Preface

Graves' Disease was first described in 1835, taking its name from the physician who identified it, Dr. Robert Graves. The disorder is caused by autoantibodies to the thyroid gland that mimic thyroid-stimulating hormone (TSH), causing the gland to overproduce thyroid hormone. This speeds up the metabolism of the patient and can lead to dangerous conditions including atrial fibrillation and heart failure. Mainstays of treatment have included antithyroid medication, surgical removal of the thyroid gland, and more recently, radiofrequency ablation of the thyroid gland. Enhancements in diagnostic testing have in turn enhanced our understanding of the natural course of the disease, creating additional therapeutic options. Furthermore, enhanced understanding of the autoimmunity behind the disorder may lead to therapeutic options that address the underlying autoimmunity. This book provides a comprehensive review of these enhancements and how they have resulted in changes in common clinical practice.

Regarding diagnostic testing, there have been improvements in serum assays that allow better characterization of the degree of hyperthyroidism and monitoring of the underlying autoimmune response. The lower limit of detectability of TSH assays has improved and can distinguish between suppression and the low end of the normal range more reliably. Free T4 measurements have effectively replaced the total T4/T3 uptake/TSI combination, allowing direct assessment of bioavailable thyroid hormone and avoiding confounding by variations in thyroglobulin levels. These improvements allow medical therapy to be titrated more effectively to achieve a euthyroid state. TSI assays have improved in accuracy and speed such that the diagnosis of Graves' Disease can often be made without the aid of a thyroid scan.

Remission was thought to be a rare event in adults (more common in children), but this may have been the result of the inability to assess the underlying immune response in a patient receiving medical treatment. Assays for thyroid-stimulating antibodies have improved in accuracy and reliability, and most importantly, the reporting time has decreased from a month to several days. Rather than treating blindly for a fixed amount of time and then initiating a trial of therapy, TSI monitoring allows for withdrawal of treatment when the thyroid-stimulating antibody levels have normalized. This has also improved our understanding of the natural course of the disorder. In particular, the appearance of a second remission after a relapse is now a recognized phenomenon and corresponds to the 'waxing and waning course of other autoimmune disorders.

The mainstays of treatment for Graves' Disease remain medical therapy with thiozonamides and/or iodine to inhibit the thyroid gland, with surgery and radiofrequency ablation providing more definitive therapy. The outcome of more definitive therapy is usually hypothyroidism, which then must be treated with levothyroxine. This is still considered the superior option, as levothyroxine is safe for long-term therapy, but it is still unsatisfying trading one disease for another. Clearly, this is an area where further advances are needed. Likewise, while our understanding of Graves' ophthalmopathy has improved, our capacity to manage it remains limited, typically involving courses of high-dose steroids.

Management of Graves' Disease in children has also benefited from advances in diagnostic and therapeutic tools. TSI monitoring is now an option in neonatal Graves' Disease, although the mix of stimulating and blocking antibodies in this condition still creates challenges to maintain a euthyroid state. Routine use of free T4 measurements (vs total T4) has been especially helpful, as for children, conditions of high or low thyroid-binding globulin may not yet have been discovered. Most importantly, radioactive iodine (RAI) therapy has been extended to ages younger than 18 years. Concerns were raised after the Chernobyl accident regarding increased risk for children of thyroid cancer after exposure to RAI. However, these appear to be the result of tissue damage after low-level radiation exposure and have not been seen after higher doses of RAI in RAI therapy.

As we learn more about the underlying autoimmunity in Graves' Disease, it is intriguing to postulate how future therapies might target this immune response rather than targeting the thyroid gland itself. As it stands now, the definitive therapies for Graves' Disease result in hypothyroidism and the need for lifelong thyroid replacement therapy. This is a superior option to current immune-suppression therapies, which have potentially dangerous side-effect profiles. However, these side effects result not from suppression of TSI production, but rather from suppression of immune function in infection and tumor surveillance. One could imagine a more targeted immune suppressant, which selectively lowers TSI, as a superior option to conventional therapy. While such therapies may seem unrealistic today, we did see similar advancements in targeted radiofrequency ablation of the thyroid gland, which avoids the complications seen with whole-body radiation treatments used for cancer therapy.

> **Robert Gensure, M.D./Ph.D.** Tufts Medical Center, Boston, MA, USA

Section 1
