THYROID

EYE

DISEASE

DIAGNOSIS AND TREATMENT

EDITED BY

JONATHAN J. DUTTON

Atlantic Eye and Face Center

Cary

and University of North Carolina

Chapel Hill, North Carolina

BARRETT G. HAIK

University of Tennessee Health Science Center

and St. Jude Children’s Research Hospital

Memphis, Tennessee

TM

Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.

Preface

Graves’ disease has been known as a clinical entity for nearly 200 years. While there is still some controversy about who should be credited with its formal medical description, it is clear that its clinical manifestations and associations were appreciated even in the dark ages. Yet, in spite of its long history and its common occurrence, until the past several decades little was known about the etiology of this disorder. During the past 10 years, more has been learned about this enigmatic disease than in the previous 165 years since Graves and von Basedow published their descriptions.

It is now clear that Graves’ disease is one of many autoimmune diseases of uncertain cause. Just why the complex immune surveillance system, which is designed to protect the body from outside challenges, turns against self antigens is not firmly understood; however, a variety of theories have been put forth, including cross-reactive activation mediated by some of those same outside challenges, such as viruses. The immune process is unusual in Graves’ and other such diseases because rather than causing destruction or apoptosis of the target tissues, antibody-antigen interaction causes stimulation of target cell protein synthesis through natural surface receptors. The target antigen is now established as the TSH receptor of the thyrocyte, resulting in hyperthyroidism.

Another unusual feature of Graves’ disease is its association with manifestations that seem unrelated to the target tissue. In Graves’ disease, this most notably involves the eyelid and orbital tissues and, less commonly, the pretibial dermis. It remains uncertain just which antigens present the primary target of immune response in the orbit, but to date the unique orbital fibroblast appears to be the principal candidate. As discussed in this volume, TSH receptor proteins have been found to be associated with these cells. Complicating this picture further is the presence of additional antibodies directed against other orbital tissues, implicating both extraocular muscles and their connective tissue sheaths in the process. While the exact role of these muscle antigens is not completely understood, it is well recognized that muscle involvement plays a major part in the overall orbital changes seen in this disease.

Once the immune reaction spreads to involve the orbit, a variety of changes ensue that result in both cosmetic impairment and functional disability. The sequence of events is only just becoming clear, emerging from numerous immunological studies. Local in-

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flammation, alterations in cellular function, proliferation of cellular byproducts, and secondary anatomical changes all seem to play a role in the process.

This book is an attempt to update the current state of our knowledge of Graves’ disease. We have invited 64 scientists from 13 countries on four continents to participate in the creation of this volume. These represent many of the foremost authorities in their fields, whose research has contributed to the rapid expansion of our understanding of Graves’ disease and its eye manifestations.

Because most of the new accumulating evidence involves the immunological basis of the disease and its extrathyroidal manifestations, we devote many chapters to this aspect of the story. In Parts I and II, we discuss general aspects of the thyroid gland, its anatomy, physiology, and clinical evaluation. Part III covers the immune system, the nature of autoimmune disease, self-tolerance, and the role of inflammatory molecules in the immune process. In Part IV, we discuss a variety of factors in systemic Graves’ disease, such as clinical features, environmental and genetic factors, its association with pregnancy and other immune diseases, and radiation and surgical treatments. Part V focuses on a review of Graves’ eye disease, the immunological mechanisms responsible for the eye changes, the role of the orbital fibroblast, associated muscle autoantibodies, changes in glycosaminoglycan synthesis, the risks of smoking and of radiotherapy of the thyroid gland, histological changes, clinical manifestations, and diagnostic techniques. Finally, Part VI explores a wide variety of treatment options, such as external beam irradiation, orbital decompression, repair of strabismus, correction of eyelid retraction, blepharoplasty, and some of the newer methods of cytokine modulation and soluble TSHR protein synthesis.

The terminology applied to the ophthalmic component of this disease has varied considerably over time and from one geographic region to another. More than 30 different names have been used in the scientific literature, most commonly Graves’ ophthalmopathy, Graves’ orbital disease, Graves’ eye disease, thyroid eye disease, thyroid-associated ophthalmopathy, and endocrine ophthalmopathy. Among our authors, 10 different terms are employed. We initially attempted to standardize this book by utilizing a single term. However, it soon became clear that there was no definitive consensus on a preferred term, even among coherent groups such as immunologists or ophthalmologists. It also became clear that no single work could establish a standardized terminology, and despite diverse usage, most workers interested in this disease have been exposed to the literature and are comfortable with the various names that have been employed. In the end, we decided to allow each author to use the terminology with which they were most comfortable.

While this volume summarizes our current state of knowledge of Graves’ disease and its eye manifestations, new research is emerging daily. This book should be viewed as an interim report only, subject to change as new evidence is presented. However, it is already clear that the next decade will present new opportunities for treatment and perhaps prevention of this disease, based on immunological modulation interventions.

We are indebted to the very many researchers and clinicians who have contributed to the growing understanding of Graves’ disease and its eye manifestations. In addition, we extend our thanks to Mary E. Smith for her help in editing the manuscripts, to Rosalyn Vu for her work in editing and preparing the index, and to Gregg Gayre, M.D., for helping to develop the initial concept of the book and editing the final proofs.

Jonathan J. Dutton

Barrett G. Haik

Contents

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