Hyperthyroidism Treatment Options

#### **Chapter 3**

## Radioactive Iodine Therapy for Hyperthyroidism

*Fida Hussain, Muhammad Adil and Mehmood Hussain*

#### **Abstract**

Hyperthyroidism is one of the most commonly encountered endocrine disorder with potentially devastating health consequences. Radioactive iodine has been used for the treatment of hyperthyroidism since 1940s. It is now widely accepted as safe, cost-effective and reliable treatment option with 50–90% cure rate in first year after therapy. With long-term follow-up hypothyroidism is inevitable especially in Grave's disease which can activate orbitopathy in predisposed individuals. Early and timely management of hypothyroidism is associated with better therapeutic outcomes. There is very little evidence of cardiovascular and cancer related mortality risk after radioactive iodine therapy. However, it is said that these risks appear to be thyroid hormone driven above all other factors.

**Keywords:** Grave's disease, hyperthyroidism, radioactive iodine, thyrotoxicosis, toxic nodular goiter

#### **1. Introduction**

Thyroid dysfunctions are commonly encountered in clinical practice affecting a considerable portion of population. However, incidence and pattern of thyroid disease vary significantly depending upon age, gender, ethnicity and geographical distribution [1]. Global prevalence of hyperthyroidism varies from 0.2 to 1.3% in different studies [2]. Thyroid dysfunction has important ramifications on health outcome especially in older population like cardiovascular, metabolism, bone and mental health. Undiagnosed and untreated hyperthyroidism causes drastic clinical complications for patients as well as health care delivery system in term of economic burden. Hence early diagnosis and prompt treatment are indispensable to reduce mortality and associated costs [3].

Radioactive Iodine (RAI) represents as an effective treatment modality for hyperthyroidism, especially in cases who do not respond to medical therapy. RAI therapy is in practice for the last 80 years. It was first used for therapeutic purpose in 1941 by Dr. Saul Hertz [4]. Over the time its therapeutic efficacy was evaluated and evolved, by 1990 it becomes preferred treatment option for Grave's disease in US. Although, previously it was reserved for patients who had a relapse after failed medical treatment. New practice guidelines of National Institute for Health and Care Excellence (NICE) recommends RAI as first line treatment option in cases of Grave's disease [5].

This chapter focuses on the role of radioactive iodine in hyperthyroidism and other related therapeutic aspects with a background knowledge of pathophysiology of thyroid gland.

#### **2. Thyroid hormone synthesis**

Thyroid hormones, L-thyroxine (tetraiodothyronine, T4) and L-triiodothyronine (T3) are the only iodine containing molecules in vertebrates with well-established biological role. Baumann was the first to report the presence of iodine in thyroid hormone in 1895 with iodine accounting for 65% of T4 and 58% of T3 weight. Iodine is an integral component and rate-limiting substrate for thyroid hormone synthesis that is provided exogenously. Ingested iodine is absorbed from small intestine as iodide into the plasma which also contains iodide released by thyroid gland and extrathyroidal deiodination of iodothyronines. This iodide is either transported in plasma and taken up by thyroid or excreted via urine.

Thyroid follicles, the structural and functional unit of thyroid are responsible for production, storage and secretion of thyroid hormones. Iodide is actively trapped into thyroid follicular cells (thyrocytes) against electrochemical gradient by sodiumiodide symporter (NIS) at basolateral membrane while efflux of iodide across apical membrane into follicular lumen is mediated by Pendrin, a potential iodide transporter. Normally, thyroid concentrates 20–50 times higher iodide as compared to plasma. Inside thyroid follicle iodide is rapidly oxidized to iodine by thyroid peroxidase (TPO) in the presence of hydrogen peroxidase generated by membrane bound NADPHoxidase. Iodine is then covalently bound to the selected tyrosyl residues of thyroglobulin (Tg) at the apical plasma membrane-follicle lumen boundary resulting in the formation of monoiodotyrosine and diiodotyrosine (MIT, DIT), a process referred to as organification or iodination. Tg is the most abundant protein in thyroid providing polypeptide backbone for thyroid hormone synthesis and storage. Subsequently, two neighboring iodotyrosyl residues on Tg molecule are coupled in the presence of TPO to produce iodothyronine; two DIT form T4 while one DIT and one MIT form T3. Iodinated Tg is stored as colloid in follicular lumen. Upon stimulation, Tg is internalized into follicular cells by pinocytosis and digested by endosomes and lysosomes resulting in release of T4 (~80%) and T3 (~20%). Deiodination of MIT and DIT by intracellular iodotyrosine dehalogenase release iodide which is again recycled for hormone synthesis [6].

#### **3. Regulation of thyroid hormone synthesis**

Thyroid hormone synthesis is primarily governed by hypothalamic-pituitarythyroid axis, a prime negative feedback mechanism that respond suitably to any challenge to maintain biochemical equilibrium. Hypothalamic hormone, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) or thyrotropin release by anterior pituitary stimulates thyroid hormone synthesis and secretion while thyroid hormones in turns inhibit the production and secretion of both TRH and TSH and vice versa. This complex interaction between TSH and thyroid hormones maintain serum hormone levels within narrow limit. However, this relationship is individual, dynamic and adaptive depending on many factors.

TSH almost influences every step in thyroid hormone synthesis and release via Gp/phospholipase C and cAMP cascade respectively. It stimulates thyroid cell *Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

proliferation and hormone synthesis by inducing expression of Tg, TPO, NIS and iodothyronine deiodinase type I (D1). Clinically serum TSH levels serves as sensitive biomarker for evaluation of thyroid dysfunction even at sub-clinical stage [7].

Beside this, genetics factors, endocrine mediators like estrogen and corticosteroids and local factors released by nerve endings, follicular cells and C cells are also involved in the regulation of biosynthesis of thyroid hormones. Sympathetic and immune system are also involved in regulation of thyroid hormone activity, however very less is known in this regard. Antithyroid drugs, iodide and some external compounds also influence thyroid hormone metabolism [8].

#### **4. Hyperthyroidism and thyrotoxicosis**

Hyperthyroidism is pathological condition characterized by inappropriately high levels of thyroid hormones due to its excess production and release by thyroid gland. The most common causes of hyperthyroidism are diffuse toxic goiter (Grave's disease), toxic multinodular goiter (Plummer disease) and toxic adenoma. The term thyrotoxicosis is often interchangeably used with hyperthyroidism and is characterized by elevated level of circulating thyroid hormones secondary to exogenous intake or excess release of preformed stored hormones. Thyroiditis, inflammation of thyroid gland resulting in release of stored hormones is the most frequent cause of thyrotoxicosis. Other rare causes of thyrotoxicosis are iodine-induced hyperthyroidism, post-partum thyroiditis, suppurative thyroiditis, beta human chorionic gonadotropin induced thyrotoxicosis and thyrotoxicosis factitia. Follicular thyroid carcinoma, TSH secreting pituitary adenoma and struma ovarii can also cause excess thyroid hormone levels.

#### **4.1 Epidemiology**

The prevalence of thyroid dysfunction varies by age, gender, ethnicity, geographic distribution, iodine status of the population under study and difference in diagnostic thresholds. In iodine-sufficient parts of the world, the prevalence of hyperthyroidism varies from 0.2 to 1.3% while in US it is estimated to be 1.2% (0.5% overt and 0.7% subclinical). Generally, areas with iodine deficiency have higher incidence of hyperthyroidism. For example, a 2.9% prevalence of hyperthyroidism was reported in Pescopagano, an iodin-deficient village in Italy [9]. In US Grave's disease is the most common etiology of hyperthyroidism, accounting for 60–80% cases of hyperthyroidism followed by subacute thyroiditis (15–20%), toxic multinodular goiter (10–15%) and toxic adenoma (3–5%). Females are more commonly affected by thyroid disorders as compared to male. Peak age of occurrence is second to fifth decade of life [10, 11].

#### **4.2 Clinical presentation**

Clinical manifestation is attributed to elevated thyroid hormones level causing widespread multiorgan effects. The spectrum of clinical presentation depends on age, duration and severity of illness, comorbidities and underlying cause and may range from asymptomatic in subclinical disease to life threatening in thyroid storm. Adults usually present with adrenergic symptoms like restlessness, tremors, anxiety while older patients lack sympathetic symptoms and tend to presents with less obvious symptoms like weight loss, decrease appetite, shortness of breath and cardiac manifestations like atrial fibrillation and tachycardia. Older patients are at increased risk of congestive heart failure and embolic stroke due to atrial fibrillation. Some symptoms are specific to underlying cause, like Grave's disease characterized by orbitopathy and pretibial myxedema [12, 13].

Patients with untreated or uncontrolled hyperthyroidism may land up in thyroid storm preceding severe physical or mental stress like infection or trauma. Thyroid storm is a rare life-threatening endocrine emergency. It is acute exaggerated clinical manifestation of thyrotoxic state and may cause death from multiorgan failure. Thyrotoxic patient with altered sensorium is the hallmark. Patient may present with agitation, delirium, convulsions, chorea like abnormal movements, severe hyperthermia, excessive diaphoresis, hypertension and refractory dysrhythmias. The incidence and mortality associated with thyroid storm is not precisely known. The reported incidence is 2–16% in hospitalized thyrotoxic patients with an overall mortality rate of 8–30% [12, 13].

#### **4.3 Pathology**

Grave's disease is the most frequent cause of hyperthyroidism in developed countries. It is one of most commonly encountered autoimmune disorder with peak incidence in second to fifth decade of life. Women are 5–10 times more affected. It was first described in 1834 by Robert Graves from Dublin. It is an autoimmune disorder in which antibodies against TSH receptors (TRAb) cause unopposed activation of TSH receptors triggering hormone synthesis. The usual negative feedback mechanism is not effective as the antibodies are directed against TSH receptors. This result in excessive production and release of T3 and T4, an enlarged thyroid gland and increased iodide extraction. Since TSH receptors are present in almost all tissues, extrathyroidal manifestations may be observed. Commonly observed extrathyroidal TRAb driven features are orbitopathy, pretibial myxedema and thyroid acropathy. The pathogenesis of Grave's disease is not fully understood. However, multiple risk factors are attributed to its pathogenesis. Genetic predisposition accounts for 79% while environmental factors account for 21% of the risk factors. Smoking, iodine excess, selenium and vitamin D deficiency are important environmental risk factors. Person with family history of hyperthyroidism or other autoimmune disease such as myasthenia gravis, type I diabetes mellitus are at increased risk of Grave's disease [14].

Toxic multinodular goiter (TMNG, Plummer's disease) is the second most common cause of hyperthyroidism in US after Grave's disease and most common in elderly living in iodine deficient areas. It was first described by Henry Plummer in 1913. Chronic low grade intermittent physiological or pathological stimuli can lead to diffuse or nodular enlargement of thyroid gland (goiter). Thyrotoxicosis occurs in long-standing goiter, with peak incidence in sixth or seventh decade of life. It is characterized by release of thyroid hormones by multiple autonomously functioning nodules or single autonomous nodule in thyroid gland. This functional autonomy is result of activating somatic mutations of TSH receptors genes in most of the cases (~60%). Autonomous nodules appear hots (hyperactive) on thyroid scintigraphy while non-autonomous appears as cold (hypoactive). TMNG has indolent progression with mild clinical symptoms. Clinical features are similar to thyrotoxicosis except presence of Grave's orbitopathy, dermopathy and acropathy. Compressive symptoms may also be present depending on size of gland [15].

Toxic adenoma is a benign autonomously functioning thyroid nodule with clinical and biochemical features suggestive of thyrotoxicosis. Iodine deficiency is well established risk factor in pathogenesis of adenoma besides other environmental

#### *Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

and genetic factors. Like TMNG, activating mutations in TSH receptor genes results in toxic adenoma. The incidence is higher in women and after 50 years of age. Hyperfunctioning adenoma is usually considered as benign lesion with less than 1% chances of malignant transformation [16].

Subacute thyroiditis or de-Quervain thyroiditis is inflammation of thyroid gland that typically follow a viral infection usually upper respiratory tract infection. Recent studies have suggested that COVID-19 infection is also associated with subacute thyroiditis. This inflammatory process leads to leakage of preformed thyroid hormones into circulation and subsequently thyrotoxicosis. Patient classically presents with upper respiratory tract symptoms followed by fever, neck pain, neck swelling. Malaise, fatigue, myalgias and arthralgias are also common. Thyroid is smoothly enlarged, firm and tender on palpation. This is a self-limiting disease and usually extend over few weeks to months. About 30% of the patients undergo hypothyroidism before returning to euthyroid status due to depletion of preformed hormone stores. Approximately 10% may develop permanent hypothyroidism and require hormone replacement therapy. Subacute thyroiditis demonstrates high ESR and CRP levels and has tendency to recur [17, 18, 19].

Painless subacute thyroiditis (autoimmune or silent) is considered as a variant of Hashimoto's thyroiditis and occurs spontaneously or following pregnancy (postpartum thyroiditis). It accounts for 0.5–5% cases of hyperthyroidism. Approximately 5–20% of the patients have characteristic sequence of hyperthyroidism followed by hypothyroidism and then recovery. Thyrotoxic stage last for 2–8 weeks followed by hypothyroid stage which is usually mild or even asymptomatic and last for few weeks. It may recur in small subset of patients. About 20% of the patients develop chronic autoimmune thyroiditis and ultimately permanent hypothyroidism. Painless subacute thyroiditis is associated with specific human leukocyte antigen (HLA-DR3). Majority of the patients have elevated serum titers of antithyroid peroxidase and antithyroglobulin antibodies [18, 19].

Suppurative thyroiditis is infection of thyroid gland most commonly caused by bacteria but can also be due to fungus, mycobacterium or parasites. Acute suppurative thyroiditis is rare but life-threatening disease with estimated mortality of 3.7–9%. It is most common in immunocompromised patients. Patient usually presents with tender erythematous anterior neck swelling, fever, dysphagia and dysphonia. Acute suppurative thyroiditis can cause airway obstruction, esophageal fistula, Horner's syndrome, extension of abscess leading to mediastinitis, pericarditis, thrombophlebitis and eventually death [12].

Iodine induced hyperthyroidism (Jod-Basedow Syndrome) usually occurs in setting of underlying autonomous thyroid disease after administration of iodine, usually iodinated contrast media. Iodine provides substrate for thyroid hormone synthesis. It is common in iodine deficient areas or areas with endemic goiter. This condition is self-limiting after withdrawal of iodine with a favorable outcome. Increased iodine intake is also associated with Grave's disease [20].

There are several other but rare causes of thyrotoxicosis that deserve consideration. Beta human chorionic gonadotropin (β-hCG) can induce thyrotoxicosis by stimulating TSH receptors. Molar hydatiform pregnancies and choriocarcinoma have high level of circulating β-hCG level. Thyrotoxicosis factitia is caused by exogenous ingestion of thyroid hormones, either intentionally for therapeutic purposes or unintentionally. Patient with thyrotoxic symptoms in absence of any diagnosed thyroid disease and deranged thyroid tests should be investigated for this condition [21]. Psychiatric patients are at more risk. Some individuals use it for cosmetic reasons and to lose weight. Follicular thyroid cancer, TSH secreting pituitary adenoma and struma ovarii can also cause thyrotoxicosis in selected population [12].

#### **4.4 Diagnosis**

Diagnosis is made on the basis of history, clinical examination and relevant investigations. All patients with suspected or confirmed hyperthyroidism should be thoroughly assessed in order to formulate a treatment plan. Older patients should also be evaluated for potential cardiovascular complications.

Serum TSH and T4 estimation should be done as initial screening test. Serum TSH is more sensitive than direct thyroid hormone estimation in assessment of thyroid hormone excess. Majority of the patients (~90%) with thyrotoxicosis have raised T4 and suppressed TSH levels. However, in patients with T3 toxicosis (~5%), T3 is raised while T4 is normal. Therefore, in patients with suspected thyrotoxicosis and normal T4 levels, T3 should be done to rule out T3 toxicosis. This represents autonomously functioning thyroid nodule or initial disease stage. In patients with pituitary dependent thyrotoxicosis TSH is usually normal with raised T3 and T4. In subclinical hyperthyroidism, TSH levels are suppressed with normalized T3 and T4 while in overt hyperthyroidism T3 and T4 are elevated with suppressed TSH levels [22].

Mostly underlying etiology is suspected on the basis of clinical features like exophthalmos and goiter in Grave's disease. However, if diagnosis is not evident based on clinical and biochemical evaluation, further evaluation can be accomplished by TRAb or TSI measurements and imaging studies like radioiodine uptake (RIU) scan and thyroid ultrasonography. TRAb can confirm the diagnosis of Grave's disease with sensitivity and specificity of 97 and 99% respectively. TRAb are detected in almost all patients with Grave's disease. In USA, TRAb is only reserved for patients in whom RAIU studies are contraindicated or unavailable while in Europe TRAb is preferred over RAIU. Thyroid peroxidase (TPO) antibodies are less sensitive and specific for Grave's disease, detected in only 70–80% of patients. They are greatly influenced by environmental factors such as iodine intake [22, 23].

Ultrasound is inexpensive, non-invasive and radiation free modality to assess thyroid blood flow and suspicious thyroid nodules warranting further testing like FNAC. Doppler ultrasound examination has greatly improved accuracy specially in cases where vascularity is needed. Increased thyroid vascularity is seen in Grave's disease while decrease vascularity is indicative of destructive thyroiditis. Thyroid echogenicity assessed by ultrasonography can be used to predict remission after initiation of medications and can also identify patients who are at increased risk of recurrence after withdrawal. However, ultrasound does not precisely establish the underlying etiology of thyrotoxicosis and is reserved for cases where RAIU is contraindicated (pregnancy and breast feeding) or unavailable according to American Thyroid Association (ATA) guidelines [22, 24].

RAIU measures the percentage of radioactive iodine trapped and organified by thyroid gland after a fixed interval. It is recommended to establish the underlying etiology of thyrotoxicosis (ATA guidelines) and is preferred over TRAb estimation except in cases where RAIU is contraindicated (pregnancy and breast feeding) or unavailable. A gamma camera is used to measure the percentage of iodine uptake by gland. RAIU scan shows diffusely increased homogenous uptake in Grave's disease, focal area of increased uptake in toxic adenoma and asymmetrically irregular uptake in TMNG with multiple focal areas of increased and suppressed uptake. RAIU will be reduced or near zero in painless and subacute thyroiditis or in those with exogenous

*Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

ingestion of thyroid hormones, excess iodine intake or exposure to iodinated contrast media in preceding 4–8 weeks. RAIU is also helpful in calculating therapeutic radioactive iodine dose. However, European Thyroid Association guidelines does not recommend routine use of RAIU except in cases where etiology cannot be established by laboratory and imaging studies. Technetium scintigraphy utilizes pertechnetate which is taken up by thyroid but not organified resulting in low range of uptake. The radiation exposure is less as compared to RAIU however RAIU provides more physiological information. It can also determine the underlying pathology in toxic nodular thyroid disease [22, 23, 24].

#### **4.5 Treatment options**

Treatment depends on underlying etiology and is influenced by coexisting medical condition and patient preference. There are multiple treatment strategies including antithyroid drugs (ATD), radioactive iodine (RAI) therapy and surgery along with medications for symptomatic relief.

#### **5. Radioactive iodine therapy for hyperthyroidism**

RAI-131 therapy is widely accepted and preferred treatment option for hyperthyroidism for the last eight decades. From benign nature of hyperthyroidism to malignant neoplasm and their metastasis, RAI-131 therapy has transformed patient and physician perspective towards treatment options. It was first used as therapeutic agent in 1941 for benign thyroid disease while approved by FDA in 1971 for treatment of toxic diffuse and nodular goiter, non-toxic nodular goiter and well differentiated thyroid cancer. Initially its use was only limited to elderly males with age above 50 years due to fear of associated potential risk factors at that time. However, its application has now been extended to women and children.

#### **5.1 Historical background**

Dr. E Bauman in 1895 for the first time discovered that thyroid gland contain iodide. 20 years later, it was found that gland can actively concentrate iodine. Henry Plummer, in 1923 introduce iodine as treatment adjunct for Grave's disease. Enrico in 1934 described the artificial production of radioactive isotopes including iodine which was a major breakthrough. Glenn and John in 1938 discovered radioactive iodine (RAI-131). Saul Hertz for the first to use RAI-131 in 1941 in human for the treatment of hyperthyroidism. Since then, millions of patients with benign and malignant thyroid disease have been successfully treated with RAI-131. The first patient with thyroid cancer was treated at Royal Cancer Hospital, London in 1949 [25, 26].

#### **5.2 Properties of RAI-131**

Iodine occurs naturally in stable form as I-127 with 37 known isotopes. All radioactive isotopes of iodine are produced in nuclear reactors by process of fission. I-131 is the most commonly used radioisotope of iodine with physical half-life of 8.02 days. I-131 decays to Xe-131 by emitting beta (β) particle and gamma (γ) photons. The first emission product is β-particle (90%) with end point energy of 0.606 MeV (89.7%). β-particles make I-131 a therapeutic agent as they have the propensity to ablate thyroid tissues. β-particles with these energies can only travel few millimeters ~3 mm, causing only local destruction. The second emission product is γ-photon (10%) with end point energy of 0.364 MeV (80.9%). It travels far from its source before depositing its energy with relatively little impact on thyroid tissue, hence cannot be employed for therapeutic purposes. It is however used as diagnostic tool to image thyroid [27, 28].

#### **5.3 Pharmacokinetics of RAI-131**

Pharmacokinetics of RAI-131 is similar to normal dietary iodine. After oral ingestion, sodium iodide I-131 is absorbed from small intestine into extracellular fluid. About 90% absorption occurs in first hour after ingestion. From extracellular compartment it is predominantly taken up by thyroid gland or eliminated through kidneys. NIS is responsible for active uptake of iodide in thyroid gland against electrochemical gradient. Under normal physiological condition, NIS can concentrate iodide 20–50 times of plasma concentration and this may increase up to 10 times in hyperthyroidism. Thyroid achieves its maximum uptake of iodide after 24–48 hours with 50% of maximum uptake after 5 hours. Normally thyroid has iodide clearance of about 10–50 ml/min. Iodide uptake is influenced by many factors including patient age, thyroid gland size, circulating iodide level and functional status of kidneys. After radioactive iodide uptake by thyroid, it is further oxidized to iodine and follow normal metabolism of thyroid hormone [29, 30].

NIS also mediates active RAI uptake in extrathyroidal tissues like salivary glands, lactating mammary glands, gastric mucosa, lacrimal sac and choroid plexus. However, these structures lack the system to oxidize iodide. RAI elimination from the body is mainly through renal pathway accounting for 37–75% while fecal excretion accounts for 10% of administered dose. Excretion through sweat glands is negligible [29].

#### **5.4 Pharmaceutical preparations of RAI-131**

I-131 is supplied as sodium iodide (NaI-131) in either capsule form or solution form for oral administration. Capsule are available in different activity ranging from 0.75–100 mCi. These are opaque white gelatin capsules packaged in shielded cylinders. I-131 is also available as stabilized aqueous solution in vial with activity ranging 5–150 mCi at the time of calibration. The pH of the solution is adjusted between 7.5 and 9. NaI-131 utilized in the preparation of solution at the time of calibration contains more than 99% I-131 [30].

#### **5.5 Mode of action of RAI-131**

RAI-131 emit beta particle with principal energy of 606 KeV and maximal tissue penetration of approximately 3 mm and hence can be used for therapeutic purposes. Beta irradiation causes cell death by direct and indirect damage to thyroid follicular cell's DNA predominantly through apoptosis and also necrosis. Indirect effect is mediated via release of reactive oxygen species. Another less understood mechanism is secondary immunoreactivity by released thyroid self-antigen in response to radioiodine. This immunoreactivity leads to intra-thyroidal inflammation [31].

#### **5.6 Effective half life of RAI-131**

Within a living tissue, a radionuclide decays either by physical decay (physical half-life) or biological elimination from the body (biological half-life) in an *Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

exponential pattern. Physical half-life is constant for a particular radionuclide while biological half-life is specific for patient. Overall decay of a particular radionuclide is cumulative effect of both half-lives and the half-life associated with overall decay is called effective half-life. Effective half-life is always less than isolated physical or biological half-life and is calculated as

1 11 / T effective / T physical / T biological 1 2/ // ( ) = 1 2 ( ) + 1 2 ( )

Effective half-life of I-131 can be estimated by measuring uptake at different time periods following administration.

#### **5.7 Common indications**

Common well-established clinical indications for RAI-131 therapy are:


However, RAI-131 therapy is not only limited to these. Persistent or recurrent hyperthyroidism after partial thyroidectomy can also be treated with RAI-131. Subclinical hyperthyroidism treatment with RAI-131 has also shown promising results when underlying etiology is solitary or multiple functioning thyroid nodules or Grave's disease [32].

#### **5.8 Treatment protocol**

#### *5.8.1 Dose calculation*

RAI-131 therapy has been considered as a safe, cost-effective and durable treatment option for thyroid pathologies particularly benign thyroid disease for the last eight decades with known risk and benefits. However, optimal method of calculating RAI-131 activity to be administered to achieve therapeutic objectives is still controversial. No consensus exist on what pre-treatment measurements are required for optimal therapeutic response, balancing the risk of partial response, unnecessary radiation exposure and therapy-induced hypothyroidism. Different protocols are in use to determine the therapeutic activity in different centers. However, fixed dose method and calculating a personalized dose using either clinical scoring or scintigraphy findings are frequently used methods reported to date and studied in animals and humans.

Standard fixed dose RAI-131 therapy is simple, with early and higher cure rate and minimal remission. In this method, nuclear physician based on his personal judgment and experience prescribed a fixed dose usually ranging from 2 to 20 mCi. Different studies have been done in this regard to establish a standardized fix dose however no hard and fast rule is applied. Higher fixed dose is associated with high cure and reduced remission rate but concomitant risk of hypothyroidism. Studies show that approximately 69% patients achieve hypothyroidism at 1 year with 10 mCi RAI-131 while 75% became hypothyroid at 6 months after receiving 15 mCi [22]. However, it has been observed that same results can be obtained with different doses indicating

that therapeutic outcome is not dependent only on administered activity. Studies have shown that thyroid mass and bio-kinetics also determines therapeutic outcome. Despite all these factors, European society still advocates administering fixed dose for benign thyroid disease owing to early therapeutic outcome and decrease need of retreatment [33, 34, 35].

Some studies also suggest to administer fixed dose per unit mass of thyroid gland without calculating I-131 uptake and effective half-life. It is time and cost effective and therapeutic outcomes are achieved earlier. This protocol is recommended by Society of Nuclear Medicine US and by European Association of Nuclear Medicine. Patient with small target mass will require less administered activity. However, variation in biological half-life results in over-dose, this aspect is over looked in this protocol [28].

Calculated dose protocol is based on individualized dosimetry taking into account patients anatomical and biological parameters. Idea is to calculate minimum effective dose to acquire therapeutic goals and to prevent unnecessary radiation exposure. Individual patient dosimetry is essential for determining dose–response relationship. Calculation of personalized activity to be administered depends on variables like thyroid mass, I-131 uptake values, effective half-life and dose to thyroid in grays (Gy). Some centers use fixed effective half-life of RAI-131 like 5 days for Grave's disease and 6 days for nodular goiter while other calculate on the basis of uptake values over a period of 1 week. However, calculating uptake measurements over a period of week is time-consuming, costly and inconvenient for patients. Radiation dose needed to be delivered to thyroid for therapeutic purposes following this protocol is controversial varying from low calculated dose (80 Gy) to high calculated dose (300 Gy). Low radiation dose activity is associated with less chances of hypothyroidism but increased rate of hyperthyroidism. Different algorithms are also used to calculate dose like Marinelli's formula which takes in account RAI-131 uptake and effective half-life [36, 37].

#### *5.8.2 Patient preparation*

Pre-therapy evaluation must emphasize on following:

Patient should be properly educated regarding procedure, its possible outcome, adverse events, complications, radiation safety measures they have to follow and need for long term follow-up by providing written as well as verbal information. Informed consent should be obtained prior to therapy containing all relevant information.

History including disease duration, previous treatment (ATD or RAI-131 therapy), use of iodinated contrast media or other iodine containing medications, medical therapy for other comorbid like amiodarone and urinary incontinence. Thyrostatic drugs lower radioiodine uptake and effective half-life, so they should discontinue before RAI-131 therapy. Usually, carbimazole and methimazole should be stopped 2–3 days before therapy while propylthiouracil should be discontinued 2–3 weeks prior to therapy due to more radioprotective effect because of presence of sulfhydral group. Exposure to iodine alter the timings of RAI-131 therapy. After administration of iodinated water-soluble contrast agent, therapy should be postponed for 6–8 weeks. In case of amiodarone use for underlying cardiac issue, therapy is usually not preferred because it leads to delay in excess iodine elimination for an average period of 6 months. Similarly, other iodine containing medications like lugols iodine, potassium iodide and topical iodine should be stopped 2–3 weeks before therapy [38].

Laboratory investigations including serum free T3, T4, TSH, TRAb levels.


RAI-131 is given orally as outdoor patient in facilities duly registered and authorized by regulatory bodies according to national policies. These facilities must have trained staff including nuclear physician and physicist, radiation safety procedures and equipment to handle contamination / spread and disposal of waste. If indoor therapy is recommended in some special cases, it should be done in shielded rooms.

In some cases where increased radiation dose to thyroid is needed, lithium can be used as it blocks radioiodine washout from gland without interfering with uptake. Similarly, recombinant human TSH (rhTSH) has been off label used in non-toxic MNG to maximize radiation dose to thyroid and minimize dose to reminder of the body. However, their use is still not fully documented and recommended [40].

In patients with uncontrolled urinary incontinence, proper catheterization should be done or even in-patient therapy should be considered. Literature also suggest lifelong ATD therapy in such cases if surgery is risky.

#### **5.9 Special conditions**

#### *5.9.1 Grave's disease*

As per American Thyroid Association guidelines, the aim of RAI-131 therapy is to render patient hypothyroid and it is considered as preferred treatment modality for Grave's disease in US. In Europe, ATDs are considered preferred treatment option unless patient has side effects or relapse after course of ATD, cardiac arrythmias and thyrotoxic periodic paralysis. Patients with comorbids increasing surgery risk, previously operated or irradiated, contraindications to ATD or females who are not planning pregnancy in near future (4–6 months) can be considered for therapy. Pregnancy, lactation, coexisting thyroid cancer, female planning pregnancy within

4–6 months and patients who are unable to follow radiation safety guidelines are contraindications [22, 23, 41].

Patients with overt hyperthyroidism and free T4 levels 2–3 times upper limit should be pre-treated with beta adrenergic blockers and ATD (methimazole) to prevent post-therapy worsening of symptoms. Elderly patients and those with comorbid like atrial fibrillation, heart failure, diabetes mellitus, pulmonary hypertension, renal failure and infection should get pre-therapy ATD along with optimization of their medical conditions. ATD should be stopped 3–5 days before therapy and again given 3–7 days after therapy till normalization of thyroid functions where it is tapered off. Levothyroxine substitution is started once patient become hypothyroid [42].

Grave's orbitopathy can be temporary and improves after definitive treatment of Grave's disease. In some instances, it can persist or even deteriorates after treatment. The risk of developing orbitopathy after RAI therapy is 15–30%, while its 10 and 16% after ATD and surgery respectively and it can develop any time after treatment. The deterioration of Grave's orbitopathy after RAI therapy is attributed to post-therapy hypothyroidism and increase serum level of thyroid autoantibodies. This deterioration is transient and can be managed by early initiation of thyroxin replacement and corticosteroids. Patients with pre-existing thyroid eye disease should be treated with higher radioiodine dose to achieve quick and sharper response and to avoid slow rise in autoantibodies level due to slow destruction of thyroid follicular cells. This higher dose activity along with early initiation of levothyroxine substitution can prevent worsening of disease. Euthyroid status in such patients before therapy is usually recommended. Smoking is a risk factor and predictor of therapeutic outcome and is associated with more frequent worsening and severe symptoms. A short course of low dose corticosteroids can be added with RAI therapy in non-smokers with mild active eye disease and smokers with mild or inactive eye disease. Patients with moderate to severe active thyroid eye disease should be consider for thyroid surgery or ATD. However, therapeutic efficacy of RAI in such cases needs to be evaluated [22, 23, 43].

#### *5.9.2 Pediatric Grave's disease*

Treatment options for pediatrics Grave's disease are ATD, RAI therapy and surgery. ATD are considered first-line treatment options, however incidence of relapse is very high in this age group with only 20–30% patients achieving remission after 2 years. Therefore, majority of patients need definitive treatment with either RAI ablation or surgery. The goal of RAI therapy is to achieve hypothyroidism, recommended by both ATA and ETA treatment guidelines. Usually administering high activity in single dose is recommended to prevent need of additional therapy and also minimize the risk of relapse. Low dose is associated with risk of developing nodules or malignancy at later stage in partially irradiated thyrocytes. Fixed dose (150 μCi/gm) or calculated dose protocol can be used to deliver optimal therapeutic dose. Majority of the patients (~95%) achieves hypothyroidism in 2–3 months after therapy and decrease in serum TSH level can be seen in within a week after therapy. RAI therapy should be avoided in patients with active orbitopathy [22, 43, 44].

#### *5.9.3 Toxic nodular goiter*

RAI and thyroidectomy are the two effective and safe treatment options for toxic nodular disease. The decision to select a particular treatment option is based on many factors taking into account patient preference as well. RAI is usually preferred

#### *Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

in old age patients, patients with significant comorbids, prior surgery or irradiation to neck, small sized goiter and lack of experienced surgeon. The goal of therapy is long term alleviation of hyperthyroid state and achieve euthyroidism and volume reduction. Euthyroidism is achieved 50–60% at 3 months and 80% at 6 months after RAI therapy. Risk of hypothyroidism is very low as compared to Grave's disease. The incidence of hypothyroidism after therapy is 3% at 1 year while 64% after 20 years and more common in patients under 50 years of age.

Pretreatment with beta blockers is recommended in patients who are at risk of worsening of symptoms after therapy including elderly or those with comorbids and overt hyperthyroidism however the use of ATD before therapy needs careful monitoring and caution. ATD use before therapy can cause normal or raised TSH levels resulting in increased radiation dose to peri-nodular and contralateral thyroid tissue leading to hypothyroidism. Focal uptake in nodule with suppressed uptake in surrounding parenchyma and TSH levels is the basis of RAI treatment. Adequate radiation should be administered in single dose to achieve therapeutic goals. RAI is either given as fixed dose activity (10–20 mCi) or calculated on the basis of thyroid size and radioiodine uptake values using 150–200 μCi/gm calculated fixed dose. There is estimated 20% risk of treatment failure of TMNG and 6–18% for adenoma [22, 43, 45].

#### *5.9.4 Non-toxic nodular goiter*

Although radioiodine therapy is less commonly indicated treatment option in this group, it is still preferred in patients with recurrent goiter after surgery and comorbids which makes surgery riskier. The aim of therapy is to relive compression symptoms by volume reduction. Radioiodine uptake in non-toxic nodular goiter is usually low, sometimes even 15–20% after 24 hours of administration effecting the efficiency. This radioiodine uptake can be enhanced by low iodine diet consumption for at least 2 weeks before therapy, lithium, avoiding diuretics and recombinant human TSH (rhTSH). rhTSH can increase radioiodine uptake up to 100% without effecting halflife. However, its use is only limited in treatment of thyroid cancer. ATD can be used to increase endogenous TSH seems promising and needs further studies [46].

#### **5.10 Follow-up**

Treated patients should be regularly reviewed to assess treatment response and timely detection of radioiodine induced hypothyroidism or post-therapy immunogenic hyperthyroidism. Usually, patient respond to therapy with normalization of thyroid function test within 4–8 weeks. Hypothyroidism commonly occur between 2 and 6 months but can occur after 4 weeks after therapy. First TSH and free T4 levels should be done 4–6 weeks after therapy to detect the early effects of therapy. Subsequent visit should be done after 3 months because some patients develop severe hypothyroidism followed by yearly follow-up depending on clinical condition. Decision to start thyroxin replacement therapy depends on serum fT4 and TSH level along with clinical features. Dose should be sub-replacement level and should be titrated according to serum free T4 levels.

In cases of overt hyperthyroidism, 3–5 days after therapy ATD are usually recommended. For patients with persistent thyrotoxicosis especially Grave's disease, retherapy is considered after 6–12 months. However, re-therapy is usually less effective due to stunning effect. In some cases, a third session may be needed if patient is still hyperthyroid. In refractory cases patient is referred for surgery [38].

#### **5.11 Contraindications**

Pregnancy and breast feeding are absolute contraindication for RAI-131 therapy. Usually, fetal thyroid tissue begins to accumulate iodine by 10–13th week of gestation. Also, radioiodine can freely cross placenta. If radioiodine is given during this period, it will damage thyroid tissue. So, all women of child bearing age should be tested for pregnancy using serum or urine β-hCG levels within 24–48 hours of therapy. Serum β-hCG level testing is more sensitive. Pregnancy test may remain negative for 7–10 days after fertilization. So, in doubtful cases patient should be counseled regarding the limitation of test and therapy be delayed till next cycle. Post-therapy conception should be delayed for 6 months to allow time for dose adjustment of thyroxin to get favorable values for pregnancy. This time also apply for male patient as well [39].

Lactating breast tissues has the ability to concentrate radioiodine maximizing radiation dose. Lactation usually ceases 4–6 weeks after child birth in the absence of breast feeding and 4–6 weeks after cessation of breast feeding. Therapy should be delayed till lactation ceases in order to minimize radiation dose to breast. Some studies suggest that breast feeding should not be resumed till birth of next child.

Uncontrolled hyperthyroidism, active thyroid eye disease especially in smokers, coexisting malignancy and non-compliance to radiation safety precautions are some other relative contraindications for therapy [47].

#### **5.12 Side effects**

Generally, RAI-131 therapy is well tolerated and majority of patients experience no side effects. However, some patients do experience adverse effect related to thyroid function, size, immunological response or as a result of extra-thyroidal irradiation.

Patients with large goiter may develop painful swelling of thyroid mimicking as sore throat lasting for up to 1 week following therapy. These symptoms are likely due to actinic thyroiditis i.e. result from radiation. It is usually managed with ice, NSAIDs and steroids if not resolved spontaneously. Slight discomfort of salivary (sialadenitis) with associated dry mouth (xerostomia) may occur in about 39% of the patients, but these are transient effects and permanent damage is very uncommon. Sialogogues or lemon juice can be used to accelerates radioiodine excretion by stimulating salivary glands resulting in approximately 40% reduction in dose to glands. This treatment should not be given in first 24 hours after therapy as it will result in increased absorbed dose due to rebound phenomena. Dry eyes (xerophthalmia) is very rare after radioiodine therapy. Mild leukopenia and thrombocytopenia can occur in some patients but it is usually temporary (6–10 weeks). Nausea and rarely vomiting can occurs immediately after therapy in some patients and resolve withing 24–72 hours [48].

Transient rise in serum thyroid hormones level may occur due to release of stored hormones leading to thyrotoxicosis. Cases of RAI-131 induced thyroid storm has also been reported with fatal outcome. This transient rise in hormone level depends on pretreatment status. Patients who have been poorly controlled before therapy usually leads to exacerbation of hyperthyroidism requiring therapy. To reduce this risk, pre-treatment with ATD before therapy can be done to deplete intrathyroidal hormone stores [49].

Post-treatment hypothyroidism is an expected result following RAI-131 therapy indicating actual therapeutic response. Some authors consider it as a side effect of therapy. Recent ATA guidelines consider hypothyroidism the ultimate outcome of therapy and is more common in Grave's disease as compared to nodular thyroid disease. It may occur in early post-treatment period or develops gradually over a period

#### *Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

of time. Delayed onset hypothyroidism incidence continues to increase with time after therapy at a rate of 4% per year in following year so that at 25 years nearly all patients become hypothyroid [41]. The ablative dosage concept for Grave's disease leads to thyroxin substitution in nearly all treated patients. In patients with toxic nodular thyroid disease incidence of hypothyroidism is greater in younger patients with age < 50 years in long-term follow-up. In general, majority of the patients usually follow transient hypothyroidism followed by euthyroidism and then permanent hypothyroidism after radioiodine therapy. Transient hypothyroidism is caused by disruption of normal hypothalamus-pituitary- thyroid axis and depletion of intra-thyroidal hormone stores.

Radioiodine induced thyroid damage can lead to immunological response due to release of thyroid autoantibodies peaking approximately 3–6 months after therapy. TRAb usually return to baseline within 1 year but remains detectable for many years. This thyroid autoimmunity results in thyroid associated orbitopathy, seen in approximately 15–30% of patients with Grave's disease and more common in patients with previous history of thyroid eye disease. The risk is associated with release of autoantibodies and development of hypothyroidism. Steroids have shown promising results in such cases. In patients with toxic or non-toxic nodular goiter, about 1–5% patients may develop de novo TRAb and occasionally orbitopathy. The risk is more pronounced in patients with previously circulating autoantibodies (TPO) and usually resolve spontaneously [48].

Fertility issues with radioiodine therapy are rare and late side effects. Some men may experience transient increase in gonadotropins and decrease spermatogenesis due to damage to germinal epithelium except in those receiving higher therapeutic doses in the range 200–300 mCi in whom permanent infertility may occur. Radiation dose associated with single ablative therapy does not cause permanent germinal epithelium damage, however patients requiring multiple therapy administration infertility can result due to cumulative dose effect. In such cases sperm storage can be considered. In female, about 20–30% experience menstrual abnormalities like amenorrhea or metrorrhagia lasting for 1 year and early menopause. RAI-131 therapy can also damage ovarian reserves in women treated at later ages [50].

Radioactive iodine therapy is thought to be associated with risk of developing cancer. This association has been extensively investigated and no convincing evidence could be established in development of thyroid cancer or secondary malignancies after therapy. A small negligible increase in relative risk of thyroid cancer after radioiodine therapy has been reported in some epidemiological studies. However, this seems to be associated with underlying thyroid disease rather the therapy itself. Some studies have reported the risk of developing secondary malignancies including stomach, kidney and breast after therapy and this risk is higher in patient with toxic nodular goiter. But this risk may be attributed to other confounding factors like age, smoking etc. Nevertheless, the risk of developing malignancy after therapy is negligible and needs further log-term studies [48, 51].

In patients with large goiter and retrosternal extension, tracheal compression can occur after therapy. In such cases therapy should be done in collaboration with otolaryngology department to address compressive emergency. Laryngeal edema, dysgeusia and recurrent laryngeal nerve palsy can occur rarely.

#### **5.13 Radiation safety procedures**

The amount of radiation received by a person from treated patient depends on activity retained in patient, distance and duration of contact. Mostly radioiodine

#### *Hyperthyroidism - Recent Updates*

therapy is administered as outpatient in registered and authorized facility. In case of indoor therapy, patient is released when no person is likely to receive greater than 5 mSv, when survey meter reading is less than 0.07 mSv/hour at 1 meter and when administered activity is less than 33 mCi or less. Before releasing the patient or after outdoor therapy, nuclear physician must instruct the patient on how to minimize unnecessary radiation exposure to surrounding people. Written information should also be provided.

Patient should be encouraged to drink plenty of water during first 8 hours and empty bladder frequently to eliminate excessive activity. Flush toilet twice and rinse sink and tub after use. Wash hands for 20 seconds. Maintain a distance of at least 3 feet from surrounding people for first 8 hours and use private car to drive home, if not possible maintain a distance of at least 3 feet from driver and passengers. Public transport should be avoided.

Do not share utensils, towels or wash clothes for 48 hours. Wash bed linen, towels and garments stained with urine, sweat or other body fluid. After washing these can be used by others.

Patient should sleep alone in separate room and avoid close physical contact for at least 7 days. Maintain a distance of 3–6 feet from pregnant females and children below 18 years of age. Infant and small children requiring nursing care should be provided with caretaker for at least 1 week. Avoid activities requiring close contact for more than 5 min for first week like public transport, movie theater, class room etc.

Both men and women should avoid pregnancy for at least 6 months. Breast feeding should not be resumed for current child. Small amount of radiation can trigger radiation sensors at airports, hospitals and sensitive buildings for up to 3 months. In such cases documentary proof regarding therapy can be obtained from concerned doctor [52].

#### **6. Conclusion**

Radioiodine therapy for hyperthyroidism is safe, cost-effective and efficient treatment modality. Patient selection, preparation and appropriate dose calculation to achieve desired therapeutic response are the corner stone of treatment. Post-therapy hypothyroidism should be anticipated and early initiation of thyroxin is associated with less clinical manifestations and also prevent worsening of orbitopathy.

*Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

#### **Author details**

Fida Hussain1 \*, Muhammad Adil1 and Mehmood Hussain<sup>2</sup>

1 Nuclear Medical Center, Armed Forces Institute of Pathology, Rawalpindi, Pakistan

2 Pak Emirates Military Hospital, Rawalpindi, Pakistan

\*Address all correspondence to: fhsnmc@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Caputo M, Pecere A, Sarro A, Mele C, Ucciero A, Pagano L, et al. Incidence and prevalence of hyperthyroidism: A population-based study in the Piedmont region, Italy. Endocrine. 2020;**69**(1):107-112

[2] Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews. Endocrinology. 2018;**14**:301-316

[3] Sánchez-Rodríguez MA, Castrejón-Delgado L, Zacarías-Flores M, Arronte-Rosales A, Mendoza-Núñez VM. Quality of life among post-menopausal women due to oxidative stress boosted by dysthymia and anxiety. BMC Women's Health. 2017;**17**(1):1-9

[4] Fahey FH, Grant FD, Thrall JH. Saul hertz, MD, and the birth of radionuclide therapy. EJNMMI Physics. 2017;**4**(1):1-7

[5] Okosieme OE, Taylor PN, Dayan CM. Should radioiodine now be first line treatment for graves' disease? Thyroid Research. 2020;**13**(1):1-7

[6] Rousset B, Dupuy C, Miot F, Dumont J. Thyroid Hormone Synthesis and Secretion. www.thyroidmanager. org. . Published by ENDOCRINE EDUCATION Inc, MA South Dartmouth, 2022 02748

[7] Sugimoto K, Mori K. Thyroid-Stimulating Hormone Regulation and Transcription in Hypothyroidism. In: Springer D, editor. Hypothyroidism - Influences and Treatments [Internet]. London: IntechOpen; 2012 [cited 2022 Oct 03] Available from: https://www. intechopen.com/chapters/27836 doi: 10.5772/32002

[8] Klein JR. The immune system as a regulator of thyroid hormone activity. Experimental Biology and Medicine. 2006;**231**(3):229-236

[9] Aghini-Lombardi F, Antonangeli L, Martino E, Vitti P, Maccherini D, Leoli F, et al. The spectrum of thyroid disorders in an iodine-deficient community: The Pescopagano survey. The Journal of Clinical Endocrinology & Metabolism. 1999;**84**(2):561-566

[10] Raheem N, Ahmed SA, Samaila MO. Histopathological pattern of thyroid diseases in Zaria: A 10-year review. Nigerian Postgraduate Medical Journal. 1 Jan 2018;**25**(1):37

[11] Sajjadi-Jazi SM, Sharifi F, Varmaghani M, Meybodi HA, Farzadfar F, Larijani B. Epidemiology of hyperthyroidism in Iran: A systematic review and meta-analysis. Journal of Diabetes & Metabolic Disorders. 2018;**17**(2):345-355

[12] Devereaux D, Tewelde SZ. Hyperthyroidism and thyrotoxicosis. Emergency Medicine Clinics. 2014;**32**(2):277-292

[13] Galindo RJ, Hurtado CR, Pasquel FJ, García Tome R, Peng L, Umpierrez GE. National trends in incidence, mortality, and clinical outcomes of patients hospitalized for thyrotoxicosis with and without thyroid storm in the United States, 2004-2013. Thyroid. 2019;**29**(1):36-43

[14] Antonelli A, Ferrari SM, Ragusa F, Elia G, Paparo SR, Ruffilli I, et al. Graves' disease: Epidemiology, genetic and environmental risk factors and viruses. Best Practice & Research Clinical Endocrinology & Metabolism. 2020;**34**(1):101387

*Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

[15] Khalid N, Can AS. Plummer disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm. nih.gov/books/NBK565856/

[16] Mulita F, Anjum F. Thyroid Adenoma. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK562252/

[17] Alfadda A, Sallam R, Elawad G, AlDhukair H, Alyahya M. Subacute thyroiditis: Clinical presentation and long term outcome. International Journal of Endocrinology. 2014;**2014**:1-7

[18] Hennessey JV. Subacute thyroiditis. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Available from: https://www.ncbi. nlm.nih.gov/books/NBK279084/

[19] Samuels MH. Subacute, silent, and postpartum thyroiditis. The Medical Clinics of North America. 2012;**96**(2):223-233

[20] Sengul I, Sengul D, Pelikan A. Iodine induced hyperthyroidism: Do you mind? Sanamed. 2020;**15**(2):215-217

[21] Hammamy R, Farooqui K, Shariff M. Factitial hyperthyroidism: A diagnostic challenge. Authorea Preprints. 2021

[22] Bahn R, Burch H, Cooper D, Garber J, Greenlee M, Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;**21**(6):593-646

[23] Kahaly G, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce S. 2018 European thyroid association guideline for the Management of Graves' hyperthyroidism. European Thyroid Journal. 2018;**7**(4):167-186

[24] Asban A, Dream S, Lindeman B. Is hyperthyroidism diagnosed and treated appropriately in the United States? Advances in Surgery. 2019;**53**:117-129

[25] McCready VR. Radioiodine—The success story of nuclear medicine. European Journal of Nuclear Medicine and Molecular Imaging. 2017;**44**:179-182

[26] Borges de Souza P, McCabe C. Radioiodine treatment: An historical and future perspective. Endocrine-Related Cancer. 2021;**28**(10):T121-T124

[27] Amdur RJ, Mazzaferri EL. Half-life and emission products of I-131. Essentials of Thyroid Cancer Management. Boston, MA: Springer; 2005 pp. 165-168

[28] Muhammad W. Radioactive iodine therapy for hyperthyroidism: Physics, treatment protocols and radiation protection. In: Handbook of Hyperthyroidism: Etiology, Diagnosis and Treatment. New York: Nova Science Publishers, Inc.; 2009. pp. 295-314

[29] Marzo K. Radiopharmaceuticals for Therapy of Thyroid Diseases. In: Bombardieri E, Seregni E, Evangelista L, Chiesa C, Chiti A, editors. Clinical Applications of Nuclear Medicine Targeted Therapy. Cham: Springer; 2018. Available from: https://doi. org/10.1007/978-3-319-63067-0\_2

[30] Bombardieri E, Seregni E, Evangelista L, Chiesa C, Chiti A. Clinical Applications of Nuclear Medicine Targeted Therapy. 1st ed. Switzerland: Springer International Publishing; 2018

[31] Riley A, McKenzie G, Green V, Schettino G, England R, Greenman J. The effect of radioiodine treatment on the diseased thyroid gland. International Journal of Radiation Biology. 2019;**95**(12):1718-1727

[32] Padda IS, Nguyen M. Radioactive iodine therapy. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK557741/

[33] Nair D, Maweni R, Constantinou C, Kandiah S, Nagala S, Aung T. Clinical efficacy of fixed-dose radioactive iodine for the treatment of hyperthyroidism at a single Centre: Our experience. Irish Journal of Medical Science (1971). 2021;**191**(4):1659-1665

[34] Allahabadia A, Daykin J, Sheppard MC, Gough SC, Franklyn JA. Radioiodine treatment of hyperthyroidism prognostic factors for outcome. Journal of Clinical Endocrinology & Metabolism. 2001;**86**(8):3611-3617

[35] Pardo FJ, Serrano RL, Cases FJ, Peña MC, Crespo-Jara A, Vicente AM, et al. A prospective comparative study of two methods for the individual calculation of 131I activity in the treatment of hyperthyroidism. Endocrinología, Diabetes y Nutrición (English ed.). 2020;**67**(9):568-577

[36] Liu M, Jing D, Hu J, Yin S. Predictive factors of outcomes in personalized radioactive iodine (131I) treatment for graves' disease. The American Journal of the Medical Sciences. 2014;**348**(4):288-293

[37] Szumowski P, Mojsak M, Abdelrazek S, Sykała M, Amelian-Fiłonowicz A, Jurgilewicz D, et al. Calculation of therapeutic activity of radioiodine in graves' disease by means of Marinelli's formula, using technetium (99mTc) scintigraphy. Endocrine. 2016;**54**(3):751-756

[38] Dietlein M. Radioiodine therapy for benign thyroid disease. In: Clinical Nuclear Medicine. Cham: Springer; 2020. pp. 815-829

[39] Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al. Guidelines of the American Thyroid Association for the diagnosis and Management of Thyroid Disease during Pregnancy and Postpartum. Thyroid. 2011;**21**(10):1081-1125

[40] Laplano NE, Mercado-Asis LB. Recombinant TSH and lithium overcomes amiodarone-induced low radioiodine uptake in a thyrotoxic female. International Journal of Endocrinology and Metabolism. 2012;**10**(4):625

[41] Clarke SE. Radioiodine therapy for benign thyroid disease. In: Clinical Nuclear Medicine. Berlin, Heidelberg: Springer; 2007. pp. 409-417

[42] Silberstein E, Alavi A, Balon H, Clarke S, Divgi C, Gelfand M, et al. The SNMMI practice guideline for therapy of thyroid disease with 131I 3.0. Journal of Nuclear Medicine. 2012;**53**(10):1633-1651

[43] Aktolun C, Urhan M. Radioiodine therapy of benign thyroid diseases: Graves' disease, Plummer's disease, non-toxic goiter and nodules. In: Nuclear Medicine Therapy. New York, NY: Springer; 2013. pp. 281-314

[44] Kaplowitz PB, Jiang J, Vaidyanathan P. Radioactive iodine therapy for pediatric Graves' disease: A single-center experience over a 10-year period. Journal of Pediatric Endocrinology & Metabolism. 2020;**33**(3):383-389

*Radioactive Iodine Therapy for Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.108128*

[45] Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: Current status and future perspectives. Endocrine Reviews. 2003;**24**(1):102-132

[46] Szumowski P, Abdelrazek S, Sykała M, Mojsak M, Żukowski Ł, Siewko K, et al. Enhancing the efficacy of 131I therapy in non-toxic multinodular goitre with appropriate use of methimazole: An analysis of randomized controlled study. Endocrine. 2020;**67**(1):136-142

[47] Gurgul E, Sowinski J. Primary hyperthyroidism—Diagnosis and treatment. Indications and contraindications for radioiodine therapy. Nuclear Medicine Review. 2011;**14**(1):29-32

[48] Bonnema SJ, Hegedüs L. Radioiodine therapy in benign thyroid diseases: Effects, side effects, and factors affecting therapeutic outcome. Endocrine Reviews. 2012;**33**(6):920-980

[49] McDermott MT, Kidd GS, Dodson LE Jr, Hofeldt FD. Radioiodine-induced thyroid storm: Case report and literature review. The American Journal of Medicine. 1983;**75**(2):353-359

[50] Navarro P, Rocher S, Miró-Martínez P, Oltra-Crespo S. Radioactive iodine and female fertility. Scientific Reports. 2022;**12**(1):1-7

[51] Lutterman S, Zwaveling-Soonawala N, Verberne H, Verburg F, van Trotsenburg A, Mooij C. The Efficacy and Short- and Long-Term Side Effects of Radioactive Iodine Treatment in Pediatric Graves' Disease: A Systematic Review. European Thyroid Journal. 2021;**10**(5):353-363

[52] Sisson TA, Freitas J, McDougall IR, Dauer LT, Hurley JR, Brierley JD, et al.

Radiation safety in the treatment of patients with thyroid diseases by radioiodine 131I: Practice recommendations of the American Thyroid Association. Thyroid. 2011;**21**(4):335-346

#### **Chapter 4**

### Therapeutic Options in Graves' Hyperthyroidism

*Javaid Ahmad Bhat, Shoiab Mohd Patto, Pooran Sharma, Mohammad Hayat Bhat and Shahnaz Ahmad Mir*

#### **Abstract**

The classical approach to treating Graves' hyperthyroidism involves rapid control of the symptoms, generally with a beta adrenergic blocker, and reduction of thyroid hormone secretion by antithyroid drugs (ATDs) and/or using one of the several modalities available, including radioactive iodine therapy (RAI), and surgery; the selection of the treatment modalities often varies according to different guidelines, patient preferences and local traditions. Thionamides are invariably used as firstline medication to control hyperthyroidism and induce remission of the disease, thereby relieving the symptoms. In case of failure of the medical therapy, which is not uncommon, definitive treatment with surgery or RAI is the standard modality of management after due consideration and discussion with the patients. However, the therapeutic options available for patients with Graves' hyperthyroidism have remained largely unchanged for the past several decades despite the current treatments having either limited efficacy or significant adverse effects. The clinical demand for new therapeutic regimens of Graves' disease has led to the emergence of several new therapeutic ideas/options like biologic, peptide immunomodulation and small molecules, currently under investigations which may lead to the restoration of a euthyroid state without the requirement for ongoing therapy, but the potential risk of immunocompromise and cost implications needs careful consideration.

**Keywords:** Graves' disease, anti-thyroid drugs, radioactive iodine, relapse and remission, thyroidectomy

#### **1. Introduction**

Graves' disease (GD) is an autoimmune thyroid disorders characterized by multi-systemic involvement, resulting from a complex interactions between genetic and environmental factors [1, 2]. It has an annual incidence of 20 to 50 cases per 100,000 individuals and is the most common cause of hyperthyroidism, accounting for 60–80% of the cases [3]. As with the other autoimmune diseases, women are affected more than men, with a peak incidence occurring between the age of 30 and 50 years, although no age is immune to the disease. It is estimated that approximately 0.5% of men and 3% of women develop Graves' disease during their lifetime [4]. Hyperthyroidism, diffuse goiter, and/or orbitopathy are the characteristic features of GD, although involvement of other organ systems is not rare. The age of the patient, severity and duration of the disease, determine the presentation and the course of the disease [5]. variety of characteristic symptoms and physical findings of the disease either results from hyperthyroidism (goiter in certain cases) or is a consequence of underlying autoimmunity [6]. Impaired quality of life, work disability [7, 8] and an increased risk of death [9] associated with GD render it imperative to understand the effectiveness of the different modalities of treatment available for the GD to acheive lasting euthyroidism for a favorable outcome. Clinical and biochemical features associated with elevated levels of thyroid hormone, particularly of a long duration and/or orbitopathy, elevated levels of TSH-receptor antibodies (TRAbs) along with a diffuse increase in radioactive iodine or technetium uptake scan, confirm the diagnosis of GD. The association of GD with plethora of systemic manifestations, including typical and atypical, and a relatively prolonged course on account of higher rates of recurrences and relapse responsible for significant morbidity and an increased risk of mortality warrant proper management of the disease and the associated complications [10]. The treatment for GD comprises rapid control of the symptoms, generally with a beta adrenergic blocker, and reduction of thyroid hormone levels using one of the several modalities available, including ATDs to block thyroid hormone synthesis, destruction of the thyroid gland by RAI, and or removal of thyroid gland by surgery respectively; the selection of the optimal approach often varies according to the patient preference, different guidelines, clinical factors and local traditions. The therapeutic options available for patients with Graves' hyperthyroidism have to some extent been successful in reliving the patients of signs and symptoms but lack of efficacy of ATDs in successful maintenance of remission after stopping these drugs in many patients and/or need for lifelong thyroid hormone replacement on account of the lack of functional thyroid tissue in patients treated with either radioiodine, or surgery and improvement in quality of life of in some patients has led to the need for newer therapeutic options with better disease outcome and improved degree of morbidity and mortality. The demand for new therapeutic options, combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves' disease. The novel therapeutic options under investigations like biologic, peptide immunomodulation and small molecule, may lead to the restoration of a euthyroid state without the requirement for ongoing therapy, but the potential risk of immunocompromise and cost implications needs careful consideration.

In this chapter we try to dwell upon the traditional treatment options, such as antithyroid drugs, radioiodine and or thyroidectomy, available for Graves' hyperthyroidism, besides new strategies under investigation and summarize the effective components of different modalities of management to restore euthyroidism for a favorable outcome of the disease.

#### **2. Management options for Graves' disease**

The management of GD has been largely directed towards controlling the hyperthyroidism despite the autoimmune mechanisms responsible for the syndrome. Treatment involves alleviation of symptoms and correction of the thyrotoxic state. Adrenergic hyperfunction is treated with beta-adrenergic blockade. Correcting the excessive thyroid hormone levels can be accomplished with antithyroid medications that block the synthesis of thyroid hormones or by treatment with radioactive iodine

#### *Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

and surgery resulting in loss of functional thyroid tissue. The therapeutic options available are: (I) antithyroid drug therapy, (II) surgery, and (III) radioiodine. These modalities are safe and cost-effective and can be the first-line treatment for hyperthyroidism not only due to GD, but also due to toxic adenoma, and toxic multinodular goiter [11]. Despite the use of these three treatments for decades, selection of the optimal therapy for GD still poses a challenge for both the physician and the patient. Each modality has its unique advantages and disadvantages with no single best therapy for all patients. A prudent approach is to make a selection after a thoughtful discussion with the patient regarding advantages, risks, and cost-effectiveness, taking into consideration the values and preferences of the patient. Autoimmune nature of the disease and lack of treatment to address the underlying autoimmune pathogenesis has turned the research focus on the potential use of immunotherapy in GD [12]. Despite the good understanding of the underlying mechanism, it is worth mentioning 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 [13].

#### **3. Antithyroid drugs therapy for GD**

ATD are used as first line therapy in the majority of patients and represent the predominant therapy in Europe, Asia, and as bridge therapy in the USA [12]. The main ATDs are thionamides, such as carbimazole (CBZ), methimazole (MMI) the active metabolite of the CBZ and propylthiouracil (PTU). CBZ, a prodrug molecule needs decarboxylation in the liver to get converted to its active substance MMI. Thionamides block the formation of thyroid hormone T3 and T4 by inhibiting enzyme thyroid peroxidase. A 12- to 18-month course of antithyroid drugs may lead to a remission in approximately 50% of patients with theoretically significant (albeit rare) adverse reactions.

Thyroid gland plays the central role in the metabolism of iodine and synthesis of thyroid hormones such as T3 and T4. Thyroid follicular cells take up the iodine from blood stream through an active transport system constituted by a transporting protein sodium iodide symporter (NIS) which is located at the basolateral membrane of these follicular cells. This iodine is used for the process of iodination whereby iodine binds to tyrosine molecule of thyroglobulin (Tg) promoted by enzyme thyroid peroxidase. The process of iodination of tyrosine molecules leads to the formation of 3-monoiodotyrosine (MIT) and 3, 5-diiodotyrosine (DIT) which is coupled afterwards leading to the formation of thyroid hormones. Triiodothyronine (T3) hormone is formed by coupling of one molecule each of MIT and DIT and thyroxine (T4) hormone is formed by coupling of two DIT molecules. These thyroid hormones are stored in the thyroid cells as colloid in a quantity enough to meet the body requirements for up to 3 months. The whole process of formation of thyroid hormones is regulated by thyroid stimulating hormone (TSH) released from anterior pituitary gland which stimulates the expression of NIS through TSH receptor (TSH-R) which then activates follicular cells. The uptake and metabolism of the radioactive iodine (I-123 and I-131) follows the same process as nutritional iodine to get incorporated into the thyroid hormones [13].

Thionamide drugs are actively transported into the thyroid where they serve as the preferential substrate for the iodinating intermediate of thyroid peroxidase and thus interfere with the iodination of tyrosine resulting in inhibition of the synthesis of T3 and T4 hormones. This whole process results in the diversion of oxidized iodine from

#### *Hyperthyroidism - Recent Updates*

the tyrosyl iodination sites in thyroglobulin. Thionamides also inhibit the coupling of iodothyronines and hence reduce the biosynthesis of thyroid hormones [14]. In addition, PTU also blocks extrathyroidal deiodination of T4 to T3 resulting in less conversion of T4 to T3, but this process of peripheral inhibition is of little clinical significance other than perhaps in the management of thyrotoxic crisis, when it is important to lower the raised serum T3 concentration as quickly as possible.

ATDs are indicated as a first-line treatment of GD, particularly in younger subjects, and also for short-term treatment of GD before definitive therapy with RAI or thyroidectomy [6]. Available only as oral preparations, they however, have been used as retention enemas in patients in whom oral intake is not possible or is contraindicated. Alteration of intrathyroidal immunoregulatory mechanisms have been reported with ATDs which is believed to contribute to long term success of maintenance of disease remission. In addition they have been reported to have immunosuppressive effect resulting in reduction of TSHR-Ab levels, soluble IL-2 receptor (sIL-2R) and intercellular adhesion molecule-1 (ICAM-1) [15]. However, this immunomodulatory effect has proved to be short-lived as is evident from the presence of frequent relapse of Graves' hyperthyroidism in patients after drug withdrawal.

Historically, CBZ has been the drug of choice in the United Kingdom, but in all other areas of the world, MMI has been the drug of choice. The use of PTU is restricted to first trimester of pregnancy and in patients who have reacted adversely to CBZ or MMI and is also widely employed in the America.

ATDs are given consideration as first line therapy in the following category of patients with Graves' disease [16].


#### **3.1 Carbimazole**

Carbimazole, a pro-drug on oral administration is converted to methimazole in liver which is an active substance. Historically, CBZ has been the drug of choice in the United Kingdom and is also available in Europe, but is not approved for use in the United States. Conversion to active substance methimazole is rapid and almost complete either in the gastrointestinal tract or immediately on absorption, as is evident from the observation that only drug concentrations of methimazole but not carbimazole are detected in the serum and thyroid gland after ingestion. Ten milligrams of carbimazole is equivalent to 6 mg of methimazole. Carbimazole acts as the substrate

#### *Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

for thyroid peroxidase (TPO) and decrease the incorporation of iodide into tyrosine molecules. In addition, it also inhibits coupling of iodinated precursor molecules like mono-iodinated and di-iodinated residues to form T4 and T3 hormones.

Carbimazole has been preferred in some patients on account of fewer side effects such as less frequent gastrointestinal problems compared with methimazole. The starting dose of CBZ is usually between 20 to 40 mg/day depending on the severity of the hyperthyroidism. The initial high dose of the drugs can be tapered down after 4 to 8 weeks in what is referred to as the titration regimen. A maintenance dose of 5 to 20 mg of CBZ is achieved by about 4 to 6 months and this is continued for 12 to 18 months. Once a patient is on a maintenance dose of CBZ, thyroid hormone assessment is done every 2 to 4 months and the treatment continued for 12 to 18 months depending on the response to achieve the immunomodulatory role of the drug to reduce the rate of recurrence of the disease. The patients are followed on regular basis based on thyroid hormone levels and clinical status of the patient. Some studies have also advocated block and replacement regimen to avoid severe hypothyroidism during treatment where CBZ/ MMI in dose of 30–50 mg daily along with thyroxin replacement is used throughout the coarse but side effects of ATD are more with this kind of regimen [17].

#### *3.1.1 Adverse effects*

Adverse effects associated with the use of antithyroid medication range from milder adverse events such subcutaneous eruptions, gastrointestinal disorders and arthralgia's to more serious complications as agranulocytosis, frank polyarthritis and hepatotoxicity (Explained in Section 2.1.2).

#### **3.2 Methimazole**

Methimazole, an antithyroid drug is an active metabolite of carbimazole- a prodrug, which belongs to the thionamide class. On entering the blood stream following oral administration, methimazole inhibits the enzyme thyroid peroxidase and thus decrease the incorporation of iodide into tyrosine residues of thyroglobulin resulting in the inhibition of the synthesis of thyroid hormones T4 and T3. Methimazole also inhibits oxidation of iodine and the coupling of iodotyrosyl residues and thus blocks the production of thyroid hormone [18].

The first line of therapeutic option for the treatment of Graves hyperthyroidism is usually Methimazole with few exceptions, due to the lower risk of hepatotoxicity compared to propylthiouracil [18]. Methimazole is usually the started from 10 to 30 mg daily in divided doses, with titration and variable maintenance doses depending on the severity of hyperthyroidism. As the disease goes in remission, dose is gradually reduced through the course of disease based on severity of the illness referred as "titration regimen". Thyroid function tests are done at 6–8 weekly intervals after initial treatment, and the dose is titrated based on T4 and T3 hormone levels. The levels of T3 & T4 are more reliable to guide the dosage of antithyroid drugs as the TSH values remain suppressed for long time. The oral route of administration and non-requirement dose adjustment except in patients with severe hepatic impairment makes the of MMI drug of choice worth consideration as ATD [18]. With the half-life exceeding 6 hours in follicular cells [19, 20], the administration of MMI in a single daily dose is considered to be effective [21, 22]. The patients with thyroid storm, require higher doses, with a starting dose of 60 to 80 mg per day with the dose divided every 4 to 8 hours, with a maximum dose of 120 mg [23].

Once a patient is on a maintenance dose of MMI, thyroid hormone assessment is done every 2 to 4 months and the treatment continued for 12 to 18 months depending on the response to achieve the immunomodulatory role of the drug to reduce the rate of recurrence of the disease.

#### *3.2.1 Adverse effects*

The adverse effects are usually not so common but serious drug reactions of methimazole seem to be dose related (40 mg/day or more). These adverse drug effects include agranulocytosis, hepatotoxicity, and teratogenicity [24].

Agranulocytosis can occur at any time during the course of MMI therapy but usually occurs in the first few months of initiation. Absolute granulocyte count of less than 500 per ml, fever and sore throat characterize the agranulocytosis. Patients are advised to stop the medication and report to the hospital for further management in case of development of such symptom. Treatment consists of stopping methimazole if the granulocyte count is less than 1000 per ml and give antibiotic treatment. Methimazole associated agranulocytosis predicts the risk of agranulocytosis due to propylthiouracil, thus necessitating the circumventing of the use of propylthiouracil in these patients.

Cholestasis characterize the MMI associated hepatotoxicity and is dose independent and shows slow recovery after discontinuation of the drug [25].

The teratogenic effects of MMI include aplasia cutis, facial dysmorphism, esophageal and choanal atresia, umbilical malformations as well as craniofacial malformations and are result of free placental crossing of the drug, especially in the first trimester. For this reason, the use of propylthiouracil in the first trimester of pregnancy is preferred [25, 26].

#### **3.3 Propylthiouracil**

Propylthiouracil is an antithyroid drug that is mostly used as a second treatment option in hyperthyroidism after MMI/CBZ owing to higher risk of hepatotoxicity. In patients with a contraindication to CBZ/MMI or radioactive iodine therapy, propylthiouracil provides an option to be used as second line treatment option. Propylthiouracil is however, preferred as the first line of treatment in patients with thyroid storm because of its greater efficacy on account of inhibition of the thyroid deiodinase resulting in the peripheral conversion of T4 to T3. Similarly in the first trimester of pregnancy, propylthiouracil is favored because of the relatively lower teratogenic profile compared to methimazole [25].

Propylthiouracil acts by inhibition of thyroid peroxidase, enzyme responsible for oxidization of iodine and its incorporation into the tyrosine molecule, resulting in inhibition of the formation of monoiodothyronine and diiodotyrosine. Unlike methimazole, propylthiouracil causes peripheral inhibition in conversion of T4 to T3 by inhibiting the enzyme deiodinase [25, 26].

The drug like CBZ is also available only as an oral preparation. The severity of the hyperthyroidism usually guides the starting dose of the propylthiouracil. The usual starting dose is 300 mg daily divided every 8 hours, with titration of the dose up to a maximum dose of 600 to 900 mg daily. However, the usual dose of propylthiouracil in patients with thyroid storm is 500 to 1000 mg daily divided every 4 hours [25, 26]. Once patient is euthyroid, the maintenance dose of propylthiouracil is around 100 to 150 mg per day.

*Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

#### *3.3.1 Adverse effects*

U.S. Food and Drug Administration's has issued a box warning highlighting higher risk of severe liver injury associated with use of propylthiouracil. As a consequence of this serious adverse effect, CBZ/MMI is preferred as first line of treatment except in patients with an adverse drug reaction to CBZ/MMI and during the first trimester of pregnancy [27, 28]. However, adverse effects of propylthiouracil has not been associated with the dose of drug unlike methimazole [24]. Hepatic injury and acute viral hepatitis like syndrome is one of the most perturbing adverse drug effects of the propylthiouracil, arising 2 to 12 weeks after starting the medication. These adverse drug reactions can occur at any time during the course of treatment but are usually observed during the first 6 months of treatment. The specific symptoms along with raised liver enzymes point to the initial diagnosis. The injury can be severe and many fatal cases have been described. The presence higher risk of hepatotoxicity in pregnancy, excludes the use of methimazole in the first trimester [25, 26].

ANCA-associated vasculitis has been associated with the use of propylthiouracil and is responsible for conditions like glomerulonephritis, alveolar hemorrhage, central nervous system compromise, and leukocytoclastic vasculitis. These conditions though less frequent, may be responsible for significant morbidity and may improve upon drug withdrawal or require additional immunosuppressive treatment [25, 26].

Agranulocytosis as an adverse reaction is seen in up to 0.5% of patients, especially in the first 3 months of treatment. The agranulocytosis may manifest with symptoms like sore throat, fever and decrease in absolute granulocyte count. Patient are educated about the possibility of this condition and instructed to stop the medication and report to the hospital for further management.

Hypersensitivity, interstitial nephritis, hypothyroidism, aplastic anemia and potential teratogenicity are the other adverse effects seen with use of propylthiouracil [25, 26].

#### **4. Radioiodine therapy**

Radioactive iodine has been used for several decades to treat thyroid disorders (both malignant and benign) and preferred first-line treatment in many cases like GD. A safe and effective management modality, RAI is used as definitive treatment for GD except for the development or worsening of thyroid eye disease in approximately 15–20% of patients [29]. RAI in GD involves systemic administration of I-131 for selective irradiation of hyper functioning thyroid gland. Radioiodine on administration is taken up by thyroid gland and is incorporated into the thyroid hormones. Ionizing damage and tissue necrosis by radioiodine is responsible for destruction of the follicle cells of the hyper functioning thyroid gland resulting in an eventual ablation of functional thyroid tissue and thus providing a definite therapy of hyperthyroidism thereby improving patient's quality of life.

Exacerbation of underlying orbitopathy apart, radioiodine therapy is well tolerated with fewer complications. The safety and efficacy of radioiodine treatment and the several beneficial effects over thyroid surgery and ATDs have been documented and are widely accepted. A beta-emitting radionuclide with a physical half-life of 8.4 days, I-131 is the radionuclide of choice to treat thyroid disorders. Beta-minus decay of I-131 results in emission of high-energy beta particles which are responsible for high

#### *Hyperthyroidism - Recent Updates*

radiation, particularly to the thyroid follicular cells, gradually leading to the destruction of these cells manifesting as volume reduction and therapy outcome in GD.

Radioiodine mediated radiobiological effects are the result of the DNA damage effected through breakage of molecular bonds, and/or through the formation of free radicals leading to genetic damage, mutations, or cell death. This leads to a decrease production of thyroid hormones and/or reduction in the size of thyroid gland. However, there are no ideal methods of predicting the clinical response or of measuring the individual radio sensitivity to RAI therapy [30].

RAI has been the most preferable treatment in USA for many years, but currently there is a tendency towards ATD therapy on account of being safe and definitive therapy for GD. The goal of RAI treatment is to radiate thyroid cells to render the patient euthyroid using low doses of I-131. Hypothyroidism being an inevitable and unpredictable progressive outcome of RAI treatment, is the desired result of RAI treatment and considered as the elimination of hyperthyroidism [31]. Though the RAI therapy is safe and effective and is considered as first line therapy in many cases but is preferably indicated for individuals who are at higher risk of surgical complications, or in those with a history of prior surgery or irradiation of the head and neck, previously operated, and after failure of ATD therapy to control hyperthyroidism and/or contraindications to ATD therapy. Similarly it is preferred modality of choice in the absence of access to an experienced thyroid surgeon and in patients with right heart failure, periodic thyrotoxic hypokalemic paralysis, congestive heart failure or pulmonary hypertension [16].

Radioablation is contraindicated in pregnant and breastfeeding women, inability to follow radiation safety rules, suspicion of thyroid cancer and in moderate to severe orbitopathy [16]. Female patients of childbearing age should undergo a pregnancy test 3 days prior to radioiodine administration and provide written signed declaration confirming the non-pregnant status. Serum pregnancy test being more sensitive is preferable to urine test [32].

Patients should be advised against the conception 6 months post RAI therapy. RAI therapy should be administrated 6 weeks to 3 months after lactation is disrupted [33].

Patients must be instructed to discontinue use of all iodine containing medications and be placed on an iodine-restricted diet in order to increase radioiodine uptake (RAIU) and thus to have desired therapeutic effect. Withdrawal of ATD for 3–7 days and iodine restriction for 1 to 2 weeks before RAI administration is also recommended.

RAI administration in hyperthyroidism provides symptomatic relief within weeks. To avoid increased failure rate and reduced the rates of hypothyroidism, ATDs can be withheld for 3–7 days before and after radioiodine administration [15, 34]. Patients at a higher risk of cardiac complications especially rhythm disturbances due to severe hyperthyroidism should be put on B-adrenergic blockade.

RAI treatment may experience some side effects of radioiodine therapy despite being considered safe. Post radiation thyroiditis an adverse effect of radiation treatment manifest as transient elevation of thyroid hormones resulting in exacerbation of hyperthyroid symptoms. The risk of eventual hypothyroidism though a desired result, is high especially after treatment of GD. However, the most undesirable and potentially troublesome adverse radiation effect is potential worsening of thyroid associated ophthalmopathy. Therefore, a close monitoring of the thyroid function is warranted to detect hypothyroidism earlier on in order to be treated as soon as possible.

Post radioiodine therapy thyroid hormones return to normal levels in the majority of the patients while resolution of clinical symptoms is observed in 4–8 weeks post

#### *Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

therapy. Hypothyroidism sets in more than 80% of the patients 16 weeks post RAI therapy. The post radiation hypothyroidism is usually permanent however, in rare cases it may be transient and the patient may return to a euthyroid state or remain hyperthyroid. In the latter scenario there is no decrease of patients thyroid size [16]. Factors observed to affect the outcome of RAI treatment include thyroid size, iodine intake (diet or iodine containing medicine), dose regimens, compensation of hyperthyroidism, and the timing of the withdrawal of ATDs.

To assess the efficacy of the radioiodine treatment and timely detection of developing hypothyroidism or persistent hyperthyroidism close monitoring of the thyroid function is essential for favorable outcome. The review of thyroid function should be carried out within 1–2 months by assessing the values of serum TSH, FT4 and FT3 to be repeated every 4–6 weeks for the first 6 months or until the patient becomes hypothyroid and is stable on levothyroxine replacement [35].

#### **5. Surgery**

Thyroidectomy is the oldest and the preferred modality of treatment for Graves' disease and has been found to be at par with ATDs and radioiodine in reducing the serum thyroid hormone levels with normalization of hormone levels within 6weeks of therapy [36]. The role of thyroid surgery particularly as an alternative to ATD in uncontrolled hyperthyroidism despite being on higher drug doses or in cases of recurrent hyperthyroidism is an attractive option. Surgical management again is a preferred option for patients in few conditions, such as in patients with large goiters with compressive symptoms, women desirous of conception shortly after treatment, younger patients with high risk of recurrence following medical management, nodular thyroid where malignancy may coexist. Patient's undergone surgical thyroidectomy is advised against the conception till they achieve euthyroidism either spontaneously or with levothyroxine replacement therapy. The surgical thyroidectomy does not appear to affect the course of Graves ophthalmopathy thus risk of its exacerbation and as such preferred mode of management in severe Graves' ophthalmopathy. Failure of antithyroid medications or radio-iodine therapy and patient preference to surgical approach are the other indication for thyroid surgery so are the patients who do not want the exposure to antithyroid drugs or radioiodine.

#### **5.1 Preoperative management**

The patients must reach euthyroidism to achieve hemodynamic stability, before they can undergo surgery. This will reduce the risk of complications [6, 37]. Preparation for surgery involves use of [38]:


#### *Hyperthyroidism - Recent Updates*

effects of iodide on new thyroid hormone synthesis, referred to as the Wolff-Chaikoff effect. However, use of iodide products has not been associated with change in outcomes in few studies.

3.1 SSKI is used as 1 to 2 drops (50mg/drop) TID and should be initiated 7 to 10days prior to surgery and discontinued on the day of surgery.

3.2 Similarly Lugol solution (KI-iodine solution) as 5 to 7 drops (8mg iodide/ iodine per drop) daily can also be used as alternative [16].

3.3 In addition, corticosteroid like betamethasone 0.5mg every 6hours) or dexamethasone (2 mg orally or intravenously 4 times daily) and cholestyramine (4 grams six hourly) can be used for rapid preparation for emergent surgery to avoid the risk of thyroid storm.

Although preoperative use of these compounds has been advocated by ATA guidelines, the advantages of use of these agents preoperatively on the outcome of surgery is still debated.


#### **5.2 Total thyroidectomy versus subtotal thyroidectomy**

Total thyroidectomy (removal all of the thyroid tissue) is preferred to subtotal thyroidectomy (leaving 4 to 7 grams of thyroid). The extent of thyroid resection in GD remains controversial. Total thyroidectomy versus subtotal thyroidectomy is a balance between risk of recurrence of hyperthyroidism in case of subtotal thyroidectomy and incidence of hypothyroidism seen with total thyroidectomy [38]. Total thyroidectomy is given the preference to subtotal thyroidectomy to avoid the risk of recurrence at the cost of rendering the patient on the side of hypothyroidism, in addition to avoid the second surgery to remove the residual tissue, which will be more difficult on account of scar tissue formation and distortion of tissue planes with prior surgery i.e., subtotal thyroidectomy [39]. In a systematic review and meta-analysis of total vs. subtotal thyroidectomy for GD by Feroci et al., the odds ratio (OR) of transient and permanent hypoparathyroidism favors subtotal thyroidectomy, the OR of the recurrence of hyperthyroidism favors total thyroidectomy [37]. One of the randomized trials involving 191 patients of GD by Barczynski et al., compared total thyroidectomy vs. subtotal thyroidectomy and followed these patients over a span of 5 years. Patients undergoing total thyroidectomy had a complete remission of the

*Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

disease and lower risk of hypoparathyroidism (transient and or permanent) compared to subtotal thyroidectomy cohort [39].

Total thyroidectomy offers a better chance of cure of hyperthyroidism than bilateral subtotal thyroidectomy despite the controversy regarding the extent of thyroid resection in GD and can be accomplished safely with slight increase in the risk of temporary and permanent hypoparathyroidism.

Total thyroidectomy has been endorsed as the procedure of choice for the surgical management of GD [40] despite other studies [41, 42] arguing that subtotal thyroidectomy especially when performed with a remnant thyroid tissue of less than 3 gm, may allow permanent cure of hyperthyroidism to ensure euthyroid state in a significant proportion of patients with lower risk of recurrent hyperthyroidism [43].

#### *5.2.1 Complications*

Nonfatal complications associated with surgery are hypoparathyroidism either permanent (1–3%) or transient (10%) and vocal cord paralysis and hypothyroidism.

#### **6. Management of Graves' disease during pregnancy**

Graves' disease affects approximately 0.1% of pregnancies and if inadequately treated carries a substantial risk of adverse effects in both mother and child [44]. Untreated hyperthyroidism results in increased risk of pre-eclampsia, preterm delivery, low birth weight and increased neonatal mortality and morbidity. The mother is also at increased risk of heart failure, thyroid storm and pre-eclampsia. Changes in thyroid hormone concentrations that are characteristic of hyperthyroidism must be distinguished from gestational thyrotoxicosis affecting as many as 20% of pregnancies resulting TSH receptor stimulation by elevated serum levels of human chorionic gonadotropin (hCG), especially in the first trimester to ensure the early recognition and management to have a favorable outcome. Fetal hyperthyroidism can be life-threatening, and needs to be recognized as soon as possible so that treatment of the fetus with antithyroid drugs via the mother can be initiated. Antithyroid drug treatment of hyperthyroidism in pregnant women is controversial because in utero exposure with the usual ATDs especially methimazole and/or carbimazole have been the associated with between severe birth defects and the alternative propylthiouracil with hepatotoxicity. As both propylthiouracil and methimazole are associated with birth defects, lowest effective dose of an antithyroid drug should be used to maintain thyroid function at the upper limit of the normal range in order to avoid overtreatment and subsequent fetal hypothyroidism [45]. The use of propylthiouracil in the first trimester and methimazole during the remainder of pregnancy is currently recommended on the basis of a consideration of potentially severe birth defects.

Thyroid function should be monitored monthly. In up to 50% of cases, antithyroid drugs may be discontinued after the first trimester as GD improves spontaneously during pregnancy, but postpartum relapse is common due to a rebound in autoimmunity [44]. Elevated Thyrotropin-receptor antibodies levels especially by a factor of more than 3 in the third trimester, identifies pregnancies at risk for neonatal hyperthyroidism [44]. Breast-feeding is safe with either methimazole or propylthiouracil, but methimazole is recommended for postpartum therapy and does not affect infant thyroid function in the doses commonly used [46, 47].

PTU is the preferred antithyroid agent during pregnancy, as congenital anomalies such as aplasia cutis (single or multiple lesions of 0.5 to 3 cm at the vertex or occipital area in the scalp), choanal and esophageal atresia are reported more frequently with MMI [48]. However, the incidence of these anomalies is quite rare and it is acceptable to continue MMI particularly in areas where PTU is not easily available. The PTU dosage is reduced to the lowest effective dose to maintain the fT4 towards the upper end of the reference range with monthly monitoring of thyroid functions [49]. The activity levels of Graves' disease may fluctuate during pregnancy, with exacerbation during the first trimester with improvement in later pregnancy with a higher chance of an exacerbation soon after delivery. Therefore, thyroid function should be monitored every 2 to 3 months for 1 year following delivery to detect early relapse.

#### **7. Newer therapeutic options**

Newer treatment options based on antigen-specific Immunotherapy, immunobiology such as biologics, small molecules and peptide immunomodulation under investigations are in different stages of development particularly aimed at achieving euthyroidism without the requirement for ongoing therapy.

#### **7.1 Antigen-specific immunotherapy**

The antigen-specific immunotherapies are intended to restore the immune tolerance to the immunodominant epitopes responsible for the aberrant autoimmune response. Lack of generalized immunosuppression and skewing of the immune response associated with these therapies pose no greater risk of infection or different immune-mediated conditions. A study by Pearce et al., investigated a combination of two TSHR peptides (ATX-GD-59) in 12 subjects with mild-to-moderate untreated hyperthyroidism that was administered 10 times to each participant over 18 weeks by intradermal injection, in 12 subjects with mild-to-moderate untreated hyperthyroidism. The treatment was also well tolerated, with 10/12 participants finishing the study and 7/10 subjects had improvement in their thyroid function over the 18 weeks of ATX-GD-59, with 50% normalizing their serum fT3 concentrations, reduction in serum TSHR autoantibodies suggesting that ATX-GD-59 may have a significant potential for effective disease-modifying therapeutic cure in GD [50].

#### **7.2 Immunomodulation**

Immunomodulation of B lymphocytes by directly targeting the B cells or their associated interactors and cytokines by molecules such as iscalimab (anti-CD40), belimumab (anti-BAFF), and rituximab (anti-CD20).

#### **7.3 Blocking of signaling**

Blocking of signaling of TSH receptors by small molecular TSHR antagonist and *TSHR stimulation by TSH or TRAbs* (K1–70 blocking),

#### **7.4 Inhibition of immunoglobulin**

Inhibition of immunoglobulin recycling by blocking the neonatal Fc receptor (efgartigimod and rozanolixizumab), which recycles endocytosed IgG antibody by

#### *Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

binding it in the acidic conditions of the lysosome and recycling it to the cell membrane for release back into the circulation [51].

These newer therapies may dawn the era of restoring a euthyroid state in the patients of GD without the need for ongoing therapy with least potential risks such as immunocompromise and render destructive radioiodine thyroid ablation and thyroidectomy obsolete.

#### **8. Conclusions**

The treatment of Graves' disease, a most common cause of hyperthyroidism should be tailored to the specific needs of each patient with the benefits and risks of each therapy explained in full. Antithyroid drugs, surgery and radioactive iodine are still therapeutic options of choice and are widely available and exercised. Antithyroid drugs continue to be the first line of treatment, except for patients with contraindications or intolerance. Surgical ablation is still an option in a smaller proportion of patients with particular conditions. Radioactive iodine therapy has gained more acceptability and in many cases it is preferred first-line treatment. RAI is a safe and effective definitive treatment for GD.

New treatment options with biological and immunomodulatory therapy are under development and in the future may be a treatment option with a lower risk of toxicity and perhaps higher rates of cure.

#### **Conflict of interest**

There is no conflict of interest.

#### **Author details**

Javaid Ahmad Bhat\*, Shoiab Mohd Patto, Pooran Sharma, Mohammad Hayat Bhat and Shahnaz Ahmad Mir Department of Endocrinology, Superspeciality Hospital, Shireen Bagh, Srinagar, Kashmir, India

\*Address all correspondence to: javaidrasool@rediffmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Tomer Y. Mechanisms of autoimmune thyroid diseases: From genetics to epigenetics. Annual Review of Pathology. 2014;**9**:147-156

[2] Brix TH, Kyvik KO, Christensen K, Hegedüs L. Evidence for a major role of heredity in Graves' disease: A populationbased study of two Danish twin cohorts. The Journal of Clinical Endocrinology and Metabolism. 2001;**86**(2):930-934

[3] Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. The Lancet Diabetes and Endocrinology. 2015;**3**(4):286-295

[4] Nyström HF, Jansson S, Berg G. Incidence rate and clinical features of hyperthyroidism in a long-term iodine sufficient area of Sweden (Gothenburg) 2003-2005. Clinical Endocrinology. 2013;**78**(5):768-776

[5] Nordyke RA, Gilbert FI, Harada AS. Graves' disease. Influence of age on clinical findings. Archives of Internal Medicine. 1988;**148**(3):626-631

[6] Smith TJ, Hegedüs L. Graves' Disease. The New England Journal of Medicine. 2016;**375**(16):1552-1565

[7] Kahaly GJ, Petrak F, Hardt J, Pitz S, Egle UT. Psychosocial morbidity of Graves' orbitopathy. Clinical Endocrinology. 2005;**63**(4):395-402

[8] Brandt F, Thvilum M, Hegedüs L, Brix TH. Hyperthyroidism is associated with work disability and loss of labour market income. A Danish registerbased study in singletons and diseasediscordant twin pairs. European Journal of Endocrinology. 2015;**173**(5):595-602

[9] Brandt F, Almind D, Christensen K, Green A, Brix TH, Hegedüs L. Excess

mortality in hyperthyroidism: The influence of preexisting comorbidity and genetic confounding: A Danish nationwide register-based cohort study of twins and singletons. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(11):4123-4129

[10] Bhat MH, Bhat JA, Masoodi SR, Qureshi W, Dar JR, Bhat MH. Clinical spectrum and outcome of patients with Graves' disease: A single-center experience from a tertiary care institution in the Kashmir Valley, India. Turkish Journal of Endocrinology and Metabolism. 2021;**25**(1):21-31

[11] Sundaresh V, Brito JP, Thapa P, Bahn RS, Stan MN. Comparative effectiveness of treatment choices for graves' hyperthyroidism: A historical cohort study. Thyroid The Official Journal of: American Thyroid Association. 2017;**27**(4):497-505

[12] Emiliano AB, Governale L, Parks M, Cooper DS. Shifts in propylthiouracil and methimazole prescribing practices: Antithyroid drug use in the United States from 1991 to 2008. The Journal of Clinical Endocrinology and Metabolism. 2010;**95**(5):2227-2233

[13] Ahad F, Ganie SA. Iodine, iodine metabolism and iodine deficiency disorders revisited. Indian Journal of Endocrinology and Metabolism. 2010;**14**(1):13-17

[14] Cooper DS. Antithyroid drugs in the management of patients with Graves' disease: An evidence-based approach to therapeutic controversies. The Journal of Clinical Endocrinology and Metabolism. 2003;**88**(8):3474-3481

[15] Abraham P, Acharya S. Current and emerging treatment options for Graves'

*Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

hyperthyroidism. Therapeutics and Clinical Risk Management. 2010;**6**:29-40

[16] Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid The Official Journal of: American Thyroid Association. 2016;**26**(10):1343-1421

[17] Cooper DS. Antithyroid drugs. The New England Journal of Medicine. 2005;**352**(9):905-917

[18] Jansson R, Lindström B, Dahlberg PA. Pharmacokinetic properties and bioavailability of methimazole. Clinical Pharmacokinetics. 1985;**10**(5):443-450

[19] Jansson R, Dahlberg PA, Johansson H, Lindström B. Intrathyroidal concentrations of methimazole in patients with Graves' disease. The Journal of Clinical Endocrinology and Metabolism. 1983;**57**(1):129-132

[20] Liu L, Lu H, Liu Y, Liu C, Xun C. Predicting relapse of Graves' disease following treatment with antithyroid drugs. Experimental and Therapeutic Medicine. 2016;**11**(4):1453-1458

[21] MacFarlane IA, Davies D, Longson D, Shalet SM, Beardwell CG. Single daily dose short term carbimazole therapy for hyperthyroid Graves' disease. Clinical Endocrinology. 1983;**18**(6):557-561

[22] Gupta SK, Mithal A, Godbole MM. Single daily dose of carbimazole in the treatment of hyperthyroidism. National Medical Journal of India. 1992;**5**(5):214-216

[23] Idrose AM. Acute and emergency care for thyrotoxicosis and thyroid storm. Acute Medicine & Surgery. 2015;**2**(3):147-157

[24] Yu W, Wu N, Li L, Wang J, OuYang H, Shen H. Side effects of PTU and MMI in the treatment of hyperthyroidism: A systematic review and meta-analysis. Endocrine Practice of Official Journal of American College of Endocrinology and American Association of Clinical Endocrinologists. 2020;**26**(2):207-217

[25] Nicholas WC, Fischer RG, Stevenson RA, Bass JD. Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. Southern Medical Journal. 1995;**88**(9):973-976

[26] Abbara A, Clarke SA, Brewster R, Simonnard A, Eng PC, Phylactou M, et al. Pharmacodynamic response to anti-thyroid drugs in Graves' hyperthyroidism. Frontiers in Endocrinology. 2020;**11**:286

[27] Bartalena L. Diagnosis and management of Graves disease: A global overview. Nature Reviews. Endocrinology. 2013;**9**(12):724-734

[28] Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. The Journal of Clinical Endocrinology and Metabolism. 2007;**92**(6):2157-2162

[29] Vasileiou M, Gilbert J, Fishburn S, Boelaert K. Thyroid disease assessment and management: Summary of NICE guidance. British Medical Journal. 2020;**368**:m41

[30] Pouget JP, Lozza C, Deshayes E, Boudousq V, Navarro-Teulon I. Introduction to radiobiology of targeted radionuclide therapy. Frontiers in Medicine. 2015;**2**:12

[31] Metso S, Jaatinen P, Huhtala H, Luukkaala T, Oksala H, Salmi J.

Long-term follow-up study of radioiodine treatment of hyperthyroidism. Clinical Endocrinology. 2004;**61**(5):641-648

[32] Tran P, Desimone S, Barrett M, Bachrach B. I-131 treatment of graves' disease in an unsuspected first trimester pregnancy; the potential for adverse effects on the fetus and a review of the current guidelines for pregnancy screening. International Journal of Pediatric Endocrinology. 2010;**2010**:858359

[33] Stokkel MPM, Handkiewicz Junak D, Lassmann M, Dietlein M, Luster M. EANM procedure guidelines for therapy of benign thyroid disease. European Journal of Nuclear Medicine and Molecular Imaging. 2010;**37**(11):2218-2228

[34] Andrade VA, Gross JL, Maia AL. The effect of methimazole pretreatment on the efficacy of radioactive iodine therapy in Graves' hyperthyroidism: One-year follow-up of a prospective, randomized study. The Journal of Clinical Endocrinology and Metabolism. 2001;**86**(8):3488-3493

[35] Rivkees SA, Sklar C, Freemark M. Clinical review 99: The management of Graves' disease in children, with special emphasis on radioiodine treatment. The Journal of Clinical Endocrinology and Metabolism. 1998;**83**(11):3767-3776

[36] Törring O, Tallstedt L, Wallin G, Lundell G, Ljunggren JG, Taube A, et al. Graves' hyperthyroidism: Treatment with antithyroid drugs, surgery, or radioiodine–a prospective, randomized study. Thyroid Study Group. The Journal of Clinical Endocrinology and Metabolism. 1996;**81**(8):2986-2993

[37] Feroci F, Rettori M, Borrelli A, Coppola A, Castagnoli A, Perigli G, et al. A systematic review and meta-analysis

of total thyroidectomy versus bilateral subtotal thyroidectomy for Graves' disease. Surgery. 2014;**155**(3):529-540

[38] Smithson M, Asban A, Miller J, Chen H. Considerations for thyroidectomy as treatment for Graves disease. Clinical Medicine Insights: Endocrinology and Diabetes. 2019;**12**:1179551419844523

[39] Barczyński M, Konturek A, Hubalewska-Dydejczyk A, Gołkowski F, Nowak W. Randomized clinical trial of bilateral subtotal thyroidectomy versus total thyroidectomy for Graves' disease with a 5-year follow-up. The British Journal of Surgery. 2012;**99**(4):515-522

[40] Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the american thyroid association and American association of clinical endocrinologists. Thyroid The Official Journal of: American Thyroid Association. 2011;**21**(6):593-646

[41] Robert J, Mariéthoz S, Pache JC, Bertin D, Caulfield A, Murith N, et al. Short- and long-term results of total vs subtotal thyroidectomies in the surgical treatment of Graves' disease. Swiss Surgery Schweizer Chirurgie Chirurgie Suisse Chirurgia Svizzera. 2001;**7**(1):20-24

[42] Werga-Kjellman P, Zedenius J, Tallstedt L, Träisk F, Lundell G, Wallin G. Surgical treatment of hyperthyroidism: A ten-year experience. Thyroid The Official Journal of: American Thyroid Association. 2001;**11**(2):187-192

[43] Lepner U, Seire I, Palmiste V, Kirsimägi U. Surgical treatment of Graves' disease: Subtotal thyroidectomy might still be the preferred option. Medicina (Kaunas, Lithuania). 2008;**44**(1):22-26

*Therapeutic Options in Graves' Hyperthyroidism DOI: http://dx.doi.org/10.5772/intechopen.106562*

[44] Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. The Lancet Diabetes and Endocrinology. 2013;**1**(3):238-249

[45] Andersen SL, Olsen J, Laurberg P. Antithyroid drug side effects in the population and in pregnancy. The Journal of Clinical Endocrinology and Metabolism. 2016;**101**(4):1606-1614

[46] Momotani N, Yamashita R, Makino F, Noh JY, Ishikawa N, Ito K. Thyroid function in wholly breastfeeding infants whose mothers take high doses of propylthiouracil. Clinical Endocrinology. 2000;**53**(2):177-181

[47] Azizi F, Khoshniat M, Bahrainian M, Hedayati M. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. The Journal of Clinical Endocrinology and Metabolism. 2000;**85**(9):3233-3238

[48] Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. The Journal of Clinical Endocrinology and Metabolism. 2001;**86**(6):2354-2359

[49] Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, et al. Management of thyroid dysfunction during pregnancy and postpartum: An endocrine society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2007;**92**(8 Suppl):S1-S47

[50] Pearce SHS, Dayan C, Wraith DC, Barrell K, Olive N, Jansson L, et al. Antigen-specific immunotherapy with thyrotropin receptor peptides in graves' hyperthyroidism: A phase I study. Thyroid. 2019;**29**(7):1003-1011

[51] Lane LC, Cheetham TD, Perros P, Pearce SHS. New therapeutic horizons for graves' hyperthyroidism. Endocrine Reviews. 2020;**41**(6):bnaa022

Section 4
