Radioiodine treatment for benign thyroid diseases
Summary
Radioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have occurred with the realization that accurate dosimetry is incapable of avoiding the risks of hypothyroidism, while more accurate assessment of the risks of other adverse effects of radioiodine such as ophthalmopathy and carcinogenesis have become available. More is also known of the potential for pretreatment with an antithyroid drug to affect the outcome of radioiodine treatment. However, we are still uncertain of the benefits of radioiodine treatment in subclinical hyperthyroidism.
During the last two decades there has been wider acceptance of radioiodine as a safe and effective therapy for benign, nontoxic goitre, coupled with waning enthusiasm for the use of levothyroxine, as the risks and benefits of this option have become more apparent. The use of recombinant TSH offers the prospect that radioiodine treatment of nontoxic goitre can be simplified and improved, although more studies of this strategy are urgently required.
Introduction
It is over 15 years since the journal last published a review on this topic.1 There have been several significant developments since that time, and the remit of the present update has been widened to include the use of radioiodine in nontoxic goitre, as this has become an increasingly used treatment in Europe.2 Within the UK, a notable influence on practice has been the survey of national practice in the administration of radioiodine for the treatment of hyperthyroidism, published by the Royal College of Physicians in 1992 which highlighted the extremely diverse regimens then in use.3 This resulted in the publication of UK guidelines for the use of radioiodine in the management of hyperthyroidism4 and these have just been revised.5 This update will therefore consider developments in the field over the last 15 years, with an emphasis on practical aspects of radioiodine treatment. Inevitably, there is still considerable diversity in practice, influenced in part by national regulatory bodies, and I have indicated where the recommendations offered are based on the recent UK guidelines.
Choice of treatment for hyperthyroidism
The general principles of treatment of hyperthyroidism are detailed elsewhere6,7 and are summarized in Table 1. Radioiodine can be administered either as first-line treatment or, in Graves’ disease, if the hyperthyroidism is not controlled or recurs after antithyroid drug treatment or thyroid surgery. 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 (see sections below). Apart from regional preferences, patient age, sex, degree of hyperthyroidism and ophthalmopathy, the presence of coexistent medical conditions (such as severe heart disease) and exposure to excess stable iodine (such as amiodarone or contrast media) all influence the choice of primary treatment. In cases of amiodarone-induced thyrotoxicosis type 1, radioiodine can be administered as definitive therapy, providing the drug has been stopped sufficiently long for the excess iodine load to be eliminated. This can take up to a year and the patient will require treatment with an antithyroid drug in the interim. If amiodarone cannot be stopped because of the underlying heart problem, then radioiodine treatment will not be feasible.
| Antithyroid drug | Surgery | Radioiodine | |
|---|---|---|---|
| Time to initial improvement | 2–4 weeks | Needs antithyroid drug pretreatment | 4–8 weeks |
| Recurrence | 60–70%* | 1–4% | 5–10% |
| Use in pregnancy/Breast feeding | Yes | Second trimester | No |
| Adverse effect on thyroid eye disease | No | Possible43 | Yes (mainly smokers) |
| Use in childhood | Initial treatment of choice | If recurrent | Increased evidence of safety |
| Interference with daily activities | No | Requires hospital admission | Need for radiation precautions |
| Key adverse effects | Rash; arthralgia; SLE–like syndrome; hepatitis; agranulocytosis | Surgical; vocal cord paralysis; hypoparathyroidism; hypothyroidism | Hypothyroidism |
- * Only indicated as definitive treatment in Graves’ disease.
Children with Graves’ disease are usually treated with a prolonged course of antithyroid drugs, often followed by thyroid surgery, because prepubertal children have a poorer remission rate after antithyroid drug therapy than pubertal children, while also having a greater risk of developing drug side effects.8 This realization has led to calls for greater use of radioiodine in children with hyperthyroidism.8,9 A recent 36-year retrospective survey of efficacy and safety in 116 patients under the age of 20 years so treated showed no increased risk of cancer or congenital anomalies in the offspring.10 Although a small data set by comparison with the information available in adults, this is the best follow-up information we are likely to have for many years to come and supports the more liberal use of radioiodine in children, coupled with careful registry-based follow-up of those so treated. Enuresis and vomiting are potential management problems after radioiodine administration in this age group and require special consideration.11
Another group of patients which also causes debate is the increasing population presenting with subclinical hyperthyroidism. Most are older patients with autonomous thyroid nodules and radioiodine would be the treatment of choice, if anything were to be given. A recent consensus statement from the USA concluded that treatment is worth considering if the TSH is persistently below 0·1 mU/l, and especially if there is coexisting heart disease and evidence of an underlying thyroid disorder.12 One small study has shown a reduction in bone loss in postmenopausal women with subclinical hyperthyroidism who were treated,13 but large randomized, controlled trials are badly needed to assess the benefits and risks of radioiodine treatment in such patients.
Pregnancy and breast feeding are all absolute contraindications to radioiodine treatment. In the UK, guidance has recently changed to stipulate that pregnancy should be avoided for 6 months after radioiodine treatment in women and for 4 months in men.14 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.15
Strategy for administration of radioiodine
The various national regulations in part determine the practical details of radioiodine treatment. In the UK for instance, the administration of radioiodine is covered by the Ionizing Radiation (Medical Exposure) Regulations 2000 (SI 2000 no. 1059) and the practitioner responsible for treatment must hold an appropriate certificate from the Administration of Radioactive Substances Advisory Committee, granted according to the Medicines (Administration of Radioactive Substances) Regulations 1978. The regulations for each country should include the need for suitable training programmes and for liaison between the clinician and medical physicist responsible for all aspects of safe administration of the radioiodine.
Determining the dose of radioiodine
There have been many studies over several decades attempting to identify an optimal regimen for radioiodine treatment, namely, one that minimizes the risks of developing hypothyroidism while maximizing the cure rate of hyperthyroidism. Put bluntly, this is biologically impossible, 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. Prospective randomized, controlled trials16,17 and detailed retrospective analyses18,19 have shown that precision dosimetry does not improve outcome, while the use of a small range of fixed doses, which can take into account clinically established variables, is safe, simple and cost-effective.
The revised UK guidelines for radioiodine treatment in hyperthyroidism aim to restore euthyroidism in around two-thirds of patients within 2 months and are summarized in Table 2. 5 These recommendations are based on previous guidelines4 which included thyroid size as a criterion for dose administration, but with a view to simplifying these guidelines in the light of recent data and the difficulty of estimating gland size by palpation. However, as with all guidelines, there is clear scope for departure from this simple scheme, providing this can be justified by the clinician. This must particularly be the case with radioiodine treatment where so much of the evidence is based on custom and practice rather than hard evidence. I therefore expect that some practitioners will continue to use a single fixed dose for all patients, while others will use a lower dose for those with a relatively small goitre and a larger dose where there is a large and possibly more vascular gland. Regular audit of outcome and comparison with national figures for rates of cure of hyperthyroidism and rates of hypothyroidism could further refine practice. Any treatment using moderate or high fixed single doses is likely to be associated with a failure rate of 5–10%19 which can be treated 6 months after the initial therapy with further radioiodine (Table 2). In one trial using a single dose of 370 MBq radioiodine, there was no difference between cure rates in patients with Graves’ disease and patients with toxic multinodular goitre, but Graves’ patients had a 20% higher chance of developing hypothyroidism.20 Hypothyroidism is less common after treatment of a toxic adenoma.
| Activity (MBq) | |
|---|---|
| Uncomplicated Graves’ disease | 400–600 |
| Uncomplicated toxic multinodular goitre | 500–800 |
| Uncomplicated toxic adenoma | 500 |
| Hyperthyroidism complicated by severe comorbidity (e.g. heart failure, psychosis, malignancy), patients with thyroid eye disease or intolerant of antithyroid drugs | 500–800 |
| Retreatment > 6 months after first dose of radioiodine | Original or higher activity |
| Subclinical hyperthyroidism* | |
| Moderate or large goitre | 600 |
| Small or no goitre | 400 |
- * See text for treatment indications.
Patients with end-stage renal failure cannot excrete radioiodine normally, reducing the dose required for treatment, and the effects of haemodialysis or peritoneal dialysis add further complications to calculating the activity required.21 Radioiodine treatment is not indicated for patients who are incontinent of urine unless they accept the need for catheterization to allow safe disposal of urine contaminated by radioiodine. The clinician must also be wary of attempts to treat patients who have been exposed to excess stable iodine. Sources such as amiodarone are easily detected, but radiocontrast media can have an adverse effect on radioiodine uptake for up to a year after administration and patients often do not volunteer the relevant information about such imaging procedures.
Effect of antithyroid drugs
Patients with uncomplicated subclinical or mild hyperthyroidism can be treated with radioiodine alone, and a beta adrenergic blocking agent can be used, providing there are no contraindications, to relieve any symptoms until a cure is achieved. There is, however, a small chance that radioiodine treatment may provoke an episode of thyrotoxic crisis (or ‘storm’) in severe thyrotoxicosis, and any risk of this complication should be particularly avoided in the elderly and those with heart problems.22,23 Antithyroid drug pretreatment depletes thyroid hormone stores and thereby reduces the risk of thyrotoxic crisis or any worsening of symptoms in the aftermath of radioiodine treatment. These drugs do not totally prevent the transient increase in circulating thyroid hormone that occurs after radioiodine therapy and discontinuing the drug, but the increase is from a lower initial level than in those who are not given an antithyroid drug, rendering the increase less likely to be clinically significant.24,25
Retrospective studies have suggested that administration of an antithyroid drug prior to radioiodine administration can reduce the cure rate and therefore have called into question the routine use of an antithyroid drug in this way.1 Recent retrospective and prospective studies have shown that pretreatment with propythiouracil does have an adverse effect on cure rate after radioiodine treatment and this effect appears to persist even if the drug is stopped up to 2 months prior to radioiodine administration.26–28 On the other hand, methimazole and carbimazole have no apparent adverse effect on cure rate, provided the drug is stopped at least a day before radioiodine treatment is given.25,29
The exact reason for the prolonged radioprotective effect of propylthiouracil is unclear but may be in part related to the 10-fold higher dose of drug given, when compared to carbimazole or methimazole.28 If a patient requires antithyroid drug treatment with propylthiouracil prior to radioiodine treatment, this protective effect can be overcome by stopping drug treatment 2 months beforehand or by giving a higher dose of radioiodine. Patients should avoid antithyroid drug treatment for at least 7 days after radioiodine treatment, as this is known to be without detriment to outcome, but it is not yet known if a shorter period before starting treatment is also without effect on outcome.30 Whether propylthiouracil has any greater potential to have an adverse effect on outcome compared to carbimazole or methimazole when given after radioiodine administration is also not clear. A beta-adrenergic blocking agent can be used as an alternative to control thyrotoxic symptoms until radioiodine takes effect.
Use of lithium
Lithium can block radioiodine release from the thyroid but does not interfere with radioiodine uptake. 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.31 Lithium treatment also prevented the rise in circulating thyroid hormones after withdrawal of antithyroid drugs and treatment with radioiodine.32 However, another randomized, controlled trial from India has found no evidence of an effect of lithium on outcome after radioiodine treatment.33 Without more information, the wider use of lithium pretreatment cannot be recommended.
Complications
Hypothyroidism
The main complication resulting from radioiodine treatment is hypothyroidism and although rates vary, this complication continues to increase over time, so that life-long follow-up is essential. Transient hypothyroidism occurring within the first 6 months after radioiodine treatment is a well-recognized trap for the unwary endocrinologist. Pretreatment prediction is not possible using current variables and late permanent hypothyroidism occurs at an earlier time subsequently in this group of patients than in those without transient hypothyroidism.34
There are conflicting reports on the importance of changes in the relative balance between TSH-receptor stimulating and blocking antibodies in causing transient hypothyroidism in Graves’ patients.34–36 Such changes clearly do occur and the rise in TSH-receptor stimulating antibodies that follows radioiodine administration may be the result of an increase in helper T cell activation directly resulting from radioiodine treatment.37 In turn, this could explain the occasional appearance of thyroid stimulating antibodies after radioiodine treatment for toxic multinodular goitre.38
Thyroid eye disease
Prospective randomized, controlled trials have shown that radioiodine treatment is associated with a greater risk of the appearance or worsening of ophthalmopathy in Graves’ patients than treatment with an antithyroid drug.39,40 The risk is increased four-fold in those who smoke cigarettes in keeping with the importance of smoking as a susceptibility factor in the development of ophthalmopathy.41 Some still dispute the significance of radioiodine as a risk factor in the development of ophthalmopathy.42 In particular, it has been suggested that more frequent episodes of hypothyroidism (possibly overlooked between follow-up visits) could account for the adverse effect of radioiodine, and there is certainly controlled trial evidence to show that the early introduction of levothyroxine replacement reduces the risk of eye disease deteriorating after radioiodine treatment.43,44
Despite the controversy, these findings have clearly altered practice, with the majority of European thyroidologists in one survey preferring to avoid the use of radioiodine in the management of Graves’ disease complicated by significant ophthalmopathy.45 It seems reasonable to recommend the avoidance of radioiodine treatment in newly diagnosed patients with active thyroid eye disease, especially in those who smoke. When there is no alternative to radioiodine treatment, deterioration of the eye disease can be avoided by prophylactic glucocorticoid treatment, as shown in a prospective trial.40 In this trial the starting dose of prednisolone was 0·4–0·5 mg/kg/day, commencing 2–3 days prior to radioiodine treatment and this was continued for 1 month before tapering over the next 2 months. The usual advice about steroid treatment precautions is, of course, necessary. Whether shorter duration regimens are as effective, with the potential for fewer side effects, has not been assessed.
Cancer risk
A long-standing concern with radioiodine use has been its potential for carcinogenesis and leukaemogenesis, which became a more public worry after the Chernobyl accident 20 years ago. Three large surveys have subsequently provided considerable reassurance. In the largest, 35 593 hyperthyroid patients, mainly from the USA, were followed up for a mean of 21 years and radioiodine was not linked to total cancer deaths or any specific cancer, except for an increase in the standardized mortality ratio for cancer of the thyroid.46 Whether the latter is related to the underlying thyroid diseases rather than to radioiodine itself could not be established but is certainly possible, and the absolute risk was very low.
In 10 552 Swedish patients treated with radioiodine and followed up for an average of 15 years, there was a very small excess mortality from malignancy (standardized mortality ratio (SMR) 1·09, confidence intervals 1·03–1·16) but this was believed to be largely due to the increased surveillance, changes in reporting and a higher proportion of smokers in the hyperthyroid population.47 In 7417 UK patients, half of whom were followed up for at least 10 years, there was a slight decrease in both the incidence of cancer, and mortality from it, although site-specific increases were seen for thyroid and small bowel cancer.48 Gastric cancer incidence was increased in a detailed breakdown of site-specific cancers in the Swedish cohort.49
Together, these data indicate that radioiodine treatment is generally safe. The possible effects of radioiodine on site-specific cancers, and the relatively low number of patients under the age of 40 years who have been followed up, indicate that continued follow-up will be worthwhile, especially if more children receive radioiodine treatment.8,9 Finally, any possible oncogenic risks from radioiodine must be carefully balanced against the definite mortality and morbidity that are caused by antithyroid drugs and thyroid surgery.
Other complications
Radioiodine may rarely cause an acute thyroiditis or sialadenitis, which is transient and responds to analgesics or in severe cases a short course of prednisolone. The theoretical risk of a genetic abnormality resulting from radioiodine treatment is estimated to be 0·003%.50 This is too small to be practically detectable or verifiable. Despite the emphasis in guidelines on the avoidance of pregnancy at the time of treatment or after radioiodine administration,4,5 such cases still continue to be reported in the literature.51 The main adverse effect is impairment of the baby's thyroid function, which should be treated promptly to minimize any neurological consequences.
All patients receiving radioiodine should be given explicit information about the treatment, as well as written instructions on avoidance of pregnancy until it is safe, and other relevant precautions to avoid exposing others to unnecessary irradiation after treatment. The precautions can be particularly difficult for women needing radioiodine treatment who have sole care of young children and who may therefore require special arrangements.52 All patients should sign a consent form indicating that they are aware of, and accept, the risks of radioiodine treatment. They should be given an information card to carry after treatment; this should include details of treatment that will prevent difficulties if port or airport security radiation alarms are triggered by retained radioiodine (for up to 95 days after treatment).53
Principles of treatment of nontoxic goitre (NTG)
This section concerns those patients who are euthyroid but require treatment for a simple, typically multinodular goitre. The management of solitary nodules is not covered and the assumption is made that any possibility of malignancy in the goitre has been excluded. Most patients with NTG have no symptoms or cosmetic concerns and therefore once malignancy and abnormalities of thyroid function have been ruled out, no further treatment is necessary.2 The majority of thyroidologists surveyed in Europe and North America would also include assessment of thyroid peroxidase autoantibodies in the initial evaluation, and would undertake thyroid ultrasound and/or scintigraphy, although there is wide disparity between European countries.54,55
This disparity is, not surprisingly, also seen in the approach to treatment of NTG. Asked for views on a hypothetical index case of a 42-year-old woman with a 50–80 g goitre causing moderate local neck discomfort, 28% of European and 36% of American clinicians would offer no treatment,54,55 although follow-up would be recommended to ensure that there was no progression, including the development of toxic multinodular goitre. The main indications for treatment of NTG are to reduce the size of a goitre that is causing cosmetic difficulties for the patient and to relieve compressive signs or symptoms. There is much variability between clinicians as well as patients over the threshold for regarding these indications as significant enough to undertake treatment. Once decided upon, treatment is a choice between levothyroxine, surgery and radioiodine treatment. The main benefits and risks of each are summarized in Table 3. Only between 30% and 58% of patients show a significant reduction in goitre size with levothyroxine56–58 and the potential adverse effects on bone and heart resulting from the supraphysiological doses of levothyroxine required for effective treatment have dissuaded many endocrinologists from using this option. However, just over half of all clinicians sampled would recommend levothyroxine for the treatment of the index case mentioned earlier.54,55
| Thyroxine | Surgery | Radioiodine | |
|---|---|---|---|
| Efficacy | Poor | Excellent | 50% reduction in 1 year |
| Relief of symptoms | Slow | Immediate | Medium term |
| Recurrence | If treatment stopped | 15–40% | Unlikely; repeat treatment feasible |
| Cost | Low | High | Low |
| Special indications | No other treatment possible | Exclusion of malignancy | Suppressed TSH; the elderly with surgical risk factors |
| Exclusions | Suppressed TSH | Surgical contraindications | Radiation protection issues |
| Side effects | Osteopaenia; atrial fibrillation | Surgical; vocal cord paralysis;hypoparathyroidism; hypothyroidism | Thyroiditis; transient enlargements Graves’ disease; hypothyroidism |
Surgery is the swiftest way to reduce goitre size and relieve any acute compressive symptoms. This option is mandatory if there are any lingering doubts about malignancy. The recurrence rate of NTG after surgery is 15–40%,59–61 which in turn has led to attempts to prevent recurrence by postoperative administration of levothyroxine to suppress TSH levels. Not only does this carry the risk of side effects just mentioned, but also there is little evidence that it is effective.59,62 Large goitres can be particularly problematic with regard to intraoperative and postoperative complications.
These considerations clearly demonstrate the need for a more effective treatment for NTG and over the last 20 years there has been considerable expansion in the use of radioiodine for this purpose. Although it would be given by only 6% of European clinicians in the index case of NTG previously described, three-fold as many would use radioiodine treatment if the patient was over 75-years-old and almost half would use it if the TSH was suppressed and the patient had subclinical hyperthyroidism.54
Outcome after radioiodine treatment in NTG
The success of radioiodine treatment in reducing the size of a NTG depends on many factors. Cystic and fibrotic areas will be resistant to shrinkage and their extent varies between patients. The decrease in size is directly related to the dose of radioiodine used and inversely to initial goitre size, because degenerative changes are more substantial.63 In a small to medium size NTG (< 100 g) the typical reduction in size after radioiodine treatment is around 50% and the efficacy of a second dose of radioiodine is comparable to the first.58,63–66 In a randomized, controlled trial comparing the use of levothyroxine and radioiodine, the latter was more effective and better tolerated; only one of the 29 patients receiving radioiodine treatment failed to achieve a size reduction of at least 13%, compared to 16 of the 28 in the levothyroxine-treated group.58
There have been fewer trials of radioiodine treatment for large goitres, because larger doses of radioiodine requiring prolonged hospitalization have been used, and there have been concerns that laryngeal oedema may result from radiation-induced thyroiditis. Nonetheless, mean reductions of around a third in goitre size have been reported, but with considerable heterogeneity in response; average goitre size did not alter acutely although changes of up to 15% can occur in the week after treatment.67,68 Caution is therefore required when treating patients with very large goitres, and although glucocorticoids (e.g. prednisolone 20–30 mg daily for 2–4 weeks) may be given to minimize any complications, it is unknown how effective this may be in preventing airways obstruction.
Dose of radioiodine and use of recombinant TSH
In the majority of studies reported, radioiodine doses have been empirically established to achieve an absorbed radiation dose of 100 Gy, requiring 3·7–5·5 MBq per gram of thyroid tissue normalized to 100% radioiodine uptake.2 The resulting doses used have varied from 200 MBq to > 3000 MBq. The maximum permitted dose of radioiodine which can be given in the outpatient setting in the UK is 800 MBq and, when restricted in this way, radioiodine administration becomes more of a problem, requiring inpatient treatment or the use of empirical fixed doses of 800 MBq or less, with the view that repeat treatment may be necessary.69
One way to reduce the amount of radioiodine required is the use of recombinant TSH to enhance radioiodine uptake and retention, as well as increasing the absorbed dose by permitting a more even distribution of radioiodine in the gland.70 Treatment with 0·03 mg recombinant TSH allowed an estimated dose reduction of 60% in the radioiodine used to treat one group of patients (from a mean of 1927 to 843 MBq) and although there was no control group, goitre size reduction was comparable to previous studies.71 Subsequently a controlled trial showed that patients treated with 0·45 mg recombinant TSH achieved a 50% greater reduction in goitre size than those given similar radioiodine doses but not receiving TSH; the price paid was an almost trebling of the rate of hypothyroidism.72 Moreover, recombinant TSH can cause significant thyrotoxicosis and transient goitre enlargement accompanied by compressive symptoms.73 The most recently published prospective, randomized and double-blind trial has shown that recombinant TSH improves thyroid size reduction by 35% with a five-fold increase in the rate of hypothyroidism.74 Further trials to optimize the best strategy are clearly needed, but when compared to the inconvenience and costs of inpatient care after radioiodine administration, the use of recombinant TSH may well offer an improved protocol for radioiodine administration in NTG.
Complications
The acute side effects of radioiodine treatment for NTG include transient thyrotoxicosis, thyroid swelling and tenderness as already mentioned. Around 1% of patients may develop Graves’ disease, presumably through the release of thyroid autoantigens and other immunogenic effects of radioiodine on thyroid-autoreactive lymphocytes.75 Others have found an even higher incidence of 5% in a smaller series of patients.76 Hypothyroidism occurs in up to 50% of patients, mostly in the first 2 years after treatment, and is particularly frequent in those with small initial goitre size, positive thyroid peroxidase antibodies and a family history of thyroid autoimmunity.63 All patients should be offered annual follow-up testing of thyroid function. The risks of a subsequent extrathyroidal malignancy are unknown. Theoretically these risks are greater than with radioiodine use in hyperthyroidism, as generally much higher doses of radioactivity are employed, providing another compelling reason to develop strategies using lower amounts of activity.
