Highlights of the 74th Annual Meeting of the American Thyroid Association

Kenneth D. Burman, MD


February 05, 2003

In This Article

Graves' Ophthalmopathy

Graves' ophthalmopathy refers to a variety of ophthalmic signs or symptoms typically associated with autoimmune thyroid disease. The term "Graves' ophthalmopathy" is misleading because a patient with these eye manifestations does not necessarily have Graves' disease. A patient may have clinical hyperthyroidism or, more rarely, even hypothyroidism. Sometimes, the patient never manifests thyroid dysfunction, or the type of thyroid function will evolve and change over time. I think it is more appropriate to conceptualize the ophthalmic problems as being related to an underlying autoimmune problem and to recognize that the clinical manifestations on the thyroid gland may vary. The ophthalmopathy may manifest as minor symptoms such as grittiness or discomfort, or as more severe manifestations such as severe inflammation of the cornea and/or extraocular muscles, diplopia, proptosis, or even impairment of visual acuity.

The etiology of Graves' ophthalmopathy is not clearly defined, but it is currently believed that autoantibodies directed at the thyroid gland may be capable of binding to orbital tissues. The prime candidates for mediating this process are thyroid-stimulating hormone (TSH) receptor antibodies that bind to TSH receptors in the thyroid gland and then stimulate thyroid hormone synthesis, resulting in hyperthyroidism. It has recently been demonstrated that a subset of TSH receptor autoantibodies can bind to orbital fat and, perhaps, extraocular muscles, and may lead to stimulation of the orbital adipocytes with resultant proliferation and secretion of substances such as glycosaminoglycans. This process leads to a vicious cycle of further stimulation and can result in the clinical manifestations noted.

Several abstracts and papers presented at the 74th Annual Meeting of the American Thyroid Association focused on the mechanisms of the development or progression of Graves' ophthalmopathy.

Lisi and colleagues[1] confirmed the presence of thyroglobulin in orbital tissues and showed that thyroglobulin binds to orbital tissues in patients with thyroid-associated ophthalmopathy. Thyroglobulin is made only by the thyroid gland, and it has been speculated that thyroglobulin may also play a role in Graves' ophthalmopathy. The issue of whether thyroglobulin actually was present in orbital tissue has been debated for decades. The abstract by Lisi and colleagues suggests that orbital thyroglobulin may bind to glycosaminoglycan, but whether this binding mediates further orbital processes is unknown.

Plicht and colleagues[2] noted that autoimmune thyroid disease is associated with the presence of a variety of autoantibodies directed against the TSH receptor, thyroid peroxidase, and thyroglobulin. They studied the clinical relationship between the presence of these autoantibodies and the development and progression of ophthalmopathy. There was a positive relationship between the presence of TSH receptor antibodies and the severity of Graves' ophthalmopathy, and the response to anti-inflammatory therapy correlated with the change in TSH receptor antibody titer. By contrast, there was a negative association between thyroid peroxidase and thyroglobulin antibodies with ophthalmopathy severity. These studies are clinical in nature, and extrapolation to pathophysiologic events is difficult. Further, correlation does not prove causation. Nonetheless, these data do suggest a role for TSH receptor antibodies in mediating Graves' ophthalmopathy.

Kahaly and colleagues[3] studied the possible role of alpha-fodrin in mediating orbital disease. Alpha-fodrin is an intracellular organ-specific cytoskeletal protein that is now known to be an autoantigen for Sjogren's and sicca syndrome. Kahaly and colleagues detected IgA alpha-fodrin autoantibodies in less than 1% of normal blood donors and in 22% of patients with Graves' ophthalmopathy. It is speculated that alpha-fodrin is an autoantigen in Graves' ophthalmopathy and that it may be important in mediating the orbital process. The relevance of IgA antibodies is that this type of immunoglobulin is found in lacrimal secretion, a relevant site for thyroid eye-related problems.

One of the most important clinical complications of Graves' ophthalmopathy is impairment of visual acuity. This problem is usually related to enlargement of the soft tissues (eg, extraocular muscles) and fluid accumulation (eg, glycosaminoglycans), with the result being increased orbital pressure exerted in a limited space. This pressure may be exerted on the optic nerves.

The most effective treatment of this severe disorder is orbital decompression. Soares-Welch and colleagues[4] studied the role of orbital decompression in patients with Graves' ophthalmopathy. This study comes from the group of Dr. James Garrity, recognized as one of the premier groups in this area. They reviewed their surgical patients (215 patients/428 eyes) from 1969 to 1989 and also sent 2 questionnaires to patients at a 10-year interval (1990 and 2000). In 314 eyes that had demonstrated visual acuity worse than 20/20 prior to surgery, there was improvement by at least 1 Snellen line 6 months following surgery. In the 205 eyes with visual acuity 20/40 or worse prior to surgery, visual acuity improved by 3 Snellen lines or more in 110 (54%). Visual field defects resolved in 93 of 194 patients (48%) and improved in 84 (43%). Proptosis was reduced by an average of 4.4 mm, and papilledema resolved in 72 of 104 eyes (69%).

Diplopia, however, as expected, was the only significant orbital aspect that did not show improvement by decompression. In the early postoperative period, diplopia was present in 88% of patients, compared with 70% preoperatively. However, over the longer follow-up period of 10 years, only 10% of patients had persistent diplopia.

Patient questionnaires at 10 years showed that 88% were satisfied with their decompression surgery. The investigators concluded that transantral orbital decompression is an effective method of treating optic neuropathy.

There are several caveats regarding this important study. As noted, the members of this group are well known to be experts in this field, and comparable results may not be attained by less experienced surgeons. This expertise, of course, relates not only to the surgery itself but also to evaluation prior to surgery, the decision of when to operate, and the follow-up care provided. On the other hand, this study does emphasize that Graves' ophthalmopathy may have serious impact on patients' well being as well as their sight. In selected patients, transantral decompression should be considered.


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