3.3.7 Radio-iodine treatment of hyperthyroidism

Radioactive iodine has been used successfully for almost 70 years since the first treatment took place at the Massachusetts General Hospital in Boston in 1941. However, it was not until after the Second World War that ¹³¹I became generally available for clinical applications (1). The radioactive iodine isotope is chemically identical to ‘stable’ iodine (¹²⁷I) and thus becomes a part of the intrathyroidal metabolism. Its principle of action is based on the emission of β-rays with a range of 0.5–2 mm in the tissue leading to high local radiation absorbed doses while sparing surrounding structures. The additional γ-ray component of ¹³¹I allows for scintigraphic imaging of the distribution in the gland and can also be used for pre- and post-therapeutic individual dosimetry (see below).

Several therapeutic options are available for the treatment of benign thyroid disorders, namely hyperthyroidism: surgical resection (hemithyroidectomy, near-total, or total thyroidectomy), long-term antithyroid drug medication (ATD), and radio-iodine therapy (RAIT) (2, 3). These different treatment modalities are used in varying frequencies depending on geographical location, e.g. iodine supply, availability and logistics, cultural background, and patient-specific features, e.g. goitre size, presence of local symptoms, age, and hormonal status. The diversity of approaches on an international scale still remains impressive and is reflected by a great heterogeneity throughout Europe and also when compared to the USA where radio-iodine therapy is still being applied more frequently than in most European countries (4–8).

Radio-iodine therapy was originally aimed at eliminating hyperthyroidism and thus leaving the patient euthyroid. Up-to-date strategies, however, established postradio-iodine induction of hypothyroidism as the treatment objective and, thus, it is included in the category of ‘cure’. This definition holds especially true for the management of Graves’ disease when long-term hypothyroidism was the rule and stabilization of euthyroidism failed in the majority of cases. In fact, the term ‘ablation’, meaning removal or destruction, has been increasingly used to characterize radio-iodine therapy and administration of larger amounts of radio-iodine have tended to make this a self-fulfilling prophecy. Although many clinicians prefer that the end result of treatment be the more easily managed hypothyroidism, others are still reluctant to give up the therapeutic ideal of euthyroidism as the preferred result of radio-iodine therapy and continue their efforts to solve the enigma of thyroid radiosensitivity.

The causes of hyperthyroidism include the following: (1) autoimmune hyperthyroidism, previously called toxic diffuse goitre (Graves’ disease), (2) toxic adenoma, (3) toxic multinodular goitre (Plummer’s disease), (4) silent thyroiditis, and (5) painful subacute thyroiditis. The first three entities constitute a clear indication for radio-iodine treatment, while silent thyroiditis and subacute thyroiditis are never treated with radio-iodine.

Recently, there has been an emerging role for ¹³¹I in the treatment of subclinical hyperthyroidism caused by any of the three first entities (5). Another potential category that is frequently regarded as a new entity for this kind of treatment are patients with nontoxic goitre (NTG). They are a group of patients who are euthyroid but may benefit from reduction of thyroid volume (9–11). The available treatment options in NTG patients in whom the risk of malignancy is considered low are a ‘wait-and-see’ policy, surgery, l-thyroxine, and radio-iodine treatment. The main indications for radio-iodine treatment of NTG are to reduce the size of a goitre to relieve compressive signs or symptoms and secondly to alleviate potential cosmetic problems for the patient. Surgery is the fastest way to reduce goitre size and relieve any acute compressive symptoms and is mandatory if there are any doubts about malignancy. Prestimulation with recombinant human thyroid-stimulating hormone may represent a future option for this condition by augmenting the effectiveness of radio-iodine (11, 12).

Radio-iodine is, in most cases, the first-line treatment for Graves’ disease and toxic adenoma, or it can be administered if hyperthyroidism is not controlled or recurs after antithyroid drug treatment (13). Surgery should only be considered if there are contraindications to radio-iodine therapy.

Pregnancy and breastfeeding are absolute contraindications to radio-iodine treatment; all females of reproductive age should have a pregnancy test immediately before administration. It is generally recommended that women should not attempt conception for 6–12 months after radio-iodine treatment. Iodine-131 is not indicated for patients who have urinary incontinence, whereas concomitant haemodialysis for renal failure is not an exclusion criterion and is routinely performed in experienced centres.

The effect of radio-iodine therapy is gradual and varies substantially among individuals, resulting in the necessity for repeated testing after the treatment to rule out persistent hyperthyroidism or short-term development of a hypothyroid state. After 8–12 weeks, a follow-up visit may scheduled to evaluate the effect of the procedure. In case of pre-existing marked hyperthyroidism, symptom relief should be achieved peritherapeutically by the administration of β-blocking agents, and resumption of antithyroid drugs should be considered when tachycardia and palpitations are present. The influence of antithyroid drugs on the efficiency of radio-iodine therapy is a permanent matter of controversy, but there is growing evidence that coadministration of methimazole and propylthiouracil during radio-iodine therapy has a negative influence on the therapeutic outcome (14–17). If tolerated, restarting antithyroid drugs should preferably be initiated 1 week after the radio-iodine has been administered to avoid altering radio-iodine kinetics in the thyroid.

Clinical exacerbation of hyperthyroidism after radio-iodine treatment appears to be relatively uncommon and is usually of minor clinical significance. It presumably is related to radiation thyroiditis, with destruction of thyroid follicles and release of thyroglobulin and stored hormone into the circulation. There may be a transient rise in free thyroxine and free triiodothyronine levels several days following administration, and patients with poorly controlled symptoms before radio-iodine therapy may encounter an exacerbation of cardiac arrhythmia and heart failure. In some patients a ‘thyroid storm’ may develop. Intravenous infusion of antithyroid drugs, corticosteroids, and β-blockers is the treatment of choice, but prophylactic measures and a thorough initial work-up are crucial.

Patients with large goitres may notice transient swelling and dyspnoea. Thyroid enlargement may last until approximately 1 week following therapy and some discomfort may be associated with it. Slight irritation of the salivary gland function may be noted, but in contrast to thyroid cancer, the risk of permanent injury is negligible due to the much lower activities applied for therapy of thyrotoxicosis.

The main side effect of radio-iodine treatment is permanent hypothyroidism. The rate of hypothyroidism varies and incidence continues to increase over time, so that lifelong follow-up is essential. Pretreatment prediction is not possible using current variables; however, the incidence is higher in Graves’ disease than in toxic nodular goitre and relatively uncommon in solitary hyperfunctioning nodules. The most prominent radiobiological factor for the determination of overall outcome, besides radiation sensitivity of the thyroid follicular cells, remains the radiation absorbed dose to the thyroid tissue; however, its exact calculation is one of the obstacles in therapeutic nuclear medicine.

Graves’ disease is frequently accompanied by ophthalmopathy; the reported incidences largely depend on the diagnostic criteria employed (18–20). Prospective randomized controlled trials have shown that radio-iodine treatment is associated with a greater risk of the appearance or worsening of ophthalmopathy in patients with Graves’ disease than antithyroid drug treatment. The risk is especially increased in patients who smoke cigarettes, in keeping with the importance of smoking as a susceptibility factor in the development of ophthalmopathy, so patients should be strongly advised to quit smoking. Oral or intravenous administration of steroids with ¹³¹I helps prevent exacerbation of ophthalmopathy, and this approach has to be considered the standard of care in patients who have clinically active ophthalmopathy at the time of treatment (21–25). A radiation absorbed dose below 200 Gy, a thyroid volume of more than 55 ml, and the use of radio-iodine without steroid medication have been shown to be associated with a higher risk of worsening of eye symptoms. Despite the controversy regarding adequate management of patients with Graves’ hyperthyroidism and thyroid eye disease, most authors agree that in the presence of predisposing risk factors, such as large goitres or heavy smoking, ablative therapy should be recommended (16) (see Chapter 3.3.10).

A small excess of mortality from malignancy was reported in one investigation but the study was biased by the increased surveillance. In other large series, no effects of radio-iodine therapy on survival have been observed, whereas some reports suggested an increased relative risk for the development of certain types of cancer (thyroid, stomach, bladder, kidney, and haematological malignancies). However, these observations still remain to be confirmed by monitoring larger patient samples, so that currently no definite conclusion with respect to risk for subsequent malignancies can be drawn (26–30).

For the treatment of Graves’ disease or Plummer’s disease (toxic nodular goitre), ¹³¹I is normally administered orally using activities between 100 and 1500 MBq. The rationale behind dosimetry for this kind of treatment is that the incidence of long-term hypothyroidism is higher with an earlier onset for patients treated with higher activities (31) resulting in an attempt to individualize and thus optimize therapy. A large variation exists in the literature on the value of target absorbed dose to be delivered to the hyperthyroid tissue to become euthyroid. Most authors indicate 70 Gy but absorbed doses as high as 200 Gy are reported (32).

For a pretherapeutic dosimetric assessment of the activity needed to achieve a certain prescribed absorbed dose to the target volume in general, an adapted version of the Quimby–Marinelli formula is recommended for use:

The activity A to be administered is calculated from:

A guide to the assessment and details of the calculation procedures can be found in the guidelines of the German Society of Nuclear Medicine (34). In short, a determination of the mass of the target volume and of the pretherapeutic iodine biokinetics are needed. For measuring the biokinetics either serial scans of the patient’s neck or probe measurements of the patient’s thyroid for at least 4–8 days are needed. Care with the appropriate calibration of the measuring system should be taken.

The thyroid or the target volume mass is generally determined by ultrasonography (35), pretherapeutic scintigraphy (36), CT (37), MRI (38), or ¹²⁴I-PET (39). A change in the thyroid mass during therapy might be considered in the calculation but the data published up to now are still under evaluation (40).

This dosimetric approach assumes that the iodine kinetics of a tracer and of a therapeutic amount of administered activity are similar. For a confirmation of the absorbed dose achieved after therapy, a post-therapeutic dose assessment is recommended as, according to some authors, a pretherapeutic tracer dose may induce ‘stunning’. This effect might limit the uptake of the therapeutic activity in the thyroid gland (41). Due to the uncertainties related to all of these procedures described above, an overall systematic uncertainty of the dose assessment process of 30–50% must be assumed (42).

Hyperthyroidism in children is mostly caused by Graves’ disease and the risk of relapse in this age group is much higher than in adults. There is good evidence that the fetal and young thyroid is particularly sensitive to radiation and it is therefore appropriate to avoid treating hyperthyroid children with radio-iodine if reasonable and safe alternatives are available. This can be a difficult decision since surgical thyroidectomy in young children has been accompanied by a relatively high morbidity and antithyroid drugs have a certain incidence of compliance problems and drug complications (43–45). At the very least, an extended trial of antithyroid drugs is advisable, although occasionally drug toxicity makes this strategy impractical. However, reports of radio-iodine therapy in young children have shown that it is effective and late follow-up has shown no deleterious effects (26, 46).