Graves' ophthalmopathy

Abstract

Graves’ ophthalmopathy, also called Graves’ orbitopathy, is a potentially sight-threatening ocular disease that has puzzled physicians and scientists for nearly two centuries.^– Generally occurring in patients with hyperthyroidism or a history of hyperthyroidism due to Graves’ disease, Graves’ ophthalmopathy is also known as thyroid-associated ophthalmopathy or thyroid eye disease, because it sometimes occurs in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis. The condition has an annual adjusted incidence rate of 16 women and 3 men per 100,000 population.

This review explores the perplexing relationship between Graves’ ophthalmopathy, hyperthyroidism, and thyroid dermopathy, the associated skin condition. I examine clinical features, histologic findings, and laboratory studies, with an emphasis on mechanisms that could be targeted in the development of new treatments for this debilitating disease.

Figure 1. Patients with Graves’ Ophthalmopathy

Panel A shows a 59-year-old woman with excess proptosis, moderate eyelid edema, and erythema with moderate eyelid retraction affecting all four eyelids. Conjunctival chemosis (edema) and erythema with bilateral edema of the caruncles, with prolapse of the right caruncle, are evident. Panel B shows a 40-yearold woman with excess proptosis, minimal bilateral injection, and chemosis with slight erythema of the eyelids. She also had evidence, on slit-lamp examination, of moderate superior limbic keratoconjunctivitis.

Figure 2. Computed Tomographic Scans of Patients with Graves’ Ophthalmopathy and of a Normal Subject

Axial images of patients with Graves’ ophthalmopathy reveal generalized enlargement of the extraocular muscles with marked bilateral proptosis (Panel A) and marked bilateral proptosis and asymmetric involvement of the extraocular muscles with expansion of the orbital fat bilaterally (Panel B). Normal orbits are shown (Panel C) for comparison.

Figure 3. Histologic Appearance of Extraocular Muscle in Graves’ Ophthalmopathy (Hematoxylin and Eosin)

The focal and perivascular interstitial inflammatory mononuclear cell infiltrate is in close association with intact striated extraocular muscle fibers widely separated by amorphous granular material.

Figure 4. Model of the Initiation of Thyrotropin-Receptor Autoimmunity in Graves’ Ophthalmopathy and Its Consequences

A failure of T cells to tolerate the thyrotropin receptor, for unknown reasons, allows for the development of autoimmunity directed against this receptor. The thyrotropin receptor is internalized and degraded by antigen-presenting cells that present thyrotropin-receptor peptides, in association with major histocompatibility complex (MHC) class II antigens, to helper T cells. These cells become activated, interact with autoreactive B cells through CD154–CD40 bridges, and secrete interleukin-2 and interferon-γ. These cytokines induce the differentiation of B cells into plasma cells that secrete anti–thyrotropin-receptor antibodies. These antibodies stimulate the thyrotropin receptor on thyroid follicular epithelial cells, leading to hyperplasia and increased production of the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄). Anti-thyrotropin-receptor antibodies also recognize the thyrotropin receptor on orbital fibroblasts and, in conjunction with the secreted type 1 helper T cytokines interferon-γ and tumor necrosis factor (TNF), initiate the tissue changes characteristic of Graves’ ophthalmopathy.

Figure 5. Model of Interactions between Orbital Fibroblasts and the Autoimmune Process Leading to the Tissue Changes Characteristic of Graves’ Ophthalmopathy

When activated by anti–thyrotropin-receptor antibodies, a subgroup of orbital fibroblasts (termed preadipocytes) begins to differentiate into adipocytes with increased thyrotropin-receptor expression, while others bearing the antigen Thy-1 are stimulated by cytokines, including interferon-γ and tumor necrosis factor (TNF), to increase their production of hyaluronan. Similarly, stimulation of the insulin-like growth factor receptor (IGF-I receptor) expressed on orbital fibroblasts results in the secretion of the chemokines interleukin-16 and RANTES (regulated upon activation normal T-cell expressed and secreted), which enhance recruitment of activated T cells and other mononuclear immune cells into the orbit. The expression of CD154 in T cells allows for their direct interaction with orbital fibroblasts through the formation of CD40–CD154 bridges, resulting in fibroblast production of interleukin-1. Activated type 1 helper T cells in patients with early Graves’ ophthalmopathy produce interferon-γ and TNF, and resident macrophages secrete interleukin-1. These cytokines stimulate orbital fibroblasts to produce high levels of prostaglandin E₂ and hydrophilic hyaluronan that accumulates between the intact extraocular muscle fibers and within the orbital adipose tissues to enlarge the volume of these tissues. Activated T cells in patients with Graves’ ophthalmopathy also produce proadipogenic prostaglandins that stimulate preadipocytes to differentiate into mature fat cells, further expanding the tissue volume. Adipocytes and fibroblasts produce interleukin-6, which augments B-cell maturation and increases the production of anti–thyrotropin-receptor antibodies by plasma cells within the orbit. Orbital fibroblasts also produce transforming growth factor β (TGF-β), which stimulates both production of hyaluronan and differentiation of the Thy-1+ subgroup into myofibroblasts that participate in the development of fibrosis, especially in late stages of the disease.