What is the role of radioiodine treatment in the management of hyperthyroidism in Graves’ disease?

Radioiodine (RAI) was first used to treat hyperthyroidism in the United States (US) back in the 1940s. Since then, it has been widely used in the US, also as a first-line treatment for patients with hyperthyroidism. In Europe, according to the 2018 European Thyroid Association (ETA) guidelines, the first-line treatment for hyperthyroidism in Graves’ disease (GD) is antithyroid drug (ATD) pharmacotherapy aimed at reducing thyroid hormone synthesis. RAI is used as a second-line therapy when an adequately long-term ATD treatment fails to induce remission of the disease or if hyperthyroidism recurs, or when a patient prefers it as a first-line treatment.1 In contrast, the 2016 American Thyroid Association (ATA) guidelines2 list all 3 methods (ATD, RAI, surgery) as equivalent, and the principles of treatment with RAI are even considered and discussed first. Thus, in the US, the approach to the use of RAI is more liberal, and physicians are more willing to refer patients for such treatment.

What are the reasons for the differences between the European and American guidelines for the treatment of hyperthyroidism in Graves’ disease?

These differences may be largely due to the fact that ETA places more importance on preserving normal thyroid function in the patients who first develop hyperthyroidism in the course of GD, rather than on ensuring that permanent hypothyroidism achieved after RAI treatment would prevent recurrence of hyperthyroidism.1 Observational data indicate that 50% to 55% of patients achieve sustained euthyroidism (ie, normal thyroid function) after completing sufficiently long (up to 18 months) ATD therapy, without the need for any further medication.1,3 Such a scenario meets the expectations of many patients, even if they are not certain that remission is permanent. According to the ETA guidelines,1 if serum thyrotropin receptor antibody (TRAb) levels remain elevated after 12 to 18 months of ATD administration, the possible options are radical treatment (RAI or thyroidectomy, to reduce the amount of active thyroid tissue) or continuing treatment with thiamazole for another 12 months, which is still accepted. Moreover, the efficacy and safety of prolonged pharmacotherapy are confirmed by the results of prospective follow-up in large groups of patients.3,4 Different preferences for RAI use between ETA1 and ATA2 may be due to several reasons, including dissimilarities in pricing of procedures on 2 continents and availability of appropriate specialized care (highly skilled surgeon vs isotope therapy; easier treatment of hypothyroidism than hyperthyroidism). In addition, many false beliefs regarding the negative effects of radioisotopes still persist among patients, especially in Central and Eastern Europe, after the Chernobyl accident. There are concerns about the impact of radiation on family members (especially children) and fertility, as well as the risk of cancer in the future, which may further discourage patients from choosing RAI as a treatment option. Moreover, in the US, treatment-induced hypothyroidism is considered not so much a complication but a goal of RAI therapy, while in European countries many patients are concerned about hypothyroidism—the difficulties associated with its treatment and the risk of suboptimal thyroid function. Many patients do not accept the risk of life-long pharmacotherapy. The ongoing war in Ukraine, crises and tensions in many regions of the world, and their potential impact on the availability of medications (including L-thyroxine) may further deepen concerns about persistent hypothyroidism and the fact that one’s health and life would largely depend on the continued availability of replacement therapy. Moreover, after RAI administration, there is a risk of exacerbating thyroid orbitopathy, which mainly affects smokers with high serum TRAb levels. However, the use of prophylactic oral corticotherapy significantly reduces this risk.5 Moderate or severe active orbitopathy is a contraindication to RAI use. In populations where the prevalence of smoking, and thus of thyroid orbitopathy, is higher, RAI is used less readily.

Is it possible to individualize the management and early use of radioiodine in the treatment of hyperthyroidism in Graves’ disease?

According to the ETA guidelines,1 in patients who do not respond to appropriate ATD treatment, that is, do not achieve hormonal (lack of sustained euthyroidism) or immunologic remission (normalization of TRAb concentrations), the second-line treatment is RAI or thyroidectomy. Although the ETA guidelines1 do not indicate RAI as a first-line treatment of Graves’ hyperthyroidism, this does not mean that it cannot be used only after a short-term preparation with ATD. Such an approach is possible, as long as the patient has been informed of the advantages and disadvantages of the alternative methods (ATD vs RAI vs thyroidectomy). However, the patient should be informed that although standard thiamazole therapy takes up to 18 months on average (12–18 months according to ETA1), normalization of free thyroid hormone levels (thyroxine [FT4] and / or triiodothyronine [FT3]) and resolution of hyperthyroidism symptoms are achieved quickly, usually within 4 weeks. Unfortunately, it is difficult to predict which patients achieve sustained remission with pharmacotherapy. However, the overall chance is about 50% to 55%, and it is possible to estimate in which individuals remission is slightly more likely.6 ATD treatment relatively more often leads to remission in women, especially those over 45 years of age, with moderately severe hyperthyroidism, a small or nonenlarged thyroid gland, and moderately increased TRAb levels. Other patients are expected to have a higher risk of hyperthyroidism recurrence after ATD therapy,6 so it is not inappropriate to consider RAI individually as an option for radical treatment of hyperthyroidism, as long as the method is acceptable to the patient. During a discussion with the patient, it should be explained that the expected outcome of RAI treatment is not only restoration of euthyroidism, but most likely permanent and irreversible hypothyroidism. In recent years, a number of studies have shown that long-term ATD treatment is safe and associated with a higher rate of sustained GD remission than standard ATD treatment, lasting 12–18 months.6,7-9 A systematic review published in 202210 showed that sustained normalization of TRAb levels is achieved after 5 years of treatment with thiamazole, and ATD treatment lasting more than 5 years is associated with a 4-year remission rate as high as 85%. Isotope therapy is a good alternative for patients who have experienced significant adverse effects of ATD (agranulocytosis, severe liver failure) or in whom the ATD therapy has proven ineffective. It is also worth considering RAI in the elderly and / or individuals with comorbid heart disease in whom, for example, treatment with amiodarone is planned or it is important to avoid the risk of atrial fibrillation associated with recurrent hyperthyroidism. RAI may also be preferred in patients with increased cardiovascular risk. The use of RAI as a radical treatment should also be considered before planned surgery in patients with an increased perioperative risk (eg, elderly patients, individuals with comorbidities), in whom it is difficult to maintain stable euthyroidism.

What are the advantages and disadvantages of radioiodine?

RAI treatment has many advantages. First of all, it is associated with a lower risk of hyperthyroidism recurrence, as compared with pharmacotherapy (about 15% vs 45%–50%).1,11 It can be performed in an outpatient setting and does not carry the risks and inconveniences associated with surgery or general anesthesia. Unlike long-term ATD treatment, RAI reduces the size of the goiter and does not entail the risk of possible side effects associated with long-term ATD therapy. However, it requires a radioisotope laboratory. A disadvantage of RAI treatment is that the patients need to comply with radiation safety rules (temporary isolation from pregnant women and young children, the need to postpone pregnancy for ≥6 months), which is difficult for many people, especially women taking care of children. In addition, it is necessary to rule out pregnancy before administering RAI (the method is contraindicated in pregnant and lactating women). In patients with clinically overt hyperthyroidism, RAI therapy is possible only after pharmacologic normalization of serum of FT4 and FT3 levels, which is necessary to avoid severe exacerbation of hyperthyroidism symptoms soon after RAI administration. A transient increase in TRAb levels after RAI can persist for up to 2 years. Therefore, RAI is not a suitable option for women planning pregnancy after the recommended waiting period of 6 months following treatment, because there is still a risk that the antibodies will induce hyperthyroidism in the fetus. The use of RAI, unlike surgical treatment, does not enable histologic verification of possible concurrent focal thyroid lesions; therefore, thyroid cancer should be excluded by fine-needle aspiration biopsy of suspicious lesions before treatment. If hyperthyroidism is accompanied by focal lesions with an increased risk of malignancy or large lesions in which cancer has been ruled out, but their size and progression pose a real risk of compressive symptoms, thyroidectomy is clearly a better choice than RAI. The RAI treatment should also not be offered to patients with moderate or severe active thyroid orbitopathy, in whom it is contraindicated. In mild active orbitopathy, prophylactic oral glucocorticotherapy is recommended to significantly reduce the risk of exacerbation of ocular symptoms after radioisotope administration. Patients opting for RAI therapy must acknowledge a relatively long waiting time for the full effect of treatment (up to 6 months) and a very high risk of developing permanent hypothyroidism that would require replacement therapy.

Would a treatment model using radioiodine as a first-line treatment for hyperthyroidism in Graves’ disease benefit most patients?

In patients with hyperthyroidism, the most important consideration is a rational assessment of the likelihood of achieving sustained remission after ATD treatment. The advantages and disadvantages of other available treatment options should also be taken into account, and RAI should be considered if it is feasible and can be beneficial for or even preferred by the patient (eg, due to shortening the treatment time for hyperthyroidism, reducing the number of medical appointments, preventing recurrence of hyperthyroidism with greater certainty, reducing the size of goiter, etc.). In line with a trend seen in other areas of medicine with regard to treatment of chronic diseases, there is an increasing emphasis on allowing patients to participate in treatment decision-making, especially if their preferences determine the choice between the 2 or 3 available treatments. However, they must be adequately prepared to do so, be aware of the expected efficacy of a given method, and know and accept other health-related effects, such as likely persistent hypothyroidism after treatment with RAI. However, this approach requires time to discuss possible treatment strategies with the patient, answer questions, and address concerns. In addition, in many countries, the network of isotope laboratories offering RAI for the treatment of hyperthyroidism may be inadequate, especially outside major cities. Thus, in the course of GD, RAI most often remains a second-line treatment, reserved for the cases when ATD therapy proves ineffective or cannot be continued, or when there are other indications, such as discussed earlier, to prefer this treatment method. It is worth noting that a number of recent studies4,7-10 have consistently supported the efficacy and safety of long-term ATD therapy. Based on the available results, we should expect a greater role of long-term pharmacotherapy rather than a push for early treatment with RAI, but we must await the conclusions of a methodologically rigorous analysis of the study data when the ETA guidelines are updated. The natural direction of change in the treatment of hyperthyroidism in the course of GD seems to be individualization of the management, rather than a radical change in the current treatment regimen.