Radioactive Iodine Therapy for Hyperthyroidism

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.

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 sodium-iodide 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 NADPH-oxidase. 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-pituitary-thyroid 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 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 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 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 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

$$1/{\text{T}}_{1/2}\left(\text{effective}\right)=1/{\text{T}}_{1/2}\left(\text{physical}\right)+1/{\text{T}}_{1/2}\left(\text{biological}\right)$$

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:

• Benign thyroid disease (Grave’s disease, TMNG, toxic adenoma and non-toxic nodular goiter)

• Differentiated follicular and papillary carcinoma; residual or recurrent disease after thyroidectomy, metastatic disease after near-total thyroidectomy

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.

• Recent thyroid scintigraphy and radioiodine uptake studies (< 6 months) to look for tracer uptake values and cold nodules.

• Recent ultrasound neck (< 3 months) for volume assessment and evaluation of nodules.

• Fine needle aspiration cytology of suspicious appearing nodules on ultrasound and hypo-functioning (cold) nodules on scintigraphy to exclude malignancy.

• Fasting for at least 4 hours prior to therapy and 2 hours after therapy is recommended to improve gastrointestinal absorption.

• Breast feeding and lactation are absolute contraindications for RAI-131 therapy. All women of child bearing age must be screened for pregnancy by serum or urine β-hCG levels within 24 hours of treatment. Serum β-hCG levels are more sensitive. Pregnancy test may remain negative for 7–10 days, so treating physician should discuss limitation of test in doubtful cases and delay therapy till next cycle. Post-therapy conception should be delayed for at least 6 months. This duration applies equally for males. Similarly, all potential women should be asked for breast feeding or lactation. If yes, therapy should be delayed till lactation ceases in order to minimize radiation dose to breast tissues as lactating breast can concentrate radioiodine. Usually, lactation ceases 4–6 weeks after childbirth without breast feeding or after omitting breast feeding [39].

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 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 half-life. 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, re-therapy 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 pre-treatment 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 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 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.