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Pathogenesis and clinical features of Graves' ophthalmopathy (orbitopathy)

Terry F Davies, MD, FRCP, FACE
Section Editor
Douglas S Ross, MD
Deputy Editor
Jean E Mulder, MD


The eye disease often associated with Graves' thyroid disease is referred to as Graves' ophthalmopathy. However, it is primarily a disease of the orbit and is better called Graves' orbitopathy. This topic review will provide an overview of the pathogenesis and clinical features of Graves' ophthalmopathy, which is an autoimmune disease of the retroorbital tissues. Treatment of this disorder is discussed separately. (See "Treatment of Graves' orbitopathy (ophthalmopathy)".)


The pathogenesis of Graves' ophthalmopathy is becoming more clearly understood. The volume of both the extraocular muscles and retroorbital connective and adipose tissue is increased, due to cellular proliferation, inflammation, and the accumulation of hydrophilic glycosaminoglycans (GAG), principally hyaluronic acid, in these tissues [1,2]. GAG secretion by fibroblasts is increased by thyroid-stimulating antibodies and activated T cell cytokines such as tumor necrosis factor (TNF) alpha and interferon gamma, implying that both B and T cell activation are important parts of this immunopathology. The accumulation of GAG causes a change in osmotic pressure, which in turn leads to a fluid accumulation, muscle swelling, and an increase in pressure within the orbit. These changes, together with retroorbital adipogenesis, displace the eyeball forward and can also interfere with the function of the extraocular muscles and the venous drainage of the orbits (figure 1 and image 1).

On histologic examination, the extraocular muscles are swollen, and some muscle fibers show loss of striation, fragmentation, and infiltration with lymphocytes, most of which are T lymphocytes (picture 1). The following observations suggest that these T cells may play a central role in the development of ophthalmopathy [3-5]:

In vitro studies of retroorbital tissue from patients with Graves' ophthalmopathy have shown that the infiltrating T cells are activated by retroorbital tissue fractions.

Retroorbital fibroblasts secrete GAG in response to cytokines such as interferon gamma and TNF alpha secreted by helper (CD4+) T cells of the Th1 type.

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Literature review current through: Nov 2017. | This topic last updated: Dec 18, 2015.
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