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Radioiodine Therapy of Hyperthyroidism (Toxic Goiter, Hyperfunctioning Nodule) and Non-Toxic Goiter: Procedures and Guidelines

  • Markus Dietlein
  • Matthias Schmidt
Chapter
Part of the Medical Radiology book series (MEDRAD)

Abstract

The purpose of the present chapter on the radioiodine-131 (I-131) therapy of benign thyroid disorders is to provide advice to nuclear medicine clinicians on how to treat toxic goiter, hyperfunctioning nodules and non-toxic goiter employing optimal I-131 activities. For this purpose, recommendations have been formulated based on the EANM procedure guidelines, recent literature and expert opinion regarding indications for I-131 therapy and alternative treatment modalities, as well as the adequate radioiodine activities in different thyroid disorders and the administration and patient preparation techniques to be used. Recommendations also are provided on pretherapeutic “radioiodine testing”. Furthermore, potential adverse effects are reviewed. The main side-effect of radioiodine treatment is hypothyroidism and levothyroxine medication is needed in all patients with elevated TSH after I-131 therapy.

Keywords

Multinodular Goiter Thyroid Volume Antithyroid Drug Radioiodine Therapy Radioiodine Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

Ab

Antibody

ATD

Antithyroid drug

FNAB

Fine needle aspiration biopsy

fT4

Free levothyroxine in serum

fT3

Free triiodothyronine in serum

I-131

Iodine-131 (radioiodine)

LT4

Levothyroxine medication

PTU

Propylthiouracil

rhTSH

Recombinant human TSH

SD

Standard deviation

Tg

Thyroglobulin

TPO

Thyroidal peroxidase

Xe-131

Xenon-131

1 Key Points

The success rate of radioiodine (I-131) therapy for toxic goiter and solitary hyperfunctioning nodules depends on thyroid volume, compensation of hyperthyroidism, timing of the withdrawal of antithyroid drugs, alimentary iodine intake, and the dose concepts in the different thyroid diseases. The aim of treatment with I-131 is to achieve a non-hyperthyroid status, which can be euthyroid or hypothyroid, recompensated by levothyroxine medication. Studies with an intended dose of 150 Gy to the toxic multinodular goiter reported a success rate of >90 %. The successful elimination of hyperfunctioning nodules occurred in 90 % of patients receiving 300 Gy to the nodule volume and in 94 % of patients receiving 400 Gy to the nodule volume. There is an emerging role for I-131 in the treatment for so-called subclinical hyperthyroidism.

The success of I-131 treatment in reducing the size of non-toxic goiters depends on the applied I-131 activities per gram thyroid tissue and the distribution of I-131 within the goiter. Disadvantageous are large cystic and fibrotic areas. Most of the shrinkage occurs within the first year and goiter volumes are decreasing continuously for several years to about 30 % of the initial size. With more effective strategies for goiter shrinkage—including the additive use of recombinant human thyrotropin—more patients will require levothyroxine medication. Radioiodine therapy for reducing the goiter size can be recommended especially for elderly people, for those with co-morbidity and for patients who want to avoid surgery.

2 Introduction

Oral administration of I-131 has been used to treat benign conditions of the thyroid gland since the 1940s. For practical purposes, it is helpful to define two subpopulations:

a. Patients with hyperthyroidism as the consequence of solitary hyperfunctioning thyroid nodule or toxic multinodular goiter (Plummer’s disease). Recently, there is an emerging role for I-131 in the treatment for so-called subclinical hyperthyroidism (McDermott et al. 2003; Col et al. 2004; Surks et al. 2004). Even a TSH-level in the lower normal range may increase the risk of atrial fibrillation in elderly patients, predominately in males (Gammage et al. 2007; Heeringa et al. 2008). In patients with hyperthyroidism, the aim of treatment with I-131 is to achieve a non-hyperthyroid status, which can be euthyroid or hypothyroid, recompensated by levothyroxine medication.

b. Patients with large non-toxic goiter (NTG) or goiter recurrence who are euthyroid but may benefit of diminishment of thyroid volume. In these patients, the aim of treatment with I-131 is to diminish the size of the goiter and, consequently, to reduce the symptoms related to gland enlargement and nodule formation. With more effective strategies for goiter shrinkage more patients will require levothyroxine medication.

The European Association of Nuclear Medicine (EANM) Therapy Committee has recently formulated procedure guidelines on the radioiodine-131 (I-131) therapy of benign thyroid disorders (Stokkel et al. 2010).

3 Treatment Options for Hyperthyroidism and Non-Toxic Goiter

Antithyroid drugs (ATD), surgery, and radioiodine therapy are useful options for treatment of hyperthyroidism (Table 1). Although antithyroid drugs—propylthiouracil (PTU), and methimazole, or its derivative carbimazole—can all normalize serum fT4, fT3, and TSH concentrations, thyrotoxicosis recurrence after cessation of therapy is greater than 90 % for multinodular goiter (Freitas 2000). In non-immune hyperthyroidism there is no chance for permanent inhibition of the thyroid hormone production, activated by somatic mutations. Apart from that, ATD treatment is not without the risk of adverse reactions, including minor rashes and, in rare instances, agranulocytosis and hepatitis.
Table 1

Main features of the three available treatments for hyperthyroidism due to toxic goiters [modified from Weetman (2007)]

 

Antithyroid drug

Surgery

Radioiodine

Time to initial improvement

2–4 weeks

Needs antithyroid drug pretreatment (toxic goiters)

Needs antithyroid drug pretreatment; 4–8 weeks after RIT

Recurrence

90–100 % (toxic goiters)

1–4 %

5–10 %

Use in pregnancy/Breast feeding

Yes (First trimester: PTU preferred)

Second trimester

No

Adverse effect on eye disease

No

No

0.1 % (1 % risk of immune hyperthyroidism; rarely eye symptoms)

Interference with daily activities

No

Requires hospital admission

Need for radiation precautions

Key adverse effects

Rash; arthralgia; hepatitis; agranulocytosis

Surgical; vocal cord paralysis; hypoparathyroidism; hypothyroidism

Hypothyroidism

Surgery is preferably performed in selected cases of nodular goiter, when there is additionally a suspicion of malignancy, when there is a severe compression of neighbouring structures, or when an immediate effectiveness of therapy is necessary due to severe adverse effects of ATDs.

Radioiodine is in most cases the first-line treatment for solitary hyperfunctioning thyroid nodules and toxic multinodular goiter without hypofunctioning nodules or large cystic degenerations. The main indications for radioiodine treatment of NTG are to reduce the size of a goiter that is causing cosmetic difficulties for the patient and to relieve compressive signs or symptoms. The available treatment options in NTG patients in whom the risk of malignancy is considered low are “wait and see” policy, surgery, levothyroxine (LT4, in a non-TSH-suppressive dosage) and radioiodine administration (Table 2). In patients with postoperative goiter recurrence, radioiodine therapy is often considered first-line therapy and the physician should not wait until the patient becomes symptomatic. The optimal timing of radioiodine therapy is important for patients with pre-existing paralysis of the N. recurrens (with or without previous thyroid surgery), especially if paralysis is contralateral to a unilateral recurrent goiter, and for patients with temporary postoperative hypoparathyroidism after the first operation. With levothyroxine medication some patients may achieve clinically relevant (>50 %) nodule or goiter shrinkage, however, it occurs only in 10–20 % of patients (Fast et al. 2008). The only available controlled long-term investigation (Papini et al. 1998) showed no significant nodule size reduction after 5 years of continuous LT4-therapy. Additionally, a comparative study showed the superiority of I-131 treatment over LT4-therapy (Wesche et al. 2001). Radioiodine treatment is indicated in patients with medical contraindications to thyroid surgery, patients with slight or moderate compressive symptoms, patients with large goiter, or patients who wish to avoid operation. The interdisciplinary approach to patients followed by well-balanced decision making and informed consent allow for an individualized selection between alternative treatment options. Special consideration should be given to the patient’s profession as I-131 is without risk for paralysis of the recurrent laryngeal nerve. There are well-known regional differences in the choice of treatment for initial or recurrent hyperthyroidism, but radioiodine is increasingly used as first-line treatment as ever more data accumulate proving its safety.
Table 2

Main features of the three available treatments for non-toxic goiter [modified from Weetman (2007)]

 

Levothyroxine

Surgery

Radioiodine

Efficacy

Poor

Excellent

50 % reduction in 1st year,

70 % reduction after 4 years

Relief of symptoms

Slow

Immediate

Medium term

Recurrence

If treatment stopped

1–40 % (depend on size of thyroid remnant)

Unlikely; repeat treatment feasible

Special indications

Small goiter; patient wish

Suspicion of malignancy; severe compression of neighbouring structures

Patient wish; elderly with surgical risk factors; postoperative goiter recurrence

Exclusions

Suppressed TSH

Surgical contraindications

Radiation protection issues

Key adverse effects

Depending on TSH-level: cardiac arrhythmia, osteopenia

Surgical; vocal cord paralysis; hypoparathyroidism; hypothyroidism

Hypothyroidism

4 Physical and Radiobiological Properties of Radioiodine

Iodine is an indispensable component of thyroid hormones levothyroxine (T4) and triiodothyronine (T3). Thyroid cells extract and concentrate iodide from plasma. Shortly after administration, radioiodine is taken up from the blood via the sodium–iodine symporter and accumulates within thyroid follicular cells (Fig. 1). About 20 % of the iodide perfusing the thyroid is removed at each passage through the gland. Ingested iodine is absorbed through the small intestine and transported in the plasma to the thyroid, where it is concentrated, oxidized, and then incorporated into thyroglobulin (Tg) and later T4 and T3. After storage in thyroid follicles, Tg is subjected to proteolysis and the released hormones are secreted into the circulation. In subjects with normal thyroid function up to 20–30 % of orally administered iodine is taken up by the thyroid. In hyperthyroid patients this fraction is increased—in individual cases up to >80 % (rationale for pretherapeutic radioiodine testing). The fraction of radioiodine which is not taken up by the thyroid gland is mainly excreted via the urine (Fig. 2).
Fig. 1

Example for the rapid I-131 thyroidal uptake demonstrated by dynamic whole-body images: 1 min after the application of an I-131 therapy capsule the activity is visible in the stomach, after 2.5 min activity in the gut, after 5 min increasing thyroidal accumulation, and after 10 min the thyroidal accumulation is dominating

Fig. 2

Modeling of iodine kinetics

Iodine-131 (I-131) is a beta- and gamma-emitting radionuclide (principle β = 0.807 MeV; gamma rays ranging from 80 to 637 keV, most abundant γ: 364 keV) with a physical half-life of 8.02 days. The average range of the 0.807 MeV beta particles in soft tissue approximates 1 mm which allows high intrathyroidal doses. Radiobiological effects of radioiodine on tissues are direct (radiation deposit within DNA) or indirect. Indirect effects produce free radicals that in turn react with the critical macromolecules. I-131 used for treatment of thyroid disorders decays to stable Xe-131 by beta emission.

The radiopharmaceutical I-131 sodium iodide is administered orally in capsules, but in patients with severe swallowing difficulties it can be administered in liquid or intravenously in patients in whom vomiting is a problem.

5 Contraindication for Radioiodine Therapy and Precautions

5.1 Pregnancy, Breast Feeding

Pregnancy and breast feeding are all absolute contraindications to radioiodine treatment. Most recommendations stipulate that pregnancy should be avoided for 4 months after radioiodine treatment in women and in men (Dietlein et al. 2007b; Cooper et al. 2009). Arguments for this waiting period are radiation protection and stability of thyroid function in women, the cycle of spermatogenesis in men. This in turn implies that the clinician must have a careful discussion with each patient for whom there may be plans for conception, and treatment must be planned with this in mind. More generally, each patient requires a careful explanation of all treatment options provided by a specialist accredited in the treatment of thyroid disease.

5.2 Uncontrolled Hyperthyroidism

Since radioiodine administration may cause a transient elevation in free T4 and free T3 levels approximately 7 days following administration, uncontrolled symptoms of hyperthyroidism or high level of free T3 constitute relative contraindications for therapy (further elevation of thyroid hormone may trigger atrial fibrillation or heart failure or, rarely, lead to thyroid storm). In that case, pretreatment with antithyroid drugs combined, if necessary, with β-blockers should be administered first. In the symptomatically well-controlled patient radioiodine therapy will have little effect on patient clinical symptoms. In highly selected cases where antithyroid drug are contraindicated (e.g., due to agranulocytosis or post-therapy liver failure) and surgery cannot be performed due to symptoms of hyperthyroidism, I-131 may be administered under the cover of steroids (usually hydrocortisone hemisuccinate 50–100 mg i.v.) and β-blockers.

5.3 Tracheal Stenosis

Patients with large goiter with tracheal narrowing <1 cm may be treated under the cover of steroids though as per authors’ experience clinically harmful thyroid swelling was never observed with tracheal diameters ≥5–6 mm. If tracheal diameter is <5–6 mm, due to risk of severe dyspnea surgery rather than radioiodine therapy should be performed. Patients with high risk of severe post-treatment complications (elderly with a risk of heart failure, patients with narrow tracheal diameter, large thyroid goiter or with uncompensated hyperthyroidism) should always be treated in inpatients facilities to provide continuous medical surveillance.

5.4 Hypersensitivity

Radioiodine administration is very unlikely to precipitate a hypersensitivity reaction because I-131 free of large stable iodine contamination is administered, so even in cases of known iodine sensitivity the I-131 therapy can be safely performed. The stable iodine content of radioiodine preparations is 0.05–0.18 μg. This is very significantly lower than average daily iodine intake.

6 Procedure

6.1 Facility and Legislation

The facilities required to perform radioiodine therapy will depend on the national legislation for the emission of pure beta- or beta–gamma-emitting therapy agents. The requirement to admit patients due to administered I-131 activity varies considerably across Europe. If in-patient therapy is required by national legislation, this should take place in an approved environment with appropriately shielded rooms. The facility in which treatment is performed must have appropriate personnel, radiation safety equipment, procedures available for waste handling and disposal, and handling of incidental contamination, monitoring personnel for accidental contamination and controlling/limiting its spread.

The restrictions on work and contact with small children depend on national dose limits. Generally in Europe, the exposition from radioiodine radiation should not exceed 1 mSv for other individuals in the general population. Usually, the patient is advised to keep as much distance as possible between themselves and others, including children, and of keeping contact times as short as possible (ICRP 2004; Koch et al. 2005; Cappelen et al. 2006; Dillehay et al. 2006).

6.2 Patient Preparation

Patient evaluation before radioiodine therapy should include:
  1. 1.

    Patient’s history with special emphasis on previous treatments (e.g., use of antithyroid drugs, iodinated contrast media, amiodarone, other iodine containing medication, iodinated multi-vitamin combinations) and urinary incontinence. Exposure to excessive stable iodine may influence the choice of primary treatment and the timing of radioiodine therapy. After the administration of iodinated water-soluble contrast agents, radioiodine therapy should be postponed for about 6–8 weeks. In cases of amiodarone induced thyrotoxicosis the elimination of the excess iodine load can take up to 1–2 years (on average 6 months) in amiodarone induced thyrotoxicosis (Eskes and Wiersinga 2009). In doubtful cases, measurement of iodine excretion in the urine is possible. If amiodarone cannot be stopped because of the underlying heart problem, then radioiodine treatment will not be feasible. In patients presenting with unmanageable urinary incontinence a lifelong medication with ATDs may be justified in case of overt hyperthyroidism. TSH-level should be kept in the lower range to avoid increase of the thyroid volume. Consequently, information on this is important and should be part of the patients’ evaluation before therapy.

     
  2. 2.

    Laboratory testing, including free T4, free T3, TSH, TPO-Ab, and Tg-Ab.

     
  3. 3.

    Thyroid scintigraphy and radioiodine testing with radioiodine 24-h uptake: The 24-h uptake should be >20 %, if lower other treatment modalities should be considered. Uptake measurements are not absolutely required when fixed activities are used.

     
  4. 4.

    Assessment of thyroid target volume (ultrasonography) (Brunn et al. 1981) and intrathoracic extension in case of large goiters (magnetic resonance imaging/computed tomography) (Moschetta et al. 2010).

     
  5. 5.

    Fine needle aspiration biopsy (FNAB) in nodules larger than 1–1.5 cm with a suspicious sonographic appearance or scintigraphically hypofunctioning. In elderly patients with large goiters, the combination of hyperfunctioning nodules (indication for radioiodine therapy) and hypofunctioning nodules (surgery as preferred option) is a common constellation. An individual risk stratification is necessary. In autonomous nodules, as the risk of malignancy is very low, FNAB should only be considered in case of suspicious sonographic features (Cooper et al. 2009). Alternatively, I-123 scintigraphy with late imaging 24 h p.i. is a strategy to confirm autonomously functioning nodules and to exclude Tc-99m pertechnetate “trapping only” nodules.

     
  6. 6.

    Female patients with child bearing potential should be routinely tested for pregnancy within 72 h or less before the administration of I-131. When patient history clearly indicates that pregnancy is excluded, a pregnancy test may be omitted at the discretion of the treating physician. Consequently, post-therapeutic contraception for 4 months after I-131 therapy is also a prerequisite.

     

6.3 Special Considerations for Medication

Antithyroid drugs are often used in the initial treatment of patients with hyperthyroidism. As pretreatment with ATDs depletes thyroid hormone stores, it constitutes a safe patient preparation for radioiodine treatment, especially beneficial in patients with overt hyperthyroidism or distinctly elevated fT3. However, since thyrostatic drugs may lower the uptake of radioiodine as well the effective half-life they can decrease effectiveness of radioiodine treatment. Another side-effect of ATDs is the possible radioprotective effect which seems to depend on chemical compounds contained in the thyrostatic medication (methimazole and carbimazole, which do not possess sulfhydryl groups probably do not have radioprotective effects) (Moka et al. 2002). The potentially negative impact of thyrostatic drugs can be compensated for by discontinuing medication shortly before treatment; carbimazole and methimazole should be withdrawn respectively for at least 2 days before planned radioiodine administration (Braga et al. 2002; Bonnema et al. 2004; Santos et al. 2004) if tolerated by the patient. PTU which has a more distinct radioprotective action that may further reduce the effectiveness of radioiodine should be stopped at least 2–3 weeks before radioiodine treatment. When data from an individual pretherapeutic dosimetry (radioiodine testing with measurement of the effective half-life) are available, a withdrawal of PTU 2 days before “radioiodine testing” and radioiodine therapy may be sufficient (Kobe et al. 2008a). Beta adrenergic antagonists (usually propranolol in dose adjusted to clinical symptoms) may be helpful for interim hyperthyroidism symptom relief during ATD withdrawal, provided that there are no contraindications.

Levothyroxine medication decreases radioiodine uptake, but may be used to optimized the distribution of radioiodine within the nodular thyroid. In patients with autonomously functioning nodules and a pretherapeutic TSH-level of >0.3 mUL−1, the levothyroxine medication lead to an exogenous suppression of the thyrotropin secretion and may be favorable to achieve euthyroidism without levothyroxine substitution. If reduction of goiter size is given priority, TSH suppression is not necessary.

Lithium can block radioiodine release from the thyroid but does not interfere with radioiodine uptake. It may enhance the effectiveness of radioiodine when given for a few days immediately after treatment, but the available data are controversial and side-effects may be experienced by 10 % of patients. In one prospective, randomized, controlled trial from Italy, lithium treatment (900 mg/day for 6 days from the time of radioiodine treatment) increased the cure rate by 11 % and induced a more rapid control of hyperthyroidism (Bogazzi et al. 1999). However, another randomized, controlled trial from India has found no evidence of an effect of lithium on outcome after radioiodine treatment (Bal et al. 2002). Therefore, the off-label use of lithium (e.g., 2 × 250 mg) is not routinely recommended. After recompensation of thyroid function in toxic goiters, there is usually no need for a prolongation of the effective half-life.

Recombinant human TSH (rhTSH) may be used to maximize I-131 uptake in the thyroid gland and to minimize the radiation dose to the remainder of the body in patients with non-toxic multinodular goiter (Silva et al. 2004; Nielsen et al. 2006a, b; Fast et al. 2009). However, rhTSH is not yet approved for this indication and administration in a patient with non-toxic goiter represents an off-label use.

7 Patient Information and Instruction

Patients should receive both written and verbal information about the procedure before receiving therapy. Written informed consent must be obtained from the patient. The following items should be discussed:
  • Therapeutic options and alternatives including watchful waiting.

  • More than one I-131 treatment course may be necessary. Pretherapeutic dosimetry before I-131 therapy and intended absorbed doses of about 100–150 Gy (toxic goiters, non-toxic goiters) and 300–400 Gy (toxic nodules) offer high rates of success of a single I-131 therapy.

  • Recommendations for radiation protection after discharge from hospital or as out-patient.

  • Early and late side-effects.

  • Need for contraception for 4 months for female and male patients.

  • Need for lifelong follow-up.

8 Radiation Dosimetry and I-131 Activity

The aim for radioiodine treatment in toxic nodules or toxic goiters is often to restore euthyroidism (Dietlein et al. 2007b). There have been many studies attempting to identify an optimal regimen for radioiodine treatment that minimizes the risks of developing hypothyroidism while maximizing the cure rate of hyperthyroidism. However, this is a challenging issue: first because a maximum cure rate inevitably results in the highest rate of hypothyroidism and second because any single dosage method cannot practically encompass all of the variables affecting outcome. These variables include age, sex, thyroid size, severity of hyperthyroidism, innate differences in radiation sensitivity, iodine intake, and preceding use of antithyroid drugs. Nevertheless, there is an ongoing discussion on the establishment of the optimal method to determine the activity that can be recommended for clinical practice: estimation (the so-called “fixed dose”) versus calculation (based on radioiodine uptake measurements). Council directive Euratom 97/43 requires that for all medical exposure of individuals for radiotherapeutic purposes exposures of target volumes will be individually planned. In principle, formulas which calculate the therapeutic I-131 activity for an individual patient differ in the time points when radioiodine uptake is measured during the radioiodine test. The Marinelli formula takes a 24-h radioiodine uptake while Hänscheid–Bockisch formula focuses on a late uptake about 5 days after ingestion of a test capsule (Marinelli et al. 1950; Bockisch et al. 1993).

In either toxic or non-toxic multinodular goiter, radioiodine doses have been empirically established. The optimal radioiodine therapy should be a single dose cure. Currently, an absorbed radiation dose of 100–150 Gy is recommended (Table 3), requiring about 3.7–5.5 MBq per gram of thyroid tissue corrected for the 24-h I-131 uptake (Hegedus et al. 2003). To increase radioiodine uptake and retention in non-toxic goiter, rhTSH was used in some studies (Braga et al. 2002; Bonnema et al. 2004). rhTSH can increase the absorbed radiation dose and permits a more equal distribution in the gland (Nieuwlaat et al. 2003; Silva et al. 2004; Nielsen et al. 2006a, b). Its future role, however, still has to be established. In patients with autonomous nodules, the recommended dose is 300–400 Gy (Fig. 3).
Table 3

Recommendations for intended target dose

 

Target volume

Dose (Gy) per g tissue

Toxic goiter

thyroid

150

Hyperfunctioning nodule

nodule

300–400

Non-toxic goiter

thyroid

120–150

Retreatment >6 months after first dose of radioiodine

 

Original dose

Fig. 3

Sonography (left) and scintigraphies (right) of a 49-year-old patient with solitary toxic nodule of 9 mL and subclinical hyperthyroidism. Tc-99m-pertechnetate scintigraphy demonstrated a hyperfunctional (hot) nodule and a suppressed uptake into the contralateral lobe (on the top right). The post-therapeutic I-131 scintigraphy confirmed radioiodine uptake in the autonomous nodule (at the bottom right)

The recommended formula to calculate the activity which is required to achieve the dose in the thyroid is as follows:
$$ A[{\text{MBq}}] = \frac{F}{\ln 2}\;\frac{{M\,[{\text{g}}]\;D\,[{\text{Gy}}]}}{{\int\limits_{0}^{\infty } {RIU(t)dt} }} $$
where

A activity; F correction factor; M mass of target volume; D required dose

In this respect, the radioiodine uptake (RIU) can be calculated as follows:
$$ {\text{RIU}} \; = \;\frac{\text{activity in thyroid gland}}{{{\text{administered}}\;{\text{activity}}}}\;{\text{X}}\;{ 1}00\;\% \, $$

The range of activities currently prescribed, irrespective of the method used, varies between 200 and 800 MBq depending on gland size or nodule size, with the majority of patients receiving 400–600 MBq. To get more insight into the procedure guidelines for pretherapeutic “radioiodine testing”, some papers are recommended in which comprehensive updates are provided for clinical practice (Leslie et al. 2003; Dietlein et al. 2007a; Sisson et al. 2007; Weetman 2007; Kobe et al. 2008a, b; Stabin and Brill 2008; Boeleart et al. 2009; de Rooy et al. 2009; Kobe et al. 2010; Salvatori and Luster 2010).

Kobe et al. (2010) analyzed the radioiodine half-life and uptake in a region with a mean alimentary iodine supply of 130–150 μg daily. Inclusion criteria were the control of hyperthyroidism and withdrawal of ATDs 2 days before preliminary radioiodine testing and therapy. Patients were treated for toxic goiter (n = 639), toxic solitary nodule (n = 365), or non-toxic goiter (n = 50). The effective half-life and uptake of I-131 were estimated by uptake measurements after 24 h and 5 days during the preliminary radioiodine test, and serial measurements over 5 days during therapy. The mean effective half-life of I-131 measured during radioiodine therapy was 6.6 days in toxic goiter, 5.7 days in toxic solitary nodule, and 6.4 days in non-toxic goiter. The mean maximal uptake of I-131 measured during radioiodine therapy was 38 % in toxic goiter, 31 % in toxic nodule, and 42 % in non-toxic goiter (Table 4).
Table 4

Effective thyroidal half-life and thyroidal I-131 uptake measured in 639 patients with toxic goiter, in 365 patients with solitary hyperfunctioning nodules, and in 50 patients with non-toxic goiter (Kobe et al. 2010)

 

Toxic goiter

Toxic solitary nodule

Non-toxic goiter

Half-life of I-131 (test)

7.3 ± 1.0

6.5 ± 1.4

7.4 ± 0.9

(days ±SD)

Half-life of I-131 (therapy)

6.6 ± 1.2

5.7 ± 1.5

6.4 ± 1.1

(days ±SD)

Maximal uptake of I-131 (test)

37 ± 15

31 ± 12

38 ± 15

(% ±SD)

Maximal uptake of I-131 (therapy)

38 ± 15

31 ± 23

42 ± 13

(% ±SD)

Inclusion criteria were the control of hyperthyroidism and withdrawal of antithyroid drugs 2 days before preliminary radioiodine testing and therapy. SD, standard deviation

Another advantage of an individual pre- and post-therapeutical dosimetry is the early detection of an unexpected low thyroid dose. If the post-therapeutically achieved dose is much lower than the intended dose, a second I-131 capsule can be administered, while patient is still hospitalized (2–3 days after the first I-131 administration). Monitoring of radioiodine kinetics during therapy in an individual patient allows intervening in case of impending therapy failure which lowers the rate of patients requiring a second therapy and represents a highly personalized approach to radioiodine therapy (Fig. 4) (Dietlein et al. 2007b; Kobe et al. 2008b).
Fig. 4

Time–activity curves during I-131 therapy of a toxic goiter. Whole-body activity (triangle) and thyroidal activity after the application of an I-131 therapy capsule (rhombus, thin line) were measured twice a day. Extrapolated values of the post-therapeutic thyroidal activity are represented by the dashed line. The time-activity-curve from the pretherapeutic I-131 testing is also visible (broader line) and allows a comparison between the expected and the achieved thyroidal dose. The national laws in Germany allow discharge from hospital at 250 MBq I-131 residual activity

Patients with end-stage renal failure cannot excrete radioiodine normally, reducing the dose required for treatment, and the effects of hemodialysis or peritoneal dialysis add further complications to calculating the activity required (Kaptein et al. 2000).

9 Side-Effects of I-131 Therapy

9.1 Acute Side-Effects

Patients with large goiters may notice transient swelling of the goiter. Thyroid swelling lasts until approximately 1 week following therapy and some discomfort may be associated with it. Treatment strategy is the sequence cooling with ice, antiphlogistic drugs, and glucocorticoids. Slight discomfort of the salivary glands may be present, but sialadenitis is transient and permanent injury uncommon. There may be a transient rise in fT4 and fT3 levels 7–10 days following radioiodine treatment, and patients who have been poorly controlled before radioiodine therapy may experience an exacerbation of heart arrhythmias and heart failure. In some patients, a thyroid storm may develop. This rare condition must be treated with intravenous infusion of antithyroid drugs, corticosteroids and β-blockers.

9.2 Hypothyroidism

The main side-effect of radioiodine treatment is hypothyroidism (Hall and Holm 1997; Boeleart et al. 2009). Its rates vary 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 small gland size than in large toxic goiter. In solitary hyperfunctioning nodules, the volume of the surrounding thyroid tissue is the decisive factor. Permanent hypothyroidism subsequently occurs at an earlier time in the group of patients without TSH suppression at the time of radioiodine therapy (e.g., for goiter shrinkage). Levothyroxine medication is needed in all patients with elevated TSH after I-131 therapy (e.g., TSH >3 mUL−1), also in patients with subclinical hypothyroidism.

9.3 Autoimmune Thyroiditis

This phenomenon is observed in 1 % of the patients following radioiodine therapy of goiter/autonomy. The risk is increased up to 10 % in patients with pre-existing thyroid peroxidase- or thyroglobulin-antibodies (Schmidt et al. 2006). In case of autoimmune thyroiditis after radioiodine therapy, about 10 % of patients will develop ophthalmopathy. Thus, the risk of ophthalmopathy is in the range of 0.1 % for patients without a pre-existing elevation of thyroid antibodies.

9.4 Radiation Induced Cancers

A small excess of mortality from malignancy (standardized mortality ratio 1.09; confidence intervals 1.03–1.16) was reported (Hall et al. 1993) but the study was biased by the increased surveillance, changes in reporting and a higher proportion of smokers in the hyperthyroid patients. A small increase in relative risk of diagnosis or death from thyroid cancer after radioiodine treatment has been reported in large epidemiological studies carried out in different countries. The reported absolute risk, however, is still very small in these studies and, in addition, it seems to be more associated with the underlying disease than treatment with radioiodine (Dobyns et al. 1974; Franklyn et al. 1999; Dickman et al. 2003; Boice 2005; Lucignani 2007).

10 Results

The success rate of radioiodine therapy depends on thyroid volume, compensation of hyperthyroidism, timing of the withdrawal of antithyroid drugs, alimentary iodine intake, and the dose concepts in the different thyroid diseases. The superiority of dosimetric approaches over the use of fixed activities or of volume-adapted activities remains controversial. The dosimetric approach is mandatory in some European countries; it allows early therapeutic intervention should the post-therapeutically achieved thyroid dose fall unexpectedly below the intended dose. In this constellation, the application of a second I-131 capsule may be appropriate.

10.1 Toxic Multinodular Goiter

Two studies with an intended absorbed dose of 150 Gy to the thyroid and higher doses in selected patients with a high Tc-99m-pertechnetate uptake under suppression reported a success rate of >90 % (Reinhardt et al. 2002; Dunkelmann et al. 1999). In a comparative study from Switzerland 3 days of carbimazole withdrawal was sufficient for a high success rate of radioiodine therapy (Walter et al. 2006).

10.2 Solitary Hyperfunctioning Nodule

Studies in which the radiation absorbed dose to the hyperfunctioning nodule has been measured post-therapeutically or, at least, a target absorbed dose has been determined pre-therapeutically have shown a success rate of 85–100 % and an incidence of hypothyroidism of 10–20 % (Reiners and Schneider 2002). In a comparative study, successful elimination of functional thyroid autonomy occurred at 12 months after radioiodine therapy in 90 % of patients receiving 300 Gy to the nodule volume and in 94 % of patients receiving 400 Gy to the nodule volume (Reinhardt et al. 2006).

10.3 Non-Toxic Multinodular Goiter

The success of radioiodine treatment in reducing the size of an NTG depends on many factors. Cystic and fibrotic areas will be resistant to shrinkage and their extent varies between patients. The volume reduction in radioiodine accumulating goiter areas increases with higher I-131 activities per gram thyroid tissue, higher achieved thyroid doses, and a homogeneous distribution of I-131 within the goiter. In most previous reports, the administered amount of radioiodine has been approximately 3.7 MBq per gram thyroid tissue, corrected for 100 % uptake in the thyroid after 24 h, leading to an absorbed dose of about 100 Gy in the thyroid. The decrease in thyroid volume ranged between 30 and 60 % (Manders and Corstens 2002). Most of the shrinkage occurred within the first year and goiter volumes continued to decrease for several years. As severe stenosis of the trachea can be excluded by adequate imaging procedures a symptomatic swelling of the goiter is uncommon. Calculations based on pretherapeutic uptake measurements over 5 days and an intended thyroid dose of 150 Gy—resulting in mean activities of 1721 ± 440 MBq I-131, equivalent to 14 ± 4.19 MBq I-131 per gram of thyroid tissue—led to a mean volume reduction of 42 % after 3 months, 66 % after 1 year, 70 % after 2 years, and nearly 75 % after 3 years in a patient group with goiters of at least 80 ml residing in an area of longstanding iodine deficiency (Bachmann et al. 2009).

Volume measurements of large goiters can be optimized by magnetic resonance imaging (MRI), which provides more objective results and less intra-/inter-observer variability than ultrasound as precise volume measurements become more difficult with increasing thyroid size (Bonnema et al. 2002). Additionally, MRI evaluates the size of an accompanying retrosternal goiters and the diameter of the trachea.

A more homogeneous radioiodine uptake and an improvement of goiter volume reduction results from radioiodine therapy after stimulation with a low dose of recombinant human thyrotropin, specially prepared for a delayed release in randomized trials (Bonnema et al. 2007).

Radioiodine therapy for reducing the size of an NTG can be recommended as effective therapy especially for elderly people, for those with co-morbidity and for patients who want to avoid surgery.

11 Follow-Up After Radioiodine Treatment

Regular review of thyroid function tests in patients who have undergone radioiodine treatment for thyroid disease is essential to assess the efficacy of the treatment and for timely detection of developing hypothyroidism or post-radioiodine immunogenic hyperthyroidism. First, TSH and fT4 examination should be performed not longer than 4–6 weeks after radioiodine therapy. Shorter intervals of about 2–3 weeks are recommended for patients who received ATDs. If the treatment was performed for (overt) hyperthyroidism, about 3–5 days after the radioiodine administration restart of antithyroid drugs should be recommended. In case of persistent hyperthyroidism radioiodine treatment can be repeated after 6–12 months. In case of post-radioiodine immunogenic hyperthyroidism, ATDs for some months appears to be adequate and a second radioiodine therapy is not necessary in most patients. Laboratory tests (at least including TSH) in annual intervals are necessary lifelong, even in patients with euthyroidism after I-131 therapy.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Nuclear MedicineUniversity Hospital of CologneCologneGermany

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