RAI Therapy for Graves' Hyperthyroidism

*Ioannis Iakovou, Evanthia Giannoula, Paraskevi Exadaktylou and Nikitas Papadopoulos*

#### **Abstract**

Graves' Disease is the most common cause of hyperthyroidism. It has multiple manifestations and it requires appropriate diagnostic and therapeutic management. Once it has been established that the patient is hyperthyroid and the cause is GD, the patient and physician must choose between three effective and relatively safe initial treatment options: antithyroid drugs (ATDs), radioiodine (RAI) therapy, or thyroidectomy. RAI has been used to treat hyperthyroidism for more than seven decades. It is well tolerated and complications are rare, except for those related to orbitopathy. Most patients are effectively treated with one therapeutic dose of I-131. The patient usually notes symptomatic improvement within 3 weeks of therapy. However, the full therapeutic effect takes 3 to 6 months because stored hormone must first be released. Radioiodine therapy may not initially be effective in up to 10% of patients. They require repeat treatment, usually with a higher administered dose.

**Keywords:** RAI, hyperthyroidism, therapy, Graves' Disease, Nuclear Medicine, theranostics, guidelines

#### **1. Introduction**

Thyrotoxicosis is a very common clinical syndrome caused by an excess of thyroid hormones in the serum. It results in a generalized acceleration of metabolic processes. Occasionally, thyrotoxicosis may be due to other causes. Graves' Disease is the commonest cause of hyperthyroidism, typically presenting in patients between 40–60 years. It is characterized by the presence of thyroid stimulating hormone receptor antibodies (TRAbs) but pathogenesis is not completely understood [1]. The thyroid stimulating hormone receptor (TSHR) is a transmembrane G-protein-coupled receptor (GPCR) and when it is activated by thyroid stimulating hormone (TSH) it stimulates thyroid hormone production [2]. TRAbs mimic the action of TSH leading to hyperthyroidism. Although autoimmune mechanisms are responsible for the syndrome of GD, management has been largely directed toward controlling the hyperthyroidism. Three therapeutic methods are available: (l) antithyroid drug therapy (ATD), (2) surgery, and (3) radioiodine treatment (RAI) and have proved to be effective, safe and cost-effective. They can be the first-line treatment for hyperthyroidism not only due to Graves' Disease, but also due to toxic adenoma, and toxic multinodular goiter [3]. Nowadays research has turned its focus on the potential use of immunotherapy in GD [4, 5]. It is remarkable that the

selection of the right therapy for each patient still poses a challenge to the clinician as there is no single best therapy for all patients [6].

Radioactive iodine (I-131), has been commonly used for the treatment of both benign and malignant thyroid conditions since the 1940s. In the early days of nuclear medicine, endocrinologists were attracted to the field by the potential of radioiodine for diagnosis and therapy. Today thyroid diagnosis and therapy continue to have an important role in the practice of nuclear medicine. The story of radioiodine started in 1935 at the Massachusetts Institute of Technology in cooperation with the Thyroid Unit of the Massachussetts General Hospital. Diagnostic thyroid studies were performed for the first time in 1937 using iodine-128. In 1938, not more than one year later, I-130 and I-131 were discovered, followed by the first treatment of benign thyroid disease in. Hertz and Roberts were the first to do so on March 31, 1941; Hamilton and John Lawrence, began on October 12, 1941. In 1946 the Oak Ridge National Laboratory produced I-131 for routine use and from this time on I-131 treatment is increasingly performed not only in benign thyroid disease but also in differential thyroid cancer (DTC) [7].

Nuclear medicine involves the administration of radiopharmaceuticals to patients for diagnostic and therapeutic purposes. The theranostic approach is an established tool for specific molecular targeting, both for diagnostics and therapy. Most radiopharmaceuticals are a combination of radioactive molecule, a radionuclide, that permits external detection and a biologically active molecule or drug that acts as a carrier and determines localization and biodistribution. For a few radiotracers (e.g., radioiodine), the radioactive atoms themselves confer the desired localization properties [8]. RAI in GD includes the systemic administration of 131-I for selective irradiation of hyperfunctioning thyroid gland. The efficacy and safety of this treatment and the advantages over thyroid surgery and ATDs have been documented and are widely accepted. Several guidelines, protocols and recommendations have been released by various scientific societies including the European Association of Nuclear Medicine (EANM), and the American Society of Nuclear Medicine Molecular Imaging (SNMMI), European Thyroid Association (ETA) and American Thyroid Association (ATA) whose procedural guidelines are updated in last decade and will be discussed in this chapter.

## **2. Physical and radiobiological properties of (radio)iodine**

Physicians responsible for treating thyroid disorders should have an understanding of the clinical pathophysiology and natural history of the disease processes. They also should be familiar with iodine uptake and metabolism. Iodine is a micronutrient of crucial importance for the health and well-being of all individuals. It is mostly obtained from food sources. Thyroid gland plays the central role in the metabolism of iodine. When iodine enters the bloodstream it is then taken up by thyroid follicular cells through an active transport system the sodium iodide symporter (NIS) which is located at the basolateral membrane of the follicular cell [9]. Then, peroxidase promotes iodine to bound to thyroglobulin (Tg) and in particular to tyrosine which is then iodinated. The latter leads to the formation of 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT) which are coupled afterwards leading to the formation of thyroid hormones. Two molecules of DIT form thyroxine (T4) hormone and when one MIT and one DIT molecule couple they form Triiodothyronine (T3) hormone. Thyroid hormones remain stored in the thyroid cells in a thick fluid that is called colloid. Colloid can store a 3 month

#### *RAI Therapy for Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.96083*

supply of thyroid hormones. Thyroid stimulating hormone (TSH) regulates thyroid hormone production. In particular it stimulates NIS expression which then activates follicular cells through TSH receptor (TSH-R). The uptake and metabolism of the radioactive iodine (I-123 and I-131) does not differ from nutritional iodine uptake in the normal or hyperfunctional gland.

I-131used for the treatment of thyroid disorders has a physical half life of 8.4 days and undergoes beta-minus decay emitting a principle primary gamma photon of 364 kiloelectron volts (keV) (81% abundance). The 364-keV photons are not optimal for gamma cameras. The detection sensitivity for I-131 (i.e. the amount of photons detected by the gamma camera) is poor. Approximately half of the photons penetrate a 3/8-inch crystal without being detected. Other higher energy I-131 emissions will pass though the collimators holes leading to image degradation. Beta-minus decay also results to emission of beta particles of 0.606 megaelectron volt (MeV) (89% abundance) which are responsible for the therapy outcome but cannot be used for imaging. The I-131 high-energy beta emissions and long physical half-life of gamma emissions result in a high radiation dose to the patient, particularly to the thyroid. Thyroid gland which is the target organ of RAI treatment receives ultimately a high radiation dose ~0.01Gy/μCi, and this defines the maximum applicable administered dose [10]. Radiobiological effects of radioiodine on tissues are direct (radiation deposit within DNA) or indirect. Indirect effects produce free radicals that in turn react with critical macromolecules. The cellular effect of the ionizing radiation leads to genetic damage, mutations, or cell death. The DNA damage from radiation is mediated via a combination of direct effects, through breakage of molecular bonds, or indirectly through the formation of free radicals. This leads to a decrease in thyroid function and/or reduction in thyroid size. There are neither good measures of individual radiosensitivity nor ideal methods of predicting the clinical response to RAI therapy [11].
