the affected retrobulbar space is noteasily accessible. The identification of patients withGraves’ ophthalmopathy is based primarily on clinicalsigns and symptoms affecting one or both eyes (4).Additional information can be obtained from conven-tional imaging methods such as magnetic resonanceimaging (MRI) or computed tomography (CT), whichallow gross changes in the retrobulbar space (e.g.muscle swelling, oedema or fibrosis) to be recognised(1, 2). By using histology, orbital infiltration withactivated T lymphocytes and evidence of local release ofcytokines and interactions of lymphocytes with retro-bulbar fibroblasts have been demonstrated, suggestingthat TAO is an organ-specific autoimmune disease (1,2, 5, 6). Although it is accepted that the pathogenesisof TAO is almost certainly multifactorial, the triggerevent seems to be the activation of T cells directedagainst a thyroid follicular cell antigen(s) that thenrecognise and bind to a similar antigen(s) in orbitaltissue (1, 2, 6). Thereafter, these activated orbital T cellsrelease a variety of substances and stimulate excessiveproduction of glycosaminoglycans and collagen byorbital fibroblasts. This causes the inflammatory andoedematous changes of thyroid ophthalmopathy (7). Infact, during the early stages of the disease, macro-phages, highly specialised T cells, mast cells and,occasionally, plasma cells infiltrate the orbital connec-tive, adipose and muscle tissue. Several cytokines, suchas interferon-g, tumour necrosis factor-a, interleukin-1 and transforming growth factor-b, as well as growthfactors, such as insulin-like growth factor-I (IGF-I) andplatelet-derived growth factor, have been detectedwithin the orbital tissues (5–8). All these substancesare probably produced both by infiltrating immuno-competent cells and by residential fibroblasts, adipo-cytes, myocytes and microvascular endothelial cells(9). Cytokines and growth factors stimulate cellproliferation, glycosaminoglycan synthesis and expres-sion of immunomodulatory molecules in orbitalfibroblasts and microvascular endothelial cells (Table2).No consensus exists regarding the common anti-gen in the orbit and thyroid, the thyrotrophin(thyroid-stimulating hormone, TSH) receptor or avariant, or on the role of circulating antibodiesagainst extraocular muscle and fibroblast compo-nents. The finding of expression of the TSH receptorin retro-orbital tissue may provide the link, pre-viously lacking, between orbital involvement andthyroid disease in Graves’ disease. Thyroid-stimulat-ing antibodies directed against the TSH receptorcould interact with the orbital components thatexpress the receptor, thus stimulating glycosamino-glycans, cellular matrix proteins and connectivetissue production and bringing about antibody-dependent cell-mediated cytotoxicity mediated bynatural killer cells. On the other hand, T cells thatreact with the TSH receptor will be targeted to theorbit where, in the presence of the antigen, they willsecrete various cytokines that stimulate fibroblasts toproliferate, to express the major complex of histo-compatibility class II antigens and to synthesizecollagen and connective tissue (10).