Pathogenesis of Graves’ ophthalmopathy




Clinical background


Graves’ disease (GD) was named for the Irish physician, Sir Robert James Graves (1797–1853), who first described the triad of hyperthyroidism, goiter, and exophthalmos. Graves’ hyperthyroidism is caused by targeting and stimulation of the G protein-coupled thyroid-stimulating hormone receptor (TSHR) by TSH receptor autoantibodies, leading to the overproduction of thyroid hormones ( Box 56.1 ). After the cloning of the TSHR in 1989, insight regarding pathogenesis of GD grew markedly. However, while recent strides have been made, the pathophysiology of Graves’ ophthalmopathy (GO) remains less well understood.



Box 56.1

Clinical background of Graves’ ophthalmology





  • Graves’ hyperthyroidism is caused by stimulation of thyroid-stimulating hormone (TSH) receptor by TSH receptor autoantibodies



  • Approximately 25–50% of patients with Graves’ disease have clinical eye involvement



  • The majority of Graves’ ophthalmology patients have an increase in both the orbital fat and extraocular muscle volumes




GD has an annual incidence in women of one per 1000 population; the annual incidence of GO in women is 16 in 100 000 and in men 3 in 100 000. Approximately 25–50% of patients with Graves’ hyperthyroidism have clinical eye involvement. A temporal relationship exists between the onset of Graves’ hyperthyroidism and the onset of GO. In 80% of affected patients, regardless of which condition occurs first, the other condition develops within 18 months.


GO patients characteristically display symptoms of a dry, gritty sensation in their eyes, blurry vision, photophobia, excessive tearing, diplopia, or a pressure sensation behind the eyes. The clinical signs of GO include ophthalmoplegia, lid lag, proptosis, chemosis, corneal ulceration, and conjunctival erythema ( Figure 56.1 ). Computed tomographic scans of the orbits in 90% of GD patients reveal characteristic orbital modifications indicating eye involvement, whether or not clinical signs are present. While the majority of GO patients have only mild congestive ocular symptomatology, in 3–5% severe eye disease is present, and compressive ischemic optic neuropathy with vision loss develops in the rare patient.




Figure 56.1


(A, B) Patients with severe Graves’ ophthalmopathy demonstrating proptosis, lid retraction, conjunctival erythema, and periorbital edema.


Although the majority of GO patients have an increase in both the orbital fat and extraocular muscle volumes, some exhibit primary involvement of only one of these tissue compartments. The age of the patient appears to influence the tissues involved as increased orbital fat is more commonly seen in patients younger than 40 years, and enlarged extraocular muscles predominate in patients over 70 years. In early disease stages, enlargement of the extraocular muscles is caused by edema and excessive accumulation of hyaluronic acid, leading to intermittent or inconstant diplopia. In later stages of the disease, the muscles may atrophy and become fibrotic due to the chronic inflammatory process, with resultant ocular malalignment and restrictive, constant diplopia.




Pathology


Histologic examination of orbital adipose and extraocular muscle tissues in GO shows an overabundance of complex carbohydrates termed glycosaminoglycans (GAGs), in which hyaluronic acid predominates. Orbital fibroblasts are the major source of these molecules and these cells are thought to be the autoimmune target in GO. In early stages of GO, muscle fibers are grossly intact, but are widely separated by edematous perimysial connective tissues resulting from accumulation of hydrophilic GAGs. Similarly, expansion of the orbital adipose tissue compartment is in part attributed to accumulation of GAGs. In addition, the expansion of orbital fat results from the differentiation of a population of preadipocytes within the orbit into mature lipid-laden adipocytes.


In addition to the excess of GAGs, histologic examination of orbital tissues in GO shows diffuse infiltration of lymphocytes. While these cells are predominantly T lymphocyte, occasional B cells are present as well. The existence of activated lymphocytes and cytokines in GO orbital tissues suggests that the disease is autoimmune in nature. The major cellular constituents are T lymphocytes showing an increase in both CD4+ and CD8+ cells, with a slight predominance of the latter. In early GO, cell-mediated T helper cell type 1 cells predominate and produce the cytokines interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-α (TNF-α). In more long-standing disease, T helper type 2 cells that participate in humoral responses are dominant and produce IL-4, IL-5, and IL-10. The resident macrophages and fibroblasts release additional inflammatory mediators including IL-1α, IL-6, IL-8, IL-16, tumor growth factor-β (TGF-ß), RANTES, and prostaglandin 2 (PGE 2 ). These inflammatory mediators and chemokines incite local inflammation and activate T-cell migration across primed endothelium ( Box 56.2 ). The stimulatory effects of proinflammatory cytokines result in high production of hyaluronan by orbital fibroblasts ; a 50% increase in hyaluronan production has been demonstrated in these cells following exposure to IFN-γ.



Box 56.2

Pathology of Graves’ ophthalmology





  • The expanded orbital fat compartment in Graves’ ophthalmology contains excess glycosaminoglycans and a diffuse infiltration of lymphocytes



  • Orbital fibroblasts produce glycosaminoglycans and a subset have the ability to differentiate into mature adipocytes



  • Orbital fibroblasts are thought to be the autoimmune target in Graves’ ophthalmology






Etiology


Genetic contributions


Several genes, including various human leukocyte antigen (HLA) alleles, cytotoxic T-lymphocyte antigen 4 (CTLA4), T-cell receptor (TCR) ß-chain, and immunoglobulin heavy chain, confer susceptibility to GD with low relative risk. However, while a number of candidate genes have been studied, including some HLA alleles, TNF-ß, CTLA4, and TSHR, none has been shown to be associated with the development of GO in patients with GD. This suggests that environmental factors may play a more significant role than genetic factors in the development of the ocular manifestations of GD.


Mechanical factors and trauma


The signs and symptoms of GO are attributable to mechanical pressures within the noncompliant, unyielding bony orbit owing to the presence of expanded orbital fat and increased extraocular muscle volume. The increased orbital tissue volume within the confines of the bony orbit leads to proptosis, or anterior displacement of the globe, which may be seen as a type of “natural” orbital decompression. The limited space for volume expansion within the bony orbit may impair venous and lymphatic outflow and result in chemosis and periorbital edema. Individual variations in the orbital contour or the vascular vessels may make some patients with GD more prone to the development of clinically significant GO.


The trauma delivered by orbital tissue expansion within a noncompliant bony orbit may aggravate the underlying inflammatory process. This could further stimulate release of proinflammatory cytokines and chemokines and lead to increased presentation of antigen within the orbit and augmentation of the autoimmune response.


Tobacco smoking


Smoking is the primary risk factor known for the development of GO in patients with GD. The odds ratio, relative to controls, has been reported to be as high as 20.2 for current smokers and 8.9 for ex-smokers, suggesting a direct and immediate effect of smoking. Smoking is highly associated with more severe GO with failure of immunosuppressive therapy, and with worsening of GO after radioiodine treatment.


Mechanisms underlying this association between smoking and GO are unclear. Smoking has been associated with other autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease, suggesting that the autoimmune process may be activated in smokers. However, circulating levels of cytokines do not appear to differ between smokers and nonsmokers, except for the presence of higher levels of IL-6 receptor in the former. Patients with both Graves’ hyperthyroidism and GO have higher levels of circulating IL-6 receptor than do hyperthyroid GD patients without clinical GO. In spite of this, there appears to be no difference in IL-6 receptor concentrations in the sera of smoking and nonsmoking GO patients. In vitro studies have demonstrated that orbital fibroblasts cultured under hypoxic conditions produce increased amounts of hyaluronic acid. In addition, exposure to cigarette smoke extract appears to stimulate both adipogenesis and secretion of hyaluronic acid by orbital fibroblasts.


Radioiodine therapy for Graves’ disease


Studies have suggested that treatment with radioiodine may worsen eye manifestations in patients with GD who have pre-existing, active GO. In one study, 443 patients with GO were prospectively treated with radioiodine, methimazole, or the combination of radioiodine and prednisone. The percentages of smokers and patients having GO at baseline in each group were comparable. Within 6 months of treatment, mild progression of ocular disease was seen in 15% of patients treated with radioiodine alone, in 2.7% of patients treated with methimazole, and in none of the patients treated with the combination of radioiodine and prednisone. Patients who experienced progression of ocular disease after receiving radioiodine were most commonly smokers and individuals having existing active GO. It appears that progression of GO owing to radioiodine therapy does occur in some patients. However, it is generally mild and can be prevented by concurrent administration of corticosteroids. Patients with pre-existing eye disease, or those who smoke or have severe thyrotoxicosis, appear to be more likely to experience this complication ( Box 56.3 ). In addition, ocular disease progression was not seen in another study in which postradioiodine hypothyroidism was prevented, suggesting that hypothyroidism itself might play a role and should be avoided. Mechanisms responsible for ocular disease progression following radioiodine are unclear but might include increased TSHR autoantibody production, release of autoantigen from the thyroid, or destruction of radiosensitive suppressor T cells within the thyroid.



Box 56.3

Etiology of Grave’s ophthalmology (GO)





  • Environmental factors may play a more significant role than genetic factors in the development of GO



  • Individual variations in orbital contour or vasculature may make some patients with Graves’ disease more prone to the development of clinically significant GO



  • Smoking is the primary known risk factor for GO and is highly associated with more severe GO, with failure of immunosuppressive therapy, and with worsening of GO after radioiodine therapy






Pathophysiology


Orbital fibroblasts


Orbital fibroblasts are phenotypically heterogeneous multipotent cells that can be divided into subpopulations even within a single tissue. These subpopulations are distinguishable on the basis of the cell surface marker Thy-1. A minority of fibroblasts originating from the orbital adipose/connective tissue compartment do not express this antigen (Thy-1 ) and are “preadipocyte fibroblasts” capable of differentiating into adipocytes in the presence of PPAR-γ agonist ( Figure 56.2 ). In contrast, perimysial fibroblasts uniformly express Thy-1 (Thy-1+) and lack the ability to undergo adipogenesis. Differences in orbital fibroblast phenotype and the distribution of these cells with orbital compartments may help to explain why some GO patients have predominant eye muscle disease while others have increased orbital adipose tissue volume as the predominant feature.




Figure 56.2


Cultured orbital fibroblasts following 10-day exposure to the PPAR-γ agonist rosiglitazone. Adipogenesis is evidenced by oil red O staining of a mature adipocyte.


Orbital fibroblasts from patients with GO appear to display amplified responses to proinflammatory cytokines compared with fibroblasts from other anatomic sites. For example, while orbital fibroblasts treated with IFN-γ or leukoregulin produce high levels of hyaluronic acid, dermal fibroblasts are only modestly stimulated by these same factors. In addition, orbital fibroblasts are capable of initiating lymphocyte recruitment via their secretion of proinflammatory cytokines which, in turn, stimulate the production of chemoattractant molecules by T cells. Two such molecules, IL-16 and RANTES, account for more than 90% of T lymphocyte migration initiated by orbital fibroblasts. This suggests that these two chemoattractants act as important molecular triggers within the orbit, directing lymphocytes to areas of tissue injury and repair. Other cytokine-induced responses with potential relevance to GO include the inhibition of adipogenesis in orbital fibroblasts by TGF-ß, IFN-γ, and TNF-α, and its promotion by IL-6. Orbital fibroblasts not only respond to cytokines, but also produce cytokines, including IL-1, IL-6, and IL-8, as well as prostaglandins, in response to ligation of their CD40 receptors by CD154 on T cells ( Box 56.4 ).



Box 56.4

Pathophysiology of Graves’ ophthalmology (GO)





  • GO orbital fibroblasts display amplified responses to proinflammatory cytokines



  • GO orbital fibroblasts are capable of initiating lymphocyte recruitment through their secretion of proinflammatory cytokines



  • Cytokine-induced responses with potential relevance to GO include the inhibition of adipogenesis in orbital fibroblasts by transforming growth factor-β, interferon-γ, and tumor necrosis factor-α and its promotion by interleukin-6




Orbital autoantibodies


TSHR autoantibodies


It is well accepted that autoantibodies directed against the thyroidal TSHR (TRAb) are responsible for Graves’ hyperthyroidism. Due to the close clinical and temporal associations between Graves’ hyperthyroidism and GO, it has been hypothesized that TRAb directed against TSHR expressed in the orbit may underlie the pathogenesis of GO. Indeed, the occurrence of GO is greatest in GD patients with the highest levels of circulating TRAbs, and the clinical activity of the disease correlates with serum levels of these autoantibodies.


A qualifying requirement to link TRAbs to the pathogenesis of GO is that the TSHR be expressed in orbital tissues. Recent studies have shown this to be the case as TSHR mRNA and protein have been demonstrated both in GO orbital adipose tissue and in normal orbital adipose tissue specimens. Further, TSHR expression levels are higher in orbital fat tissues from GO patients than in those from normal individuals. Additional support for this hypothesis lies in the positive correlation found between patients’ clinical activity scores and TSHR mRNA levels measured in their orbital tissues removed during decompression surgery.


Studies in vitro show that orbital preadipocyte fibroblasts can be induced to differentiate into mature adipocytes, and in doing so increase their expression of TSHR. When cultured in the presence in adipogenic PPAR-γ agonists, levels of TSHR mRNA, as well as mRNA encoding various adipocyte-associated genes, increase roughly 10-fold in these cells. Studies of uncultured orbital fat specimens obtained from GO patients also show high levels of these genes compared with normal orbital fat specimens, suggesting that adipogenesis is increased within the orbit in GO. Whether this is directly caused by TRAb targeting TSHR on these cells is an area of active investigation.


Gene array studies comparing GO and normal orbital adipose tissues also reveal increased expression of adipocyte-related genes in GO tissues. In addition, these studies demonstrate high expression of secreted frizzled-related protein-1 (sFRP-1), a known inhibitor of wingless type (Wnt) signaling ( Box 56.5 ). As active Wnt signaling inhibits adipogenesis, it is possible that sFRP-1 acts within the GO orbit to turn off this signaling system and thereby stimulate adipogenesis within these tissues.


Aug 26, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Pathogenesis of Graves’ ophthalmopathy

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