Radioiodine for Graves' Disease Therapy

*Aisyah Elliyanti*

### **Abstract**

Radioiodine-131 (RAI) is an isotope of the chemical element iodine and is commonly used for hyperthyroidism, including Graves' Disease. It is given orally, and its concentration in the thyroid gland. The RAI transport involves a natrium iodide symporter (NIS) role that brings two cations sodium (Na+) and one anion of iodide (I-) across the membrane. The process is facilitated by the enzyme Na+/ K+ ATPase. RAI is a beta (β) and gamma (γ) particles emitter. β particle is used for therapy and γ particle for imaging (theranostic). β particle inhibits cell growth by inducing cell death through apoptosis or necrosis of some of the sufficient thyroid cells. The aim of RAI therapy in Graves' Disease is to control hyperthyroidism and render the patient hypothyroidism. It is easier to manage patients with hypothyroidism with levothyroxine and fewer complications. This review will focus on RAI's therapeutic approach in Graves' Disease, including patient preparation, selecting activity dose, adverse events, contraindication, controversies issues such as malignancy and fertility, the follow-up to ensuring the patient remains euthyroid or need a replacement therapy if they become hypothyroidism. RAI therapy is safe as definitive therapy and cost-effective for Graves' Disease therapy.

**Keywords:** hyperthyroidism, hypothyroidism, malignancy, pregnancy, replacement therapy

#### **1. Introduction**

Graves' Disease is an autoimmune disorder that affects the thyroid gland, and it causes 50–80% of hyperthyroid cases and is associated with a firm diffuse goiter [1–3]. Its etiology is not entirely understood. The disease occurs in patients with having a genetic history and combination with environmental factors and lifestyles. Graves' Disease (GD) is characterized by elevated thyroid-stimulating receptor antibodies with increased thyroid hormone production [4–6]. GD can also affect other organs, including the eyes and skin. The annual incidence rate has been estimated at 14–50 cases per 100,000 persons. The peak incidence is between 30–50 years. Even though the disease may affect every age, the incidence is higher in women than men, with a 6:1 ratio [2, 5].

Graves' Disease treatments depend on the presentation. The treatment consists of symptomatic therapy and reduction of thyroid hormone synthesis. The symptomatic therapy, such as a beta-adrenergic blocker, is given for patients with tachycardia, a history of cardiovascular disease, and elderly patients [2, 6]. Therapies for reducing thyroid hormone synthesis are antithyroid drugs (ATDs), radioactive iodine (RAI), and thyroidectomy [2, 3, 6–8]. All three options have advantages and disadvantages. There is no consensus on which one is the best choice, and it is one of the more debatable issues. The treatment choice is likely to be influenced by local availability, treatment cost, patient's preferences, and socio-economy that caused vary from country to country.

Antithyroid drugs are widely used in Europe and most of Asia as first-line therapy. However, RAI is used by most physicians in the United States of America. [3, 6–8]. Hertz and Roberts were used radioiodine I-130 for the first time on March 31, 1941, for hyperthyroidism treatment [9, 10]. Its radiation was delivered rapidly to the thyroid cells over a day or two. Since the Atomic Energy Commission was allowed to supply the fission products for peaceful medical use in August 1946, I-130 was replaced by I-131 because I-131 was much cheaper [9]. RAI is used for therapy and imaging (theranostic). It is a beta (β) and gamma (γ) emitter with a half-life of 8.05 days. A β particle has a peak energy of 0.606 MeV, with a maximum range of ~3 mm in the tissue used for therapy. The peak of γ particle is 0.364 MeV is used for imaging [4, 11, 12]. The longer physical half-life of RAI ensures long-term irradiation of the target tissues, becoming a potential advantage.

RAI therapy aims to treat hyperthyroidism by destroying sufficient thyroid cells to reach either euthyroid or hypothyroid conditions. Radioactive iodine is safe as definitive therapy, cure rates ~80–90%, and cost-effective, rarely or minor side-effects. [4, 6, 7, 11–14]. The choice of therapy depends on the patient's preference. The choice of therapy should take into account local availability and costeffectiveness. In practical terms, RAI is administrated as an outpatient visit, and it is an advantage. RAI is recommended for optimal treatment of Graves' Disease by the American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) guidelines for the management of thyrotoxicosis 2011 and ATA 2016 [3, 6, 15]. The recent guidelines of the United Kingdom (UK) National Institute for Health and Care Excellence (NICE) recommend that radioiodine should now be the first-line treatment for Graves' Disease in the UK [7].

#### **2. Transport radioiodine**

RAI is administrated in a capsule or liquid. Once it is ingested, it is quickly absorbed into the bloodstream in the gastrointestinal (GI) tract. It is taken up by

#### **Figure 1.**

*Natrium iodide symporter brings two cations of sodium (Na+ ) and one anion of iodide (I− ) cross the epithelial thyroid cells' at the basolateral membrane. The process is facilitated by the enzyme Na+/K+ ATPase.*

*Radioiodine for Graves' Disease Therapy DOI: http://dx.doi.org/10.5772/intechopen.96949*

thyroid cells through active transport, which is the same natural iodine process. The transport involves a natrium iodide symporter (NIS) role that brings two cations sodium (Na<sup>+</sup> ) and one anion of iodide (I<sup>−</sup> ). The process is facilitated by an enzyme Na+/K+ ATPase, as shown in **Figure 1**. NIS is a transmembrane glycoprotein that contains 13 membrane-spanning segments and three N-linked carbohydrates. It resides in the basolateral membrane of epithelial thyroid cells [16–20]. Besides the thyroid cell, NIS is expressed by extra-thyroid tissues [20]. NIS expression increased RAI uptake for diagnostic and therapy in thyroid extra-thyroid organ.

#### **3. The mechanism action of RAI**

β particle of RAI inhibits cell growth by inducing cell death through apoptosis or necrosis. Cell responses to radiation are influenced by various factors that lead to different responses between cells. The amount of RAI radiation received by cells is affected by the capture and accumulation of RAI and its biological half-life, which correlates with the effects. Cell responses to radiation are influenced by the cell's sensitivity and the complexity of the cells' micro-environments [21, 22]. Due to the small therapeutic range of β particles within the tissues, naturally, no β particles escape from the thyroid. So, the remaining non-target tissue (i.e., parathyroid glands) still safe even though high activity RAI dose is given to the patients. [4, 11, 23].

A β particle of RAI has a low Linear Energy Transfer (LET) value (0.2 KeV/ μm). It causes cell death, direct and indirect. The decay of radioisotopes in the cell (self-dose) cause DNA damage through direct breakage of molecular bonds. The formation of free radicals or the decay of radioisotopes in adjacent cells (cross-fire) indirectly causes cell death, as shown in **Figure 2**. The condition leads to a reduction of thyroid function and diminished thyroid size [24, 25].

#### **Figure 2.**

*RAI radiation damages a DNA directly (lethal and sub-lethal) or indirectly from adjacent cell radiation (cross-fire/bystander).*

#### **4. Treatment protocol**

Many studies reported various approaches to RAI therapy published by different institutions. It remains a matter of debate when choosing the treatment protocols, whether a calculated dose that considers radioiodine uptake (RAIU) and thyroid volume measurements versus a fixed-dose, or a high dose versus a low dose, or whether short term versus long term medical management. RAI administrates as low as reasonably achievable (ALARA) dose that is an essential principle for radiation treatment [23, 25].

#### **5. Radioiodine dose**

RAI therapy is well established for the definitive treatment of GD. However, Its approach remains controversial due to differing treatment control goals. It is between hyperthyroidism versus avoidance of hypothyroidism. Various methods of RAI doses have been used to deliver adequate radiation to the thyroid gland. Radiation dose to the thyroid depends on the RAI uptake, thyroid volume, and biologic half-life of the RAI. Actually, RAI activity dose measured based an amount of the radiation delivered to the thyroid gland rather than administered activity, but few publications confirm this unequivocally [23]. Three approaches for determining the administered RAI activity doses. 1. Based on the calculation of thyroid volume and the RAI uptake 24 hours. 2. Based on thyroid volume, RAI uptake, effective half-life. 3. Fixed activity dose [4, 11].

In calculation approaches, the thyroid volume, RAI uptake, and effective halflife are factors determine the activity dose. It is recommended a delivered activity of RAI about 3–8 MBq (80–220 μCi) per gram of thyroid mass, with absorbed radiation dose 100–150 Gy to restore a euthyroid status, whereas the total ablation dose is in the range 200–300 Gy [12, 14, 23]. Naturally, the normal thyroid mass is about 20 grams. Ultrasound, x-ray/MRI studies, and scintigraphy thyroid can be used to evaluate thyroid volume. However, ultrasonography is superior to all of these techniques because of its relatively low cost, wide availability, ease of technically.

The RAI uptake should be appropriately prepared to ensure its real thyroid uptake. The patient should be advised to avoid meals for at least 2 hours before and 2 hours after the oral administration of RAI for the test. The thyroid uptake can also be measure by intravenous administration of Tc-99 m pertechnetate. The pertechnetate is trapped but not be organification by the thyroid. The measurement usually after 20 minutes of the injection [6, 11, 23]. GD uptakes usually high unless the patient has a history of iodine intake recently. However, the calculated dose versus fixed-dose effectiveness is an equally successful outcome [6, 26]. Radioactive iodine uptake (RAIU) can be calculated using formula (1) [12].

$$\text{RIAU} \left( \% \right) = \frac{\text{thyroid counts} \left( cpm \right)}{\text{Administrated counts} \left( cpm \right)} \text{\textsuperscript{} 100.} \tag{1}$$

An effective half-life is needed for an accurate absorbed dose calculation to the thyroid [6, 11]. Effective half-life is the combination of the physical half-life (constant for a particular nucleus) and the biological half-life (varies from patient to patient). A radionuclide in a living tissue decays in two ways, physical decay and biological elimination from the body is called biological half-life. The effective half-life of RAI in the thyroid can be determined by measuring its uptake at several

#### *Radioiodine for Graves' Disease Therapy DOI: http://dx.doi.org/10.5772/intechopen.96949*

different periods following RAI administration. It may vary from 1.2 to 7.5 days in hyperthyroidism (i.e., the variation factor is 6.25). The effective half-life calculation is cumbersome. It has a lot of calculations and assumptions that may have a human error. Effective half-life calculation will increase the accuracy of RAI activity dose [11]. However, the outcome has not been shown to be better, so the method is rarely used [6].

Fixed-dose of RAI activities is a simple protocol and convenient to use. It can be administered as a single dose and be repeated as necessary, with a range of 185–740 MBq (5- 20 mCi). The administration dose is given based on validated clinical parameters and an estimated thyroid size by palpation or measurement by ultrasonography or scintigraphy [26, 23, 25].

The majority of patients cure with a single RAI dose [11, 13]. Many physicians prefer a single high RAI dose, which leads to hypothyroidism. Cure rate high dose reach 85% - 94.4%, and 66–74% for low dose [4, 11, 14]. A single high dose or ablative dose concept is preferred by a physician today. It can avoid patients' frequent visits and laboratory testing for hypothyroid onset detection. It decreases the risk of persistent or recurrent hyperthyroidism [23]. A low dose is administered to achieve a euthyroid state to avoid hypothyroidism. 50%–90% of patients become hypothyroidism within 3–12 months [13]. Around 14% of hyperthyroid patients required second therapy. Persistence hyperthyroidism showed 7.3% after received 555 MBq (15 mCi) RAI [12, 13].

On the other hand, the low activity dose is generally not recommended because many patients need RAI retreatment. Furthermore, most patients will become hypothyroid after RAI [4, 23, 25]. Finally, therapy aims to control hyperthyroidism and render the patient to be hypothyroidism. The therapy outcome can be accomplished equally by administering a fixed RAI activity dose or calculating the activity based on the thyroid RAIU and size.
